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10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.

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SUBMITTER: DiNardo CD

PROVIDER: S-EPMC7549397 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.

DiNardo Courtney D CD Maiti Abhishek A Rausch Caitlin R CR Pemmaraju Naveen N Naqvi Kiran K Daver Naval G NG Kadia Tapan M TM Borthakur Gautam G Ohanian Maro M Alvarado Yesid Y Issa Ghayas C GC Montalban-Bravo Guillermo G Short Nicholas J NJ Yilmaz Musa M Bose Prithviraj P Jabbour Elias J EJ Takahashi Koichi K Burger Jan A JA Garcia-Manero Guillermo G Jain Nitin N Kornblau Steven M SM Thompson Philip A PA Estrov Zeev Z Masarova Lucia L Sasaki Koji K Verstovsek Srdan S Ferrajoli Alessandra A Weirda William G WG Wang Sa A SA Konoplev Sergej S Chen Zhining Z Pierce Sherry A SA Ning Jing J Qiao Wei W Ravandi Farhad F Andreeff Michael M Welch John S JS Kantarjian Hagop M HM Konopleva Marina Y MY

The Lancet. Haematology 20200905 10

<h4>Background</h4>Venetoclax combined with hypomethylating agents is a new standard of care for newly diagnosed patients with acute myeloid leukaemia (AML) who are 75 years or older, or unfit for intensive chemotherapy. Pharmacodynamic studies have suggested superiority of the longer 10-day regimen of decitabine that has shown promising results in patients with high-risk AML in phase 2 trials. We hypothesised that venetoclax with 10-day decitabine could have improved activity in patients with n ...[more]

PMID: 32896301

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Project description:BackgroundDiagnosis of acute myeloid leukemia (AML) is associated with poor outcome in elderly and unfit patients. Recently, approval of the BCL-2 inhibitor venetoclax (VEN) in combination with hypo-methylating agents (HMA) led to a significant improvement of response rates and survival. Further, application in the relapsed or refractory (r/r) AML setting or in context of allogeneic stem cell transplantation (alloHSCT) seems feasible.Methods and patientsFifty-six consecutive adult AML patients on VEN from January 2019 to June 2021 were analyzed retrospectively. Patients received VEN either as first-line treatment, as subsequent therapy (r/r AML excluding prior alloHSCT), or at relapse after alloHSCT. VEN was administered orally in 28-day cycles either combined with HMA or low-dose cytarabine (LDAC).ResultsAfter a median follow-up of 11.5 (range 6.1-22.3) months, median overall survival (OS) from start of VEN treatment was 13.3 (2.2-20.5) months, 5.0 (0.8-24.3) months and 4.0 (1.5-22.1) months for first-line, subsequent line treatment and at relapse post-alloHSCT, respectively. Median OS was 11.5 (10-22.3) months from start of VEN when subsequent alloHSCT was carried out. Relapse-free survival (RFS) for the total cohort was 10.2 (2.2 - 24.3) months. Overall response rate (composite complete remission + partial remission) was 51.8% for the total cohort (61.1% for VEN first-line treatment, 52.2% for subsequent line and 42.8% at relapse post-alloHSCT). Subgroup analysis revealed a significantly reduced median OS in FLT3-ITD mutated AML with 3.4 (1.9-4.9) months versus 10.4 (0.8-24.3) months for non-mutated cases, (HR 4.45, 95% CI 0.89-22.13, p = 0.0002). Patients harboring NPM1 or IDH1/2 mutations lacking co-occurrence of FLT3-ITD showed a survival advantage over patients without those mutations (11.2 (5-24.3) months versus 5.0 (0.8-22.1) months, respectively, (HR 0.53, 95% CI 0.23 - 1.21, p = 0.131). Multivariate analysis revealed mutated NPM1 as a significant prognostic variable for achieving complete remission (CR) (HR 19.14, 95% CI 2.30 - 436.2, p < 0.05). The most common adverse events were hematological, with grade 3 and 4 neutropenia and thrombocytopenia reported in 44.6% and 14.5% of patients, respectively.ConclusionDetailed analyses on efficacy for common clinical scenarios, such as first-line treatment, subsequent therapy (r/r AML), and application prior to and post-alloHSCT, are presented. The findings suggest VEN treatment combinations efficacious not only in first-line setting but also in r/r AML. Furthermore, VEN might play a role in a subgroup of patients with failure to conventional chemotherapy as a salvage regimen aiming for potential curative alloHSCT.

Project description:BackgroundHypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules.MethodsEligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or <60 years if unsuitable for intensive chemotherapy with an anthracycline plus cytarabine). The first 40 patients were allocated equally to the two treatment groups by computer-generated block randomisation (block size 40), after which a response-adaptive randomisation algorithm used all previous patients' treatment and response data to decide the allocation of each following patient favouring the group with superior response. Patients were assigned to receive 20 mg/m2 decitabine intravenously for 5 or 10 consecutive days as induction therapy, every 4-8 weeks for up to three cycles. Responding patients received decitabine as consolidation therapy on a 5-day schedule for up to 24 cycles. We assessed a composite primary endpoint of complete remission, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete haematological recovery (CRi) achieved at any time and assessed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01786343.FindingsBetween Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26-60, and 17 [40%] of 43 in the 10-day schedule group, 26-54, p=0·78; difference 3%, -21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1-11·7) in the 5-day group and 6·0 months (1·9-11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3-4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups.InterpretationIn older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule.FundingUniversity of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.

Dataset Information

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.

Publications

10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.

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