Real‐world experience with venetoclax and hypomethylating agents in myelodysplastic syndromes with excess blasts
Authors: Naseema Gangat, Kristen McCullough, Isla Johnson, Aref Al‐Kali, Kebede H. Begna, Mrinal M. Patnaik, Mark R. Litzow, William Hogan, Mithun Shah, Hassan Alkhateeb, Abhishek Mangaonkar, James M. Foran, Talha Badar, Jeanne M. Palmer, Lisa Sproat, Cecilia Y. Arana Yi, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2022)

Venetoclax (Ven) in combination with hypomethylating agents (HMA) is FDA approved for elderly or unfit acute myeloid leukemia (AML) and currently under investigation in treatment naïve and relapsed/refractory myelodysplastic syndrome (MDS).1, 2 Ongoing clinical trials with Ven and azacitidine in MDS yielded overall response rates of 80% and 39% in treatment naïve and relapsed/refractory patients, respectively.1, 2 Moreover, responses were observed with TP53 (83%), ASXL1 (82%), and RUNX1 (71%) mutations.3 The utility of Ven + HMA in MDS has been investigated outside the context of clinical trials.4 In a retrospective analysis of 44 patients with treatment naïve or relapsed MDS, overall response rate was 59% and 63% of responding patients proceeded to allogeneic hematopoietic stem cell transplant (AHSCT).4 In that particular study, the presence of very poor risk international prognostic scoring system revised (IPSS-R) cytogenetics was predictive of inferior response.4 The aforementioned prospective and retrospective series included all higher-risk MDS patients. Herein, we focus on patients with MDS and excess blasts (MDS-EB) and describe our experience with Ven + HMA treatment outside the clinical trial setting in 40 consecutive cases of MDS-EB, including an assessment of efficacy and toxicity, and determination of clinical and genetic predictors of response and survival. The current study includes 40 consecutive patients with MDS-EB treated with Ven + HMA at the Mayo Clinic (Rochester MN, Arizona, Florida) between June 2018 and January 2022. Study patients were retrospectively recruited after institutional review board approval. Diagnosis of MDS-EB was established by the World Health Organization 2016 criteria; patients with ≥20% blasts in either peripheral blood or bone marrow were excluded. Clinical details at the time of initiation of Ven + HMA including type of MDS, prior HMA exposure, which included receipt of at least 1 cycle of therapy and HMA failure entailed completion of at least 4 cycles of therapy, cytogenetic and molecular studies performed by conventional karyotype, and next-generation sequencing (NGS), respectively, were abstracted. All patients received at least one cycle of Ven + HMA, with Ven dose adjusted based on drug interactions, particularly with azole antifungal prophylaxis utilized in the majority of cases (n = 31). Azacitidine 75 mg/m2 days 1–7 or decitabine 20 mg/m2 days 1–5 were administered as part of the combination therapy. Bone marrow biopsy was obtained after either cycle 1 or 2 in the majority of cases based on treating physician discretion with response assessed according to the International Working Group (IWG) response criteria.5 Follow-up was updated in January 2022. Determinants of treatment response were assessed by Chi-square or Fisher's exact test for nominal data and Wilcoxon rank-sum test for continuous variables. Overall survival was evaluated by the Kaplan–Meier method with differences compared by the log-rank test. Analyses were performed using JMP Pro 16.0.0 software package, SAS Institute, Cary, NC. A total of 40 patients with MDS-EB (median age 71 years, range 37–87; 58% males) received Ven + HMA. Sixteen patients each were treatment naïve and HMA refractory, while the remainder were HMA exposed. Our cohort was enriched in MDS-EB2 (n = 30, 75%), and de novo MDS (n = 20, 70%). IPSS-R risk distribution among evaluable patients was as follows: intermediate (n = 2, 13%), high (n = 3, 20%), and very high (n = 10, 67%); IPSS-R cytogenetic categories included good (n = 16, 41%), intermediate (n = 6, 15%), poor (n = 5, 13%), and very poor (n = 12, 31%). Mutations involved TP53 in 15 patients (38%), ASXL1 in 12 (30%), RUNX1 in 7 (18%), TET2 in 7 (18%), DNMT3A in 5 (13%), SRSF2 in 5 (13%), IDH2 in 4 (10%), and U2AF1 in 4 (10%) patients. Table S1 provides information regarding patient characteristics at the time of initiation of Ven + HMA, response rates, toxicity, and overall outcome. Twenty-three (57%) patients received decitabine and the remainder azacitidine with median final Ven dose of 200 mg (range, 70–400 mg) administered for a median of 2.5 cycles (range, 1–23 cycles). Ven was administered for 28 days in 29 patients (73%), while 9 (23%) and 2 (5%) patients received therapy for 14 days and 21 days, respectively. Twenty (50%) patients experienced cycle delays/interruptions; moreover, Ven and HMA dose reductions were instituted in 16 (41%) and 9 (23%) patients, respectively. Pancytopenia related to therapy was noted in 23 (58%) patients and was complicated by neutropenic fever in 16 cases (40%). The high rates of febrile neutropenia were likely due to the myelosuppression associated with 28 days of venetoclax therapy. Treatment was discontinued due to toxicity in 8 of 30 (27%) patients. One death occurred within 90 days, which was unrelated to therapy. Response was evaluable in 38 patients with complete remission (CR) and marrow CR (mCR) documented in 27 (67.5%) patients: 12 (30%) patients with CR and 15 (37.5%) with mCR. Among 15 patients who achieved mCR, 4 (27%) demonstrated hematologic improvement. The remainder of the responses included stable disease in 7 (17.5%) patients while disease progression was noted in 4 (10%) cases. Among 27 patients who achieved CR/mCR, median time to response was 2.2 months (range; 