Impact of Graft Versus Host Disease Following Allogeneic Hematopoietic Cell Transplantation on Leukemia Free Survival in Hematologic Malignancies: A CIBMTR Analysis

Relapse is a leading cause of mortality in children after hematopoietic cell transplantation (HCT) for hematologic malignancies . Graft-versus-host disease (GVHD) has been reported as protective against relapse. We aimed to evaluate impact of acute and chronic GVHD on relapse in children with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) adjusted for disease risk. We included patients <18 years who received first allogeneic HCT for ALL (n=1292) or AML (n=1036) following myeloablative conditioning between 2008-2017. We assigned the pediatric disease risk index (pDRI) which encompasses age, disease status including MRD and cytogenetics (for AML), and is validated for disease-free survival (DFS): AML was categorized as low/intermediate (63%), and high/very high risk (28%), and ALL as low (36%), intermediate (58%), and high risk (2%). Most patients had pre-HCT comorbidity index 0-2 (83% AML/ALL), received unrelated donor (AML 39%, ALL 34%) and bone marrow grafts (AML 53%, ALL 48%). The predominant GVHD prophylaxis was calcineurin inhibitor/methotrexate (AML 46%, ALL 45%). Chronic GVHD was included as a time-varying covariate while aGVHD was analyzed at the day 100 landmark, excluding patients who relapsed, died, or had cGVHD prior. At day 100, 47% of AML patients developed aGVHD: grade I (17%), grade II (19%), grade III (8%) and grade IV (3%), and 27% had cGVHD: limited (10%) and extensive (17%). In ALL patients, 52% had aGVHD: grade I (17%), grade II (21%), grade III (9%) and grade IV (4%), and 30% developed cGVHD: limited (11%), extensive (19%). On univariate analysis , cumulative incidence of relapse at 6 months, 1 year, and 2 years was not statistically different among patients with no aGVHD and any aGVHD grade (adjusted DFS and relapse shown in figure 1 ). Both cohorts had inferior DFS and overall survival (OS), with higher non-relapse mortality (NRM) among those with grades III-IV aGVHD. In multivariate analysis including disease and HCT characteristics, neither aGVHD nor cGVHD had significant impact on relapse for AML (p=0.59 and 0.85 respectively) or ALL (p= 0.48 and 0.61 respectively). pDRI categories for AML high/very high, ALL intermediate, and ALL high risk had increased risk of relapse (HR 1.87, p<0.0001, HR 1.54, p=0.0029, and 3.45, p=0.0078 respectively). Extensive cGVHD and severe aGVHD grades III-IV had increased NRM for both cohorts. Grade IV aGVHD was associated with worse DFS in AML (HR 2.24, p=0.004) and ALL (HR 1.79, p=0.014) and aGVHD grades II-IV had worse OS. cGVHD was not associated with DFS or OS. For AML, pDRI high/very high had worse OS. For ALL, pDRI intermediate and high risk pDRI had worse OS. We conclude that neither acute nor chronic GVHD portend protection against relapse when the aggressiveness of the underlying disease is adjusted for with the pDRI. Conversely, severe grades of GVHD are associated with increased NRM and inferior overall survival .

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