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.