Phase II Study of Venetoclax Added to Cladribine + 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)

Background
Treatment of older patients with newly diagnosed AML has been limited by modest response rates with low-intensity therapy and higher levels of toxicity with intensive therapy. We previously reported on a low-intensity backbone of cladribine + LDAC (CLAD/LDAC) alternating with hypomethylating agent (HMA) for older patients with AML, yielding higher rates of CR and improved outcomes compared to HMAs alone. Recently, addition of the BCL-2 inhibitor venetoclax to HMAs was shown, in a randomized study, to improve survival over HMAs alone. We hypothesized that the addition of venetoclax to the low intensity CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients.

Methods
This is a phase II clinical trial studying the combination of venetoclax with CLAD/LDAC alternating with 5-azacytidine (AZA) in older (age ≥ 60y) or unfit patients with newly diagnosed AML (excluding APL, CBF). Induction was cladribine 5 mg/m2 IV over 30 minutes on D1-5 followed by araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV on D1-3 + araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 cycles. Venetoclax 400 mg was added on days 1-21 of each cycle with dose adjustments for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed.

Results
A total of 48 patients were treated on study, with a median age of 68 yrs (57-84); 18 (38%) pts were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. 12 (25%) patients had secondary AML (sAML) and 12 (25%) had adverse karyotype. The baseline patient characteristics are summarized in Table 1. Among 48 evaluable pts, 37 (77%) achieved a complete remission (CR), 8 (17%) had a CR with incomplete count recovery (CRi) for a CR/CRi rate of 94%. The median number of cycles to response was 1 (1-3) and 36 (80%) pts were negative for MRD by multi-parameter flow cytometry at the time of CR/CRi. Among the subset of patients who had CR with complete count recovery, the MRD negative rate was 92% (34/37). Among pts with sAML or with adverse karyotype, the CR/CRi rate was 83% (58%/25%) and 83% (50%/33%), respectively. The regimen was well tolerated, with 4- and 8-week mortality rates of 0% and 6%, respectively. The most frequent grade 3/4 non-heme adverse events were neutropenic fever (n=20), lung infection (9), decreased urine output (2), nausea (1), acute kidney injury (1), dizziness (1), and mucositis (1). Eleven (24%) of the 45 responding pts proceeded with allogeneic stem cell transplant (SCT). With a median follow-up of 11+ months, the median overall survival (OS) has not been reached (NR), with 6- and 12-month OS rates of 86% and 70%, respectively (Figure 1). The median OS of pts with or without MRD at CR were 10.7m and NR, respectively (P=0.056). For pts with sAML vs. de novo AML, the median OS was 10.6m vs. NR, respectively (P=0.09). OS by cytogenetic risk is shown in Figures 2. OS among different subgroups are summarized in Table. The median RFS was not reached, with 6- and 12-month RFS rates of 79% and 64%, respectively.

Conclusion
CLAD/LDAC plus venetoclax alternating with AZA plus venetoclax is an effective, lower-intensity regimen that is well tolerated among older patients with newly diagnosed AML, producing high rates of durable MRD negative remission and meaningful blood count recovery. With approximately 1-year follow-up, the rates of overall and relapse-free survival are encouraging in this cohort of older AML patients. Further study of this backbone in combination approaches is warranted.