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).

Prospective Study of a Novel, Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform for Primary Immunodeficiency Diseases

“…The relatively uniform achievement of high myeloid chimerism early post-BMT is notable, and we postulate this to be related to a potent and early graft-versusmarrow effect, as the preparative regimen was not myeloablative. The use of DLI was not infrequent in this study, as similarly reported with other RIC-BMT approaches and best captured in a multicenter, phase II trial of RIC-BMT for PID by Allen and colleagues [27] in which 50% of patients had graft failure or required DLI for falling/low donor chimerism and the 1-year probability of being alive with sustained engraftment (>5% donor cells in whole blood) without intervention was 39%, with 61% alive with sustained engraftment with or without intervention. Using the same engraftment definitions, our platform compares favorably, with 1-year probability of survival with sustained engraftment without intervention of 75% and with or without intervention of 85%; most patients became full-donor chimeras without intervention, often following the cessation of GVHD prophylaxis with sirolimus.…”

“…Using the same engraftment definitions, our platform compares favorably, with 1-year probability of survival with sustained engraftment without intervention of 75% and with or without intervention of 85%; most patients became full-donor chimeras without intervention, often following the cessation of GVHD prophylaxis with sirolimus. The ability of unconditioned DLI to improve mixed chimerism after BMT may ultimately be low, but data presented here and by others suggest that mixed chimerism may not require intervention with DLI, given that it can be stable over time and sufficient for phenotype reversal for some PIDs [23,24,27,32]. Although PTCy is known to decrease chronic GVHD incidence effectively, including in PID patients [23,25,[33][34][35], the complete absence of chronic GVHD in this study, confirmed on serial, comprehensive evaluations, is one of the most clinically important and promising findings.…”

“…This prospective study demonstrates promising outcomes with a novel RIC-BMT platform, enabling the use of alternative donors and unmanipulated, T-cell-replete grafts across a range of diseases in high-risk PID patients, with partial to complete phenotype reversal in all surviving patients, overall low toxicity, indication that thymic function and gonadal function may be preserved, and markedly low rates of GVHD. The platform and patient population differ from previously published, largely retrospective reports of other promising RIC-BMT approaches for PID [23][24][25][26][27][28] in that our conditioning was radiation free, there was no in vivo T cell depletion with serotherapy or ex vivo graft manipulation, and both pediatric and adult patients were included. The rates of graft failure, GVHD, and TRM seen here are lower than other reports of RIC-BMT outcomes for PID where 1 or more of these complications were more frequent [29][30][31].…”

Incorporation of thiotepa in a reduced intensity conditioning regimen may improve engraftment after transplant for HLH

“…As with other alemtuzumab‐based RIC approaches, sustained engraftment was poor with fewer than half (41% of patients with HLH) being engrafted without secondary graft failure, need for donor lymphocyte infusion (DLI) or second transplant and alive at one year. Although the survival outcomes compared favourably to MAC regimens, long‐term durable engraftment was suboptimal (Allen et al , ).…”

“…We report our results incorporating thiotepa into the fludarabine/melphalan/alemtuzumab (day‐14) backbone (Marsh et al , ; Allen et al , ). In recent reports, the addition of thiotepa during conditioning was shown to be safe and was associated with enhanced engraftment across a range of donor sources (Ciurea et al , ; Larsen et al , ).…”