Outcome of Hematopoietic Stem Cell Transplantation in patients with Mendelian Susceptibility to Mycobacterial Diseases

Mary A Slatter,Sophie Hambleton,Terry Flood,Eleri Williams,Andrew R Gennery,Su Han Lum,Stephen Owens,Nesrine Radwan,Zohreh Nademi,Mario Abinun

doi:10.1007/s10875-021-01116-1

Abstract

Predisposition to mycobacterial infection is a key presenting feature of several rare inborn errors of intrinsic and innate immunity. Hematopoietic stem cell transplantation (HSCT) can be curative for such conditions, but published reports are few. We present a retrospective survey of the outcome of 11 affected patients (7 males, 4 females) who underwent HSCT between 2007 and 2019. Eight patients had disseminated mycobacterial infection prior to transplant. Median age at first transplant was 48 months (9 -192); three patients were successfully re-transplanted due to secondary graft failure. Donors were matched family (1), matched unrelated (3), and mismatched unrelated and haploidentical family (5 each). Stem cell source was peripheral blood (9), bone marrow (4), and cord blood (1). TCRαβ/CD19 + depletion was performed in 6. Conditioning regimens were treosulfan, fludarabine (4), with additional thiotepa (in 8), and fludarabine, melphalan (2); all had serotherapy with alemtuzumab (8) or anti T-lymphocyte globulin (6). Median hospital stay was 113 days (36–330). Three patients developed acute grade I-II skin and one grade IV skin graft versus host disease. Four patients had immune-reconstitution syndrome. Two reactivated cytomegalovirus (CMV), 1 Epstein-Barr virus, and 3 adenovirus post HSCT. Nine are alive, 1 died early post-transplant from CMV, and the other was a late death from pneumococcal sepsis. Patients with active mycobacterial infection at HSCT continued anti-mycobacterial therapy for almost 12 months. In conclusion, HSCT is a successful treatment for patients with mycobacterial susceptibility even with disseminated mycobacterial infection and in the absence of an HLA matched donor.

Highlights

Mendelian susceptibility to mycobacterial disease (MSMD) is a group of rare inborn errors of immunity (IEI) characterized by selective susceptibility to mycobacteria including BCG-derived Mycobacterium bovis and environmental mycobacteria [1, 2]
Mycobacterial infection complicating non-SCID IEI shows a wide range of clinical manifestations, from localized to disseminated, acute to chronic infections, plus immature or mature granulomas [7,8,9]
Patients with some genetic mutations benefit from recombinant IFN-γ, treatment of mycobacterial infection may not be curative without correction of the underlying condition as is the case with absent IFNGR where hematopoietic stem cell transplantation (HSCT) is the only treatment [11]

Summary

Introduction

Mendelian susceptibility to mycobacterial disease (MSMD) is a group of rare inborn errors of immunity (IEI) characterized by selective susceptibility to mycobacteria including BCG-derived Mycobacterium bovis and environmental mycobacteria [1, 2]. Patients with some genetic mutations benefit from recombinant IFN-γ, treatment of mycobacterial infection may not be curative without correction of the underlying condition as is the case with absent IFNGR where hematopoietic stem cell transplantation (HSCT) is the only treatment [11]. Between 2007 and 2019, we transplanted 8 children with a history of infection with atypical mycobacteria or disseminated BCG due to 6 different genetic diseases (deficiency of IRF8 (AR), NEMO (IKBKG), GATA2, STAT1 (AR), IFNGR2 (AR), gain of function in NFKBIA (AD)).

Results

Conclusion