339 results on '"Vinod Pullarkat"'
Search Results
102. Venetoclax with azacitidine or decitabine in patients with newly diagnosed acute myeloid leukemia: Long term follow-up from a phase 1b study
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Qi Jiang, Brenda Chyla, Anthony Letai, Martha Arellano, Marina Konopleva, Andrew H. Wei, Brian A. Jonas, Daniel A. Pollyea, Keith W. Pratz, Michael J. Thirman, Vinod Pullarkat, Wan Jen Hong, Pamela S. Becker, Courtney D. DiNardo, and Jalaja Potluri
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Male ,medicine.medical_specialty ,Myeloid ,Azacitidine ,Decitabine ,Neutropenia ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,Febrile Neutropenia ,Aged, 80 and over ,Sulfonamides ,Venetoclax ,business.industry ,Myeloid leukemia ,Anemia ,Hematology ,Middle Aged ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Thrombocytopenia ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Female ,business ,Febrile neutropenia ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
This analysis represents the longest-term follow-up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine. Adults with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in an open-label, non-randomized, multicenter phase 1b trial of venetoclax with azacitidine (AZA; 75 mg/m2 ; days 1-7) or decitabine (DEC; 20 mg/m2 ; days 1-5). Endpoints included safety, response rates (complete remission [CR], CR with incomplete blood count recovery [CRi]), response duration and overall survival (OS). The median follow-up time was 29 and 40 months for patients treated with venetoclax plus AZA and DEC combinations, respectively. Key Grade ≥ 3 AEs (AZA and DEC) were febrile neutropenia (39% and 65%), anemia (30% and 26%), thrombocytopenia (25% and 23%), and neutropenia (20% and 10%). The CR/CRi rate was 71% for venetoclax plus AZA and 74% for venetoclax plus DEC. The median duration of CR/CRi was 21.9 months and 15.0 months, and the median OS was 16.4 months and 16.2 months, for venetoclax plus AZA and DEC, respectively. These results support venetoclax plus hypomethylating agents as highly effective frontline AML therapies for patients unfit for intensive chemotherapy.
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- 2020
103. Levocarnitine for pegasparaginase-induced hepatotoxicity in acute lymphoblastic leukemia
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Dat Ngo, Elena Trang, Amandeep Salhotra, Jason Chen, Vinod Pullarkat, and Ibrahim Aldoss
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Cancer Research ,medicine.medical_specialty ,Asparaginase ,Lymphoblastic Leukemia ,Antineoplastic Agents ,Gastroenterology ,Levocarnitine ,Polyethylene Glycols ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Carnitine ,medicine ,Humans ,Retrospective Studies ,business.industry ,hemic and immune systems ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Elevated transaminases ,Chemical and Drug Induced Liver Injury ,business ,030215 immunology - Abstract
Pegasparaginase (PEG-Asp), commonly used in acute lymphoblastic leukemia (ALL), is associated with hyperbilirubinemia and elevated transaminases. Treatment of acute hepatotoxicity is limited to case studies reporting success with levocarnitine (LC). In a retrospective analysis, 25 ALL patients experienced Grade ≥3 hyperbilirubinemia and/or elevated transaminases following a single dose of PEG-Asp where 12 patients received LC compared to 13 patients with no intervention. Median LC dose was 50 mg/kg/day for a median of 11 days. Median values were greater in the LC group: total bilirubin 5.2 mg/dL vs 4.5 mg/dL (
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- 2020
104. Targeting the alpha subunit of IL-3 receptor (CD123) in patients with acute leukemia
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Joo Y. Song, Vinod Pullarkat, Mary C. Clark, and Ibrahim Aldoss
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030231 tropical medicine ,Immunology ,Interleukin-3 Receptor alpha Subunit ,Review ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Humans ,030212 general & internal medicine ,G alpha subunit ,Pharmacology ,Acute leukemia ,business.industry ,Myeloid leukemia ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Receptors, Interleukin-3 ,Haematopoiesis ,Leukemia ,Leukemia, Myeloid, Acute ,Cancer research ,Interleukin-3 receptor ,Stem cell ,business ,Alpha chain - Abstract
The IL-3 alpha chain receptor (CD123) is a cell surface protein that is widely expressed by various subtypes of acute leukemia, including acute myeloid leukemia (AML), acute lymphoblastic leukemia and blastic plasmacytoid dendritic cell neoplasm. Notably, CD123 is preferentially overexpressed in leukemia stem cells (LSC) in contrast to normal hematopoietic stem cells, and this differential expression allows for the selective eradication of LSC and leukemic blasts through therapeutic targeting of CD123, with less impact on hematopoietic cells. The level of CD123 expression in AML correlates with both treatment response and outcomes. Therefore, targeting CD123 represents a promising universal therapeutic target in advanced acute leukemias irrespective of the individual leukemia phenotype. There are currently 31 ongoing clinical trials examining the utility of CD123-based targeted therapies. Here we focus our review on current efforts to target CD123 in acute leukemia through various therapeutic constructs.
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- 2020
105. Iron Overload is Associated with Delayed Engraftment and Increased Non-Relapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation
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Stephen J. Forman, Sanjeet Dadwal, David S. Snyder, Sally Mokhtari, Dongyun Yang, Joo Y. Song, Ibrahim Aldoss, Auayporn Nademanee, Thai Cao, Vinod Pullarkat, Guido Marcucci, Ryotaro Nakamura, Monzr M. Al Malki, and Chatchada Karanes
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medicine.medical_specialty ,Transplantation Conditioning ,Iron Overload ,Platelet Engraftment ,Iron ,Gastroenterology ,Umbilical cord ,Article ,Internal medicine ,medicine ,Transplantation, Homologous ,Humans ,Nonrelapse mortality ,Serum ferritin ,Retrospective Studies ,Transplantation ,Neutrophil Engraftment ,Hematopoietic cell ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,Fetal Blood ,medicine.anatomical_structure ,Cord Blood Stem Cell Transplantation ,business - Abstract
The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.
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- 2020
106. The efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia with extramedullary involvement
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Ibrahim Aldoss, Salman Otoukesh, Jianying Zhang, Vinod Pullarkat, Stephen J. Forman, Ryotaro Nakamura, Anthony S. Stein, and Guido Marcucci
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Oncology ,Cancer Research ,medicine.medical_specialty ,Disease ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Extramedullary Involvement ,Medicine ,Humans ,Sulfonamides ,business.industry ,Venetoclax ,fungi ,food and beverages ,Myeloid leukemia ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Myeloid, Acute ,chemistry ,030220 oncology & carcinogenesis ,business ,030215 immunology - Abstract
To the EditorExtramedullary disease (EMD) is not an uncommon presentation at the time of acute myeloid leukemia (AML) diagnosis and/or relapse, and can present either as an isolated disease (myeloi...
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- 2020
107. Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia
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Stephen J. Forman, David S. Snyder, Karamjeet S. Sandhu, Sally Mokhtari, Ni-Chun Tsai, Samer K. Khaled, Vinod Pullarkat, Eileen P. Smith, Monzr M. Al Malki, Ibrahim Aldoss, Ryotaro Nakamura, Haris Ali, Matthew Mei, Amandeep Salhotra, Guido Marcucci, and Anthony S. Stein
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Melphalan ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Population ,Graft vs Host Disease ,Disease ,Tacrolimus ,Article ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,Medicine ,Humans ,Cumulative incidence ,education ,Aged ,Retrospective Studies ,Sirolimus ,Transplantation ,education.field_of_study ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Fludarabine ,Graft-versus-host disease ,surgical procedures, operative ,030220 oncology & carcinogenesis ,business ,Vidarabine ,030215 immunology ,medicine.drug - Abstract
Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome–positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.
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- 2020
108. Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia
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Stephen J. Forman, David S. Snyder, Matthew Mei, Sally Mokhtari, Ryotaro Nakamura, Monzr M. Al Malki, Ahmed Aribi, Thai Cao, Haris Ali, Samer K. Khaled, Vinod Pullarkat, Elizabeth Budde, Karamjeet S. Sandhu, Ibrahim Aldoss, Dongyun Yang, Amandeep Salhotra, Ricardo Spielberger, Guido Marcucci, and Anthony S. Stein
- Subjects
Adult ,Subset Analysis ,Oncology ,medicine.medical_specialty ,Platelet Engraftment ,Salvage therapy ,Article ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,Antibodies, Bispecific ,Medicine ,Humans ,Salvage Therapy ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Minimal residual disease ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Cohort ,Blinatumomab ,business ,030215 immunology ,medicine.drug - Abstract
Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.
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- 2020
109. Azacitidine and venetoclax in previously untreated acute myeloid leukemia
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Jacqueline S. Garcia, Andrew H. Wei, Brian A. Jonas, Elizabeth A. Koller, Hartmut Döhner, Jun-Ho Jang, Marina Konopleva, Mehmet Turgut, Michael J. Thirman, Sung-Soo Yoon, Courtney D. DiNardo, Ying Zhou, Keith W. Pratz, Roman Hájek, David Lavie, Vinod Pullarkat, Jordi Esteve, Brian Leber, Su-Peng Yeh, Pierre Fenaux, Kazuhito Yamamoto, Kimmo Porkka, Árpád Illés, Vlatko Pejša, Roberto M. Lemoli, Jianxiang Wang, Wan-Jen Hong, Jalaja Potluri, Anthony Letai, Violaine Havelange, UCL - SSS/DDUV/MEXP - Médecine expérimentale, and UCL - (SLuc) Service d'hématologie
- Subjects
Oncology ,Myeloid ,Male ,endocrine system diseases ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,chemistry.chemical_compound ,0302 clinical medicine ,Older patients ,Recurrence ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,80 and over ,Medicine ,030212 general & internal medicine ,Aged ,Aged, 80 and over ,Azacitidine ,Bridged Bicyclo Compounds, Heterocyclic ,Double-Blind Method ,Female ,Follow-Up Studies ,Humans ,Intention to Treat Analysis ,Leukemia, Myeloid, Acute ,Leukopenia ,Middle Aged ,Pneumonia ,Remission Induction ,Sulfonamides ,Thrombocytopenia ,Leukemia ,Heterocyclic ,Myeloid leukemia ,General Medicine ,3. Good health ,medicine.anatomical_structure ,After treatment ,medicine.drug ,medicine.medical_specialty ,Acute ,03 medical and health sciences ,Bridged Bicyclo Compounds ,Internal medicine ,neoplasms ,business.industry ,Venetoclax ,medicine.disease ,Hypomethylating agent ,chemistry ,business - Abstract
BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P
- Published
- 2020
110. Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to de novo acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients
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Ni-Chun Tsai, Thomas P. Slavin, Ahmed Aribi, Thai Cao, Stephen J. Forman, Joo Y. Song, Ricardo Spielberger, Haris Ali, Tracey Stiller, Monzr M. Al Malki, Ibrahim Aldoss, Matthew Mei, N. Achini Bandara, Guido Marcucci, Vinod Pullarkat, Anthony S. Stein, Amandeep Salhotra, Ryotaro Nakamura, Margaret R. O'Donnell, David S. Snyder, and Samer K. Khaled
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,business.industry ,Lymphoblastic Leukemia ,Cytogenetics ,hemic and immune systems ,Hematology ,Gene rearrangement ,3. Good health ,Transplantation ,Clinical trial ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Adult Acute Lymphoblastic Leukemia ,business ,Survival rate ,030215 immunology - Abstract
Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the MLL gene rearrangement compared to those with other cytogenetics. When compared to de novo acute lymphoblastic leukemia, therapy-related patients were older (P
- Published
- 2018
111. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia
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Stephen J. Forman, Ahmed Aribi, Amandeep Salhotra, David S. Snyder, Monzr M. Al Malki, Ibrahim Aldoss, Dongyun Yang, Haris Ali, Samer K. Khaled, Vinod Pullarkat, Karamjeet S. Sandhu, Anthony S. Stein, Matthew Mei, Margaret R. O'Donnell, Guido Marcucci, and Ryotaro Nakamura
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Oncology ,medicine.medical_specialty ,Myeloid ,Drug resistance ,Decitabine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Text mining ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Neoplasm ,Online Only Articles ,Survival analysis ,Sulfonamides ,business.industry ,Venetoclax ,Myeloid leukemia ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,medicine.disease ,Survival Analysis ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Retreatment ,business ,030215 immunology - Published
- 2018
112. Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia
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Bin Zhang, Mhairi Copland, Herman Wu, Stephen J. Forman, Dandan Zhao, Ravi Bhatia, Huafeng Wang, Guido Marcucci, Le Xuan Truong Nguyen, Adrienne M. Dorrance, David S. Snyder, Piotr Swiderski, Tessa L. Holyoake, Ching-Cheng Chen, Vinod Pullarkat, Allen Lin, Bijender Kumar, Lisa E. M. Hopcroft, Tinisha McDonald, Haris Ali, Anthony S. Stein, Francesca Pellicano, Estelle Troadec, Danilo Perrotti, Nadia Carlesso, Casey J Brewer, Ya-Huei Kuo, Ling Li, Marcin Kortylewski, Calvin J. Kuo, Yu-Lin Su, and Yate Ching Yuan
- Subjects
0301 basic medicine ,Fusion Proteins, bcr-abl ,Down-Regulation ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Extracellular Vesicles ,Mice ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Bone Marrow ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,LSC ,medicine ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Cell Self Renewal ,Stem Cell Niche ,Kinase activity ,Protein Kinase Inhibitors ,CML ,BM niche ,microRNA ,Gene Expression Regulation, Leukemic ,Endothelial Cells ,chemoresistance ,General Medicine ,Hematopoietic Stem Cells ,medicine.disease ,3. Good health ,MicroRNAs ,Haematopoiesis ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Neoplastic Stem Cells ,Cancer research ,Bone marrow ,Stem cell ,Chronic myelogenous leukemia - Abstract
Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR–ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals. Downregulation of miR-126 levels in CML LSCs was due to phosphorylation of Sprouty-related EVH1-domain-containing 1 (SPRED1) by BCR–ABL, which led to inhibition of the RAN–exportin-5–RCC1 complex that mediates miRNA maturation. Endothelial cells (ECs) in the BM supply miR-126 to CML LSCs to support quiescence and leukemia growth, as shown using mouse models of CML in which Mir126a (encoding miR-126) was conditionally knocked out in ECs and/or LSCs. Inhibition of BCR–ABL by TKI treatment caused an undesired increase in endogenous miR-126 levels, which enhanced LSC quiescence and persistence. Mir126a knockout in LSCs and/or ECs, or treatment with a miR-126 inhibitor that targets miR-126 expression in both LSCs and ECs, enhanced the in vivo anti-leukemic effects of TKI treatment and strongly diminished LSC leukemia-initiating capacity, providing a new strategy for the elimination of LSCs in individuals with CML.
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- 2018
113. Favorable outcomes for allogeneic hematopoietic cell transplantation in elderly patients with NPM1-mutated and FLT3-ITD-negative acute myeloid leukemia
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Dongyun Yang, Anthony S. Stein, Stephen J. Forman, Amandeep Salhotra, Guido Marcucci, Ryotaro Nakamura, Vinod Pullarkat, and Ibrahim Aldoss
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Transplantation ,NPM1 ,Hematopoietic cell ,business.industry ,Hematopoietic Stem Cell Transplantation ,Nuclear Proteins ,Myeloid leukemia ,Hematology ,Prognosis ,Leukemia, Myeloid, Acute ,fms-Like Tyrosine Kinase 3 ,Mutation ,Cancer research ,Humans ,Medicine ,business ,Nucleophosmin ,Aged ,Flt3 itd - Published
- 2019
114. Response to single agent dasatinib post allogeneic transplant in B-cell acute lymphoblastic leukemia with NUP214-ABL1
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Vinod Pullarkat and Ibrahim Aldoss
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Oncology ,Cancer Research ,medicine.medical_specialty ,ABL ,Oncogene Proteins ,business.industry ,Induction chemotherapy ,hemic and immune systems ,Hematology ,B-cell acute lymphoblastic leukemia ,Transplantation ,Dasatinib ,Text mining ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Homologous chromosome ,business ,medicine.drug - Abstract
Trial registration: ClinicalTrials.gov identifier: NCT02420717.Trial registration: ClinicalTrials.gov identifier: NCT02883049.The majority of Philadelphia-like (Ph-like) acute lymphoblastic leukemi...
- Published
- 2019
115. Will immunotherapy lead to a breakthrough in the treatment of older adults with ALL?
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Vinod Pullarkat, Anjali S. Advani, and Ibrahim Aldoss
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Antigens, CD19 ,Clinical Biochemistry ,Population ,Immunotherapy, Adoptive ,Recurrence ,Internal medicine ,medicine ,Humans ,Dosing ,Young adult ,education ,Aged ,education.field_of_study ,business.industry ,Immunotherapy ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Minimal residual disease ,Chimeric antigen receptor ,Tolerability ,Blinatumomab ,business ,medicine.drug - Abstract
Historically, older adults with B-cell acute lymphoblastic leukemia (ALL) have done poorly with chemotherapy-based treatment. Therefore, new innovative approaches are urgently needed to improve outcomes for this population. CD19-targeted immunotherapies such as blinatumomab and chimeric antigen receptor (CAR) T cell therapy have produced remarkable responses in relapsed/refractory (r/r) B-cell ALL, including clearance of minimal residual disease (MRD). Available data support the efficacy and safety of blinatumomab in older adults with advanced B-cell ALL. Therefore, its application is being extended to frontline regimens for B-cell ALL, particularly in older adults. There are several studies actively examining the role of blinatumomab alone or in combination with attenuated dosing of conventional chemotherapy or novel agents in older adults with newly diagnosed ALL and early data are encouraging. While CD19-targeted CAR (CD19CAR) T cell therapy is active in children and young adults with r/r B-cell ALL, data supporting its efficacy and safety in older adults with ALL is scarce. Furthermore, the commercially FDA approved CD19CAR T cell therapy product for r/r ALL is restricted only to patients ≤25 years of age. Although there are concerns about older adults tolerating the expected toxicities associated with CAR T cell therapy, which may be life threatening, tailored approaches for prophylactic and pre-emptive interventions combined with utilization of safer CAR T cell platforms may improve tolerability and further extend the use of this promising treatment to older patients with ALL. In this review, we will discuss the progress in immunotherapies for older adults with B-cell ALL and their potential for transforming frontline therapy for newly diagnosed patients.
