57 results on '"J. Senapati"'
Search Results
2. P369: A PHASE II STUDY OF MINI-HYPER-CVD PLUS VENETOCLAX IN PATIENTS WITH PHILADELPHIA CHROMOSOME-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA
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J. Senapati, H. Kantarjian, N. Short, M. Konopleva, F. Ravandi, N. Jain, P. A. Thompson, N. Pemmaraju, W. G. Wierda, G. Borthakur, T. M. Kadia, G. Garcia-Manero, M. Yilmaz, J. Thankachan, M. Zhao, C. Loiselle, M. T. Talley, M. I. Kwari, R. S. Garris, and E. J. Jabbour
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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3. P367: LONG TERM OUTCOMES OF NEWLY DIAGNOSED CRLF2 REARRANGED B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA
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J. Senapati, E. J. Jabbour, N. J. Short, F. Ravandi, P. Kebriaei, T. M. Kadia, G. Borthakur, N. Pemmaraju, R. S. Garris, D. Bansal, S. Konoplev, S. Wang, W. Wang, G. Tang, K. P. Patel, M. Konopleva, and N. Jain
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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4. P497: PROGNOSTIC IMPACT OF RAS AND C-KIT MUTATIONS (SINGLE VS. MULTIPLE) IN CORE-BINDING FACTOR ACUTE MYELOID LEUKEMIA TREATED WITH FLUDARABINE, CYTARABINE, G-CSF (FLAG) BASED REGIMEN
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T. Abuasab, J. Senapati, T. Kadia, F. Ravandi, C. DiNardo, N. Pemmaraju, M. Ohanion, Y. Alvarado, H. Kantarjian, and G. Borthakur
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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5. P541: OUTCOMES AND MANAGEMENT OF PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA PRESENTING WITH HYPERLEUKOCYTOSIS
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F. Haddad, K. Sasaki, T. Abuasab, S. Venugopal, D. Rivera Delgado, A. Bazinet, R. Babakhanlou, K. Kim, J. Senapati, F. Ong, S. Desikan, N. Short, N. Pemmaraju, G. Borthakur, C. DiNardo, N. Daver, E. Jabbour, G. Garcia-Manero, F. Ravandi, and T. Kadia
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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6. P575: IMPACT OF MOLECULAR RESPONSE AND CHEMOTHERAPY REGIMEN ON OUTCOMES IN CORE BINDING FACTOR AML
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J. Senapati, F. Haddad, F. Ravandi, T. Kadia, C. DiNardo, N. Daver, N. Pemmaraju, Y. Alvarado, M. A. Brandt, H. Kantarjian, and G. Borthakur
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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7. P576: A PHASE I/II STUDY OF MILADEMETAN (DS3032B) IN COMBINATION WITH LOW DOSE CYTARABINE WITH OR WITHOUT VENETOCLAX IN ACUTE MYELOID LEUKEMIA
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J. Senapati, J. Ishizawa, H. A. Abbas, S. Loghavi, G. Borthakur, G. C. Issa, S. I. Dara, R. Pourebrahim, N. Daver, E. J. Jabbour, S. M. Kornblau, N. Pemmaraju, G. Garcia-Manero, F. Ravandi, M. Muftuoglu, J. Khoury, C. DiNardo, and M. Andreeff
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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8. P1052: IMPACT OF SF3B1 MUTATION IN MYELOFIBROSIS
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J. Senapati, S. Verstovsek, L. Masarova, N. Pemmaraju, G. Montalban Bravo, S. Pierce, L. Zhou, G. Garcia-Manero, H. Kantarjian, and P. Bose
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2022
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9. Detection of PNH Clones can Aid in the Distinction of Aplastic Anemia vs Inherited BM Failure Syndromes: A Single Center Experience and Review of the Literature.
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Nasnas P, Ling J, Gerstein Y, Wang SA, Loghavi S, Hammond D, Montalban-Bravo G, Senapati J, Pemmaraju N, Corredor J, Pierce S, Roth M, Ravandi F, Cuglievan B, Kadia T, and DiNardo CD
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- Humans, Male, Female, Adult, Middle Aged, Aged, Adolescent, Diagnosis, Differential, Young Adult, Anemia, Aplastic genetics, Anemia, Aplastic diagnosis, Hemoglobinuria, Paroxysmal diagnosis, Hemoglobinuria, Paroxysmal genetics, Bone Marrow Failure Disorders genetics
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Competing Interests: Disclosures Dr C.D.D. declares research support (to institution): Abbvie, Astex, Beigene, Calithera, BMS, Cleave, ImmuneOnc, and Loxo; consultant/advisory boards: Abbvie, Astellas, BMS, Daiichi-Sankyo, GenMab, GSK, Immunogen, Notable Labs, Servier, and Stemline. Dr. T.K. reports grant or research support from BMS, Celgene, Pfizer, Amgen, Jazz, AstraZeneca, and Genetech; consultant fees from Agios, Jazz, Genetech, and Novartis. Dr. F.R. reports research funding from BMS, Amgen, Xencor, Macrogenics, Orsenix, Abbvie, Prelude, Astex; consultancy and honoraria from Celgene, BMS, Amgen, Astellas, Xencor, Agios, AstraZeneca, and Orsenix. Dr N.P reports research contributions from Affymetrix, Stemline Therapeutics, AbbVie, Daiichi Sankyo, Plexxikon, Cellectis, Novartis, Samus Therapeutics; grant support from Affymetrix, SagerStrong; and honoraria from Stemline Therapeutics, LFB Biotechnologies, MustangBio, Incyte Corporation, Celgene, DAVA Oncology, Blueprint Medicines, Novartis, and Roche Diagnostics. The other authors have no conflict of interest.
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- 2024
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10. Lower intensity therapy with cladribine/low dose cytarabine/venetoclax in older patients with acute myeloid leukemia compares favorably with intensive chemotherapy among patients undergoing allogeneic stem cell transplantation.
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Senapati J, Kantarjian HM, Bazinet A, Reville P, Short NJ, Daver N, Borthakur G, Bataller A, Jabbour E, DiNardo C, Haddad F, Sasaki K, Popat U, Oran B, Alousi AM, Loghavi S, Shpall E, Garcia-Manero G, Ravandi F, and Kadia TM
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- Humans, Male, Aged, Female, Middle Aged, Retrospective Studies, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Cladribine administration & dosage, Cladribine therapeutic use, Cytarabine administration & dosage, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Transplantation, Homologous, Sulfonamides administration & dosage, Sulfonamides therapeutic use, Hematopoietic Stem Cell Transplantation methods, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic therapeutic use
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Background: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes., Methods: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m
2 and anthracyclines during induction/consolidation., Results: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486)., Conclusion: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower., (© 2024 American Cancer Society.)- Published
- 2024
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11. TP53 Y220C mutations in patients with myeloid malignancies.
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Gener-Ricos G, Bewersdorf JP, Loghavi S, Bataller A, Goldberg AD, Sasaki K, Famulare C, Takahashi K, Issa GC, Borthakur G, Kadia TM, Short NJ, Senapati J, Carter BZ, Patel KP, Kantarjian H, Andreeff M, Stein EM, and DiNardo CD
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- Humans, Myeloproliferative Disorders genetics, Myeloproliferative Disorders diagnosis, Male, Genetic Predisposition to Disease, Female, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes diagnosis, Middle Aged, Tumor Suppressor Protein p53 genetics, Mutation
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- 2024
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12. Longitudinal follow up of a phase 2 trial of venetoclax added to hyper-CVAD, nelarabine and pegylated asparaginase in patients with T-cell acute lymphoblastic leukemia and lymphoma.
