Multicenter Experience of Hematopoietic Stem Cell Transplantation in WHIM Syndrome

Alexandra Laberko,Anna Shcherbina,Alexey Maschan,Dmitry Balashov,Kanchan Rao,Ekaterina Deordieva,Gergely Krivan,Austen Worth,Saleh Bhar,David H Mcdermott,Yuta Kawahara,Vera Goda

doi:10.1007/s10875-021-01155-8

Abstract

PurposeWHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published.MethodsTo summarize current information on HSCT efficacy in disease treatment, seven pediatric patients with WHIM syndrome who underwent allogeneic HSCT were identified in five centers worldwide.ResultsAll patients presented early after birth with neutropenia. Two of seven patients exhibited severe disease complications: poorly controlled autoimmunity (arthritis and anemia) in one and progressive myelofibrosis with recurrent infections in the other. The remaining patients received HSCT to correct milder disease symptoms (recurrent respiratory infections, progressing thrombocytopenia) and/or to preclude severe disease course in older age. All seven patients engrafted but one developed graft rejection and died of infectious complications after third HSCT. Three other patients experienced severe viral infections after HSCT (including post-transplant lymphoproliferative disease in one) which completely resolved with therapy. At last follow-up (median 6.7 years), all six surviving patients were alive with full donor chimerism. One patient 1.4 years after HSCT had moderate thrombocytopenia and delayed immune recovery; the others had adequate immune recovery and were free of prior disease symptoms.ConclusionHSCT in WHIM syndrome corrects neutropenia and immunodeficiency, and leads to resolution of autoimmunity and recurrent infections, including warts.

Highlights

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare autosomal dominant primary immunodeficiency (PID), caused by CXCR4 gene mutations [1]
CXCR4 gene gain of function mutations in WHIM syndrome lead to a phenotype of combined immunodeficiency and abundant mature apoptotic neutrophil accumulation in bone marrow, or myelokathexis, resulting in neutropenia in peripheral blood [3]
The current study describes a multicenter hematopoietic stem cell transplantation (HSCT) experience in a series of patients with WHIM syndrome

Summary

Introduction

Hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare autosomal dominant primary immunodeficiency (PID), caused by CXCR4 gene mutations [1]. CXCR4 is a chemokine receptor expressed by hematopoietic stem and progenitor cells, mature leukocytes, and some non-hematopoietic cells [2]. CXCR4 gene gain of function mutations in WHIM syndrome lead to a phenotype of combined immunodeficiency and abundant mature apoptotic neutrophil accumulation in bone marrow, or myelokathexis, resulting in neutropenia in peripheral blood [3]. Other clinical presentations vary and include bacterial upper and lower respiratory tract and skin infections, human papillomavirus (HPV) positive warts, as well as laboratory findings such as neutropenia, lymphopenia, hypogammaglobulinemia, and thrombocytopenia. Despite the features of combined primary immunodeficiency (PID), opportunistic infections other than HPV are not common in WHIM syndrome. Up to 18% of patients develop autoimmunity (Geier CB et al, submitted), and up to 30% develop lymphoid and HPV-related malignancies at an older age (19–65 years) [5, 6]

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Conclusion