Hypomethylating agents plus venetoclax for high-risk MDS and CMML as bridge therapy to transplant: a GESMD study

Abstract

Background: High-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) remain therapeutic challenges with suboptimal outcomes. The only potentially curative treatment is allogeneic stem cell transplantation (allo-SCT). The most frequent pre-allo-SCT treatment is monotherapy with hypomethylating agents (HMA), but approximately 40% of patients cannot proceed to allo-SCT, mainly due to disease progression. Recent evidence suggests that combining HMA with venetoclax (HMA/VEN) could increase HMA efficacy in HR-MDS but it remains unclear if this combination could bridge more patients to allo-SCT.

Methods: We retrospectively evaluated HMA/VEN as a bridge to allo-SCT in 30 patients with HR-MDS or CMML eligible for transplant. Eighteen patients were treatment-naïve and 12 were refractory or relapsed (R/R).

Results: As defined by the IWG 2023 criteria, the overall response rate (ORR) was 90% and the composite complete response rate was 77%. For the R/R patients, ORR was 83%. The allo-SCT rate was 83%, and the allo-SCT rate of those patients treated exclusively with HMA/VEN without further bridge therapies was 76%. One- and two-year post-allo-SCT survival was 75% and two-year cumulative incidence of relapse was 30.5%. Follow-up of measurable residual disease identified some molecular relapses that were controlled with preemptive treatment.

Conclusions: Our findings indicate that HMA/VEN combination therapy shows promise as a bridging strategy to allo-SCT in HR-MDS and CMML.

Keywords: Allo-SCT; Bridge therapy; CMML; Cytoreductive therapy; HMA/VEN; MDS; MDS/MPN; MRD; Molecular follow-up.

Fig. 1

Flow chart of patients included in the study. Allo-SCT allogenic stem-cell transplant, MDS myelodysplastic syndrome, CMML chronic myelomonocytic leukemia, aCML atypical chronic myeloid leukemia, NR no response, PD progressive disease, mCR marrow complete response (by Savona criteria)

Fig. 2

Oncoplot showing the mutational landscape of high-risk MDS/CMML patients A at baseline, B pre-allo-SCT, and C at relapse. Blue squares indicate mutations; grey squares indicate wild-type; white squares indicate untested; red squares indicate acquired mutations; green squares indicate lost mutations. The frequency (%) of each gene mutation can be seen on the right side of the plot. The number of mutations (n) is shown at the top

Fig. 3

A Alluvial plot of the best responses achieved according to the International Working Group (IWG) 2006, IWG 2023, and European Leukemia Net (ELN) 2022 criteria. B Summary of responses for treatment-naïve patients, R/R patients, HR-MDS patients, CMML patients, and TP53-mutated patients. CR complete response, CR_L complete response with limited count recovery, CRh complete response with hematologic recovery, CRi complete response with incomplete recovery, mCR marrow complete response, HI hematologic improvement, PR partial response, NR no response, PD progressive disease, ORR overall response rate, CRc composite complete response rate

Fig. 4

Swimmer plot of treatment duration, best response, allo-SCT and relapse for each patient. HMA/VEN was started at time 0. White areas indicate the duration HMA/VEN treatment. Grey areas indicate the duration of follow-up. Black squares indicate the time of allo-SCT. Colored dots indicate the time of best response. Red triangles indicate the time of relapse. The status of each patient (alive or deceased) at the time of data cutoff is shown at the end of each bar

Fig. 5

Overall survival (OS) and cumulative incidence of relapse (CIR). A OS of the entire cohort. B Post-allo-SCT OS of the 23 who underwent allo-SCT after HMA/VEN treatment. C Post-allo-SCT CIR (black line) and cumulative incidence of non-relapse mortality (red line)

Fig. 6

Molecular follow-up of mutations by droplet digital PCR (ddPCR) in four patients. A Monitoring of ZRSR2 c.195_198del alteration in sequential samples of a CMML patient detected early molecular relapse three months after allo-SCT. B An MDS-IB2 patient with RUNX1 c.313_314insCG molecular positivization nine months after allo-SCT. In sequential samples, this mutation was detected at a low level two years after allo-SCT but the patient remained in morphologic CR. C An EZH2 R690H mutation was present at diagnosis of an MDS-IB2 patient. The mutation was not detected in sequential samples but the patient suffered a morphological relapse two months after allo-SCT. D An IDH2 R140Q mutation was detected in an MDS-IB2 patient at the time of a morphological relapse six months post-allo-SCT