Etuvetidigene Autotemcel (Waskyra)
Number: 1097
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses etuvetidigene autotemcel (Waskyra) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.
Waskyra has been identified as an Aetna Gene-based, Cellular & Other Innovative Therapies (GCIT®) product. It receives dedicated review by the Aetna GCIT team for Commercial and Medicare lines of business.
Note: Requires Precertification:
Precertification of etuvetidigene autotemcel (Waskyra) is required of all Aetna participating providers and members in applicable plan designs. For precertification of etuvetidigene autotemcel (Waskyra), contact National Medical Excellence (NME) at 877-212-8811.
Note: Unless member's health plan has elected not to require, gene and cellular therapies must be administered at an Aetna Institutes® Gene Based, Cellular and Other Innovative Therapy (GCIT®) Network. For etuvetidigene autotemcel (Waskyra), see Aetna Institutes® GCIT Designated Networks.
-
Prescriber Specialties
This medication must be prescribed by or in consultation with an immunologist, hematologist, or physician who specializes in the treatment of Wiskott-Aldrich syndrome (WAS).
-
Criteria for Initial Approval
Aetna considers a one-time administration of etuvetidigene autotemcel (Waskyra) medically necessary for the treatment of Wiskott-Aldrich syndrome (WAS) when all of the following criteria are met:
- Member is 6 months of age or older; and
- Member has a diagnosis of Wiskott-Aldrich Syndrome (classis WAS) confirmed by the presence of a pathogenic variant in the WAS gene and either of the following:
- Absent or truncated Wiskott-Aldrich Syndrome protein (WASP) expression assessed by flow cytometry, or
- Severe clinical phenotype (Zhu clinical score greater than or equal to 3, see Appendix); and
-
Member is an appropriate candidate for hematopoietic stem cell transplant (HSCT), and meets either of the following criteria:
- Member is 5 years of age or older and has no human leukocyte antigen (HLA)-identical sibling donor, or
- Member is less than 5 years of age and has no HLA-identical sibling donor, suitable 10/10 HLA matched unrelated donor, or 6/6 HLA matched unrelated cord blood donor; and
- Member does not have evidence of residual cells of donor origin if the member has received a prior allogeneic hematopoietic stem cell transplant (allo-HSCT) and has not received allo-HSCT in the past 6 months; and
- Member is negative for human immunodeficiency virus (HIV) and hepatitis C infection; and
- Member does not have acute or chronic stable hepatitis B; and
- Member does not have symptomatic herpes zoster that is unresponsive to specific treatment; and
- Member does not have evidence of acute tuberculosis; and
- Member is not affected by malignant neoplasia (except local skin cancer); and
- Member does not have a documented history of hereditary cancer syndrome; and
- Member is not affected by cytogenic alterations typical of myelodysplastic syndrome or acute myelogenous leukemia; and
- Member is not affected by end-organ dysfunction, severe active infection, or any other severe disease that, in the opinion of the provider, would make the member an inappropriate candidate for treatment with the requested medication; and
- Member will be assessed and monitored for evidence of engraftment failure, cytopenia, infection, hepatic veno-occlusive disease, and malignancies as outlined in the manufacturer’s prescribing information; and
- Member has not received Waskyra or any other gene therapy previously.
Aetna considers all other indications as experimental, investigational, or unproven.
-
Related Policies
Dosage and Administration
Etuvetidigene autotemcel is available as Waskyra, a single-dose cell suspension for autologous use and administered as a one-time intravenous infusion. Waskyra is packaged in one to eight infusion bags overall containing a suspension of 2 to 11.4 x 106 cells /mL (1.9 to 11.4 x 106 CD34+ cells/mL) in a cryopreservative solution.
Individuals are required to undergo hematopoietic stem and progenitor cell (HSPC) mobilization followed by apheresis to obtain CD34+ cells for Waskyra manufacturing.
Dosing is based on the number of CD34+ cells in the infusion bag(s) per kg of body weight at the time of infusion.
The minimum recommended dose of Waskyra is 7 × 106 CD34+ cells/kg based on individual's body weight at the time of infusion.
