Allogeneic Hematopoietic Stem Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) reverses the bone marrow failure syndrome due to GATA2 deficiency. The intensity of conditioning required to achieve reliable engraftment and prevent relapse remains unclear. Here, we describe the results of a prospective study of HSCT in 22 patients with GATA2 deficiency using a busulfan-based conditioning regimen. The study included 2 matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor (HRD) recipients. MRD and URD recipients received 4 days of busulfan and 4 days of fludarabine. HRD recipients received low-dose cyclophosphamide for 2 days, fludarabine for 5 days, 2 to 3 days of busulfan depending on cytogenetics, and 200 cGy total body irradiation. MRD and URD recipients received tacrolimus and short-course methotrexate for graft-versus-host disease (GVHD) prophylaxis. HRD recipients received high-dose post-transplant cyclophosphamide (PTCy) followed by tacrolimus and mycophenolate mofetil. At a median follow-up of 24 months (range, 9 to 50), 19 of 22 patients were alive with reversal of the disease phenotype and correction of the myelodysplastic syndrome, including eradication of cytogenetic abnormalities. Three patients died: 1 from refractory acute myelogenous leukemia, 1 from GVHD, and 1 from sepsis. There was a 26% incidence of grades III to IV acute GVHD in the MRD and URD groups and no grades III to IV acute GVHD in the HRD cohort. Similarly, there was a 46% incidence of chronic GVHD in the MRD and URD cohorts, whereas only 28% of HRD recipients developed chronic GVHD. Despite excellent overall disease-free survival (86%), GVHD remains a limitation using standard prophylaxis for GVHD. We are currently extending the use of PTCy to the MRD and URD cohorts to reduce GVHD.

Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

“…The ability of unconditioned DLI to improve mixed chimerism after BMT may ultimately be low, but data presented here and by others suggest that mixed chimerism may not require intervention with DLI, given that it can be stable over time and sufficient for phenotype reversal for some PIDs [23,24,27,32]. Although PTCy is known to decrease chronic GVHD incidence effectively, including in PID patients [23,25,[33][34][35], the complete absence of chronic GVHD in this study, confirmed on serial, comprehensive evaluations, is one of the most clinically important and promising findings. The low incidence of severe acute and chronic GVHD may be partly related to the gradual increase in donor T cells noted in most patients, allowing for early mixed chimerism, which may be tolerogenic.…”

“…At present, there are no published PTCy-based haplo transplant approaches for patients with PID that similarly avoid serotherapy, radiation, and/or myeloablation for direct comparison to this platform. Approaches that do include 1 or more of these factors have resulted in high engraftment rates with haplo donors in patients with PID [23,35,40,41]. Regardless, further improving engraftment without sacrificing the favorable aspects of this platform is desirable.…”

GATA2 deficiency and haematopoietic stem cell transplantation: challenges for the clinical practitioner

“…In contrast, patients in whom a bone marrow clone has a proliferative advantage may need a more intensive conditioning regimen to eradicate that clone (Hickstein, ). Finally, the administration of PTCy after HSCT with matched (un)related donors has recently shown promising results in terms of reducing the severity of both acute and chronic GVHD, and is now being evaluated in the context of GATA2 deficiency (Parta et al , ; McCurdy et al , ). Prospective multicentre studies are recommended to further optimise HSCT in GATA2‐deficient patients.…”

“…The onset of clinical symptoms spans from infancy to late adulthood, with most patients presenting in adolescent and early adult years. The only curative treatment is allogeneic HSC transplantation (allo-HSCT), which can reverse the haematological, immunological and pulmonary manifestations (Parta et al, 2018). Although recent advances have led to a better knowledge of this syndrome, many issues still need to be addressed (McReynolds et al, 2018).…”

“…First, although matched related donors remain the first choice, haploidentical HSCT using an adjusted conditioning regimen and PTCy has proven to be an effective alternative to matched-donor HSCT with similar survival rates and lower grade GVHD (Parta et al, 2018;Hickstein, 2018). Second, bone marrow stem cells are preferred over peripheral blood stem cells, and umbilical cord blood is to be avoided (Parta et al, 2018;Simonis et al, 2018). Third, intensive but non-myeloablative conditioning regimens have been successful (Parta et al, 2018;Simonis et al, 2018).…”