Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders

Abstract

Children with many inherited nonmalignant disorders can be cured or their condition alleviated by hematopoietic stem cell transplantation (HSCT). Umbilical cord blood (UCB) units are a rapidly available stem cell source and offer great flexibility in HLA matching, allowing nearly uniform access to HSCT. Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections have limited their use in chemotherapy-naive patients. We prospectively evaluated a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa with a single-unit UCB graft in 44 consecutive patients with inborn errors of metabolism, immunity, or hematopoiesis. In addition, 5% of the UCB graft was re-cryopreserved and reserved for cord donor leukocyte infusion (cDLI) posttransplant. All patients engrafted at a median of 15 days posttransplant, and chimerism was >90% donor in the majority of patients at 1-year posttransplant with only 1 secondary graft failure. The incidence of grade II to IV graft-versus-host disease (GVHD) was 27% (95% confidence interval [CI], 17-43) with no extensive chronic GVHD. Overall survival was 95% (95% CI, 83-99) and 85% (95% CI, 64-93) at 1 and 5 years posttransplant, respectively. No significant end-organ toxicities were observed. The use of cDLI did not affect GVHD and showed signals of efficacy for infection control or donor chimerism. This RIC transplant regimen using single-unit UCB graft resulted in outstanding survival and remarkably low rates of graft failure. Implementation of the protocol not requiring pharmacokinetic monitoring would be feasible and applicable worldwide for children with inherited disorders of metabolism, immunity, or hematopoiesis. This trial was registered at www.clinicaltrials.gov as #NCT01962415.

Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Neutrophil and platelet engraftment. (A) Neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count >500 cells/µL. Neutrophil engraftment occurred in all patients at a median of 15 days posttransplantation (range, 10-33 days). (B) Platelet engraftment was defined as the first of 7 consecutive days with a platelet count >20 000 cells/µL or >50 000 cells/µL without transfusion support. Platelet engraftment >20 000 cells/µL occurred in all evaluable patients at a median of 32 days posttransplantation (range, 15-56 days), and platelet engraftment >50 000 cells/µL occurred in all evaluable patients at a median of 37 days posttransplantation (range, 27-79 days).

Figure 2.

Donor chimerism analysis. Donor chimerism was measured by short tandem repeat analysis in peripheral whole blood and, when sufficient CD3+ cells were present in peripheral blood, in sorted CD3+ cells. Donor chimerism >95% in whole blood was seen in 81%, 83%, 76%, and 65% of patients and in 71%, 53%, 63%, and 71% for CD3+ cells at days (D) 100 and 180 and at 1 and 2 years posttransplantation, respectively.

Figure 3.

GVHD. (A) The cumulative incidence of grade II to IV GVHD was 27% (95% CI, 10-48) and the cumulative incidence of grade III to IV GVHD was 11% (95% CI, 1-40). The median onset day for grade II to IV GVHD was 40 days posttransplantation (range, 14-145 days). (B) The cumulative incidence of limited chronic GVHD was 42% (95% CI, 25-58). No patients developed severe or extensive chronic GVHD.

Figure 4.

Survival. (A) Overall survival was 95% (95% CI, 83-99) at 1 year, and EFS was 93% (95% CI, 80-98) at 1 year. (B) Overall survival was 85% (95% CI, 67-94) at 5 years posttransplantation and 83% (95% CI, 66-92) at 5 years posttransplantation.

Figure 5.

Immune reconstitution posttransplantation. (A) Absolute numbers of CD3, CD4, CD8+, and CD4/CD45RA/CD62L+ T cells, B cells, and natural killer cells as measured by flow cytometry are shown. Each box extends from the 25th to 75th percentile with a line at the median and whiskers extending 1.5 times the interquartile range. (B) The number of signal joint TRECs, normalized per 1 × 106 CD3 cells, and TCR Vβ repertoire, measured as TCR spectrotype complexity score (TCR SCS), which counts the number of peaks/TCR Vβ subfamily (maximum score, 208); they were measured pretransplantation and posttransplantation to better assess thymic recovery. (C) A representative example of pretransplantation and posttransplantation TCR SCS.

Figure 6.

Alemtuzumab levels and immune reconstitution. (A) Day 0 alemtuzumab levels were measured in 26 subjects. The median alemtuzumab concentration was 0.58 μg/mL (range, 0-2.82 μg/mL) at day 0. (B-D) Subjects with alemtuzumab above the median had lower absolute CD3, CD4, and CD8 counts at 30 and 60 days posttransplantation compared with subjects with alemtuzumab levels below the median. *P < .05; **P < .01.

Figure 7.

Effect of cDLI posttransplantation. (A) Nine subjects received cDLI for mixed whole-blood or T-cell chimerism. Improvement in T-cell chimerism was reported in the majority of patients at 120 days after cDLI. (B) Ten subjects received cDLI for viral infection (7 with viremia, 3 with symptomatic viral gastroenteritis). Improvement in viremia and/or clinical symptoms was seen in 6 of 10 subjects. (C) Seven subjects received cDLI for delayed immune reconstitution. Improvement in absolute CD3 count was noted in all 7 subjects. (D) The cumulative incidence of acute GVHD or progression of acute GVHD was 47% (95% CI, 23-69) in subjects who received cDLI and 48% (95% CI, 28-66) in those who did not.