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Ravandi F, Senapati J, Jain N, Short NJ, Kadia T, Borthakur G, Konopleva M, Wierda W, Huang X, Maiti A, Issa G, Balkin H, Garris R, Ferrajoli A, Garcia-Manero G, Alvarado Y, Kebriaei P, Jabbour E, and Kantarjian HM
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Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, p = 0.03) and 2-year DOR (93.6% versus 69.2%, p = 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, p = 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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13. Decitabine, venetoclax, and ponatinib for advanced phase chronic myeloid leukaemia and Philadelphia chromosome-positive acute myeloid leukaemia: a single-arm, single-centre phase 2 trial.
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Short NJ, Nguyen D, Jabbour E, Senapati J, Zeng Z, Issa GC, Abbas H, Nasnas C, Qiao W, Huang X, Borthakur G, Chien K, Haddad FG, Pemmaraju N, Karrar OS, Nguyen D, Konopleva M, Kantarjian H, and Ravandi F
- Abstract
Background: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases., Methods: For this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m
2 intravenously on days 8-12, venetoclax orally daily with ramp-up to a maximum dose of 400 mg on days 8-28, and ponatinib 45 mg orally daily on days 8-28. Cycles 2-24 consisted of decitabine 20 mg/m2 intravenously on days 1-5, venetoclax orally 400 mg on days 1-21, and ponatinib orally daily on days 1-28. Response-based dosing of ponatinib was implemented in consolidation cycles, with reduction to 30 mg daily in patients who reached complete remission or complete remission with an incomplete haematological recovery and a reduction to 15 mg daily in patients with undetectable BCR::ABL1 transcripts. The primary endpoint was the composite rate of complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT04188405) and is still ongoing., Results: Between July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, and 14 (70%) patients had at least one high-risk additional chromosomal abnormality or complex karyotype. The median duration of follow-up was 21·2 months (IQR 14·1-24·2). The complete remission or complete remission with an incomplete haematological recovery rate was 50% (10 of 20 patients); complete remission in one [5%] patient and complete remission with incomplete haematological recovery in nine [45%]). An additional six (30%) patients had a morphologic leukaemia-free state. The most common grade 3-4 non-haematological adverse events were febrile neutropenia in eight (40%) patients, infection in six (30%), and alanine or aspartate transaminase elevation in five (25%). Eight (40%) patients had at least one cardiovascular event of any grade. There were three on-study deaths, none of which was considered related to the study treatment and all from infections in the setting of refractory leukaemia., Interpretation: The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted., Funding: Takeda Oncology, the National Institutes of Health, and the National Cancer Institute Cancer Center., Competing Interests: Declaration of interests NJS has received consulting fees from Pfizer, GlaxoSmithKline, NKARTA, Autolus, and Sanofi; research funding from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and NextCure; and honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer, Astellas Pharma, Sanofi, and BeiGene. EJ has received consulting fees and research funding from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, ASTX Pharmaceuticals, AstraZeneca, Autolus, BMS, Genenenctech, Hikma, Kite, Novartis, Pfizer, Takeda Oncology, and Jazz. HA has received consulting fees from Molecular Partners; research funding from Genentech, GlaxoSmithKline, and EBD-300; and honoraria from Illumina. MK has received consulting fees from AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F Hoffman-La Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, and Vincerx; research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, and Stemline; honoraria from AbbVie, Baxk Therapeutics, Genentech, and Stemline Therapeutics; stock options in Reata Pharamceuticals; and holds patents with Novartis, Eli Lilly, and Reata Pharmaceutical. HK has received research funding from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, and Novartis and honoraria from AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda Oncology. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)- Published
- 2024
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14. Liver elastography for risk-assessment of liver toxicity and risk factors for Sinusoidal obstruction syndrome in patients with acute lymphoblastic leukemia receiving inotuzumab ozogamicin.
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Senapati J, Jabbour E, Short NJ, Jain N, Haddad F, Bathala T, Kovalenko I, Bidikian A, Ravandi F, Khouri I, Kadia TM, Garris R, Montalban Bravo G, Chien K, Shpall E, Kebriaei P, and Kantarjian HM
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- Humans, Male, Female, Middle Aged, Risk Factors, Adult, Liver diagnostic imaging, Liver pathology, Liver drug effects, Risk Assessment, Aged, Chemical and Drug Induced Liver Injury etiology, Chemical and Drug Induced Liver Injury diagnosis, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Agents, Immunological therapeutic use, Hepatic Veno-Occlusive Disease chemically induced, Hepatic Veno-Occlusive Disease diagnostic imaging, Hepatic Veno-Occlusive Disease diagnosis, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma complications, Inotuzumab Ozogamicin adverse effects, Inotuzumab Ozogamicin therapeutic use, Elasticity Imaging Techniques
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- 2024
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15. Outcomes of Patients With Newly Diagnosed AML and Hyperleukocytosis.
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Haddad FG, Sasaki K, Senapati J, Xiao L, Park G, Abuasab T, Venugopal S, Rivera D, Bazinet A, Babakhanlou R, Kim K, Ong F, Desikan S, Pemmaraju N, Loghavi S, Borthakur G, DiNardo C, Abbas HA, Short NJ, Daver N, Jabbour E, Garcia-Manero G, Ravandi F, Kantarjian H, and Kadia T
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Purpose: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality., Methods: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 10
9 /L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS., Results: The median age was 65 years (range, 23-86); the median WBC was 146 × 109 /L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3 , NPM1 , and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 109 /L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS., Conclusion: Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.- Published
- 2024
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16. Characteristics and outcomes of patients with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia after failure of a frontline ponatinib-containing therapy.
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Short NJ, Jabbour E, Nasr LF, Jain N, Haddad FG, Issa GC, Sasaki K, Senapati J, Kebriaei P, Garris R, Konopleva M, Ravandi F, and Kantarjian H
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- Humans, Male, Female, Middle Aged, Aged, Adult, Antineoplastic Agents therapeutic use, Antineoplastic Agents adverse effects, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors adverse effects, Pyridazines therapeutic use, Pyridazines adverse effects, Pyridazines administration & dosage, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Imidazoles therapeutic use, Imidazoles adverse effects, Imidazoles administration & dosage, Philadelphia Chromosome, Recurrence
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- 2024
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17. Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.
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Kittai AS, Bond D, Huang Y, Bhat SA, Blyth E, Byrd JC, Chavez JC, Davids MS, Dela Cruz JP, Dowling MR, Duffy C, Ho C, Jacobson C, Jaglowski S, Jain N, Lin KH, Miller C, McCarthy C, Omer Z, Parry E, Rai M, Rogers KA, Saha A, Schachter L, Scott H, Senapati J, Shadman M, Siddiqi T, Stephens DM, Vanguru V, Wierda W, Woyach JA, and Thompson PA
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- Humans, Retrospective Studies, Male, Middle Aged, Aged, Adult, Female, Aged, 80 and over, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Progression-Free Survival, Antigens, CD19 therapeutic use, Antigens, CD19 immunology, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen therapeutic use, Receptors, Chimeric Antigen immunology
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Purpose: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established., Methods: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion., Results: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR., Conclusion: CAR-T demonstrates clinical efficacy for patients with RT.
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- 2024
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18. SOHO State of the Art Updates and Next Questions | Next Questions: Acute Lymphoblastic Leukemia.
