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Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.).

SUBMITTER: Burroughs LM

PROVIDER: S-EPMC7273831 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.

Burroughs Lauri M LM Petrovic Aleksandra A Brazauskas Ruta R Liu Xuerong X Griffith Linda M LM Ochs Hans D HD Bleesing Jack J JJ Edwards Stephanie S Dvorak Christopher C CC Chaudhury Sonali S Prockop Susan E SE Quinones Ralph R Goldman Frederick D FD Quigg Troy C TC Chandrakasan Shanmuganathan S Smith Angela R AR Parikh Suhag S Dávila Saldaña Blachy J BJ Thakar Monica S MS Phelan Rachel R Shenoy Shalini S Forbes Lisa R LR Martinez Caridad C Chellapandian Deepak D Shereck Evan E Miller Holly K HK Kapoor Neena N Barnum Jessie L JL Chong Hey H Shyr David C DC Chen Karin K Abu-Arja Rolla R Shah Ami J AJ Weinacht Katja G KG Moore Theodore B TB Joshi Avni A DeSantes Kenneth B KB Gillio Alfred P AP Cuvelier Geoffrey D E GDE Keller Michael D MD Rozmus Jacob J Torgerson Troy T Pulsipher Michael A MA Haddad Elie E Sullivan Kathleen E KE Logan Brent R BR Kohn Donald B DB Puck Jennifer M JM Notarangelo Luigi D LD Pai Sung-Yun SY Rawlings David J DJ Cowan Morton J MJ

Blood 20200601 23

Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WA ...[more]

PMID: 32268350

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Project description:ImportanceWiskott-Aldrich syndrome is a rare primary immunodeficiency associated with severe microthrombocytopenia. Partially HLA antigen-matched allogeneic hematopoietic stem cell (HSC) transplantation is often curative but is associated with significant comorbidity.ObjectiveTo assess the outcomes and safety of autologous HSC gene therapy in Wiskott-Aldrich syndrome.Design, setting, and participantsGene-corrected autologous HSCs were infused in 7 consecutive patients with severe Wiskott-Aldrich syndrome lacking HLA antigen-matched related or unrelated HSC donors (age range, 0.8-15.5 years; mean, 7 years) following myeloablative conditioning. Patients were enrolled in France and England and treated between December 2010 and January 2014. Follow-up of patients in this intermediate analysis ranged from 9 to 42 months.InterventionA single infusion of gene-modified CD34+ cells with an advanced lentiviral vector.Main outcomes and measuresPrimary outcomes were improvement at 24 months in eczema, frequency and severity of infections, bleeding tendency, and autoimmunity and reduction in disease-related days of hospitalization. Secondary outcomes were improvement in immunological and hematological characteristics and evidence of safety through vector integration analysis.ResultsSix of the 7 patients were alive at the time of last follow-up (mean and median follow-up, 28 months and 27 months, respectively) and showed sustained clinical benefit. One patient died 7 months after treatment of preexisting drug-resistant herpes virus infection. Eczema and susceptibility to infections resolved in all 6 patients. Autoimmunity improved in 5 of 5 patients. No severe bleeding episodes were recorded after treatment, and at last follow-up, all 6 surviving patients were free of blood product support and thrombopoietic agonists. Hospitalization days were reduced from a median of 25 days during the 2 years before treatment to a median of 0 days during the 2 years after treatment. All 6 surviving patients exhibited high-level, stable engraftment of functionally corrected lymphoid cells. The degree of myeloid cell engraftment and of platelet reconstitution correlated with the dose of gene-corrected cells administered. No evidence of vector-related toxicity was observed clinically or by molecular analysis.Conclusions and relevanceThis study demonstrated the feasibility of the use of gene therapy in patients with Wiskott-Aldrich syndrome. Controlled trials with larger numbers of patients are necessary to assess long-term outcomes and safety.

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Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.

Publications

Excellent outcomes following hematopoietic cell transplantation for Wiskott-Aldrich syndrome: a PIDTC report.

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