- Published
- 2021
116. Safety and Pharmacokinetics of Calaspargase Pegol in Adults with Newly Diagnosed Philadelphia-Negative ALL: A Phase 2/3 Study
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Jian J Zhu, Daniel J. DeAngelo, Mark Mogul, Jonathan Webster, Shuchi S. Pandya, Adrien Tessier, Maher Abdul-Hay, Ryan D. Cassaday, Jae H. Park, Wendy Stock, Ashkan Emadi, Yelena Shvenke, and Vinod Pullarkat
- Subjects
Philadelphia negative ,Pediatrics ,medicine.medical_specialty ,Pharmacokinetics ,business.industry ,Calaspargase pegol ,Immunology ,medicine ,Cell Biology ,Hematology ,Newly diagnosed ,business ,Biochemistry - Abstract
Background: Overall survival (OS) in adults with ALL remains around 40%, but treatment with asparaginase (ASP)-containing pediatric-inspired regimens demonstrated a 3- or 4-year OS of 67-76%, including in patients with T-cell ALL, with manageable toxicities (Geyer 2020, Stock 2019, DeAngelo 2015). Recent studies in adults with reduced pegaspargase (PEG-ASP) doses showed survival outcomes similar to those with standard doses, with reduced toxicities, including pancreatitis, hepatic and thromboembolic events (Derman 2020, Patel 2020). Calaspargase pegol (ASPARLAS; Cal-PEG), similar to PEG-ASP, is an E. coli L-asparaginase covalently conjugated to monomethoxy polyethylene glycol, but with a more chemically stable succinimidyl carbonate linker, providing sustained asparagine depletion with less frequent dosing (every 21 days). The efficacy and safety of Cal-PEG 2500 U/m 2, vs PEG-ASP 2500 U/m 2, was evaluated in 2 multicenter, randomized clinical trials (AALL07P4 [n=166] and DFCI 11-001 [n=239]) in newly diagnosed patients with ALL ≤21 years. Complete remission (CR), minimal residual disease (MRD), event-free survival (EFS), and OS were similar in both arms, with a 94% 5-year OS for Cal-PEG. The safety profile was consistent with that of PEG-ASP, with similar rates of hypersensitivity, pancreatitis, thrombosis, and hyperbilirubinemia (Vrooman 2021). Plasma asparaginase activity (PAA) levels were ≥0.1 U/mL 25 days after the induction dose in 95% of patients (Angiolillo 2014). The absence of a standardized treatment and the inadequate outcome of adult treatment regimens, as well as a lack of targeted immunotherapies for T-ALL, highlight a critical unmet need for improved therapeutic approaches. A treatment protocol with less frequent Cal-PEG administration due to a more sustained asparaginase activity as well as age- and weight-based dose adjustments may improve clinical outcomes without added toxicities, and possibly extend the upper age limit of ASP-containing regimen for older adults. Trial Design: We present a clinical trial design of an ongoing, multicenter, phase 2/3 study (NCT04817761) assessing the safety and anti-leukemic activity of Cal-PEG in newly diagnosed patients with Philadelphia-negative B- or T-cell ALL. Patients aged ≥22 years are eligible with ECOG performance status 0-2, no known history of pancreatitis, coagulopathy, CNS thrombosis or severe hepatic impairment. This trial comprises two parts: dose confirmation run-in (part 1) and the expansion phase (part 2). Part 1 is open for enrollment and is the focus of this abstract. Starting doses of Cal-PEG are based on the patients' age and BMI, with older patient groups assigned to lower doses (Table 1). A minimum of 4 (initial cohort) and up to 8 patients will be admitted per patient group. A total of 6 Cal-PEG doses will be administered during the treatment period as part of a multiagent chemotherapy regimen based on CALGB 10403 trial (Figure 1; Table 2), with end of treatment visit 1 year after the induction dose, and an additional 2 years of survival follow-up. The primary endpoints in part 1 are 1) the safety of Cal-PEG, including incidence of pre-defined unacceptable toxicities (UT) within 30 days after the induction dose and 2) PAA profiles, including achieving PAA ≥0.1 U/mL at pre-specified time points. Secondary endpoints include immunogenicity, CR, end of induction and consolidation MRD, and 1-, 2- and 3-year EFS, disease-free survival, and OS. Bayesian optimal interval design (BOIN) will be used to evaluate UT with specified boundaries for dose confirmation, expansion, or reduction. For each patient group, the observed UT rate at a dose level will be compared with the safety boundary (23.6%) and toxicity boundary (35.8%) to guide safety confirmation. PAA data from previous pediatric studies and each run-in cohort will also be used to confirm the tested dose through population PK modeling-based predictions. The decision to confirm or adjust the dose will be based on the accumulated safety and induction PAA data at end-of-cohort meetings with the investigators, sponsor and in consult with DSMB recommendations. Part 1 started in July 2021 and will enroll ≈16-32 patients at multiple sites in the US. Part 2 will commence once the safety and PAA data from part 1 are analyzed and the expansion doses are confirmed. Up to 122 patients are expected to be enrolled in both phases of the trial. Clinical trial information: NCT04817761 Figure 1 Figure 1. Disclosures Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Park: Kura Oncology: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Affyimmune: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; BMS: Consultancy; PrecisionBio: Consultancy; Minerva: Consultancy; Innate Pharma: Consultancy; Curocel: Consultancy; Servier: Consultancy; Artiva: Consultancy. Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. Abdul-Hay: Jazz: Other: Advisory Board, Speakers Bureau; Servier: Other: Advisory Board, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Takeda: Speakers Bureau. Cassaday: Kite/Gilead: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding; Pepromene Bio: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Webster: AmGen: Consultancy; Pfizer: Consultancy. Pandya: Servier: Current Employment; Agios: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mogul: Servier Pharmaceuticals: Current Employment. Shvenke: Servier Pharmaceuticals: Current Employment. Zhu: Servier Pharmaceuticals: Current Employment. Tessier: Servier: Current Employment. DeAngelo: Abbvie: Research Funding; Incyte Corporation: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Shire: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Agios: Consultancy; Autolus: Consultancy; Forty-Seven: Consultancy; Blueprint Medicines Corporation: Consultancy; Jazz: Consultancy; GlycoMimetics: Research Funding. OffLabel Disclosure: Calaspargase pegol is an asparagine specific enzyme indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia in pediatric and young adult patients age 1 month to 21 years, with recommended dosage of 2,500 units/m2 intravenously no more frequently than every 21 days
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- 2021
117. Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents
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Sunil Babu, Vinod Pullarkat, Jalaja Potluri, Andrew H. Wei, Brian A. Jonas, Christian Recher, Monique Dail, Courtney D. DiNardo, Andre C. Schuh, Yan Sun, Keith W. Pratz, Daniel A. Pollyea, and Brenda Chyla
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Oncology ,medicine.medical_specialty ,Poor risk ,business.industry ,Venetoclax ,Immunology ,Cytogenetics ,Cell Biology ,Hematology ,Tp53 mutation ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,In patient ,business - Abstract
Introduction Patients (pts) with acute myeloid leukemia (AML) with poor-risk cytogenetics at diagnosis have inadequate responses to standard treatment. Pre-clinical and clinical data show that TP53mutation (mut) is associated with poor outcomes with venetoclax (Ven). However, the clinical impact of AML with poor-risk cytogenetics with and without a TP53 mut treated with a hypomethylating agent (HMA) and Ven is unknown. Herein, we evaluated the efficacy and safety of the Ven + azacitidine (Aza) or HMA combination in pts with treatment-naïve AML with poor-risk cytogenetics with TP53wt or TP53mut. Methods Treatment-naïve pts with AML unfit for intensive chemotherapy either due to age ≥75 years or co-morbidities were enrolled. Data were pooled from an ongoing phase 3 study (NCT02993523) comparing pts treated with Ven+Aza or placebo (Pbo)+Aza, and a phase 1b study (NCT02203773), in which pts were treated with Ven and an HMA, either Aza or decitabine (Dec). Ven 400 mg daily, Aza 75 mg/m 2 (days 1-7), or Dec 20 mg/m 2 (days 1-5), were administered over 28-day cycles. Cytogenetic risk was determined locally pre-treatment per NCCN (2016) criteria with the following abnormalities associated with poor outcomes: complex (≥3 clonal chromosomal abnormalities), monosomal karyotype, -5,5q, -7,7q, 11q23-non t(9;11) inv(3), t(3;3), t(6;9), and t(9;22). TP53mut status was assessed from pre-treatment BM aspirates at screening and analyzed centrally using MyAML panel assays (covering all coding and non-coding exons, limit of detection 1%; Invivoscribe). Pts without a result either due to an inconclusive test or missing specimen were excluded from the analysis. Response assessments were performed per modified International Working Group response criteria for AML. Results The pooled analysis included 546 pts; 353 and 145 pts in the Ven+Aza and Aza groups, respectively, with poor-risk cytogenetics observed in 127 (36%; TP53wt, 50; TP53mut, 54) and 56 (39%; TP53wt, 22; TP53mut, 18) pts. There were 401 pts in the Ven+HMA group with poor-risk cytogenetics observed in 152 (38%, TP53wt, 61; TP53mut, 68). The median variant allele frequency for TP53 was 42.9% (range 6.5 ─ 93.4) for Ven+Aza and 42.9% (3.5 ─ 93.7) for Aza. Key pt demographics are shown in the Table. In pts with poor-risk cytogenetics +TP53wt who received Ven+Aza vs. Aza, the composite remission rates (CRc: complete remission [CR] + CR with incomplete hematologic remission [CRi]) were 70% vs. 23%, median duration of remission (DoR) was 18.37 (95% CI 9.63 ─ not evaluable [NE]) vs. 8.51 (1.05 ─ NE) months (mos), and median overall survival (OS) was 23.43 (95% CI 11.93 ─ NE) vs. 11.29 (4.90 ─ 12.78) mos (Figure A). Similar results were observed in pts treated with Ven+HMA: CRc rate was 74%, median DoR 16.72 (95% CI 8.08 ─ 20.99) mos, and median OS was 21.13 (95% CI 11.93 ─ 29.01) mos (Figure B).These poor-risk cytogenetics + TP53wt results were comparable to those of pts with intermediate-risk cytogenetics + TP53wt (Ven+Aza [n=166]: CRc 72%, DoR 21.91 mos, OS 19.15 mos; Ven+HMA [n=187]: CRc 72%, DoR 21.19 mos, OS 19.81 mos). In pts with poor-risk cytogenetics + TP53mut who received Ven+Aza or Aza, CRc rates were 41% vs. 17%, median DoR was 6.54 (95% CI 2.79 ─ 10.61) vs. 6.7 (6.7 ─ NE) mos, and median OS was 5.17 (95% CI 2.17 ─ 6.83) vs. 4.9 (2.14 ─ 9.3) mos. In pts treated with Ven+HMA, the CRc rate was 47%, median DoR was 6.54 (95% CI 3.58 ─ 12.09) mos, and median OS was 5.42 (95% CI 3.71 ─ 7.39) mos. In pts with poor-risk cytogenetics + TP53 wt, the common ≥ grade 3 (G3) adverse events (AEs) on Ven+Aza or Aza were thrombocytopenia (36%/36%), febrile neutropenia (32%/14%), anemia (26%/6%), neutropenia (24%/27%), and pneumonia (18%/23%). In pts with poor-risk cytogenetics + TP53 mut, the common ≥G3 AEs on Ven+Aza or Aza were also febrile neutropenia (43%/22%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/32%), and pneumonia (26%/33%). In pts treated with Ven+HMA, the most common ≥G3 AEs in pts with poor-risk cytogenetics + TP53 wt or TP53 mut were similar. Conclusion Among pts with poor-risk cytogenetics +TP53wt, treatment with Ven+Aza or Ven+HMA was associated with higher remission rates and prolonged DoR and OS compared to pts treated with Aza alone. Outcomes were similar to intermediate-risk TP53wt Ven+Aza pts. In contrast, for similarly treated pts with poor-risk cytogenetics + TP53mut, improved response rates did not translate into improved DoR or OS.No new toxicities were noted. Figure 1 Figure 1. Disclosures Pollyea: Syndax: Honoraria; Takeda: Honoraria; Novartis: Consultancy, Honoraria; Foghorn: Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Honoraria; Karyopharm: Consultancy, Honoraria; Kiadis: Honoraria; Amgen: Honoraria; Teva: Research Funding; Celgene: Honoraria; Syros: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Aprea: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Pratz: Millenium: Research Funding; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Agios: Consultancy; BMS: Consultancy, Honoraria; Cellgene: Consultancy, Honoraria; University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding. Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Jonas: 47, AbbVie, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, Treadwell: Research Funding; AbbVie, BMS, Genentech, GlycoMimetics, Jazz, Pfizer, Takeda, Treadwell: Consultancy; AbbVie: Other: Travel reimbursement. Recher: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Janssen: Honoraria; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MaatPharma: Research Funding; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Babu: BMS: Consultancy, Honoraria, Other: Travel accommodations, expenses, Research Funding, Speakers Bureau; Novartis: Research Funding; Alexion: Consultancy, Honoraria, Other: Travel, accommodations, expenses, Speakers Bureau; Genentech/Roche: Other: Travel, accommodations, expenses, Research Funding; Janssen Oncology: Other: Travel, accommodations, expenses, Research Funding; Amgen, TG Therapeutics, AbbVie, Nektar, Sanofi, Argenx: Research Funding; Lily: Honoraria, Other: Travel, accommodations, expenses, Research Funding; Astra-Zeneca: Consultancy, Honoraria, Research Funding; Bayer, Castle Biosciences: Honoraria. Schuh: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Research Funding; Kite/Gilead: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dail: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Sun: AbbVie: Current Employment. Potluri: AbbVie: Current Employment. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding.
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- 2021
118. A Randomized Open Label Pilot Study of Clostridium Butyricum Miyairi 588 (CBM588) in Recipients of Allogeneic Hematopoietic Cell Transplantation
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Leslie Popplewell, Dongyun Yang, Karamjeet S. Sandhu, Amandeep Salhotra, Guido Marcucci, Ricardo Spielberger, Stephen J. Forman, Vinod Pullarkat, Sarah K. Highlander, Sanjeet Dadwal, Thai Cao, Andrew S. Artz, Ibrahim Aldoss, Harry Xu, Myo Htut, Lucy Ghoda, Anthony S. Stein, Monzr M. Al Malki, Haris Ali, Elizabeth Budde, Lauren Reining, Sally Mokhtari, and Ryotaro Nakamura
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biology ,Hematopoietic cell ,business.industry ,Immunology ,Cell Biology ,Hematology ,biology.organism_classification ,Biochemistry ,Transplantation ,Medicine ,Open label ,business ,Clostridium butyricum - Abstract
The gut microbiota plays an important role in maintaining intestinal homeostasis by regulating the maturation of the mucosal immune system, which constitutes an immune barrier for the integrity of the intestinal tract. In recent years, the role of the human GI microbiota in graft-versus-host disease (GVHD) and other outcomes after allogeneic hematopoietic cell transplantation (HCT) has been increasingly evaluated in observational studies. However, there have been limited interventional trials specifically designed to alter the microbiota of HCT recipients. CBM588 (clostridium butyricum MIYAIRI 588) is a novel Live Biotherapeutic Product (LBP) that produces short chain organic acids, mainly butyric acid, which plays a key role in the maintenance of colonic homeostasis by regulating fluid and electrolyte uptake, epithelial cell growth, and inflammatory responses. In this pilot trial (NCT03922035) we sought to determine the safety, feasibility, biologic activities, and preliminary efficacy of CBM588 in HCT recipients. Patients age ≥18 years, scheduled to undergo HCT from an 8/8 or 7/8 matched related/unrelated donor with reduced intensity conditioning (RIC) were eligible. Following the patient safety lead-in (SLI; n=6), 30 patients were randomized (1:1 ratio) to receive either standard peri-transplant supportive care alone (control arm) or with CBM588 (treatment arm, open label) at the fixed dose of 160 mg orally (2x/day) from day -8 or hospital admission until day +28 or discharge (figure 1). Patients received prophylactic antibiotics per intuitional SOPs. Study objectives were to evaluate the safety/feasibility of CBM588 (Primary), and to compare the incidence and severity of adverse events (AE), HCT outcomes including GVHD, and gut microbiome diversity between the Treatment and Control arms. Feasibility was defined as the ability to consume CDM588 for 14 days during the SLI phase. For microbiome analysis, we isolated DNA from weekly collected stool samples, and amplified the V4 region of the bacterial 16S rRNA gene from each total DNA sample. Between April, 2018 and January, 2020, we enrolled 36 patients (20 were female) at the median age of 66 years (range: 34-77). The indication for HCT was Leukemias (n=22), MDS (n=5), lymphoma (n=3), myeloma (n=3), or other (n=3). All but one patient received fludarabine/melphalan-based RIC and tacrolimus/sirolimus-based GVHD prophylaxis. Graft source was peripheral blood stem cell from a matched related (n=13) or unrelated (n=23) donor (Table 1). One patient assigned to the Treatment arm declined to receive CBM588 before the first dose; but remained on the study with clinical data/biospecimen collections and safety/feasibility/biologic endpoints were analyzed as treated for this patient. All the other patients who were assigned to the treatment arm (n=21, including the patients in SLI segment) were able to take the prescribed study drug; with the median 52 doses (range: 0-55), and 19 of 21 subjects (90.5%) consumed at least 14 days of the study drug. There were no serious adverse events (SAE) related to CBM588. The overall AEs and infection- or GI-specific AEs were similar between the Treatment and Control arms. All but one patient (who died of sepsis in the Control arm - on day 8) engrafted with a median of 15 days for neutrophils. The 100-day non-relapse mortality (NRM) was 0% in the Treatment and 6.7% in the Control arm. According to the intent-to-treat principle, acute GVHD (grade 2-4) was observed in 4 of 15 patients in the Treatment arm and 5 of 15 in the Control arm. The lower GI GVHD was seen in 2 patients in the Treatment and 4 in the control arm. As treated analyses showed the overall grade 2-4 GVHD in 3 of 14 (21.4%) with the use of CBM588 and 6 of 16 (37.5%) without CBM588 (one case of lower GI GVHD with CBM, 5 cases without; (Table 2). The Shannon Diversity Index was similar between the two groups at each time point tested. (Figure 1). However, had favorable microbial profile was detected as the pathogens Enterobacteriaceae, Clostridium baratii, and Clostridiodes difficile were reduced in the treatment group. (Figure 2) In summary, our data demonstrate the feasibility and safety of CBM588 administration during the peri-transplant period, which was associated with an intended biologic impact on the gut microbiome, and an early favorable sign of GI-GVHD incidence and HCT outcomes in this older population who underwent RIC HCT. Figure 1 Figure 1. Disclosures Dadwal: Astellas: Speakers Bureau; Aseptiscope: Consultancy; Shire/Takeda: Research Funding; AlloVir: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Other: Investigator; Karius: Other: Investigator. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria. Al Malki: CareDx: Consultancy; Neximmune: Consultancy; Hansa Biopharma: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Budde: Roche: Consultancy; BeiGene: Consultancy; IGM Biosciences: Research Funding; Merck, Inc: Research Funding; Gilead: Consultancy; AstraZeneca: Research Funding; Mustang Bio, Inc: Research Funding; Novartis: Consultancy; Amgen: Research Funding. Popplewell: Hoffman La Roche: Other: Food; Pfizer: Other: Travel; Novartis: Other: Travel. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy.
