In Wiskott-Aldrich syndrome, platelet count matters

In a retrospective analysis of the French Registry of patients with Wiskott-Aldrich Syndrome (WAS), Mahlaoui et al have identified severe refractory thrombocytopenia (SRT) early in life as a major risk factor for poor outcome.¹ 

In an attempt to use phenotypic criteria to define WAS disease severity, Zhu and colleagues proposed a scoring system according to which a score of 5, corresponding to the most severe phenotype, was reserved for subjects developing autoimmunity or malignancies.²  Initially, the degree and persistence of thrombocytopenia were not used to grade severity of the disease, and were subsequently introduced only to mark the mildest form of the disease, intermittent X-linked thrombocytopenia (score < 1).³  However, persistent and severe thrombocytopenia is associated with a significant risk of hemorrhage. In particular, in a large, multi-institutional retrospective study of patients with WAS, life-threatening bleeding had been recorded in 30% of the patients.⁴  Therefore, Mahlaoui et al have decided to modify Zhu et al's scoring system by attributing a score of 5 also to patients with SRT, defined as platelet count persistently ≤ 10 × 10⁹/L. In a series of 160 patients with WAS enrolled in the French nationwide registry, they noticed that the risk of developing a score of 5 was significantly higher during the first 2 years of life. Among 26 patients who were attributed a score of 5 during the first 2 years of life, 13 had SRT; for 12 of them SRT represented the inaugural manifestation leading to a score of 5. Autoimmune hemolytic anemia and vasculitis were also common, being present in 15 and 6 patients, and marking the onset of severe disease in 9 and 5 patients, respectively. Only 1 of the 26 patients developed malignancies, and major infections, while observed in 12 patients, were not an inaugural manifestation. By contrast, malignancies were observed in 7 of 21 patients who were attributed a score of 5 beyond 2 years of age; in this group of patients, autoimmune hemolytic anemia and SRT were recorded in only 4 and 3 patients, respectively.¹  These data are novel and important because they indicate that phenotypic features consistent with severe WAS may have a different distribution in infants versus older patients.

In the study by Mahlaoui et al, occurrence of severe disease early in life was associated with high mortality and morbidity risk. Among the 26 patients who reached a score of 5 in the first 2 years of life, hemorrhages involving the brain, gut, and lungs were observed in 9 patients, and all 4 patients who were not treated by hematopoietic cell transplantation (HCT) died of severe hemorrhage.¹  This observation reinforces the notion that profound and persistent thrombocytopenia in WAS represents a major risk factor. Accordingly, the proposal to include SRT among the criteria to score WAS disease severity should be welcomed as a useful and appropriate addition.

The study by Mahlaoui et al also confirms that HCT is an effective form of treatment for WAS, and suggests that it should be performed as soon as possible especially in patients who manifest severe disease early in life. A recent multicenter analysis of 194 patients with WAS treated by HCT has confirmed significant improvement of outcome, with a 5-year survival approaching 90% for transplants performed since the year 2000.⁵  In particular, excellent results were demonstrated after unrelated donor (URD) HCT. In the study by Mahlaoui et al, all 7 patients with severe early-onset disease who received URD-HCT were reported to be alive and well.¹  In the past decade, improved outcome has been also reported after haploidentical transplantation for WAS.⁵  However, this remains a risky procedure. This is also confirmed in the study by Mahlaoui et al; among 12 patients with severe early-onset disease who received haploidentical HCT, 4 died and 1 required a second transplant from a matched sibling donor.¹  Recently, gene therapy has become available for patients with WAS. The first clinical trial with use of a gammaretroviral vector offered proof of principle that gene therapy may cure the disease,⁶  but also illustrated the risks of leukemia due to insertional mutagenesis.⁷  Since then, novel vectors with improved safety profile have been developed for the treatment of WAS, and one such self-inactivated lentiviral vector is currently in use in clinical trials in Milan, Paris, London, and Boston.⁸  Gene therapy may be especially attractive for patients with severe disease who lack matched related and unrelated donors.

Development of strategies that may facilitate identification of patients with WAS who would most benefit from HCT or gene therapy and who should be promptly referred to treatment remains an important goal in the clinical management of this disease. In this sense, revision of Zhu et al's scoring system, as proposed by Mahlaoui et al, may help, because it broadens the spectrum of severe phenotypic features that are associated with poor outcome. However, this approach may not allow identification of patients at higher risk of poor outcome before severe manifestations of the disease have occurred. In addition, in the study by Mahlaoui et al only 4 of the 9 patients with severe early-onset disease who developed severe organ hemorrhages had been diagnosed with SRT,¹  indicating that even inclusion of SRT in the WAS scoring system may not correctly predict the risk of potentially fatal hemorrhagic events. Mahlaoui et al have also reported that analysis of immunologic parameters did not distinguish patients with a score of 5 from those with a lower score, thus demonstrating that assessment of the status and function of the immune system is not sufficient to describe severity of the disease. By contrast, some studies have suggested that presence of null mutations and lack of WAS protein (WASp) expression correlate—albeit not perfectly—with development of a severe clinical phenotype.⁹  Unfortunately, incomplete information on genotype and WASp expression was available in the manuscript by Mahlaoui et al, reflecting the retrospective nature of the study, based on registry data. Large prospective studies, with nationwide or even international registries, are needed to validate the possible predictive value of these and other biomarkers.