Reduced-intensity conditioning is required before infusion of Waskyra.
The maximum volume of Waskyra to be administered should remain less than 20% of the individual's estimated plasma volume.
Source: Fondazione Telethon ETS, 2025
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
- Waskyra is indicated for the treatment of pediatric patients aged 6 months and older and adults with Wiskott-Aldrich syndrome (WAS) who have a mutation in the WAS gene and for whom hematopoietic stem cell transplantation (HSCT) is appropriate and no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available.
Etuvetidigene autotemcel, branded as Waskyra (Fondazione Telethon ETS), is an autologous gene therapy that uses a patient’s own hematopoietic stem cells to correct the underlying genetic defect in Wiskott‑Aldrich syndrome (WAS). The therapy involves mobilizing CD34+ stem cells into the bloodstream, which are then collected through apheresis and genetically modified ex vivo using a self-inactivating lentiviral vector (LVV) derived from human immunodeficiency virus-1. This vector is engineered to deliver a functional copy of the WAS gene under the control of the endogenous WAS promoter. After transduction, the modified cells are formulated into a suspension, cryopreserved, and later thawed for intravenous infusion following reduced-intensity conditioning of the patient to prepare the bone marrow for engraftment. Once infused, the gene-corrected cells migrate to the bone marrow, engraft, and reconstitute hematopoiesis by producing healthy lymphoid and myeloid progenitor cells that express functional WAS protein. The restoration of this protein facilitates normal regulation of the actin cytoskeleton within blood cells, effectively addressing the immunologic and platelet dysfunction associated with Wiskott-Aldrich syndrome.
Contraindications for Waskyra include hypersensitivity to the active substance or any of the excipients, previous treatment with hematopoietic stem cell transplantation (HSCT) within six months prior to screening or HSCT with evidence of residual donor cells, prior treatment with hematopoietic stem cell gene therapy, and any contraindications related to the mobilization and conditioning regimen.
Labeled warnings and precautions for Waskyra include the potential for hypersensitivity and infusion-related reactions, such as anaphylaxis, which may occur due to the presence of dimethylsulfoxide (DMSO) as an excipient. There is a risk of engraftment failure, defined as the inability to achieve an absolute neutrophil count (ANC) greater than 500 cells/μL, along with no evidence of bone marrow recovery (i.e., hypocellular marrow) by day 60 following Waskyra infusion. Additionally, severe cytopenias, including anemia, neutropenia, and thrombocytopenia, may persist for several weeks after reduced intensity conditioning and Waskyra administration. Serious infections have also been reported, and the concomitant use of rituximab and the conditioning regimen may increase susceptibility to infections.
Furthermore, Waskyra is manufactured using human and bovine-derived reagents, which are tested for viruses, bacteria, fungi, and mycoplasma prior to use. Despite these precautions, there remains a risk of transmitting infectious diseases or agents. Hepatic veno-occlusive disease has been observed in patients receiving Waskyra, and there is a lifelong risk of lentiviral vector (LVV)-mediated insertional oncogenesis and secondary malignancies. Patients treated with Waskyra may test positive for HIV through polymerase chain reaction (PCR) assays due to LVV provirus insertion, leading to false-positive results for HIV. Therefore, it is advised not to use PCR-based assays for HIV screening in these patients. Additionally, individuals who have received Waskyra should refrain from donating blood, organs, tissues, or cells for transplantation at any time in the future. This critical information is provided in the Patient Alert Card, which should be given to patients after treatment.
The most common adverse reactions (incidence of 20% or more) are catheter related infections, bacterial and viral infections, diarrhea, vomiting, stomatitis, liver injury, head injury, rhinitis, cough, rash, petechiae, hypersensitivity, anemia, febrile neutropenia, epistaxis, pyrexia, catheter site complications.
