Browsing by Author "Hiwase, Devendra"

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    Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial
    (Springer Nature, 2021-08-28) Ravandi, Farhad; Roboz, Gail J.; Wei, Andrew H.; Döhner, Hartmut; Pocock, Christopher; Selleslag, Dominik; Montesinos, Pau; Sayar, Hamid; Musso, Maurizio; Figuera‑Alvarez, Angela; Safah, Hana; Tse, William; Sohn, Sang Kyun; Hiwase, Devendra; Chevassut, Timothy; Pierdomenico, Francesca; La Torre, Ignazia; Skikne, Barry; Bailey, Rochelle; Zhong, Jianhua; Beach, C. L.; Dombret, Herve; Medicine, School of Medicine
    Background: Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors' clinical experience treating patients in the trial. Methods: QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. Results: A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1-80) oral azacitidine treatment cycles or 6 (1-73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3-4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. Conclusion: Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy.
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    Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41
    (American Society of Hematology, 2023) Homan, Claire C.; Drazer, Michael W.; Yu, Kai; Lawrence, David M.; Feng, Jinghua; Arriola-Martinez, Luis; Pozsgai, Matthew J.; McNeely, Kelsey E.; Ha, Thuong; Venugopal, Parvathy; Arts, Peer; King-Smith, Sarah L.; Cheah, Jesse; Armstrong, Mark; Wang, Paul; Bödör, Csaba; Cantor, Alan B.; Cazzola, Mario; Degelman, Erin; DiNardo, Courtney D.; Duployez, Nicolas; Favier, Remi; Fröhling, Stefan; Rio-Machin, Ana; Klco, Jeffery M.; Krämer, Alwin; Kurokawa, Mineo; Lee, Joanne; Malcovati, Luca; Morgan, Neil V.; Natsoulis, Georges; Owen, Carolyn; Patel, Keyur P.; Preudhomme, Claude; Raslova, Hana; Rienhoff, Hugh; Ripperger, Tim; Schulte, Rachael; Tawana, Kiran; Velloso, Elvira; Yan, Benedict; Kim, Erika; Sood, Raman; Hsu, Amy P.; Holland, Steven M.; Phillips, Kerry; Poplawski, Nicola K.; Babic, Milena; Wei, Andrew H.; Forsyth, Cecily; Fan, Helen Mar; Lewis, Ian D.; Cooney, Julian; Susman, Rachel; Fox, Lucy C.; Blombery, Piers; Singhal, Deepak; Hiwase, Devendra; Phipson, Belinda; Schreiber, Andreas W.; Hahn, Christopher N.; Scott, Hamish S.; Liu, Paul; Godley, Lucy A.; Brown, Anna L.; NISC Comparative Sequencing Program; Pediatrics, School of Medicine
    Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.