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

Lauri M Burroughs, Aleksandra Petrovic, Ruta Brazauskas, Xuerong Liu, Linda M Griffith, Hans D Ochs, Jack J Bleesing, Stephanie Edwards, Christopher C Dvorak, Sonali Chaudhury, Susan E Prockop, Ralph Quinones, Frederick D Goldman, Troy C Quigg, Shanmuganathan Chandrakasan, Angela R Smith, Suhag Parikh, Blachy J Dávila Saldaña, Monica S Thakar, Rachel Phelan, Shalini Shenoy, Lisa R Forbes, Caridad Martinez, Deepak Chellapandian, Evan Shereck, Holly K Miller, Neena Kapoor, Jessie L Barnum, Hey Chong, David C Shyr, Karin Chen, Rolla Abu-Arja, Ami J Shah, Katja G Weinacht, Theodore B Moore, Avni Joshi, Kenneth B DeSantes, Alfred P Gillio, Geoffrey D E Cuvelier, Michael D Keller, Jacob Rozmus, Troy Torgerson, Michael A Pulsipher, Elie Haddad, Kathleen E Sullivan, Brent R Logan, Donald B Kohn, Jennifer M Puck, Luigi D Notarangelo, Sung-Yun Pai, David J Rawlings, Morton J Cowan, Lauri M Burroughs, Aleksandra Petrovic, Ruta Brazauskas, Xuerong Liu, Linda M Griffith, Hans D Ochs, Jack J Bleesing, Stephanie Edwards, Christopher C Dvorak, Sonali Chaudhury, Susan E Prockop, Ralph Quinones, Frederick D Goldman, Troy C Quigg, Shanmuganathan Chandrakasan, Angela R Smith, Suhag Parikh, Blachy J Dávila Saldaña, Monica S Thakar, Rachel Phelan, Shalini Shenoy, Lisa R Forbes, Caridad Martinez, Deepak Chellapandian, Evan Shereck, Holly K Miller, Neena Kapoor, Jessie L Barnum, Hey Chong, David C Shyr, Karin Chen, Rolla Abu-Arja, Ami J Shah, Katja G Weinacht, Theodore B Moore, Avni Joshi, Kenneth B DeSantes, Alfred P Gillio, Geoffrey D E Cuvelier, Michael D Keller, Jacob Rozmus, Troy Torgerson, Michael A Pulsipher, Elie Haddad, Kathleen E Sullivan, Brent R Logan, Donald B Kohn, Jennifer M Puck, Luigi D Notarangelo, Sung-Yun Pai, David J Rawlings, Morton J Cowan

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.).

Conflict of interest statement

Conflict-of-interest disclosure: L.M.B. received support for the conduct of a clinical trial through the Fred Hutchinson Cancer Research Center by Medac GmbH, including supply of the study drug Treosulfan. S. Chaudhury is on the Mesoblast Advisory Panel. S.E.P. receives support for the conduct of sponsored trials through Memorial Sloan Kettering from Atara Biotherapeutics and Mesoblast Advisory Panel Mesoblast. R.P. is on the advisory board for Orchard Therapeutics. M.D.K. is on the advisory board for Gilead Sciences. The remaining authors declare no competing financial interests.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Age at HCT. Histogram shows percentage of subjects at ages 0 to 22 years at the time of HCT.
Figure 2.
Figure 2.
Probabilities of acute and chronic GVHD in patients with WAS after HCT. Shown is the cumulative incidence of acute grades 2 to 4 and 3 to 4 GVHD (A) (n = 128) up to 100 days after HCT and of chronic GVHD (B) (n = 123) up to 24 months.
Figure 3.
Figure 3.
OS probabilities in 129 patients with WAS. Shown are the probabilities of OS by age (A), conditioning regimen intensity (B), donor type (C), and hematopoietic cell source (D). The P-values were obtained by log-rank test.
Figure 4.
Figure 4.
Donor CD3+ T-cell, CD19+ B-cell, and myeloid chimerism vs conditioning regimen intensity (RIC vs MAC) over the first 2 years after HCT. Donor chimerism: full, >95%; high-level, 50% to 95%; low-level, 5% to 49%; rejection, <5%. MAC resulted in a higher percentage of patients with full donor (>95%) CD3+ T-cell chimerism compared with RIC at day 100 (P < .001), 6 months (P = .006), and 1 year (P = .002) after HCT. This difference was not significant at 2 years after HCT. MAC resulted in a higher percentage of patients with full donor (>95%) B-cell chimerism at day 100 (P = .004) and myeloid chimerism at 6 months (P = .023), compared with RIC. The differences at all other time points were not significant.
Figure 5.
Figure 5.
Box plots of platelet count vs donor myeloid chimerism at 1 and 2 years and 3 to 5 years after HCT. Donor myeloid chimerism: full, >95%; high-level, 50% to 95%; low-level, 5% to 49%. Recovery of platelet counts after HCT was related to the degree of donor myeloid chimerism. Specifically, platelet counts for patients who had low-level (5% to 49%) donor myeloid engraftment remained inferior to those who had attained full (>95%) donor myeloid engraftment at 1 year (P < .0001), 2 years (P < .0001), and 3 to 5 years (P = .0002). In addition, platelet counts were lower in patients with low-level (5% to 49%) donor myeloid engraftment compared with those who attained high level (50% to 95%) donor myeloid engraftment at 1 year after HCT (P = .011); however, this was not significant at 2 or 3 to 5 years after HCT. All other pairwise comparisons were not significant.

Source: PubMed

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