168 results on '"Talha Badar"'
Search Results
52. CPX-351 for Blast-Phase Myeloproliferative Neoplasm (MPN-BP): Mayo Clinic Experience in 10 Consecutive Patients
- Author
-
Rimal Ilyas, Kristen McCullough, Talha Badar, Mrinal M.M. Patnaik, Hassan B. Alkhateeb, Abhishek A. Mangaonkar, Animesh Pardanani, Ayalew Tefferi, and Naseema Gangat
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
53. Feasibility and Safety of Outpatient Hypomethylating Agent (HMA) + Venetoclax (Ven) Initiation +/- Ramp-up for Patients (pts) with Newly-Diagnosed Acute Myeloid Leukemia (AML)
- Author
-
Rory Michael Shallis, Julian Weiss, Eric S. Winer, Talha Badar, Alok Swaroop, Peter Doukas, Emily Geramita, Henry Le, Sonal Agarwal, Man Yee Merl, Annie Im, Yasmin Abaza, Mark R. Litzow, and Nikolai A. Podoltsev
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
54. Outcomes of Adults Treated with a Hypomethylating Agent Plus Venetoclax for Relapsed/Refractory Acute Myeloid Leukemia: A Multicenter Retrospective Study
- Author
-
Emily Geramita, Hong Wang, Melissa Bastacky, Jessica Cohen, Rory Michael Shallis, Talha Badar, Mark R. Litzow, and Annie Im
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
55. Therapy-Related Myelodysplastic Syndromes with Isolated Del(5q): Comparative Analysis of Phenotype and Long-Term Survival
- Author
-
Farah Fleti, Amritpal Singh, Aref Al-Kali, James M. Foran, Michelle A Elliott, Kebede Begna, Talha Badar, Nandita Khera, Mithun V. Shah, Hassan B. Alkhateeb, Maymona Abdelmagid, Kaaren K. Reichard, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat, and Ayalew Tefferi
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
56. U2AF1 Mutant Clonal Hematopoiesis Is Infrequent, Context Dependent, and Commonly Co-Occurs with BCOR Mutations
- Author
-
Stephanie L. Pritzl, Talha Badar, Alejandro Ferrer, Terra Lasho, Christy Finke, Abhishek A. Mangaonkar, Kristen McCullough, Naseema Gangat, Jenna A. Fernandez, Aref Al-Kali, David S. Viswanatha, Rong He, James M. Foran, and Mrinal M. Patnaik
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
57. Clinical and Genetic Characteristics of STAG2 Mutations in Myeloid Neoplasms
- Author
-
Bahga Katamesh, Ahmad Nanaa, Rong He, David S. Viswanatha, Phuong L Nguyen, Patricia Greipp, Kurt Bessonen, Naseema Gangat, Kebede H. Begna, Abhishek A. Mangaonkar, Mrinal M.M. Patnaik, William J. Hogan, Ayalew Tefferi, Mark R. Litzow, Mithun V. Shah, Cecilia Arana Yi, James M. Foran, Talha Badar, Hassan B. Alkhateeb, and Aref Al-Kali
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
58. Co-mutational pattern of somatic GATA2-mutated myeloid neoplasms
- Author
-
Bahga Katamesh, Ahmad Nanaa, Rong He, David Viswanatha, Phuong Nguyen, Patricia Greipp, James Foran, Kebede Begna, Naseema Gangat, Mrinal Patnaik, Ayalew Tefferi, Mark Litzow, Abhishek Mangaonkar, Mithun Vinod Shah, Talha Badar, Hassan B. Alkhateeb, and Aref Al-Kali
- Subjects
Hematology ,General Medicine - Published
- 2022
59. Sequencing of novel agents in relapsed/refractory B‐cell acute lymphoblastic leukemia: Blinatumomab and inotuzumab ozogamicin may have comparable efficacy as first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia
- Author
-
Emily Curran, Amy Wang, Michaela Liedtke, Aniko Szabo, Ryan J. Mattison, Madelyn Burkart, Caitlin Siebenaller, Ehab Atallah, Anand Patel, Jay Yang, Muhammad Ali Khan, Martha Wadleigh, Rory M. Shallis, Shukaib Arslan, Suresh Kumar Balasubramanian, Mehrdad Hefazi, Shira Dinner, Nikolai A. Podoltsev, Mark R. Litzow, Anjali S. Advani, Talha Badar, Ilana R. Yurkiewicz, Eric Kuo, and Ibrahim Aldoss
- Subjects
Adult ,Male ,Subset Analysis ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Drug Administration Schedule ,Young Adult ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Refractory ,Internal medicine ,Antibodies, Bispecific ,medicine ,Humans ,Inotuzumab Ozogamicin ,030212 general & internal medicine ,Adverse effect ,Aged ,Retrospective Studies ,Aged, 80 and over ,Inotuzumab ozogamicin ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Discontinuation ,Treatment Outcome ,Withholding Treatment ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,Blinatumomab ,business ,medicine.drug - Abstract
Background The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. Methods In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. Results Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). Conclusions Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.
- Published
- 2020
60. Real‐world experience with venetoclax and hypomethylating agents in myelodysplastic syndromes with excess blasts
- Author
-
Naseema Gangat, Kristen McCullough, Isla Johnson, Aref Al‐Kali, Kebede H. Begna, Mrinal M. Patnaik, Mark R. Litzow, William Hogan, Mithun Shah, Hassan Alkhateeb, Abhishek Mangaonkar, James M. Foran, Talha Badar, Jeanne M. Palmer, Lisa Sproat, Cecilia Y. Arana Yi, Animesh Pardanani, and Ayalew Tefferi
- Subjects
Sulfonamides ,Myelodysplastic Syndromes ,Azacitidine ,Humans ,Hematology ,Bridged Bicyclo Compounds, Heterocyclic - Published
- 2022
61. Outcomes of TP53-mutated AML with evolving frontline therapies: Impact of allogeneic stem cell transplantation on survival
- Author
-
Talha Badar, Ehab Atallah, Rory M. Shallis, Aaron D. Goldberg, Anand Patel, Yasmin Abaza, Jan P. Bewersdorf, Antoine N. Saliba, Guilherme Sacchi De Camargo Correia, Guru Murthy, Adam Duvall, Madelyn Burkart, Maximilian Stahl, Yuanhang Liu, Shira Dinner, Neil Palmisiano, Mark R. Litzow, and James M. Foran
- Subjects
Leukemia, Myeloid, Acute ,Hematopoietic Stem Cell Transplantation ,Humans ,Hematology ,Tumor Suppressor Protein p53 - Published
- 2022
62. Real-world experience with luspatercept and predictors of response in myelodysplastic syndromes with ring sideroblasts
- Author
-
Faiqa Farrukh, Deandra Chetram, Aref Al‐Kali, James Foran, Mrinal Patnaik, Talha Badar, Kebede Begna, Christopher Hook, William Hogan, Kristen B. McCullough, Abhishek Mangaonkar, Rong He, Naseema Gangat, and Ayalew Tefferi
- Subjects
Activin Receptors, Type II ,Myelodysplastic Syndromes ,Recombinant Fusion Proteins ,Humans ,Hematology ,Immunoglobulin Fc Fragments - Published
- 2022
63. Prospect of CAR T-cell therapy in acute myeloid leukemia
- Author
-
Talha Badar, Alak Manna, Martha E. Gadd, Mohamed A. Kharfan-Dabaja, and Hong Qin
- Subjects
Pharmacology ,Leukemia, Myeloid, Acute ,Receptors, Chimeric Antigen ,T-Lymphocytes ,Humans ,Pharmacology (medical) ,General Medicine ,Immunotherapy ,Immunotherapy, Adoptive - Abstract
Long-term outcome of patients with acute myeloid leukemia (AML) remains dismal, especially for those with high-risk disease or who are refractory to conventional therapy. CAR T-cell therapy provides unique opportunity to improve outcome by specifically targeting leukemia cells through genetically engineered T cells.We summarize the progress of CAR T-cells therapy in AML. We examine its shortcomings in AML therapy and the strategies that are being implemented to improve its safety and effectiveness. PubMed Central, ClinicalTrials.gov, and ASH annual meeting abstracts were searched. Search terms used to identify clinical trials were 'CAR T-cells in AML' OR CAR T-cells in leukemia". Relevant clinical trials and CAR T-cell research data were reviewed from June 2009 till July 2021.CAR T-cell therapy has shown promise as a novel therapy, but there are number of barriers to overcome to achieve its full therapeutic potential in AML. Targeting leukemia-specific antigen such as CLL1, to avoid myelotoxicity, incorporating checkpoint inhibitors to overcome leukemia-induced immunosuppression and allogenic CAR T cells to increase accessibility to patients with proliferative disease are among the strategies that are being explored to make CAR T cell a successful immunotherapy for patient with AML.
- Published
- 2022
64. Bladder Myeloid Sarcoma with TP53 mutated Myelodysplastic Syndrome/Myeloproliferative Neoplasm Overlap syndrome: Response to Decitabine-Venetoclax regimen
- Author
-
Nikeeta Mandhan, Farah Yassine, Ke Li, and Talha Badar
- Subjects
Decitabine-venetoclax ,Oncology ,hemic and lymphatic diseases ,MDS/MPN overlap ,TP53 mutation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Hematopoietic stem cell transplantation ,Hematology ,Myeloid sarcoma ,RC254-282 ,Article - Abstract
Myeloid sarcoma (MS) is a rare extramedullary blast proliferation of immature cells of myeloid origin. It is commonly associated with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or myeloproliferative neoplasm (MPN), and may precede, coincide with, or follow the diagnosis of a myeloid disorder. MS treatment is controversial, but AML induction like regimens is usually recommended. We present an unusual case of de novo TP53 mutated MDS/MPN overlap with bladder MS. Due to the high-risk nature of the disease, the patient was induced with decitabine and venetoclax combination therapy, resulting in complete remission. The response was further consolidated by an allogeneic hematopoietic stem cell transplantation.
- Published
- 2021
65. Early relapse identifies MCL patients with inferior survival after intensive or less intensive frontline therapy
- Author
-
Stephanie P. Mathews, Michael C. Churnetski, Steven I. Park, Kami J. Maddocks, Talha Badar, Narendranath Epperla, Kristie A. Blum, Mary-Kate Malecek, Veronika Bachanova, Alexey V. Danilov, Jin Guo, Natalie S Grover, James N. Gerson, Brad S. Kahl, Max J Gordon, Stefan K. Barta, Brian T. Hill, Alina S. Gerrie, Madelyn Burkart, Oscar Calzada, Mehdi Hamadani, Yazeed Sawalha, Bhaskar Kolla, Nilanjan Ghosh, Edward Maldonado, Jeffrey M. Switchenko, Peter Martin, Reem Karmali, Krithika Shanmugasundaram, Christopher R. Flowers, Jonathon B. Cohen, Diego Villa, Subir Goyal, Timothy S. Fenske, and David A. Bond
- Subjects
Adult ,medicine.medical_specialty ,Lymphoma ,Population ,Early Relapse ,Lymphoma, Mantle-Cell ,Rare Diseases ,Recurrence ,Internal medicine ,Medicine ,Humans ,In patient ,Prospective Studies ,Prospective cohort study ,education ,Cancer ,education.field_of_study ,business.industry ,Prevention ,Hematology ,Mantle-Cell ,medicine.disease ,Prognosis ,Point of delivery ,Treatment Outcome ,Cohort ,Mantle cell lymphoma ,business ,Progressive disease - Abstract
Although an expanding array of effective treatments has resulted in recent improvement in survival of patients with mantle cell lymphoma (MCL), outcomes remain heterogeneous, and identification of prognostic factors remains a priority. We assessed the prognostic impact of time to progression of disease (POD) after first-line therapy among 455 patients with relapsed MCL. Patients were categorized by duration of first remission as PRF/POD6, defined as progressive disease during induction or POD within 6 months of diagnosis (n = 65; 14%); POD6-24, defined as POD between 6 and 24 months after diagnosis (n = 153; 34%); and POD>24, defined as POD >24 months after diagnosis (n = 237; 53%). The median overall survival from POD (OS2) was 1.3 years (95% confidence interval [CI], 0.9-2.4) for patients with PRF/POD6, 3 years (95% CI, 2-6.8) for those with POD6-24, and 8 years (95% CI, 6.2-NR) for those with POD>24. Median OS2 was inferior in patients with early POD (defined as PRF/POD6 or POD6-24) after both intensive and less intensive frontline treatment. The prognostic performance of time until POD was replicated in an independent cohort of 245 patients with relapsed MCL, with median OS2 of 0.3 years (95% CI, 0.1-0.5) for PRF/POD6, 0.8 years (95% CI, 0.6-0.9) for POD6-24, and 2.4 years (95% CI 2.1-2.7) for POD>24. Early POD is associated with inferior OS2 in patients with relapsed MCL, identifying a high-risk population for future prospective studies.
