Medical Policy

This document addresses gene therapy for Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome. The condition is a rare and serious genetic disease that causes primary immunodeficiency, microthrombocytopenia, eczema, infections and an increased risk for autoimmune manifestations and malignancies. One gene therapy is approved by the Food and Drug Administration (FDA) to treat WAS: etuvetidigene autotemcel (Waskyra^®). Etuvetidigene autotemcel is an infusion of autologous CD34+ hematopoietic stem and progenitor cells transduced by a lentiviral vector encoding for the WAS gene.

Note: For additional information regarding other disease modifying treatments for WAS, please see:

• TRANS.00029 Hematopoietic Stem Cell Transplantation for Genetic Diseases and Aplastic Anemias

Note: For information regarding supportive therapies for WAS, including but not limited to immunoglobulin replacement therapy (IVIG/SCIG), please refer to clinical pharmacy criteria used by the plan.

Note: For a high-level overview of this document, please see “Summary for Members and Families” below.

Investigational and Not Medically Necessary:

Infusion of etuvetidigene autotemcel (Waskyra) is considered investigational and not medically necessary.

This document describes clinical studies and expert recommendations, and explains whether use of etuvetidigene autotemcel (Waskyra) is appropriate. The following summary does not replace the medical necessity criteria or other information in this document. The summary may not contain all of the relevant criteria or information. This summary is not medical advice. Please check with your healthcare provider for any advice about your health.

Key Information

Waskyra is a one-time gene therapy treatment for Wiskott-Aldrich syndrome (WAS), a rare genetic disease that weakens the immune system and causes blood clotting problems, infections, skin problems, and a higher cancer risk. Waskyra uses a person’s own blood-forming stem cells, which are collected, modified in a lab to add a healthy WAS gene, and then returned to the body. It is proposed to treat children 6 months and older and adults who have a confirmed WAS gene mutation and are eligible for a stem cell transplant but do not have a matched donor. The treatment received FDA approval in December 2025. Though it may improve health, more research is needed on long-term safety, especially regarding possible cancer risk from genetic changes.

What the Studies Show

Stem cell transplant from a matched donor is the standard treatment for WAS, but some people do not have a suitable donor. Waskyra has been proposed as a new gene therapy option that modifies a person’s own stem cells to carry a healthy WAS gene. Several early studies have shown promising results. People who received Waskyra had fewer infections, improved immune function, higher platelet counts, and better overall health. In some studies, eczema and autoimmune problems improved or went away. Hospital stays and bleeding episodes also decreased.

However, although these results are promising, most studies had fewer than 10 people and were done at expert centers with a lot of experience treating WAS. One study using an older type of gene delivery method led to several people having leukemia. This older method is no longer used. More recent studies used safer gene transfer methods and have not seen similar cancer risks in short-term follow-up. Still, longer follow-up and studies with more people are needed to know if Waskyra is safe over time, especially since cancer risk can take years to appear. Waskyra may help people who lack matched donors, but it is still being researched and is not ready for general use at this time.

Is this clinically appropriate?

This treatment is not appropriate because there are possible serious risks of harm that require further study. Although early studies show that Waskyra may improve immune function and decrease risk of bleeding problems, these results come from small studies with short follow-up times. Studies with larger numbers of people who are followed for a longer period of time are needed to confirm safety and effectiveness. Of particular concern is the risk of cancer caused by the treatment’s genetic changes inserting themselves in the wrong place within a cell’s DNA. This was seen in earlier gene therapy studies using different, yet similar, methods.

(Return to Description/Scope)

Summary

This document evaluates gene therapy for Wiskott-Aldrich syndrome (WAS), specifically the FDA-approved autologous lentiviral hematopoietic stem cell gene therapy etuvetidigene autotemcel (Waskyra; Fondazione Telethon ETS, Rome Italy). It includes an overview of the condition, description of the therapy, and review of published clinical evidence regarding safety, efficacy, and long-term risk. It also identifies relevant professional guidance related to WAS diagnosis and management.

