Successful Allogeneic Hematopoietic Cell Transplantation (HCT) with Low Toxicity and Gvhd in a Heterogeneous Cohort of Primary Immunodeficiency (PID) Patients

HCT has been used for decades as a definitive therapy for patients with PIDs. These patients often enter HCT with significant comorbidities and disease sequelae and may have limited donor options if family members are also affected, so the ability to offer HCT to all who require it remains suboptimal. Twenty-nine children and adults with various underlying PIDs received a serotherapy-free, radiation-free reduced intensity conditioning platform designed with the goals of optimizing immune reconstitution, minimizing complications such as graft-versus-host disease (GVHD), and permitting use of alternative donors. Conditioning consisted of pentostatin, low-dose cyclophosphamide and 2 days of busulfan, and GVHD prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. All received T cell replete bone marrow or peripheral blood stem cell allografts. Patient and donor characteristics are shown in Fig 1a . Neutrophil recovery occurred at median day +17 (range 14-42). With median follow-up of 14 months (range 3-33), graft-failure-free, steroid-refractory grade 3-4 GVHD-free survival was estimated at 82% at 1 year ( Fig 2 ). Two deaths occurred in patients with HCT-CI scores of 6 (bacterial sepsis and invasive Aspergillosis, day +44) and 8 (presumed viral encephalitis, day +110). There were 3 graft failures (1 primary, with autologous recovery on day +14 and 2 secondary on day +34 and +159). Two patients were successfully retransplanted with eventual full donor chimerism, while the third's infection was sufficiently temporized by the first transplant to make an immediate retransplant not necessary.  The kinetics of donor chimerism differed between myeloid and lymphoid compartments. Most patients had complete donor myeloid chimerism by day +28 but a slower rise in donor CD3 chimerism (median 77% at day +28 to 94% at day +60) ( Fig 3 ). GVHD rates have been low, with cumulative incidence of steroid-responsive grade 2-4 acute GVHD at 1 year of 14% (death and graft failure as competing risks) and no chronic GVHD to date.  HCT-related outcomes and complications are listed in Fig 1b . Of note, BK-associated hemorrhagic cystitis occurred at high rates, but serious viral complications were infrequent. Some degree of phenotype reversal is evident in all evaluable patients. All 10 patients with lymphoma or lymphoproliferative disorder are in remission, and, of 24 engrafted survivors, only two continue to require immunoglobulin replacement beyond 6 months post-HCT. Future directions include reducing the duration of post-HCT immunosuppression to hasten improved viral control and increasing pre-HCT lymphodepletion for selected patients at high risk for graft failure. Continued long term follow up is needed to better characterize phenotype reversal, graft durability, immune reconstitution and late toxicities of the platform.