1–6 months) with median duration of response of 7.2 months (range, 0.4–41 months). Importantly, achievement of CR/mCR enabled 11 (41%) of 27 responding patients to undergo AHSCT. Relapses occurred in 6 of 27 (22%) responding patients, one of which occurred following AHSCT. We observed no difference in CR/mCR rates between patients who received Ven + HMA upfront (69%) or after HMA exposure (50%) or failure (75%; p = .46), azacitidine (71%) or decitabine (65%; p = .72), with MDS-EB1 (60%) or MDS-EB2 (70%; p = .56), de novo (71%) or therapy-related MDS (58%; p = .42), IPSS-R risk (very high/high/intermediate; 60%/67%/100%; p = .55), IPSS-R cytogenetic category (very poor/poor; 53%; intermediate; 83% vs. good; 75%; p = .36). Notably, CR rate was similar among patients who were HMA naïve versus HMA exposed/failure (35% vs. 26%; p = .53). However, CR/mCR was more likely to occur in younger patients (median age, 69 years vs. 77 years; p = .02), in the presence of ASXL1 (92% vs. 57%, p = .02), SRSF2 (100% vs. 63%, p = .04), or IDH2 mutation (100% vs. 64%, p = .07). Multivariable analysis confirmed the favorable impact of ASXL1 mutation on CR/mCR (p = .02). Of 12 ASXL1 mutated patients, 11 (92%) attained CR/mCR, while one patient had stable disease (Table S2). None of the other mutations impacted response, CR/mCR rates were, in the presence or absence of TP53 (60% vs. 72%; p = .31), RUNX1 (71% vs. 67%, p = .81), TET2 (71% vs. 67%; p = .81), DNMT3A (80% vs. 66%; p = .51), and NRAS (50% vs. 68%; p = .60) (Figure 1A). After a median follow-up of 9.6 months from initiation of Ven + HMA, 8 (20%) patients underwent leukemic transformation and 20 (50%) have died with causes of death known in 13 patients: progressive disease (n = 6), infection (n = 4), graft versus host disease (n = 2), and cerebrovascular accident (n = 1). Among 11 patients bridged to AHSCT, 5 have died from transplant-related complications. Overall median survival was 14 months (range; 0.5–43 months) and longer in patients achieving CR (not reached) versus those in mCR (10.2 months; p = .02) (Figure 1B). On univariate analysis, presence of ASXL1 mutation (not reached vs. 10.2 months; p = .01), achievement of CR (not reached vs. 10.2 months; p = .01), and AHSCT (19 vs. 10 months; p = .04) were associated with prolonged survival. Multivariable analysis confirmed the positive influence of ASXL1 mutation (p = .01) and achievement of CR (p = .04) on survival, independent of age, cytogenetics, and AHSCT. Furthermore, we observed superior short-term survival with achievement of CR but not mCR regardless of AHSCT (Figure 1C,D). An independent overall survival advantage from AHSCT was not appreciated due to the short follow-up and early transplant-related mortality. Predictors of shortened survival included presence of P53 mutation (8 vs. 19 months; p = .005) and very poor/poor IPSS-R cytogenetics (8 vs. 16 [intermediate] vs. 33 months [good]; p = .01). The current study on Ven + HMA treatment outcomes in MDS-EB is particularly relevant in light of recent discussions on the optimal blast percentage used to distinguish AML from MDS.6 The high overall response observed in our series is consistent with clinical trials with Ven and azacitidine in MDS and AML.1 Salient observations include the favorable impact of ASXL1 mutation on treatment response and survival outcomes; moreover, achievement of CR but not mCR was essential in securing short-term survival benefit, while AHSCT continues to be important for long-term survival. Similarly, favorable responses with Ven + HMA have been reported in patients with relapsed/refractory AML harboring ASXL1 mutation.7 Moreover, there is suggestion that the detrimental prognostic impact of ASXL1 mutation might be limited to MDS without excess blasts. Our novel findings regarding the impact of ASXL1 mutation on treatment response and survival differ from clinical trials likely due to the 28-day venetoclax schedule utilized in the majority of cases as MDS-EB is often treated akin to AML. The current observations, which require validation in prospective studies, corroborate pre-clinical observations regarding ASXL1 mutations and enhanced sensitivity to Ven and azacitidine through alterations in DNA methylation and bcl2 upregulation.8 Notwithstanding the limitations of a retrospective study with lack of a validation cohort and short follow-up, the current report suggests ASXL1 mutation is a marker for favorable response to Ven + HMA therapy in patients with MDS-EB. Naseema Gangat and Ayalew Tefferi designed the study, collected data, performed analysis, and co-wrote the paper. Kristen McCullough, Isla Johnson, Aref Al-Kali, Kebede H. Begna, Mrinal M. Patnaik, Mark R. Litzow, William Hogan, Mithun Shah, Hassan Alkhateeb, Abhishek Mangaonkar, James M. Foran, Talha Badar, Jeanne M. Palmer, Lisa Sproat, Cecilia Y. Arana Yi, Animesh Pardanani contributed patients. All authors reviewed and approved the final draft of the paper. The data that support the findings of this study are available from the corresponding author. Mark R. Litzow and James M. Foran: AbbVie – research funding. The data that support the findings of this study are available from the corresponding author. Mark R. Litzow and James M. Foran: AbbVie – research funding. Table S1. Clinical characteristics at time of treatment with hypomethylating agent (HMA) and venetoclax for 40 patients with myelodysplastic syndrome with excess blasts (MDS-EB) stratified by achievement of complete response (CR) or marrow CR (mCR). Table S2. Clinical characteristics at time of treatment with hypomethylating agent (HMA) and venetoclax and outcomes for ASXL1 mutated patients with myelodysplastic syndrome with excess blasts (MDS-EB). 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.