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Background: Relapse is the primary cause of treatment failure after alloHCT for hematologic malignancies. We describe the presentation, management, and outcomes of children with post-HCT relapse, specifically focusing on post-HCT minimal residual disease (MRD), to improve monitoring and intervention strategies.
Design: This was a single institution, retrospective cohort study of children with relapse or progression of acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), mixed phenotypic acute leukemia (MPAL) or myelodysplastic syndrome (MDS) post-alloHCT between January 1, 2003 and December 31, 2010. MRD was defined as disease detectable by immunophenotypic, cytogenetic or molecular methods that did not meet classic morphologic criteria for relapse (defined as ≥ 5% disease). Relapse was defined as any evidence for disease detected after previously negative results, including MRD. Progressive disease was defined as an increase in any measure from baseline results.
Results: 40 of 93 (43%) patients who underwent a first alloHCT experienced relapse, including patients with AML (n=18), ALL (n=16), MPAL (n=4) and MDS (n=2). The median time from alloHCT to relapse was 144 days (range 1 month- 58 months). Nine patients with post-HCT MRD as the first evidence for relapse, presented at a median time of 35 days post-HCT (range 28-182 days), with the majority having rapid progression of disease. Median survival after relapse was 123 days (range 4 days-5 years). Estimated 6-month and 1-year post-relapse survival was 30% and 17.5%, respectively. Five of 40 (12.5%) patients are currently alive with a median follow-up of 39 months, including 1 patient with active disease. 1 survivor had MDS and presented with MRD alone. The remaining 4 (with leukemia) presented with overt disease between 146 and 411 days post-HCT. 3 of 5 survivors underwent a second HCT. 11 patients who were able to undergo a second transplant, experienced a 3-year 27% OS starting after relapse. (Figure 1). No patients with AML survived after relapse.
Conclusion: Although pre-emptive treatment of relapse in the setting of MRD is felt to be ideal, it may not be feasible. In our study, patients with MRD presented very early post-HCT at a time when complications can be high and therapeutic options are limited. Once MRD was detected, disease progression was rapid limiting the chance to respond to frontline immunotherapeutic options. Accordingly, there was no survival advantage for pediatric patients with leukemia whose relapse was detected as MRD compared to overt disease. Given the poor outcomes of post-HCT relapse and limited ability to treat relapse at the stage of MRD, efforts should focus on developing effective therapies for relapse prevention by identifying those at highest risk of relapse as candidates for novel methods to enhance efficacy of alloHCT.
Figure 1: OS by Second HCT for Patients with Post-HCT Relapse