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- 2021
119. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Adults with Ph-like ALL
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Dongqing Gu, Vinod Pullarkat, David S. Snyder, Hooi Yew, Sally Mokhtari, Milhan Telatar, Samer Khaled, Shukaib Arslan, Ibrahim Aldoss, Matthew Mei, Paul Koller, Stephen J. Forman, Haris Ali, Anthony S. Stein, Patricia Aoun, Vanina Tomazian, Monzr M. Al Malki, F. Mark Stewart, Guido Marcucci, Karamjeet S. Sandhu, Zhaohui Gu, Andrew S. Artz, Peter T. Curtin, Raju Pillai, Michelle Afkhami, Ahmed Aribi, Ryan Jackson, Ryotaro Nakamura, Amandeep Salhotra, and Dongyun Yang
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Transplantation ,Hematopoietic cell ,business.industry ,Immunology ,Cancer research ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,Ph-like ALL - Abstract
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) represents 20% of newly diagnosed adults with B cell ALL (B-ALL), with increased frequency in adults with Hispanic ethnicity. Ph-like ALL harbors a diverse range of genetic alterations with CRLF2-rearrangement/overexpression (CRLF2r) being the most common one. When treated with chemotherapy, Ph-like ALL is associated with inferior response, high relapse rate, and low overall survival (OS). Allogenic hematopoietic cell transplantation (alloHCT) is a well-established curative modality for adults with high-risk ALL. Considering that Ph-like ALL is a high-risk leukemia subtype, it is appealing to recommend alloHCT consolidation routinely for this entity in adults. However, large datasets describing alloHCT outcomes in patients with Ph-like ALL is lacking. In this study, we retrospectively analyzed archived DNA samples from 125 consecutive adult patients with Ph-negative ALL who underwent alloHCT in complete remission (CR) at our center between 2006 and 2020. Classification of Ph-like versus non-Ph-like was performed according to WHO 2017 classification using accumulative results from RNAseq, conventional cytogenetics, FISH, and whole genome array studies. A proprietary RNA sequencing assay covering 1,188 genomic regions from 235 genes was designed to detect all the clinically significant fusions and expressions for Ph-like ALLs. In addition, an algorithm employing the RNAseq data was developed to further aid in classification of Ph-like ALL. Boruta feature selection (R package "Boruta" version 7.0.0) was used to identify the most informative genes for prediction with an out-of-bag error of 9.62%. The following 24 genes were identified: CCND2, SOX11, PAX5, DENND3, RARA, MME, ID4, SH3BP5, HOXA9, CA6, MUC4, CYB5R2, CD97, EPOR, IL2RA, RAB29, PDGFRA, MLLT4, RHOA, JAK2, DNM2, ASXL1, BCL2A1, and KDR. The results were used to predict Ph-like status by a Random Forest model (R package "randomForest" version 4.6-14) that generates a probability/similarity score of Ph gene expression profile (Ph score). The testing samples with Ph score over 50% and without other subtype-defining lesions are defined as Ph-like. We identified Ph-like genetic alterations in 66 (53%) patients, of whom 42 (66%) were carrying CRLF2r and 24 (36%) were non-CRLF2r. Compared to non-Ph-like ALL (n=59), Ph-like ALL patients were younger (42 vs 36 years old, p=0.022), more frequently Hispanic (56% vs 83%, p=0.003), less frequently carried high-risk cytogenetics (39% vs 9%, p1 regimen to achieve their first complete remission (CR1; 30% vs 55%, p=0.025). However, we did not detect any significant difference between the two groups in disease status (CR1 vs. CD2/3; p=0.81) or minimal residual disease clearance at the time of HCT (negative vs. positive; p=0.17), donor type (match related/unrelated vs mismatch vs haplo vs cord blood; p=0.88), conditioning regimen intensity (myeloablative vs non-myeloablative/ reduced intensity; p=0.59), GVHD prophylaxis (tacrolimus/sirolimus-based vs PTCy-based; p=0.84), Karnofsky Performance Status (KPS; p=0.24) or HCT comorbidity index (0 vs 1-2 vs >2; p=0.42). With the median follow-up of 3.2 years, we observed similar 3-years leukemia-free survival (LFS) (40% vs 47%; p=0.95), OS (44% vs 54%; p=0.96), relapse rate (33% vs 34%; p=0.96) and non-relapse mortality (NRM) (27% vs 19%; p=0.92) between non-Ph-like and Ph-like ALL patients, respectively. (Figure) In multivariable analysis, disease status at the time of HCT (HR=2.63, 95% CI: 1.57-4.41; p In conclusion, our data suggest that alloHCT consolidation results in favorable outcomes in adult patients with Ph-like ALL with comparable outcomes to non-Ph-like ALL. Our data support utilization of alloHCT for adults with Ph-like ALL in CR. Figure 1 Figure 1. Disclosures Al Malki: Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Hansa Biopharma: Consultancy; CareDx: Consultancy. Khaled: Omeros: Honoraria; Alexion: Honoraria, Speakers Bureau; Janssen: Current Employment; Astellas: Honoraria; Jazz: Honoraria. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Aribi: Seagen: Consultancy. Mei: BMS: Research Funding; Epizyme: Research Funding; TG Therapeutics: Research Funding; EUSA: Honoraria; Janssen: Honoraria; Morphosys: Research Funding; Beigene: Research Funding. Koller: Novartis: Consultancy. Artz: Radiology Partners: Other: Spouse has equity interest in Radiology Partners, a private radiology physician practice. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Marcucci: Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings. Forman: Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company; Allogene: Consultancy. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria.
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- 2021
120. Phase 1b Study of Lower-Dose CPX-351 Plus Venetoclax As First-Line Treatment for Patients with AML Who Are Unfit for Intensive Chemotherapy: Preliminary Safety and Efficacy Results
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Robert K. Stuart, Ronald S. Cheung, Vinod Pullarkat, Vijayalakshmi Chandrasekaran, Qi Wang, Stefan Faderl, Divya Chakravarthy, Tara L. Lin, Praneeth Baratam, and Geoffrey L. Uy
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Oncology ,medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Cell Biology ,Hematology ,Intensive chemotherapy ,Biochemistry ,First line treatment ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Medicine ,business - Abstract
Background: CPX-351 (United States: Vyxeos ®; Europe: Vyxeos ® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults and pediatric patients aged ≥1 year in the United States and in adults in the European Union. In a phase 3 study in adults aged 60 to 75 years with newly diagnosed high-risk/secondary AML who were eligible for intensive chemotherapy (IC), after 5 years of follow-up CPX-351 significantly improved median overall survival versus conventional 7+3 cytarabine/daunorubicin, with a comparable safety profile. Venetoclax (VEN; BCL-2 inhibitor) + low-dose cytarabine has demonstrated efficacy in unfit patients with AML, and preclinical data support a rationale for combining CPX-351 + VEN. This study evaluates the safety and efficacy of lower-dose CPX-351 + VEN in adults with newly diagnosed AML who are considered unfit to receive IC. Methods: This is an ongoing, open-label, multicenter, phase 1b study (NCT04038437) to determine the recommended phase 2 dose (RP2D) and evaluate the safety and efficacy of lower-dose CPX-351 + VEN in adults with newly diagnosed AML who are considered unfit to receive IC. The dose-exploration phase (3+3 design; n ≤24) evaluated multiple dose levels of CPX-351 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 of each cycle to determine the RP2D. Patients who achieve at least partial remission after 1 or 2 cycles may receive up to 4 similar cycles of CPX-351 + VEN. During the expansion phase, 20 additional patients will receive CPX-351 + VEN at the RP2D. Patients are assessed for response by morphology and measurable residual disease (MRD) testing and are monitored for safety and survival. Results: This preliminary analysis includes data from 14 enrolled patients. Patients were considered unfit for IC based on age ≥75 years (n = 7 [50%]) or health (aged 18 to 74 years with an EGOC performance status of 2 or 3 [n = 3 (21%)] and/or comorbidities [n = 5 (36%]). Overall, 50% of the patients had poor-risk cytogenetics, 64% were male, 71% had a diagnosis of de novo AML, and 29% had mutated TP53 (Table 1). Four patients received dose level 1 (CPX-351 20 units/m 2 [daunorubicin 8.8 mg/m 2 + cytarabine 20 mg/m 2] + VEN), with no dose-limiting toxicities (DLTs) observed in the 3 evaluable patients. Seven patients were subsequently enrolled in dose level 2 (CPX-351 40 units/m 2 [daunorubicin 17.6 mg/m 2 + cytarabine 40 mg/m 2] + VEN), with 6 patients evaluable for DLTs. At dose level 2, 1 patient experienced 2 DLTs (grade 3 tumor lysis syndrome and liver injury); review of the overall safety profile led to a protocol amendment that permitted de-escalation to dose level 1b (CPX-351 30 units/m 2 [daunorubicin 13.2 mg/m 2 + cytarabine 30 mg/m 2] + VEN). Three patients received dose level 1b with no DLTs and a safety profile comparable to dose level 1. Together, these data established dose level 1b as the RP2D. The most common nonhematologic treatment-emergent adverse events (TEAEs) were gastrointestinal events and peripheral edema (Table 2). The majority (86%) of patients experienced a grade ≥3 TEAE, primarily myelosuppression; the only nonhematologic grade ≥3 TEAE in >10% of patients was tumor lysis syndrome (14%). No patient experienced early mortality by Day 30; the mortality rate at Day 60 was 7% due to 1 death in the dose level 1 cohort (myocardial infarction considered unrelated to treatment). Among the 12 patients evaluable for efficacy across dose levels, 8 (67%) achieved a best response of complete remission (CR): 3/4 (75%) in dose level 1, 3/5 (60%) in dose level 2, and 2/3 (67%) in dose level 1b. All patients who achieved a best response of CR entered into either CR or CR with incomplete neutrophil or platelet recovery after the first treatment cycle. Confirmation of MRD status is currently ongoing. Conclusions: Preliminary results from this ongoing phase 1b study established a RP2D of CPX-351 30 units/m 2 on Days 1 and 3 + VEN 400 mg on Days 2 to 21 in adults with newly diagnosed AML who were considered unfit to receive IC. The combination of lower-dose CPX-351 + VEN was generally well tolerated and demonstrated promising initial efficacy, with achievement of CR in the majority of patients. This study is ongoing and enrolling 20 additional patients to further evaluate the RP2D. Figure 1 Figure 1. Disclosures Uy: Novartis: Consultancy; GlaxoSmithKline: Consultancy; Agios: Consultancy; AbbVie: Consultancy; Macrogenics: Research Funding; Astellas: Honoraria, Speakers Bureau; Genentech: Consultancy; Jazz: Consultancy. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria. Baratam: Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stuart: Sunesis Pharmaceuticals: Consultancy; Sunesis Pharmaceuticals: Honoraria; Sunesis Pharmaceuticals: Other: Travel Support; Agios, Astellas Pharma, Bayer AG, Incyte, Jazz Pharmaceuticals, Ono Pharmaceuticals, and Sunesis Pharmaceuticals: Research Funding. Faderl: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chandrasekaran: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chakravarthy: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. OffLabel Disclosure: combination of CPX-351 [Vyxeos] and venetoclax in adults with previously untreated AML
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- 2021
121. Outcomes of Venetoclax and Hypomethylating Agents (HMA) in Adult Patients with KMT2A-Rearranged Leukemias
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Salman Otoukesh, Paul Koller, Ryotaro Nakamura, Monzr M. Al Malki, Brian Ball, Guido Marcucci, Vinod Pullarkat, Eileen P. Smith, Ahmed Aribi, Shukaib Arslan, Ibrahim Aldoss, Forrest Stewart, I. Amanam, Karl Gaal, Michelle Afkhami, Haris Ali, Amandeep Salhotra, Joyce Murata-Collins, and Raju Pillai
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Oncology ,medicine.medical_specialty ,biology ,Adult patients ,Venetoclax ,business.industry ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,chemistry.chemical_compound ,KMT2A ,chemistry ,Internal medicine ,medicine ,biology.protein ,business - Abstract
Background Rearrangements of lysine methyltransferase 2A (KMT2A) gene, previously known as the MLL gene, occur in 3 to 5% of adult patients with de novo AML and are enriched in therapy-related disease after treatment with topoisomerase II inhibitors (Bill, M et al. PNAS. 2020). KMT2A encodes a histone H3 lysine 4 methyltransferase and KMT2A rearrangements result in fusion proteins that induce aberrant Hox gene expression. (Armstrong, SA et al. Nature. 2002) Among patients with KMT2A rearranged AML (rAML) receiving intensive chemotherapy, the fusion partner impacts prognosis, and KMT2A-MLLT3 is associated with an intermediate risk while other KMT2A rearrangements are associated with adverse risk in the ELN classification. (Dohner, H et al. Blood. 2017) Here we evaluate the outcomes of patients with newly diagnosed and relapsed or refractory (R/R) AML with KMT2A rearrangements receiving venetoclax and hypomethylating agents (HMA). Methods Medical records of 333 patients with newly diagnosed or R/R AML receiving venetoclax in combination with HMAs at City of Hope National Medical Center between 11/1/2015 and 4/15/2020 were reviewed. Criteria for inclusion were a pathologically confirmed diagnosis of AML, age > 18 years, treatment with either decitabine or azacitidine in combination with venetoclax. KMT2A rearrangements were detected by karyotype and confirmed by FISH or RNA sequencing. Responses were evaluated per the ELN criteria (Dohner, H et al. Blood. 2017) Minimal residual disease flow cytometry was performed at the University of Washington. Patient characteristics were summarized by frequency and associations between overall response and patient and disease characteristics were tested by Fisher's exact test. OS was evaluated by the Kaplan-Meier method and the difference between groups was determined by log-rank test. All statistical analyses were performed using SPSS and Prism. Results We identified 18 patients (5.4%) with KMT2A rAML who met criteria for inclusion. MLLT3 was the predominant fusion partner, occurring in nine patients followed by ELL (n=2), AFDN (n=2), MLLT6 (n=1), MLLT10 (n=1), AFF1 (n=1), CBL (n=1), and TET1 (n=1). The cohort included both newly diagnosed (n=10) and R/R (n=8) AML patients. 44% had therapy-related or secondary AML. NRAS or KRAS mutations occurred in 4 out of 13 patients (31%) with available sequencing prior to treatment. Decitabine was the predominant HMA used in combination with venetoclax and 56% of all patients received 10-day dosing during the first cycle. For the total cohort, 9 patients achieved an overall response (ORR 50%), including 8 patients with a complete remission (CR/CRi 44%) and 1 (6%) patient with a morphologic leukemia free state, Figure 1. All six of the responders who were tested for MRD were negative. For treatment naïve patients, we observed a CR/CRi rate of 70% and a median survival of 11 months. On univariate analysis, R/R disease was the only factor associated with a significant decrease in response (ORR 12.5% vs. 80%, p=0.015, Table 1). With a median follow-up of 14.4 months for responding patients, median OS for the cohort was 6.59 months and 19.15 months for responding patients (Figure 2). The presence of NRAS or KRAS mutations was the only factor significantly impacting survival (HR 6.04, log rank 0.05, Table 1). Notably, the KMT2A fusion partner type did not impact response or survival. Allogeneic stem cell transplant was performed in 4 out of 9 (44%) responding patients. Conclusion Here, we show that venetoclax in combination with HMA led to a high rate of response and prolonged survival in a high-risk KMT2A rAML population. The outcomes of newly diagnosed KMT2A rAML patients after treatment with venetoclax and HMA in this study are similar to chemotherapy outcomes in patients aged < 60 years (CR 68% and median OS 0.9 months; Bill, M et al. PNAS. 2020). Consistent with previous studies, we found that MLLT3 was the most common fusion partner, occurring in 50% of patients and that RAS mutations were also common (~30%). In contrast to what has been reported for chemotherapy outcomes and in the ELN classification, the KMT2A-MLLT3 translocation was not associated with improved outcomes when compared to other KMT2A translocations. While this study was limited in being retrospective and having a small and heterogeneous population, our findings suggest that venetoclax and HMA are effective in KMT2A rAML and warrant further investigation. Figure 1 Figure 1. Disclosures Koller: Novartis: Consultancy. Al Malki: Hansa Biopharma: Consultancy; Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; CareDx: Consultancy. Aribi: Seagen: Consultancy. Ali: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Marcucci: Novartis: Other: Speaker and advisory scientific board meetings; Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings. Pullarkat: AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees; Amgen, Dova, and Novartis: Consultancy, Honoraria.