- Published
- 2021
66. Safety and efficacy of pracinostat in combination with gemtuzumab ozogamicin (PraGO) in patients with relapsed/refractory acute myeloid leukemia
- Author
-
Sameem M. Abedin, Talha Badar, Katelyn Gauger, Laura C. Michaelis, Lyndsey Runaas, Karen-Sue Carlson, GS Guru Murthy, and Ehab Atallah
- Subjects
Leukemia, Myeloid, Acute ,Cancer Research ,Oncology ,Humans ,Benzimidazoles ,Hematology ,Gemtuzumab - Published
- 2022
67. MDS-353 Clinical Outcome of Myelodysplastic Syndrome Progressing on Hypomethylating Agents With Evolving Frontline Therapies: Continued Challenges and Unmet Needs
- Author
-
Ahmad Ghorab, Aref Al-Kali, Michelle Elliot, Naseema Gangat, Hasan Alkhateeb, Mithun Shah, Cecilia Arana Yi, Hemant Murthy, Mohamed Kharfan Dabaja, Ayalew Tefferi, Mrinal Patnaik, Mark Litzow, and Talha Badar
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
68. Poster: MDS-353 Clinical Outcome of Myelodysplastic Syndrome Progressing on Hypomethylating Agents With Evolving Frontline Therapies: Continued Challenges and Unmet Needs
- Author
-
Ahmad Ghorab, Aref Al-Kali, Michelle Elliot, Naseema Gangat, Hasan Alkhateeb, Mithun Shah, Cecilia Arana Yi, Hemant Murthy, Mohamed Kharfan Dabaja, Ayalew Tefferi, Mrinal Patnaik, Mark Litzow, and Talha Badar
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
69. Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma
- Author
-
Didier Blaise, Tycel Phillips, Jason T. Romancik, Roch Houot, Robert Lowsky, Martina Sollini, Jean Marc Schiano De Colella, Amer Beitinjaneh, Gunjan L. Shah, Lazaros J. Lekakis, Stephen D. Smith, Paolo Corradini, Mohamad Mohty, Maryam Rahimian, Luca Castagna, Taiga Nishihori, Asad Bashey, Talha Badar, Reid W. Merryman, Mehdi Hamadani, Carmelo Carlo-Stella, Dipenkumar Modi, Sally Arai, Kamal Bouabdallah, Valter Torri, Joseph P. McGuirk, Guillaume Manson, Anna Guidetti, Yi-Bin Chen, Hatcher J. Ballard, Julio C. Chavez, Pier Luigi Zinzani, Tatyana Feldman, Sunita Nathan, Anurag K. Singh, Massimo Magagnoli, Marie Pierre Moles-Moreau, Beatrice Casadei, Anthony Serritella, Michael Byrne, Radhakrishnan Ramchandren, Miguel-Angel Perales, Chiara De Philippis, Samantha Jaglowski, Justin Kline, Remy Dulery, Laura Giordano, Alex F. Herrera, Jonathon B. Cohen, Philippe Armand, Armando Santoro, Aspasia Stamatoulas, Stephen M. Ansell, Michael A. Spinner, Lori Dahncke, Corentin Orvain, Chloé Spilleboudt, Geoffrey Shouse, Robin Joyce, Vincent T. Ho, Matthew J. Frigault, Ryan C. Lynch, Uttam Rao, Jakub Svoboda, David A. Bond, Yago Nieto, Dana-Farber Cancer Institute [Boston], Humanitas Clinical and Research Center [Rozzano, Milan, Italy], Università degli Studi di Milano = University of Milan (UNIMI), University of Bologna/Università di Bologna, Ohio State University [Columbus] (OSU), Stanford University, Memorial Sloane Kettering Cancer Center [New York], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Jules Bordet [Bruxelles], Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen (CLCC Henri Becquerel), CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Bordeaux [Bordeaux], Humanitas University [Milan] (Hunimed), P01 CA23766, U.S. Department of Health & Human Services | National Institutes of Health, U.S. Department of Health & Human Services | National Institutes of Health, 20575, Associazione Italiana per la Ricerca sul Cancro, Università degli Studi di Milano [Milano] (UNIMI), University of Bologna, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Merryman R.W., Castagna L., Giordano L., Ho V.T., Corradini P., Guidetti A., Casadei B., Bond D.A., Jaglowski S., Spinner M.A., Arai S., Lowsky R., Shah G.L., Perales M.-A., De Colella J.M.S., Blaise D., Herrera A.F., Shouse G., Spilleboudt C., Ansell S.M., Nieto Y., Badar T., Hamadani M., Feldman T.A., Dahncke L., Singh A.K., McGuirk J.P., Nishihori T., Chavez J., Serritella A.V., Kline J., Mohty M., Dulery R., Stamatoulas A., Houot R., Manson G., Moles-Moreau M.-P., Orvain C., Bouabdallah K., Modi D., Ramchandren R., Lekakis L., Beitinjaneh A., Frigault M.J., Chen Y.-B., Lynch R.C., Smith S.D., Rao U., Byrne M., Romancik J.T., Cohen J.B., Nathan S., Phillips T., Joyce R.M., Rahimian M., Bashey A., Ballard H.J., Svoboda J., Torri V., Sollini M., De Philippis C., Magagnoli M., Santoro A., Armand P., Zinzani P.L., and Carlo-Stella C.
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,allogenic stem cell transplantation, PD-1 blockade, Hodgkin lymhpoma ,[SDV]Life Sciences [q-bio] ,Programmed Cell Death 1 Receptor ,Salvage therapy ,0302 clinical medicine ,Young adult ,Immune Checkpoint Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Prognosis ,Hodgkin Disease ,3. Good health ,Survival Rate ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Female ,medicine.drug ,Adult ,medicine.medical_specialty ,Allogeneic transplantation ,Cyclophosphamide ,Adolescent ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Survival rate ,Aged ,Retrospective Studies ,Salvage Therapy ,business.industry ,Retrospective cohort study ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Blockade ,Transplantation ,030104 developmental biology ,Drug Resistance, Neoplasm ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies - Abstract
International audience; Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
- Published
- 2021
70. Multi-center analysis of practice patterns and outcomes of younger and older patients with mantle cell lymphoma in the rituximab era
- Author
-
Max J. Gordon, Timothy S. Fenske, Peter Martin, Natalie S Grover, Mary Malecek, Bhaskar Kolla, Brian T. Hill, Jeffrey M. Switchenko, Madelyn Burkart, Reem Karmali, Kami J. Maddocks, Jin Guo, David A. Bond, Stephanie Mathews, Narendranath Epperla, Michael C. Churnetski, Alexey V. Danilov, Talha Badar, Nilanjan Ghosh, Jonathon B. Cohen, Subir Goyal, Steven I. Park, Kristie A. Blum, Krithika Shanmugasundaram, James N. Gerson, Veronika Bachanova, Brad S. Kahl, Stefan K. Barta, Christopher R. Flowers, Yazeed Sawalha, and Mehdi Hamadani
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Multivariate analysis ,Lymphoma, Mantle-Cell ,Blastoid ,Article ,Antineoplastic Agents, Immunological ,Internal medicine ,Medicine ,Humans ,Progression-free survival ,Aged ,Retrospective Studies ,Univariate analysis ,biology ,Practice patterns ,business.industry ,Age Factors ,Hematology ,Middle Aged ,biology.organism_classification ,medicine.disease ,Survival Analysis ,Progression-Free Survival ,Treatment Outcome ,Cytarabine ,Mantle cell lymphoma ,Rituximab ,Female ,business ,medicine.drug - Abstract
Clinical outcomes and predictors of survival in patients with newly diagnosed mantle cell lymphoma (MCL) treated in the rituximab era (2000-2015) at 12 US academic centers were assessed to identify determinants of survival across age groups. Objectives were to characterize and compare practice patterns, outcomes and prognostic factors for survival in younger patients (age < 65) and older patients (age ≥ 65 years). Among 1162 patients included, 697 were younger and 465 were older. In younger patients, 2-year progression free survival (PFS) and overall survival (OS) rates were 79% and 92% respectively; blastoid histology, ECOG ≥ 2, and lack of maintenance rituximab (MR) remained statistically relevant to poor OS on univariate analysis (UVA) and multivariate analysis (MVA). In older patients, 2-year PFS and OS rates were 67% and 86% respectively; lack of maintenance rituximab remained significantly associated with inferior PFS and OS on UVA and MVA (p < 0.001). Two-year PFS rates were 79%, and 67% and 2-year OS rates were 92% and 86% for ages < 65 and ≥ 65 respectively (p < 0.001). First-line high-dose cytarabine exposure and/or MR lessened the negative impact of age on survival. Taken collectively, survival outcomes for older patients remain inferior to those of younger patients in the rituximab era. However, maintenance rituximab and potentially high-dose cytarabine-based induction can mitigate the negative impact of age on survival.
- Published
- 2021
71. Do histone deacytelase inhibitors and azacitidine combination hold potential as an effective treatment for high/very-high risk myelodysplastic syndromes?
- Author
-
Talha Badar and Ehab Atallah
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Pracinostat ,Azacitidine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Effective treatment ,Humans ,Pharmacology (medical) ,Aged ,Randomized Controlled Trials as Topic ,Pharmacology ,biology ,business.industry ,Myelodysplastic syndromes ,Patient Selection ,Hematopoietic Stem Cell Transplantation ,Drug Synergism ,General Medicine ,medicine.disease ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Histone ,Clonal Hematopoietic Stem Cell ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,biology.protein ,business ,Very high risk ,medicine.drug - Abstract
Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder, predominantly seen in elderly patients with variable clinical outcome and high tendency for leukemic transformation. Allogeneic hematopoietic stem cell transplantation (alloHCT) is the only potential curative option but limited to a selected group of patients, for the rest, disease control is the goal and enrollment in clinical trial is always encouraged. Mechanistically, azacitidine (AZA) and histone deacetylase inhibitors (HDACi) is a promising combination for patient with high-risk MDS to improve clinical outcome, but the combination has yet to demonstrate its efficacy in randomized clinical trials.In this review the authors discuss the salient features, pharmacokinetics, safety, and efficacy data of AZA and HDACi combination in patients with MDS. Future strategies on how to possibly improve clinical outcome of patients with MDS using AZA and HDACi combination are discussed.Pre-clinical and clinical data demonstrated synergistic activity of AZA and HDACi in patients with MDS. So far, the efficacy of this combination is undermined by toxicity; mainly gastrointestinal. Careful patient selection and alternative dosing schedule is needed in future clinical trials to evaluate clinical outcome.
- Published
- 2021
72. Postrelapse survival in diffuse large B-cell lymphoma after therapy failure following autologous transplantation
- Author
-
Neeraj Saini, Nirav N. Shah, Timothy S. Fenske, Aniko Szabo, Steve Borson, Talha Badar, Romil Patel, Amanda F. Cashen, John A. Vaughn, Mehdi Hamadani, Sairah Ahmed, and Narendranath Epperla
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Gastroenterology ,Disease-Free Survival ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Risk of mortality ,Humans ,Medicine ,Autologous transplantation ,Autografts ,Survival rate ,Aged ,Lymphoid Neoplasia ,business.industry ,Surrogate endpoint ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Survival Rate ,Transplantation ,Female ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma - Abstract
Outcomes for diffuse large B-cell lymphoma (DLBCL) patients relapsing after autologous hematopoietic cell transplantation (auto-HCT) have been historically poor. We studied outcomes of such patients using data from 4 transplantation centers. Eligibility criteria included adult patients (age ≥18 years) with DLBCL experiencing disease relapse after auto-HCT performed during 2006 to 2015. The time period was stratified into 2 eras (era 1, 2006-2010; era 2, 2011-2015). The primary end point was postrelapse overall survival (PR-OS). Secondary end points were factors prognostic of PR-OS. Of the 700 patients with DLBCL who underwent auto-HCT, 248 (35%) relapsed after auto-HCT. Median PR-OS of all relapsed DLBCL patients after auto-HCT (n = 228) was 9.8 months (95% confidence interval [CI], 7-15). Median PR-OS was significantly better for patients in complete (17.8 months; 95% CI, 7.9-41.6) vs partial remission at auto-HCT (7.1 months; 95% CI, 5.4-11; P = .01), those undergoing auto-HCT >1 year (12.8 months; 95% CI, 7.6-24.9) vs ≤1 year after DLBCL diagnosis (6.3 months; 95% CI, 4.5-9.2; P = .01), and those with late (56.4 months; 95% CI, 23.7-∞) vs early relapse (5.9 months; 95% CI, 4.5-8.8; P < .0001). On multivariate analysis, although late relapse (hazard ratio [HR], 0.21; 95% CI, 0.13-0.34; P < .0001) was associated with significantly lower mortality, the risk of mortality increased with age (HR, 1.25 per decade; 95% CI, 1.06-1.48; P = .009). This is the largest study to date to evaluate outcomes of DLBCL patients relapsing after auto-HCT. Our study provides benchmarking for future trials of chimeric antigen receptor T cells and other promising agents evaluating PR-OS after auto-HCT.