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Senapati J, Kantarjian H, Haddad FG, Short NJ, Welch MA, Jain N, and Jabbour E
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- Humans, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy
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The integration of immune and targeted therapies into the treatment of acute lymphoblastic leukemia (ALL) has significantly improved outcomes, reduced the intensity and duration of chemotherapy, and the reliance on allogeneic stem cell transplantation (SCT). In younger patients with Philadelphia chromosome (Ph)-negative ALL, treatment with Hyper-CVAD and blinatumomab +/- inotuzumab has improved the 3-year overall survival (OS) to above 85%. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year OS rate to 50%. In Ph
+ ALL, the chemotherapy-free combinations of blinatumomab and ponatinib (or dasatinib) have become a new standard of care resulting in 3-year OS of 85% to 90%. Because the methotrexate-cytarabine courses were omitted in the nonchemotherapy regimens, central nervous system (CNS) relapses were noted, particularly in patients with a WBC count > 70 × 109 /L, requiring to consider increasing the number of prophylactic intrathecals (from 12 to 15) and perhaps developing a CNS risk-directed high-dose systemic chemotherapy. In relapsed/refractory ALL, a dose-dense regimen integrating blinatumomab and inotuzumab with low-intensity chemotherapy followed by consolidation with chimeric antigen receptor T-cell therapy is being investigated. The detection of measurable residual disease (MRD) following ALL therapy is predictive of disease relapse. Using next-generation sequencing allows the detection of MRD at 1 × 10-6 which was shown to be superior to multiparameter flow cytometry and polymerase chain reaction in predicting relapse, and could be used to decide on the duration of therapy or need to change therapy. Herein, we review the recent updates and areas of unmet need in ALL., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2024
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19. A phase 1/2 study of mini-hyper-CVD plus venetoclax in patients with relapsed/refractory acute lymphoblastic leukemia.
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Short NJ, Jabbour E, Jain N, Senapati J, Nasr L, Haddad FG, Li Z, Hsiao YC, Yang JJ, Pemmaraju N, Ohanian M, Wierda WG, Montalban-Bravo G, Borthakur G, Han L, Xiao L, Huang X, Abramova R, Zhao M, Garris R, Konopleva M, Ravandi F, and Kantarjian H
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- Adult, Humans, Inotuzumab Ozogamicin therapeutic use, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Cardiovascular Diseases chemically induced, Sulfonamides
- Abstract
Abstract: Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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20. Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission.
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Jabbour E, Haddad FG, Short NJ, Senapati J, Jain N, Sasaki K, Jorgensen J, Wang SA, Alvarado Y, Wang X, DiNardo C, Masarova L, Kadia T, Garris RS, Ravandi F, and Kantarjian H
- Subjects
- Humans, Young Adult, Adult, Middle Aged, Aged, Inotuzumab Ozogamicin adverse effects, Recurrence, Neoplasm, Residual drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Hepatic Veno-Occlusive Disease chemically induced
- Abstract
Abstract: The detection of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). Using inotuzumab ozogamicin in the setting of MRD may improve outcomes. Patients with ALL in first complete remission (CR1) or beyond (CR2+) with MRD ≥ 1 × 10-4 were enrolled in this phase 2 trial. Inotuzumab was administered at 0.6 mg/m2 on day 1 and 0.3 mg/m2 on day 8 of cycle 1, then at 0.3 mg/m2 on days 1 and 8 of cycles 2-6. Twenty-six consecutive patients with a median age of 46 years (range, 19-70 years) were treated. Nineteen (73%) were in CR1 and seven (27%) in CR2+; 16 (62%) had Philadelphia chromosome-positive ALL. Fifteen (58%) had baseline MRD ≥ 1 × 10-3. A median of 3 cycles (range, 1-6) were administered. Eighteen (69%) patients responded and achieved MRD negativity. After a median follow-up of 24 months (range, 9-43), the 2-year relapse-free survival rate was 54% and the 2-year overall survival rate was 60% in the entire cohort. Most adverse events were low grade; sinusoidal obstruction syndrome was noted in 2 patients (8%). In summary, inotuzumab ozogamicin resulted in favorable survival, MRD negativity rates, and safety profiles for patients with ALL and MRD-positive status. This study was registered at www.ClinicalTrials.gov as #NCT03441061., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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21. An Update on the Management of Advanced Phase Chronic Myeloid Leukemia.
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Short NJ, Senapati J, and Jabbour E
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- Humans, Protein Kinase Inhibitors adverse effects, Blast Crisis drug therapy, Fusion Proteins, bcr-abl genetics, Drug Resistance, Neoplasm genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Purpose of Review: While most patients with chronic myeloid leukemia (CML) present in a chronic phase and are expected to have a normal life expectancy, some patients present with or progress to a more aggressive accelerated phase (AP) or blast phase (BP) of CML. Herein, we discuss the diagnostic considerations of advanced phase CML and review its contemporary management., Recent Findings: Later-generation, more potent BCR::ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib may result in superior outcomes in patients with advanced phase CML. For CML-BP, combination approaches directed against the blast immunophenotype appear superior to TKI monotherapy. The role of allogeneic stem cell transplantation is controversial in CML-AP but has consistently been shown to improve outcomes for patients with CML-BP. Advanced phase CML, particularly CML-BP, remains a poor risk subtype of CML. However, novel combination approaches using later-generation TKIs are being explored in clinical trials and may lead to improved outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2023
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22. Venetoclax abrogates the prognostic impact of splicing factor gene mutations in newly diagnosed acute myeloid leukemia.
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Senapati J, Urrutia S, Loghavi S, Short NJ, Issa GC, Maiti A, Abbas HA, Daver NG, Pemmaraju N, Pierce S, Chien KS, Sasaki K, Kadia TM, Hammond DE, Borthakur G, Patel K, Ravandi F, Kantarjian HM, Garcia-Manero G, and DiNardo CD
- Subjects
- Humans, Aged, RNA Splicing Factors genetics, Prognosis, Serine-Arginine Splicing Factors genetics, Splicing Factor U2AF genetics, Mutation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted., (© 2023 by The American Society of Hematology.)
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- 2023
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23. Phase I Results of Bromodomain and Extra-Terminal Inhibitor PLX51107 in Combination with Azacitidine in Patients with Relapsed/Refractory Myeloid Malignancies.
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Senapati J, Fiskus WC, Daver N, Wilson NR, Ravandi F, Garcia-Manero G, Kadia T, DiNardo CD, Jabbour E, Burger J, Short NJ, Alvarado Y, Jain N, Masarova L, Issa GC, Qiao W, Khoury JD, Pierce S, Miller D, Sasaki K, Konopleva M, Bhalla KN, Borthakur G, and Pemmaraju N
- Subjects
- Humans, Azacitidine, Nuclear Proteins, Transcription Factors, Recurrence, Proto-Oncogene Proteins c-bcl-2, Antineoplastic Combined Chemotherapy Protocols adverse effects, RNA-Binding Proteins, Cell Cycle Proteins, Myelodysplastic Syndromes drug therapy, Myelodysplastic Syndromes genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology
- Abstract
Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies., Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy., Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1-9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders., Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit., (©2023 American Association for Cancer Research.)
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- 2023
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24. Maintenance therapy in acute myeloid leukemia: advances and controversies.
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Senapati J, Kadia TM, and Ravandi F
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- Humans, Quality of Life, Recurrence, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Hematopoietic Stem Cell Transplantation
- Abstract
The last decade has seen steadfast progress in drug development in acute myeloid leukemia (AML) which has moved progressively towards genomic-based therapy. With these advances, outcomes in AML have improved but remains far from satisfactory. One approach towards preventing relapse in AML is to use maintenance therapy in patients, after attaining remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective post-remission therapy that has been proven to reduce the risk of relapse. However, in patients who are ineligible for HSCT or have a high risk of relapse, other effective measures to prevent relapse are needed. There is also a need for post-HSCT maintenance to reduce relapse in high-risk subsets. Over the last 3 decades maintenance therapy in AML has evolved from the use of chemotherapeutic agents to more targeted therapies and better modulation of the immune system. Unfortunately, improvements in survival outcomes as a result of using these agents have not been consistently demonstrated in clinical trials. To derive the optimum benefit from maintenance therapy the time points of therapy initiation need to be defined and therapy must be selected precisely with respect to the AML genetics and risk stratification, prior treatment exposure, transplant eligibility, expected toxicity and the patient's clinical profile and desires. The far-reaching goal is to facilitate patients with AML in remission to achieve a normal quality of life while improving remission duration and overall survival. The QUAZAR trial was a welcome step towards a safe maintenance drug that is easy to administer and showed survival benefit but leaves many open issues for discussion. In this review we will discuss these issues, highlighting the development of AML maintenance therapies over the last 3 decades.