Key Findings

• Early γ-retroviral studies (Boztug 2010; Braun 2014) demonstrated clinical improvement in immune function, platelet counts, infections, eczema, and autoimmunity, but significant genotoxicity, including insertional leukemias in the majority of treated participants.
• Lentiviral vector trials (Hacein-Bey 2015; Ferrua 2019; additional long-term data from Magnani 2022 and Labrosse 2023) showed:
  • Successful engraftment of gene-corrected cells.
  • Sustained WASP expression across hematopoietic lineages.
  • Reductions in infections, improved immune reconstitution, improved bleeding symptoms, and improvement/resolution of eczema and autoimmunity.
  • No vector-related leukemias detected during available follow-up.
• Improvements in platelet counts were consistent. Although most participants did not achieve normal platelet levels, the improved platelet counts were sufficient to prevent severe bleeding.
• Serious adverse events were primarily related to the conditioning chemotherapy and underlying disease rather than the vector itself.
• Limitations across studies include very small sample sizes, lack of control groups, treatment exclusively at expert centers, and limited long-term follow-up, leaving uncertainty about late-onset adverse effects, including oncogenesis.

Overall, current evidence demonstrates promising short-term hematologic and immunologic correction, but insufficient long-term data to fully evaluate safety or comparative effectiveness relative to standard hematopoietic stem cell transplantation (HSCT).

Professional Guidance

• 2015 American Academy of Allergy, Asthma & Immunology (AAAAI) Primary Immunodeficiency Practice Parameter
  • Advises that X-linked immunodeficiencies, including WAS, may rarely present in females due to extreme X-inactivation.
• 2021 AAAAI guidance on mild WAS
  • Recommends routine vaccinations except live vaccines, which are contraindicated due to immunodeficiency; titers may be checked to assess response.
• 2023 AAAAI/ACAAI Atopic Dermatitis Guidelines
  • Notes that rare syndromes such as WAS may present with atopic dermatitis and should follow standard guideline-based management.
• The document also states that no professional society has issued specific recommendations regarding lentiviral autologous HSC gene therapy for WAS.

Discussion

Etuvetidigene autotemcel  is an autologous hematopoietic stem cell-based gene therapy approved by the Food and Drug Administration (FDA) for the treatment of children aged 6 months and older and adults with WAS who have a confirmed WAS mutation, would be an appropriate candidate for HSCT, but for whom no suitable human leukocyte antigen (HLA)-matched stem cell donor is available. Etuvetidigene autotemcel is a one-time infusion of autologous CD34+ hematopoietic stem and progenitor cells that have been transduced by a lentiviral vector encoding for the WAS gene.

Boztug (2010) reported the first clinical application of autologous hematopoietic stem-cell gene therapy for severe WAS. This early-phase study conducted in Germany described the treatment of two 3-year-old males with severe WAS. Both had no detectable WAS protein (WASP) before therapy and had experienced severe infections, thrombocytopenia, eczema, and autoimmunity. Autologous CD34+ HSCs transduced ex vivo with gammaretroviral WASP-expressing vector were reinfused after busulfan conditioning. The gammaretroviral vector used in this study was different than the lentiviral vector used in etuvetidigene autotemcel production. The 2 participants were followed for approximately 3 years. Outcomes measured were engraftment and protein expression, hematologic correction, immunologic function, autoimmunity and clinical manifestations. The findings demonstrated highly polyclonal hematopoiesis: 5709 unique insertion sites were identified for participant 1 and 9538 sites were identified for participant 2. Notably, some integrations occurred near known proto-oncogenes regions associated with prior leukemia cases in gene therapy. Clonal skewing was detected but no persistent clonal dominance or malignant transformation was found at 3 years. The study provides moderate-quality early-phase evidence that autologous stem-cell gene therapy can restore WASP expression across hematopoietic lineages, improve immune function, reduce infections, resolve autoimmune manifestations, raise platelet counts, improve quality of life and reduce bleeding risk. The authors concluded that gammaretroviral WAS gene therapy remains investigational due to insertional mutagenesis risk and that lentiviral-based WAS gene therapy could have stronger safety and efficacy evidence.

Braun (2014) reported the long-term outcomes of 10 children with severe WAS treated in the same γ-retroviral gene-therapy program initially described in the earlier Boztug report. The Braun publication provides the first complete clinical and molecular analysis for the full cohort and extends follow-up to as long as 6-7 years. Eligible individuals were males with classic severe WAS characterized by pathogenic WAS mutations and clinical features such as recurrent infections, autoimmunity, eczema, and hemorrhagic diathesis. Exclusion criteria included recent hematopoietic stem cell transplantation, prior myelodysplasia or AML, major organ dysfunction, HIV infection, and revertant mosaicism in more than 5% of lymphoid cells.

In this single-arm, open-label phase 1/2 study, autologous CD34+ progenitors mobilized with G-CSF with or without plerixafor were transduced ex vivo with a γ-retroviral WAS vector and infused following busulfan conditioning. The therapy produced sustained WASP expression across lymphoid and myeloid lineages, improved platelet counts and size, restored T-cell and NK-cell functional deficits, and ameliorated bleeding, infections, eczema, and autoimmune manifestations in most participants.

