Long‐Term Outcomes of Stem Cell Transplant in Older Patients With Acute Myeloid Leukemia Treated With Venetoclax‐Based Therapies

Allogeneic hematopoietic stem cell transplantation (SCT) remains the most effective curative treatment for patients with intermediate- and poor-risk acute myeloid leukemia (AML). Patients ineligible for intensive chemotherapy due to age or comorbidities have historically not been candidates for SCT. Venetoclax in combination with hypomethylating agents (HMA) decitabine or azacitidine demonstrated rapid and durable remission in newly diagnosed AML patients ineligible for intensive chemotherapy and is approved globally for this indication [1, 2]. An increase in patients achieving remission with alternative induction therapies could allow more patients to proceed to SCT, since reduced intensity conditioning regimens used for older patients have similar post-SCT outcomes compared with myeloablative conditioning [3]. This analysis evaluates long-term clinical outcomes of patients receiving SCT after venetoclax plus HMA therapy. A combined cohort of patients enrolled to the randomized phase 3 trial VIALE-A (NCT02993523) and open-label phase 1b dose-escalation and expansion trial M14-358 (NCT02203773) was included. Study designs have been reported previously [1, 2]. Briefly, enrolled patients were ineligible for intensive chemotherapy due to age (≥ 75 years old) or comorbidities and had no prior AML-related therapy. Patients enrolled in VIALE-A were administered 400 mg oral venetoclax daily plus azacitidine, while patients in M14-358 were administered oral venetoclax at either 400 or 800 mg daily in combination with either azacitidine (75 mg/m2 subcutaneously or intravenously on Days 1–7) or decitabine (20 mg/m2 intravenously on Days 1–5) in 28-day cycles. The data cutoff was July 19, 2019, for M14-358 and December 1, 2021, for VIALE-A. Outcomes were assessed before and after allogeneic SCT. Overall survival (OS) was assessed from randomization or first dose of venetoclax. Best response was assessed per modified International Working Group criteria for AML [4]. A measurable residual disease (MRD)-negative response was defined as < 10−3 leukemia cells/leukocyte. MRD was assessed by flow cytometry [1, 2]. Additional outcomes included time to best response, 2-year post-SCT remission, and 2-year post-SCT OS. Results are reported using descriptive statistics unless otherwise specified. Survival analyses and estimates were calculated using the Kaplan–Meier method. Patients who were lost to follow-up were censored at the date of the last study visit or the last known date alive, whichever was later. In total, 33 patients from VIALE-A (n = 2) and M14-358 (n = 31) received SCT after venetoclax plus HMA therapy. Patients were a median age of 69 years (range, 63–76). Most had de novo AML (69.7%) and adverse risk disease (54.5%) based on 2022 European LeukemiaNet categories (Table S1). Baseline mutations were identified with TP53 in 2 patients (11.1%), FLT3 (either ITD or TKD) in 5 patients (25.0%), NPM1 in five patients (27.8%), and IDH1 or IDH2 in seven patients (35.0%). Patients were administered venetoclax with azacitidine (63.6%) or decitabine (36.4%). Patients received a median (range) of 4 (1–26) cycles of venetoclax plus HMA prior to SCT. Median (range) time from first dose of study treatment to transplant was 5.98 months (3.2–33.1). At the time of SCT, 28 patients (85%) were in either complete remission (CR), CR with incomplete blood count recovery (CRi), or morphologic leukemia-free state (MLFS) (Figure 1). Of the remaining five patients, two patients initially had a best response of CR but relapsed before SCT, while the other three exhibited resistant disease. The median (range) time to a best response of CR/CRi was 1.9 months (0.8–7.1). Nine patients experienced an MRD-negative response, including four (12%) who had a CR at the time of transplantation. Of the other 24 patients, 16 had MRD-positive disease and eight were unevaluable. With a median follow-up of 31.6 months after SCT, the median OS (95% CI) among all 33 patients was 29.9 months (15.8–not reached [NR]) and median duration of remission was NR (28.2–NR) (Figure 2A, Table S2). The 12-month and 24-month estimated survival rates (95% CI) were 69.1% (50.2%–82.1%) and 61.6% (42.2%–76.3%), respectively (Table S3). Among the 28 patients who were in remission or marrow clearance (CR/CRi/MLFS) at the time of transplant, median OS (95% CI) after SCT was 29.9 months (15.8–NR; Figure 2B). The estimated post-SCT OS (95% CI) was 74.3% (53.5%–86.8%) at 12 months and 65.8% (44.3%–80.6%) at 24 months. Median OS was NR (95% CI, 0.9 months–NR) among the nine patients who had an MRD-negative response before SCT and was 28.2 months (95% CI, 6.1–NR) among the 24 patients with MRD-positive responses or unevaluable for MRD (Figure 2C). Two patients with an MRD-negative response died within the 1st year after SCT, resulting in a 12-month OS estimate of 76.2% (95% CI, 33.2%–93.5%). Among the 24 patients with MRD-positive/MRD unevaluable responses, the 