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- 2023
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25. Blastic plasmacytoid dendritic cell neoplasm: a comprehensive review in pediatrics, adolescents, and young adults (AYA) and an update of novel therapies.
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Cuglievan B, Connors J, He J, Khazal S, Yedururi S, Dai J, Garces S, Quesada AE, Roth M, Garcia M, McCall D, Gibson A, Ragoonanan D, Petropoulos D, Tewari P, Nunez C, Mahadeo KM, Tasian SK, Lamble AJ, Pawlowska A, Hammond D, Maiti A, Haddad FG, Senapati J, Daver N, Gangat N, Konopleva M, Meshinchi S, and Pemmaraju N
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- Child, Humans, Adolescent, Young Adult, Aged, Dendritic Cells pathology, Hematologic Neoplasms pathology, Skin Neoplasms pathology, Hematopoietic Stem Cell Transplantation, Myeloproliferative Disorders pathology
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients., (© 2023. The Author(s).)
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- 2023
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26. Understanding the barriers to AML care in India.
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Senapati J, Panda T, Rajendra A, and Aggarwal M
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- Humans, India epidemiology, Leukemia, Myeloid, Acute therapy
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- 2023
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27. A Phase I study of Milademetan (DS3032b) in combination with low dose cytarabine with or without venetoclax in acute myeloid leukemia: Clinical safety, efficacy, and correlative analysis.
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Senapati J, Muftuoglu M, Ishizawa J, Abbas HA, Loghavi S, Borthakur G, Yilmaz M, Issa GC, Dara SI, Basyal M, Li L, Naqvi K, Pourebrahim R, Jabbour EJ, Kornblau SM, Short NJ, Pemmaraju N, Garcia-Manero G, Ravandi F, Khoury J, Daver N, Kantarjian HM, Andreeff M, and DiNardo CD
- Subjects
- Adult, Humans, Young Adult, Middle Aged, Aged, Aged, 80 and over, Tumor Suppressor Protein p53, Myeloid Cell Leukemia Sequence 1 Protein, Proteomics, Cytarabine, Leukemia, Myeloid, Acute drug therapy
- Abstract
In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response., (© 2023. The Author(s).)
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- 2023
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28. Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial.
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Jabbour E, Short NJ, Senapati J, Jain N, Huang X, Daver N, DiNardo CD, Pemmaraju N, Wierda W, Garcia-Manero G, Montalban Bravo G, Sasaki K, Kadia TM, Khoury J, Wang SA, Haddad FG, Jacob J, Garris R, Ravandi F, and Kantarjian HM
- Subjects
- Humans, Male, Female, Aged, Inotuzumab Ozogamicin therapeutic use, Philadelphia Chromosome, Antineoplastic Combined Chemotherapy Protocols adverse effects, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Hepatic Veno-Occlusive Disease drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy
- Abstract
Background: The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients., Methods: For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The induction chemotherapy consisted of mini-hyper-CVD and has been published before; inotuzumab ozogamicin was administered intravenously on day 3 of the first four cycles at a dose of 1·3-1·8 mg/m
2 in cycle 1, followed by 1·0-1·3 mg/m2 in subsequent cycles (cycles 2-4). Maintenance therapy with dose-reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was given for 3 years. From patient 50 onwards, the study protocol was amended to fractionate inotuzumab ozogamicin to a maximum cumulative dose of 2·7 mg/m2 (0·9 mg/m2 during cycle 1 fractionated into 0·6 mg/m2 on day 2 and 0·3 mg/m2 on day 8 of cycle 1, and 0·6 mg/m2 in cycles 2-4 fractionated into 0·3 mg/m2 on day 2 and 0·3 mg/m2 on day 8) followed by blinatumomab for four cycles (cycles 5-8). POMP maintenance was shortened to 12 cycles with one cycle of blinatumomab administered by continuous infusion after every three cycles of POMP. The primary endpoint was progression-free survival and was analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT01371630) and the present data is from the newly diagnosed, older subgroup of patients treated on the phase 2 portion of this trial; the trial is still enrolling patients., Results: Between Nov 11, 2011, and March 31, 2022, 80 patients were enrolled and treated (32 female and 48 male patients; median age 68 years [IQR 63-72]), 31 of whom were treated after the protocol amendment. With a median follow-up of 92·8 months (IQR 8·8-67·4), the 2-year progression-free survival was 58·2% (95% CI 46·7-68·2) and 5-year progression-free survival was 44·0% (31·2-54·3). At a median follow-up of 104·4 months (IQR 6·6-89·2) for the patients treated before the protocol amendment and 29·7 months (8·8-41·0) for those treated after the protocol amendment, median progression-free survival did not differ significantly between the two groups (34·7 months [95% CI 15·0-68·3] vs 56·4 months [11·3-69·7]; p=0·77). The most common grade 3-4 events were thrombocytopenia in 62 (78%) patients and febrile neutropenia in 26 (32%) patients. Six (8%) patients developed hepatic sinusoidal obstruction syndrome. There were eight (10%) deaths due to infectious complications, nine (11%) from complications related to secondary myeloid malignancy, and four (5%) from sinusoidal obstruction syndrome., Interpretation: Inotuzumab ozogamicin with or without blinatumomab added to low-intensity chemotherapy showed promising activity in terms of progression-free survival in older patients with B-cell acute lymphocytic leukaemia. Further attenuation of the chemotherapy regimen might improve tolerability while maintaining efficacy in older patients., Funding: Pfizer and Amgen., Competing Interests: Declaration of interests EJ reports research grants from AbbVie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Genentech, Incyte, Novartis, Pfizer, and Takeda. NJS reports research grants from Takeda Oncology, Astellas Pharma, Xencor, and Stemline Therapeutics; consultancy fees from Pfizer and Jazz Pharmaceuticals; and honoraria from Novartis, Amgen, Sanofi, and BeiGene. ND reports research funding from Daiichi-Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Servier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen; and served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. HK reports research grants from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Daiichi-Sankyo, Immunogen, Jazz, Novartis, and Pfizer; and honoraria from AbbVie, Amgen, Aptitude Health, Ascentage, Astellas Health, Astra Zeneca, Ipsen, Pharmaceuticals, KAHR Medical, NOVA Research, Novartis, Pfizer, Precision Biosciences, and Taiho Pharmaceutical Canada. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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29. Characteristics of patients with myelodysplastic neoplasm and spliceosome mutations.
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Urrutia S, Li Z, Almanza E, Bataller A, Kanagal-Shamanna R, Senapati J, Sasaki K, Chien K, Montalban-Bravo G, DiNardo C, Borthakur G, Bueso-Ramos C, Pierce S, Kantarjian H, and Garcia-Manero G
- Subjects
- Humans, Spliceosomes genetics, Spliceosomes metabolism, Mutation, RNA Splicing genetics, RNA Splicing Factors genetics, RNA Splicing Factors metabolism, Neoplasms, Myelodysplastic Syndromes genetics
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- 2023
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30. Outcomes of adult patients with relapsed/refractory CRLF2 rearranged B-cell acute lymphoblastic leukemia.
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Desikan SP, Senapati J, Jabbour E, Abuasab T, Short N, Tang G, Wang S, Kebriaei P, Kadia T, Borthakur G, Ravandi F, Roberts K, Mullighan C, Konopleva M, Kantarjian H, and Jain N
- Subjects
- Humans, Adult, Receptors, Cytokine genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Burkitt Lymphoma
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- 2023
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31. A phase 2 study of nivolumab combined with ibrutinib in patients with diffuse large B-cell Richter transformation of CLL.