- Published
- 2019
73. Characteristics and prognosis of DDX41- and GATA2-mutated myeloid neoplasms
- Author
-
Ahmad Nanaa, Hassan B. Alkhateeb, Talha Badar, James M. Foran, Lisa Ostrosky Sproat, Cecilia Ysabel Arana Yi, Phuong L. Nguyen, Dragan Jevremovic, Patricia T. Greipp, Naseema Gangat, Ayalew Tefferi, Mark Robert Litzow, Mithun Vinod Shah, Abhishek Avinash Mangaonkar, Mrinal Patnaik, David Viswanatha, Rong He, and Aref Al-Kali
- Subjects
Cancer Research ,Oncology - Abstract
e19010 Background: Mutated DEAD-box helicase 41 (m DDX41), and mutated GATA2 are germline mutations associated with familial predisposition syndromes. In this study, we compare the clinical characteristics and survival outcomes (OS) of m DDX41 and m GATA2 MN patients (pts). Methods: We retrospectively screened pts who had next-generation sequencing (NGS) (OncoHeme panel) performed at Mayo Clinic. 4,524 consecutive pts (2018-2021) were screened for DDX41 mutations and 3,872 for GATA2 mutations (2015-2020) and included 36 MN pts with m DDX41 genetic alterations, and 55 m GATA2 MN pts. m GATA2 cases were included at NGS date while m DDX41 were included at diagnosis date. Germline workup was not done in all cases. JMP 16.2.0 Software was used for statistical analysis. Results: Patient characteristics: The most common diagnosis was MDS (N = 22, 61% in m DDX41 N = 17, 31% in m GATA2 group; p = .0044). MDS/MPN overlap was seen in m GATA2 group only; (29% vs. 0%; p = .0004). Majority of pts were males with median age of 68 and 67 years for m DDX41 and m GATA2 pts; respectively (p = .7). m DDX41 pts had higher hemoglobin, platelets, and MCV (< .0001, 0.005, < .0001; respectively) and significantly lower white blood cells (WBC) count compared to m GATA2 pts (< .0001). All m DDX41-AML pts were (ELN) intermediate-risk, and 64% of m DDX41 MDS were intermediate risk (IPSS-R). In contrast, of m GATA2 pts 62% of AML were adverse risk and 44% of MDS very high risk. Majority of m DDX41 pts had normal karyotype (N = 32; 91% vs. N = 19, 37%; p < .0001), had isolated mutations (N = 23; 64%) and the most common co-mutations were DNMT3A (38%), ASXL1 (30%), JAK2 (23%). The majority of m GATA2 pts were co-mutated (96%) with a different co-mutation pattern ASXL1 (60%), SRSF2 (34%), RUNX1 (19%). Germline data: One m GATA2 pts had proven germline mutation, and 10/11 (91%) m DDX41 pts were confirmed Survival and progression in MDS/AML: After median follow-up of 30 months in MDS/AML, 7 (21%) m DDX41 and 23 (77%) m GATA2 pts died with superior OS in m DDX41 compared to m GATA2 pts with median OS of (136.7 vs. 6.8 months, p < .0001). Seven (31%) of 22 m DDX41 and 6 (35%) m GATA2 MDS pts progressed into AML with a median time to progression of (11.2 vs. 5.2 months, p = .045). The leukemia free survival (LFS) for m DDX41 MDS pts was significantly longer than LFS of m GATA2 MDS pts (24.4 vs. 6 months, p < .0001). Conclusions: We compare the outcomes of two unique mutations associated with germline predisposition. We found m DDX41 pts had fewer cytogenetic aberrations, no MDS/MPN overlap, and lower WBC count. Majority of m DDX41 MDS/AML pts were intermediate risk category, compared to predominance of adverse risk disease in m GATA2 pts, translating into better OS and LFS. This study is limited by the small size, lack of germline workup in all cases, and retrospective nature. However, it supports the favorable prognosis and indolent course of m DDX41 pts recently described.
- Published
- 2022
74. Characteristics and prognosis of mutated STAG2 myeloid neoplasms
- Author
-
Bahga Katamesh, Ahmad Nanaa, Rong He, David Viswanatha, Phuong L. Nguyen, Patricia T. Greipp, Naseema Gangat, Kebede Begna, Abhishek Avinash Mangaonkar, Mrinal Patnaik, William J. Hogan, Mark Robert Litzow, Mithun Vinod Shah, Cecilia Ysabel Arana Yi, James M. Foran, Talha Badar, Hassan B. Alkhateeb, and Aref Al-Kali
- Subjects
Cancer Research ,Oncology - Abstract
e19014 Background: Stromal Antigen 2 ( STAG2), located on Xq25, is the most mutated (m) cohesin-complex gene in myeloid neoplasm (MN) patients (pts). mSTAG2 is present in around 5% of MN and has been linked to secondary AML and potential poor impact on outcome. Methods: We retrospectively screened MN pts who had next-generation sequencing (NGS) (OncoHeme) performed at Mayo Clinic between 2018-2021. m STAG2 pts were included at the date of NGS. Charts were reviewed for clinical information after obtaining IRB approval. BlueSky Software V7.40 was used for statistical analysis. Results: Characteristics: 70 pts with mSTAG2 MN were identified, their median age was 72 years (range 25-91); with 55 pts (79%) being males. Complete blood counts showed median white blood cell count of 2.8 x109/L, hemoglobin of 8.9 gm/dL and platelets of 89 x109/L. The diagnosis was MDS in 38 pts (54%), AML in 20 (29%), MDS/MPN in 9 (13%), MPN in 2 (3%), and CCUS in 1 (1%). 11 cases (16%) were defined as therapy-related MN (tMN). Cytogenetics were normal in 45 pts (64%) and abnormal in 22 (31%). 10/50 non-AML pts progressed to AML (after median time of 9.8 months). Hematopoietic cell transplantation (HCT) was done in 20 pts (29%). mSTAG2: median VAF (mVAF) was 50% (range, 5%-100%). Males had higher mVAF compared to females (64% vs. 27%, p= .001), and tMN pts had higher mVAF compared to de novo (dn) MN pts (66% vs. 43%, p= .03). mVAF had no correlation with disease classification (50% in AML, 52% in MDS, 41% in MDS/MPN, 36% in MPN and 5% in CCUS, p= .5). STAG2 mutations were nonsense, frameshift, and splice site in 50%, 37%, and 13%, respectively. Co-mutations : median number of co-mutations was 3 (range, 0-6). Most common co-mutations were ASXL1 (66%), SRSF2 (37%), TET2 (36%), RUNX1 (29%), IDH2 (21%), BCOR (20%) and U2AF1 (16%) while least common were TP53, SETBP and ZRSR2 (1% each). Neither number (p= .08) nor type of co-mutation correlated with MN classification. There was no difference in the co-mutational pattern between tMN and dnMN pts. Survival : median overall survival (mOS) was 16.3 months with a median follow up time of 24.5 months. Pts who received HCT had better OS compared to non-HCT pts (mOS not reached vs. 14.9 months, p= .003). Pts with an isolated m STAG2 had better OS than co-mutated pts (p= .04), while the type of STAG2 mutation did not affect OS (p= .3). Pts with tMN had worse OS than dnMN pts (9.9 vs. 20.4 months, p= .02). VAF ≥75% had a negative impact on OS (20.5 vs 8.1 months, p= .008). mOS did not differ based on MN diagnosis. On multivariate analysis, only HCT (HR 0.3, p= .01) and VAF ≥75% (HR 2.3, p= .02) had impact on OS. Conclusions: mSTAG2 was more common in elderly males and MDS diagnosis. mSTAG2 was uncommon as an isolated mutation, indicating a possible role in disease progression with preferred certain co-mutations ( ASXL1/SRSF2/RUNX1/IDH2). mOS was poor regardless of MN diagnosis indicating a molecularly driven significance of an aggressive disease. The study needs to be validated by larger studies.
- Published
- 2022
75. Phase II trial of luspatercept with or without hydroxyurea for the treatment of patients with myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts
- Author
-
Abhishek Avinash Mangaonkar, Cecilia Ysabel Arana Yi, Hemant S. Murthy, Talha Badar, James M. Foran, Susan Michelle Geyer, Kristen Beth McCullough, Erinayo S Baba Lola, Jean Hanson, Aref Al-Kali, Hassan B. Alkhateeb, Mithun Vinod Shah, Kebede Begna, Michelle A. Elliott, Naseema Gangat, Mark Robert Litzow, Alexandra P. Wolanskyj-Spinner, William J. Hogan, Ayalew Tefferi, and Mrinal Patnaik
- Subjects
Cancer Research ,Oncology - Abstract
TPS7080 Background: Myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) are classified as a distinct category under the World Health Organization (WHO) classification of myeloid neoplasms. MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) and MDS/MPN, unclassifiable with > 15% bone marrow ring sideroblasts (MDS/MPN-U-RS) have similar clinical and pathological characteristics with symptomatic or transfusion-dependent anemia as the predominant morbidity. Luspatercept has been approved in myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/MPN overlap syndromes, based on the phase 3 MEDALIST clinical trial which primarily included MDS-RS patients with an objective erythroid response rate of approximately 40 per cent. In this trial, some MDS-RS patients also experienced an increase in neutrophil and platelet counts. This raises a safety concern for MDS/MPN patients with elevated platelet or WBC counts such as MDS/MPN-RS-T and MDS/MPN-U-RS. Previous studies have shown clinical and biological differences between MDS-RS and MDS/MPN-RS-T, with the latter group at a significantly elevated risk for thrombotic events. Additionally, several MDS/MPN-RS-T patients are on hydroxyurea which may blunt the erythroid response of luspatercept. Therefore, it is imperative to establish the safety and efficacy of luspatercept in this patient group. Methods: This is an investigator-initiated, prospective, phase II study of luspatercept in MDS/MPN overlap neoplasms with ring sideroblasts and thrombocytosis or unclassifiable with ring sideroblasts with 2 arms; hydroxyurea-independent (cohort A) and hydroxyurea-dependent (cohort B). Hydroxyurea and/or aspirin use is allowed as per investigator discretion. The primary goal is to study the efficacy and safety of luspatercept in MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic anemia. The primary endpoint is to assess erythroid response rate as per the 2015 International Working Group MDS/MPN response criteria. Secondary endpoints include response duration, time to acute myeloid leukemia (AML) transformation, thrombosis rate, AML-free and overall survival. Inclusion criteria include newly diagnosed or relapsed/refractory adult patients with WHO-defined diagnosis of MDS/MPN-RS-T or MDS/MPN-U-RS with symptomatic or transfusion-dependent anemia and unlikely to respond (EPO level > 200 IU/L) or intolerant to erythropoiesis stimulating agent (ESA) therapy. Prior therapy with lenalidomide, hypomethylating agents or immunosuppressive therapy is allowed. The overall plan is to enroll 54 patients across the three Mayo Clinic sites, Minnesota, Arizona and Florida. Enrollment to the trial began in January 2022 with 1 patient enrolled at the time of abstract submission. Clinical trial information: NCT05005182.