Wiskott-Aldrich Syndrome
Wiskott–Aldrich syndrome is a rare X‑linked recessive immunodeficiency caused by pathogenic variants in the WAS gene, which lead to defective Wiskott-Aldrich syndrome protein (WASP) function and impaired T‑ and B‑cell activity. It typically presents in newborns or young infants with the classic triad of eczema, recurrent infections, and bleeding due to microthrombocytopenia. Affected individuals also face increased risks of autoimmune disease and hematologic malignancies. Management has relied on supportive measures—including antimicrobial prophylaxis, intravenous immune globulin (IVIG) replacement, eczema and autoimmune disease control, and platelet transfusions—with allogeneic hematopoietic cell transplantation (HCT) serving as the only curative option. The disorder primarily affects males with an estimated prevalence of about 3 per million in the United States and approximately 1:100,000 live births worldwide (Malik and Masab, 2023; Ochs, 2024).
Mutations in the WAS gene lead to a range of clinical phenotypes that correlate with the type of mutation and its impact on WAS protein (WASP) expression. Patients are generally classified into three main groups: classic Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN). While there is a notable correlation between phenotype and genotype, exceptions exist, making it challenging to predict individual clinical outcomes based solely on the type of mutation. The most reliable correlation is seen when patients are categorized as WASP+ (expressing a mutated, nonfunctional protein) or WASP- (lacking or expressing truncated WASP). Typically, patients with mutations allowing for the expression of normal-sized mutated protein exhibit the XLT phenotype, whereas those with absent or truncated WASP are more likely to present with classic WAS. A disease scoring system, such as the Zhu Clinical Scoring System, aids in the clinical categorization of WAS patients and may help predict disease severity and outcomes following HCT. However, this scoring should not be applied to infants under two years, as the clinical phenotype can evolve over time and may be incomplete in younger males. A score of 1 or 2 indicates XLT, while scores of 3 to 4 identify classic WAS, and a score of 5 is assigned to patients with either XLT or classic WAS who develop autoimmunity or malignancies. The scoring system does not account for the specific type of mutation or WASP expression, but most patients with missense mutations in the early exons of the WAS gene tend to have a milder disease phenotype. XLN, caused by gain-of-function mutations in the WAS gene, presents as severe congenital neutropenia and is associated with increased infection risk and myelodysplasia. XLT, a milder variant of WAS, is characterized by congenital thrombocytopenia and a generally better prognosis, although patients still face risks for severe complications. Classic WAS presents in early childhood with severe symptoms, including thrombocytopenia, recurrent infections, and eczema, often leading to autoimmune complications and malignancies. There are rare cases of females exhibiting WAS phenotypes due to heterozygous mutations or WIP deficiency, which can also be treated with HCT.
Approximately 50% of patients with WAS gene mutations have the classic WAS phenotype, and nearly all others have the XLT phenotype, a milder form of WAS. WAS gene mutations causing XLN are very rare, with only 12 patients in four families reported (Ochs, 2024).
Historically, life expectancy was reduced due to severe infections, hemorrhage, autoimmune complications, and cancer. Patients with classic WAS who do not receive HCT or gene therapy have a reduced life expectancy, with premature death often resulting from infections, hemorrhage, autoimmune diseases, and malignancies, with bleeding being the primary cause of death. Malignancies in these patients are frequently fatal; for instance, in one study, only 1 out of 21 patients diagnosed with a malignancy survived more than two years. In contrast, patients with a milder form of WAS (XLT) in resource-abundant countries have a life expectancy comparable to that of the general male population, despite a reduced event-free survival rate (median 10.2 years, range 0.1 to 74 years) and the potential for serious complications such as central nervous system hemorrhage, autoimmunity, and malignancies at any age (Ochs, 2024).
