Total marrow and lymphoid irradiation (2000 cGy) together with cyclophosphamide and etoposide prior to allogeneic hematopoietic cell transplantation is an effective regimen for Relapsed/Refractory leukemia, with low non-relapse mortality

Abstract

Abstract Background: Total marrow and lymphoid irradiation (TMLI) delivers augmented doses of radiation to the bone marrow (BM) and lymph nodes (LNs) while maintaining low doses to normal organs. A previous study comparing total body irradiation (TBI) doses (1200 cGy to 1575 cGy) demonstrated a dose-dependent response to radiation therapy, with higher doses associated with lower relapse risk. However, this benefit was offset by increased toxicity, resulting in no overall survival gain. Herein we report a single-arm phase 2 trial combining TMLI (2000 cGy to BM and LNs) with high-dose cyclophosphamide (Cy) and etoposide (VP-16) as a conditioning regimen prior to allogeneic hematopoietic cell transplantation (HCT) in 104 patients (pts) with relapsed/refractory (r/r) acute leukemia. Methods: TMLI was given on days -9 to -5 (200 cGy per fraction, twice a day), VP-16 60 mg/kg (adjusted body weight) on day -4, and Cy 100mg/kg (ideal body weight) on day -2. BM (n=7) or peripheral blood stem cells (n=97) from sibling (n=57) or matched (n=24) or one allele mismatched (n=23) unrelated donors were infused on day 0. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus and sirolimus (NCT02094794). Results: Between 05/2014–04/2024, 104 subjects were enrolled. All subjects had r/r disease (including MRD+ by flow). The median age was 40.7 years (range: 16.5-59.9). The median total number of prior regimens was 3 (range: 1-9). Eighty-two (79%) pts had acute myeloid leukemia (AML) and 22 (21%) acute lymphoblastic leukemia (ALL). In pts with AML, 53 (65%) had adverse and 29 (35%) had intermediate cytogenetic risk (ELN 2017) at baseline, and in ALL, 17 (77%) had unfavorable and 5 (23%) had intermediate cytogenetic risk (SWOG). A total of 37 (36%) pts had prior venetoclax exposure. The median baseline blasts in the BM was 12% (range: 0-95%), with 39 (38%) pts having ≥25% blasts in the BM. The median baseline peripheral blasts in blood was 0% (range: 0-86%), and 18 (17%) pts had ≥20% peripheral blasts. Eleven (11%) pts had extramedullary disease (EMD) at HCT. Twenty-seven pts had MRD+ disease. (These pts had received prior cytoreductive therapy in an attempt to proceed to HCT.) The median follow-up was 3.0 years (range: 1.0-5.9) among survivors. A total of 103 (99%) pts achieved a neutrophil recovery at a median of 15 days, and 94 (90%) achieved platelet engraftment at a median of 18 days. One patient died of conditioning-related sinusoidal obstruction syndrome on day 30. Ninety-eight (96%) pts achieved a CR/CRi after HCT. The cumulative incidence of relapse/progression and non-relapse mortality (NRM) at 2 years post-HCT were 51% (95%CI: 41-61%) and 14% (95%CI: 7.8-21%), respectively. Two-year estimates of overall survival (OS) and progression/relapse-free survival (PFS) were 47.3% (95%CI: 37.3-56.6%) and 35.1% (95%CI: 26-44.3%), respectively. There was no increased incidence of acute and chronic GVHD relative to historical data. For 82 subjects with AML, to identify the key risk factors associated with higher hazard of progression/relapse/death, we first fitted 5 univariate Cox proportional hazards models for each of the factors including cytogenetic risk (intermediate/adverse), peripheral blasts at time of transplant (<20%/≥20%), BM blasts at time of transplant (<25%/≥25%), number of prior regimens received (including induction and salvage regimens) (continuous), and prior venetoclax-based salvage regimens (yes/no). The number of regimens prior to HCT (including remission induction and salvage regimens), peripheral blasts ≥20% at time of transplant, and BM blasts ≥25% at time of transplant were each associated with higher hazard for PFS. The first 2 factors were further included in the multivariable Cox proportional hazards model. The hazard of experiencing relapse/progression or death post-HCT was associated with a 30% increase for each additional prior regimen (aHR: 1.3 [95%CI: 1.1-1.5], p=0.001), and tended to be 80% higher in subjects with peripheral blasts ≥20% (vs <20%) at HCT (aHR: 1.8 [95%CI: 0.96-3.2], p=0.068).Conclusion: 1) Toxicities and NRM were low, likely due to organ sparing by TMLI, despite delivering 2000 cGy radiation to the BM and LNs; 2) The regimen was associated with improvement in two-year OS and PFS for r/r leukemia, compared to historical estimates; 3) We did not observe an increase in EMD over that from TBI regimens; 4) AML pts with <20% peripheral blasts and fewer prior regimens appear to benefit most.