Reconsidering an age-old question

In this issue of Blood Advances, Nishitani et al¹ present the results of Center for International Blood and Marrow Transplant Research registry study intended to reexamine the effect of recipient age on risk for graft-versus-host disease (GVHD) in pediatric hematopoietic cell transplantation. This is a matter that has been examined numerous times before. What distinguishes this study is its enormous (14 099 patients) and diverse sample, encompassing large numbers of patients with varying diseases, who received differing conditioning regimens, graft and donor types, and forms of GVHD prophylaxis. This study not only adds value but is sure to be of lasting value.

The investigators examined the influence of recipient age on the risks for acute GVHD (aGVHD) and chronic GVHD (cGVHD) separately for patients who received a transplant for malignant and nonmalignant diseases. A secondary objective of the study was to assess the impacts of aGVHD and cGVHD on survival, again, separately for patients who received a transplant for malignant and nonmalignant diseases.

The size and heterogeneity of the study sample allowed the investigators to draw 2 broadly applicable and important conclusions from the primary analysis. First, that older recipient age is associated with increased relative risk for severe aGVHD in patients with nonmalignant diseases, but not in those with malignant diseases. Second, that older recipient age is associated with increased relative risk for moderate to severe cGVHD in patients with malignant diseases as well in those with nonmalignant diseases. Although a limited number of subgroup analyses were performed, suggesting that breadth of the overall sample may have obscured differences across subgroups, the differences identified were minor and should not preclude generalizing their findings across subgroups. Nishatani at al are to be congratulated for providing pediatric transplant clinicians with a more coherent way to think and speak about the impact of age on GVHD risk.

In their secondary analysis, Nishatani et al demonstrated that severe aGVHD and moderate to severe cGVHD are each associated with mortality in patients who received a transplant for malignant disease as well as in those who received a transplant for nonmalignant diseases. As the authors note, a significant limitation of their study is that their sample was drawn from a time period that largely predates the introduction of new agents for the treatment of aGVHD (ruxolitinib and remestemcel-L-rknd)^2,3 and cGVHD (ibrutinib, ruxolitinib, belumosudil, and axatilimab).⁴ Importantly, some of these agents are not yet available for use in the youngest/smallest pediatric patients. It is conceivable, then, that the reported results overestimate the impact of GVHD on mortality. We, therefore, urge caution when trying to apply these results to current practice. As the number of pediatric patients treated with these agents increases, we think it will be important to repeat this analysis. To make it more informative it could be done across successive time periods.

It is important to appreciate that the relevance of the study’s findings differs for patients who received a transplant for nonmalignant diseases and those who received a transplant for malignant diseases. Although the study showed that older age was associated with higher risk for GVHD in both groups (albeit only cGVHD in patients with malignant diseases), older age only affected survival in patients with nonmalignant diseases. This is not surprising, because transplant-related mortality, much of it stemming from GVHD, is the sole source of mortality in transplant for nonmalignant diseases, whereas relapse remains a far more important source of mortality in transplant for malignant diseases.^5,6 This has 2 important implications. First, age is an important prognostic factor in transplant for nonmalignant diseases and, as such, justifies the impetus to perform transplant at a younger age in some inherited nonmalignant conditions, like sickle cell disease and Diamond-Blackfan anemia.^7,8 Age, in contrast, has little prognostic significance in transplant for pediatric patients with malignant diseases. Second, although all patients, regardless of underlying disease, stand to benefit from advances in GVHD prevention and treatment, substantive improvements in survival for patients with malignant disease will only come with more effective approaches for preventing posttransplant relapse.

Conflict-of-interest disclosure: The authors declare no competing financial interests.