Ferrua et al. (2019) conducted a non-randomized, open-label, phase 1/2 clinical study to evaluate the safety and efficacy of lentiviral vector-mediated gene therapy for (WAS, a rare and life-threatening X-linked primary immunodeficiency characterized by microthrombocytopenia, infections, eczema, autoimmunity, and malignancies. The study included pediatric patients with severe WAS, defined by either a WAS gene mutation, absent WASP expression, or a Zhu clinical score of 3 or higher, who lacked an HLA-identical sibling donor or a suitable matched unrelated donor. Following treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received a single intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding human WAS cDNA. The primary safety endpoints focused on the safety of the conditioning regimen and the lentiviral gene transfer, while the primary efficacy endpoints included overall survival, sustained engraftment of genetically corrected HSPCs, WASP expression, improved T-cell function, antigen-specific responses to vaccinations, and normalization of platelet counts. The interim analysis was conducted after the first six patients completed at least three years of follow-up, with the trial registered on ClinicalTrials.gov (NCT01515462) and EudraCT (2009-017346-32). Between April 20, 2010, and February 26, 2015, nine male patients were enrolled, with eight treated, aged 1.1 to 12.4 years. At the time of the interim analysis (data cutoff April 29, 2016), the median follow-up was 3.6 years. All patients achieved 100% overall survival, and successful engraftment of genetically corrected HSPCs was observed. The proportion of WASP-positive lymphocytes increased from a median of 3.9% before therapy to 66.7% at 12 months post-therapy, while WASP-positive platelets rose from 19.1% to 76.6%. Immune function improved, evidenced by normalized T-cell function and the successful discontinuation of immunoglobulin supplementation in seven patients, along with positive responses to vaccinations. Severe infections decreased significantly from 2.38 per patient-year of observation before therapy to 0.31 in the second year and 0.17 in the third year post-therapy. Platelet counts, previously below 20 × 109 per L in seven patients, increased significantly, leading to independence from transfusions and no severe bleeding events. Although 27 serious adverse events occurred in six patients post-therapy, the majority were infectious and primarily occurred within the first six months, with no adverse reactions to the investigational product or abnormal clonal proliferation reported. The findings suggest that gene therapy offers a promising treatment option for patients with severe WAS, especially those without suitable HSPC donors.
Quaranta et al. (2024) explored the phenotype and function of circulating hematopoietic stem/progenitor cells (cHSPCs) in humans through immunophenotyping, transcriptome sequencing, functional assays, and clonal tracking. Their findings revealed that cHSPCs decline with age, are enriched with early committed progenitors, and exhibit a distinct transcriptional profile compared to their bone marrow counterparts. These cells are primed for differentiation and contribute to hematopoiesis at extramedullary sites. While adult hematopoiesis primarily occurs in the bone marrow, rare HSPCs can also be found in peripheral blood (PB). Despite the known existence of cHSPCs, their characterization in humans has been limited due to their rarity. Previous studies have linked PB-CD34+ cell counts to various pathological conditions, but recent advancements in single-cell technology have allowed for a more detailed transcriptional characterization of human extramedullary HSPCs, revealing lineage priming and an erythroid transcriptional signature. However, the migratory fate and role of cHSPCs in hematopoietic homeostasis relative to bone marrow-resident counterparts remain unclear. This study provides a comprehensive characterization of human cHSPCs, generating the largest reference dataset for analyzing HSPC subsets from both bone marrow and peripheral blood. The results indicate a strong correlation between phenotype, transcriptional commitment, and function of HSPC subsets from the two sources, highlighting their distinct compositions and biological roles in maintaining hematopoietic homeostasis. Specifically, the high proliferation and metabolic activity of bone marrow HSPCs suggest their continuous support of hematopoietic turnover, while the preactivated state of PB-HSPCs indicates their role in rapidly responding to peripheral tissue needs. Additionally, the low-replicative state of cHSPCs may serve as a protective mechanism against various stimuli. The study also discusses the mechanisms driving HSPC egress from the bone marrow and the identity of cHSPC subpopulations with organ-specific seeding properties, noting the downregulation of CXCR4 in PB-HSPCs, which may play a crucial role in their recirculation. The findings suggest that PB-transitioning multipotent progenitors are likely directed to the spleen to support extramedullary hematopoiesis, while the presence of lymphoid progenitors in circulation indicates their potential role in thymic seeding. Furthermore, the study highlights the translational implications of cHSPCs as biomarkers for bone marrow HSPC states, providing insights into their homing and differentiation properties, and suggesting their potential as an alternative stem cell source for clinical applications, particularly in pediatric populations. Overall, the research underscores the active contribution of cHSPCs to hematopoiesis and their relevance in understanding hematopoietic disorders. In summary, Quaranta et al. demonstrated that circulating CD34⁺ hematopoietic stem and progenitor cell subsets actively contribute to human hematopoietic homeostasis, which may provide mechanistic support for the biological suitability of mobilized peripheral blood CD34⁺ cells used in Waskyra’s ex vivo gene‑corrected stem cell product.
