Alemtuzumab, Fludarabine, Melphalan, and Thiotepa As Reduced-Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation in Inborn Errors of Immunity
Authors: Pfeiffer Thomas , Hyde Stephanie , Shenoy Shalini , Mavers Melissa , Hayashi Robert J. , Gao Feng , Madden Lisa , Quigg Troy , Eckrich Michael J. , Bhatt Sima , Bednarski Jeffrey J. 
Published: December 2024

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 &gt;10 kg, 30 mg if &lt;10 kg), fludarabine days −8 to −4 (150 mg/m2 or 5 mg/kg if &lt;10 kg), thiotepa day -4 (8 mg/kg total) and melphalan day −3 (140 mg/m2or 4.7 mg/kg if &lt;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 &lt; 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 &gt; 5% without an intervention at last follow up.
Graft loss (decline in myeloid or lymphoid donor chimerism to &lt; 5%) occurred in 9 patients at median of 109 days from allo-HCT (range 47 - 673 days). Five (56%) of these patients were &lt; 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 &gt; 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.