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- 2021
122. A Phase II Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Efficacy of Cmvpepvax for Preventing CMV Reactivation/Disease after Matched Related/Unrelated Donor Hematopoietic Cell Transplant
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Stephen J. Forman, Joshua A. Hill, Monzr M. Al Malki, Vinod Pullarkat, Qiao Zhou, Ryotaro Nakamura, Chetan Raj Lingaraju, Ibrahim Aldoss, Corinna La Rosa, Michael R. Verneris, Jeffrey Longmate, Thai Cao, Cynthia Slape, Lupe Duarte, Jennifer Drake, Jeffrey S. Miller, Ahmed Aribi, Dongyun Yang, Don J. Diamond, Steven M. Devine, Armin Rashidi, and Hannah Choe
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medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Immunology ,Cell Biology ,Hematology ,Disease ,Cmv reactivation ,Placebo ,Biochemistry ,Gastroenterology ,Double blind ,Unrelated Donor ,Internal medicine ,Multicenter trial ,Medicine ,business - Abstract
Cytomegalovirus (CMV) infection remains a major cause of morbidity/mortality after allogeneic hematopoietic cell transplantation (HCT). Preemptive antiviral therapy is associated with drug-induced toxicities, and prophylactic therapy with letermovir is associated with late reactivations and delayed antiviral immune reconstitution. Therefore, substituting antivirals with a vaccine that harnesses the native immune response to CMV may improve outcomes for HCT recipients. Our group has developed a peptide vaccine, CMVPepvax, composed of an HLA-A*0201 restricted pp65 495-503 CD8 T cell epitope, covalently linked to a universal tetanus T helper epitope and co-administered with PF-03512676 adjuvant. CMV PepVax was safe and immunogenic in a healthy volunteer study (La Rosa et al. PMID: 22402037;) and a phase Ib HCT recipient trial (Nakamura, et al. PMID: 26853648) with the latter demonstrating a promising sign of efficacy in reducing CMV viremia. In this double blind, placebo-controlled, randomized phase 2 trial (NCT02396134), HCT recipients were enrolled at four USA transplant centers. Eligible patients were CMV seropositive, HLA A*0201-positive, 18-75 years, receiving HCT from a matched related/unrelated donor. T-cell depleting agents (i.e. ATG) or recipients of ex-vivo T-cell-depleted grafts were excluded. Prophylactic antiviral therapy was not allowed. Patients were enrolled prior to day 0 of HCT and reassessed on day +28 for eligibility and randomization to the vaccine (VA) or placebo arm (PA), stratified by donor CMV serostatus. PepVax was administered subcutaneously on days +28 and +56 post-HCT. The primary endpoint of the trial was CMV viremia ≥1250 IU/m or CMV disease through 100 days post-HCT. A total of 96 patients were planned to be randomized at 1:1 ratio, providing 90% power to detect a reduction of viremia from 40% to 15%. CMVpp65-specific immune reconstitution was monitored by measuring levels of CD8 T cells binding to MHC class I pp65 495-503 and HIVgag 77-85 (as control) multimers (Immudex Dextramers), as well as CD28 and CD45 memory markers (BD Biosciences). The intensity of the fluorescent labels was measured using a Gallios flow cytometer with Kaluza software (Beckman Coulter). Enrollment started in June 2015 but was stopped in November 2017 when a planned interim analysis suggested futility for the primary efficacy endpoint. By that time, 76 subjects had been consented, of whom 61 met the day 28 eligibility criteria and were randomized to the VA (n=32) or PA (n=29). The unblinded data were released when the planned one-year follow up was completed for these 61 subjects. The two groups were overall balanced in their demographics and HCT characteristics. There was no difference in the primary endpoint of CMV reactivation/disease between VA (25.1%) and PA (13.8%, p=0.15). The incidence of preemptive therapy was similar between the two arms. PepVax was well tolerated with no increase in adverse events. Transplant outcomes were also similar between the two groups with regards to 1-year overall survival, relapse-free survival, non-relapse mortality, relapse, and acute GVHD. In subjects in VA who reached the primary endpoint (n=8), CMV viremia occurred at a median of 20 days (interquartile range: 15-23 days; range, 0-48) after the first vaccine, suggesting that there was insufficient time for the vaccine-induced T cell expansion. Significantly higher levels of long lasting pp65-specific T cells with effector memory phenotype were measured in non viremic participants in the VA compared to those in the PA; this effect was driven by differences observed late after vaccination (p = 0.004 by GEE analysis; Figure, panel A). In patients who controlled viremia, robust expansion of functional pp65-specific CD8 T cells was observed following PepVax injections (Figure, panels B-C). Our results confirm safety and immunogenicity of PepVax in CMV seropositive HCT recipients. However, the trial failed to demonstrate a clinical efficacy of PepVax in reducing CMV viremia/disease despite favorable CD8 T cell responses. Early CMV reactivation/disease detected before receipt of the second vaccine may have reduced the ability of PepVax to elicit a protective T cell response. Transfer of vaccine-induced immunity through donor CMV immunization combined with recipient booster immunization may overcome this issue and lead to faster immune reconstitution post-HCT. Figure 1 Figure 1. Disclosures Hill: Amplyx: Consultancy; OptumHealth: Consultancy; CRISPR therapeutics: Consultancy; Gilead: Consultancy, Research Funding; Allogene therapeutics: Consultancy; Octapharma: Consultancy; Allovir: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; CLS Behring: Consultancy; Karius: Research Funding. Al Malki: Hansa Biopharma: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; Neximmune: Consultancy; Rigel Pharma: Consultancy; CareDx: Consultancy. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Aribi: Seagen: Consultancy. Devine: Tmunity: Current Employment, Research Funding; Magenta Therapeutics: Current Employment, Research Funding; Sanofi: Consultancy, Research Funding; Johnsonand Johnson: Consultancy, Research Funding; Orca Bio: Consultancy, Research Funding; Be the Match: Current Employment; Vor Bio: Research Funding; Kiadis: Consultancy, Research Funding. Verneris: Novartis: Other: advisory board; jazz: Other: advisory board; Fate Therapeutics: Consultancy. Miller: Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees. Forman: Allogene: Consultancy; Lixte Biotechnology: Consultancy, Current holder of individual stocks in a privately-held company; Mustang Bio: Consultancy, Current holder of individual stocks in a privately-held company. Diamond: Pfizer Inc: Other; Helocyte Inc: Membership on an entity's Board of Directors or advisory committees, Other, Patents & Royalties.
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- 2021
123. Preliminary Results By Age Group of Treatment with CPX-351 Plus Venetoclax in Adults with Newly Diagnosed AML: Subgroup Analysis of the V-FAST Phase 1b Master Trial
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Mark J. Levis, Vijayalakshmi Chandrasekaran, Divya Chakravarthy, Vinod Pullarkat, Gabriel N. Mannis, Harry P. Erba, Stefan Faderl, Tara L. Lin, Ronald S. Cheung, and Stephen A. Strickland
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medicine.medical_specialty ,Group (mathematics) ,Venetoclax ,business.industry ,Immunology ,Subgroup analysis ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,business - Abstract
Introduction: CPX-351 (United States: Vyxeos ®; Europe: Vyxeos ® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of newly diagnosed therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes in adults and pediatric patients aged ≥1 year in the United States and in adults in the European Union. In a phase 3 study in adults aged 60 to 75 years with newly diagnosed high-risk/secondary AML, after 5 years of follow-up CPX-351 significantly improved median overall survival and remission rates versus conventional 7+3 cytarabine/daunorubicin, with a comparable safety profile. Preclinical data suggest CPX-351 may have synergistic activity with targeted agents, including the BCL-2 inhibitor venetoclax (VEN). Interim results from the V-FAST (Vyxeos - First Phase Assessment with Targeted Agents) study have demonstrated the safety and preliminary efficacy of CPX-351 in combination with VEN or midostaurin. Herein, we report the preliminary results of a subgroup analysis of adults with newly diagnosed AML treated with CPX-351 + VEN, based on age, to provide insights into the tolerability of this novel combination in younger versus older adults with AML. Methods: V-FAST is an ongoing, open-label, multicenter, multi-arm, nonrandomized, phase 1b master trial (NCT04075747) to evaluate the safety and preliminary efficacy of CPX-351 combined with targeted agents (venetoclax, midostaurin, enasidenib). Each combination arm had a dose-exploration phase (3+3 design; n ≤12) and a subsequent expansion phase (n = 20) to determine the recommended phase 2 dose (RP2D), safety, and initial efficacy of that treatment combination. Eligible patients included adults aged 18 to ≤75 years with newly diagnosed AML who were deemed fit for intensive chemotherapy and had an ECOG performance status of 0 to 2. Patients assigned to treatment with CPX-351 + VEN were to have wild type FLT3 and IDH2 based on molecular testing. The RP2D of this treatment arm was determined to be dose level 1, in which patients received CPX-351 100 units/m 2 (daunorubicin 44 mg/m 2 + cytarabine 100 mg/m 2) on Days 1, 3, and 5 + VEN 400 mg on Days 1 to 14 of the first induction. At this dose level, 1 of 6 patients in the dose-exploration phase experienced 2 dose-limiting toxicities (grade 4 neutropenia [Day 16] and grade 4 thrombocytopenia [Day 18]) that extended beyond 49 days; no dose adjustments were required and the study enrolled an additional 21 patients at this dose level. For this subgroup analysis, patients were grouped by age: 18 to ≤59 years (younger) and 60 to ≤75 years (older). Results: A total of 21 patients received CPX-351 + VEN and had sufficient data to be included in the analysis, comprising 14 patients aged 18 to ≤59 years and 7 patients aged 60 to ≤75 years. Patient baseline characteristics are shown in Table 1. The most common TEAEs of any grade in younger adults were neutropenia, febrile neutropenia, and constipation; the most common TEAEs in older adults were febrile neutropenia, thrombocytopenia, and nausea (Table 2). The most common grade ≥3 TEAEs in both age groups included febrile neutropenia, thrombocytopenia, neutropenia, and leukopenia (Table 2). TEAEs categorized as serious events included febrile neutropenia (n = 3 [younger]; n = 1 [older]), sepsis (n = 2 [younger]), ischemic stroke (n = 1 [older]), skin infection (n = 1 [older]), and AML (n = 1 [younger]). Six evaluable patients in the younger age group and 1 in the older age group died during the study due to primary causes of relapse/progression (n = 4), adverse event (n = 2), and other (n = 1; sepsis and multiorgan failure after early termination from treatment). Median platelet and neutrophil recovery times were similar between age groups (Table 3) and consistent with the previously reported safety profile of CPX-351 monotherapy. Complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) evaluable younger adults and 4/6 (67%) evaluable older adults, including 5/14 (36%) and 3/6 (50%) who achieved CR. Conclusions: This analysis of preliminary results by age group from the V-FAST study supports the conclusion that the combination of CPX-351 + VEN is equally feasible with a manageable safety profile in both younger and older adult patients with newly diagnosed AML. Promising remission rates were also reported for both age groups. Figure 1 Figure 1. Disclosures Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Levis: Astellas and FujiFilm: Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Mannis: AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy; Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding. Strickland: Sunesis: Research Funding; AbbVie, ArcherDx, Genentech, Incyte, Kura Oncology, Novartis, Pfizer, and Syros: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Faderl: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chakravarthy: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Chandrasekaran: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Erba: AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, and PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas Pharma, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Covance (AbbVie): Other: Independent Review Committee . OffLabel Disclosure: combination of CPX-351 [Vyxeos] and venetoclax in adults with previously untreated AML
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- 2021
124. A Phase 2 Study of Bezuclastinib (CGT9486), an Oral, Selective, and Potent KIT D816V Inhibitor, in Adult Patients with Advanced Systemic Mastocytosis (AdvSM)
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Hina Jolin, Prithviraj Bose, Michael W. Deininger, Vinod Pullarkat, Jessica Sachs, Jason Gotlib, Daniel J. DeAngelo, Tsewang Tashi, Tracy I. George, Amanda Pilla, and Francis Payumo
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medicine.medical_specialty ,Adult patients ,business.industry ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Gastroenterology ,Kit d816v ,Internal medicine ,medicine ,Systemic mastocytosis ,business ,health care economics and organizations - Abstract
Systemic mastocytosis (SM) is characterized by excessive accumulation of mast cells in bone marrow and other extracutaneous tissues encompassing a spectrum of variants ranging from non-advanced to advanced disease (Shomali et al, 2018). Advanced systemic mastocytosis (AdvSM) is an aggressive and life-threatening form of SM with an overall survival from The molecular pathogenesis of SM is driven by mutations in the KIT gene leading to ligand-independent proliferation of mast cells, with 95% of patients carrying the D816V mutation in exon 17 (Garcia-Montero et al, 2006; Jara-Acevedo et al, 2015; Vaes et al, 2017). Bezuclastinib, an oral, highly selective tyrosine kinase inhibitor with potent activity against KIT D816V has shown preliminary clinical activity and a tolerable safety profile in a Ph 1/2 study of patients with advanced solid tumors including gastrointestinal stromal tumor (GIST). In that study, a reduction in KIT exon 17 mutational burden was observed in subjects treated with bezuclastinib. This reduction was temporally associated with a reduction in tumor burden supporting bezuclastinib as an active therapy in KIT-driven diseases (Wagner et al, 2018). Other agents targeting the KIT D816V mutations have shown activity in the treatment of AdvSM; however, toxicities such as cognitive impairment, intracranial hemorrhage, and edema may limit dosing and appropriateness of these therapies. Besides targeting KIT D816V, bezuclastinib was designed to avoid other closely related kinases with known liabilities, such as PDGFRα, PDGFRβ, wild-type KIT, VEGFR2 (KDR), and CSF1R (FMS). Additionally, minimal brain penetration has been observed with bezuclastinib, and no CNS toxicities have been identified in preclinical studies. This is a multi-center, Phase 2, open-label, 2-part clinical study to evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of bezuclastinib in subjects with AdvSM. This study will enroll subjects who meet WHO diagnostic criteria for AdvSM, have measurable SM-related organ damage according to modified IWG-MRT-ECNM consensus eligibility and response criteria, and have a baseline serum tryptase of ≥20 ng/mL. The diagnosis of AdvSM and evidence of measurable disease will be confirmed by an Eligibility Committee prior to enrollment. This study will enroll approximately 140 patients. Part 1 will consist of a dose optimization period to determine the optimal dose of bezuclastinib for subjects with AdvSM. Subjects will be randomized into one of four dose cohorts (50, 100, or 200 mg twice daily, or 400 mg once daily) in a 1:1:1:1 manner. A planned interim analysis to assess safety, efficacy, and biomarker endpoints will occur when approximately half the planned number of Part 1 patients have been evaluated through at least 2 cycles of treatment. After all subjects in Part 1 complete at least two cycles, the optimal dose will be selected. Part 2 will enroll subjects at the selected dose level to determine efficacy of bezuclastinib and to further characterize safety, PK, and PD. The primary assessment of efficacy is overall response rate, defined as the percentage of subjects classified as confirmed responders (CR, CR with incomplete hematologic recovery [CRh], partial response [PR], and clinical improvement [CI]) according to modified IWG-MRT-ECNM response criteria as assessed by a Central Response Review Committee (CRRC). Data from this study will support continued development of bezuclastinib in SM including Non-Advanced SM. This study opened in June 2021. Disclosures Gotlib: BMS: Research Funding; Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. George: Celgene: Consultancy; Blueprint Medicines: Consultancy; Bristol Meyers Squibb: Consultancy; Incyte Corporation: Consultancy. Deininger: Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. Tashi: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board. Pullarkat: Amgen, Dova, and Novartis: Consultancy, Honoraria; AbbVie, Amgen, Genentech, Jazz Pharmaceuticals, Novartis, Pfizer, and Servier: Membership on an entity's Board of Directors or advisory committees. Bose: Celgene Corporation: Honoraria, Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Novartis: Honoraria; Promedior: Research Funding; BMS: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Sierra Oncology: Honoraria; Incyte Corporation: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding. Payumo: Cogent Biosciences, Inc: Current Employment. Pilla: Cogent Biosciences: Current Employment. Jolin: Cogent Biosciences: Current Employment. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. OffLabel Disclosure: Study is for investigational agent
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- 2021
125. Total Marrow and Lymphoid Irradiation to 20 Gy Combined With Post-Transplant Cyclophosphamide Graft vs. Host Disease (GvHD) Prophylaxis is Associated With Low Non-Relapse Mortality Rates and Favorable GvHD-Free/Relapse-Free Survival in AML
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Joycelynne Palmer, Vinod Pullarkat, Dongyun Yang, Ricardo Spielberger, S.V. Dandapani, An Liu, S.J. Forman, Chunhui Han, Joseph Rosenthal, M. Al Malki, Len Farol, Guido Marcucci, S.K. Hui, Anthony S. Stein, Amandeep Salhotra, Ryotaro Nakamura, and J.Y.C. Wong
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Cancer Research ,medicine.medical_specialty ,Radiation ,Cyclophosphamide ,business.industry ,Spleen ,medicine.disease ,Relapse free survival ,Gastroenterology ,Tacrolimus ,Transplantation ,medicine.anatomical_structure ,Oncology ,Internal medicine ,Toxicity ,medicine ,Radiology, Nuclear Medicine and imaging ,Esophagus ,business ,Stomatitis ,medicine.drug - Abstract
Purpose/Objective(s) Allogeneic hematopoietic cell transplantation (alloHCT) offers the highest curative rate for AML with intermediate or high-risk cytogenetics in remission. GvHD is a main cause of alloHCT mortality and morbidity. This trial evaluated the feasibility of a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 20 Gy combined with post-transplant cyclophosphamide (PTCy), which was designed to reduce the chronic GvHD risks using PTCy and reduce relapse rates with TMLI, thereby improving GRFS rates compared to standard myeloablative conditioning regimens. Materials/Methods Eighteen patients with AML in first or second complete remission were treated with TMLI 20 Gy (2 Gy twice daily) to bone, lymph nodes and spleen (liver and brain 12 Gy) on days -4 to 0; stem cell infusion on day 0; PTCy 50 mg/kg/day on days +3 and +4; and tacrolimus 1 mg continuous infusion on days +5 to +90. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). GRFS was defined as grade 3-4 acute GvHD (aGvHD), chronic GvHD (cGvHD) requiring systemic treatment, relapse, or death (from any cause). Results The median age was 40 (range 19-56). Seventeen of 18 patients had intermediate to high-risk cytogenetics. The average (range) Dmean organ doses (Gy) were lungs 8.1 (7.5-9.5), kidneys 7.5 (6.3-9.2), heart 7.3 (6.6-8.3), oral cavity 4.4 (3.0–6.7), esophagus 6.4 (4.7-7.6), upper GI 9.1 (7.3-12.0), lower GI 10.2 (8.9-12.1), and bladder 10.0 (6.8-14.6). Median follow-up was 12.5 months (range 5.9 to 25.4) for surviving patients (n = 17). All patients engrafted. Bearman toxicity data were available for all patients. Grade 2 toxicities were bladder (n = 3) and stomatitis (n = 1). No grade 3-4 toxicities or toxicity-related deaths were observed. aGvHD developed in 2 patients with grade III-IV in only 1 patient (100-day Grade III-IV aGvHD: 5.6%, 95% CI: 0.3-23.1). Five patients developed chronic GvHD with one patient developing moderate to severe cGVHD (1-year cGvHD rate: 28.6%, 95% CI: 7.5%-54.7%). The GRFS rate at 1 year was 60.6% (95% CI: 34.6-79.0). One-year estimates of OS and relapse-free survival were 100% and 83.3% (95% CI: 62.8-96.1), respectively. Disease relapse at 1 year was 16.7% (95% CI: 3.9-37.2). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusion This TMLI 20 Gy only conditioning regimen, together with PTCy and tacrolimus, is associated with low toxicity and NRM. All patients achieved engraftment. Participants with ≥ 1-year follow-up have discontinued immunosuppressive therapy. The results suggest an improved GRFS rate compared to traditional myeloablative regimens reported. A larger phase II trial is planned.