On December 9, 2025, the U.S. Food and Drug Administration (FDA) announced the approval of Waskyra as the first cell-based gene therapy indicated for the treatment of WAS in patients 6 months and older who have a mutation in the WAS gene and for whom hematopoietic stem cell transplantation (HSCT) is appropriate and no suitable human leukocyte antigen (HLA)-matched related stem cell donor is available. FDA approval of Waskyra was granted based on the assessment of its safety and effectiveness through two open-label, single-arm, multinational clinical studies (Study 1 [NCT01515462]; Study 2 [NCT03837483]) and an expanded access program involving 27 patients with severe Wiskott-Aldrich syndrome (WAS). These studies demonstrated significant and sustained clinical benefits, including substantial reductions in the primary disease manifestations that contribute to morbidity and mortality. Specifically, the rate of severe infections decreased by 93% during the six to 18 months following treatment compared to the year prior, while moderate and severe bleeding events were reduced by 60% in the first 12 months post-treatment relative to the previous year. Notably, most patients did not experience moderate to severe bleeding four years after treatment.
Study 1 (NCT01515462) was a prospective, open-label, single-arm, single-center study involving 8 participants that compared the safety and efficacy of the fresh formulation of Waskyra to outcomes from the 12 months prior to treatment. Study 2 (NCT03837483) is an ongoing, open-label, single-arm, multicenter study with 10 participants evaluating the efficacy of the cryopreserved formulation of Waskyra against pre-treatment outcomes. The expanded access program included Hospital Exemption (HE) 205030 with 3 patients and Compassionate Use Program (CUP) 206257 with 6 patients, providing Waskyra treatment to individuals with WAS. All enrolled patients had a confirmed diagnosis of WAS through genetic mutation and met at least one of the following criteria: a severe clinical score (Zhu clinical score ≥ 3), a severe WAS mutation, or absent WASP expression, and all lacked a suitable HLA-matched donor. Exclusion criteria included prior allogeneic HSCT within 6 months, evidence of residual donor cells, prior gene therapy, HIV infection, and cytogenetic alterations. Patients underwent hematopoietic stem-cell (HSC) collection via bone marrow (n=5), apheresis after HSC mobilizing agents (n=21), or both (n=1). Prior to treatment, patients received rituximab and a conditioning regimen of busulfan and fludarabine. Rituximab was administered as a single dose of 375 mg/m² on Day -22, while busulfan was given in eight doses every 6 hours from Days -4 to -2, adjusted based on pharmacokinetic monitoring to achieve a target cumulative AUC of 48,000±10% ng/mL per hour. Fludarabine was administered at a total dose of 60 mg/m², split into two doses on Days -4 and -3. Following this, patients received a single infusion of Waskyra through central venous access at a dose range of 7–31×106/kg CD34+ cells (median dose: 16.90×106/kg). The demographic characteristics included a median age of 2.6 years (range 1 to 35 years), with all patients being male; 74% were White, 15% Asian, 7% African American, and 4% American Indian or Alaska Native, with 11% identifying as Hispanic or Latino. Of the 27 patients, 26 were included in the efficacy evaluation, as one was excluded due to mobilization failure. The primary efficacy outcomes measured were the rates of severe infections and moderate to severe bleeding episodes during the 6 to 18 months post-Waskyra infusion compared to the 12-month pre-treatment period. The rate of severe infections decreased from 2.0 (95% CI: 1.50, 2.61) infections per patient-year observation (PYO) in the pre-treatment period to 0.2 (95% CI: 0.04, 0.40) per PYO in the 6-18 months post-treatment period. Similarly, the rate of moderate and severe bleeding events dropped from 2.0 (95% CI: 1.50, 2.61) events per PYO in the pre-treatment period to 0.8 (95% CI: 0.49, 1.22) events per PYO in the 12 months following Waskyra treatment.