However, 7 of the 10 individuals developed insertional leukemias, with T-ALL arising 488 to 1813 days after infusion (approximately 1.3 to 5 years) and AML occurring either 1165 days after gene therapy (approximately 3.2 years) or as secondary AML developing shortly after remission from T-ALL. Each leukemia was associated with dominant vector integrations at proto-oncogenes such as LMO2, MDS1/EVI1, or MN1, often accompanied by additional cytogenetic abnormalities.

Strengths of the study include its unusually deep clonal tracking (> 140,000 unique insertion sites) and sufficiently long follow-up to establish a clear mechanistic link between vector biology and leukemogenesis. Limitations include the small cohort size, absence of a control arm, heterogeneity in mobilization approaches, and, most importantly, the reliance on a γ-retroviral vector with known genotoxic risks, which limits applicability to modern self-inactivating lentiviral platforms. Overall, the Braun report simultaneously demonstrates the biological efficacy of HSC gene therapy for WAS and conclusively documents the unacceptable long-term genotoxicity of γ-retroviral vectors, resulting in the discontinuation of this vector class in clinical WAS gene-therapy development.

Hacein-Bay Abina (2015) published an open-label, nonrandomized, two-center clinical study in France and England, (n=7). Participants were aged 0.8-15.5 years, had severe WAS (Zhu scores 3-5), and lacked suitable HLA-matched donors. The Zhu clinical score is a numeric system developed to describe how severe an individual’s disease is based on their symptoms (see Definitions section). A Zhu clinical score of 3 indicates microthrombocytopenia together with both eczema and infections requiring medical treatment (classic WAS). This score generally indicates a more severe clinical phenotype. Participants underwent myeloablative conditioning with busulfan and fludarabine followed by infusion of autologous CD34+ cells transduced with a lentiviral vector. The lentiviral vector used in this study is significantly different than the γ-retroviral vectors used in the studies published by Borztug and Braun and has been shown to have lower genotoxic risks.

The primary outcomes measured in this study were improvements in clinical manifestations of WAS including frequency and severity of infections, bleeding episodes, autoimmune manifestations, and eczema. Secondary outcomes measured were correction of immunologic and hematologic parameters and vector safety (integration analysis). At the 24 months analytic checkpoint, 1 fatality had occurred 7 months following treatment. The cause of death was a preexisting drug-resistant herpesvirus infection. In all 6 surviving participants, only minor nonrecurrent infections were reported, eczema resolved or markedly improved for all survivors, autoimmunity improved in 5/5 evaluable participants, no severe post-treatment bleeding occurred and all survivors were weaned from transfusion and platelet stimulating agents. Additionally, the median days of hospitalization decreased from 25 days in the 2 years prior to treatment to a median of 0 days in the 2 years following treatment. No vector-associated leukemias were detected, and toxicities were related to the underlying disease or conditioning rather than the vector itself.

The study provided strong early evidence that lentiviral autologous HSC gene therapy can substantially improve clinical outcomes with an acceptable short-term safety profile in severe WAS. While results are promising, the therapy requires further long-term safety follow-up beyond 3 years with larger-scale evaluation to determine definitive efficacy relative to HSCT, consistent platelet normalization, optimal conditioning and dosing parameters, and to confirm the lack of mutagenesis. The authors concluded that evidence from larger cohorts or confirmatory trials are needed and that lentiviral autologous HSC gene therapy is not yet appropriate for widespread substitution for HSCT when matched donors are available. Although the reported ages ranged from infancy through adolescence, the study did not provide age-stratified outcomes, and no evaluable conclusions can be drawn regarding differential safety or efficacy by age.

Subsequent longer-term follow-up from Magnani (2022) strengthens the early observations reported by Hacein-Bey Abina by demonstrating durable engraftment of gene-corrected cells across lymphoid and myeloid lineages and sustained improvement in clinical manifestations over a median of 7.6 years. Notably, severe infections and eczema resolved for most participants, and autoimmune complications generally lessened over time. However, this study also highlighted important limitations that remain unresolved. Platelet recovery was partial and inconsistent, with most individuals continuing to have subnormal platelet counts and persistent abnormalities in platelet size and function, despite meaningful clinical improvement. Autoimmunity, while reduced overall, did not fully normalize in all participants and new immune-mediated conditions occurred in isolated cases. Although no insertional oncogenesis or clonal dominance was detected during the follow-up period, the sample size remained small and insufficient to exclude rare delayed adverse events. Taken together, these longer-term data suggest that lentiviral autologous HSC gene therapy may provide sustained immunologic benefit, but key uncertainties persist regarding its long-term safety, reliability of platelet correction, and generalizability outside expert centers. As with the earlier trial, these findings support continued cautious evaluation rather than broad substitution for allogeneic HSCT when high-quality donors are available.

