Efficacy of Venetoclax-Based Therapy Followed By Allogeneic Transplantation in Newly Diagnosed and Relapsed/Refractory AML Patients
Authors: Fanin Matteo , Lazzarotto Davide , Sperotto Alessandra , Tanasi Ilaria , Leoncin Matteo , Gurrieri Carmela , Fili Carla , Callegari Chiara , Battaglia Giulia , Simeone Erica , Zannier Maria Elena , Tosoni Luca , Morelli Gian Luca , Bergnach Melissa , Gottardi Michele , Tamellini Edoardo , Consolo Sara , Skert Cristina , Angotzi Francesco , Lessi Federica , Krampera Mauro , Patriarca Francesca , Damiani Daniela , Fanin Renato , Tiribelli Mario 
Published: December 2024

Introduction: Despite recent advances, the only curative approach for most acute myeloid leukemia (AML) patients remains allogeneic hematopoietic cell transplant (HCT). Results of HCT are superior when performed in complete remission (CR), and the prognosis of patients with refractory or relapsed (R/R) AML remains dismal. In recent years venetoclax (VEN)-based combinations emerged as a standard of care in older/unfit patients, but VEN favorable efficacy and safety profile prompted its use also in R/R patients and the inclusion of VEN in induction chemotherapy for younger patients deemed candidate to transplant. However, to date, little is known on the role of VEN-based therapy as first-line or salvage therapy followed by allogeneic HCT in the real-world setting.
Aim: The aim of this study is to retrospectively analyze the efficacy of VEN-based therapy as a bridge to transplant either when used as induction therapy or as a salvage option for R/R AML.
Methods:We gathered data from 49 AML patients treated at 5 centers in the Triveneto region (Northeastern Italy) from 2020 to 2024, who received VEN in association with hypomethylating agents azacitidine (AZA) or decitabine (DEC), either as first-line treatment (group 1, n=13) or as a salvage therapy (group 2, n=36), followed by allogeneic HCT. Among patients with R/R AML, 24 (66%) received VEN as 2nd line, 10 (28%) as 3rd line and 2 (5%) as 4th line therapy. In group 1, median age at AML diagnosis was 64 years (range: 40-73), ELN 2022 risk was intermediate in 5 patients (38%) and adverse in 8 (62%), with 10 patients (77%) presenting MDS-related changes. VEN was administered for a median of 5 cycles (range: 1-10) at a median dose of 100 mg (due to concomitant posaconazole prophylaxis), in association with AZA or DEC in 9 (69%) and 4 (31%) patients, respectively. Group 2 had a median age at diagnosis of 54 years (range: 21-73), AML risk was favorable in 7 (19%), intermediate in 12 (33%) and adverse in 14 (39%); 13 patients (36%) presented MDS-related changes. In this group VEN was administered for a median of 3 cycles (range: 1-6) at a median dose of 100 mg, combined with AZA in 29 cases (80%), DEC in 6 (17%) and FLAI in 1 (3%). The R/R patients received, prior to VEN, a variety of intensive regimens including 3+7 alone or in combination with midostaurin or GO (10/36, 28%), CPX-351 (10/36, 28%), FLAI (10/36, 28%), MEC (3/36, 8%) or other (3/36, 8%). Regarding allogeneic HCT, among the 13 patients in group 1, median HCT-CI score was 2 (range: 0-4), and donor was HLA-identical sibling in 1 (8%), matched unrelated in 7 (54%), mismatched unrelated in 2 (15%) and haploidentical in 3 (23%). In group 2, median HCT-CI score was 1 (range: 0-6), and donor type was as follows: HLA-identical sibling 7 (19%), matched unrelated in 13 (36%), mismatched unrelated in 1 (3%) and haploidentical in 15 (42%).
Results: In group 1, after VEN-based therapy 3/13 patients (23%) attained molecular CR (MR), 6 (46%) cytological CR, 1 (8%) morphological leukemia-free state (MLFS), 2 (15%) partial remission (PR) and 1 (8%) had a primary refractory disease. After HCT, 9 patients (69%) are alive and in molecular or cytological CR, while 4 patients (31%) had died, 2 for transplant related mortality (TRM) while in CR and 2 after AML relapse. Median OS in group 1 is 17.2 months, with a 12-month OS of 81.8% and 36-month OS of 40.9%. In group 2, before VEN-based therapy 23/36 patients (64%) had active AML, 1 (3%) was in PR, 4 (11%) were in molecular relapses and only 8 patients (22%) were in CR (cytological in 7 and molecular in 1). After VEN, 10 patients (28%) attained molecular CR, 17 (47%) cytological CR, 1 (3%) MLFS, 5 (14%) PR while only 3 patients (8%) still had active disease. After HCT, 24 patients (67%) are alive, with 22 in sustained molecular or cytological CR and 2 with relapsed AML, and 12 (33%) had died, 5 for TRM (4 while in CR) and 7 for AML progression. Median OS in this group is 46.2 months, 12-month OS is 88.9%, 36-month OS is 40.9% and 60-month OS is 26.9%.Conclusions: with the limit of a small sample size, our data suggest that VEN-based regimens are an effective strategy to induce response before allogeneic HCT. Of note, VEN therapy as a “bridge to transplant” in R/R AML, even in heavily pre-treated patients, grants high rates of CR, also molecular, thus allowing to perform allogeneic HCT with low leukemia burden.