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Jain N, Senapati J, Thakral B, Ferrajoli A, Thompson P, Burger J, Basu S, Kadia T, Daver N, Borthakur G, Konopleva M, Pemmaraju N, Parry E, Wu CJ, Khoury J, Bueso-Ramos C, Garg N, Wang X, Lopez W, Ayala A, O'Brien S, Kantarjian H, Keating M, Allison J, Sharma P, and Wierda W
- Subjects
- Humans, Middle Aged, Aged, Aged, 80 and over, Nivolumab therapeutic use, Programmed Cell Death 1 Receptor, B-Lymphocytes pathology, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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32. Philadelphia-Like Genetic Rearrangements in Adults With B-Cell ALL: Refractoriness to Chemotherapy and Response to Tyrosine Kinase Inhibitor in ABL Class Rearrangements.
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Senapati J, Jabbour E, Konopleva M, Short NJ, Tang G, Daver N, Kebriaei P, Kadia T, Pemmaraju N, Takahashi K, DiNardo C, Sasaki K, Borthakur G, Thakral B, Kanagal-Shamanna R, Patel K, Ravandi F, Roberts K, Mullighan C, Kantarjian H, and Jain N
- Subjects
- Humans, In Situ Hybridization, Fluorescence, Retrospective Studies, Transcriptome, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics, Gene Rearrangement, Tyrosine Kinase Inhibitors
- Abstract
Purpose: Philadelphia-like (Ph-like) B-cell ALL is a high-risk subtype of B-cell ALL that shares a gene expression profile with Ph-positive ALL, but without a BCR::ABL1 fusion. A subgroup of these patients have fusions or rearrangements involving genes such as ABL1 , ABL2 , PDGFRβ , JAK2 , and EPOR , some of which are potentially sensitive to tyrosine kinase inhibitors (TKIs). Prompt identification of these genetic aberrations are important for prognostication and treatment decisions., Patients and Methods: We performed a retrospective review of patients with B-cell ALL treated at MD Anderson Cancer Center to identify recurrent genetic fusions commonly seen in Ph-like ALL and focus on patients treated with TKI., Results: We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had ABL class fusions (eight ABL1 , one ABL2, and five PDGFRβ ) and nine had JAK2 class fusions (five JAK2 and four EPOR ). Notably, several of these fusions were cryptic by conventional cytogenetics and fluorescent in situ hybridization (FISH) assays and identified only by multiplex fusion assay. Thirteen of these 23 patients received a TKI as part of their treatment; this included ABL1 fusion (n = 8), PDGFRβ fusion (n = 4), and EPOR fusion (n = 1). All four patients with ABL1 fusions who received TKI with induction chemotherapy are alive in first remission., Conclusion: Understanding the genomics of B-cell ALL is important for disease prognostication and for precise treatment planning. Besides conventional cytogenetics and directed FISH testing, multiplex fusion assays can help identify recurrent chromosomal translocations that are seen in patients with Ph-like ALL. Early initiation of TKI appears beneficial; larger studies are required to fully understand the benefit of TKI and to design rational combination therapies for these patients.
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- 2023
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33. Management of chronic myeloid leukemia in 2023 - common ground and common sense.
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Senapati J, Sasaki K, Issa GC, Lipton JH, Radich JP, Jabbour E, and Kantarjian HM
- Subjects
- Humans, Dasatinib therapeutic use, Imatinib Mesylate therapeutic use, Protein Kinase Inhibitors adverse effects, Fusion Proteins, bcr-abl genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Antineoplastic Agents adverse effects
- Abstract
With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient's comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results., (© 2023. The Author(s).)
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- 2023
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34. Common kinase mutations do not impact optimal molecular responses in core binding factor acute myeloid leukemia treated with fludarabine, cytarabine, and G-CSF based regimens.
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Senapati J, Abuasab T, Haddad FG, Ravandi F, Kadia T, DiNardo C, Daver N, Pemmaraju N, Alvarado Y, Brandt MA, Kantarjian H, and Borthakur G
- Subjects
- Humans, Granulocyte Colony-Stimulating Factor therapeutic use, Vidarabine therapeutic use, Mutation, Core Binding Factors, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
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- 2023
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35. A phase 1 study to evaluate the safety, pharmacology, and feasibility of continuous infusion nelarabine in patients with relapsed and/or refractory lymphoid malignancies.
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Boddu PC, Senapati J, Ravandi-Kashani F, Jabbour EJ, Jain N, Ayres M, Chen Y, Keating MJ, Kantarjian HM, Gandhi V, and Kadia TM
- Subjects
- Humans, Adolescent, Young Adult, Adult, Middle Aged, Aged, Feasibility Studies, Arabinonucleosides adverse effects, Remission Induction, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Lymphoma, Non-Hodgkin drug therapy
- Abstract
Background: Nelarabine is a purine nucleoside analogue prodrug approved for the treatment of relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL) and lymphoblastic lymphoma (T-LBL). Although effective in R/R T-ALL, significant neurotoxicity is dose-limiting and such neurotoxicity associated with nucleoside analogues can be related to dosing schedule., Methods: The authors conducted a phase 1 study to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion (CI) for 5 days (120 hours), rather than the standard, short-infusion approach., Results: Twenty-nine patients with R/R T-ALL/LBL or T-cell prolymphocytic leukemia (T-PLL) were treated, with escalating doses of nelarabine from 100 to 800 mg/m
2 /day × 5 days. The median age of the patients was 39 years (range, 14-77 years). The overall response rate was 31%, including 27% complete remission (CR) or CR with incomplete platelet recovery (CRp). Peripheral neuropathy was observed in 34% of patients, including four ≥grade 3 events related to nelarabine. Notably, there was no nelarabine-related central neurotoxicity on study. The maximum tolerated dose was not reached. Pharmacokinetic data suggested no relationship between dose of nelarabine and accumulation of active intracellular ara-GTP metabolite. Higher intracellular ara-GTP concentrations were statistically associated with a favorable clinical response., Conclusion: Preliminary evaluation of continuous infusion schedule of nelarabine suggests that the safety profile is acceptable for this patient population, with clinical activity observed even at low doses and could broaden the use of nelarabine both as single agent and in combinations by potentially mitigating the risk of central nervous system toxicities., (© 2022 American Cancer Society.)- Published
- 2023
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36. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need.
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Pemmaraju N, Kantarjian H, Sweet K, Wang E, Senapati J, Wilson NR, Konopleva M, Frankel AE, Gupta V, Mesa R, Ulrickson M, Gorak E, Bhatia S, Budak-Alpdogan T, Mason J, Garcia-Romero MT, Lopez-Santiago N, Cesarman-Maus G, Vachhani P, Lee S, Bhatt VR, Blum W, Walter RB, Bixby D, Gojo I, Duvic M, Rampal RK, de Lima M, Foran J, Fathi AT, Hall AC, Jacoby MA, Lancet J, Mannis G, Stein AS, Mims A, Rizzieri D, Olin R, Perl A, Schiller G, Shami P, Stone RM, Strickland S, Wieduwilt MJ, Daver N, Ravandi F, Vasu S, Guzman M, Roboz GJ, Khoury J, Qazilbash M, Aung PP, Cuglievan B, Madanat Y, Kharfan-Dabaja MA, Pawlowska A, Taylor J, Tallman M, Dhakal P, and Lane AA
- Subjects
- Child, Humans, Aged, Standard of Care, Interleukin-3 Receptor alpha Subunit, Dendritic Cells pathology, Neoplasm Recurrence, Local pathology, Acute Disease, North America, Myeloproliferative Disorders pathology, Hematologic Neoplasms pathology, Skin Neoplasms pathology
- Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein., (© 2023 by The American Society of Hematology.)
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- 2023
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37. Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia.
