Discussion
Disease relapse remains the leading cause of mortality for children undergoing HCT for MDS. Treatment options for those who recur early post HCT are limited, and cure is unlikely. Despite the high risk of mortality, a second HCT can achieve long-term survival in well-selected patients16,17,19-21. In a retrospective analysis of pediatric patients with acute leukemia and MDS who received a second HCT the single predictor for long term survival was disease control at time of HCT16.
We report a pediatric patient who received multimodal therapy for recurrent MDS. Given the proximity of her first recurrence to initial HCT, a second HCT was initially not felt to be a therapeutic option given concern for disease refractoriness and risk of treatment related mortality (TRM). Treatment with azacytidine and DLI followed by a myelosuppressive reinduction achieved a second remission until about 12 months from first HCT, at which point she was felt to be a suitable second transplant candidate. Though there is limited evidence for using an alternative donor for a second HCT16 we chose an unrelated fully matched donor to facilitate graft versus leukemia effect18. While ultimately her disease was incurable, the therapies utilized from time of initial recurrence onward afforded her excellent QOL for 2.5 years - most of her time was spent outpatient with a high-performance score (Figure 2C).
Low disease burden at the time of HCT for MDS has been associated with improved outcome6,21, however cytoreductive treatment prior to HCT is associated with inferior outcome5,29making the role of chemotherapy prior to HCT in pediatric MDS highly controversial. With the increasing utilization of novel targeted therapeutics in pediatric MDS, we may discover that the advantages of lower disease burden due to cytoreduction outweigh the possible toxicities. The combination of a hypomethylating agent or cytarabine with the Bcl-2 inhibitor venetoclax has been well tolerated in pediatric myeloid disease and is equally efficacious to conventional chemotherapy in adult MDS30-33. Novel therapeutic approaches include enhancement of GVL effect by checkpoint inhibition but risk of GvHD remains a major concern27,34. While cure of pediatric MDS recurring early post HCT remains unlikely, novel treatment approaches should be considered. We utilized multiple therapeutic approaches, including second HCT, DLI, maintenance chemotherapy and experimental cellular treatments towards the goal of minimizing toxicity and maximizing QOL while still striving for cure. Investigational approaches in pediatric MDS should be considered (Table 1)7-9,11,35-37. The role of a third HCT in relapsed MDS is controversial given the risk of toxicity and should be done within the context of a clinical trial.