Activity of Venetoclax-Based Therapy in CMML and CMML with Blast Transformation

Introduction: There are no standard salvage options for patients (pts) with chronic myelomonocytic leukemia (CMML) after progressing on hypomethylating agents (HMA). Outcomes are especially poor after blast transformation (BT). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an efficacious treatment for pts with AML. To the best of our knowledge, the outcomes of VEN based therapies specifically in CMML, with or without BT, have not been reported.

Methods: We retrospectively reviewed pts with CMML, both with and without BT, treated with VEN-based therapy at our institution from 2016 to present. Mutation testing at baseline (N=31) and loss of response was performed using an amplicon-based next-generation sequencing panel. Pts were stratified according to CPSS-Mol and whether VEN was given for chronic vs. transformed disease. Responses for CMML and CMML-BT were defined by IWG 2006 and ELN 2017 criteria, respectively. Cox proportional hazard regression and the Kaplan-Meir product limit method were used to study association of variables with survival. Overall survival was defined as the time from start of VEN therapy to death or last follow up and was not censored at date of transplant.

Results: Thirty-two pts were identified: 17 CMML, 15 CMML-BT. Pt characteristics are shown in Figure 1A. The median age was 70 years in both groups; most pts were men with a PS of 0-1. The majority of pts treated for CMML had proliferative subtype (53%) and CPSS-Mol intermediate-2/high (76%) risk disease at diagnosis. Both groups were enriched for diploid karyotype (53 and 60%). Frequency of mutations prior VEN-based therapy are shown in Figure 1B; TET2 (71%), ASXL1 (55%), RUNX1 (45%), and NRAS (39%) were the most common. Forty-one percent (CMML) and 67% (BT) of pts had received ≥2 previous lines of therapy, and most (88% CMML, 87% BT) received VEN following HMA failure. The median per-cycle dosing of VEN was 100 mg x 14 days (CMML) and 200 mg x 21 days (BT). VEN was given in combination with HMA in 76% of the CMML group, whereas in the BT group it was partnered with HMA (47%), intensive chemotherapy (20%), or other agents (33%). Almost all pts were concurrently on a triazole antifungal. Forty-seven percent of pts in both groups required admission to hospital for infection and/or fever while on VEN. After a median of 1 (range 1-6 CMML, 1-16 BT) cycle in both groups, ORR was 59% (CR 0%, mCR 53%, PR 6%) in the CMML and 67% (CR/CRi 53%, MLFS 7%, PR 7%) in the BT group. Five out of the 7 pts in the BT group with CR/CRi responses and evaluable MRD by flow cytometry (sensitivity 0.01%) were MRD negative. Presence of a RAS pathway mutation was associated with lower likelihood of achieving CR (17% vs 83%, OR 5.5, 95% CI 0.92-33.2, p<0.001), NPM1 mutations with higher likelihood of CR (100% vs 14%, p=0.032) and RUNX1 with a trend to higher ORR (OR 4.13, 95% CI 0.84-29.28, p=0.081). Two pts had IDH mutations and both achieved CR. Thirty percent of responding pts in both groups were bridged directly to SCT. Four pts (24%) in the CMML group had leukemic transformation on VEN, all within the first 6 months on therapy. Excluding 1 outlier in the BT group, the median duration of response was 4.0 and 5.6 months in CMML and BT, respectively. Emergence of previously undetectable mutations at relapse on VEN occurred in 6 pts; half of these mutations involved the RAS pathway (Figure 1B). With a median follow-up of 10.9 and 23.4 months from initiation of VEN-based therapy, the median OS was 9.0 and 10.7 months in the CMML and BT groups, respectively (Figure 1C). Presence of RAS pathway mutations was associated with a trend to shorter survival among pts with BT (median OS 1 vs 14 months, p=0.059), but not in CMML (median OS 9.0 vs 3.5 months, p=0.076) (Figure 1D).

Conclusions: Combination therapy with venetoclax has activity in both CMML and secondary AML arising out of CMML, even in the challenging setting of relapsed/refractory disease post HMA failure. It appears particularly useful as a means to clear excess marrow blasts and to serve as a bridge to allogeneic SCT. Without a subsequent consolidative strategy, however, response durations are short. RAS pathway mutations were associated with lower likelihood of CR and often emerge at relapse. NPM1 mutations predict for CR and RUNX1 mutations are associated with a trend to higher ORR. The high incidence of neutropenic infections in this cohort suggests that venetoclax dosing should be carefully tailored to minimize myelosuppression.