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- 2021
126. Peri-Transplant Administration of Ruxolitinib (Rux) in Patients with Myelofibrosis (MF) Is Safe and Effective. A Pilot Study
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Timothy W. Synold, Haris Ali, Vinod Pullarkat, Matthew Mei, Ryotaro Nakamura, Stephen J. Forman, David S. Snyder, Ni-Chun Tsia, Syed Rahmanuddin, Sally Mokhtari, Ji-Lian Cai, Joycelynne Palmer, and Amandeep Salhotra
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Transplantation ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Peri ,Cell Biology ,Hematology ,medicine.disease ,Internal medicine ,Molecular Medicine ,Immunology and Allergy ,Medicine ,In patient ,business ,Myelofibrosis ,Administration (government) ,medicine.drug - Published
- 2021
127. Healthcare Resource Utilization in Transplant Patients Who Are at a Higher-Risk to Develop Cytomegalovirus Infection during Their Primary Transplant-Related Hospitalization
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Eileen P. Smith, Alfredo G. Puing, Vinod Pullarkat, Bernard Tegtmeier, Deepa Nanayakkara, Dongyun Yang, Monzr M. Al Malki, John A. Zaia, David S. Snyder, Ricardo Spielberger, Joycelynne Palmer, Sally Mokhtari, Stephen J. Forman, Ryotaro Nakamura, Anthony S. Stein, Karamjeet S. Sandhu, Amandeep Salhotra, Randy Taplitz, Jana Dickter, and Sanjeet Dadwal
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medicine.medical_specialty ,business.industry ,Medical record ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Transplantation ,Letermovir ,Internal medicine ,Epidemiology ,Cohort ,medicine ,Lost to follow-up ,business ,Packed red blood cells ,Viral load ,medicine.drug - Abstract
Cytomegalovirus reactivation commonly referred to as CMV infection (CMVi) is a frequent event after allogeneic hematopoietic cell transplantation (HCT), with studies associating CMVi within the first 100 days post-HCT with higher risk of non-relapse mortality (NRM) and decreased overall survival (OS). In addition, understanding the impact of CMVi on resource utilization during the primary HCT admission is critical. Together, this knowledge of epidemiology and resource utilization may be used to inform preventive strategies to minimize CMVi, e.g., use of antiviral agent letermovir. After receiving IRB approval, we retrospectively reviewed institutional electronic medical records and CMVi database from 824 patients who underwent their first allogeneic HCT between 2011 and 2016 at City of Hope (pre-letermovir era). Patients were censored at death, disease relapse or lost to follow up. Data collected: demographics, HCT indication, conditioning regimen, CMV serostatus of the donor and recipient (D/R), length of stay (LOS) for primary HCT admission (all allo HCT were performed as inpatient), readmission rates in first 100 days, and use of supportive care. CMV viral load of >250 genomic copies/ml constituted a diagnosis of CMVi. CMV viral load surveillance in MUD recipients began at engraftment or day +21 post-HCT, whichever occurred earlier. For Haplo and cord blood (CB) HCT, CMV viral load surveillance started on day +14. The primary endpoint of the study was LOS for HCT admission. Supportive care use, transfusions, growth factors and antiviral usage were secondary endpoints. The differences in resource utilization between different groups were examined by CMVi during the primary HCT admission period, using Wilcoxon test or chi-square test whenever appropriate. Median age of patients at the time of HCT was 52 years (range: 1-78), with 57% of patients being male. The most common diagnoses included: AML (39%), ALL (21%) and MDS/MPN (17%). Patients underwent MUD (n=627, 76%), Haplo (n=102, 12%), or CB-HCT (n=95, 12%), and 44% of patients received myeloablative conditioning regimen. Majority of the patients were CMV seropositive (83.7%). Graft source was peripheral blood stem cells in 75% of the recipients. Most commonly used graft-versus-host disease prophylaxis consisted of post-transplant cyclophosphamide (100%), Tacrolimus/sirolimus (83%), and cyclosporine/cellcept (78%) in Haplo, MUD, and CB-HCT recipients, respectively. During the primary HCT admission, rate of CMVi was 7%, 36% and 28% in all of MUD, Haplo, and CB-HCT, respectively (compared to 25%, 71.6%, and 50.5% in MUD, Haplo and CB-HCT respectively in the first 100 days after HCT). Rate of CMVi in CMV+ recipients was 8.2% in MUD, 41.6% Haplo and 34.2% in CB-HCT (Table 1). Majority of patients with CMVi received antiviral therapy (85.8%), with Haplo and CB-HCT more likely to be treated than MUD (p=0.023). LOS was longer among CMVi patients compared to no CMVi patients in each donor type, median of 59 vs. 36 days for the overall cohort (p0.2). Transfusion of packed red blood cells (PRBC) and platelet units were significantly higher among CMVi recipients of MUD and Haplo (p0.82). There was no significant difference in hospital readmission by CMVi across donor type in the first 100 days (p>0.5). In conclusion, the rate of CMVi during primary HCT admission was high, particularly in the Haplo and Cord HCT (>50% of the CMVi occurring within 100 days of HCT). Given the relatively high CMV viral load cut-off values and later CMV surveillance initiation, the rate could, in fact, have been underestimated in our cohort. CMVi during primary HCT admission was associated with significantly higher health care resource utilization; longer hospital LOS and supportive care utilization (CMV specific antiviral usage, transfusion and growth factors use). Prophylactic strategies to prevent early CMVi in alloHCT should be considered to decrease NRM and improve value based care delivery. Disclosures Dadwal: Shire/ Takeda: Research Funding; Karius: Research Funding; Astellas: Speakers Bureau; Janssen: Other: Advisory board meeting; Ansun Biopharma: Research Funding; Chimerix: Research Funding; Gilead: Research Funding; Merck: Consultancy, Honoraria, Other: Advisory board meeting, Research Funding, Speakers Bureau. Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Taplitz:Merck: Other: Immunocompromised Advisory Group. Al Malki:Neximmune: Consultancy; Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Nakamura:NapaJen Pharma: Consultancy; Magenta Therapeutics: Other: Advisory board meeting; Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Celgene: Other: Support on seminar; Viracor: Consultancy; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting.
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- 2020
128. Total Marrow and Lymphoid Irradiation (TMLI) at a Dose of 2000cGy in Combination with Post-Transplant Cyclophosphamide (PTCy)-Based Graft Versus Host Disease (GvHD) Prophylaxis Is Safe and Associated with Favorable GvHD-Free/Relapse-Free Survival at 1 Year in Patients with Acute Myeloid Leukemia (AML)
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Susanta K. Hui, David S. Snyder, Andrew S. Artz, Ryotaro Nakamura, Samer K. Khaled, Ni-Chun Tsai, Joycelynne Palmer, Vinod Pullarkat, Guido Marcucci, Joseph Rosenthal, Ahmed Aribi, Len Farol, Jeffrey Y.C. Wong, Ibrahim Aldoss, Anthony S. Stein, Stephen J. Forman, Dongyun Yang, Ricardo Spielberger, Amandeep Salhotra, Monzr M. Al Malki, Eric Radany, Haris Ali, An Liu, James F. Sanchez, and Chatchada Karanes
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Oncology ,medicine.medical_specialty ,Post transplant cyclophosphamide ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Relapse free survival ,Graft-versus-host disease ,Internal medicine ,Medicine ,Gvhd prophylaxis ,In patient ,business - Abstract
Background: Allogeneic hematopoietic cell transplantation (alloHCT) is the approach that offers the highest curative rate for acute myelogenous leukemia (AML) with intermediate or high-risk cytogenetics. Graft versus host disease (GvHD) has remained the main cause of post-transplantation mortality and morbidity, despite advances in prophylaxis and therapy, adding significant economic burden and affecting quality of life. It would be desirable to reduce the rate of GvHD among patients in complete remission (CR) without increasing the risk of relapse. In this study, we have developed a novel conditioning regimen of total marrow and lymphoid irradiation (TMLI) at 2000 cGy, together with post-transplant cyclophosphamide (PTCy), to 1) reduce the possibly increased risk of relapse from PTCy, by using escalated radiation doses of TMLI, as increasing radiation doses has the potential to decrease the post-transplantation relapse rate (Blood, vol 76, pp. 1867-1871, 1990); and 2) reduce the risk of chronic GvHD by using PTCy. The major goal of this pilot study of TMLI and PTCy (clinicaltrials.gov: NCT03467386), was to thus improve GvHD-free/relapse-free survival (GRFS), reported to be 45% from total body irradiation (TBI) and tacrolimus/sirolimus prophylaxis (BBMT, vol 26(2), pp. 292-299, 2020), in patients with AML in remission. Patients and Methods: A total of 18 patients were enrolled and treated (see Table) between March 2018 and December 2019. Key criteria were ages 18 to 60, first or second CR, minimal residual disease negative by multi-color flow cytometry, and normal organ function. TMLI was administered on days -4 to 0 without addition of chemotherapy. The radiation dose for all patients (n=18) was 2000 cGy, delivered in 200 cGy fractions twice daily. The radiation dose delivered to the liver and brain was kept at 1200 cGy. Remaining organs were considered non-targeted. All patients received peripheral blood stem cells on day 0. Cyclophosphamide was given on days +3 and +4, 50 mg/kg each day for GVHD prevention. Tacrolimus, 1 mg continuous infusion adjusted to maintain levels from 5 to 10 ng/mL was given from day +5 to day +90, and G-CSF 5 µg/kg daily was administered at day +5 until recovery of neutrophil counts. Endpoints included toxicity, GRFS at 1 year, engraftment, overall survival (OS), and non-relapse mortality (NRM). Toxicities were defined according to the Bearman and CTCAE 4.03 scales, the latter for hematologic toxicity. A patient safety lead-in segment (n=6) was conducted to ensure that there were no unexpected toxicities, allowing for a dose de-escalation to 1800 cGy. GRFS was defined as grade 3-4 acute GvHD, chronic GvHD requiring systemic treatment, relapse, or death (from any cause), whichever occurred first. Results: Bearman toxicity data are available for all patients. Among these patients, grade 2 toxicities were bladder toxicity and stomatitis. No grade 3-4 toxicities or toxicity-related deaths were observed. Acute GVHD (aGVHD) developed in 2 of patients (100-day Grade II-IV aGVHD: 11.1%, 95%CI: 1.7-30.4); of those, only 1 patient developed Grades III-IV (100-day Grade III-IV aGVHD: 5.6%, 95%CI: 0.3-23.1). Five patients developed mild chronic GVHD (1-year cGVHD rate: 28.6%, 95%CI: 7.5%-54.7%). The GRFS rate at 1 year was 59.3% (95% CI: 28.8-80.3) (Figure). The median follow up was 11.3 months (range 4.7 to 25.4) for surviving patients (n=17). All patients engrafted. Time to neutrophil and platelet recovery were 14 days (range 13-32 days) and 20 days (range 11-49 days), respectively. One-year estimates of OS and relapse-free survival were 100% and 80.8% (95% CI: 50.5-93.6), respectively (Figure). Disease relapse at 1 year was 19.2% (95% CI: 4.1-42.6). The estimates of NRM at 100 days and 1 year were both 0%. Relapsed disease after transplant occurred in 3 patients (16.7%). One patient died after relapse. Conclusions: 1) This chemotherapy-free conditioning regimen, together with PTCy and tacrolimus, is safe and feasible, with no NRM. 2) All patients achieved engraftment. 3) Participants with ≥1 year follow-up have discontinued immunosuppressive therapy, reducing financial burden and leading to improved quality of life. The preliminary results suggest an improved GRFS rate. A larger phase 2 trial is in preparation to corroborate these data. Disclosures Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Al Malki:Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Rigel Pharma: Consultancy. Ali:Incyte Corporation: Consultancy. Aribi:Seattle Genetics: Consultancy. Marcucci:Novartis: Speakers Bureau; Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Nakamura:Alexion: Other: Support on a meeting presentation; Kyowa-Kirin: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; NapaJen Pharma: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Salhotra:Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees.
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- 2020
129. Venetoclax and Navitoclax in Pediatric Patients with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma
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Norman J. Lacayo, John Pesko, Mohamed Badawi, Theodore W. Laetsch, Kathryn G. Roberts, Jeffrey E. Rubnitz, Thomas B. Alexander, Bo Tong, Lindsey Rosenwinkel, Charles G. Mullighan, Joseph T. Opferman, Seong Lin Khaw, Su Young Kim, Deeksha Vishwamitra, and Vinod Pullarkat
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medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Lymphoblastic lymphoma ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Tumor lysis syndrome ,Transplantation ,chemistry.chemical_compound ,chemistry ,Tolerability ,Internal medicine ,medicine ,business ,Adverse effect ,Febrile neutropenia - Abstract
Background: Improved therapeutic strategies for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) remain an unmet need. Venetoclax (Ven), a potent, highly selective, oral B-cell lymphoma 2 (BCL-2) inhibitor, and navitoclax (Nav), an oral BCL-2, BCL-XL, and BCL-W inhibitor, directly bind their BCL-2 family member targets to promote apoptosis. Ven and Nav have shown synergistic antileukemic effects in ALL preclinical models, suggesting dependence on BCL-2 family members. The addition of Ven to low-dose Nav may potentiate efficacy without the dose-limiting thrombocytopenia associated with Nav monotherapy (J Clin Oncol. 2012;30:488). Ven in combination with Nav and chemotherapy are under investigation in a Phase 1, multicenter, open-label, dose-escalation study in patients with R/R ALL and LL (NCT03181126). The results of a previous report on the overall study population (adult and pediatric patients) showed the triplet combination was well tolerated, with promising response rates observed (Jabbour, et al. EHA 2020. Abstract 2389). For the first time, reported here are safety, tolerability, pharmacokinetics, and antitumor activity of Ven with Nav and chemotherapy among the pediatric patients treated in that Phase 1 study. Methods: Eligible pediatric patients (aged ≥4- Results: As of June 23, 2020, 18 pediatric patients (pts) have enrolled (12 in dose-escalation; 6 in safety expansion); 13, 3, and 2 pts had B-ALL, T-ALL, and LL, respectively. Among pts in the dose-escalation phase, 6 received 25 mg Nav and 6 received 50 mg. Median age was 10 years (range, 6-16 years), 56% of pts were male, and the median number of prior therapies was 2 (range, 1-6). Median time on study was 10.4 months. All pediatric pts experienced treatment-emergent adverse events (TEAEs), and the most common were febrile neutropenia (50%), vomiting (44%), hyperglycemia (39%), and hypokalemia (39%). Grade 3/4 TEAEs occurred in 89% of pediatric pts, and the most common were febrile neutropenia (50%), neutropenia (33%), thrombocytopenia (33%), and anemia (28%). The only Grade 3/4 nonhematologic TEAEs related to Ven or Nav that occurred in >1 pediatric pt were alanine aminotransferase increased (n=2) and vomiting (n=2). Of 8 dose-limiting toxicities (DLTs), 2 occurred in pediatric pts. The 2 DLTs included delayed count recovery (25 mg Nav) and sepsis (50 mg Nav, occurred after database lock). No pediatric pts experienced tumor lysis syndrome. No Grade 5 TEAEs occurred in pediatric pts; 8 pediatric pts (44%) died from disease progression. Ten pediatric pts (56%) achieved complete response (CR)/CR incomplete recovery (CRi)/CR without platelet recovery (CRp); 7 pts (39%) achieved undetectable MRD. Median overall survival was 11.4 months (95% CI, 2.9 months-not estimable). Eight pts (44%) proceeded to transplantation (n=5) or CAR T-cell therapy (n=3; cells harvested before start of study; Figure). Weight-based dosing of Ven and Nav achieved comparable exposures in pediatric pts. Exploratory correlative biomarker analyses, including BH3 profiling and genomic analyses, are underway and will be presented. Conclusion: In this Phase 1 study, Ven with Nav and chemotherapy was well tolerated and had promising efficacy in heavily pretreated pediatric patients with ALL and LL. Given that there were four DLTs with 100 mg Nav without evidence of increased efficacy, the recommended Phase 2 dose for adult and pediatric patients is 400 mg Ven with 50 mg Nav for patients weighing ≥45 kg and 25 mg Nav for patients weighing Figure Disclosures Rubnitz: AbbVie Inc.: Research Funding. Alexander:Abbvie, Inc.: Other: Travel Support. Laetsch:Bayer: Consultancy, Research Funding; Cellectis: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Khaw:Amgen: Other: Travel Support, Research Funding; Novartis: Other: Travel Support; AbbVie, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz Pharmaceuticals: Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: recipient of a share in royalty payments . Pullarkat:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Opferman:St. Jude Children's Research Hospital: Current Employment; AbbVie, Inc.: Research Funding; National Institutes of Health: Research Funding. Rosenwinkel:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Mullighan:Illumina: Consultancy, Honoraria, Speakers Bureau; AbbVie, Inc.: Research Funding; Pfizer: Honoraria, Research Funding, Speakers Bureau. OffLabel Disclosure: Yes, venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of acute lymphoblastic leukemia is not an approved indication.
