Allogeneic Bone Marrow Transplantation for Primary Immunodeficiencies: Pilot Trial of a Novel, Reduced Intensity Platform

Allogeneic bone marrow transplantation (alloBMT) has long been used to correct primary immunodeficiency diseases (PIDs), but significant challenges remain. Given the nature of PIDs, the ideal alloBMT platform should minimize the intensity and toxicity of the preparative regimen, optimize immune reconstitution, and result in low rates of graft failure, graft-versus-host disease (GVHD), and infectious complications. Here, we present the early clinical outcomes of a novel, reduced intensity, radiation-free alloBMT platform for patients with PID. Reduced intensity conditioning included pentostatin, low-dose cyclophosphamide, and two days of busulfan. Post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus were used as GVHD prophylaxis (Figure 1). Grafts were T-cell-replete bone marrow. Of the 8 patients treated to date, 3 received 10/10 HLA-matched related, 3 10/10 HLA-matched unrelated, and 2 HLA-haploidentical allografts. Patient ages ranged from 6 to 58 years. Median HCT-CI score was 4 (range 1-11). PIDs transplanted included STAT3 deficiency (Job's, n = 2), IFNGR1 deficiency (n = 2), MagT1 deficiency (n = 2, both early after alloBMT with minimal follow-up), PI3KCD gain of function (n = 1), and unidentified genetic defect (n = 1). Most patients had active infectious issues at the time of alloBMT. (Table 1)Table 1Patient Characteristics and Outcomes All evaluable patients engrafted at median day +16 (range 15-20). Neutropenia was brief, lasting a median 8 days (range 6-21). The kinetics of donor chimerism showed marked differences between myeloid and lymphoid compartments, with evaluable patients (n = 6) achieving high percentages of donor myeloid cells by day +28 (median 98%, range 84-100%) but experiencing a slower rise in donor lymphoid cells (median 34%, range 12-100% at day +28; median 92%, range 59-100% at day +60). With median follow-up of 5 months (range .5-10), 6 are evaluable for the primary endpoint of graft-failure-free, steroid-refractory grade 3-4 GVHD-free survival, which is 100%. Only one patient has developed any GVHD, which was steroid-responsive gut grade 3 acute GVHD. There has been no invasive CMV disease, no EBV+ lymphoproliferation, and no clinically significant reactivation of other viruses, including HHV6, adenovirus, and JC virus. Three patients had BK cystitis and two had CMV reactivation, one of which required CMV-specific cytotoxic T cells in addition to antivirals. This alloBMT platform appears to be well tolerated and effective, with minimal transplant-related toxicities, universal engraftment, low rates of GVHD, and few clinically significant infectious complications to date. The early split chimerism with a slow rise in donor CD3 cells is notably different than that seen with other PTCy-based platforms and may augment the protective effects of PTCy. Longer term follow-up will more clearly delineate the extent of phenotype reversal in these patients.