12- and 24-month OS estimates were 66.7% (95% CI, 44.3%–81.7%) and 57.1% (95% CI, 34.8%–74.3%), respectively. Among the 18 patients with adverse risk disease, the median OS (95% CI) was 15.8 months (4.5–29.9), with a 12-month estimated survival of 55.6% (95% CI, 30.5%–74.8%) (Figure 2D). Of the two patients with TP53 mutations, one died at 0.9 months post-SCT for causes unrelated to disease progression, while the other died of progressive disease at 28.2 months post-SCT. With a median of 37.0 months (95% CI, 23.5–NR), OS rates were sustained for the 33 patients who underwent SCT versus 14.1 months (95% CI, 11.8–16.6) for patients who did not (Figure S1). Among the 28 patients who received transplant while in remission or marrow clearance, six died of progressive disease and six from other causes. Among the five patients who had resistant disease or relapse before SCT, one died of disease progression and two died from other causes. One serious adverse event of pneumonia occurred. Treatment-emergent adverse events among patients in this analysis (Table S4) were consistent with expectations for patients with AML undergoing venetoclax, azacitidine, or decitabine therapy, and with the broader VIALE-A and M14-358 trial populations [1, 2]. Outcomes for patients with AML ineligible for intensive chemotherapy are poor. A CR/CRi with an MRD-negative response prior to SCT is favorable when assessing SCT eligibility, as the risk of post-SCT mortality is increased among patients with MRD or an incomplete response to therapy [3, 5]. Intensive chemotherapy is a reliable method to achieve a CR, but it is associated with an increased mortality risk among unfit older patients or patients with comorbidities. In this analysis, patients who were ineligible for intensive chemotherapy and received venetoclax plus HMA therapy followed by SCT experienced a median OS just over 2.5 years. Survival rates among patients who achieved a CR/CRi or MRD-negative response were comparable to studies of SCT after intensive chemotherapy or reduced intensity regimens [3, 5]. These results support venetoclax plus HMA as an alternative induction therapy before SCT for patients with newly diagnosed AML ineligible for intensive chemotherapy. Attaining an MRD-negative remission is a strong predictor of improved survival outcomes after SCT. However, survival outcome data are limited among patients without an MRD-negative response who undergo lower intensity regimens before SCT. A meta-analysis that included three reports of outcomes with lower intensity regimens and 12 with intensive chemotherapy found similarly poor survival rates among patients with MRD positivity irrespective of chemotherapy intensity, with 2-year survival rates of ≤ 40% [6]. In this analysis, patients with an MRD-positive response to venetoclax plus HMA therapy before SCT exhibited a 2-year survival rate of 57.1%, while median OS among those with an MRD-negative response was NR. These results support further investigation of SCT in patients with or without an MRD-negative response to venetoclax plus HMA induction therapy. Lastly, the subset of CR/CRi patients who achieved MRD-negative response on VIALE-A had a median OS of 34.2 months in long-term follow-up [2], further complicating optimal timing and the role of SCT for older adult patients with AML with MRD-negative responses. This analysis was limited by the number of patients who underwent SCT and length of follow-up post-SCT. Additionally, the decision to proceed to SCT was per investigator discretion, which could have biased this population toward patients with an expected favorable response. Although patients with an Eastern Cooperative Oncology Group performance status of three were enrolled in VIALE-A [2], none underwent SCT to be included in this analysis, and few patients ≥ 75 years old underwent SCT. Most patients in this analysis presented with other adverse prognostic factors; 54.5% of patients had adverse ELN risk, and 36% had poor cytogenetic risk. Additionally, the magnitude of survival benefit that patients received from therapy was greater in those with lower ELN risk and those with an MRD-negative response, consistent with observations using chemotherapy regimens [6]. The results of this analysis, with 31.6 months median follow-up, suggest that venetoclax plus HMA therapy can be a successful regimen to enable SCT after reassessing SCT eligibility and lead to long-term survival in patients with newly diagnosed AML who are ineligible for intensive chemotherapy. These findings are consistent with previous studies exploring venetoclax plus HMA before SCT [7-9]. Post-SCT survival outcomes were encouraging among patients with or even without an MRD-negative response after therapy and support further investigation of venetoclax plus HMA therapy as an effective therapy before SCT. K.W.P., C.D.D., M.A., M.J.T., V.P., P.S.B., B.D.S., and D.A.P. conducted the study, interpreted the results, and participated in drafting and critically revising the manuscript. M.Z. extracted and analyzed the data. K.M. and J.P. interpreted the results and participated in drafting and critically revising the manuscript. The authors thank Chenglong Liu of AbbVie for support with statistical analyses. Medical writing support was provided by Amrita Balachandran, PhD, of AbbVie, Rohina Rubicz, PhD, Liz Gooch, PhD, and Sohil Kapadia, PharmD, of Bio Connections LLC, funded by AbbVie. Venetoclax is being developed in collaboration between AbbVie and Genentech. VIALE-A was sponsored by AbbVie and Genentech. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Medical writing support was provided by Amrita Balachandran, PhD, of AbbVie, Rohina Rubicz, PhD, Liz Gooch, PhD, and Sohil Kapadia, PharmD, of Bio Connections LLC, funded by AbbVie. AbbVie and Genentech sponsored the studies (NCT02203773, NCT02993523), contributed to their design, collection, analysis, and interpretation of the data, and participated in the writing, review, and approval of the manuscript. All authors had access to relevant data. Venetoclax (ABT-199/GDC-0199) is being developed in collaboration between AbbVie and Genentech. No honoraria or payments were made for authorship. The trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines of the International Council for Harmonization. The protocol was approved by ethics committees. All patients provided written informed consent. Keith W. Pratz: Research funding from AbbVie, Agios, Daiichi Sankyo, Millennium; advisory board member for AbbVie, Astellas, AstraZeneca, Boston BioMedical, Bristol Myers Squibb, Celgene, Novartis, Jazz Pharmaceuticals, and Servier. Courtney D. DiNardo: Research funding from AbbVie/Genentech, Agios, BMS, Calithera, Cleave, Foghorn, Immune-Onc, Loxo, Servier; consultant/advisory board member for AbbVie, BMS, Daiichi Sankyo, Genmab, GSK, Jazz Pharmaceuticals, Immune-Onc, Servier, and Notable Labs. Martha Arellano: Research support for Cephalon Oncology; consultancy/advisory board for Gilead Sciences. Michael J. Thirman: Grant support, consulting fees, advisory board fees for expert testimony from AbbVie and Roche-Genentech, grant support, consulting fees and advisory from Janssen Pharmaceutica and Pharmacyclics, grant support from Gilead Sciences, Merck, Syndax Pharmaceuticals, TG Therapeutics and Tolero Pharmaceuticals; consulting fees and advisory board fees from AstraZeneca and Celgene. Vinod Pullarkat: Advisory board fees and fees for serving on a speaker's bureau from Genentech, Pfizer, Jazz Pharmaceuticals, Novartis, Servier, and Amgen; honoraria and consultancy from AbbVie. Pamela S. Becker: Research support from AbbVie, GPCR Therapeutics Inc. Medical advisor for CVS Caremark. B. Douglas Smith: Consultant for Pfizer, Novartis, Bristol Myers Squibb, and Servier. Meng Zhang, Kaylee Miu, and Jalaja Potluri: employees of AbbVie and may hold stock or stock options. Daniel A. Pollyea: Research funding from AbbVie, Karyopharm, Teva, and Bristol Myers Squibb and served as a consultant or advisory board member for ImmunoGen, Novartis, AstraZeneca, Syros, Kura, Bristol Myers Squibb, Ryvu, AbbVie, Magenta, Qihan, Zentalis, Medivir, HiberCell, LINK, Daiichi Sankyo, Schrödinger, Aptevo, Rigel, Sumitomo Pharma, Adicet, and Gilead. AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymized, individual, and trial-level data (analysis data sets), as well as other information (e.g., protocols, clinical study reports, synopses, or statistical analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent, scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Use Agreement (DUA). Data requests can be submitted at any time after approval in the United States and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home.” Table S1: Baseline pat ent and disease characteristcs. aAt the t me of study enrollment. bELN classification was based on 2022 ELN guidelines. AML, acute myeloid leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; ELN, European LeukemiaNet; NCCN, National Comprehensive Cancer Network. Table S2: Time from SCT to progression/relapsea for pat ents who achieved CR, CRi, CRh. or MLFS post-transplant by MRD-negativity before SCT. Aza, azacitidine; CR, complete remission; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete blood count recovery; Dec, decitabine; MLFS, morphologic leukemia-free state; MRD, measurable residual disease; N/A, not available; NR, not reached; SCT, stem cell transplantation; Ven, venetoclax. Table S3: Survival rates among all pat ents and by disease characteristcs at t me of transplant. ELN, European LeukemiaNet; MRD, measurable residual disease; SCT, allogeneic hematopoietic stem cell transplant. Table S4: Treatment-emergent adverse events with venetoclax plus HMA therapy that occurred in > 2 patients (any grade) per NCI CTCAE v4.0 criteria. AE, adverse event; HMA, hypomethylating agent; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events. Figure S1: Overall survival of pat ents who underwent SCT compared with pat ents who did not. NR, not reached; OS, overall survival; SCT, stem cell transplantation. 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.