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- 2020
130. Clinical Outcomes of Patients with Secondary Acute Myeloid Leukemia (sAML) Treated with Hypomethylating Agent Plus Venetoclax (HMA-Ven) or Liposomal Daunorubicin Cytarabine (CPX-351)
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Andrew S. Artz, Lihua E. Budde, Karamjeet S. Sandhu, Vinod Pullarkat, Shukaib Arslan, Anthony S. Stein, Dat Ngo, Stephen J. Forman, Ibrahim Aldoss, Jianying Zhang, Ryotaro Nakamura, Amandeep Salhotra, Ahmed Aribi, Monzr M. Al Malki, Haris Ali, Pkoller Koller, David S. Snyder, Sanjeet Dadwal, Samer K. Khaled, and Guido Marcucci
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Oncology ,medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,Liposomal daunorubicin ,chemistry.chemical_compound ,chemistry ,Hypomethylating agent ,Internal medicine ,Ven ,Cytarabine ,Medicine ,Secondary Acute Myeloid Leukemia ,business ,medicine.drug - Abstract
The "7+3" regimen is recommended for treatment in patients with new diagnosis of acute myeloid leukemia (AML) who are fit for intensive chemotherapy. Patients with secondary AML (sAML) [i.e. AML evolving from antecedent hematologic disorders (AHD-AML) or after previous exposure to chemo/radiation therapy for unrelated cancer (t-AML)], have inferior outcomes with "7+3" regimen. A recent phase 3 study demonstrated superior CR rates and overall survival (OS) with upfront use of CPX-351 compared to "7+3" regimen in older patients (≥60 years) with sAML (Lancet et al JCO 2018). The combination of HMA+Ven is FDA approved for upfront treatment in newly diagnosed AML patients > 75 or those unfit for intensive chemotherapy based on CR+ CRi rates of 67% and median OS of 17.5 months. Herein, we compared the outcomes of older patients with sAML who received upfront treatment with either HMA+Ven or CPX-351 at our institution. Our analysis includes 47 consecutive patients with previously untreated sAML treated between 2018-2020 . Patients were treated with either HMA+Ven (n=27) or CPX-351 (n=20) based on physician preference. WHO criteria were used for the diagnosis AHD-AML and review of medical records for documenting exposure to leukemogenic agent for t-AML. Complete remission (CR) was defined by presence of 1000/µL and platelets ≥100,000/µL) were defined as CRh (hematologic recovery) and CR without blood count recovery as CRi (incomplete blood count recovery). Minimal residual disease (MRD) assessment was done on day-28 BM aspirate using multiparametric flow cytometric assay with lower limit of sensitivity of 0.01%. Patients demographic and disease features are summarized in Table 1. Mean age (p=0.39), mean blast percentage in BM aspirate (P=0.82), high-risk cytogenetics (P=0.37) and high-risk molecular mutations (P=0.737) were similar in both treatment groups. Of the 27 cases of sAML in HMA+Ven group, 8 were t-AML arising after prior chemotherapy (Hodgkin's Disease n=2; paraganglioma, desmoid tumor, breast cancer, NHL, multiple myeloma, ALL: one each) while 19 were AHD-AML. In CPX-351 group, 6 cases were t-AML arising after prior chemotherapy (NHL n=2, breast cancer n=2, T-Lymphoblastic Lymphoma and colon cancer one each) while 14 were secondary to AHD. The mean number of cycles were 3.3 (range 1-18) in HMA+Ven group and 1.45 (1-3) in CPX-351 group. Two-sample t test was used to compare continuous and normally distributed covariates, such as age and BM blasts, between HMA+Ven or CPX-351 arms. Pearson Chi-square or Fisher exact test was used to assess the associations between treatment and clinical outcomes. Kaplan-Meier method and log-rank test were used to assess OS or LFS. A P value of ≤ 0.05 was considered as statistically significant. The CR rate in patients treated on HMA+Ven group was 78% (n=21; 95% CI: 58-91%) vs 50% (n=10; 95% CI: 27-73%) in CPX-351 group (P=0.047). CRi was achieved in 52% (n=14) patients in HMA+Ven group compared to 25%(n=5) patients in CPX-351 group(p=0.064). MRD negative remission was achieved in 52% (n=14) patients in HMA+Ven group and in 25% (n=5) patients in CPX-351 group (p=0.064). In HMA+Ven group, 52% patients (n=14) achieved remission after one cycle of therapy compared to 45% (n=9) patients in CPX-351 arm (p=0.642). With a median follow-up of 6.7 months for all patients, the median leukemia free-survival (LFS) for HMA+Ven vs CPX-351 treatments is 16.2 vs NA months (P = 0.098) and the median OS is 13.2 vs NA months (P = 0.395). Ten patients in each group (37% in HMA+Ven and 50% in CPX-351; p=0.47) underwent allo-HCT. At last follow up, 14 patients (52%) have died in HMA+Ven group from: relapsed AML (n=10), sepsis (n=2), congestive heart failure (n=1) and unknown (UK) in one patient, whereas in CPX-351 group, 8 patients (40%) have died from relapsed AML in (n=5), respiratory failure (n=2) and UK causes in one patient. In patients resistant to initial therapy, the median OS is 3.5 vs 6.0 months between HMA+ Ven and CPX-351 groups (P = 0.224). Conclusion: In patients presenting with sAML, upfront treatment with HMA+Ven is feasible and associated with significantly better CR rates and a favorable trend for higher rates of negative MRD compared to CPX-351. A randomized prospective trial in patients with sAML is warranted to determine the most effective frontline regimen in this high-risk AML subgroup. Disclosures Salhotra: Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees. Al Malki:Rigel Pharma: Consultancy; Neximmune: Consultancy; Jazz Pharmacuticals, Inc: Consultancy. Aribi:Seattle Genetics: Consultancy. Ali:Incyte Corporation: Consultancy. Budde:Gilead Sciences: Consultancy; Merck: Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Consultancy; Mustang Therapeutics: Research Funding; AstraZeneca: Research Funding; Roche: Consultancy. Dadwal:Ansun Biopharma: Research Funding; Karius: Research Funding; Shire/ Takeda: Research Funding; Gilead: Research Funding; Merck: Consultancy, Honoraria, Other: Advisory board meeting, Research Funding, Speakers Bureau; Chimerix: Research Funding; Janssen: Other: Advisory board meeting; Astellas: Speakers Bureau. Nakamura:NapaJen Pharma: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Viracor: Consultancy; Magenta Therapeutics: Other: Advisory board meeting; Celgene: Other: Support on seminar; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Marcucci:Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Merck: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial). Pullarkat:Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: off label use of HMA+venetoclax in secondary AML
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- 2020
131. Venetoclax Synergizes with the RNA-Directed Nucleoside Analog 8-Chloro-Adenosine in Acute Myeloid Leukemia in Vitro and In Vivo
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Dinh Hoa Hoang, Ralf Buettner, Lisa S. Chen, Vinod Pullarkat, Guido Marcucci, Steven T. Rosen, Lucy Ghoda, Corey Morales, Varsha Gandhi, Bin Amber Zhang, Le Xuan Truong Nguyen, and Timothy W. Synold
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Oncology ,medicine.medical_specialty ,Venetoclax ,business.industry ,Immunology ,Myeloid leukemia ,Decitabine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Clinical trial ,chemistry.chemical_compound ,Haematopoiesis ,Leukemia ,chemistry ,Internal medicine ,Ven ,medicine ,Cytarabine ,business ,medicine.drug - Abstract
Relapse of acute myeloid leukemia (AML) is attributed to the persistence of quiescent leukemia stem cells (LSCs). Bcl-2 inhibition has been shown to target primitive leukemia progenitors. Venetoclax (VEN) is a FDA-approved Bcl-2-selective inhibitor for the treatment of AML. Although the activity of single agent VEN in AML patients (pts.) is modest, clinical efficacy in newly diagnosed, older pts. unfit for intense chemotherapy has been shown when VEN is combined with the hypomethylating agents (HMAs) azacytidine and decitabine or with low-dose nucleoside analog cytarabine. We have recently shown that VEN in combination with HMAs augments oxidative stress in AML cells and provided a molecular mechanism for the VEN-HMA-regulated NF-E2-related factor 2 (Nrf2) antioxidant pathway that could explain the results observed in early clinical studies in AML. Although about 70% of pts. initially respond to these VEN treatment regimens, about 30% of pts. do not and diminished efficacy of VEN combination treatments have been observed in pts. harboring poor-prognosis markers such as FLT3-ITD. In addition, future relapse of a percentage of pts. treated with VEN combinations is expected. Thus, novel treatment options for are urgently needed. We previously reported that the ribose containing, RNA-directed nucleoside analog 8-chloro-adenosine (8-Cl-Ado) demonstrates cytotoxic activity against AML cells and LSCs in vitro and in vivo, without significantly affecting normal hematopoietic stem cells. Importantly, our initial, unpublished results from a phase I/II clinical trial with single agent 8-Cl-Ado in pts. with refractory/relapsed AML demonstrate encouraging clinical benefits. Moreover, we have reported that FLT3-ITD AML is particularly sensitive to 8-Cl-Ado, thus suggesting 8-Cl-Ado plus VEN as a potential novel therapeutic regimen for treatment of AML. We here report that the VEN plus 8-Cl-Ado combination inhibited in vitro growth and induced apoptosis in AML primary cells, LSCs and cell lines significantly more compared to treatment with the individual agents. For in vitro cell growth studies, combination indices of LSCs depend on amino acid metabolism-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for energy production. VEN is known to target LSCs through inhibition of OXPHOS by targeting amino acid uptake/metabolism. We report here that 8-Cl-Ado inhibited the FAO pathway and down-regulated the oxygen consumption rate (OCR), a marker for OXPHOS, in LSCs. However, whereas 500 nM of 8-Cl-Ado was sufficient to induce MV4-11 growth inhibition, 1 microM of 8-Cl-Ado was needed for maximum inhibitory effect on FAO. We also report that 8-Cl-Ado increased expression of the anti-apoptotic protein p53. It was previously reported that p53 induces FAO in LSCs. Knockdown of p53 by siRNA augmented the inhibitory effect of 8-Cl-Ado on FAO and OCR. Importantly, addition of VEN could completely overcome the p53-induced activation of FAO and OCR. Mechanistically, we show that 8-Cl-Ado inhibited ribosomal RNA (rRNA) synthesis, a prerequisite for cellular proliferation, through down-regulation of the transcription initiation factor 1 (TIF-IA) protein. Since TIF-1A negatively regulates p53 expression, the inhibition of TIF-1A by 8-Cl-Ado resulted in up-regulation of p53 and subsequent p53-induced upregulation of FAO and OCR, thus diminishing the suppressive effects of 8-Cl-Ado on FAO and OCR. We further show that the VEN plus 8-Cl-Ado combination strongly induced p53 signaling, as shown by activation and inhibition of downstream p21 and PCNA proteins, respectively. This combination also augmented DNA fragmentation and apoptosis in LSCs. Thus, our data suggest that the synergy seen in AML with the VEN plus 8-Cl-Ado combination can be explained at least in part due to augmented inhibition of FAO and OXPHOS and represents a promising novel treatment for AML. Disclosures Pullarkat: Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Marcucci:Iaso Bio: Membership on an entity's Board of Directors or advisory committees; Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Merck: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial). Rosen:Celgene: Speakers Bureau; NeoGenomics: Consultancy; Seattle Genetics: Consultancy; Aileron Therapeutics: Consultancy; Novartis: Consultancy; paradigm Medical Communications: Speakers Bureau; Abbvie: Speakers Bureau; Pebromene: Consultancy.
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- 2020
132. Hemorrhagic Cystitis in Patients Undergoing Allogeneic Hematopoietic Cell Transplant with Post Transplant Cyclophosphamide As GvHD Prophylaxis
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Monzr M. Al Malki, Saloomeh Mokhtari, Jason Chen, Ahmed Aribi, Vinod Pullarkat, Pkoller Koller, Karamjeet S. Sandhu, Stephanie Mac, Guido Marcucci, Eileen P. Smith, Haris Ali, Dongyun Yang, Andrew S. Artz, Anthony S. Stein, Shukaib Arslan, Ibrahim Aldoss, Nicole Karras, Ryotaro Nakamura, David S. Snyder, Chatchada Karanes, Dat Ngo, Samer K. Khaled, Amandeep Salhotra, Stephen J. Forman, and Thai Cao
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medicine.medical_specialty ,Cyclophosphamide ,business.industry ,Incidence (epidemiology) ,Immunology ,Phases of clinical research ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Clinical trial ,Internal medicine ,Cohort ,medicine ,Dosing ,business ,medicine.drug ,Hemorrhagic cystitis - Abstract
The use of post-transplant cyclophosphamide (PTCy) as graft-versus-host-disease (GvHD) prophylaxis after hematopoietic cell transplantation (HCT) has increased significantly over the past decade due to expansion of donor pool with haploidentical and mismatched unrelated donors. A recently completed phase 2 study, PROGRESS-2 (NCT02345850), has highlighted the efficacy of PTCy in the matched donor setting. Hemorrhagic cystitis (HC) is the most notable toxicity associated with high dose Cy. However, data specific to the incidence and severity of HC in the post HCT setting is sparse, with no consensus on best practices to prevent HC in patients receiving PTCy. Current strategies to prevent HC in PTCy setting have been adapted from data in pre-HCT Cy (conditioning setting), such as hyperhydration with forced diuresis, continuous bladder irrigation, mesna as an intermittent and continuous infusion, or a combination of these methods. The aim of our study was to describe the incidence and severity of HC in patients undergoing HCT with PTCy as GvHD prophylaxis, identifying potential risk factors and impact of HC on HCT outcomes. We retrospectively reviewed 194 consecutive patients who underwent their first HCT with PTCy from 2014 to 2018 at our center. More than half of the patients (53%) received myeloablative conditioning regimen with majority receiving peripheral blood stem cells (81%) from haploidentical donors (96%). GvHD prophylaxis was unified with PTCy (50 mg/kg on Days +3 and +4), in addition to MMF (1 gm 3x daily starting on Day +5) and tacrolimus (1 mg as a continuous infusion daily starting on Day +5). Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was based on physician documentation or presence of blood in urinalysis up to Day +100. To determine severity of HC, CTCAE 5.0 grading system was used. Median age of patients was 45 years (range: 2-73), with 60% of patients being male. KPS was ≥80% in 83% of patient and 40% had HCT-CI of ≥2. The most common diagnoses included: AML (41%), ALL (24%) and MDS/MPN (19%). There were 55 patients who received ≥3 lines of therapy, 116 patients received In conclusion, hyperhydration with forced diuresis added to aggressive mesna dosing is an effective strategy in preventing severe HC in HCT patients receiving PTCy as GvHD prophylaxis. Incidence of Grade 3 or 4 HC was low and transient and did not impact HCT outcomes. Viral HC had a significantly later onset than non-viral HC, suggesting a different pathophysiology. Older age and myeloablative conditioning were independent factors for higher incidence of HC in our cohort. Disclosures Ali: Incyte Corporation: Consultancy. Salhotra:Celgene: Research Funding; Kadmon: Membership on an entity's Board of Directors or advisory committees. Aribi:Seattle Genetics: Consultancy. Pullarkat:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy, Speakers Bureau. Marcucci:Merck: Other: Research Support (Investigation Initiated Clinical Trial); Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Iaso Bio: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Research Support (Investigation Initiated Clinical Trial). Nakamura:NapaJen Pharma: Consultancy; Viracor: Consultancy; Kadmon Corporation: Other: Advisory board meeting; Magenta Therapeutics: Other: Advisory board meeting; Celgene: Other: Support on seminar; Kyowa-Kirin: Other: Support on a meeting presentation; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting. Al Malki:Rigel Pharma: Consultancy; Jazz Pharmacuticals, Inc: Consultancy; Neximmune: Consultancy.
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- 2020
133. Outcomes of Therapy with Venetoclax Combined with Hypomethylating Agents in Favorable-Risk Acute Myeloid Leukemia (AML)
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Anthony S. Stein, Jenna A. Moran, Jianying Zhang, Nuthana Naidoo, Jennifer Lombardi Story, Ibrahim Aldoss, Amir T. Fathi, Shukaib Arslan, Vinod Pullarkat, George Yaghmour, Prajwal Dhakal, Guido Marcucci, and Vijaya Raj Bhatt
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Response rate (survey) ,medicine.medical_specialty ,business.industry ,Venetoclax ,Immunology ,Significant difference ,Genetic Alteration ,Cell Biology ,Hematology ,Biochemistry ,Clinical trial ,chemistry.chemical_compound ,Older patients ,chemistry ,Internal medicine ,Cohort ,Medicine ,In patient ,business ,health care economics and organizations - Abstract
Introduction: Venetoclax (VEN) in combination with a hypomethylating agents (HMA) is associated with a high rate of composite remission (complete remission [CR] and complete remission with incomplete recovery [CRi]) among older and unfit patients with untreated AML. However, data regarding the activity of VEN-HMA in those patients with favorable-risk AML is limited, particularly in those with core-binding factor (CBF) alterations. Although more frequent among younger patients, favorable-risk alterations are also observed among older patients, often unfit for intensive regimens. Even among the subset of older patients (>60 years) with favorable-risk AML eligible for intensive regimens, long-term outcomes are poorer in comparison to younger patients. Methods: We retrospectively analyzed outcomes of 46 patients with favorable-risk AML who underwent therapy with VEN-HMA between 2016-2020 at 4 academic cancer centers in US. Favorable-risk AML was defined by the presence of either CBF [t(8;21) and inv(16) or t(16;16)], NPM1 mutation in the absence of FLT-3 ITD mutations; or bi-allelic CEBPA mutations. Results: Forty-six patients with favorable risk AML were treated with HMA-VEN, including 26 (57%) with newly diagnosed (ND) and 20 (43%) with relapsed/refractory (R/R) AML (Table1). Ten (22%) patients had CBF, 21 (46%) had NPM1 mutations (NPM1m), and 13 (28%) had bi-allelic CEBPA mutations (CEBPAm). The median age was 70 years, and 54% were females. Patients with R/R AML were younger than ND patients (56 vs. 72 yrs, p=0.003). Twenty (44%) patients had secondary or therapy-related AML, including half of ND patients. The median lines of prior therapy were 2(1-4) in patients with R/R AML, including 6 (30%) who had failed prior allogeneic HCT. Eleven (24%) patients had received HMA prior to HMA-VEN therapy, including 1 patient in the ND cohort for prior MDS. Eleven (24%) patients received azacitidine in combination with VEN, while the rest (76%) of patients received decitabine, including 14 patients who received 10-day decitabine during the first cycle. The CR/CRi rate among the whole cohort was 80%, including 52% CR and 28% CRi. There was no statistically significant difference in CR/CRi rate between ND and R/R patients (88% vs. 70%, P =0.15). However, patients with history of prior HMA exposure had lower response rate compared to HMA-naïve patients (55% vs. 88%, p= 0.025). No difference in response was observed based on the favorable genetic alteration subgroups (80% in CBF vs. 86% in NPM1m vs. 77% in CEBPAm, p=0.44). Furthermore, no difference in response was observed according to patient age (p= 0.83), AML types (de novo vs. secondary; p= 0.47), prior transplant (p=1.00), or the type and schedule of HMA (P=0.66). Among the responders who had MRD assessment done (n= 26), 22 (85%) achieved MRD negativity by multicolor flow cytometry. Post response, 13 (35%) patients underwent allogeneic transplant consolidation. The median overall survival (OS) for the whole cohort was 18 months (12.5-NA). Median leukemia-free survival (LFS) was 13.2 months (7-20.2) for all responders, 11.2 months (1.7-NA) for ND responders, and 14.0 months (1-NA) for RR responders (p=0.986). The 30- and 60-day mortality for the whole cohort was 0% and 9%, respectively. Conclusion: In patients with favorable-risk AML, VEN-HMA combination is associated with a highly promising CR/CRi rate, with durable responses. The majority of responders achieved MRD negativity. Patients with prior use of HMA had lower response rate with VEN-HMA, nonetheless, over half of these patients responded despite most being treated in the R/R setting. Disclosures Pullarkat: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Marcucci:Abbvie: Speakers Bureau; Merck: Other: Research Support (Investigation Initiated Clinical Trial); Novartis: Speakers Bureau; Pfizer: Other: Research Support (Investigation Initiated Clinical Trial); Takeda: Other: Research Support (Investigation Initiated Clinical Trial); Iaso Bio: Membership on an entity's Board of Directors or advisory committees. Yaghmour:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau. Bhatt:Omeros: Consultancy; Agios: Consultancy; Rigel: Consultancy; Tolero: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Partnership for health analytic research: Consultancy; Takeda: Consultancy; Jazz: Research Funding; National Marrow Donor Program: Research Funding; Oncoceutics: Other. Fathi:Takeda: Consultancy, Research Funding; Jazz: Consultancy; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Amphivena: Consultancy; Blueprint: Consultancy; Kura Oncology: Consultancy; Boston Biomedical: Consultancy; Astellas: Consultancy; Trovagene: Consultancy; Novartis: Consultancy; PTC Therapeutics: Consultancy; Agios: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Kite: Consultancy; Pfizer: Consultancy; Trillium: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Abbvie: Consultancy; Newlink Genetics: Consultancy.