- Published
- 2022
76. Racial disparities in patients with TP53 mutated acute myeloid leukemia
- Author
-
Talha Badar, Mark Robert Litzow, Rory Shallis, Maximilian Stahl, Jan Philipp Bewersdorf, Antoine N Saliba, Guilherme Sacchi de Camargo Correia, Anand Ashwin Patel, Yasmin Abaza, Guru Subramanian Guru Murthy, Adam Duvall, Madelyn Burkart, Aref Al-Kali, Neil Palmisiano, Shira Dinner, Aaron David Goldberg, and Ehab L. Atallah
- Subjects
Cancer Research ,Oncology - Abstract
e19007 Background: While clinical outcomes of patients (pts) with TP53 mutated (m) acute myeloid leukemia (AML) are dismal, subsets of pts with eligibility to curative intent therapies can do better. As racial disparities are known to impact outcome in hematological malignancies, we sought to explore disparities in TP53m AML. Methods: We conducted a multicenter study of 304 TP53m AML pts, divided into 2 groups, White (n= 240) and Black/Hispanic (n=64), to compare difference in disease characteristics and clinical outcome. We grouped Black and Hispanic together as the number of pts were small in each group and our aim was to evaluate outcome in under-represented races/ethnicities. Results: Baseline characteristics are summarized in Table. The median age of the pts was comparable between White and Black/Hispanic (p= 0.97). A significantly higher proportion of Black/Hispanic pts (23%) had diabetes mellitus when compared with White (14%) pts (p= 0.02). A higher proportion of Black/Hispanic pts had therapy-related AML (33% vs. 20%, p= 0.03), complex cytogenetics (98% vs. 87%, p= 0.003) and co-mutations (70% vs. 57%, p= 0.02). The proportion of pts who received hypomethylating agent + venetoclax (29% vs 20%, p= 0.20) or CPX-351 (22% vs 20%, p= 0.13) were comparable between White and Black/Hispanic, respectively. A higher proportion of Black/Hispanic pts received supportive care (17% vs. 4%, p= 0.002). White pts had higher rates of complete remission with or without count recovery (25% vs. 19%, p= 0.07). Only 6% of Black/Hispanic pts received allogeneic stem cell transplantation (alloHCT) compared to 16% for White pts (p= 0.01). The median event free survival was 2 months (mo) (95% CI;1.52-2.41) and 2.5 mo (95% CI:1.62-3.31) in White and Black/Hispanic pts, respectively (p= 0.71). The median overall OS was shorter for Black/Hispanic (6.37 mo [95% CI:2.88-9.85]) than for White (6.90 mo [95% CI:5.55-8.24] [p= 0.009]). Conclusions: Our study demonstrates poorer OS in Black/Hispanic pts with TP53m AML. Potential drivers of this disparity include lower alloHCT rates, higher rates of pts receiving supportive care, and higher-risk disease in Black/Hispanic pts.[Table: see text]
- Published
- 2022
77. Clinicopathologic characteristics and treatment outcomes of de novo myeloid sarcoma
- Author
-
Justin J. Kuhlman, Benjamin J. McCormick, Talha Badar, James M. Foran, Zaid H. Abdel Rahman, and Hemant S. Murthy
- Subjects
Cancer Research ,Oncology - Abstract
e19002 Background: Extramedullary disease in acute myeloid leukemia (AML), also known as myeloid sarcoma (MS), is an uncommon presentation of de novo AML. Clinicopathologic characteristics and optimal treatment strategies of de novo MS remain unclear in both isolated MS without bone marrow (BM) involvement and synchronous MS with BM involvement. Methods: In a single-site retrospective study, medical records of patients with de novo extramedullary AML who received oncological care at any Mayo Clinic site between 1996 and 2021 were analyzed. Using BlueSky Statistics software, survival outcomes were analyzed using Kaplan-Meier and Cox-proportional hazard models for univariate and multivariate analysis, respectively. Results: 83 patients with de novo MS were identified; 49 (59%) presented with synchronous MS and 34 (41%) exhibited isolated MS. Median age at diagnosis was 56 years (range, 17-89); 63% were male. Next-generation sequencing of the blood +/- BM revealed abnormalities in 24/27 (88%) analyzed patients; aberrations included mutations in RTK-RAS pathways (12/27), NPM1 (10/27), TET2 (6/27), and IDH2 (4/27). Median length of follow-up was 1.73 years (95% CI; 0.03-3.0); 53 patients (64%) had expired. Median event free survival was 0.64 years and 0.61 years in isolated and synchronous MS, respectively (p = 0.5). Median overall survival (mOS) in isolated and synchronous MS was 2.1 years and 1.5 years, respectively (p = 0.5). Induction treatment with intensive chemotherapy (IC) was administered in 70 patients (84%). IC regimens included 7+3, MEC, CLAG-M, and hyper-CVAD. Variables associated with improved survival in both groups included treatment with IC +/- allogenic stem cell transplant (alloSCT) (p < 0.001), normal or favorable risk karyotype (p = 0.001), and age less than 60 (p = 0.001). Localized therapy (LT) did not provide an added survival benefit. Patients with synchronous MS were more likely to relapse in the BM and blood than isolated MS (p = 0.02). Conclusions: Enriched with RTK-RAS mutations, de novo MS remains an aggressive form of AML, particularly in patients with intermediate or high-risk genomics or those with skin, soft tissue, or lymphatic involvement. IC should be employed with consideration of alloSCT in eligible patients, particularly in synchronous MS due to a heightened risk for medullary and leukemic relapse.[Table: see text]
- Published
- 2022
78. A phase 1 study of CD38-bispecific antibody (XmAb18968) for patients with CD38 expressing relapsed/refractory acute myeloid leukemia and T-cell acute lymphoblastic leukemia
- Author
-
Guru Subramanian Guru Murthy, Tyce Kearl, Weigo Cui, Bryon Johnson, Karin Hoffmeister, Alexandra Harrington, Aniko Szabo, Talha Badar, Adam Duvall, Jessica Taft Leonard, Cecilia Ysabel Arana Yi, Arielle Baim, Shahriar Yaghoubi, Bijal D. Shah, Wendy Stock, and Ehab L. Atallah
- Subjects
Cancer Research ,Oncology - Abstract
TPS7070 Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) have remained poor. CD38 is a transmembrane glycoprotein with several important functions including its role in immune escape of tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in T-ALL and AML and is targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We hypothesize that targeting CD38 in relapsed/refractory T-ALL and AML would be safe and feasible using XmAb18968. Methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with relapsed/refractory T-ALL or AML (including measurable residual disease relapse), CD38 expression ≥ 20% by flow cytometry, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. The primary objective is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary objectives include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory objectives include correlation of responses with genomic profile, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design. Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and Group B for subjects with AML. Patients will be entered sequentially to each dose level [0.8mg cohort, 1mg cohort, 1.3mg cohort, 1.5mg cohort). The observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the 3 treated subjects, or no more than 1 of the 6 treated subjects’ experiences a dose limiting toxicity. A minimum of 24 and a maximum of 60 patients will be enrolled. The study is being conducted at 6 sites in United States and is currently open for enrollment. Clinical trial information: NCT05038644.
- Published
- 2022
79. Outcomes with Allogeneic Hematopoietic Stem Cell Transplant in Therapy-Related Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis
- Author
-
Moazzam Shahzad, Qamar Iqbal, Hira Shaikh, Mamoon Ahmad, Huda Fatima, Amna yousaf Shah, Muhammad Salman Faisal, and Talha Badar
- Subjects
Transplantation ,Molecular Medicine ,Immunology and Allergy ,Cell Biology ,Hematology - Published
- 2022
80. Multi-institutional study evaluating clinical outcome with allogeneic hematopoietic stem cell transplantation after blinatumomab in patients with B-cell acute lymphoblastic leukemia: real-world data
- Author
-
Jay Yang, Rory M. Shallis, Caitlin Siebenaller, Ehab Atallah, Shukaib Arslan, Danielle Cenin, Michaela Liedtke, Ibrahim Aldoss, Mark R. Litzow, Talha Badar, Anjali S. Advani, Aniko Szabo, Shira Dinner, Emily Curran, Ryan J. Mattison, Anand Patel, Ilana R. Yurkiewicz, Martha Wadleigh, Nikolai A. Podoltsev, Madelyn Burkart, Suresh Kumar Balasubramanian, and Mehrdad Hefazi
- Subjects
Transplantation ,medicine.medical_specialty ,B-Lymphocytes ,business.industry ,medicine.medical_treatment ,Hematopoietic Stem Cell Transplantation ,Hematology ,B-cell acute lymphoblastic leukemia ,Hematopoietic stem cell transplantation ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Clinical trial ,Internal medicine ,Acute lymphocytic leukemia ,Antibodies, Bispecific ,medicine ,Humans ,Blinatumomab ,In patient ,Cumulative incidence ,Progression-free survival ,business ,medicine.drug - Abstract
Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36–59%) and 58% (95% CI: 45–69%), respectively. The cumulative incidence of GIII–IV aGVHD at 3 months was 9.9% (95% CI: 5.0–16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7–45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5–89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8–75.4%]) prior to alloHCT (p = 0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL.
- Published
- 2020
81. Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with blinatumomab
- Author
-
Ehab Atallah, Ilana R. Yurkiewicz, Madelyn Burkart, Mark R. Litzow, Emily Curran, Anjali S. Advani, Michaela Liedtke, Shira Dinner, Shukaib Arslan, Ibrahim Aldoss, Caitlin Siebenaller, Anand Patel, Nikolai A. Podoltsev, Martha Wadleigh, Elizabeth Schultz, Suresh Kumar Balasubramanian, Mehrdad Hefazi, Muhammad Ali Khan, Jay Yang, Aniko Szabo, Rory M. Shallis, Talha Badar, and Ryan J. Mattison
- Subjects
Oncology ,Adult ,medicine.medical_specialty ,Adolescent ,Clinical Trials and Observations ,Young Adult ,Acute lymphocytic leukemia ,Internal medicine ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Antibodies, Bispecific ,medicine ,Humans ,Survival analysis ,Aged ,Retrospective Studies ,Aged, 80 and over ,B-Lymphocytes ,business.industry ,Hazard ratio ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Minimal residual disease ,Log-rank test ,Transplantation ,Cytokine release syndrome ,Blinatumomab ,business ,medicine.drug - Abstract
The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the “real-world” setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD−). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD− at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest “real-world” experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study.
- Published
- 2020
82. Delayed neurotoxicity after axicabtagene ciloleucel therapy in relapsed refractory diffuse large B-cell lymphoma
- Author
-
Mehdi Hamadani, Talha Badar, and Bryon D. Johnson
- Subjects
Transplantation ,Biological Products ,business.industry ,Antigens, CD19 ,Hematology ,medicine.disease ,Immunotherapy, Adoptive ,Delayed neurotoxicity ,Relapsed refractory ,medicine ,Cancer research ,Humans ,Lymphoma, Large B-Cell, Diffuse ,business ,Diffuse large B-cell lymphoma - Published
- 2020
83. Clinical activity of ibrutinib in classical Hodgkin lymphoma relapsing after allogeneic stem cell transplantation is independent of tumor BTK expression
- Author
-
John Astle, Katie Zellner, Talha Badar, Mehdi Hamadani, Parameswaran Hari, and Imran K Kakar
- Subjects
Adult ,Transplantation Conditioning ,chemistry.chemical_compound ,Piperidines ,Classical Hodgkin lymphoma ,Agammaglobulinaemia Tyrosine Kinase ,Medicine ,Bruton's tyrosine kinase ,Humans ,Transplantation, Homologous ,Aged ,biology ,business.industry ,Adenine ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Hodgkin Disease ,Transplantation ,chemistry ,Ibrutinib ,biology.protein ,Cancer research ,Stem cell ,Neoplasm Recurrence, Local ,business - Published
- 2020
84. African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States
- Author
-
Mohamed A. Kharfan-Dabaja, Baldeep Wirk, Hillard M. Lazarus, Nina Shah, Heather Landau, Hemant S. Murthy, Qaiser Bashir, Taiga Nishihori, Kenneth R. Meehan, Nosha Farhadfar, David H. Vesole, Talha Badar, Melhem Solh, Raphael Fraser, Reinhold Munker, Binod Dhakal, Yago Nieto, Jesus G. Berdeja, Cindy Lee, Natalie S. Callander, Parameswaran Hari, Ehsan Malek, Robert A. Kyle, Saurabh Chhabra, Cesar O. Freytes, Shahrukh K. Hashmi, Omar Davila, Sundar Jagannath, Gerhard C. Hildebrandt, Ravi Vij, Shaji Kumar, Miguel Angel Diaz, Siddhartha Ganguly, Rammurti T. Kamble, Anita D'Souza, and Cesar Rodriguez Valdes
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Transplantation Conditioning ,Chromosomal translocation ,Transplantation, Autologous ,Article ,Translocation, Genetic ,White People ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,Humans ,030212 general & internal medicine ,Prospective Studies ,Stage (cooking) ,Multiple myeloma ,Hematopoietic cell ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,medicine.disease ,Confidence interval ,United States ,Transplantation ,Black or African American ,030220 oncology & carcinogenesis ,Female ,business ,Multiple Myeloma - Abstract
Background Multiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard-risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent. Methods This study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187). Results African Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). Fewer African Americans with t(11;14) (21%) had a coexistent high-risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression-free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT-CI, and receipt of maintenance. Conclusions Race may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.