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Senapati J, Jabbour E, Kantarjian H, and Short NJ
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- Humans, Blast Crisis drug therapy, Protein Kinase Inhibitors therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Hematopoietic Stem Cell Transplantation
- Abstract
The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has been a model for cancer therapy development. Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase (AP) and blast phase (BP), both of which have a relatively poor prognosis. The rates of progression have reduced significantly from over >20% in the pre-TKI era to <5% now, largely due to refinements in CML therapy and response monitoring. Significant insights have been gained into the mechanisms of disease transformation including the role of additional cytogenetic abnormalities, somatic mutations, and other genomic alterations present at diagnosis or evolving on therapy. This knowledge is helping to optimize TKI therapy, improve prognostication and inform the development of novel combination regimens in these patients. While patients with de novo CML-AP have outcomes almost similar to CML in chronic phase (CP), those transformed from previously treated CML-CP should receive second- or third- generation TKIs and be strongly considered for allogeneic stem cell transplantation (allo-SCT). Similarly, patients with transformed CML-BP have particularly dismal outcomes with a median survival usually less than one year. Combination regimens with a potent TKI such as ponatinib followed by allo-SCT can achieve long-term survival in some transformed BP patients. Regimens including venetoclax in myeloid BP or inotuzumab ozogamicin or blinatumomab in lymphoid BP might lead to deeper and longer responses, facilitating potentially curative allo-SCT for patients with CML-BP once CP is achieved. Newer agents and novel combination therapies are further expanding the therapeutic arsenal in advanced phase CML., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2023
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38. Impact of SF3B1 mutation in myelofibrosis.
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Senapati J, Verstovsek S, Masarova L, Pemmaraju N, Patel KP, Montalban-Bravo G, Pierce SA, Zhou L, Garcia-Manero G, Kantarjian HM, and Bose P
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- Humans, Mutation, Phosphoproteins genetics, Primary Myelofibrosis diagnosis, Primary Myelofibrosis genetics, RNA Splicing Factors genetics
- Published
- 2022
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39. Antibody-Drug Conjugates in Myeloid Leukemias.
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Senapati J, Daver NG, and Pemmaraju N
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- Humans, Inotuzumab Ozogamicin, Gemtuzumab therapeutic use, Immunoconjugates pharmacology, Immunoconjugates therapeutic use, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Abstract: Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field., Competing Interests: Conflicts of Interest and Source of Funding: N.P.: leadership: ASH and ASCO; honoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, Springer, Aptitude Health, NeoPharm, and CareDX; consulting or advisory role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers Squibb, ClearView Healthcare Partners, Astellas Pharma, Protagonist Therapeutics, Triptych Health Partners, and CTI BioPharma Corp; research funding: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix/Thermo Fisher Scientific, Daiichi Sankyo, Plexxikon, and MustangBio; travel, accommodations, expenses: Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology and MustangBio; uncompensated relationships: Dan's House of Hope and Oncology Times. N.G.D.: consulting or advisory role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium Therapeutics, Gilead Sciences, Arog, and Shattuck Labs; research funding: Bristol Myers Squibb, Pfizer, Immunogen, Genentech, AbbVie, Astellas Pharma, Sevier, Daiichi Sankyo, Gilead Sciences, Amgen, Trillium Therapeutics, Hanmi, Trovagene, FATE Therapeutics, Novimmune, and GlycoMimetics. For J.S., none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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40. CD123-directed allogeneic chimeric-antigen receptor T-cell therapy (CAR-T) in blastic plasmacytoid dendritic cell neoplasm (BPDCN): Clinicopathological insights.
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Pemmaraju N, Wilson NR, Senapati J, Economides MP, Guzman ML, Neelapu SS, Kazemimood R, Davis RE, Jain N, Khoury JD, Sugita M, Cai T, Smith J, Frattini MG, Garton A, Roboz G, and Konopleva M
- Subjects
- Acute Disease, Cytokines metabolism, Dendritic Cells pathology, Humans, Interleukin-3 Receptor alpha Subunit, RNA metabolism, RNA therapeutic use, Hematologic Neoplasms pathology, Hematopoietic Stem Cell Transplantation methods, Myeloproliferative Disorders pathology, Receptors, Chimeric Antigen metabolism, Receptors, Chimeric Antigen therapeutic use, Skin Neoplasms metabolism
- Abstract
Purpose: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy associated with overexpression of CD123. Allogeneic chimeric antigen receptor T cells (CAR-T) directed against CD123 in BPDCN have been studied in clinical trials. We performed post-mortem analysis of a patient treated with anti-CD123 CAR-T to elucidate cause of death, development of cytokine release syndrome (CRS), and tissue distribution of UCART123 cells., Methods: A post-mortem multidisciplinary clinicopathologic analysis was performed with digital droplet polymerase chain reaction of isolated blood and tissue ribonucleic acid (RNA) to evaluate tissue distribution of infused CAR-T. Multiparameter flow cytometry for detection of CAR-T was used for whole blood samples. Cytokine levels in plasma were measured using multiplex bead assay. Gene expression profiling on isolated RNA was performed using semi-custom Nanostring immune gene panel and RNA-sequence method. RNA in situ hybridization was performed using CAR-specific probe., Results: The patient developed severe clinical CRS refractory to corticosteroids, tocilizumab, and lymphodepletion. Despite significant reduction in BPDCN lesions, the patient passed away on day 9 of CAR-T. Autopsy results show that following lymphodepletion and UCART123 administration, the patient remained severely lymphopenic with few UCART123 cells detected, predominantly localized to spleen., Conclusions: No definitive cause of death was determined, but we hypothesized that the patient may have succumbed to CAR-T-mediated cardiopulmonary toxicity. UCART123 cells displayed low overall distribution, with predominance in immune organs and tissues. Mechanism of CRS development is still poorly understood in patients receiving CAR-T therapy. Future directions in the field developing CD123-targeted agents in BPDCN are discussed., Competing Interests: Disclosure of Conflict of Interest M Konopleva: Consulting/honorarium: AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji. Research funding/clinical trials support: AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, and Astra Zeneca. Stock options/Royalties: Reata Pharmaceutical. N Pemmaraju: Consulting/honorarium: Celgene, Stemline, Incyte Corporation, Novartis, MustangBio, Roche Diagnostics, and LFB. Research funding/clinical trials support from Stemline, Novartis, Abbvie, Samus, Cellectis, Plexxikon, Daiichi-Sankyo, Affymetrix, and SagerStrong Foundation. M Guzman: Consulting/honorarium: SeqRx. Research funding: AI Therapeutics, TemedOn, Cellectis. S Neelapu: Consulting fees or honorarium from Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Athenex, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics, Bluebird Bio, Sana Biotechnology, Caribou, Astellas Pharma, Sellas Life Sciences; research funding from Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio; royalty income from Takeda Pharmaceuticals; stock options from Longbow Immunotherapy; and patents related to cell therapy. MG Frattini: Employment and Equity ownership: Cellectis, Inc. A Garton: Employment and Equity ownership: Cellectis, Inc. J. Smith: Employment and Equity ownership: Cellectis, S.A., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2022
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41. AbdomenNet: deep neural network for abdominal organ segmentation in epidemiologic imaging studies.
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Rickmann AM, Senapati J, Kovalenko O, Peters A, Bamberg F, and Wachinger C
- Subjects
- Abdomen diagnostic imaging, Cohort Studies, Humans, Water, Magnetic Resonance Imaging methods, Neural Networks, Computer
- Abstract
Background: Whole-body imaging has recently been added to large-scale epidemiological studies providing novel opportunities for investigating abdominal organs. However, the segmentation of these organs is required beforehand, which is time consuming, particularly on such a large scale., Methods: We introduce AbdomentNet, a deep neural network for the automated segmentation of abdominal organs on two-point Dixon MRI scans. A pre-processing pipeline enables to process MRI scans from different imaging studies, namely the German National Cohort, UK Biobank, and Kohorte im Raum Augsburg. We chose a total of 61 MRI scans across the three studies for training an ensemble of segmentation networks, which segment eight abdominal organs. Our network presents a novel combination of octave convolutions and squeeze and excitation layers, as well as training with stochastic weight averaging., Results: Our experiments demonstrate that it is beneficial to combine data from different imaging studies to train deep neural networks in contrast to training separate networks. Combining the water and opposed-phase contrasts of the Dixon sequence as input channels, yields the highest segmentation accuracy, compared to single contrast inputs. The mean Dice similarity coefficient is above 0.9 for larger organs liver, spleen, and kidneys, and 0.71 and 0.74 for gallbladder and pancreas, respectively., Conclusions: Our fully automated pipeline provides high-quality segmentations of abdominal organs across population studies. In contrast, a network that is only trained on a single dataset does not generalize well to other datasets., (© 2022. The Author(s).)
