TOPLINE: 

An alternating regimen of cladribine plus low-dose cytarabine and venetoclax with azacitidine plus venetoclax yielded high rates of composite complete remission (CRc) and measurable residual disease (MRD)‑negative status and was associated with prolonged survival in patients with newly diagnosed acute myeloid leukemia (AML). Among 190 patients, 84% achieved CRc, and 75% achieved MRD-negative remission; the median overall survival (OS) was 52 months, and 43% of responders proceeded to allogeneic hematopoietic stem cell transplantation (HSCT).

METHODOLOGY: 

• Venetoclax combined with hypomethylating agents improves remission rates in older or unfit patients with AML but only modestly improves long‑term survival and has limited efficacy in genomically defined subgroups (ie, patients with TP53, RAS, and FLT3‑ITD mutations). Purine nucleoside analogues such as cladribine have shown synergy with venetoclax and potential activity in genomically defined, venetoclax‑resistant subtypes of AML. This study tested the efficacy of an alternating cladribine-cytarabine-venetoclax and azacitidine-venetoclax regimen to increase the chance of deep remissions.
• This single-center, open-label, single-arm phase 2 study enrolled 190 patients (median age, 68 years) with newly diagnosed AML who were unsuitable for intensive chemotherapy. Overall, 14% had therapy-related AML, 19% had secondary AML, and 48% had AML with myelodysplasia-related gene mutations; the most frequent mutations were in DNMT3A (26%), TET2 (22%), TP53 (19%), SRSF2 (19%), and NPM1 (18%).
• Participants received induction with cladribine 5 mg/ m² intravenously, low‑dose cytarabine 20 mg subcutaneously twice daily, and venetoclax ramped to 400 mg in a 28‑day cycle. Consolidation alternated cladribine-low-dose cytarabine-venetoclax with azacitidine 75 mg/ m² plus venetoclax, with the duration of venetoclax administration shortened (7-14 days) based on MRD (O) status.
• The primary outcome was CRc (defined as complete remission or complete remission with incomplete blood count recovery) within the first two cycles; secondary outcomes included OS, disease-free survival, event-free survival, toxicity, and induction mortality. The median follow-up duration was 30 months.
• Cytogenetic analysis was performed using conventional karyotyping and fluorescence in situ hybridization, and mutational analysis using an 81-gene next-generation sequencing panel; MRD was assessed using an eight-color multiparameter flow cytometer with a sensitivity of 0.01%-0.1%. 

TAKEAWAY: 

• Overall, the rate of CRc was 84% (160/190), including 73% for complete remission and 12% for complete remission with incomplete blood count recovery. Among responders, 75% achieved MRD-negative status, 20% had detectable MRD, and 43% proceeded to allogeneic HSCT after a median of two cycles of therapy.
• By TP53 mutational status, the rate of CRc among patients with TP53 wild-type vs TP53-mutated AML was 91.5% vs 51.1%; single-hit vs multi-hit mutational status was associated with a higher 2-year OS rate (83% vs 33%).
• The median OS rate was 52 months, and the median event-free survival was 50 months; the 2‑ and 5‑year OS rates were 60% and 45%, respectively, and the 2‑ and 5‑year EFS rates were 56% and 43%, respectively. Among patients who achieved a response, the median disease-free survival was 51 months, and the 2- and 5-year disease-free survival rates were 62% and 50%, respectively.
• The 2-year OS rates for groups stratified according to the European LeukemiaNet 2024 classification were 69% for favorable risk, 59% for intermediate risk, and 35% for adverse risk (P < .001); by MRD status, the 2-year overall survival rate was 70% among patients with MRD-negative CRc vs 38% among those with MRD-positive status (P < .001). Patients with MRD-positive vs MRD-negative status had a higher incidence of relapse (2-year cumulative incidence, 44.6% vs 13.6%).
• Early mortality was low, with 4-week and 8-week mortality rates being 1% and 3%, respectively, and the median time to absolute neutrophil count recovery (> 1 × 10⁹/L) and platelet count recovery (> 100 × 10⁹/L) after induction was 27 and 24 days, respectively. Adverse events of grade 3-4 occurred in 47% of patients, most commonly infections: febrile neutropenia (20%), lung infection (12%), and sepsis (5%); 12 deaths occurred during the study period.

IN PRACTICE:

The results "demonstrate cladribine, low‑dose cytarabine, and venetoclax alternating with azacitidine plus venetoclax is a highly effective and tolerable lower‑intensity regimen for older patients with AML," the authors wrote, adding that "high levels of measurable residual disease‑negative complete remissions and rates of HSCT may allow exploration of this approach in select patients younger than age 60 years and as an alternative to standard 7 + 3," and that the regimen "may be preferable to hypomethylating agent plus venetoclax in certain genetic subgroups (RAS, NPM1) and is an effective bridge to allogeneic HSCT."

SOURCE:

The study, led by Tapan M. Kadia, MD, The University of Texas MD Anderson Cancer Center in Houston, was published online in American Journal of Hematology.

LIMITATIONS: 

The study was single‑center and single‑arm, and the findings could not be extrapolated to community settings. Certain subgroups, such as ones with treated‑secondary AML, were underrepresented, limiting generalizability.

DISCLOSURES:

The study received funding through The University of Texas MD Anderson Cancer Center Support Grant. Kadia disclosed receiving consulting fees from Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, Agios, Daiichi Sankyo/UCB Japan, Liberum, Sanofi, Servier, Pinot Bio, Sellas Life Sciences, and Bristol Myers Squibb/Celgene; and research funding from Bristol Myers Squibb, Celgene, Amgen, BioLineRx, Incyte, Genentech/AbbVie, Pfizer, and other sources. Full disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.