Outcomes of venetoclax-based therapy in chronic phase and blast transformed chronic myelomonocytic leukemia.

Abstract

Chronic myelomonocytic leukemia (CMML) is a clonal myeloid disorder characterized by peripheral blood (PB) monocytosis (absolute monocyte count (AMC) ≥ 1 × 109/L and ≥ 10% of the total white blood cell count (WBC) and features overlapping with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms.1 Blast transformation (BT) is associated with high mortality in CMML (median survival < 6 months).2, 3 Hypomethylating agents (HMA) are thus far the only U.S. Food and Drug Administration (FDA) approved therapies for CMML, largely based on the inclusion of a limited number of predominantly dysplastic CMML patients in MDS centered trials.4 The prospective DACOTA trial was the first to randomize higher risk proliferative CMML patients to decitabine versus hydroxyurea and showed no differences in overall survival (OS) and event-free survival (EFS).5 Based on the results of phase II and III studies of HMA/low-dose cytarabine (LDAC) and venetoclax, a novel bcl-2 inhibitor, these combination therapies have been approved by the U.S. FDA for the management of elderly or medically unfit patients with acute myeloid leukemia (AML).6, 7 While these combinations were associated with a median OS of 15 months in AML, based on preclinical data, these were not anticipated to be effective in CMML given the disease dependence on MCL-1 and the presence of factors shown to lead to resistance in AML, including monocytosis and oncogenic RAS-pathway mutations.8 A recent retrospective study using venetoclax based regimens documented an overall response rate (ORR) of 67% in CMML and 81% in CMML-BT patients.9 The median duration of response was reported to be 4.0 months for both the CMML and CMML-BT groups.9 In an attempt to add to the clinical literature, we conducted this study to describe the characteristics and outcomes of patients with CMML and CMML-BT who received venetoclax-based regimens at our institution. After institutional review board approval, we retrospectively reviewed our enterprise-wide institutional database (Arizona, Florida and Minnesota) for patients with CMML and CMML-BT who had received at least one cycle of venetoclax-based combination therapy, with a HMA (azacitidine or decitabine) or LDAC between April 2017 to April 2021. Both CMML and CMML-BT were defined per the World Health Organization (WHO) 2016 criteria.1 Our study excluded patients with de novo acute myelomonocytic leukemia or AML with myelodysplasia-related changes (AML-MRC) without an antecedent history of CMML. All patients underwent bone marrow (BM) aspiration and biopsy with morphology, reticulin staining, cytogenetics, and molecular genetics at diagnosis.10 Categorical variables were compared by Fisher exact test. Continuous variables were compared by Wilcoxon test. The OS was defined as the time from venetoclax-based therapy to death from any cause. For CMML-BT, complete remission (CR), complete remission with incomplete hematologic recovery (CRi), partial remission (PR), and morphologic leukemia-free state (MLFS) were defined according to the 2017 European LeukemiaNet criteria.11 For CMML, response was defined according to the MDS/MPN International Working Group 2015 criteria.12 Overall response rate (ORR) included (i) CR, CRi, PR, and MLFS for CMML-BT and (ii) CR, marrow CR (mCR), and PR for CMML. And, OS was estimated by the Kaplan–Meier method. We identified 20 patients, median age 74 years (range, 39–83 years), 25% female, who met inclusion criteria for (i) diagnosis of CMML or CMML-BT and (ii) treatment with at least one cycle of venetoclax-based combination therapy. Six (30%) patients had CMML (all CMML-2) and 14 (70%) had CMML-BT at initiation of venetoclax-based therapy. Baseline characteristics are described in Figure 1A. Median age at first diagnosis of CMML was 71 years (39–81 years). Median time from diagnosis of CMML to initiation of venetoclax-based treatment was 19 months (range: 0–80) and median time from CMML diagnosis to CMML-BT was 13 months (range: 1–71). Fifty percent and 57.1% of patients had proliferative disease at CMML diagnosis in the CMML and CMML-BT cohorts, respectively. Fifty percent of CMML and 57.1% of CMML-BT patients had a normal karyotype, with trisomy 8 being the most common abnormality identified in 50.0% of CMML and 21.4% of CMML-BT patients. The frequency of somatic mutations prior to venetoclax-based therapy is shown in Figure 1A, with the most common somatic mutations being TET2 (nine patients, 47.4%), SRSF2 (nine patients, 47.4%), and ASXL1 (eight patients, 42.1%). Three (50.0%) of six CMML and 10 (71.4%) of 14 CMML-BT patients had received at least one prior line of therapy, with seven (50.0%) CMML-BT patients and three (50.0%) CMML patients having received prior HMA. Two (33.3%) CMML and four (28.6%) CMML-BT patients had received ≥ 2 lines of leukemia-directed therapies (Table S1). Patients received a median of 2.5 cycles of venetoclax-based therapy (range: 1–37), with the venetoclax being administered on days 1–28 for each cycle. The ORR was 