- Published
- 2022
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42. Chromosomal Instability in Chronic Myeloid Leukemia: Mechanistic Insights and Effects.
- Author
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Senapati J and Sasaki K
- Abstract
The most recent two decades have seen tremendous progress in the understanding and treatment of chronic myeloid leukemia, a disease defined by the characteristic Philadelphia chromosome and the ensuing BCR::ABL fusion protein. However, the biology of the disease extends beyond the Philadelphia chromosome into a nebulous arena of chromosomal and genetic instability, which makes it a genetically heterogeneous disease. The BCR::ABL oncoprotein creates a fertile backdrop for oxidative damage to the DNA, along with impairment of genetic surveillance and the favoring of imprecise error-prone DNA repair pathways. These factors lead to growing chromosomal instability, manifested as additional chromosomal abnormalities along with other genetic aberrations. This worsens with disease progression to accelerated and blast phase, and modulates responses to tyrosine kinase inhibitors. Treatment options that target the genetic aberrations that mitigate chromosome instability might be a potential area for research in patients with advanced phase CML.
- Published
- 2022
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43. Activity of decitabine as maintenance therapy in core binding factor acute myeloid leukemia.
- Author
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Senapati J, Shoukier M, Garcia-Manero G, Wang X, Patel K, Kadia T, Ravandi F, Pemmaraju N, Ohanian M, Daver N, DiNardo C, Alvarado Y, Aldrich J, and Borthakur G
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Core Binding Factors genetics, Cytarabine, Decitabine therapeutic use, Humans, Neoplasm, Residual diagnosis, Prognosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML., Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%., Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received parenteral DAC as maintenance therapy. Fifteen patients (48.3%) had completed FLAG-based induction/consolidation but with positive MRD (0.35%, range = 0.01%-0.91%) (Group 1). Sixteen patients (51.7%) could not complete recommended consolidations with FLAG-based regimen (due to older age or complications) and were switched to DAC maintenance (Group 2). In Group 2, eight patients (50%) had undetectable MRD (Group 2A) (all had qRTPCR ≤ 0.01%) and the other eight patients (50%) had residual fusion product by qRTPCR (0.1%, range = 0.02%-0.36%) (Group 2B) prior to starting DAC. Amongst the 23 patients who had a PCR ≥ 0.01% before maintenance therapy (Groups 1 and 2B), 12 patients (52%) attained a CMR as their best response (responders). The median pre-DAC qRTPCR amongst responders were 0.03% compared to 0.14% in nonresponders (p = .002). The median estimated molecular RFS amongst responders were 93.9 months. At a median follow-up of 59.3 months (13.2-106 months) from DAC initiation, 16 patients (51.6%) had to be initiated on a second line of therapy (40%, 25%, and 100% patients, respectively, in Groups1, 2A, and 2B). The median estimated time to new treatment between responders was 112.4 versus 5.8 months in nonresponders (hazard ratio = 0.16, 95% confidence interval = 0.04-0.54); however, there were no difference in overall survival between these groups (p = .37)., Conclusion: DAC is an effective maintenance therapy for CBF-AML patients with persistent fusion transcript at a low level after FLAG-based regimen. Attainment of CMR with DAC maintenance can lead to long-term remission in patients who have persistent MRD positive after FLAG-based regimen or are unable to receive the full course of consolidation therapy., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)
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- 2022
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44. Disease Status at Transplant has a Significant Impact on Outcomes of Autologous Transplantation (ASCT) in Patients with Hodgkin Lymphoma-A Single Center Experience.
- Author
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Senapati J, Devasia AJ, Korula A, Fouzia NA, Kulkarni U, Lakshmi KM, Lionel S, Abraham A, Srivastava A, Mathews V, and George B
- Abstract
High dose chemotherapy followed by autologous stem cell transplantation is the treatment of choice for relapsed Hodgkin lymphoma (HL). We analyzed 100 consecutive patients who underwent ASCT at our center between January 1999 and June 2019 for relapsed or refractory disease with a median age of 28 years (range: 9-65). At ASCT, 59 were in complete remission (CR) while 31 achieved partial remission (PR) and 10 had refractory disease (RD). Most had BEAM conditioning with a median infused cell dose of 4.84 × 10
6 CD 34 cells/kg. Prompt engraftment occurred in 97 patients at a median of 11 days. The day 100 transplant related mortality (TRM) was 5%. At a median of 37 months follow up, 79 patients are alive while 34 have relapsed. The 3-year event free survival (EFS) and overall survival (OS) are 62.3 ± 0.5% and 77.9 ± 4.4% respectively . The 3-year OS for patients in CR, PR and RD were 83.0 ± 5.2%, 78.4 ± 8.1% and 38.9 ± 1.7 respectively [ p = 0.007] while the 3-year EFS for CR, PR and RD were 73.1 ± 6.2%, 61.3 ± 9.2% and 25.0 ± 1.5 respectively [ p = 0.005] . Only disease status at time of ASCT was found to correlate with both OS and EFS. ASCT for HL is associated with good outcomes and low TRM. Disease status at ASCT impacted both OS and EFS and strategies to improve outcomes in patients with refractory disease needs to be explored., Competing Interests: Conflicts of interestNo conflict of interest for any of the authors., (© Indian Society of Hematology and Blood Transfusion 2021.)- Published
- 2022
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45. Which FLT3 Inhibitor for Treatment of AML?
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Senapati J and Kadia TM
- Subjects
- Humans, Mutation, Protein Kinase Inhibitors therapeutic use, Transplantation, Homologous, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Opinion Statement: Treatment options in acute myeloid leukemia (AML) have improved significantly over the last decade with better understanding of disease biology and availability of a multitude of targeted therapies. The use of FLT3 inhibitors (FLT3i) in FLT3-mutated (FLT3
mut ) AML is one such development; however, the clinical decisions that govern their use and dictate the choice of the FLT3i are evolving. Midostaurin and gilteritinib are FDA-approved in specific situations; however, available data from clinical trials also shed light on the utility of sorafenib maintenance post-allogeneic stem cell transplantation (allo-SCT) and quizartinib as part of combination therapy in FLT3mut AML. The knowledge of the patient's concurrent myeloid mutations, type of FLT3 mutation, prior FLT3i use, and eligibility for allo-SCT helps to refine the choice of FLT3i. Data from ongoing studies will further precisely define their use and help in making more informed choices. Despite improvements in FLT3i therapy, the definitive aim is to enable the eligible patient with FLT3mut AML (esp. ITD) to proceed to allo-SCT with regimens containing FLT3i incorporated prior to SCT and as maintenance after SCT., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2022
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46. Prevention and management of carbapenem-resistant Enterobacteriaceae in haematopoietic cell transplantation.
