Venetoclax duration (14 vs. 21 vs. 28 days) in combination with hypomethylating agent in newly diagnosed acute myeloid leukemia: Comparative analysis of response, toxicity, and survival
Authors: Omer Karrar, Maymona Abdelmagid, Masooma Rana, Moazah Iftikhar, Kristen McCullough, Aref Al‐Kali, Hassan B. Alkhateeb, Kebede H. Begna, Michelle A. Elliott, Abhishek Mangaonkar, Antoine Saliba, Mehrdad Hefazi Torghabeh, Mark R. Litzow, William Hogan, Mithun Shah, Mrinal M. Patnaik, Animesh Pardanani, Talha Badar, Hemant Murthy, James Foran, Jeanne Palmer, Lisa Sproat, Nandita Khera, Cecilia Arana Yi, Ayalew Tefferi, Naseema Gangat
Journal: American Journal of Hematology (2023)

Overall survival and response rates of 270 patients with newly diagnosed acute myeloid leukemia receiving venetoclax (Ven) plus hypomethylating agent, stratified by Ven dosing schedule (Cycle 1 Ven 14 vs. 21 vs. 28 days). Venetoclax (Ven) and hypomethylating agent (HMA) combination chemotherapy is the current standard of care in elderly or physically unfit patients with newly diagnosed acute myeloid leukemia (AML).1 In the pivotal phase 3 study of Ven-azacitidine compared to placebo-azacitidine (VIALE-A; n = 431 including 286 patients receiving Ven-azacitidine),2 in elderly or unfit patients with previously untreated AML, Ven was administered once daily in 28-day cycles; complete remission with (CR) or without (CRi) count recovery was higher with Ven-azacitidine (66.4%; median survival 14.7 months) versus placebo-azacitidine (28.3%; median survival 9.6 months). The study also reported Grade 3 or higher thrombocytopenia in 45% of patients receiving Ven-azacitidine, neutropenia in 42% and infections of any grade in 85%.2 More recently, we have described our retrospective experience with Ven-HMA, in 301 elderly or unfit patients with newly diagnosed AML, and reported a CR/CRi rate ranging from 36% to 91% and median survival ranging from 3.1 to 28.9 months, based on the presence or absence of specific genetic and clinical risk factors3; adverse events included Grade 3 or higher infections in 36% of patients. Unlike the case with the aforementioned VIALE-A study,2 patients in our retrospective series received either azacitidine or decitabine and Ven for variable duration.3 In the current study, we compared treatment efficacy and toxicity as well as post-treatment survival among patients receiving Ven for a duration of 14 versus 21 versus 28 days, in a 28-day cycle. Patients with newly diagnosed AML treated with frontline Ven-HMA outside of clinical trials at the Mayo Clinic between 2018 and 2023 were retrospectively recruited after institutional review board approval. Follow-up was updated in August 2023. All patients received Cycle 1 of azacitidine 75 mg/m2 days 1–7 or decitabine 20 mg/m2 days 1–5 plus Ven with dose adjusted based on azole antifungal prophylaxis, administered for a duration of 14, 21, or 28 days, in a 28-day cycle, per treating physician discretion. Patients receiving alternative Ven dosing schedules were excluded from the current analysis. Treatment response was assessed after Cycle 1 or 2 according to the 2022 European Leukemia Net (ELN) criteria.4 Toxicity was graded per common terminology criteria for adverse events (CTCAE v5.0), and hematological toxicity was considered treatment-emergent in cases with baseline absolute neutrophil and platelet count >1 and 50 × 109/L, respectively. Survival was estimated from the time of Ven-HMA treatment start to last follow-up or death and evaluated by the Kaplan–Meier method with differences compared by the log-rank test. Univariate and multivariate Cox proportional hazards models were used to evaluate impact of relevant clinical and genetic variables on overall survival. Statistical analysis was performed using JMP Pro 17.1.0 software package, SAS Institute, Cary, NC. A total of 270 newly diagnosed AML patients (median age 73 years, 64% male, 61% de novo) received azacitidine (n = 86) or decitabine (n = 184) with median Ven dose of 200 mg daily (range 50–400 mg) for 14 days (n = 40, 15%), 21 days (n = 41, 15%), and 28 days (n = 189, 70%). 75%, 51%, and 70% of patients received decitabine plus Ven for 14, 21, and 28 days, respectively (p = .04). Median/range Ven dose was 200 mg (100–200 mg), 100 mg (100–400 mg), and 200 mg (50–400 mg), in patients receiving Ven for 14, 21, and 28 days, respectively (p = .55). Supplemental Table 1 provides a comparison of clinical and laboratory characteristics of patients with AML receiving frontline Ven-HMA, stratified by Ven treatment duration (14 vs. 21 vs. 28 days). Patients receiving Ven for 14 days, compared with those receiving Ven for 21 or 28 days were older (median age; 77 vs. 75 vs. 71 years; p < .01), displayed lower circulating blast percentage (median; 6.5% vs. 15% vs. 17%; p = .01), and were more likely to harbor ELN non-adverse cytogenetics (78% vs. 63% vs. 59%; p = .08) and IDH2 mutations (18% vs. 17% vs. 8%; p = .09). On the other hand, gender distribution, type of AML (de novo vs secondary), baseline hemoglobin level, leukocyte count, and platelet count were similar among the Ven treatment groups (p > .1). One hundred seventy-one (63%) patients achieved CR or CRi, including CR in 38%; median time to CR/CRi was 1.4 months (range 1–10) with response duration of 8.7 months (range 1–51). Measurable residual disease (MRD) by flow cytometry was performed at the time of CR/CRi and was negative in 80 of 105 (76%) of evaluable patients. Notably, CR/CRi rates were similar in patients receiving Ven for 14 (n = 27, 68%) versus 21 (n = 27, 66%) versus 28 days (n = 117, 62%; p = .75); corresponding MRD-negative rates were 65%, 72%, versus 81% (p = .34) (Table 1). In addition, duration of response was similar in patients receiving Ven for 14 days (median/range; 8.7 [1–37 months]) vs. 28 days (median/range; 8.3 [1–51 months]) (p = .12). Relapse was documented in 67 of 171 (39%) patients achieving CR/CRi, which included 9 of 27 (33%), 11 of 27 (41%), and 47 of 117 (40%), receiving Ven for 14, 21, and 28 days, respectively (p = .79). 