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

Carl E. Allen, Rebecca Marsh, Peter Dawson, Catherine M. Bollard, Shalini Shenoy, Philip Roehrs, Rabi Hanna, Lauri Burroughs, Leslie Kean, Julie-An Talano, Kirk R. Schultz, Sung-Yun Pai, K. Scott Baker, Jeffrey R. Andolina, Elizabeth O. Stenger, James Connelly, Alyssa Ramirez, Christopher Bryant, Mary Eapen and Michael A. Pulsipher

Key Points

  • A prospective reduced-intensity HCT trial for HLH/primary immunodeficiency resulted in low early mortality and 1-year OS of 80%.

  • Conditioning with fludarabine, melphalan, and alemtuzumab was associated with high rates of mixed chimerism and graft failure.

Publisher's Note: There is a Blood Commentary on this article in this issue.

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).

  • Submitted January 18, 2018.
  • Accepted July 1, 2018.
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