Salvage use of venetoclax-based therapy for relapsed AML post allogeneic hematopoietic cell transplantation
Authors: Maansi Joshi, Joselle Cook, Kristen McCullough, Ahmad Nanaa, Naseema Gangat, James M. Foran, Hemant S. Murthy, Mohamed A. Kharfan-Dabaja, Lisa Sproat, Jeanne Palmer, Animesh Pardanani, Ayalew Tefferi, Kebede Begna, Michelle Elliot, Aref Al-Kali, Mrinal Patnaik, Mithun V. Shah, William J. Hogan, Mark R. Litzow, Hassan B. Alkhateeb
Journal: Blood Cancer Journal (2021)

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only potentially curative treatment option available for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS).Despite advances in optimizing conditioning regimens, graft-vs-host-disease (GVHD) management and supportive care, post-transplant relapse remains the Achilles heel impeding long-term survival 1 .Availability of effective therapies for these patients is an urgent area of unmet need.BCL-2 is an anti-apoptotic protein and is present on leukocytes including leukemia stem cells.BCL-2 inhibitor venetoclax (VEN) has changed the treatment paradigm of AML in patients deemed unfit for intensive chemotherapy especially in frontline setting.Pollyea et al. 2 showed the synergistic effect of azacitidine and venetoclax in selectively inhibiting oxidative phosphorylation in leukemia stem cells which disrupts the energy metabolism resulting in cellular death.A phase III trial by DiNardo et al. 3,4 recruited elderly newly diagnosed AML patients (≥65 years) unfit for standard induction therapy.They showed a response rate of approximately 70% when treated with VEN in combination with a hypomethylating agent (HMA), a significant improvement on previously reported response rates of 20-30% with HMA alone [5][6][7] .Although a prospective study is yet to be conducted, a moderate benefit has been suggested by retrospective studies in relapsed or refractory AML patients treated with VEN (or VEN-based regimens).A report of 43 patients treated with VEN in combination with HMA or low dose cytarabine (LDAC) demonstrated an overall response rate of 21% with 6-month overall survival of 24% 8 .In another study of VEN + HMA in 33 patients with r/r AML, 13 of whom had previously undergone an allo-HCT, the overall response rate was 64% with 50% CR + CRi and 1-year overall survival of 53%.The response rate in patients who underwent a prior allo-HCT was 46% (6 out of 13 patients) 9 .The utility of VEN in the post-transplant setting remains poorly studied.Here, we report on our cohort of patients who underwent VEN-based therapy for post-allograft relapse.After institutional review board approval, we conducted a retrospective analysis on consecutive patients with relapsed AML post allo-HCT who received VEN-based therapy in the salvage setting within the 3-site Mayo Clinic Cancer Center (Minnesota, Arizona, and Florida).Comprehensive disease and transplant history were recorded.Patients were risk stratified and response was reported according to the ELN 2017 guidelines 10 .Overall survival was defined from the date of initiation of venetoclax to date of death from any cause.Leukemia-free survival was calculated from date of initiation of venetoclax to date of disease progression or death.Statistical analysis and Kaplan-Meier curves were computed using JMP 14 software.Between December 2017 and April 2020, 29 patients (52% female) received VEN-based therapy for post-transplant relapse (Table 1).The median age at diagnosis was 58 years (range 20-72 years).Eleven patients (38%) had de novo