Ferrua (2019) reported interim results from a single-arm, open-label phase 1/2 study evaluating autologous hematopoietic stem progenitor cell (HSPC) gene therapy using a self-inactivating lentiviral vector for children with severe WAS who lacked a suitable allogeneic donor. Severe WAS was defined by either a severe WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression, or a Zhu clinical score of 3 or higher. The study assessed whether genetically corrected CD34+ cells, delivered after reduced-intensity conditioning, could sustain engraftment, restore WASP expression, improve immune function, and ameliorate thrombocytopenia while maintaining an acceptable safety profile. The trial enrolled 8 male children with classic severe WAS, characterized by recurrent infections, eczema, autoimmunity, and profound microthrombocytopenia. The participants were considered high-risk because none had access to a fully matched sibling or high-quality unrelated donor for HSCT. Exclusion criteria were a prior recent HSCT, cytogenic abnormalities associated with myelodysplastic syndrome or acute myelogenous leukemia, major comorbid organ dysfunction, or HIV infection. The conditioning regimen (busulfan + fludarabine + rituximab pre-treatment) and the manufacturing processes were standardized, and follow-up at the interim analysis extended to a median of 3.6 years. The maximum follow-up was 5.6 years in the earliest treated participants.

Overall survival was 100%. All participants achieved successful and durable engraftment of lentiviral vector-modified autologous HSPCs. Restoration of WASP expression was demonstrated at 12 months by an increase in WASP-positive lymphocytes from a median of 3.9% (range 1.8-35.6) at baseline to 66.7% (55.7-98.6) after treatment, and WASP-positive platelets from 19.1% (4.1-31.0) to 76.6% (53.1-98.4). Immune reconstitution was demonstrated by normalization of in-vitro T-cell function, discontinuation of immunoglobulin replacement in 7 participants at 1 year or greater, and the development of protective antigen-specific vaccine responses. Clinical benefit was further reflected by a marked reduction in severe infections, decreasing from 2.38 events per participant-year (95% confidence interval [CI], 1.44-3.72) in the year prior to gene therapy to 0.31 (0.04-1.11) in the second year and 0.17 (0.00-0.93) in the third year post-treatment. Severe thrombocytopenia improved substantially: 7 of 8 participants had platelet counts less than 20 × 10^⁹/L pre-treatment, whereas at last follow-up 1 participant reached 20-50 × 10^⁹/L, 5 reached 50-100 × 10^⁹/L, and 2 exceeded 100 × 10^⁹/L. All became independent of platelet transfusions and none experienced severe bleeding.

A total of 27 serious adverse events occurred in 6 participants. These were predominantly infections (85%), including pyrexia, device-associated infections with one case of sepsis, and viral gastroenteritis (including rotavirus). These events clustered in the first 6 months after treatment and were consistent with expected post-conditioning immunosuppression. No infusion-related reactions, evidence of clonal dominance, or leukemias were observed.

As an initial feasibility and safety study, the trial lacked a control group and relied on within-participant comparisons. The study design introduces the potential for confounding by maturation (as participants age, baseline infection risk changes), temporal improvements in supportive care over time, and regression to the mean. Nevertheless, many of the study’s endpoints such as WASP expression, vector copy number, platelet counts, infection rates, and hospitalization days are objective measures, which reduce the likelihood of outcome-assessment bias. The findings demonstrated robust biological correction: all participants showed sustained engraftment of gene-corrected progenitors, with durable vector marking across lymphoid and myeloid lineages and progressive restoration of WASP expression. Immune reconstitution was shown by improved T-cell proliferation responses and the ability to produce protective vaccine titers. Most participants were able to discontinue immunoglobulin replacement. The thrombocytopenia characteristic of WAS also improved: platelet counts increased from severely low pre-treatment levels to ranges associated with markedly reduced bleeding risk though counts did not reach the normal range. Rates of severe infections dropped and hospitalizations, anti-infective use, bleeding episodes, and transfusion requirements all decreased. Autoimmune manifestations and eczema also improved or resolved in most participants. Survival was 100%, with no cases of clonal proliferation, oncogenesis, or replication-competent lentivirus observed during the available follow-up.

