Gene therapy shows sustained benefit in Wiskott–Aldrich syndrome

1. In this analysis of data from over two dozen individuals with Wiskott-Aldrich syndrome, treatment with etuvetidigene autotemcel (etu-cel) was associated with lower frequency of severe infections and moderate or severe bleeding.

2. Gene-corrected cells engrafted durably, although serious infections were common during early recovery. 

Evidence Rating Level: 2 (Good)

Study Rundown: Wiskott–Aldrich syndrome is a rare inherited disorder of both platelets and immune cells which is associated with bleeding, recurrent infections, eczema, and autoimmune disease. Allogeneic stem-cell transplantation can be potentially curative, but some patients lack a suitable donor, and transplantation carries risks of graft rejection and graft-versus-host disease. Etuvetidigene autotemcel (etu-cel) offers another approach: a patient’s own stem cells are genetically modified to restore a functioning WAS gene, then returned after conditioning treatment. In this combined analysis from prospective studies and an expanded-access program, it was found that initiation of etuvetidigene autotemcel was associated with fewer severe infections and clinically important bleeding compared to the year before treatment. There was also evidence of immune reconstitution; gene-corrected cells remained detectable, platelet counts increased, and immune function improved. Surviving participants were eventually able to stop sustained immunoglobulin replacement. Further, there was no evidence of abnormal growth of gene-corrected cells during follow-up. This analysis was limited by a small sample size and the lack of a concurrent control group, precluding direct comparison to stem-cell transplantation or supportive care. However, this study demonstrated that etuvetidigene autotemcel was associated with sustained clinical improvement in patients with Wiskott-Aldrich syndrome. 

Click to read the study in NEJM

Relevant Reading: Long-term safety and efficacy of lentiviral stem-cell gene therapy for Wiskott–Aldrich syndrome.

In-Depth [prospective cohort]: This analysis included 27 individuals with Wiskott-Aldrich syndrome: eight from a phase 1–2 study, ten from a phase 3 study, and nine treated through expanded access. Participants received a single infusion of autologous, lentiviral-vector–modified stem and progenitor cells after reduced-intensity busulfan–fludarabine conditioning and rituximab. Median age at treatment was 2.6 years, and median follow-up among survivors was 5.7 years. Primary endpoints were overall survival, severe infections beyond six through eighteen months, and moderate or severe bleeding during the first year. Estimated survival at both one and five years was 96% (95% confidence interval [CI], 76 to 99). One participant died after deterioration of a preexisting neurologic condition. Severe infections declined from 2.00 events per person-year (95% CI, 1.50 to 2.61) in the pretreatment year to 0.15 (95% CI, 0.04 to 0.39) during the prespecified post-treatment window. Moderate or severe bleeding declined from 2.00 (95% CI, 1.50 to 2.61) to 0.80 (95% CI, 0.49 to 1.22) events per person-year during the first year after treatment. Median platelet count rose from 18 × 10⁹/L at baseline to 59 × 10⁹/L at one year and 68.3 × 10⁹/L at five years. All 26 surviving participants had stopped sustained immunoglobulin replacement by their latest assessment. All treated participants experienced transient grade 4 neutropenia after conditioning. Nineteen had serious adverse events; the majority occurred in the first six months, and more than half were infections. No insertional oncogenesis was detected. Overall, these results suggest that gene therapy may produce a durable clinical benefit in Wiskott-Aldrich syndrome. 

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