A Phase II Study of Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukemia in Older Patients Using Fludarabine and Total Body Irradiation
Authors: Jamy Omer Hassan , Arora Sankalp , Salzman Donna , Di Stasi Antonio , Minagawa Kentaro , Mineishi Shin , Saad Ayman 
Published: November 2021

Abstract
Background: Older adults with acute lymphoblastic leukemia (ALL) have poor survival outcomes. Although allogeneic hemaptopoietic stem cell transplantation (allo-hsct) can be curative when used as consolidation after complete remission (CR), advanced age, limited performance status and comorbidities are risk factors for increased non-relapse mortality (NRM) after myeloablative allo-hsct. The 1-year disease-free survival (DFS) for patients ≥40 years who receive an allo-hsct for ALL is often estimated to be 40-50%. Previous studies have demonstrated the efficacy of Total Body Irradiation (TBI) based regimens in adults with ALL when combined with cyclophosphamide (Cy). High-dose Cy is, however, associated with cardiac, hemorrhagic and hepatic toxicities. Fludarabine (Flu) has emerged as a safer substitute of Cy (e.g. Flu/Bu replacing Bu/Cy) with favorable toxicity profile. Given the efficacy of TBI-based regimens in ALL, we hypothesized that a myeloablative regimen of Flu/TBI 12 Gy is almost as effective as Cy/TBI 12 Gy in older adults with ALL undergoing allo-hsct.
Methods: We conducted a single center, single-arm phase II clinical trial (NCT01991457) of Flu 40 mg/m 2 IV daily (days -7 to -4) and TBI 2 Gy X2 (days -3 to -1) (12 Gy total) as myeloablative conditioning for older adults (≥40 years old) or younger adults with significant comorbidities with ALL. The primary endpoint of the study was DFS. Secondary endpoints include overall survival (OS), relapse rate, NRM rate and incidence and severity of acute and chronic graft vs. host disease (GVHD). GVHD prophylaxis consisted of Tacrolimus and Methotrexate. Rabbit anti-thymocyte globulin (rATG) was added for unrelated donor type.
Results: Nineteen patients were enrolled between October 2013 and February 2019 (Table 1). The median age was 54 years (44-63 years). There were 9 (47%) females and 19 (100%) Non-Hispanic Whites (NHW). The median KPS was 80 (70-100) and 3 (16%) patients had an HCT-CI of ≥3.
Seven (37%) patients had Ph-negative B-cell ALL, 9 (47%) had Ph-positive B-cell ALL and 3 (16%) had lymphoid blast phase of chronic myeloid leukemia (CML-LBP). All patients were in CR1 at the time of transplant. Twelve (63%) patients had an 8/8 matched unrelated donor (MUD) and 7 (37%) had a matched related donor (MRD). The median time to neutrophil engraftment was 12 days (10-24 days). Day 100 post-transplant grades III-IV non-hematological and non-infectious adverse effects included mucositis (16%), acute kidney injury (16%), cardiovascular (11%) and elevated liver enzymes (5%).
The cumulative incidence (CI) of grades II-IV and III-IV aGVHD at day 100 post-transplant was 26.1% (95% CI 19.3%-39.2%) and 16.2% (95% CI 12.4%-31.3%), respectively. The 2-year CI of mild, moderate and severe cGVHD was 5.0% (95% CI 2.1%-12.3%), 11.3% (95% CI 7.4%-33.3%) and 21.1% (95% CI 13.5%-40.3%), respectively (Table 2). There were 4 cases of cGVHD of the lungs (3=severe, 1=moderate). Other organs involved included skin (n=5), oral (n=5) and ocular (n=4).
The CI of relapse and NRM at 2-years was 7.1% (95% CI 5.4%-20.7%) and 31.4% (95% CI 19.4%-50.1%), respectively (Figure 1). The 2-year DFS and OS rates were 63.2% and 68.4%, respectively (Figure 2a and 2b). The median OS was 40 months (95% CI 8.5-71.5).
Conclusion: Flu/TBI (12 Gy) resulted in low incidence of relapse with a high DFS and OS rate in an older population with ALL. Increased incidence of severe cGVHD of the lungs was observed with this regimen. Further investigation into this regimen, as a myeloablative regimen for older patients with ALL, is warranted.
Figure 1 Figure 1.

Disclosures
Di Stasi: University of Alabama at Birmingham: Current Employment; Syndax Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees. Saad: Incyte Pharmaceuticals: Consultancy; careDx: Consultancy; Amgen: Research Funding; Kadmon: Research Funding; OrcaBio: Research Funding; Magenta Therapeutics: Consultancy.