- Published
- 2020
85. Chimeric Antigen Receptor T Cell Therapy for Acute Lymphoblastic Leukemia
- Author
-
Nirav N. Shah and Talha Badar
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Cost-Benefit Analysis ,T-Lymphocytes ,Cell ,Antigens, CD19 ,Receptors, Antigen, T-Cell ,Hematopoietic stem cell transplantation ,Immunotherapy, Adoptive ,Lymphocyte Depletion ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Medicine ,Humans ,Pharmacology (medical) ,Receptor ,Tumor microenvironment ,Clinical Trials as Topic ,Receptors, Chimeric Antigen ,business.industry ,Hematopoietic Stem Cell Transplantation ,Disease Management ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Combined Modality Therapy ,Tumor antigen ,Clinical trial ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Chimeric Antigen Receptor T-Cell Therapy ,business ,Genetic Engineering ,human activities - Abstract
Chimeric receptor antigen (CAR) T cells are an innovative cellular immunotherapeutic approach that involves genetic modification of T cells to express CAR targeting tumor antigen. Prior to the development of CAR-T, the only potential cure for patients with relapsed or refractory (RR) acute lymphoblastic leukemia (ALL) was allogeneic hematopoietic stem cell transplantation (HSCT). Several CAR-T cell products have been studied in prospective clinical trials which ultimately have resulted in the approval of one anti-CD19 CAR-T cell product in pediatric RR ALL: tisagenlecleucel (CD3ζ and 41BB). While some patients achieve durable responses with CAR-T, lack of response and relapse remains clinical challenges. Reasons for sub-optimal response include lack of CAR-T cell persistence and target antigen down-regulation. Future CARs are under development to improve long-term persistence and to be able to overcome resistance mechanisms associated with the disease and the hostile tumor microenvironment. With evolving understanding about CARs and new constructs under investigation, there is optimism that future products will improve the safety and efficacy from the current standard of care.
- Published
- 2020
86. Interrogation of molecular profiles can help in differentiating between MDS and AML with MDS-related changes
- Author
-
Rami Komrojki, Talha Badar, Mohammad Hussaini, David A. Sallman, Aniko Szabo, Jefferey Lancet, Jinming Song, and Eric Padron
- Subjects
Cancer Research ,business.industry ,Hematology ,03 medical and health sciences ,Leukemia, Myeloid, Acute ,0302 clinical medicine ,Oncology ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Myelodysplastic Syndromes ,Genomic Profile ,Mutation ,Cancer research ,Medicine ,Humans ,business ,neoplasms ,Nucleophosmin ,030215 immunology - Abstract
A subset of AML with myelodysplastic syndrome (MDS)-related changes (MRCs) occurs without a documented MDS phase. We studied genomic profile of 646 patients: 310 with MDS, 167 with AML without (w/o) MRC, 99 with primary (p) AML-MRC, and 70 with secondary (s) AML-MRC and sought to find differences in mutational patterns. Among the 32-myeloid associated genes studied
- Published
- 2020
87. Real-World Outcomes of Adult B-Cell Acute Lymphocytic Leukemia Patients Treated With Inotuzumab Ozogamicin
- Author
-
Elizabeth Schultz, Martha Wadleigh, Michaela Liedtke, Ibrahim Aldoss, Nikolai A. Podoltsev, Madelyn Burkart, Suresh Kumar Balasubramanian, Mehrdad Hefazi, Amy Wang, Caitlin Siebenaller, Ehab Atallah, Shira Dinner, Shukaib Arslan, Mark R. Litzow, Eric Kuo, Talha Badar, Anjali S. Advani, Emily Curran, Jay Yang, Rory M. Shallis, Aniko Szabo, and Ryan J. Mattison
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Acute lymphocytic leukemia ,Internal medicine ,Medicine ,Humans ,Inotuzumab Ozogamicin ,Survival analysis ,Aged ,Retrospective Studies ,Inotuzumab ozogamicin ,Aged, 80 and over ,Cumulative dose ,business.industry ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Chemotherapy regimen ,Confidence interval ,Transplantation ,Log-rank test ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Background Inotuzumab ozogamicin (InO) is an anti-CD22 monoclonal antibody–drug (calicheamicin) conjugate that has shown superior efficacy compared to conventional chemotherapy in relapsed/refractory (RR) B-cell acute lymphocytic leukemia (ALL) patients. We sought to find the safety and efficacy of InO in a real-world setting. Patients and Methods A multicenter cohort analysis on 84 RR ALL patients who received InO outside of clinical trials was conducted to evaluate response and toxicity. Results The median (range) age of patients at InO initiation was 50 (20-87) years. Forty patients (48%) had ≥ 3 therapies and 23 patients (27%) underwent allogeneic hematopoietic stem-cell transplantation (allo-HCT) before InO. The median (range) number of cycles of InO provided was 2 (1-6), and cumulative dose was 3.3 (1.8-9.3) mg/m2. Overall response rate (complete remission/complete remission with incomplete count recovery) was 63%; 44% had complete remission with minimal residual disease negativity. Twenty-three patients (27%) with response received allo-HCT. The median duration of response was 11.5 months and when censored at allo-HCT was not reached (51% in remission at 2 years). The median overall survival after InO was 11.6 months and when censored at time of allo-HCT was 13.6 months. The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), veno-occlusive disease (2%), and hyperglycemia (2%). In multivariate analysis, allo-HCT after InO did not retain favorable significance for duration of response (hazard ratio = 1.27; 95% confidence interval, 0.89-1.61; P = .2) or overall survival (hazard ratio = 1.10; 95% confidence interval, 0.37-3.25; P = .85). Conclusion InO was well tolerated and had significant efficacy in RR B-cell ALL patients.
- Published
- 2020
88. Referee report. For: Case Report: Simultaneously diagnosed gastric adenocarcinoma and pernicious anemia – a classic association [version 1; peer review: 1 approved, 1 approved with reservations]
- Author
-
Talha Badar
- Published
- 2020
- Full Text
- View/download PDF
89. OUTCOMES FOR PATIENTS WITH MANTLE CELL LYMPHOMA EXPERIENCING FRONTLINE TREATMENT FAILURE: A MULTICENTER RETROSPECTIVE STUDY
- Author
-
Michael C. Churnetski, Talha Badar, Nilanjan Ghosh, Jonathan Cohen, David A. Bond, Madelyn Burkart, Brian T. Hill, Jeffrey M. Switchenko, Timothy S. Fenske, Reem Karmali, Stephanie P. Mathews, Steven I. Park, Kristie A. Blum, Narendranath Epperla, Alexey V. Danilov, Edward Maldonado, Veronika Bachanova, Subir Goyal, Peter Martin, James N. Gerson, Y. Salwaha, Mary Malecek, Christopher R. Flowers, Jin Guo, Bhaskar Kolla, Krithika Shanmugasundaram, Mehdi Hamadani, Natalie S Grover, Brad S. Kahl, Stefan K. Barta, Kami J. Maddocks, Max J. Gordon, and Oscar Calzada
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Retrospective cohort study ,Hematology ,General Medicine ,medicine.disease ,Treatment failure ,Internal medicine ,medicine ,Mantle cell lymphoma ,business - Published
- 2019
90. MAINTENANCE RITUXIMAB IS ASSOCIATED WITH IMPROVED OVERALL SURVIVAL IN MANTLE CELL LYMPHOMA PATIENTS RESPONDING TO INDUCTION THERAPY WITH BENDAMUSTINE + RITUXIMAB (BR)
- Author
-
Jonathon B. Cohen, Jeffrey M. Switchenko, Jin Guo, Reem Karmali, Yazeed Sawalha, Brad S. Kahl, Stefan K. Barta, Bhaskar Kolla, Nilanjan Ghosh, Alexey V. Danilov, Stephanie P. Mathews, Mehdi Hamadani, Natalie S Grover, Michael C. Churnetski, Kami J. Maddocks, Talha Badar, Oscar Calzada, Max J. Gordon, Steven I. Park, Brian T. Hill, Kristie A. Blum, James N. Gerson, Narendranath Epperla, Christopher R. Flowers, David A. Bond, Mary Malecek, Subir Goyal, Veronika Bachanova, Madelyn Burkart, Edward Maldonado, Peter Martin, Timothy S. Fenske, and Krithika Shanmugasundaram
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Hematology ,General Medicine ,Bendamustine/rituximab ,medicine.disease ,Induction therapy ,Internal medicine ,medicine ,Overall survival ,Mantle cell lymphoma ,Rituximab ,business ,medicine.drug - Published
- 2019
91. A Phase 1 Study of XmAb18968, a CD3-CD38 Bispecific Antibody for the Treatment of Patients with Relapsed/Refractory Acute Leukemia and T Cell Lymphoblastic Lymphoma
- Author
-
Karen Carlson, Kazuhiro Aoki, Jessica Leonard, Arielle Baim, Keith W. Pratz, Weiguo Cui, Bryon D. Johnson, Adam S. DuVall, Talha Badar, Tyce J. Kearl, Guru Subramanian Guru Murthy, Bijal D. Shah, Sameem Abedin, Aniko Szabo, Laura C. Michaelis, Shahriar S. Yaghoubi, Karin M. Hoffmeister, Alexandra M. Harrington, Lyndsey Runaas, Selina M. Luger, Wendy Stock, and Ehab Atallah
- Subjects
Bispecific antibody ,Acute leukemia ,biology ,business.industry ,T cell ,CD3 ,Immunology ,Lymphoblastic lymphoma ,Cell Biology ,Hematology ,CD38 ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Relapsed refractory ,Cancer research ,medicine ,biology.protein ,business - Abstract
Background: Outcomes of adults with relapsed/refractory T-cell acute lymphoblastic leukemia or lymphoma (T-ALL or T-LBL respectively) and acute myeloid leukemia (AML) have remained poor despite the availability of newer agents. CD38 is a 45 kDa transmembrane glycoprotein expressed by lymphoid and myeloid cells with several important functions including a role in immune escape from tumor cells [Chillemi A et al. Front Immunol 2017, Furano A et al. J Immunol 1990]. Several studies have demonstrated that CD38 is expressed in tumor cells of patients with T-ALL and AML and potentially targetable using CD38 blocking agents [Naik J et al. Haematologica 2019, Bride KL et al. Blood 2018, Tembhare et al. J Immunother Cancer 2020, Farber M et al. ASH 2018]. XmAb18968 is structurally distinct CD3-CD38 bi-specific T-cell engager with a full fragment crystallizable (Fc) domain modified to minimize Fcγ receptor binding and non-selective activation of T cells and other immune effector cells. XmAb18968 has optimized relative affinities for both CD3 and CD38 which results in reduced cytokine release without compromising target cell killing. We hypothesize targeting CD38 in relapsed/refractory- T-cell ALL/LBL and AML is safe and feasible using XmAb18968, a novel CD3-CD38 bispecific antibody. Study design and methods: This is an investigator-sponsored multi-institutional phase I study evaluating the safety and tolerability of XmAb18968. Patients aged 18 years or above with T-ALL, T-LBL or AML (including undifferentiated leukemia and bi phenotypic leukemia), in relapsed/refractory status (at least one line of prior therapy) including measurable residual disease relapse, CD38 expression ≥ 20%, and adequate organ function will be eligible. Major exclusion criteria are hematopoietic cell transplantation (HCT) within 6 months of enrollment, active acute GVHD, veno-occlusive disease, and acute promyelocytic leukemia. The study is planned to be conducted at 6 sites in United States. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of XmAb18968. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of responses with genomic profile, assessment of serum cytokine response, identifying the changes in phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in the transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy and direct glycopeptide analysis. The study will follow 3+3 design for dose escalation and de-escalation in case of dose limiting toxicity (DLT). Dose escalation will proceed in two separate groups: Group A for subjects with T-ALL and T-LBL and Group B for subjects with AML. Patients will be entered sequentially to each dose level, starting with the first dose level. The DLT observation period for dose-escalation will be 28-days. RP2D will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experience a DLT. A minimum of 24 and a maximum of 60 patients will be needed for the dose escalation phase. Disclosures Guru Murthy: Curio Sciences: Honoraria; Techspert: Consultancy; Qessential: Honoraria; CancerExpertNow: Honoraria; DAVA Oncology: Honoraria; TG Therapeutics: Other: Advisory board meeting; Cardinal health: Honoraria; Guidepoint: Consultancy. Johnson: Miltenyi Biotec: Research Funding. Abedin: AltruBio: Research Funding; Amgen: Honoraria; Agios: Honoraria; Helsinn: Research Funding; Pfizer: Research Funding; Astellas Pharma Inc.: Research Funding; Actinium: Research Funding. 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. Shah: Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Servier Genetics: Other; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding. Leonard: Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Pratz: Agios: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Millenium: Research Funding; University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Pfizer: Consultancy, Research Funding.