Study limitations include the small cohort size and the short follow-up duration, which may be insufficient to rule out late-onset leukemias; a known risk in gene-modified hematopoietic stem/progenitor cell (HSPC) therapies. Despite the promising results, the authors appropriately concluded that the study’s design limits its ability to support definitive comparative effectiveness. It remains uncertain how this approach performs relative to contemporary HSCT in similar-risk individuals, or whether some observed improvements might have occurred with optimized supportive care alone. Additionally, all participants were treated at a single expert center in Italy, which may limit generalizability to other treatment settings.

Scala (2023) conducted an exploratory, non-randomized analysis to investigate how the source of hematopoietic stem and progenitor cells (bone marrow vs. mobilized peripheral blood) influences the composition of the gene-therapy graft, subsequent hematopoietic reconstitution, and long-term clonal architecture in individuals receiving lentiviral HSPC gene therapy for Wiskott-Aldrich syndrome. The report was based on post-hoc analysis of data generated in the study reported by Ferrua. Using detailed graft phenotyping, lineage-specific vector-copy measurements, and longitudinal insertion-site tracking, the study found that mobilized peripheral blood contains substantially higher proportions of primitive HSCs and multipotent progenitor subsets and yields faster hematopoietic recovery, higher long-term gene-corrected chimerism, and greater clonal diversity. This study’s strengths include a homogeneous treatment platform, rich mechanistic sampling, and concordant preclinical data. Limitations include small sample size, post-hoc source comparison without randomization, potential confounding by era or clinical characteristics, and reliance on surrogate biological endpoints rather than prespecified clinical outcomes. Further prospective study is needed to determine the relative effectiveness of using bone-marrow-derived and mobilized peripheral-blood-derived stem cells for this gene therapy.

Labrosse (2023) (NCT01410825) reported long-term outcomes from a phase 1/2 trial evaluating lentiviral gene therapy for severe Wiskott-Aldrich syndrome, with all individuals alive and maintaining durable multilineage engraftment at a median 7.6 years of follow-up. The study demonstrated broad and sustained immunologic improvement, including normalization of T-cell proliferative responses, diversification of the T-cell receptor repertoire, reconstitution of multiple B-cell subsets, and consistent clinical reductions in infections and eczema. A major strength of the study is its unusually deep mechanistic profiling such as cytoskeletal correction in myeloid cells, macrophage polarization assays, and comprehensive T- and B-cell functional testing paired with long-term integration-site analyses confirming stable polyclonal engraftment and no vector-related oncogenesis. However, platelet and myeloid recovery remained heterogeneous and occurred primarily in individuals with high vector copy number within transduced progenitors, highlighting limitations in consistency of hematologic correction. Additionally, two individuals with pre-existing autoimmunity experienced post-treatment flares linked to incomplete recovery of Treg and IL-10-producing B-regulatory cell compartments, suggesting that autoimmunity may persist despite adequate gene marking. Other weaknesses include the very small sample size, single-center design, and product-manufacturing variability in 1 participant, which collectively limit generalizability. Overall, the trial supports durable partial correction of the WAS phenotype with an acceptable safety profile, while underscoring key uncertainties regarding platelet correction and autoimmune outcomes.

Early clinical evidence, although derived from small, single-arm studies with limited long-term follow-up demonstrates that Etuvetidigene autotemcel  provides meaningful hematologic and immunologic correction in individuals with WAS. Across published lentiviral HSPC gene therapy trials, sustained engraftment of gene-corrected cells, restoration of WASP expression, reduced infection rates, improvement in immune function, and clinically significant increases in platelet counts have been consistently observed, with no detection of replication-competent lentivirus or vector-related clonal expansion during the follow-up periods reported.

It needs to be noted that, in the early report by Boztug as reported above, no persistent clonal dominance or malignant transformation was detected at 3 years, although integrations occurred near known proto-oncogenes. Subsequent extended follow-up of this γ-retroviral program (reported by Braun) demonstrated a high rate of insertional leukemias. Although the vectors used in Boztug and Braun differ from the lentiviral platform used in more recent studies, all integrating vectors insert genetic material into the host genome, and the potential for oncogenesis must be thoroughly evaluated.

The available clinical evidence for etuvetidigene autotemcel remains limited and investigational. The principal data come from the Ferrua phase 1/2 trial, which treated 8 male children aged 1.1 to 12.4 years, with no adolescents older than 12.4 years or adults included. Although a separate British-French program (Hacein-Bey Abina) screened an adult in his mid-30s, he was not part of the analyzable dataset, and no complete safety or efficacy data exist for adults in any published lentiviral WAS gene-therapy study. Current literature also provides insufficient evidence to evaluate the long-term effects of etuvetidigene autotemcel on the clinical manifestations of WAS or the risk of oncogenesis, and the small number of studies, conducted exclusively in highly specialized treatment centers, further limits the generalizability of results to broader clinical practice.