42.9% for the CMML-BT group [two (14.3%) CR, three (21.4%) CRi, one (7.1%) MLFS] after a median of 1.5 cycles (range: 1–2) of therapy and 50.0% for the CMML group (three mCR) after a median of two cycles (range: 1–5) of therapy. One (16.7%) patient with CMML and two (14.3%) patients with CMML-BT were successfully bridged to allogeneic hematopoietic stem cell transplantation (SCT). The patient with CMML experienced prolonged remission for 13 months (ongoing at the time of data analysis) while those with CMML-BT died of graft-versus-host disease related complications and unknown causes, respectively. Cumulative RAS pathway mutations (NRAS, KRAS, CBL, and PTPN11) did not appear to be associated with response or lack of response in CMML (33.3% in responders vs. 50.0% in non-responders) or CMML-BT (50.0% in responders vs. 37.5% in non-responders). Specifically, KRAS mutations were detected in one (33.3%; p.D33E) responding patient with CMML (vs. none in non-responders) and in three (50.0%; including p.G13D and p.V14I) responding patients with CMML-BT (vs. 12.5% in non-responders; p.G12R). Thirteen (65.0%; four with CMML and nine with CMML-BT) patients died from disease relapse. At last follow-up (median 7.2 months), median OS was estimated at 8.1 months for the combined cohort, 5.8 months for the CMML-BT group, and 13.8 months for the CMML group (Figure 1B). In this series, the adverse event profile was similar to previously reported AML-clinical trial data with venetoclax-based combination regimens. The treatment-emergent adverse events (graded per the Common Terminology Criteria for Adverse Events, version 5.0) included cytopenias (with 100.0% experiencing at least one grade 3–4 cytopenia including neutropenia, anemia, and/or thrombocytopenia), grade 3 neutropenic fever (15.0%), grade 3–4 heart failure (10.0%), grade 3–4 sepsis (10.0%), grade 2–3 COVID-19 respiratory infection (10.0%), grade 3 tumor lysis syndrome (10.0%; venetoclax was adequately ramped up in both patients, while one patient did have hyperleukocytosis with a white blood cell count of 97 × 103/μL at the time of bone marrow assessment and 240 × 103/μL at the time of presentation, he did receive pretreatment with one session of leukapheresis and hydroxyurea, and HMA with venetoclax therapy was initiated when the white blood cell count was 19 × 103/μL), grade 2 neutropenic enterocolitis (5.0%), grade 3 pneumonia (5.0%), grade 2 intracranial hemorrhage (5.0%), and bilateral retinal hemorrhage (5.0%), with seven (35.0%) patients requiring at least one hospital admission while on venetoclax-based therapy (median:1, range: 1–3). Our manuscript focuses on the benefit derived from venetoclax-based therapies in CMML and AML arising from antecedent CMML. In our series of 20 patients with CMML and CMML-BT, ORR with venetoclax-based therapies (50.0% for CMML and 42.9% for CMML-BT) was lower than what has been recently reported in the literature (67.0% in CMML and 81.0% in CMML-BT), with CR rates of 10.0%.9 While this combination has certainly improved outcomes in AML patients ineligible for induction chemotherapy, its role in CMML and CMML-BT needs to be better defined.7 The ORR of 50.0% in CMML (33.3% in patients previously treated with HMA) is fairly similar to response rates seen with HMA alone (40%–50%), raising questions regarding the efficacy of venetoclax in monocytic neoplasms. The ORR in CMML-BT (42.9% in the BT subgroup and 42.9% in patients previously treated wih HMA) was also similar to those seen in blast phase MPN (42.0%), where OS was similar with HMA monotherapy versus the combination of HMA and venetoclax.13, 14 The limitations of our study include its retrospective design, small sample size, lack of longitudinal genomic data, and lack of measurable residual disease data. The smaller patient numbers could potentially explain why RAS mutations were not predictive of response/resistance. While off-label use of venetoclax-based therapies in CMML and CMML-BT can be considered in the absence of other approved therapies, especially as a bridge to allogenic SCT in eligible patients, randomized prospective clinical trials are clearly needed to assess for efficacy and durability of responses. The authors acknolwedge the contributions of Zhuoer Xie, MD, MS, Evandro D. Bezerra, MD, Paul J. Hampel, MD, Caleb J. Scheckel, DO, Hassan Alkhateeb, MD, Mohamed A. Kharfan Dabaja, MD, MBA, Kebede H. Begna, MD, Sikander Ailawadhi, MD, Mithun V. Shah, MD, PhD, James L. Slack, MD, and Kristin McCullough, PharmD, RPh. The authors declare no conflict of interest. Antoine N. Saliba, Abhishek A. Mangaonkar, and Mrinal M. Patnaik analyzed the data and wrote the manuscript draft. Antoine N. Saliba, Abhishek A. Mangaonkar, and Mrinal M. Patnaik designed the research study. All authors were involved in reviewing and editing the manuscript. All authors approved the final version. The data that support the findings of this study are available from the corresponding author upon reasonable request. Table S1. Therapies preceding venetoclax-based therapy in CMML and CMML-BT patients. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.