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.

Objectives-chronic graft vs. host disease (cGVHD) is associated with substantial morbidity and mortality. We aimed to analyze advances in treatment strategy and outcomes during the last decade due to the incorporation of novel immunosuppressive therapy (IST) drugs in the armamentarium. Methods-we retrospectively analyzed all patients > 18 years with cGVHD after their first hematopoietic cell transplantation (HCT) between 2012 and 2020 (n = 91), divided into three treatment periods: 2012-2014, 2015-2017, and 2018-2020 (groups 1, 2, and 3, respectively). Results-mean cumulative steroid dose and dose/total cGVHD-treatment days was lower in groups 2-3 compared to 1 (p = 0.008 and p = 0.042, respectively). The median IST-free survival was 79 (95%CI54-94) months, with more patients in group 3 (47% (95%CI 25-54%) discontinuing IST at 3 years, p = 0.1). Groups 2-3 compared to 1 had better glycemic control (p < 0.01), higher bone density (p = 0.06), and fewer cardiovascular events. The number of admissions/patient dropped from 0.7/year in group 1 to 0.24/year and 0.36/year in groups 2-3, respectively (p = 0.36). Employment reintegration was higher in groups 2-3 compared with 1 (p = 0.05) and so was earlier return to work (p = 0.01). There were no differences in survival outcomes. Conclusions-the incorporation of novel agents appears to be associated with reduced overall steroid burden, improved cGVHD control, and fewer long-term side effects.

Data are scarce regarding both the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing immune cell therapy; thus, we prospectively evaluated these two domains in patients receiving this vaccine after allogeneic hematopoietic cell transplantation (HCT; n = 66) or after CD19-based chimeric antigen receptor T cell (CART) therapy (n = 14). Overall, the vaccine was well tolerated, with mild non-hematologic vaccine-reported adverse events in a minority of the patients. Twelve percent of the patients after the first dose and 10% of the patients after the second dose developed cytopenia, and there were three cases of graft-versus-host disease exacerbation after each dose. A single case of impending graft rejection was summarized as possibly related. Evaluation of immunogenicity showed that 57% of patients after CART infusion and 75% patients after allogeneic HCT had evidence of humoral and/or cellular response to the vaccine. The Cox regression model indicated that longer time from infusion of cells, female sex, and higher CD19+ cells were associated with a positive humoral response, whereas a higher CD4+/CD8+ ratio was correlated with a positive cellular response, as confirmed by the ELISpot test. We conclude that the BNT162b2 mRNA COVID-19 vaccine has impressive immunogenicity in patients after allogeneic HCT or CART. Adverse events were mostly mild and transient, but some significant hematologic events were observed; hence, patients should be closely monitored.

Introduction: Prognosis in patients with post allogeneic HCT-early relapse of AML is dismal and response to salvage treatment is less than 20%. Venetoclax has been shown to be safe and efficacious in frail/elderly patients with AML. Treatment results in an increase of pro-apoptotic function, thus the addition of alloreactive T cells may augment the anti-leukemic potency. We hypothesized that the combination of donor lymphocyte infusion may further enhance this response. Methods: Eligibility criteria for this protocol were - age>18 y, early (<6 months post allogeneic HCT) relapse and no concurrent GVHD. Venetoclax was administered at a daily dose of 400 mg for up to 6 cycles with DLI in escalating doses for up to 4 doses. Additional chemotherapy was allowed according to physician discretion. Primary endpoint of study included assessment Overall response (CR/CRi/CRp) rate at 3 months post treatment. Secondary endpoints included 1-year OS, rate of acute and chronic GVHD, documented infections, hematological complications, and other safety measures. Results: From January 2017 until May 2019, 19 patients were given the study protocol. Median age was 60 (43-75) years, Table. There were no cases of tumor lysis syndrome. Microbiology documented infections occurred in 5 patients (26%) and 2 patients were admitted during protocol (10%). No cases of significant bleeding were observed, and majority of patients were able to tolerate the protocol without any admissions. Acute GVHD was observed in 2 (10%) patients and chronic GVHD was observed in 4 (21%) patients. Overall response was observed in 8 (47%) patients (CR, n=3; CRi, n=2; CRp, n=3). Median time to response was 28 (18-67) days (median number of courses 2 (1-6)) and duration of response was 106 (31-395) days. Survival at 6 months was 3.5 months (95% CI 1.5-5.5). Median survival of patients achieving complete remission was 16.2 months (CI not det.), Figure. On univariate analysis there was no association between patients and disease's characteristics and overall survival, however any type of GVHD (entered to the model as a time dependent variable) was associated with a lower rate of mortality (HR=0.2, p= .03). Conclusions: These results may endorse the hypothesis that enhancing alloreactivity as a therapy may lead to a chemotherapy free approach to relapsed AML. A phase 2 study is under preparation with a larger sample size and a standardized approach to additional salvage chemotherapy added versus Venetoclax + DLI regimen only for a more robust analysis of this therapeutic approach. Disclosures No relevant conflicts of interest to declare.