Wiskott-Aldrich Syndrome (WAS) is a disease characterized by immunological deficiency and reduced ability to form blood clots. Signs and symptoms include easy bruising or bleeding due to a decrease in the number and size of platelets, susceptibility to infections and to immune and inflammatory disorders, and an increased risk for some cancers (such as lymphoma). A skin condition known as Severe eczema is common in people with WAS.

WAS is caused by genetic mutations, also known as pathogenic variants, in the WAS gene. Genetic mutations can be hereditary, when parents pass them down to their children, or they may randomly occur when cells are dividing. They may also result from contracted viruses, environmental factors, or a combination of any of these. Additionally, as people age, somatic mutations (changes in DNA acquired during life from environmental exposures and normal cellular processes) tend to accumulate in tissues over time, increasing the overall burden of exposure-related mutations with age (Ren, 2022).

WAS is inherited in an X-linked manner, therefore the condition almost exclusively affects males (National Organization of Rare Diseases, 2025). However, the American Academy of Allergy Asthma & Immunology Practice Parameter For The Diagnosis and Management of Primary Immunodeficiency (2015) notes:

The possibility of an X-linked primary immunodeficiency diseases should be considered, even in female patients, when other possibilities have been ruled out. Extreme nonrandom X-chromosome inactivation can lead to expression of the phenotype associated with an X-linked recessive disease in a female carrier. This has been described for …Wiskott-Aldrich syndrome (WAS).

Additionally, WAS X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN) are conditions known as 'WAS-related disorders'. Classic WAS, WAS XLT, and WAS XLN are all caused by genetic changes in the WAS gene and have overlapping symptoms ranging from mild to severe, with classic WAS presenting as the most severe form. It is estimated that fewer than 5,000 people in the United States have WAS. Symptoms may start to appear at birth to infancy (National Institutse of Health-Genetic and Rare Disease Information Center [GARD], 2025).

Several body systems are affected by the disease which may result in a constellation of symptoms and conditions. The most frequently described include:

• Acute Leukemia
• Anemia
• Autoimmunity
• Bruising frequency
• Chronic Leukemia
• Eosinophilia
• Fever
• Internal hemorrhage
• Immunodeficiency
• Lymphocytopenia
• Recurrent respiratory infections
• Sinusitis
• Spontaneous hematomas
• Thrombocytopenia
• Otitis media (middle ear infection)

Hematopoietic stem cell transplantation (HSCT) with a human leukocyte antigen (HLA)-matched donor remains the standard curative therapy for WAS. Optimal outcomes are achieved using fully matched related or unrelated donors; however, in individuals without an HLA-matched donor, haploidentical HSCT can also yield favorable results. Overall post-transplant survival averages approximately 80%, while the prognosis for individuals lacking a suitable donor remains poor, with significantly reduced life expectancy, particularly in the presence of malignancy.

Cell based gene therapy has emerged as an alternative disease-modifying strategy for individuals ineligible for optimal HSCT. Etuvetidigene autotemcel (Waskyra), is proposed as a cell based gene therapy for the treatment of WAS. Etuvetidigene autotemcel treatment consists of a one-time infusion of autologous CD34+ hematopoietic stem and progenitor cells genetically modified ex vivo with a self-inactivating lentiviral vector encoding the functional WAS gene. The product first became available in Italy in August 2023 under a special access authorization from the European Medicines Agency (EMA). In November 2025, the EMA recommended granting a marketing authorization in the European Union for etuvetidigene autotemcel to treat people aged 6 months and older with WAS who have a mutation in the WAS gene.

