During a debate series, Michael Pulsipher, MD, of Huntsman Cancer Institute, and Rayne H. Rouce, MD, of Baylor College of Medicine, offer their opinion on whether allogeneic hematopoietic cell transplant is still necessary for pediatric patients with acute lymphoblastic leukemia.
Get a sneak preview of their point of view in this article.
In the past decade, the introduction of highly effective immune and cell therapies has dramatically changed our ability to treat children with ALL. Blinatumomab has markedly improved outcomes in relapsed ALL and similarly improved survival when used up front in standard-risk ALL, leading to universal adoption of use in first remission for all but the lowest risk ALL cohorts.
CD19-targeted CAR T cells have markedly improved remission rates in patients highly refractory to all forms of therapy, including blinatumomab, improving event-free and overall survival in relapsed/refractory ALL.
In spite of these advancements, the role of HCT in children with ALL has continued and, in some cases, increased. There is clear evidence that consolidation of CAR-T therapy with HCT improves survival, and patients losing B-cell aplasia early after CAR-T therapy strongly benefit from HCT. Monitoring of next-generation sequencing measurable residual disease after CAR-T and prior to HCT had allowed careful planning of HCT to either maximize efficacy or minimize toxicity depending upon risk.
Patients previously unable to get into remission are achieving remissions through immunotherapy and are now eligible to receive a first and sometimes second chance at curative HCT. Until we develop universally available CAR T cells or bispecific/conjugated immunotherapies that target multiple antigens and have persistent effects, HCT will remain an important tool to treat and cure children with refractory or high-risk relapsed ALL.
This is a simple yet loaded question—one that pediatric leukemia, transplantation, and cellular therapy specialists have continuously grappled with in light of the paradigm-shifting success of B-ALL targeted immunotherapies. The advent of new therapies, contemporary prognosticators, and sophisticated MRD monitoring have shifted this charged question from a one-size-fits all inquiry (“Is there a role for allogeneic HCT in pediatric ALL?”) to one that warrants a more customized response: “For whom and when should we consider allogeneic HCT in pediatric ALL?”
Despite the curative potential and sophisticated risk mitigation of modern HCT approaches, clear evidence exists that consolidative HCT does not offer event-free or overall survival benefit in a subset of patients who achieve remission with CD19 CAR-T. Furthermore, while consolidative HCT remains common practice in many patients receiving cellular and non-cellular immunotherapies, whether we are transplanting some out of habit versus necessity remains less clear. We must continue to pursue clinical trials designed to answer this question, given the morbidity, mortality, and late effects that persist despite current HCT strategies.
Can contemporary prognostic algorithms accurately define patient subpopulations for whom we can confidently avoid HCT? Is there a subset of patients in whom post-immunotherapy remission can be maintained without HCT? Can we salvage patients who show signs of diminished efficacy, limited persistence, or residual disease post-CAR-T with non-HCT approaches? Could non-HCT consolidative regimens transform from a “salvage” to curative consideration, and how will they measure up to less toxic, more sophisticated modern HCT strategies designed to improve efficacy and reduce morbidity?
Thus, while HCT will continue to play a role, it will likely be for a smaller subset of patients for whom evidence continues to show benefit.
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