Medical Policy

This document addresses gene therapy for Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, 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^®; Fondazione Telethon ETS, Rome Italy). 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.

Medically Necessary:

A one-time infusion of etuvetidigene autotemcel is considered medically necessary in individuals with Wiskott-Aldrich Syndrome (WAS) when all of the following criteria are met:

1. Diagnosis of Wiskott-Aldrich Syndrome meeting both of the following criteria (1 and 2):
   1. A confirmed WAS gene mutation; and
   2. One of the following indicators of severe WAS:
      1. Absent Wiskott-Aldrich Syndrome Protein (WASP) expression; or
      2. A severe WAS phenotype meeting all of the following criteria (Zhu score greater than or equal to 3):
         1. Thrombocytopenia with bleeding manifestations (for example: petechiae, epistaxis, or other clinically significant bleeding); and
         2. Eczema requiring medical therapy; and
         3. A history of infections requiring medical treatment;
            and
2. The individual is a candidate for an allogeneic hematopoietic cell transplantation, but ineligible due the absence of a donor*; and
3. None of the following contraindications are present:
   1. Currently diagnosed with a neoplastic condition; or
   2. Cytogenic alterations typical of myelodysplastic syndrome or acute myeloid leukemia; or
   3. HIV infection; or
   4. Severe comorbid condition that contraindicates use of the pretreatment conditioning regimen.

* Documentation that a suitable donor has not been identified.

Investigational and Not Medically Necessary:

Infusion of etuvetidigene autotemcel is considered investigational and not medically necessary when the above criteria are not met.

This document describes clinical studies and expert recommendations, and explains when use of gene therapy with etuvetidigene autotemcel (Waskyra) is clinically 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

Etuvetidigene autotemcel is a gene therapy used to treat Wiskott-Aldrich syndrome, a rare genetic disease that affects the immune system and blood clotting. This treatment uses a person’s own stem cells, which are cells in the blood that make other blood cells, including red blood cells, white blood cells, and platelets, to help treat WAS. Stem cells are collected from the person and changed in a lab to include a working copy of the WAS gene. When given back as a one-time infusion, the changed stem cells start to work and create new blood cells that are able to make the protein that the body needs for proper immune and blood cell function. The aim of this treatment is to improve immune function, reduce infections and bleeding, and help manage symptoms like eczema. It is used for people who are sick enough to need a stem cell transplant, but do not have a suitable donor.

What the Studies Show

Studies show that people treated with etuvetidigene autotemcel had fewer infections, less bleeding, and better immune system function after treatment. Some were able to stop other treatments like immune globulin therapy. Platelet counts improved, but often did not reach normal levels. Even so, the increase was enough to lower the risk of serious bleeding. Side effects seen in studies were mostly related to the chemotherapy needed before  infusion of the changed etuvetidigene autotemcel cells, including infections and low immunity for a short time. However, most studies included only a small number of people and did not follow them for a long time. Because of this, better studies are still needed to know how well this treatment improves health over the long term and to fully understand risks such as cancer.

When is etuvetidigene autotemcel Clinically Appropriate?

Etuvetidigene autotemcel may be appropriate in these situations:

• The person has a confirmed mutation in the WAS gene; and
• The person has severe disease; and
• The person is healthy enough to undergo stem cell transplant treatment; and
• There is no suitable matched stem cell donor available; and
• None of the following are present:
  • Active cancer; or
  • Certain abnormal blood cell changes linked to leukemia; or
  • HIV infection; or
  • A serious health condition that makes treatment unsafe.

When is this not Clinically Appropriate?

Etuvetidigene autotemcel is not clinically appropriate when the above criteria are not met. This is because studies have only shown benefit in people who meet these specific conditions. Research has been done in small groups without comparison to other treatments, so it is not clear if it helps people outside these groups. Better studies are needed to know if they improve health in other situations. Using treatments that are not proven can expose people to health risks without any demonstrated health benefit.

(Return to Description/Scope)

Summary

Etuvetidigene autotemcel, an FDA-approved autologous lentiviral hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome (WAS), appears to offer meaningful clinical benefit for individuals with severe disease who are eligible for transplant but lack a suitable matched donor, based on small early-phase studies showing durable engraftment of gene-corrected cells, restored WASP expression, fewer infections, improved immune function, better control of eczema and autoimmunity, and platelet increases that, while often still below normal, were generally sufficient to reduce serious bleeding risk. In contrast to earlier γ-retroviral gene therapy studies, which demonstrated clinical improvement but caused insertional leukemias, the lentiviral studies reported no vector-related leukemias during available follow-up periods, with most serious adverse events attributed instead to conditioning chemotherapy or the underlying disease. Still, the evidence remains limited by very small uncontrolled studies conducted at expert centers and by incomplete long-term follow-up, so uncertainty remains about rare late toxicities such as oncogenesis. Professional guidance, including from the Allergy, Asthma & Immunology (AAAAI), cited in the document addresses broader WAS diagnosis and management, including recognition that X-linked disease can rarely present in females, avoidance of live vaccines, and standard management of associated atopic dermatitis, but no major professional society has issued specific recommendations for lentiviral autologous HSC gene therapy in WAS.

Discussion

Wiskott-Aldrich syndrome (WAS), also known as eczema-thrombocytopenia-immunodeficiency syndrome, is a rare, X-linked primary immunodeficiency characterized by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. WAS is caused by mutations in the WAS gene, which encodes the Wiskott-Aldrich syndrome protein (WASP). WASP is expressed in hematopoietic cells, where it links intracellular signaling pathways to actin cytoskeleton remodeling. Loss or dysfunction of WASP results in defective actin dynamics leading to impaired migration, adhesion, immunologic synapse formation, and cytotoxic function of immune cells.

