Towards a standard of care in transplant for WAS

In this issue of Blood, Albert et al¹ continue the tradition established in 1968 of punctuating the timeline of hematopoietic transplant with important advances in the treatment of this rare nonmalignant disorder. In their article, they demonstrate that, even in the absence of prospective trials, uniform adoption of a limited number of regimens combined with the use of novel composite end points allows a meaningful analysis that establishes a standard of care for these boys.

Wiskott-Aldrich syndrome (WAS) was first identified in 1936 and affects just 1 in ∼100 000 males born worldwide, causing bleeding, immune deficiency, and eczema, in addition to a predisposition to autoimmunity and malignancy. The identification of the WAS gene in 1994 quickly led to the realization that a range of disease severity was related to mutations in the WAS gene and that disease severity could be predicted by protein expression.² For some boys with WAS, prognosis based on phenotype can be made at the time of diagnosis. Although advances in diagnosis and supportive care have improved the outcome for boys not undergoing definitive therapy, especially those with less severe disease, patients with severe disease continue to have a poor chance of surviving into the third decade.² Stem cell transplantation has long been studied as a definitive therapy for WAS. One of the first allogeneic hematopoietic stem cell transplants (HSCTs) was performed in 1968 in a boy with WAS.³ This child had only partial correction of disease. Subsequent studies showed that myeloablation, initially with total body irradiation⁴ and shortly thereafter with busulfan,⁵ was associated with durable and complete chimerism and improved outcomes. Correction of the WAS phenotype was one of the first targets of ex vivo gene therapy; however, unfortunately, it was also one of the first examples of the potential genotoxicity of γ-retroviral vector therapies.⁶ 

Cooperative groups have performed retrospective analyses for this rare genetic disorder, documenting serial improvements in transplant outcomes, especially those using alternative donors. These groups have demonstrated the power of cooperation and pooling of results in identifying modifiable variables associated with superior results in boys transplanted at a younger age⁷ who achieve complete donor chimerism.⁸ These findings have led to practice changes in the age at which boys are transplanted and heightened attention to complete donor chimerism as an outcome of interest associated with myeloablative or busulfan containing regimens.⁹ The study of Albert et al demonstrates several important principles in a contemporary cohort.

In 2005, the European Bone Marrow Transplant Inborn Errors Working Party made recommendations for the use of a limited number of transplant regimens. For transplant for WAS, they recommended 2 regimens: busulfan and fludarabine or treosulfan and fludarabine. Depending on the specifics of the patient, donor, and center, allowance was made for the addition of thiotepa and/or serotherapy to these regimens. As a result, 197 of 347 boys received one or the other of these conditioning regimens and have complete data available for analysis such that this group is now in the position to analyze a large group of boys transplanted between 2006 and 2017. As the largest retrospective study of HSCT outcomes for patients with WAS, this study shows excellent overall survival (OS) and event-free survival (EFS), regardless of conditioning regimen, donor type, and stem cell source. Older age at HSCT remains a significant risk factor for decreased OS and EFS, as found in previous studies.

In addition, the authors have extended their analysis beyond simple OS and EFS to include analyses of end points including chronic graft-versus-host disease (GVHD)-free, relapse-free survival and a modified GVHD-free, relapse-free survival (GRFS) that captures events including graft failure, death, grade III to IV acute GVHD, extensive/moderate/severe chronic GVHD, or any secondary procedure (conditioned or unconditioned second HSCT, donor lymphocyte infusion, or splenectomy). Composite end points have relatively recently been introduced and have limitations¹⁰ but are especially critical when evaluating outcomes for nonmalignant disease where it can be difficult to capture/define “relapse.” Underlining the importance of this analysis is the finding that the modified GFRS at 3 years with treosulfan/fludarabine was 59.4% compared with 78.7% with busulfan/fludarabine (P = .007). It can be difficult to identify a single variable driving differences in composite end points, but in this instance, the difference was largely because of the cumulative incidence of secondary procedures, which was significantly higher in the treosulfan/fludarabine group (26.6% vs 6.2%). These findings support the concept that full myeloablation may be advantageous in WAS, especially in young patients without additional risk factors for organ toxicity. This finding is partially confounded by the treosulfan cohort more frequently having received serotherapy (exposure of which was also not consistently dosed based on measured or predicted exposure); it is still reasonable to conclude that treosulfan/fludarabine, with or without serotherapy, at currently used doses, and without pharmacodynamic and pharmacokinetic monitoring of exposure, may not be as myeloablative as busulfan/fludarabine. Missing from the analysis performed thus far is full assessment of milestones of immune reconstitution.

Importantly, one of the clear ways in which outcomes for transplant for WAS have improved is that donor type and age did not significantly influence GRFS. One of the findings in this study, like the recently published study by the Primary Immunodeficiency Treatment Consortium,⁹ was an improvement in the outcomes for all patients, including those transplanted from alternative donors. As the authors state, HSCT from matched sibling donor/matched family donor remains the gold standard, but the outcomes demonstrated in transplant for this rare disorder with the implementation of standardized regimens and analysis using appropriate composite end points move the field toward an improved standard of care and sets the stage for the next advancements in transplant for WAS. These next advancements will likely include more uniform monitoring of exposure to the agents used in cytoreduction with the goal of improving outcomes by attainment of full donor chimerism and meaningful milestones of immune reconstitution.