Venetoclax Combined with Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Produces High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.2647-2647
• Main Authors: Kadia, Tapan M., Cortes, Jorge E., Konopleva, Marina Y, Borthakur, Gautam M., Pemmaraju, Naveen, Daver, Naval G., Montalban Bravo, Guillermo, Issa, Ghayas C., Naqvi, Kiran, Short, Nicholas J., DiNardo, Courtney D., Bhalla, Kapil N., Jabbour, Elias, Takahashi, Koichi, Sasaki, Koji, Kornblau, Steven M., Malla, Rashmi, Pierce, Sherry A., Wang, Xuemei, Estrov, Zeev E., Andreeff, Michael, Garcia-Manero, Guillermo, Ravandi, Farhad, Kantarjian, Hagop M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-122477

Treatment of older patients with newly diagnosed AML remains challenging, 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 decitabine for older patients with AML, yielding higher rates of CR and improved outcomes compared to historical experience with hypomethylating agents (HMAs) in this setting (Lancet Haematology 2018). Recently, the combination of the BCL-2 inhibitor venetoclax with HMAs demonstrated significant improvements in response rates and survival over experience with HMAs alone. We hypothesized that the addition of venetoclax to the CLAD/LDAC backbone may further improve response rates and outcomes for this group of patients. We designed 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). Induction was cladribine 5 mg/m2 IV over 30 minutes on days 1-5 followed by araC 20mg SQ BID on days 1-10. Consolidation/maintenance consisted of 2 cycles of cladribine 5 mg/m2 IV over 30 minutes on days 1-3 + araC 20 mg SQ BID on days 1-10 alternating with 2 cycles of AZA 75 mg/m2 on days 1-7, for up to 18 cycles. Venetoclax was added on days 1-21 of each cycle with dose adjustments (50-400 mg) for concomitant CYP3A inhibitors. One cycle was 4 weeks and up to 2 cycles of induction were allowed. All patients underwent pre-treatment cytogenetic analysis and mutational testing using a customized 81-gene next generation sequencing panel. MRD was assessed using multiparameter flow cytometry in the marrow at the time of remission. Twenty-six patients have been treated on study, with a median age of 69 yrs (57-84); 11 (42%) pts were ≥ 70 yrs and 1 pt < 60 yrs who was unfit for intensive chemotherapy was enrolled. The baseline patient characteristics are summarized in Table 1. Among 24 evaluable pts, 18 (75%) achieved a complete remission (CR), 3 (13%) had a CR with incomplete platelet recovery (CRp), and 1 (4%) had CR with incomplete neutrophil recovery (CRn) for a CR/CRp rate of 88% an overall response rate of 92%. The median number of cycles to response was 1 (1-3) and 83% of pts were negative for MRD by multi-parameter flow cytometry at the time of CR. Among 9 evaluable pts with diploid karyotype, the CR rate was 100% with full count recovery. Rates of CR/C