Alemtuzumab, Fludarabine, Melphalan, and Thiotepa As Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation in Inborn Errors of Immunity

Background.Inborn errors of immunity (IEI) are characterized by impaired lymphoid or myeloid immune cell function, resulting in premature mortality. Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative. The ideal conditioning regimen offers rapid engraftment, reduced organ toxicity and low rates of graft-versus-host disease (GvHD). Here, we report our experience of a phase 2 clinical trial utilizing a reduced intensity conditioning (RIC) regimen consisting of alemtuzumab, fludarabine, melphalan, and thiotepa for the treatment of IEI.

Methods. This IRB-approved study (NCT01821781) aimed to estimate the overall survival (OS) and characterize longitudinal engraftment in patients with IEI undergoing RIC allo-HCT. RIC consisted of alemtuzumab days −14 to −12 (cumulative dose 45 mg in children >10 kg, 30 mg if <10 kg), fludarabine days −8 to −4 (150 mg/m² or 5 mg/kg if <10 kg), thiotepa day -4 (8 mg/kg total) and melphalan day −3 (140 mg/m²or 4.7 mg/kg if <10 kg). Graft sources included unmanipulated bone marrow (BM), peripheral blood stem cells (PBSC), or umbilical cord blood (UCB). PBSC grafts were CD34⁺ selected and administered along with 1 x 10⁶/kg CD3⁺ T cells. All patients received GvHD prophylaxis with tacrolimus and an antimetabolite. In unrelated donor (URD) transplants, patients also received 1 mg/kg/d of prednisone from day +7 through day +28 with subsequent taper.

Results. Twenty-eight patients with median age of 3 years (range 0-21) were treated. Seven patients (25%) were less than 1 year of age. Common diagnoses included hemophagocytic lymphohistiocytosis (HLH, n=8), chronic granulomatous disease (CGD, n=7) and severe combined immune deficiency (SCID, n=5). HLA-matched (n=18, 64%) or mismatched (n=6, 21%) URD were the predominant graft source. Patients received BM (n=21, 75%), PBSC (n=5, 18%) or UCB (n=2, 7%). 1-year and 3-year OS for the entire cohort was 92% (95% CI 71%-98%) and 83% (95% CI 60%-93%), respectively. 1-year and 3-year OS was 94% and 87% in children ≥ 1-year-old, and 86% and 71% in children < 1-year-old.

No instances of primary graft failure were observed. Myeloid engraftment at day 30 was ≥ 90% in all but one patient. Of 24 patients with evaluable lymphocyte counts at day 30, half (n=12) had full donor T cell chimerism. 11 patients (46%) had mixed T cell chimerism with a median donor engraftment of 65% (range 25-93%). One patient with CGD had no T cell engraftment. Nineteen patients (68%) had sustained myeloid and lymphoid donor chimerism > 5% without an intervention at last follow up.

Graft loss (decline in myeloid or lymphoid donor chimerism to < 5%) occurred in 9 patients at median of 109 days from allo-HCT (range 47 - 673 days). Five (56%) of these patients were < 1 year of age. The cumulative incidence of graft loss was 32.2% (95% CI 14.8%-51.0%) at 1 year and 37.1% (95% CI 18.0%-56.3%) at 3 years. Eight patients underwent second allo-HCT, all from the same transplant donor. Six of these eight patients are alive at last follow up with > 90% myeloid and lymphoid donor engraftment.

Four patients died during the follow up period at a median of 346 days (range 248 - 434) from allo-HCT. Three patients (CDG, n=2; DOCK8 deficiency, n=1) died from disease recurrence and infectious complications. The death of an infant with SCID was unrelated to transplant. The 1-year treatment related mortality was 4% (95% CI 0.3%-18%).

Acute GVHD developed in 4 (14%) patients and all occurrences were grade 3, involving skin (n=2) and GI tract (n=2). Six patients (21%) developed chronic GVHD (extensive, n=5; limited, n=1). Severe (grade 4) non-hematologic, regimen-related toxicities were noted in 5 (18%) patients. CMV, EBV, and adenovirus infection occurred in 4 (14%), 8 (29%), and 7 (25%) patients, respectively. Sixteen (57%) patients had one or more bacterial infections. At 1 year post-transplant, median absolute numbers of CD3⁺, CD4⁺, CD8⁺, CD19⁺, and CD16⁺CD56⁺ populations in 15 patients without graft loss were 1044, 531, 405, 447 and 201 cells/μL, respectively.

Conclusions.This study reports outcomes of radiation-free RIC allo-HCT for the treatment of IEI. Advantages included tolerability with low toxicity even in the very young, yielding high overall survival rates. Two-thirds of patients had sustained myeloid and lymphoid engraftment at last follow up without intervention and remained disease-free. The majority of patients with graft loss were successfully salvaged with a second allo-HCT.

Quigg:Alexion AstraZeneca Rare Disease: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Eckrich:Vertex Pharmaceuticals: Consultancy. Bhatt:Disc Medicine: Current Employment, Current holder of stock options in a privately-held company.