27/40 (68%) 8.7 (0.3–37) 27/41 (66%) 6.6 (0.3–19) 117/189 (62%) 8.3 (0.9–51) In a separate analysis of patients with ELN non-adverse karyotype (n = 169), CR/CRi rates were similar in the Ven 14 versus 21 versus 28-day treatment groups, (81%, 69%, and 74%, respectively, p = .60). On the other hand, among patients with ELN adverse cytogenetics (n = 101), CR/CRi rates were non-significantly higher in patients receiving Ven for 21 days (60%), versus 28 days (44%), versus 14 days (22%) (p = .18). Ven treatment duration did not appear to influence response rates in patients harboring one or more unfavorable mutations (TP53, FLT-ITD, RUNX1) without favorable mutations (NPM1, IDH2, DDX41) (n = 82; p = .77); furthermore, CR/CRi rates were similar in patients with multi-hit TP53 mutations (n = 60) (20% vs. 20% vs. 23% with Ven 14 vs. 21 vs. 28 days; p = .81). Similarly, we did not find a significant difference in CR/CRi rates among patients harboring one or more favorable mutations (NPM1, IDH2, DDX41) without unfavorable mutations (TP53, FLT-ITD, RUNX1) (n = 51) receiving Ven for 14 versus 21 versus 28 days (92%, 90%, and 100%; p = .19). In regard to hematological toxicity, the respective incidence rates for Grade 3 or higher neutropenia and thrombocytopenia were 45%/48%, 39%/38, 42%/41%, among patients receiving Ven for 14, 21, and 28 days (p > .1). Moreover, time to neutrophil or platelet count recovery was similar with Ven 14 versus 21 versus 28 days (median time to neutrophil/platelet recovery; 45/28 days versus 35/29 versus 44/28 days; p > .1). On the other hand, a non-significantly higher rate of Grade 3 or higher infections was documented in patients on Ven for 28 versus 21 versus 14 days (28% vs. 18% vs. 20%; p = .29; Table 1). In addition, drug cost was two-fold higher in patients receiving Ven for 28 (range $2811–15 829) compared to 14 days (range $1360–$7544) (Supplemental Table 2). After a median follow-up of 9.1 months (range 0.8–56), 12.7 months for living patients, 148 (55%) deaths, and 40 (15%) allogeneic hematopoietic stem cell transplant (AHSCT) were documented. Median overall survival was 14.1 months with 1-, 2-, and 3-year survival rates of 54%, 33%, and 27%, respectively. Survival was similar in patients receiving Ven for 14, 21, versus 28 days, with respective median survival (3-year rate) of 18.6 (22%), 21.3 (0%), and 13.2 (28%) months (p = .94) (Figure 1). Furthermore, results were unchanged when analysis was adjusted for age (p = .96), karyotype (p = .52), presence of TP53 (p = .83), and IDH2 mutations (p = .90). The current study suggests that a 14-day Ven administration might be as effective as a 21- or 28-day Ven administration, per 28-day treatment cycle, in inducing CR/CRi, in newly diagnosed AML, without compromising survival. Our study was enriched with cytogenetic and molecular information that allowed us to query their impact on treatment efficacy stratified by duration of Ven administration. In this regard, we were surprised by the lack of influence from specific mutations while a non-significant difference in likelihood of response to a 14-day treatment duration favored patients without adverse karyotype and a 21-day those with adverse karyotype. Interestingly, we were not able to decipher significant differences in toxicity between the 14- versus 21- versus 28-day Ven treatment durations. Our observations are similar to those from a recently reported small study of 13 patients with newly diagnosed AML receiving Ven-azacitidine where 8 of the 13 patients received Ven for 14 days and 5 patients for 28 days duration per cycle5; the authors reported composite CR rates of 75% and 80%, respectively, and a significantly lower risk of febrile neutropenia and shorter hospital stay for the 14-day treatment group. In addition, in a separate study of 82 patients with newly diagnosed AML receiving Ven-azacitidine (7 + 7 scheme), similar to our study, overall CR/CRi rate was 68%, and median time to neutrophil and platelet recovery, 36 and 31 days, respectively; moreover, 49% of patients developed Grade 3/4 febrile neutropenia.6 The possibility that shorter duration of Ven might be as effective and possibly less toxic, in the treatment of AML in general, has also been suggested by others7; such an approach might also be economically advantageous (Supplemental Table 2) and the possibility of further shortening the duration of Ven administration to 7–10 days is appealing and worthy of further investigation, at least in patients without adverse karyotype, and is in line with the assumed mechanism of action for the combination treatment, which is synergistic induction of cell death.8 Our findings require confirmation through an ongoing Phase 2 randomized study (NCT03013998), comparing the efficacy and toxicity of 28- versus 14 day-Ven-azacitidine in patients with newly diagnosed AML. The authors declare no conflicts to interest. The data that support the findings of this study are available from the corresponding author (N. G.) upon reasonable request. Data S1. Supporting information. 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.