- Published
- 2021
92. Epidemiologic and Clinical Analysis of Tumor Mutational Burden (TMB) in Acute Myeloid Leukemia (AML): Exome Sequencing Study of the Mayo Clinic AML Epidemiology Cohort (MCAEC)
- Author
-
Michael G. Heckman, Yesesri Cherukuri, Yan W. Asmann, Zaid Abdel Rahman, Laura Finn, Yanyan Lou, Liuyan Jiang, Hemant S. Murthy, James M. Foran, Lisa Z. Sproat, Talha Badar, Mikolaj Wieczorek, and James R. Cerhan
- Subjects
Oncology ,medicine.medical_specialty ,Clinical pathology ,business.industry ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Internal medicine ,Cohort ,Epidemiology ,medicine ,business ,Exome sequencing - Abstract
TMB is used to guide PD-1-directed immunotherapy in solid tumor Oncology. However, it has not been systematically studied in AML, where the focus has been on cytogenetic risk and individual driver gene mutations (GM's). TMB contribution to AML epidemiology is also uncertain. We therefore studied its association with epidemiologic risk factors; driver GM's and somatic mutations (SM's) in AML risk genes which we recently demonstrated (ABCB1; CYP1A1; CYP2B6; EPHX1; ERCC1,2,& 5; MEFV; MTRR; and TERT); clinical and cytogenetic features; and outcome after therapy in the MCAEC, a highly annotated clinical epidemiology cohort of consecutive AML pts [Finn, Cancer Epidemiol 39:1084, 2015]. Methods: We obtained somatic leukemia DNA from remnant diagnostic cytogenetic pellets in 98 MCAEC patients (pts), as previously described [Foran, Blood (2017) 130:570a]. Whole exome sequencing (WES) was performed at depth of ~100 million paired end 100bp reads using Agilent SureSelectXT Human All Exon V5 + UTRs target enrichment kit. Reads were mapped to human genome build hg19 using BWA-MEM. Single nucleotide variants (SNVs) and small INDELs were identified using Mayo Clinic (MC) analytic pipeline GenomeGPS 4.0.1 following Broad GATK variant discovery best practices of alignment, realignment and recalibration, and multi-sample joint genotyping; and filtered using both germline whole exome and genome sequencing of ~1200 MC Biobank samples and public germline variant databases of 1000 genome project, 6500 individuals in exome sequencing project, and HapMap phase 3. Remaining variants were annotated using ANNOVAR, and functional variants of non-synonymous, truncating, frame-shift, and splice-sites were used in the statistical association analyses. TMB was defined as the number of functional mutations per Mb of coding region, heterozygous or homozygous. TMB associations with epidemiologic risk, clinical characteristics, and SM's in AML risk genes (listed above) or driver GM's (occurring in 5 or more pts: ASXL1, BCOR, CEBPA, DNMT3A, FLT3, IDH2, KRAS, MLL2-5, NF1, NPM1, NRAS, PHF6, RUNX1, SF3B1, STAG2, TET2, TP53, U2AF1) were evaluated using linear regression models; a rank transformation of TMB was utilized due to its skewed distribution. Multivariable analysis (MVA) models were adjusted for variables with p-value Results Median age at AML diagnosis was 70 yrs (Range: 19-94 yrs), and 67 pts were male. Cytogenetic risk group was favorable (7%), intermediate-normal (46%) or abnormal (20%), and poor risk (27%). 40/61 pts (66%) achieved complete remission (CR). With a median follow-up of 8.0 months (Range: 0.1 - 186), 80 pts (82%) died and 20 (20%) underwent allogeneic transplantation (AlloBMT). Median TMB was 18.2 (Range: 15.0-70.1). In MVA, significant associations with increased TMB were observed in pts with history of prior immunosuppressive therapy or solid organ transplantation (β=19.48, P=0.015), and with FLT3 (β=21.12, P=0.015), MLL2 (β=20.91, P=0.001), and MLL3 (β=11.31, P=0.031) GM's. A borderline association was observed for U2AF1 (β=16.14, P=0.057). TMB was also associated with SM's in TERT (β=25.13, P=0.028); a borderline association with SM's in ABCB1 was not confirmed in MVA (β=-17.98, P=0.069). Additionally, cytogenetic risk group was associated with TMB in MVA (P=0.005), being highest in intermediate-normal and lowest in poor risk groups. Body Mass Index was inversely associated with TMB (unadjusted β=-16.99, P=0.005), but unconfirmed in MVA (β=-8.29, P=0.12). There was no association with CR (OR=0.93, P=0.46), use of (HR=0.96, P=0.64) or relapse risk (HR=1.00, P=0.98) following AlloBMT, or survival (HR=0.97, P=0.56) (Figure). Conclusions Measurement of TMB is feasible in this AML epidemiologic cohort, and we observed important associations with AML risk factors, risk gene SM's, cytogenetic risk group, and driver GM's. We acknowledge the relatively small sample size and possibility of type II error, and therefore these observations require validation in a large prospective cohort which is planned. Figure 1 Figure 1. Disclosures Foran: OncLive: Honoraria; certara: Honoraria; actinium: Research Funding; boehringer ingelheim: Research Funding; novartis: Honoraria; abbvie: Research Funding; servier: Honoraria; taiho: Honoraria; pfizer: Honoraria; revolution medicine: Honoraria; gamida: Honoraria; takeda: Research Funding; sanofi aventis: Honoraria; trillium: Research Funding; syros: Honoraria; aptose: Research Funding; bms: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Finn: Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Speakers Bureau. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Cerhan: Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; Genentech: Research Funding; NanoString: Research Funding; Regeneron Genetics Center: Other: Research Collaboration.
- Published
- 2021
93. Characteristics and Clinical Outcome of Patients with Clonal Cytopenias of Undetermined Significance: A Large Retrospective Multi-Center International Study
- Author
-
Catherine C. Coombs, Talha Badar, Charlton Tsai, Amer M. Zeidan, Catherine Lai, Afaf Osman, Pinkal Desai, Jan Philipp Bewersdorf, Yazan F. Madanat, Cecilia Arana Yi, Hetty E. Carraway, Meredith C. Hyun, Mrinal M. Patnaik, Thomas Prebet, Najla Al Ali, Namrata S. Chandhok, Justin Taylor, Abhay Singh, Lionel Ades, Aref Al-Kali, Elizabeth A. Griffiths, Joshua F. Zeidner, Andrew M. Brunner, H. Joachim Deeg, Deborah Soong, Ashwin Kishtagari, James M. Foran, Michael R. Savona, Rami S. Komrokji, and Zhuoer Xie
- Subjects
Pediatrics ,medicine.medical_specialty ,business.industry ,Immunology ,medicine ,Center (algebra and category theory) ,Cell Biology ,Hematology ,business ,Biochemistry ,Outcome (game theory) - Abstract
Background: Clonal cytopenia of undetermined significance (CCUS) is defined as persistent unexplained cytopenia with evidence of clonality [myeloid-associated somatic mutations (MTs) or cytogenetic [CG] abnormalities] but without definitive evidence of myeloid neoplasms (MN). The outcomes in CCUS patients (pts) are not well understood. Methods: The CCUS International Study database includes pts from 17 institutions who meet the criteria of CCUS and do not have other causes of cytopenia. Pts with MDS defining CG abnormalities were excluded. We collected baseline clinical data, laboratory parameters, CGs, molecular genetics, treatment, and disease course. Diverse gene panels from different institutions were collated to include a total of 70 myeloid-related somatic genes (30 genes in common). 2018 IWG MDS response criteria were used to determine response rate (RR). Disease progression (DP) is defined by progression to MN. The relationship between independent variables and DP and death was assessed using Cox proportional hazards models. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method. All statistical analysis was performed using SAS. Results: A total of 258 pts were captured by July 2021. The median age was 71 (IQR 63-77) years, and 66% were male. Among 73 (28%) pts with known malignancy history, 27 (37%) pts received previous chemo- or radiation therapy. 27 (10%) pts had non-malignant hematology comorbidities. 91 (35%) had cardiovascular disease, and 33 (13%) had inflammatory disease. (Table 1) The red blood cell and platelet transfusion-dependent rates were 7.3% and 2.3%, respectively. The median number of MTs was 2 (IQR 1-3), with 221 (86%) pts had ≥1 MT, of which 116 (53%) had ≥ 2 MTs. The most common 5 MTs were TET2 (n=78, 30%), SRSF2 (n=50, 19%), DNMT3A (n=47, 18%), ASXL1 (n=40, 16%), and U2AF1 (n=22, 9%) (Figure 1). The median VAF (mVAF) was 28% (IQR: 9.2%, 43%) with VAF < 10% in 47 (18%) and VAF ≥40% in 78 (30.2%) of the MTs. mVAF of the all genes are shown in Figure 2. Among pts with CG abnormalities (n=62, 24%), trisomy 8 and -Y are the most common karyotypes (n=15 for each, 24%) (Table 2). Eighty one (31%) patients received various treatments for CCUS with modest RR, including growth factors (n=47, 18.2%, RR: 25.5%), supportive care (n=23, 9%, RR: 26%), immunoglobulin/immunosuppressive therapy (n=15, 6%, RR: 40%), and DNMTi (n=8, 3%, RR=13%). The median length of follow-up was 15.6 (IQR 6.9-30.6) months. 24 pts progressed to MN, 14 (58.3%) of which were MDS, 8 (33.3%) CMML, and 2 (8.3%) AML. The 2-year PFS was 86.1% (95% CI: 80-93%) with a median PFS of 16.3 (IQR: 3.7, 21) months. In the multivariable model, positive MT of KRAS (HR: 8.4, 95% CI: 1.9-36.9, p=0.005) and CBL (HR: 16.5, 95% CI: 3.7-73.8, p=0.003) were significantly associated with DP. In the functional pathway analysis, having at least 1 splicing factor MT was significantly associated with DP (HR: 2.6, 95% CI:1.2-5.9, p=0.02). TP53 was not significantly associated with DP (HR: 1.2, 95% CI: 0.2-8.7, p=0.88). Having >1 MT (HR: 3.57, 95% CI: 1.19-10.7, p=0.02) compared to a single MT was significantly associated with DP (Figure 3). Over the follow-up period, 35 pts died. The 2-year OS was 81% (95% CI: 74.9-87.9%). In the multivariable model, MT of KRAS (HR: 6.1, 95% CI: 1.8-20, p=0.003), CBL (HR: 7.3, 95% CI: 1.7-31, p=0.007), and FLT3 (HR: 19.9, 95% CI: 2.5-155, p=0.004) were significantly associated with inferior survival. In the functional pathway analysis, MTs in activated signaling pathway were significantly associated with death (HR: 4.1, 95% CI: 1.8-9, p1 MT was not statistically significantly associated with higher risk of death (HR: 1.5, 95% CI: 0.7-3.0, p=0.28) (Figure 4). After adjustment for co-MT status and comorbidities, baseline Hb Conclusion: This large retrospective study summarizes the CCUS pts' characteristics, with different MT patterns and VAF. We confirmed the impact of having >1 MT on DP, but not OS. Genes involved in activated signaling had a significant impact on both DP and OS. TP53 MT was not associated with worse outcome. Findings may be due to limited cases in the particular genes and different gene panels from multiple institutions. A longer follow-up is planned to further describe the predictors for outcome in this ongoing study. Figure 1 Figure 1. Disclosures Komrokji: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy. Zeidan: BioCryst: Other: Clinical Trial Committees; Kura: Consultancy, Other: Clinical Trial Committees; Ionis: Consultancy; Geron: Other: Clinical Trial Committees; Incyte: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Janssen: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Aprea: Consultancy, Research Funding; AstraZeneca: Consultancy; Agios: Consultancy; BeyondSpring: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Jazz: Consultancy; Astex: Research Funding; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Pfizer: Other: Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Jasper: Consultancy; Astellas: Consultancy; ADC Therapeutics: Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Madanat: Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Onc Live: Honoraria; Geron Pharmaceutical: Consultancy. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda Oncology: Consultancy, Honoraria; Taiho Oncology: Consultancy, Honoraria; Apellis Pharmaceuticals: Research Funding; Novartis: Honoraria; Alexion Pharmaceuticals: Consultancy, Research Funding; Boston Biomedical: Consultancy; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Abbvie: Consultancy, Honoraria. Lai: Astellas: Speakers Bureau; Jazz Pharma: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Speakers Bureau; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foran: trillium: Research Funding; actinium: Research Funding; kura: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; abbvie: Research Funding; aptose: Research Funding; pfizer: Honoraria; novartis: Honoraria; servier: Honoraria; bms: Honoraria; revolution medicine: Honoraria; OncLive: Honoraria; gamida: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Desai: Astex: Research Funding; Janssen R&D: Research Funding; Kura Oncology: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy. Ades: ABBVIE: Honoraria; CELGENE/BMS: Honoraria; NOVARTIS: Honoraria; TAKEDA: Honoraria; JAZZ: Honoraria, Research Funding; CELGENE: Research Funding. Brunner: Novartis, Celgene, Takeda, AstraZeneca: Research Funding; Celgene, Forty Seven Inc, Jazz: Other: Advisory Board. Carraway: Celgene, a Bristol Myers Squibb company: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Other: Independent review committee; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Other: Independent review committee; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astex: Other: Independent review committee; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Prebet: BMS: Research Funding; BMS, Curios, Daichi: Consultancy. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution.