The EMA’s recommendation was based on data from a clinical development program involving a total of 27 participants with WAS. The main study was a single-arm clinical trial conducted in 10 children between 1 and 9 years of age, supported by data from another clinical trial and an expanded access program including people treated via compassionate use, comprising a total of 17 participants between 1-35 years of age. Overall, the data showed that the annualized rate of severe infections decreased from 2.0 events in the 12 months before treatment to 0.15 events in the 1-2 years post-treatment and to 0.12 events in the 2-3 years post-treatment. Similarly, the annualized rate of moderate and severe bleeding episodes decreased from 2.0 events in the 12 months before treatment to 0.16 events in the 2-3 years post-treatment. The most common side effects reported were due to procedures and medications required to receive the gene therapy such as the conditioning regimen, pre-treatment and infections related to the infusion device and bleeding at catheter sites. In its overall assessment of the available data, the Committee for Advanced Therapies (CAT), EMA's expert committee for cell- and gene-based medicines, found that the benefits of  etuvetidigene autotemcel outweighed the possible risks in people with WAS requiring an HSCT for whom no suitable donor is available. The EMA’s Human Medicines Committee, agreed with the CAT’s assessment and positive opinion, and recommended approval of this medicine (EMA, 2025). The manufacturer subsequently submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) in November 2025. In December 2025 the application was granted Orphan Drug, Rare Pediatric Disease, and Regenerative Medicine Advanced Therapy designations. On December 9, 2025, etuvetidigene autotemcel became the first gene therapy in the United States approved by the FDA for the treatment of WAS for pediatric individuals six months and older and adults with WAS who have a mutation in the WAS gene and for whom HSCT is appropriate and no suitable HLA-matched related stem cell donor is available.

Relevant professional society recommendations:

The American Academy of Allergy Asthma and Immunology (AAAAI) Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency (2015) notes in Summary Statement 8:

The possibility of an X-linked primary immunodeficiency diseases (PIDD) should be considered, even in female patients, when other possibilities have been ruled out. Extreme nonrandom X-chromosome inactivation can lead to expression of the phenotype associated with an X-linked recessive disease in a female carrier. This has been described for Wiskott-Aldrich syndrome.

In 2021 AAAI also provided the following guidance for individuals with mild WAS:

Patients with WAS can receive all the routine recommended vaccines except for live vaccines which are contraindicated. The virus that is used in these "live virus vaccines" are "attenuated or weakened', i.e., they are not killed but have a reduced power to produce disease in the recipient. When they are given to patients who are immunodeficient, these "attenuated" viruses can cause serious disease. They are therefore contraindicated. Under certain circumstances, such as for travel, some of these live virus vaccines may be given after consultation with an immunologist who is familiar with the disease. Patients with WAS should not assume that they are protected from the disease because they have received a vaccine. Measuring titers after the vaccine can determine if the vaccine was efficient and if the patient needs booster doses.

The 2023 AAAAI/American College of Allergy, Asthma, and Immunology (ACAAI) Atopic Dermatitis (eczema) Guidelines by the Joint Task Force and Institute of Medicine acknowledged that rare syndromes such as WAS may present with atopic dermatitis and should follow the guideline based parameters for management.

At the time of this writing no specific recommendations or position statements have been made specifically regarding the use of lentiviral vector autologous hematopoietic stem cells for the treatment of WAS by the AAAAI, ACAAI, or the American Academy of Pediatrics (APA).

Acute Leukemia: A malignant hematopoietic disorder with an acute onset, affecting the bone marrow and the peripheral blood. The malignant cells show minimal differentiation and are called blasts, either myeloid blasts (myeloblasts) or lymphoid blasts (lymphoblasts)

Anemia: A reduction in red blood cells or hemoglobin concentration

Autoimmunity: The occurrence of an immune reaction against the organism's own cells or tissues

Chronic Leukemia: A slowly progressing leukemia characterized by a malignant proliferation of maturing and mature myeloid cells or mature lymphocytes

Eosinophilia: Elevated eosinophils which may lead to atopy (eczema, food allergies) and high Ige levels.

Immunodeficiency: The failure of the immune system to protect the body adequately from infection

Lymphocytopenia: Reduced numbers of lymphocytes or dysfunctional lymphocytes. Lymphocytes are specialized white blood cells that coordinate immune defense and help the body recognize and eliminate infectious organisms. Lymphocytopenia may result in increased susceptibility to infection, poor vaccine response, increased risk for auto-immune diseases, increased risk of malignancy, severe eczema, and food allergies

Spontaneous hematoma(s): The development of hematomas (bruises) without significant trauma

Thrombocytopenia: Thrombocytopenia is a reduction in the number of circulating platelets. Platelets are small, cell-derived fragments in the bloodstream that help initiate clot formation and prevent bleeding. In Wiskott-Aldrich syndrome, this typically includes microthrombocytopenia, meaning platelets are not only decreased in number but are also abnormally small, which can further impair their function. Low platelet counts and reduced platelet function increase the risk of easy bruising, mucocutaneous bleeding, and potentially severe hemorrhage, and are therefore central to assessing disease severity, monitoring response to therapy, and determining medical necessity for interventions that aim to restore platelet production or function.

