Sequential therapy with fitcy preparative regimen for patients above the age of 70 years with active AML – a single center retrospective analysis

Abstract Introduction - Patients aged over 70 years with relapsed or refractory acute myeloid leukemia (AML) have an extremely poor prognosis, with median overall survival of only 2 months using standard care approaches. Given the limited efficacy of salvage chemotherapy in this population and the low likelihood of long-term survival, we adopted a modified reduced-intensity conditioning (RIC) regimen—FITCy (fludarabine, cytarabine ± idarubicin, and cyclophosphamide with 4 Gy total body irradiation)—in elderly patients with available donors, aiming to proceed directly to allogeneic hematopoietic cell transplantation (HCT) despite active disease. Methods – All patients who were diagnosed with AML and were above the age of 70 years, were identified by the transplantation coordinator nurse and underwent donor evaluation within 2 days from diagnosis. Patients treated with 7+3 or venetoclax-azacitidine underwent bone marrow assessment on day 14 or day 21, respectively. In cases where leukemic blasts were detected, donor search was promptly prioritized. These patients went on to have a day 28 bone marrow examination to confirm refractory disease. All consecutive patients, diagnosed with either primary refractory or relapse AML, underwent HCT with the FITCy regimen in the Tel Aviv Sourasky Medical Center. The protocol was amended on January 2018 to include ATG for all patients after interim analysis showed a high rate of GVHD. Venetoclax was added for the first 12 days of preparative regimen since January 2020 to increase efficacy. Results– Between January 2014 and December 2024, 51 patients were identified with primary (n=35)/relapse (n=16) refractory disease and were treated with the FITCy regimen. Twenty-three (45%) patients were treated with venetoclax-based induction therapy. Median age was 72 (range, 70-78) years. Median Karnovski score and HCTCI were 80% (range, 50%-90%) and 3 (range, 0-8), respectively. The majority of patients (n=36, 71%) received an allograft from a matched unrelated donor. Median follow-up was 34 (range, 10-91) months. Median days to engraftment of neutrophils (500/dL) and of platelets (20000/dL) were 11 (range, 9-21), and 15 (9-37) days, respectively. No patient had primary/secondary graft rejection. Severe mucositis was observed in only 2 patients (4%) and was mostly observed in the lower gut. Three (6%) patients developed sinusoidal obstruction syndrome and 15 (29%) patients developed microbiology documented infections during the neutropenic period, leading to death in 3 (6%). Among the 48 evaluable patients on day 30, 46 (90%) patients had complete remission state, and median whole marrow donor chimerism of 98% (range, 84%-100%). Cumulative incidences of grade 2-4 and 3-4 acute GVHD by day 200 were 57%(95%CI 41%-72%) and 9%(95%CI 3%-22%), respectively. Cumulative incidences of overall and moderate-severe chronic GVHD at 1 year after HCT were 35%(95%CI 2%-52%) and 26%(95%CI 15%-43%), respectively. Cumulative incidences of relapse at 1 and 3 years post HCT were 22%(95%CI 12%-35%) and 27%(95%CI 17%-41%), respectively. There was 1 case of relapse beyond 5 years from HCT. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 10% (95%CI 3%-21%), 25% (95%CI 15%-40%), and 35% (95%CI 23%-52%), respectively. Incidences of GVHD-relapse-free survival at 1 and 3 years were 39% (95%CI 21%-48%) and 29% (95%CI 15%-42%), respectively. In the Cox regression model, venetoclax-based induction therapy (HR=.35, p=.03), primary refractory disease (as opposed to relapse disease, HR=.27, p.001), and ATG (HR=.19, p=.005) were associated with improved GRFS, while addition of venetoclax to the preparative regimen, sex, age, and HCTCI had no effect. Cumulative incidences at 1- and 3-years overall survival were 53%(95%CI 37%-65%) and 42%(95%CI 13%-49%). In the Cox regression model, venetoclax-based induction therapy (HR=.26, p=.014), primary refractory disease (HR = 0.23, p.001), ATG (HR=.17, p=.003), and lower HCTCI (HR=.67, p=.04) were associated with improved OS, while addition of venetoclax to the preparative regimen, age, and sex had no effect. Conclusions – Sequential therapy in elderly patients with active AML demonstrates a strong anti-leukemic effect. Improved GVHD prophylaxis and early referral (primary vs. relapse setting) were associated with better GRFS and OS. Age alone should not be a barrier to this strategy, though it must be weighed against emerging targeted therapies.