- Published
- 2021
94. Clinical Characteristics and Prognosis of Thirty-Three Patients with Myeloid Neoplasms and DDX41 Mutation: Mayo Clinic Experience
- Author
-
James M. Foran, Lisa Z. Sproat, Mrinal M. Patnaik, Rong He, Phuong L. Nguyen, Mohamed E. Salama, Mark R. Litzow, Ayalew Tefferi, Naseema Gangat, Patricia T. Greipp, Hassan B. Alkhateeb, Mithun Vinod Shah, Ahmad Nanaa, Talha Badar, Dragan Jevremovic, David S. Viswanatha, Aref Al-Kali, and Abhishek A. Mangaonkar
- Subjects
Oncology ,medicine.medical_specialty ,Myeloid ,medicine.anatomical_structure ,business.industry ,Internal medicine ,Immunology ,Mutation (genetic algorithm) ,medicine ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background: The DEAD-box helicase 41 (DDX41), an RNA helicase, have been described as a component of the RNA spliceosome (Cheah et al. International Journal of Hematology 2017). Although DDX41 mutations predispose to late-onset higher grade myeloid neoplasms (MN), these patients may have a trend toward favorable prognosis and outcomes. In this work, we describe the clinical characteristics and survival outcomes of isolated and co-mutated DDX41 patients (pts). Methods: We retrospectively analyzed 4,524 consecutive pts who underwent next-generation sequencing (NGS) (OncoHeme 42 genes panel, Mayo Clinic) testing and included 32 pts harboring pathogenic DDX41 mutation and one pt with proven DDX41 germline variant of unknown significance (VUS). Chart review of DDX41-mutated (m) cases between 2009 and 2021 was conducted after IRB approval. We compared overall survival (OS) of unmatched 27 t(8;21)AML and 40 inv(16) AML pts with 10 m DDX41-AML pts. JMP® Pro 14.1.0 Software was used for statistical analysis. Results: DDX41 mutations characteristics: Our cohort included 19 (58%) myelodysplastic syndromes (MDS), 10 (30%) acute myelogenous leukemia (AML), 2 (6%) myeloproliferative neoplasms (MPN), one clonal cytopenia of undetermined significance (CCUS) (3%) and one (3%) germline carrier. Germline testing was carried out in 10 pts, 9 of whom (90%) were confirmed to be germline). The start-loss variant (p.M1I) was the most common mutation type (N=10, 31%). Other types were frameshift (N=9, 28%), missense mutation (N=8, 25%), nonsense (N=3, 9%), and splice site mutation (N=2, 2%). Twenty-one (65.6%) DDX41 mutations clustered in the N-terminus (NT), 7 (22%) in the helicase-C domain (HCD), and 4 (12.5%) in the DEAD-box domain. Compared to NT mutations, patients with HCD mutation had no family history of solid tumors and were more likely to have an accompanying additional DDX41-VUS (0% vs 70%; p=.001) and (N=6, 86% vs. N=2,10%; p=.0001); respectively. I solated vs. co-mutated DDX41: Twenty (60%) pts were isolated-DDX41 and 13 (40%) were co-mutated. The median DDX41-VAF was 48% vs. 45% (p= .2) in the isolated compared to the co-mutated cases, respectively. The median number of co-mutations in the 13 co-mutated cases was 1 (range,1-3) with DNMT3A (38%), ASXL1 (30%), JAK2 (N=3, 23%), and EZH2 (N=2, 15%) were the most common co-mutations detected. Isolated DDX41 had more males (85% vs. 54%, p=.05), the p.M1I variant (47% vs. 8%, p=.02), normal cytogenetics (100% vs. 91%, p= .02), and less family history of solid tumors (77% vs. 33%, p= .02) compared to their co-mutated counterparts. However, there was no difference in OS (p=.99). Comparison of clinical characteristics and hematological features of isolated and co-mutated DDX41 pts are reported in (Table 1). Treatment and survival outcomes in DDX41-MDS/AML : Twenty-three (80%) patients were treated, MDS pts received hypomethylating agents (HMA) (N=10, 71%), HMA plus Venetoclax (HMA+VEN) (N=1, 7%), erythropoiesis-stimulating agents (N=2, 14%) and lenalidomide (N=1 ,7%). AML pts were treated with induction chemotherapy (N=6, 67%) and HMA+VEN (N=3, 33%). Overall response rate of MDS/AML patients was 77% and 100% of AML pts achieved complete remission (CR) when treated with induction chemotherapy or HMA+VEN regimen. There was no significant difference in OS between responders vs. non-responders 2-yr-OS (90% vs. 50%; p=.38) and treated vs. untreated 2-yr-OS (83% vs. 100%; p=.52). Comparing m DDX41-AML vs. core binding factor-AML: After a median follow-up of 33.3 months, all m DDX41-AML patients were alive. There was a significantly better OS in mDDX41-AML patients compared to pts with t(8;21) AML with 2-yr-OS (100% vs. 51%; p=.024) and a trend of better survival when compared to inv(16) AML 2-yr-OS (100% vs. 84%; p=.2). Conclusion We describe the characteristics and outcomes of m DDX41 patients. We demonstrated that isolated and co-mutated m DDX41 patients have different features. Isolated DDX41 patients had male predominance, more p.M1I variant, normal cytogenetics and less family history of solid tumors. In this study we found that m DDX41 AML has high response to treatment and has comparable (if not possibly better) OS compared to other "favorable risk" AML. This study, although limited by the small number of patients, supports the universal testing for DDX41 mutation in adults with MN diagnosis. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Foran: abbvie: Research Funding; OncLive: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; pfizer: Honoraria; takeda: Research Funding; revolution medicine: Honoraria; bms: Honoraria; gamida: Honoraria; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; servier: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Biosight: Other: Data monitoring committee; Amgen: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board. Patnaik: Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2021
95. DDX41 Variant of Unknown Significance (VUS) Have Distinct Clinical and Diagnostic Features but Are Associated with Similar Prognosis and Co-Mutation Patterns As Pathogenic DDX41: Analysis of the Mayo Clinic (MC) Myeloid Next-Generation Sequencing (NGS) Cohort
- Author
-
James M. Foran, Lisa Z. Sproat, Aref Al-Kali, Ahmad Nanaa, David S. Viswanatha, Hassan B. Alkhateeb, Emily L. Godsey, Mrinal M. Patnaik, Rong He, Talha Badar, Mohamed A. Kharfan-Dabaja, and Mark R. Litzow
- Subjects
Genetics ,Unknown Significance ,Myeloid ,medicine.anatomical_structure ,Immunology ,Cohort ,Mutation (genetic algorithm) ,medicine ,Cell Biology ,Hematology ,Biology ,Biochemistry ,DNA sequencing - Abstract
Background: DDX41 gene is located on chromosome 5q35 and is believed to be a tumor suppressor gene involved in splicing of mRNA. Mutated DDX41 have been identified as germline mutation (m) in families with cases of myeloid neoplasm and have shown to cause acquisition of other somatic mutations resulting in MDS/AML. At the same time, somatic pathogenic DDX41 mutations are known to occur. Variant of unknown significance (VUS) is an intermediate tier between benign and pathogenic (path) mutations (hence uncertain) and can be re-classified based on their clinical impact. In this report we analyzed the clinical impact and relevance of DDX41VUS in patients (pts) being evaluated for myeloid disorders. Methods: We reviewed 4,524 consecutive pts who underwent NGS (MC OncoHeme 42 genes panel) testing between 2018 and 2021 performed on cases of suspected or known myeloid disorders. We identified 58 (1%) consecutive pts with DDX41VUS, among them one pt had proven concurrent DDX41 germline VUS and 7 pts with DDX41VUS had concurrent DDX41path mutation. We analyze clinical characteristics of pts with DDX41VUS and compared it with cohort of 32 DDX41path mutated pts. Results: Baseline characteristics are summarized in Table 1, and Figure 1 illustrates DDX41VUS per case with variant allele frequency (VAF) and observed concurrent mutations. The median VAF for DDX41 VUS was 48 % (range, 14-91%). Co-mutations were found in 14 (28%) pts with VUS, and the reminder (n=44, 72 %) had isolated DDX41VUS. Among them AML (16 [32%]), MDS (14 [28%]), cytopenia (14 [28%]) MPN (3 [6%]), CNL (1 [2%]) and aplastic anemia (1 [2%]) were the commonly occurring myeloid disorder (Table 1, Figure 1). Eleven of 14 pts with isolated cytopenia had isolated DDX41VUS. Conversely, among 15 evaluable pts with isolated DDX41VUS, 13 (87%) pts had normal cytogenetics and 40% of pts had family history of solid or hematological malignancies. We observed a significant difference in hematologic diagnoses: DDX41VUS patients were significantly less often diagnosed with MDS or CCUS, and more often associated with cytopenias NOS. Recurrent, non-random DDX41VUS sequences were observed; most frequent occurring amino acid change among the 58 pts were Gly173Arg (n=6), Met155lle (n=5), Pro258Leu (n=3) Arg479Gln (n=3), Val303Met (n=2), Lys331del (n=2), Arg479His (n=2) and Tyr33His (n=2) (Figure 1). 5 of 6 pts with Gly173Arg had isolated DDX41VUS, and among them 4 were diagnosed with MDS suggesting this could be a clonal event, and possible driver mutation, notable in Figure 1. The median overall survival (OS) of pts with high risk MDS/AML harboring DDX41VUS was not reached (60% alive at 2 years). Between pts with DDX41path and DDX41VUS, proportion of pts with co-mutations (p >0.99), cytogenetic abnormalities (p >0.99), family history of malignancies (p 0.52), time to treatment (p >0.99), MDS progression to AML (p 0.36) and OS (among high risk MDS/AML pts) (p 0.55) was not significantly different, suggesting that phenotypic features of DDX41VUS are similar to DDX41path , and that both carry a similar, more indolent prognosis (Table 1). Conclusion: Our reports demonstrated that DDX41VUS occurs in 1% of patients with myeloid disorders and shares distinct diagnostic features but comparable prognostic features vs. DDX41path, including family history of hematological malignancies. It is possible that many of the cases with 'cytopenias' and DDX41VUS would meet criteria for CCUS if the variant was isolated classified as pathogenic, confirming the importance of extending our understanding of DDX41 variants. Further analysis to characterize the biological impact of DDX41VUS is underway. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. Foran: boehringer ingelheim: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; novartis: Honoraria; pfizer: Honoraria; aptose: Research Funding; taiho: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; actinium: Research Funding; gamida: Honoraria; OncLive: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.
- Published
- 2021
96. Trial in Progress: A Phase 2 Single Arm, Multicenter Trial to Evaluate the Efficacy of the BiTE ® Antibody Blinatumomab (Blincyto) and Vincristine Sulfate Liposomal Injection (Marqibo) in Adult Subjects with Relapsed/Refractory Philadelphia Negative CD19+ Acute Lymphoblastic Leukemia
- Author
-
Bijal D. Shah, David A. Rizzieri, Zhiguo Li, Talha Badar, Franklin Chen, and Jessica Leonard
- Subjects
Philadelphia negative ,Oncology ,medicine.medical_specialty ,Vincristine Sulfate ,biology ,business.industry ,Lymphoblastic Leukemia ,education ,Immunology ,Cell Biology ,Hematology ,Biochemistry ,CD19 ,Internal medicine ,Multicenter trial ,Relapsed refractory ,biology.protein ,Medicine ,Blinatumomab ,Antibody ,business ,health care economics and organizations ,medicine.drug - Abstract
Background: Relapsed Acute Lymphoblastic Leukemia (ALL) is not curable with standard therapies. Effective outpatient treatment, allowing patients to maintain a good quality of life, while offering a meaningful chance of remission, is an appealing alternative to prolonged admission required for currently available multi-agent regimens. Vincristine sulfate liposomal injection (Marqibo) was approved in 2012 for treatment Ph-ALL in second or greater relapse, originally developed to overcome pharmacokinetic and pharmacodynamic limitations of vincristine. Approved dosing is 2.25 mg/m 2 without a dose cap. Pre-clinical studies showed it increases plasma circulation time, increases tumor tissue delivery, accumulates in tumor tissue, and slowly releases vincristine in tumor tissues rather than into systemic circulation. In a phase 2 trial, as a weekly administered single agent, CR/CRi rate was 20%, with median duration of 23 weeks and overall response rate of 35%. Blinatumomab is a murine recombinant single-chain antibody construct belonging to a class of bispecific T-cell engager (BITE) immuno-oncology. BITE molecules are designed to direct T-effector memory cells towards target cells, triggering cell-specific cytotoxicity. Blinatumomab specifically targets cells that express CD19 and the presence of both, CD19+ target cells and T cells are required for its cytotoxic activity. In previous phase 2 trials, responses to single agent blinatumomab in the relapsed setting were near 60%, although only 34% (44%, including partial and incomplete hematologic recovery) in the pivotal phase 3. Median duration of remission was only 7.3 months and half were very heavily pretreated. Here, we describe a trial designed to target ALL cells with Marquibo as a microtubule inhibitor and blinatumomab as a BiTE immuno-oncology therapy and evaluate whether this combination results in an effective and safe therapeutic option for relapsed/refractory ALL patients. We anticipate additive benefits of the regimen and define a clinically meaningful outcome as >75% (CR/CRi) rate and median progression-free survival (PFS) of ≥1 year. This higher rate of response is expected as many patients are using blinatumomab at first relapse, and therefore we anticipate less prior therapy than overall in the pivotal phase 3 study. Further, we hypothesize that the combination will result in a high rate of response, allowing enhanced immunologic recovery. Study Design/Methods: This is a phase 2, single arm, trial to evaluate the efficacy of blinatumomab and vincristine sulfate liposomal injection. The study will include up to 35 participants who are ≥18years of age, with Ph-, CD19+ ALL, and are either relapse or refractory to ≥2 prior regimens, have ≥5% blasts in the bone marrow or peripheral blood or persistent extranodal/marrow site or have an Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The active study period includes a 3-week screening phase, followed by a treatment period (induction phase and consolidation phase) of up to 58 weeks (6 cycles), a safety follow-up 30 days later and a long-term follow-up period of up to 18 months. The induction phase includes two cycles of blinatumomab and liposomal vincristine. A single cycle is defined as 6 weeks in duration, which includes 4 weeks of continuous intravenous infusion (CIVI) of blinatumomab (initial dose 9 μg/day for first 7 days, then escalated to 28 μg/day starting on day 8 (week 2) through day 29 (week 4), followed by a 2-week treatment-free interval and 3 weekly doses of liposomal vincristine, administered intravenously at 2.25 mg/m 2, with no dose cap (per label),in the outpatient setting over 1 hour. Subjects who achieve at least stable disease within 2 induction cycles may continue to the consolidation phase to receive up to a maximum of 6 cycles under the same treatment schedule. The primary objectives are to evaluate whether the combination will result in a median PFS of ≥1 year, and if the CR/CRi rate is ≥75% following 2 cycles and duration of remission. Secondary outcomes will include evaluation of the rate of Minimal Residual Disease (MRD) and duration, the proportion of patients who are able to progress to allogeneic transplantation, the safety of blinatumomab and liposomal vincristine sulfate in combination and the effect of the combination and response on measures of immune reconstitution. Figure 1 Figure 1. Disclosures Rizzieri: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acrotech: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria; Pharmacyclics: Honoraria. Leonard: Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Shah: Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Adaptive Biotechnologies: Consultancy; Novartis: Consultancy, Other: Expenses; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Precision Biosciences: Consultancy; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy.