Vector Copy Number (VCN): Vector copy number is the average number of integrated copies of the therapeutic lentiviral vector per cell genome in a population of gene-modified cells. VCN is typically measured by quantitative molecular methods such as droplet digital PCR, which compare the amount of vector-derived sequence with a reference human gene to determine how many vector insertions are present per cell. VCN is used to assess the extent of gene transfer and to monitor safety, because higher numbers of integrations can increase the potential biological risk associated with insertional events.

X-Linked inheritance: When the genetic mutation is located on the X chromosome, one of the sex chromosomes. The male sex chromosome pair consists of one X and one Y chromosome (XY). The female sex chromosome pair consists of two X chromosomes (XX). Because males have just one X chromosome, it takes only one copy of the mutated gene to cause the disease. Females that have one copy of the mutated gene may have symptoms similar to those experienced by affected males, but usually have less severe symptoms, or no symptoms at all.

Zhu score: A clinical severity scoring system used to categorize the manifestations of Wiskott-Aldrich syndrome. The score incorporates the presence and severity of microthrombocytopenia, eczema, recurrent infections, autoimmunity, and malignancy. Scores range from 0 to 5, with higher scores indicating more severe disease and scores of 3 or higher typically reflecting classic, severe Wiskott-Aldrich syndrome.

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services are Investigational and Not Medically Necessary:
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Peer Reviewed Publications:

1. Boztug K, Schmidt M, Schwarzer A, et al. Stem-cell gene therapy for the Wiskott-Aldrich syndrome. N Engl J Med. 2010; 363:1918-1927.
2. Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci Transl Med. 2014; 6(227):227ra33.
3. Ferrua F, Cicalese MP, Galimberti S, et al. Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study. Lancet Haematol. 2019; 6(5):e239-e253.
4. Hacein-Bey A, Pai S-Y, Gaspar HB, et al. A modified γ-retrovirus vector for X-linked severe combined immunodeficiency. JAMA. 2015; 313(15):1550-1563.
5. Labrosse R, Chu JI, Armant MA, et al. Outcomes of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Blood. 2023; 142(15):1281-1296.
6. Magnani A, Semeraro M, Adam F, et al. Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott-Aldrich syndrome. Nat Med. 2022; 28(1):71-80.
7. Ochs HD, Filipovich AH, Veys P, et al. Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment. Biol Blood Marrow Transplant. 2009; 15(1 Suppl):84-90.
8. Ren P, Dong X, Vijg J. Age-related somatic mutation burden in human tissues. Frontiers in Aging. 2022; 3:1018119.
9. Zhu Q, Zhang M, Blaese RM, et al. Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood. 1997; 90(7):2680-2689.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Bonilla FA, Bernstein IL, Khan DA, et al. American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(5 Suppl 1):S1-63. Erratum in: Ann Allergy Asthma Immunol. 2006; 96(3):504.
2. European Medicines Agency (EMA). First gene therapy to treat rare disease Wiskott-Aldrich syndrome. November 15, 2025. Available at: https://www.ema.europa.eu/en/news/first-gene-therapy-treat-rare-disease-wiskott-aldrich-syndrome. Accessed on January 28, 2026.
3. National Institutes of Health. National Cancer Institute. Center for Cancer Research. October 27, 2023. Available at: https://ccr.cancer.gov/news/article/gene-therapy-proves-successful-in-children-with-wiskott-aldrich-syndrome. Accessed on January 28, 2026.
4. National Institutes of Health. Genetic and Rare Disease Information Center (GARD). Wiskott-Aldrich syndrome. September, 2025. Available at: https://rarediseases.info.nih.gov/diseases/7895/x. Accessed on January 28, 2026.
5. United States Food and Drug Administration (FDA). Rockville, MD: FDA. Waskyra (etuvetidigene autotemcel) suspension for intravenous use. Initial U.S. Approval: December, 2025. Available at: https://www.fda.gov/media/190096/download?attachment. Accessed on January 28, 2026.

1. National Organization for Rare Disorders (NORD^®). Available at: https://rarediseases.org/mondo-disease/wiskott-aldrich-syndrome/. Accessed on January 28, 2026.
2. Wiskott-Aldrich Foundation. Available at: https://www.wiskott.org/. Accessed on January 28, 2026.

Acute Leukemia
Anemia
Autoimmunity
Chronic Leukemia
Eosinophilia
Immunodeficiency
Lymphocytopenia
Spontaneous hematoma
Thrombocytopenia
X-Linked inheritance
Zhu score

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