Allogeneic Hematopoietic Stem Cell Transplant Reverses the Phenotype of GATA2 Deficiency.

Recently, sporadic and heritable mutations in the zinc finger transcription factor GATA2 were shown to be responsible for four different syndromes in young adults coupling opportunistic infection with a predilection to develop myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). These four syndromes are: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome, lymphedema and MDS with monosomy 7; and familial MDS/AML. Life-threatening infections, and the transformation to AML, either alone or together, constitute a rationale for allogeneic hematopoietic stem cell transplant (HSCT) for GATA2 deficiency.

We evaluated matched related, unrelated, and umbilical cord blood as donor sources for nonmyeloablative conditioning for HSCT in GATA2 deficiency. Twelve patients with GATA2 deficiency underwent allogeneic transplant: 4 received peripheral blood stem cells (PBSCs) from matched related-donors (MRD), 4 received PBSC from matched unrelated-donors (MUD), and 4 received umbilical cord blood (UCB) units. Recipients of MRD and MUD transplant received fludarabine and 200cGy of total body irradiation (TBI), while UCB recipients received cyclophosphamide 50 mg/kg, fludarabine, and 200cGy of TBI. All patients received tacrolimus and sirolimus for GVHD prophylaxis.

This cohort of patients had considerable pre-transplant morbidity: two patients required baseline oxygen for pulmonary alveolar proteinosis, one of whom was on a ventilator at the time of transplant; one patient had active hepatitis C that was not responding to therapy; one patient had RAEB-2; two patients were platelet transfusion-dependent; one patient had recurrent strokes and culture negative endocarditis two months before transplant.

Median follow-up for patients was 14.4 months (range 0.2–38.2 months). Ten of 11 patients engrafted at a median of 10 days (range 0–76); engraftment was not evaluable in a recipient of an UCB transplant due to death early in the post-transplant period. One rejection occurred in a recipient of a double UCB transplant who had been heavily transfused pre-transplant. All patients who engrafted had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of NTM infection and extensive human papilloma virus infections regressed starting around 6 months post transplant. Two patients required a single cycle of pre-transplant chemotherapy for RAEB-1 and RAEB-2, respectively. In both patients the monosomy 6 and monosomy 7 clones have not recurred, now 2.5 years and 9 months following single UCB and MUD transplant, respectively.

Three patients died, two early after transplant. One recipient of UCB, who had pre-transplant hepatitis C, died on day+7 of fulminant liver failure and sepsis. A second patient, who was intubated at the time of transplant because of severe pulmonary alveolar proteinosis and pulmonary hypertension, died on day + 88 of grade IV GVHD after MRD transplant. The third patient died 9 months after transplant of sepsis. One recipient of a MRD relapsed from her MDS at 1 year following transplant and was retransplanted using a myeloablative conditioning regimen. She is alive with no evidence of MDS at 3 months. Acute GVHD developed in 6 patients, five of which were steroid-responsive. One patient developed chronic GVHD. Other complications included immune mediated cytopenias that responded to rituximab and eltrombopag.

Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B and NK cell populations and reversal of the infection susceptibility phenotype. The TRM in this cohort of patients with severe comorbidities was 25%. Now that genetic testing for GATA2 mutations is available, we anticipate that earlier diagnosis will enable patients to be transplanted earlier in the course of disease, before significant organ damage or clonal evolution of MDS to AML.

No relevant conflicts of interest to declare.