Reduced-intensity conditioning for hematopoietic cell transplant for HLH and primary immune deficiencies

Abstract

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).

Graphical abstract

Figure 1.

OS. (A) Survival curve demonstrates OS (solid line) with 95% CIs (dashed lines). (B) HLH and non-HLH survival. Survival curve illustrates probability of survival for HLH (blue) and subjects with other PID (red).

Figure 2.

Engraftment. (A) Probability of intervention-free engraftment, all transplanted patients. Kaplan-Meier curve illustrates probability of sustained engraftment without intervention. (B) Probability of intervention-free engraftment, by primary disease. Kaplan-Meier curve illustrates probability of sustained engraftment without intervention by primary disease (solid line, HLH; dashed line, other PID).

Figure 3.

Immune reconstitution. Graphs describe absolute cell counts and quantitative Ig levels (mg/dL) with HLH (blue) and other PID patients (red), and group medians in bold lines. Quantitative IgG is censored at time of starting intravenous immune globulin (IVIG).