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Clinical Trial
. 2018 Sep 27;132(13):1438-1451.
doi: 10.1182/blood-2018-01-828277. Epub 2018 Jul 11.

Reduced-intensity Conditioning for Hematopoietic Cell Transplant for HLH and Primary Immune Deficiencies

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Free PMC article
Clinical Trial

Reduced-intensity Conditioning for Hematopoietic Cell Transplant for HLH and Primary Immune Deficiencies

Carl E Allen et al. Blood. .
Free PMC article

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).

Conflict of interest statement

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

Figures

None
Figure 1.
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.
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.
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).

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