Severe WAS is associated with markedly reduced survival, with most affected individuals dying in childhood or adolescence without curative treatment. The only established curative therapy for severe WAS is allogeneic hematopoietic stem cell transplantation (HSCT) from a closely matched donor; however, many individuals with severe disease lack an appropriate donor.

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 Background and Definitions sections). 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.

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.

 In 2023, the National Cancer Institute (NCI) reported results from a clinical trial (Labrosse, 2023) evaluating lentiviral vector-mediated gene therapy in 5 children with WAS. The investigational approach involved autologous CD34+ hematopoietic stem cell collection, ex vivo transduction using a lentiviral vector encoding the functional WAS gene, and subsequent reinfusion following myeloablative chemotherapy. Vector integration analyses demonstrated successful gene transfer in all participants, with each participant’s reconstituted hematopoietic cells acquiring at least one functional WAS gene copy. Several participants exhibited multicopy integration. With a median follow-up duration of 7.6 years, sustained multi-lineage expression of WAS protein translated into clinically meaningful improvements, including enhanced immune function, resolution of eczema, reduction in infection frequency, and decreased bleeding episodes. A dose-response effect was noted: participants whose cells received two or more copies of the vector showed better hematologic improvements, with platelet counts rising to near-normal levels. Although limited by small sample size consistent with the ultra-rare nature of WAS, the long-term data provide robust early evidence supporting the safety and durable clinical benefit of lentiviral gene therapy. The findings suggest that autologous gene-corrected HSCT may serve as a viable therapeutic alternative for individuals lacking suitable allogeneic donors or for whom allogeneic HSCT poses an elevated risk profile (NCT01410825).

Early clinical evidence, although derived from small, single-arm studies with limited long-term follow-up demonstrates that etuvetidigene autotemcel (Waskyra) provides meaningful hematologic and immunologic correction in individuals with Wiskott-Aldrich syndrome (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. Taken together, the preliminary but favorable safety and efficacy profile supports the use of etuvetidigene autotemcel for children 6 months of age or older and adults with a confirmed WAS gene mutation and a severe WAS phenotype who are eligible for HSCT but lack a suitable HLA-matched related donor. The available data suggest that this autologous, lentiviral vector-mediated gene therapy represents a viable alternative to allogeneic HSCT in appropriately selected individuals, pending confirmation through longer-term outcomes and larger post-marketing cohorts.

Relevant professional society recommendations:

The 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, AAAAI 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 (IOM) 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 (AAP).

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). Severe eczema is common in people with WAS.

WAS is caused by mutation 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 viral infections, 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 or in infancy (National Institutes 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)

The severity of Wiskott-Aldrich Syndrome is reported using the WAS clinical score (also known as the Zhu score), which is a 5-point scale ranging from 0 to 5 based on the presence and severity of five key clinical features: thrombocytopenia, eczema, immunodeficiency, autoimmune disorders, and malignancy. The scoring system assigns a score of 0 for X-linked neutropenia/myelodysplasia without thrombocytopenia; a score of 1 for isolated thrombocytopenia (X-linked thrombocytopenia, XLT); a score of 2 for thrombocytopenia with mild or transient eczema and infrequent infections (XLT); a score of 3 for thrombocytopenia with persistent but responsive eczema and recurrent infections (classical Wiskott-Aldrich syndrome); a score of 4 for thrombocytopenia with severe, uncontrolled eczema and severe infections (classical Wiskott-Aldrich syndrome); and a score of 5 for any combination of features with the presence of autoimmune disorders or malignancy. This scoring system facilitates clinical categorization and helps predict disease severity, with scores of 1-2 generally indicating milder disease and scores of 3-5 indicating severe, classical Wiskott-Aldrich syndrome. Importantly, individuals may progress from lower to higher scores over time, as disease severity can worsen with age, making the score a dynamic assessment tool that requires ongoing monitoring.

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 one such 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.

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 may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, or for all other diagnoses not listed.

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. Chandra S, Nagaraj CB, Sun M, et al. WAS-Related Disorders. Updated February 26, 2026. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews^® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1178/. Accessed March 27, 2026.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Ren P, Dong X, Vijg J. Age-related somatic mutation burden in human tissues. Frontiers in Aging. 2022; 3:1018119.
10. 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. American Academy of Allergy Asthma & Immunology. Current status of management of guidelines in inborn errors of immunity. September 1, 2025. Available at: https://www.aaaai.org/tools-for-the-public/latest-research-summaries/the-journal-of-allergy-and-clinical-immunology/2025/inborn. Accessed March 18, 2026.
2. 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.
3. 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 March 17, 2026.
4. 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 March 17, 2026.
5. 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 March 17, 2026.
6. United States Food and Drug Administration (FDA). Rockville, MD: FDA. Waskyra (etuvetidigene autotemcel) suspension for intravenous use. Initial U.S. December, 2025. Available at: https://www.fda.gov/media/190096/download?attachment. Accessed on March 17, 2026.
7. United States Food and Drug Administration (FDA). Rockville, MD: FDA. Approved Cellular and Gene Therapy Products. Waskyra. BLA125846. January 9, 2026. Available at: https://www.fda.gov/vaccines-blood-biologics/waskyra. Accessed on March 18, 2026.

1. National Organization for Rare Disorders (NORD^®). Wiskott-Aldrich syndrome. Available at: https://rarediseases.org/mondo-disease/wiskott-aldrich-syndrome/. Accessed on March 17, 2026.
2. Wiskott-Aldrich Foundation. Available at: https://www.wiskott.org/. Accessed on March 17, 2026.

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

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