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- 2020
134. Biology and Treatment of Leukemia and Bone Marrow Neoplasms
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Vinod Pullarkat, Guido Marcucci, Vinod Pullarkat, and Guido Marcucci
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- Hematology, Oncology, Medicine—Research, Biology—Research
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This book provides a concise update on current understanding of the biology of acute and chronic leukemias and other bone marrow neoplasms, including myelodysplastic and myeloproliferative disorders, and explores new and emerging treatments. There is a particular focus on the molecular abnormalities that are drivers of leukemia and on their detection by modern molecular techniques. Knowledge of the ways in which genomic and metabolic abnormalities in the hematologic neoplasms affect prognosis and treatment decision making is reviewed. Detailed attention is devoted to targeted therapies, including novel drugs, and to potential targets for future drug development. In addition, readers find in-depth discussion of cellular and antibody-based immunotherapies as well as the role of hematopoietic stem cell transplantation in the treatment of leukemias and bone marrow malignancies. The book is of special interest for hematologists, oncologists, and cancer researchers; it is also of value for hematology trainees and medical students.
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- 2021
135. Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine
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Brenda Chyla, Jacqueline S. Garcia, Brian A. Jonas, Nicola Stefano Fracchiolla, Christian Recher, Ying Zhou, Su-Peng Yeh, Hartmut Döhner, Muhit Ozcan, Courtney D. DiNardo, Árpád Illés, Michael J. Thirman, Keith W. Pratz, Monique Dail, Andre C. Schuh, Jun Ho Jang, Jalaja Potluri, Vladimir I. Vorobyev, Kazuhito Yamamoto, and Vinod Pullarkat
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Oncology ,Cancer Research ,medicine.medical_specialty ,Disease Response ,Venetoclax ,business.industry ,Azacitidine ,Complete remission ,Myeloid leukemia ,chemistry.chemical_compound ,chemistry ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
7018 Background: In the phase 3 VIALE-A trial, rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and measurable residual disease response (MRD-3) were higher in patients (pts) treated with venetoclax (Ven) + azacitidine (Aza) compared to Aza alone (23.4%/7.6%, p-3 in the VIALE-A trial (NCT02993523). Methods: Enrolled pts were ≥18 years and unfit for intensive chemotherapy. Pts received Ven 400 mg orally; days 1–28 and Aza 75 mg/m2; days 1-7/28-day cycle. Bone marrow aspirate samples for multiparametric flow cytometry assessments by integrated leukemia-associated immunophenotypes and different than normal procedures were collected for central analysis (Covance Central Laboratory Services) at baseline, end of cycle 1, and every 3 cycles thereafter. Assessments were performed independent of disease responses. MRD response was defined as -3). CRc, DoR, OS, and EFS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: 211/286 (74%) pts treated with Ven+Aza with at least one valid post-baseline MRD assessment were considered MRD evaluable; 78/211 (37%) achieved MRD-3 and 133/211 (63%) had MRD≥10-3. Median age (MRD-3/ MRD≥10-3) was 76 (range: 49-89)/77 (58-91) yrs. Pts (MRD-3/ MRD≥10-3) received median of 14.5 (range: 1-28) /7.0 (1-30) cycles of Ven+Aza. At median follow-up of 22.0 (range: 20.1-23.0)/20.8 (19.8-22.3) months (mos), CRc + MRD-3/ MRD≥10-3 was achieved by 67 (86%)/ 97 (73%); 20/67 (30%) achieved CRc + MRD-3 by end of cycle 1. Median DoR, OS, and EFS were not reached in pts with CRc + MRD-3 response (Table). The 12-mo estimates for DoR, OS, and EFS for pts with CRc + MRD-3response were 81.2%, 94.0%, and 83.2%, respectively. Adverse events ≥grade 3 (MRD-3/ MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population. Conclusions: Pts with best response of CRc who achieved MRD-3 response with Ven+Aza treatment had longer DoR, OS, and EFS than pts who were CRc and MRD positive. Clinical trial information: NCT02993523. [Table: see text]
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- 2021
136. Preliminary results of V-FAST, a phase 1b master trial to investigate CPX-351 combined with targeted agents in newly diagnosed AML
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Vinod Pullarkat, Stefan Faderl, Tara L. Lin, Vijayalakshmi Chandrasekaran, Ronald S. Cheung, Stephen A. Strickland, Divya Chakravarthy, Mark J. Levis, Harry P. Erba, and Gabriel N. Mannis
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Drug ,Cancer Research ,Liposome ,Daunorubicin ,business.industry ,media_common.quotation_subject ,Newly diagnosed ,Pharmacology ,Oncology ,Cytarabine ,medicine ,business ,media_common ,medicine.drug - Abstract
7026 Background: CPX-351 (US: Vyxeos; EU: Vyxeos Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar drug ratio, is approved by the US FDA and EMA for adults with newly diagnosed t-AML or AML with myelodysplasia-related changes. Preclinical data suggest CPX-351 may exert synergistic activity when combined with agents such as the BCL-2 inhibitor venetoclax (VEN) or FLT3 inhibitor midostaurin (MIDO). Methods: V-FAST (Vyxeos – First Phase Assessment With Targeted Agents) is an open-label, multicenter, phase 1b master trial (NCT04075747) to evaluate safety and establish the recommended phase 2 dose (RP2D) of CPX-351 combined with targeted agents in patients (pts) aged 18-75 y with untreated AML who are fit for intensive chemotherapy. The study includes a dose-exploration phase (3+3 design) and subsequent expansion phase. Pts received CPX-351 (dose level 1 for first induction [DL1]: 100 units/m2 on Days 1, 3, and 5) plus VEN (Arm A; DL1: 400 mg on Days 1-14), MIDO (Arm B; DL1: 50 mg BID on Days 8-21), or the IDH2 inhibitor enasidenib ([ENA] Arm C; DL1: 100 mg on Days 8-28) based on mutation testing. Results: Among 21 pts with available data enrolled by 11/06/20 (24 pts enrolled total; data cut-off: 01/19/21), the median age was 54 y (range: 35, 69). In Arm A (n = 17), 11 (65%) pts had de novo AML, 5 (29%) had an antecedent hematologic disorder (2 [12%] had myelofibrosis), and 2 (12%) had t-AML; 12 (71%) had adverse-risk AML; and 6 (35%) had mutated TP53. In Arms B (n = 3) and C (n = 1), all pts had intermediate-risk de novo AML. DL1 was the RP2D in Arms A and B; the RP2D in Arm C is still under investigation. In Arm A, 1/6 pts in the dose-exploration phase had 2 dose-limiting toxicities (DLTs) of grade 4 neutropenia and thrombocytopenia that extended beyond 49 days; no DLTs have occurred for Arms B and C. The combinations exhibited manageable safety profiles (Table). Of pts with available response data, complete remission (CR) or CR with incomplete platelet or neutrophil recovery was achieved by 6/14 (43%) pts in Arm A, including 4 (29%) with CR. All pts in Arms B and C achieved CR. Conclusions: These preliminary results suggest CPX-351 can be combined with VEN and MIDO with manageable toxicities in newly diagnosed AML pts, with DL1 determined to be the RP2D. The study is ongoing and actively enrolling pts; updated results will be presented at the meeting. Clinical trial information: NCT04075747. [Table: see text]
- Published
- 2021
137. Venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with therapy-related myeloid neoplasms, antecedent myelodysplastic syndromes, or myelodysplastic/myeloproliferative neoplasms
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Andre C. Schuh, Martha Arellano, Hartmut Döhner, Kiran Naqvi, Jalaja Potluri, Marina Konopleva, Pierre Fenaux, Keith W. Pratz, Vinod Pullarkat, Jun Ho Jang, Courtney D. DiNardo, Jun Yu, Gunnar Juliusson, Arnaud Pigneux, Jean Ridgeway, Andrew H. Wei, Christian Recher, Kazuhito Miyazaki, Michael J. Thirman, and Dominik Selleslag
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Oncology ,Cancer Research ,medicine.medical_specialty ,Chemotherapy ,Therapy related ,Myeloid ,business.industry ,Antecedent (logic) ,Venetoclax ,Myelodysplastic syndromes ,medicine.medical_treatment ,Azacitidine ,medicine.disease ,stomatognathic diseases ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Internal medicine ,Medicine ,business ,medicine.drug - Abstract
7011 Background: Patients (pts) with therapy-related myeloid neoplasms (tMN), antecedent myelodysplastic syndrome, or antecedent myelodysplastic/myeloproliferative neoplasms (A-MDS/MPN) may have poor outcomes due to age and adverse genetic/karyotypic features. In the VIALE-A study, pts with tMN and A-MDS/MPN unfit for intensive chemotherapy treated with venetoclax (Ven) and azacitidine (Aza) demonstrated superior response rates and overall survival (OS) than Aza alone. Herein, the efficacy and safety of Ven+Aza among pts with tMN and A-MDS/MPN are described. Methods: Data were pooled from pts enrolled in VIALE-A (NCT02993523) comparing pts who received Ven+Aza or placebo (Pbo)+Aza and a prior phase 1b study (NCT02203773) where pts received Ven+Aza. Enrolled pts were ≥18 years, treatment-naïve with no prior exposure to hypomethylating agents, and ineligible for intensive chemotherapy. Pts on Ven+Aza received Ven 400 mg orally (days 1–28) and Aza (75 mg/m2; days 1-7/28-day cycle). Composite complete remission rate (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]), duration of response (DoR), and OS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: In this pooled analysis, tMN was observed in (Ven+Aza/Pbo+Aza) 31/9 and A-MDS/MPN in 59/26 pts. Poor-risk cytogenetics were observed in 18 (58%)/6 (67%) with tMN (5 or 5q deletion [del]: 4/1 ; 7 or 7q del: 6/1 ; complex [≥ 3 clonal abnormalities]: 10/4), and 19 (32%)/13 (50%) with A-MDS/MPN (5 or 5q del: 10/5; 7 or 7q del: 6/1; complex: 14/9). TP53 mutation was observed in 5/3 pts with tMN and 8/0 pts with A-MDS/MPN. Pts with tMN received a median (Ven+Aza/Pbo+Aza) of 5/4 cycles of treatment. CRc was achieved by 19 (61%)/1 (11%). The mDoR was not reached (NR) (95% CI: 17.8, NR)/8.5 (NR, NR) months. The mOS was 16.4 (95% CI: 4.1, NR)/11.3 (0.6, 17.5) months. Pts with A-MDS/MPN received a median (Ven+Aza/Pbo+Aza) of 9/5 cycles of treatment. CRc was achieved by 39 (66%)/7 (27%) pts with mDoR of 17.3 (95% CI: 9.6, NR)/5.8 (1.1, NR) mos. The mOS was 15.9 (95% CI: 11.5, NR)/10.1 (4.7, 14.5) mos. Common grade≥3 adverse events (Ven+Aza/Pbo+Aza) were febrile neutropenia (tMN: 39%/11% and A-MDS/MPN: 36%/12%) neutropenia (tMN: 29%/33%; A-MDS/MPN: 39%31%), and thrombocytopenia (tMN: 32%/33%; A-MDS/MPN: 39%/62%). Conclusions: Ven+Aza compared to Aza monotherapy resulted in higher CRc rates with longer DoR and median OS among treatment-naïve pts with tMN and A-MDS/MPN ineligible for intensive chemotherapy. The safety profile was similar to overall pts with the Ven+Aza combination. Outcomes by cytogenetic and molecular risk-groups will be presented. Clinical trial information: NCT02993523, NCT02203773.
- Published
- 2021
138. Efficacy of blinatumomab for MRD relapse in ALL post allogenic HCT
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Anthony S. Stein, Stephen J. Forman, Haris Ali, Guido Marcucci, Ryotaro Nakamura, Ibrahim Aldoss, Vinod Pullarkat, and Amandeep Salhotra
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Oncology ,Cancer Research ,medicine.medical_specialty ,Text mining ,business.industry ,Internal medicine ,medicine ,Blinatumomab ,Hematology ,MRD RELAPSE ,business ,medicine.drug - Published
- 2021
139. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion
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Anthony S. Stein, Jodi Murakami, D. L. Digiusto, Vinod Pullarkat, Lihong Weng, Bijender Kumar, Tinisha McDonald, S.K. Hui, Mayra Garcia, Xiaoman Jung, Guido Marcucci, Nadia Carlesso, Xingbin Hu, Ravi Bhatia, Ching-Cheng Chen, Allen Lin, Ya-Huei Kuo, and A. R. Kumar
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0301 basic medicine ,Cancer Research ,Stromal cell ,Myeloid ,Biology ,Exosomes ,Exosome ,Cell Line ,Mice ,03 medical and health sciences ,Bone Marrow ,hemic and lymphatic diseases ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Stem Cell Niche ,neoplasms ,Mice, Knockout ,Tumor microenvironment ,Osteoblasts ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Mesenchymal Stem Cells ,X-Ray Microtomography ,Hematology ,Hematopoietic Stem Cells ,medicine.disease ,Coculture Techniques ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,Leukemia ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Immunology ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Original Article ,Bone marrow ,Biomarkers - Abstract
Little is known about how leukemia cells alter the bone marrow (BM) niche to facilitate their own growth and evade chemotherapy. Here, we provide evidence that acute myeloid leukemia (AML) blasts remodel the BM niche into a leukemia growth-permissive and normal hematopoiesis-suppressive microenvironment through exosome secretion. Either engrafted AML cells or AML-derived exosomes increased mesenchymal stromal progenitors and blocked osteolineage development and bone formation in vivo. Preconditioning with AML-derived exosomes 'primed' the animals for accelerated AML growth. Conversely, disruption of exosome secretion in AML cells through targeting Rab27a, an important regulator involved in exosome release, significantly delayed leukemia development. In BM stromal cells, AML-derived exosomes induced the expression of DKK1, a suppressor of normal hematopoiesis and osteogenesis, thereby contributing to osteoblast loss. Conversely, treatment with a DKK1 inhibitor delayed AML progression and prolonged survival in AML-engrafted mice. In addition, AML-derived exosomes induced a broad downregulation of hematopoietic stem cell-supporting factors (for example, CXCL12, KITL and IGF1) in BM stromal cells and reduced their ability to support normal hematopoiesis. Altogether, this study uncovers novel features of AML pathogenesis and unveils how AML cells create a self-strengthening leukemic niche that promotes leukemic cell proliferation and survival, while suppressing normal hematopoiesis through exosome secretion.
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- 2017
140. Allogeneic Hematopoietic Cell Transplantation for Adult T Cell Acute Lymphoblastic Leukemia
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Madan Jagasia, Veronika Bachanova, Khoan Vu, Betty K. Hamilton, Christopher R. Flowers, Dennis Dong Hwan Kim, Steven M. Devine, Auro Viswabandya, Anjali S. Advani, Melody Smith, Rizwan Romee, Siddharth Ganguly, Karamjeet S. Sandhu, Miguel-Angel Perales, Joseph P. McGuirk, Donna Abounader, Lisa Rybicki, Kehinde Adekola, Simon B. Zeichner, Stacey Brown, Sarah A Wall, Navneet S. Majhail, Vinod Pullarkat, Ibrahim Aldoss, Masumi Ueda, Vanessa E Kennedy, Asad Bashey, and Marcos deLima
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Survival analysis ,Aged ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Total body irradiation ,Survival Analysis ,Surgery ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology - Abstract
Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P = .021), age >35 years (HR, 1.55; P = .025), and disease status at HCT (HR, 1.98; P = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure.
