CLAG-M or FLAG-Ida Followed Immediately By Allogeneic Hematopoietic Cell Transplantation for Adults with Relapsed/Refractory Acute Myeloid Leukemia or Other High-Grade Myeloid Neoplasm

Background: Allogeneic hematopoietic cell transplantation (HCT) is critical for cure for most adults with relapsed/refractory (R/R) acute myeloid leukemia (AML) or other high-grade myeloid neoplasm. Commonly, remission induction is attempted but is associated with long cytopenia and risk of HCT-prohibitive toxicities. Direct allografting is pursued as alternative but typically includes conditioning with agents that have limited anti-leukemia efficacy. Here, we developed a new HCT platform that combines high-intensity chemotherapy with CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) or FLAG-Ida (fludarabine, cytarabine, idarubicin, and G-CSF) followed immediately by lower dose total body irradiation (TBI) and allografting to maximize the treatment’s anti-leukemia efficacy and minimize its duration of cytopenia.

Methods: Adults ≥18 years with AML or other high-grade myeloid neoplasm (≥10% blasts in marrow and/or blood) were eligible for this Phase 1 study if they were in morphologic remission with evidence of measurable residual disease or had R/R disease. Patients (pts) received CLAG-M or FLAG-Ida starting on day -9 and then received 3, 4 or 5 Gy TBI in a dose escalation trial on days -1/0, followed by allografting on day 0 using HLA-matched related/unrelated (RD/URD) or HLA-haploidentical donors. GVHD prophylaxis included post-transplant cyclophosphamide (PTCy), mycophenolate mofetil, and cyclosporine. The primary objective was to identify which one of 3 doses of TBI was associated with acceptable rates of HCT failure (combined, graft rejection and/or disease progression ≤50%) and non-relapse mortality (NRM; ≤25%) within 200 days of HCT. The initial 12 pts received CLAG-M with 3 Gy TBI. Because of a HCT failure rate of >50%, subsequent CLAG-M pts received 4 Gy TBI. Following the observation of delayed chimerism in a subset of CLAG-M pts, a parallel arm used FLAG-Ida with 4 Gy TBI, hypothesizing fludarabine might facilitate engraftment better than cladribine. Donor/host chimerism studies were performed at day 28, at days 80, and at 1-year post-HCT on unsorted bone marrow (BM) and on peripheral blood (PB) FACS isolated CD33+ and CD3+ cells.

Results: Between December 2020 and June 2024, 46 pts were enrolled (CLAG-M with 3 Gy TBI (1^st cohort) n=12; CLAG-M with 4 Gy TBI (2^nd cohort) n=24, FLAG-Ida with 4 Gy TBI (3^rd cohort) n=10). Pts characteristics were similar between the 3 groups. The median age of the entire population was 67 (34–76) years; 21 pts (45%) had an HCT-CI of ≥3. Pts had either AML (n=27) or MDS (n=19). Thirty-seven pts (80%) received HCT from an URD, 6 (13%) from a RD, and 3 (7%) from a haplo donor. Active disease was present in 17 pts (37%) with a median of 10% (6-70%) BM blasts, with 11/17 pts having circulating blasts. The remaining pts had measurable residual disease by flow cytometry, cytogenetics, and/or NGS. Median time to neutrophil and platelet engraftment was 22 (15-37) and 24 (11-89) days, respectively. Four pts experienced graft failure (3 in the 1^st cohort and 1 in the 2^nd cohort). At day+28 post-HCT, 43 (94%) and 29 (63%) pts had BM and CD3 PB donor chimerism >90%, respectively. Five (10%) pts died before day +28 BM evaluation (fungal infection [n=3], cardiac arrest [n=1], disease progression [n=1]). 37 of 41 evaluable pts achieved a complete remission with/without full hematologic recovery. Median follow-up of the surviving pts was 11 (2-36) months (30 months in 1^st cohort, 11 months in 2^nd cohort, 4 months in 3^rd cohort). A total of 7 pts relapsed (4 in 1^st cohort, 3 in 2^nd cohort) and 12 pts died (6 in 1^st cohort, 5 in 2^nd cohort, 1 in 3^rd cohort). Across all pts, the 1-year overall survival (OS) and disease-free survival (DFS) were 77% (95% CI: 60-87) and 57% (39-71), respectively. OS and DFS estimates were lower for pts treated in the 1^st cohort (65% [33-86%] and 33% [10-58%]) than the 2^nd cohort (76% [50-89%] and 59% [35-77%]); follow-up was too short for survival estimates in the 3^rd cohort. Grade III-IV GVHD was observed in 3 pts.

Conclusions: CLAG-M or FLAG-Ida followed directly by TBI in combination with PTCy-based GVHD prophylaxis is well tolerated, has significant anti-leukemic efficacy, and enables stable engraftment of HLA-matched or haploidentical allografts in pts with R/R AML or other high-grade myeloid neoplasm. Efforts are ongoing to explore augmentation of this HCT platform with additional anti-leukemic agents.