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Adding Venetoclax to Cladribine + Low-Dose Cytarabine Alternating with Azacitidine Is Effective and Well-Tolerated by Older Patients with AML

Conference Correspondent

This was a phase 2 clinical trial assessing the addition of venetoclax (VEN) to a low-intensity backbone of cladribine (CLAD) plus low-dose Ara-C (LDAC) alternating with 5-azacitidine (AZA) among older adults with acute myeloid leukemia (AML). The hypothesis of this study was that this regimen would improve response rates and outcomes in this population.

This study included patients with newly diagnosed AML who were aged ≥60 years, younger patients who were unfit for intensive chemotherapy. Patients with acute promyelocytic leukemia or core binding factor leukemia were excluded. Induction was comprised of CLAD 5 mg/m2 IV over 30 minutes on days 1 to 5 followed by Ara-C 20 mg subcutaneously twice daily on days 1 to 10. Consolidation and maintenance included 2 cycles of CLAD 5 mg/m2 intravenously on days 1 to 3 plus Ara-C 20 mg subcutaneously twice daily on days 1-10 alternating with 2 cycles of AZA 75 mg/m2 on days 1 to 7, for up to 18 cycles. Venetoclax 400 mg was added on days 1 to 21 of each cycle, with dose adjustments for concomitant CYP3A inhibitors. Each cycle was 4 weeks with ≤2 induction cycles allowed.

In total, 55 patients were treated with a median age of 68 years (range, 57-84 years). Twenty-two patients (40%) were aged ≥70 years. One patient was enrolled was <60 years of age and unfit for intensive chemotherapy. Adverse karyotype was present in 12 (25%) patients. There were 54 evaluable patients. The number of patients achieving a complete remission (CR) and a CR with incomplete hematologic recovery (CRi) was 42 (78%) and 8 (15%), respectively. Thus, the CR/CRi rate was 93%. The median number of cycles to response was 1 (range, 1-3). A total of 42 (84%) patients were negative for minimal disease residual (MRD) at the time of CR/CRi as assessed by multiparameter flow cytometry. The MRD-negativity rate was 93% in patients achieving CR. Among patients with adverse karyotype, the CR/CRi rate was 100%. Treatment was well-tolerated. The 4-week and 8-week morality rates were 2% and 4%, respectively. The most frequent nonhematologic grade 3/4 adverse events (AEs) were infections (14; neutropenic fever, pneumonia, bacteremia, and colitis). Additional grade 3/4 AEs were arthralgia (1), mucositis (1), constipation (1), and increased creatinine (2). The median overall survival (OS) for patients moving on to allogeneic stem-cell transplantation has not been reached (NR), with a 6-month OS of 86% and a 12-month OS rate of 69%. The median OS of patients with MRD-negativity was 11.8 months and the median OS of patients with MRD-negativity status was NR (P = .003).

In summary, VEN alternating with AZA and VEN plus CLAD/LDAC was an effective, lower-intensity regimen that was well-tolerated among older patients with newly diagnosed AML. This combination produced meaningful blood count recovery and high rates of durable MRD-negative remission. With a follow-up duration of approximately 1 year, the observed rates of OS and relapse-free survival among older patients with AML are encouraging.

Reference

Kadia TM, Borthakur G, Pemmaraju N, et al. Phase II Study of Venetoclax Added to Cladribine plus Low Dose AraC (LDAC) Alternating with 5-Azacitidine Demonstrates High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) and Excellent Tolerability in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML). Presented at: 62nd American Society of Hematology Annual Meeting & Exposition; December 5-8, 2020. Abstract 25.

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