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- 2017
141. Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status
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Victoria Bedell, Ricardo Spielberger, Ketevan Gendzekhadze, Vinod Pullarkat, Thai Cao, Raju Pillai, Anh Pham, David S. Snyder, Ahmed Aribi, Stephen J. Forman, Sierra Min Li, Milhan Telatar, Monzr M. Al Malki, Hao Hong, Dennis D. Weisenburger, Samer K. Khaled, David Senitzer, Abbas Padeganeh, Joyce Murata-Collins, Patricia Aoun, Ibrahim Aldoss, Haris Ali, Ryotaro Nakamura, Joycelynne Palmer, Guido Marcucci, Amandeep Salhotra, Michelle Afkhami, Margaret R. O'Donnell, and Anthony S. Stein
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Oncology ,medicine.medical_specialty ,Allogeneic transplantation ,Disease ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,business.industry ,Myelodysplastic syndromes ,Neoplasms, Second Primary ,Hematology ,medicine.disease ,Prognosis ,Transplantation ,ETV6 ,Leukemia, Myeloid, Acute ,International Prognostic Scoring System ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Immunology ,Mutation ,Stem cell ,Tumor Suppressor Protein p53 ,business ,Complication ,030215 immunology - Abstract
Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P
- Published
- 2017
142. Autoimmune Myelofibrosis: Clinical Features, Course, and Outcome
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Donald I. Feinstein, Imran Siddiqi, Casey O'Connell, Maria E. Vergara-Lluri, Caroline I. Piatek, Vinod Pullarkat, and Russell K. Brynes
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Adult ,Male ,medicine.medical_specialty ,Pathology ,Myeloid ,medicine.medical_treatment ,Splenectomy ,Polymorphism, Single Nucleotide ,Autoimmune Diseases ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,hemic and lymphatic diseases ,Humans ,Medicine ,Eosinophilia ,Myelofibrosis ,Aged ,Autoantibodies ,Retrospective Studies ,medicine.diagnostic_test ,business.industry ,Autoantibody ,Hematology ,General Medicine ,Janus Kinase 2 ,Middle Aged ,medicine.disease ,Dermatology ,Bone marrow examination ,Treatment Outcome ,medicine.anatomical_structure ,Basophilia ,Primary Myelofibrosis ,030220 oncology & carcinogenesis ,Concomitant ,Splenomegaly ,Female ,medicine.symptom ,Calreticulin ,business ,Receptors, Thrombopoietin ,Immunosuppressive Agents ,030215 immunology - Abstract
Background: Autoimmune myelofibrosis (AIMF) is an underrecognized cause of nonmalignant bone marrow fibrosis which occurs in the presence or absence of a defined systemic autoimmune disease. Patients with AIMF present with cytopenias and autoantibodies, and have a distinctive nonclonal myelofibrosis on bone marrow examination. AIMF is distinguished from primary myelofibrosis by the absence of splenomegaly, eosinophilia, or basophilia, and the absence of abnormal myeloid, erythroid, or megakaryocytic morphology. Objectives: The objective of the study was to describe the clinical presentation and outcomes of patients with AIMF. Methods: We conducted a single-institution, retrospective chart review of patients diagnosed with AIMF to investigate clinical presentations, therapies, and outcomes. Results: Twelve patients with AIMF were identified with a mean follow-up of 5.8 years. All patients had detectable autoantibodies and the majority had concomitant autoimmune disorders. Four patients experienced a complete response of cytopenias and 3 patients experienced a partial response (PR) of cytopenias with immunosuppressive therapy. One patient achieved a PR following splenectomy. No patients were diagnosed with myeloproliferative neoplasms during the follow-up period. Conclusions: AIMF contributes to cytopenias in the subset of patients with various autoimmune disorders. The majority of patients with AIMF experience an improvement in cytopenias with immunosuppressive therapy.
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- 2017
143. Retreatment with venetoclax and hypomethylating agents among AML patients who have relapsed after initial response and subsequent interruption of therapy
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Ibrahim Aldoss, Stephen J. Forman, Anthony S. Stein, Matthew Mei, Tamer Othman, Vinod Pullarkat, Guido Marcucci, and Jianying Zhang
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Oncology ,Cancer Research ,medicine.medical_specialty ,Newly diagnosed ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Sulfonamides ,Venetoclax ,business.industry ,Myeloid leukemia ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic ,Leukemia, Myeloid, Acute ,Regimen ,chemistry ,Hypomethylating agent ,030220 oncology & carcinogenesis ,Retreatment ,business ,030215 immunology - Abstract
The combination of venetoclax and a hypomethylating agent (VEN-HMA) as an induction regimen for newly diagnosed acute myeloid leukemia (AML) has become widely used due to ease of administration and...
- Published
- 2020
144. Assessment of Anti-Oxidant Markers of Inflammation in Patients with Chronic Graft-Versus-Host Disease
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Weimin Tsai, Vinod Pullarkat, Haris Ali, Stephen J. Forman, Amandeep Salhotra, Badri Modi, Karamjeet S. Sandhu, Monzr M. Al Malki, Ryotaro Nakamura, Dongyun Yang, Jasmine Zain, and Sally Mokhtari
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Transplantation ,medicine.medical_specialty ,business.industry ,Autoantibody ,Inflammation ,Hematology ,medicine.disease ,Gastroenterology ,Scleroderma ,Tacrolimus ,Graft-versus-host disease ,Internal medicine ,Sirolimus ,Medicine ,medicine.symptom ,business ,Prospective cohort study ,medicine.drug - Abstract
Chronic graft-versus-host disease (cGVHD) is a late-occurring inflammatory condition post- allogeneic hematopoietic cell transplantation (HCT), which involves multiple distinct interactions among alloreactive dysregulated T and B cells. Prior studies have shown that autoantibodies to platelet-derived growth factor receptor (PDGFR) induce tyrosine phosphorylation and accumulation of Reactive Oxygen Species (ROS), causing expression of collagen type-1 gene through the Ha-Ras-Erk1/2–ROS signaling pathway. We hypothesize that antioxidant markers of inflammation (8-OHdG, total antioxidant levels, CXCL4 and pH2Ax) will be elevated in patients with scleroderma cGVHD compared to patients who do not develop cGVHD or have non-scleroderma cGVHD. Patients (n=36) were consented on an IRB-approved protocol for a cross-sectional single time point biospecimen collection. Patients with established cGVHD (n=29) or ≥2 years post-HCT without clinical manifestations of cGVHD (n=7) were included. Patients with cGVHD were divided into Scleroderma cGVHD (n=14) and Non-scleroderma cGVHD (n=15). Median age was 49 (range: 21-69) and 56 years (range: 18-72) for patients with scleroderma (group 1) and without scleroderma or no GVHD (group 2), respectively. Median prior lines of therapy was 3.2 (range: 2-5) for patients in group 1. All patients is group 1 and 77% of patients in group 2 received PBCSs as the graft source. Transplant was from a matched unrelated (group 1: 75%, group 2: 73%) or a matched sibling donor (group 1: 25%, group 2: 23%). Tacrolimus/sirolimus was the most commonly used GVHD prophylactic regimen in both groups (group 1: 83% and group 2: 64%). Peripheral blood samples were drawn at a single time point post-HCT, and serum samples were used for ELISA assays for levels of total antioxidants, 8-OHdG, and CXCL4. Flow cytometric analysis was performed to investigate percentage of Tregs and pH2AX+ cells. There were no differences in the total antioxidant levels, CXCL4 and Tregs between groups 1 and 2. Using a cutoff threshold of 10 ng/ml of 8-OHdG, 11 patients (78%) in group 1 and 9 patients (40.9%) in groups 2 had elevated levels of 8-OHdG (p=0.029, Fisher's exact). Percentage of pH2AX expressing cells was lower in group 2. At the cutoff threshold of 37%, only one patient (7%) in group 1 and 13 patients (59%) in group 2 had more than 37% pH2AX-expressing CD45+ cells in their peripheral blood (p=0.002, Fisher's exact). In conclusion, our pilot cross-sectional study showed that scleroderma cGVHD is associated with increased ROS levels (8-OHdG) without elevation of pH2AX cells in peripheral blood T cells. Our results indicate that ROS elevation in scleroderma patients may be a stress response to inflammatory milieu and is independent of DNA damage. Our data justify further prospective cohort studies to define the role of ROS markers in scleroderma cGVHD and to develop novel strategies to treat/prevent cGVHD.
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- 2020
145. Dasatinib-Induced Colitis after Allogeneic Stem Cell Transplantation for Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
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Ibrahim Aldoss, Monzr M. Al Malki, Vinod Pullarkat, Karl Gaal, Haris Ali, Ryotaro Nakamura, and Stephen J. Forman
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Adult ,Male ,medicine.drug_class ,medicine.medical_treatment ,Dasatinib ,Graft vs Host Disease ,Tyrosine-kinase inhibitor ,Diagnosis, Differential ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Transplantation, Homologous ,Philadelphia Chromosome ,Colitis ,Protein Kinase Inhibitors ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Immunosuppression ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Minimal residual disease ,030220 oncology & carcinogenesis ,Immunology ,Female ,Steroids ,business ,030215 immunology ,medicine.drug - Abstract
The tyrosine kinase inhibitor dasatinib is often used after allogeneic hematopoietic cell transplantation to treat minimal residual disease in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Colitis, sometimes hemorrhagic, has occasionally been described with the use of dasatinib for both chronic myeloid leukemia and Ph+ ALL. The pathogenesis of dasatinib-induced colitis is unclear but may be related to effects of dasatinib on immune function. We describe a series of 5 patients who had 7 episodes of colitis during dasatinib use. No patient had obvious large granular lymphocytosis in peripheral blood. The histopathologic and immunohistochemical features of these cases were indistinguishable from control cases of gut graft-versus-host disease (GVHD). In all patients symptoms resolved upon discontinuation of dasatinib in addition to therapy with local or low-dose systemic steroids. An additional 3 patients who developed cytomegalovirus (CMV) colitis while on dasatinib therapy were identified and studied. Dasatinib colitis may have an immune-mediated mechanism similar to GVHD, and dasatinib use may be associated with CMV colitis. Awareness of this association is important for avoiding unnecessary intensification of immunosuppression for suspected gut GVHD.
- Published
- 2016
146. Venetoclax and hypomethylating agents in TP53 ‐mutated acute myeloid leukaemia
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Ryotaro Nakamura, James F. Sanchez, Matthew Mei, Raju Pillai, Stephen J. Forman, Guido Marcucci, Anthony S. Stein, Jianying Zhang, Geoffrey Shouse, Ibrahim Aldoss, and Vinod Pullarkat
- Subjects
Adult ,Aged, 80 and over ,Male ,Sulfonamides ,business.industry ,Venetoclax ,Decitabine ,Hematology ,Middle Aged ,Bridged Bicyclo Compounds, Heterocyclic ,Article ,Leukemia, Myeloid, Acute ,chemistry.chemical_compound ,chemistry ,Mutation ,Cancer research ,Humans ,Medicine ,Female ,Tumor Suppressor Protein p53 ,Myeloid leukaemia ,business ,Aged ,Retrospective Studies ,medicine.drug - Published
- 2019
147. Requirement of GTP binding for TIF-90-regulated ribosomal RNA synthesis and oncogenic activities in human colon cancer cells
- Author
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Quoc Trung Ly, Bin Zhang, Tram Kim Thi Pham, Lokesh Nigam, Trung Quoc Lam, Le Xuan Truong Nguyen, Yasmin Elhajmoussa, Guido Marcucci, Dai Dong Thi Nguyen, Vinod Pullarkat, Vo Thanh Thao Nguyen, Trinh To Tat, Ya-Huei Kuo, Lianjun Zhang, Flavia Pichiorri, Dinh Hoa Hoang, Michael S. Nelson, Dang Quan Nguyen, and Huu Duc Ho
- Subjects
0301 basic medicine ,GTP' ,Transcription, Genetic ,Physiology ,Nucleolus ,Carcinogenesis ,Clinical Biochemistry ,DNA, Ribosomal ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,RNA Polymerase I ,Cell Line, Tumor ,RNA polymerase I ,Humans ,Enhancer ,Ribosomal DNA ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,Chemistry ,Cell Biology ,Ribosomal RNA ,HCT116 Cells ,Cell biology ,030104 developmental biology ,RNA, Ribosomal ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Guanosine Triphosphate ,Ribosomes ,Signal Transduction ,Transcription Factors - Abstract
Transcription initiation factor 90 (TIF-90), an alternatively spliced variant of TIF-IA, differs by a 90 base pair deletion of exon 6. TIF-90 has been shown to regulate ribosomal RNA (rRNA) synthesis by interacting with polymerase I (Pol I) during the initiation of ribosomal DNA (rDNA) transcription in the nucleolus. Recently, we showed that TIF-90-mediated rRNA synthesis can play an important role in driving tumorigenesis in human colon cancer cells. Here we show that TIF-90 binds GTP at threonine 310, and that GTP binding is required for TIF-90-enhanced rRNA synthesis. Overexpression of activated AKT induces TIF-90 T310, but not a GTP-binding site (TIF-90 T310N) mutant, to translocate into the nucleolus and increase rRNA synthesis. Complementing this result, treatment with mycophenolic acid (MPA), an inhibitor of GTP production, dissociates TIF-90 from Pol I and hence abolishes AKT-increased rRNA synthesis by way of TIF-90 activation. Thus, TIF-90 requires bound GTP to fulfill its function as an enhancer of rRNA synthesis. Both TIF variants are highly expressed in colon cancer cells, and depletion of TIF-IA expression in these cells results in significant sensitivity to MPA-inhibited rRNA synthesis and reduced cell proliferation. Finally, a combination of MPA and AZD8055 (an inhibitor of both AKT and mTOR) synergistically inhibits rRNA synthesis, in vivo tumor growth, and other oncogenic activities of primary human colon cancer cells, suggesting a potential avenue for the development of therapeutic treatments by targeting the regulation of rRNA synthesis by TIF proteins.
- Published
- 2019
148. Association of leukemia genetics with response to venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia
- Author
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Ahmed Aribi, Raju Pillai, Vinod Pullarkat, Dongyun Yang, Weili Sun, Monzr M. Al Malki, Guido Marcucci, Ryotaro Nakamura, Ibrahim Aldoss, Stephen J. Forman, James F. Sanchez, Karamjeet S. Sandhu, Haris Ali, Anthony S. Stein, Amandeep Salhotra, Margaret R. O'Donnell, David S. Snyder, Samer K. Khaled, and Matthew Mei
- Subjects
Adult ,Male ,Myeloid ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Kaplan-Meier Estimate ,Decitabine ,Risk Assessment ,Neoplasm genetics ,Article ,Disease-Free Survival ,Remission induction ,chemistry.chemical_compound ,Young Adult ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged ,Retrospective Studies ,Aged, 80 and over ,Sulfonamides ,business.industry ,Venetoclax ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,High-Throughput Nucleotide Sequencing ,Hematology ,DNA, Neoplasm ,Middle Aged ,medicine.disease ,Allografts ,Bridged Bicyclo Compounds, Heterocyclic ,Combined Modality Therapy ,Neoplasm Proteins ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,chemistry ,Relapsed refractory ,Mutation ,Cancer research ,Azacitidine ,Female ,business - Published
- 2019
149. Pulmonary hypertension is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation for myelofibrosis
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Vinod Pullarkat, Ibrahim Aldoss, Dongyun Yang, Matthew Mei, Chendri Chendri, Anthony S. Stein, Ahmed Aribi, Joycelynne Palmer, Stephen J. Forman, Surime Dobrin, Ryotaro Nakamura, David S. Snyder, Kalyanasundaram Venkataraman, Guido Marcucci, Samer K. Khaled, Michael Tran, Haris Ali, Karamjeet S. Sandhu, Rohan Gupta, Monzr M. Al Malki, Amandeep Salhotra, and Faizi Jamal
- Subjects
Transplantation ,medicine.medical_specialty ,Hematopoietic cell ,business.industry ,Hypertension, Pulmonary ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Pulmonary hypertension ,Gastroenterology ,Blood pressure ,Primary Myelofibrosis ,Risk Factors ,Internal medicine ,medicine.artery ,Pulmonary artery ,Medicine ,Humans ,Risk factor ,Complication ,business ,Myelofibrosis ,Retrospective Studies - Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is the only curative therapy for primary myelofibrosis (MF) as well as myelofibrosis secondary to other myeloproliferative neoplasms (MPN). Pulmonary hypertension (PH) is a known complication of MF and may occur in up to 50% of such patients. PH (defined as a mean pulmonary artery pressure ≥25 mmHg at rest) can eventually lead to right heart failure and may be associated with complications after alloHCT. We examined the association of PH with alloHCT outcome in patients with MF associated with MPN. Pre- and post-HCT echocardiograms were reviewed to estimate the peak pulmonary artery systolic pressure (PASP). Median PASP was 37.0 mmHg (range: 16.0-57.9) prior to HCT with 37 of 65 patients (57%) studied. With median follow-up of 35.0 months (range: 3.3–119.4) PH was significantly associated with inferior OS (58.9% vs. 88.8%, P = 0.025), primarily due to increased NRM (21.6% vs. 7.1%, P = 0.007). The majority of the deaths (8 of 14) in patients with PH occurred within 100 days after HCT. In patients with an available post-HCT echocardiogram (n = 33), the median PASP was 30 mmHg (range: 5.0–56.2); eight patients (24%) had persistent PH. Compared with pre-HCT values, PASP was significantly reduced after HCT (p
- Published
- 2019
150. Hypomethylating agents in combination with venetoclax for acute myeloid leukemia: Update on clinical trial data and practical considerations for use
- Author
-
Matthew Mei, Vinod Pullarkat, Ibrahim Aldoss, and Guido Marcucci
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,Decitabine ,Antineoplastic Agents ,Drug Administration Schedule ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Survival analysis ,Clinical Trials as Topic ,Sulfonamides ,Venetoclax ,business.industry ,Remission Induction ,Myeloid leukemia ,Drug Synergism ,Hematology ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Survival Analysis ,Clinical trial ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Azacitidine ,Conventional chemotherapy ,business ,030215 immunology ,medicine.drug - Abstract
One of the most promising developments in therapy for acute myeloid leukemia (AML) in recent years has been the combination of hypomethylating agents (HMA, either decitabine or 5-azacytidine) with the Bcl-2 inhibitor venetoclax (VEN). Although both classes of drugs have single-agent activity in AML, the combination has resulted in high rates of complete remission (CR) both in the frontline and relapsed settings suggesting synergy between these two agents. Recent data have suggested that CR + CR with incomplete count recovery rate may exceed 70% for frontline VEN-HMA. Moreover, this activity has been observed across various genetic subtypes of AML including those known to have very poor response to conventional chemotherapy. Although VEN has only recently obtained FDA approval for treatment of AML, there has been increasing on and off-label use of this combination given its striking efficacy and excellent toxicity profile. In this article, we summarize the current available data on this combination and offer practical guidelines for management of patients receiving VEN-HMA. Our recommendations are based on protocol guidelines, published data from clinical trials as well as from analysis of real world evidence from patients treated with this combination.
- Published
- 2018
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