This article reviews the results of a phase 2 clinical trial studying the combination of venetoclax with the low-intensity backbone of cladribine (CLAD) plus low-dose Ara-C (LDAC) alternating with 5-azacitidine (AZA) in older adults with acute myeloid leukemia (AML). The hypothesis of this study was that the addition of venetoclax to the low-intensity CLAD/LDAC backbone would improve response rates and outcomes for these patients.
Patients eligible for this study were aged ≥60 years, or younger patients unfit for intensive chemotherapy, with newly diagnosed AML (excluding acute promyelocytic leukemia or core binding factor leukemia). Induction included CLAD 5 mg/m2 intravenously 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 consisted of 2 cycles of CLAD 5 mg/m2 intravenously on days 1 to 3 plus Ara-C 20 mg subcutaneously twice daily on days 1 to 10 alternating with 2 cycles of AZA 75 mg/m2 on days 1 to 7, for up to 18 cycles. Venetoclax 400 mg, with dose adjustments for concomitant CYP3A inhibitors, was added on days 1 to 21 of each cycle. Each cycle was 4 weeks and no more than 2 cycles of induction were allowed.
A total of 55 patients were treated. The median age was 68 years (range, 57-84 years) with 22 (40%) patients aged ≥70 years. A single patient aged <60 years was enrolled due to being unfit for intensive chemotherapy. Twelve (25%) patients had adverse karyotype. Of the 54 evaluable patients, 42 (78%) achieved a complete remission (CR) and 8 (15%) had a CR with incomplete hematologic recovery (CRi), resulting in a 93% CR/CRi rate. The median number of cycles to response was 1 (range, 1-3). At the time of CR/CRi, 42 (84%) patients were negative for minimal disease residual (MRD) by multiparameter flow cytometry. Among the subset of patients in CR, the MRD-negativity rate was 93%. The CR/CRi rate among patients with adverse karyotype was 100%. Treatment was well-tolerated with a 4-week mortality rate of 2% and an 8-week mortality rate of 4%. The most frequent grade 3/4 nonhematologic adverse events were infections (N = 14), including neutropenic fever, pneumonia, bacteremia, and colitis. Grade 3/4 AEs also included arthralgia, mucositis, constipation, and dyspnea (N = 1 each) as well as increased creatinine (N = 2). For patients who proceeded to allogeneic stem-cell transplant, median overall survival (OS) has not been reached (NR), with 6- and 12-month OS rates of 86% and 69%, respectively. The median OS of patients with MRD-positive versus MRD-negative status while at CR was 11.8 months versus NR, respectively (P = .003).
In conclusion, CLAD/LDAC plus venetoclax alternating with AZA plus venetoclax was an effective, lower-intensity regimen that was well-tolerated among older patients with newly diagnosed AML and produced high rates of durable MRD-negative remission and meaningful blood count recovery. The current rates of OS and relapse-free survival are encouraging in this cohort of older AML patients with a follow-up duration of approximately 1 year.
Kadia TM, Borthakur G, Pemmaraju N, et al. Phase II Study of Venetoclax Added to Cladribine plus Low Dose AraC (LDAC) Alternating with 5-Azacytidine 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.