Activity of venetoclax-based therapy in chronic myelomonocytic leukemia

Abstract

Chronic myelomonocytic leukemia (CMML) is a hematological disorder [1, 2] with limited therapeutic options, high risk of transformation to acute myeloid leukemia (AML) and poor prognosis [3, 4]. Hypomethylating agents (HMAs) are the standard of care for these patients, but only up to 40% of patients respond to therapy, and HMA treatment failure precedes reduction in survival time [5]. To date, the cellular and biological mechanisms of resistance to HMA therapy are not fully understood. The B-cell Leukemia/ Lymphoma-2 (BCL2) protein is overexpressed in hematological malignancies as a mechanism of enhanced cell survival, and represents a mechanism of HMA resistance and progression in MDS [6]. Preliminary results from a phase 1b study of azacitidine and venetoclax in frontline or relapsed higher-risk MDS reported complete remission (CR) rates of up to 32% and 13%, respectively [7, 8]. RAS/ MAPK activating mutations, which are observed in up to 30% of patients with CMML, have been associated with Myeloid leukemia Cell differentiation protein 1 (MCL1) upregulation and resistance to BCL2 inhibition [9]. Moreover, both the molecular and metabolic properties of monocytic clones in AML have been linked to venetoclax resistance [10]. The efficacy of venetoclax in combination with azacitidine in CMML has not yet been explicitly reported. In addition, despite the activity and survival benefit of the combination of azacitidine and venetoclax in AML, specific data on AML with myelodysplasia-related changes (AML-MRC) evolving from previously-treated CMML is lacking. In this study, we evaluated all patients who received venetoclax-based regimens as any line of therapy for CMML and as frontline therapy for AML-MRC after CMML at the University of Texas MD Anderson Cancer Center (MDACC) from 2016 to 2020. Informed consent was obtained according to protocols approved by the MDACC institutional review board in accordance with the Declaration of Helsinki. Whole bone marrow (BM) DNA was subjected to 81 gene targeted next-generation sequencing (NGS) analysis (Supplementary Table S1) prior to venetoclax therapy. Responses were evaluated per the MDS/MPN International Working Group response criteria [11] for CMML and per European LeukemiaNet 2017 criteria for AML-MRC [12]. On selected cases, immunohistochemical staining was performed on 4 μm thick formalinfixed paraffin-embedded BM sections using standard procedures, as described elsewhere, using a mouse monoclonal antibody for BCL2 oncoprotein (Bcl-2/100/D5; 1:50, Leica [13]). Fifty-three patients were identified: 27 with CMML and 26 with AML-MRC with anteceding CMML. Patient characteristics are shown in Table 1. Among patients with CMML, the median age was 70 years, with the majority having myeloproliferative (MP-CMML) subtype (56%), CPSS-Molecular Intermediate-2/high-risk disease (81%), These authors contributed equally: Guillermo Montalban-Bravo, Danielle Hammond