In conclusion, the advancements in gene therapy, particularly with the approval of Waskyra, represent a significant breakthrough in the treatment of Wiskott–Aldrich syndrome, offering hope for improved clinical outcomes and quality of life for affected patients. Continued research and clinical application of these innovative therapies will be essential in further understanding and addressing the complexities of this rare immunodeficiency.
Appendix
The Zhu Clinical Scoring System was developed to quantify the severity of disease in Wiskott-Aldrich syndrome (WAS) and related X-linked thrombocytopenia (XLT) phenotypes. This system assigns scores based on the presence and intensity of key clinical manifestations, including thrombocytopenia, eczema, immunodeficiency, autoimmune disorders, and malignancy, allowing for the stratification of patients along a continuum from mild intermittent XLT (score <1) to classic severe WAS (score 5). A score of 5 indicates the most severe phenotype, traditionally associated with the onset of autoimmune disease or malignancy; however, later adaptations have broadened this definition to include severe refractory thrombocytopenia (with a platelet count of ≤10 × 10⁹/L). In clinical practice, the Zhu system aids in categorizing WAS-related disorders by phenotype, guiding prognosis, determining the timing and urgency of interventions such as hematopoietic stem cell transplantation (HSCT) or gene therapy, and monitoring disease progression, particularly during the first two years of life when the phenotype may change.
| Feature | Score | Phenotype | ||||
| Thrombocytopenia | Eczema | Immunodeficiency | Autoimmune Disorders | Malignancy | ||
| Absent | Absent | Absent | Absent | Absent | 0 | XLN / myelodysplasia |
| Present | Absent | Absent | Absent | Absent | 1 | XLT |
| Present | Mild or transient | Infrequent infections | Absent | Absent | 2 | |
| Present | Persistent but responsive | Recurrent infections | Absent | Absent | 3 | Wiskott-Aldrich syndrome |
| Present | Severe, not controlled | Severe infections | Absent | Absent | 4 | |
| Present | Any | Any | Present | Present | 5 | XLT/Wiskott-Aldrich syndrome with autoimmunity and/or malignancy |
XLN = X-linked neutropenia; XLT = X-linked thrombocytopenia
Source: Bosticardo et al., 2009; Chandra et al., 2004
References
The above policy is based on the following references:
- Bosticardo M, Marangoni F, Aiuti A, et al. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood. 2009;113(25):6288-6295.
- Chandra S, Nagaraj CB, Sun M, et al. WAS-related disorders. GeneReviews [Internet]. Adam MP, Bick S, Mirzaa GM, et al., eds. Seattle, WA: University of Washington, Seattle; September 30, 2004.
- 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.
- Fondazione Telethon ETS. Waskyra (etuvetidigene autotemcel) suspension, for intravenous use. Prescribing Information. Rome, Italy: Fondazione Telethon ETS; December 2025.
- Malik MA, Masab M. Wiskott-Aldrich Syndrome. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; updated June 26, 2023.
- Ochs HD. Wiskott–Aldrich syndrome. UpToDate [online serial]. Waltham, MA: UpToDate; updated November 2024.
- Quaranta P, Basso-Ricci L, Jofra Hernandez R, et al. Circulating hematopoietic stem/progenitor cell subsets contribute to human hematopoietic homeostasis. Blood. 2024;143(19):1937-1952.
- U.S. Food and Drug Administration (FDA). FDA approves first gene therapy treatment for Wiskott-Aldrich syndrome. FDA News Release. Silver Spring, MD: FDA; December 9, 2025.
- Wiskott-Aldrich Foundation. Classification of WAS [website]. 2025. Available at: https://www.wiskott.org/About-WAS/understanding-was/-classification-of-was. Accessed January 19, 2026.