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Sahitya DSK, Jandiyal A, Jain A, Senapati J, Nanda S, Aggarwal M, Kumar P, Mohapatra S, Ray P, Malhotra P, Mahapatra M, and Dhawan R
- Abstract
Carbapenem-resistant Enterobacteriaceae (CRE) infections are associated with high morbidity and mortality rates in haematopoietic cell transplantation (HCT) recipients. Factors like mucositis, neutropenia, prolonged hospital stay, and frequent use of prophylactic antimicrobials make HCT recipients especially susceptible to CRE infections. Low culture positivity rates, delay in microbiological diagnosis, and resistance to empirical antimicrobial therapy for febrile neutropenia are responsible for high mortality rates in HCT recipients infected with CRE. In this review we discuss the epidemiology, diagnosis, and management of CRE infections with particular emphasis on patients undergoing HCT. We emphasise the need for preventive strategies like multidisciplinary antimicrobial stewardship, and pre-emptive screening for CRE colonisation in prospective HCT patients as measures to mitigate the adverse impact of CRE on HCT outcomes. Newer diagnostic tests like polymerase chain reaction and matrix-assisted laser desorption ionisation-time of flight (MALDI-TOF) assay that enable earlier and better identification of CRE isolates are discussed. Antimicrobial agents available against CRE, including newer agents like ceftazidime-avibactam and meropenem-vaborbactam, have been reviewed. We also discuss the data on promising experimental treatments against CRE: phage therapy and healthy donor faecal microbiota transplant. Finally, this review puts forth recommendations as per existing literature on diagnosis and management of CRE infections in blood and marrow transplant (BMT) unit., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s), 2021.)
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- 2021
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47. Tele-Medicine Services in Hematological Practice During Covid Pandemic: Its Feasibility and Difficulties.
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Kumar P, Aggarwal M, Dhawan R, Dass J, Kumar G, Sharma V, Mirza S, Senapati J, Ganju N, Vaid T, Vijayran M, Panda T, Pragna GS, Krishna SS, Khandelwal A, Verghese R, Tyagi S, Seth T, and Mahapatra M
- Abstract
In COVID 19 pandemic, delivery and access of health care services have become challenging. Telemedicine services can be considered for management of patients with hematological diseases. This study included all patients who enrolled for telemedicine facility for hematology from May 15 to July 15, 2020. Patient's demographic and disease related parameters were recorded during the teleconsultation call. Overall satisfaction of attending doctor and patients were also recorded. A total of 1187 teleconsultation appointments were taken, of which 944 (79.6%) were successfully attended. Median age of patients was 38 years (range- 0.5-78 years), with 38% females. 55% of successful calls were from patients suffering a malignant hematological disorder. 24% had an active complaint pertaining to their disease or treatment. Of these, 162 (17%) were asked for a physical consultation. A significant association was found between the requirement of physical consultation and diagnosis ( p < 0.001), absence of active complaint (< 0.0001) and education level of responder ( p = 0.008). Patients understand that teleconsultation is helpful in preventing COVID-19 infection (71.4%) and avoids outpatient department rush (14.5%) associated with physical appointments; and around 80% patients were satisfied with the teleconsult. With the emergence of COVID 19, many localities under partial lockdown with constant fear of contacting virus amongst patients and health care providers, we can clearly see the advantages as well as feasibility of telemedicine services for our patients. The acute surge in telemedicine could be harnessed in the future to provide comprehensive and integrated care to patients of hematological disorders., (© Indian Society of Hematology and Blood Transfusion 2020.)
- Published
- 2021
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48. Effect of MRI acquisition acceleration via compressed sensing and parallel imaging on brain volumetry.
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Dieckmeyer M, Roy AG, Senapati J, Wachinger C, Grundl L, Döpfert J, Bertran PF, Lemke A, Zimmer C, Kirschke JS, and Hedderich DM
- Subjects
- Adult, Cerebrospinal Fluid diagnostic imaging, Female, Gray Matter diagnostic imaging, Healthy Volunteers, Humans, Image Processing, Computer-Assisted, Imaging, Three-Dimensional, Magnetic Resonance Imaging standards, Male, Neuroimaging, Parenchymal Tissue diagnostic imaging, Reproducibility of Results, White Matter diagnostic imaging, Acceleration, Brain diagnostic imaging, Magnetic Resonance Imaging methods
- Abstract
Objectives: To investigate the effect of compressed SENSE (CS), an acceleration technique combining parallel imaging and compressed sensing, on potential bias and precision of brain volumetry and evaluate it in the context of normative brain volumetry., Materials and Methods: In total, 171 scans from scan-rescan experiments on three healthy subjects were analyzed. Each subject received 3D-T1-weighted brain MRI scans at increasing degrees of acceleration (CS-factor = 1/4/8/12/16/20/32). Single-scan acquisition times ranged from 00:41 min (CS-factor = 32) to 21:52 min (CS-factor = 1). Brain segmentation and volumetry was performed using two different software tools: md.brain, a proprietary software based on voxel-based morphometry, and FreeSurfer, an open-source software based on surface-based morphometry. Four sub-volumes were analyzed: brain parenchyma (BP), total gray matter, total white matter, and cerebrospinal fluid (CSF). Coefficient of variation (CoV) of the repeated measurements as a measure of intra-subject reliability was calculated. Intraclass correlation coefficient (ICC) with regard to increasing CS-factor was calculated as another measure of reliability. Noise-to-contrast ratio as a measure of image quality was calculated for each dataset to analyze the association between acceleration factor, noise and volumetric brain measurements., Results: For all sub-volumes, there is a systematic bias proportional to the CS-factor which is dependent on the utilized software and subvolume. Measured volumes deviated significantly from the reference standard (CS-factor = 1), e.g. ranging from 1 to 13% for BP. The CS-induced systematic bias is driven by increased image noise. Except for CSF, reliability of brain volumetry remains high, demonstrated by low CoV (< 1% for CS-factor up to 20) and good to excellent ICC for CS-factor up to 12., Conclusion: CS-acceleration has a systematic biasing effect on volumetric brain measurements., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
49. Venetoclax and azacitidine (VenAZA) combination therapy in young unfit patients with AML: a perspective from a developing country.
- Author
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Senapati J, Dhawan R, Aggarwal M, Kumar P, Kumar Vishwanathan G, Dass J, Tyagi S, Mahapatra M, and Seth T
- Subjects
- Bridged Bicyclo Compounds, Heterocyclic, Developing Countries, Humans, Sulfonamides, Azacitidine, Leukemia, Myeloid, Acute drug therapy
- Published
- 2021
- Full Text
- View/download PDF
50. Transfusion practices during the COVID-19 pandemic: An experience from a hematology daycare in India.
- Author
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Senapati J, Aggarwal M, Louis L, Mirza SA, Kumar P, Dhawan R, Dass J, Vishwanathan GK, Pandey HC, Coshic P, Tyagi S, Seth T, and Mahapatra M
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Female, Hematology, Humans, India epidemiology, Infant, Male, Middle Aged, Retrospective Studies, Blood Component Transfusion, COVID-19 epidemiology, COVID-19 therapy, Pandemics, Platelet-Rich Plasma, SARS-CoV-2
- Abstract
The Coronavirus disease-19 (COVID-19) pandemic has in multiple ways affected healthcare delivery to non-COVID patients throughout the world. Adequate transfusion services are fundamental in ongoing therapy of patients with hematological ailments. We present the transfusion services in the hematology daycare under the department of Hematology and supported by the Blood Bank at our institution for the period 12th April 2020-30th June 2020, which saw the stringent lockdown and unlocking Phase I in India, declared in lieu of the pandemic. A 56 % reduction in total transfusion sessions was observed in 2020 (588 sessions given to 176 patients) compared to 1336 sessions in 516 patients over the same period in 2019. The reductions were seen across the different blood components (packed red blood cells [PRBC]: 585 vs. 1840, platelet rich plasma: 372 vs. 1313, single donor platelet 18 vs. 16), with a significant reduction in the mean PRBC transfused per PRBC transfusion session (1.11 vs 1.99, p<0.001) in 2020, compared to 2019. There were however no major differences in the transfusion practices across the different phases of the lockdown. Our study highlights the detrimental reduction in transfusion services due to the COVID-19 pandemic and related lockdown and showcases the remedial strategies taken to maximize transfusion support to patients during this period. Our observations might help to provide insights to adequately combat possible similar adverse situations in the future., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
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