- Published
- 2021
97. Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival
- Author
-
Ehab Atallah, Rory M. Shallis, Antoine N. Saliba, Aaron D Goldberg, Jan Philipp Bewersdorf, Mark R. Litzow, Maximilian Stahl, Talha Badar, James M. Foran, and Guilherme sacchi De Camargo Correia
- Subjects
Oncology ,Transplantation ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Cell Biology ,Hematology ,Stem cell ,business ,Biochemistry - Abstract
Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.
- Published
- 2021
98. Improved Clinical Outcome of Patients with Myelodysplastic Syndrome (MDS) Progressing after Hypomethylating Agent: In the Era of Novel Therapies
- Author
-
Talha Badar, Mohamed A. Kharfan-Dabaja, Hemant S. Murthy, Aref Al-Kali, Mark R. Litzow, Jeanne Palmer, Mithun Vinod Shah, James M. Foran, Ahmad Ghorab, and Michelle Elliot
- Subjects
Oncology ,medicine.medical_specialty ,Hypomethylating agent ,business.industry ,Internal medicine ,Immunology ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,Outcome (game theory) - Abstract
Introduction: Historically, clinical outcome of patients with myelodysplastic syndrome (MDS), progressing on hypomethylating agents (HMA; azacitidine or decitabine) has been dismal with median overall survival (OS) of less than 6 months (Jabbour et al. Cancer 2010). With recent approval of venetoclax based combinations for acute myeloid leukemia (AML) and CPX-351 for AML with MDS related changes (primary or secondary), clinical outcome has improved in sub-set of high-risk patients compared to historical cohorts. Hence, we analyzed clinical outcome of MDS patients progressing on HMA, in the current era of novel therapies. Methods: We retrospectively analyzed clinical outcome of 43 MDS patients who progressed on HMA-based therapy and treated at the Mayo Clinic between February 2015 and February 2021. We describe clinical characteristics of these patients, therapies received after progressing on HMA-based therapy, duration of response attained after 1st line therapy post HMA-based therapy and OS from time of HMA failure till death or last follow up. We also performed Cox regression multivariate analysis for OS after progression on HMA-based therapy. Results: Baseline characteristics are summarized in Table 1.The median age of the patients were 69 years (range [R], 48-93). R-IPSS score in this cohort of patients was very low (2[5%]), low (5[12%]), intermediate (5 [12%]), high (11[26%]) and very high (20 [46.5%]). Forty-nine percent of patients had complex cytogenetics. Most commonly occurring mutations (≥ 5%) were TP53 (42%), splicing mutation (SRSF2/SF3B1/ or U2AF1) (16%), ASXL1 (12%), RUNX1 (7%), DNMT3A (5%) and IDH1/ or IDH2 (5%). The HMA-based therapy patients received were azacitidine (40%), decitabine (30%) and HMA plus venetoclax (30%). The median time to progression from time of initiation of HMA-based therapy was 5 months (R= 1-30). Sixty-three percent (n= 27) of patients progressed to AML after HMA-based therapy. The most common 1 st line therapies post HMA was venetoclax-based (12 [28%]), CPX-351 (12 [28%]), and allogeneic stem cell transplantation (SCT) (4 [9%]). Fifteen (45.5%) patients achieved CR/CRi, 17 (51.5%) patients progressed and 1 (3%) patient had stable disease. The percentage of patients received venetoclax with HMA, 1 st and 2 nd line therapy post HMA were 26%, 28% and 10%, respectively. Overall, 11 (25%) patients received SCT in this cohort of patients. The median duration of response after 1 st line therapy post HMA was not reached (NR; 66% progression free at 1 year) (Figure 1A). The median OS after HMA failure was 12.7 months (95% CI: 3.1-22.2) (Figure 1B). In the univariate analysis for OS after HMA failure, SCT at any time point (p = 0.01) and achieving CR/CRi after 1 st line therapy post HMA (p= Conclusions: To the best of our knowledge, this is the first report analyzing outcome of MDS patients progressing on HMA in the recent era. Acknowledging the limitations of retrospective analysis, our report suggests improved outcome of these high-risk patients compared to historical data. Utilizing venetoclax plus HMA combination earlier in patients with high-risk MDS as being evaluated in VERONA trial and consolidation therapy with SCT in eligible patients have potential to improve long term outcome of this group of high-risk patients. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Palmer: PharmaEssentia: Research Funding; Incyte: Research Funding; Protagonist: Consultancy, Research Funding; CTI BioPharma: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding. Murthy: CRISPR Therapeutics: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Amgen: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Foran: pfizer: Honoraria; takeda: Research Funding; trillium: Research Funding; boehringer ingelheim: Research Funding; syros: Honoraria; sanofi aventis: Honoraria; revolution medicine: Honoraria; servier: Honoraria; bms: Honoraria; certara: Honoraria; abbvie: Research Funding; OncLive: Honoraria; gamida: Honoraria; taiho: Honoraria; novartis: Honoraria; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees.
- Published
- 2021
99. A case control study of syngeneic transplantation versus autologous transplantation for multiple myeloma: two decades of experiences from a single center
- Author
-
Muhammad Salman Faisal, Ghulam Rehman Mohyuddin, Ruby Delgado, Elisabet E. Manasanch, Gabriela Rondon, Jatin J. Shah, Nina Shah, Muzaffar H. Qazilbash, Sheeba K. Thomas, Richard E. Champlin, Talha Badar, Krina K. Patel, Chitra Hosing, Robert Z. Orlowski, Donna M. Weber, Uday R. Popat, and Qaiser Bashir
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Transplantation Conditioning ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Hematopoietic stem cell transplantation ,Single Center ,Transplantation, Autologous ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Autologous transplantation ,Multiple myeloma ,business.industry ,Hematopoietic Stem Cell Transplantation ,Case-control study ,Hematology ,medicine.disease ,Transplantation ,Transplantation, Isogeneic ,Treatment Outcome ,surgical procedures, operative ,Case-Control Studies ,030220 oncology & carcinogenesis ,Immunology ,Syngeneic transplantation ,Multiple Myeloma ,business ,030215 immunology - Abstract
High dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) are the standard of care for eligible patients with newly diagnosed myeloma [1]. Unfortunately, relapse rate...
- Published
- 2017
100. Clinical Outcome with Allogeneic Hematopoietic Stem Cell Transplantation after Blinatumomab or Inotuzumab Ozogamicin in Patients with B-Cell Acute Lymphoblastic Leukemia: Real World Experience
- Author
-
Amy Wang, Caitlin Sienbenaller, Muhammad Ali Khan, Jay Yang, Madelyn Burkart, Mark R. Litzow, Ehab Atallah, Anjali S. Advani, Shira Dinner, Shukaib Arslan, Ibrahim Aldoss, Ryan J. Mattison, Emily Curran, Rory M. Shallis, Eric Kuo, Elizabeth Schultz, Nikolai A. Podoltsev, Talha Badar, Anand Patel, Ilana R. Yurkiewicz, Michaela Liedtke, Martha Wadleigh, Suresh Kumar Balasubramanian, and Mehrdad Hefazi
- Subjects
Inotuzumab ozogamicin ,Transplantation ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Hematology ,Hematopoietic stem cell transplantation ,B-cell acute lymphoblastic leukemia ,Gastroenterology ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,Refractory ,030220 oncology & carcinogenesis ,Internal medicine ,Cord blood ,Toxicity ,medicine ,Blinatumomab ,In patient ,business ,030215 immunology ,medicine.drug - Abstract
Introduction Blinatumomab (Blina) and inotuzumab ozogamicin (Ino) have shown remarkable responses in relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL), however, a significant number of patients (pts) relapse. Prior reports suggest that allogeneic hematopoietic stem cell transplantation (SCT) consolidation after Blina/Ino may be associated with increased transplant related complications. To address this issue, we assembled a large retrospective multi-center cohort of RR ALL pts who received SCT after Blina/Ino. Methods Medical records of RR ALL pts who received SCT after Blina or Ino at 11 academic transplant centers across USA were reviewed. These pts were evaluated for response and toxicity after SCT. Results From December 2014 to May 2019, 223 and 86 pts who received Blina and Ino, respectively, for RR ALL outside clinical trials were identified. Among them 85 (38%) pts in the Blina group (gp) and 21 (25%) pts in the Ino gp who achieved remission and underwent SCT were included in this analysis. Median age of pts in the Blina and Ino gp was 59 (range [R], 18-72) and 43 (R, 20-75) years, respectively. Median number (no.) of therapies (Rx) prior to SCT in Blina and Ino gp was 2, ranging from 2-5 and 2-6, respectively. Five (6%) and 2 (5%) pts in the Blina and Ino gp, respectively, received second SCT. Median time from remission to SCT in Blina gp was 1.7 months (mo) (R, 0.20 to 13.2) and in Ino gp was 4.3 mo (R, 1-13.3). In the Blina and Ino gp: 36.5% vs. 38%, 42% vs. 42%, 15% vs. 9.5% and 6% vs. 9.5% had matched related donor (MRD), matched unrelated donor (MUD), haploidentical and cord blood SCT, respectively. Acute graft versus host disease (aGVHD), chronic (c) GVHD, veno-occlusive disease (VOD) and infectious complications post SCT were observed in 28 (33%), 14 (16.5%), 2 (2%) and 12 (14%) pts, respectively, in the Blina gp. While in the Ino gp, 8 (38%), 1 (5%), 3 (14%) and 4 (19%) pts had these complications, respectively. Six (7%) and 2 (9%) pts had TRM within 100 days of SCT in Blina and Ino gp, respectively. The median PFS and OS in Blina gp was not reached (NR); 66% were progression free and 62% were alive at 2 yrs (Fig 1 A & B). Similarly, median PFS and OS in the Ino gp was NR; 53% were progression free at 6 mo and 53% were alive at 1 yr mark (Fig 1 C & D). In the Blina gp, history of CRS (p= 0.41), no. of prior Rx (p= 0.5), time from response to SCT (p=0.48), and type of donor (p= 0.7) were not significantly associated with GVHD. Similarly, in the Ino gp, no. of prior Rx (p= 0.6), time from response to SCT (p=0.84), type of donor (p= 0.9) were not significantly associated with GVHD. Occurrence of VOD in the Ino gp was not significantly associated with type of donor (p= 0.3), second SCT (p= 0.1), no. of prior Rx (p= 0.6), myeloablative conditioning (p> 0.9) or time from response to SCT (p= 0.5). Conclusion Our real-world analysis suggests that SCT is feasible and effective after Blina or Ino in pts with RR ALL.
- Published
- 2020
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.