An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis

Rebecca A Marsh, Mi-Ok Kim, Chunyan Liu, Denise Bellman, Laura Hart, Michael Grimley, Ashish Kumar, Sonata Jodele, Kasiani C Myers, Sharat Chandra, Tom Leemhuis, Parinda A Mehta, Jack J Bleesing, Stella M Davies, Michael B Jordan, Alexandra H Filipovich, Rebecca A Marsh, Mi-Ok Kim, Chunyan Liu, Denise Bellman, Laura Hart, Michael Grimley, Ashish Kumar, Sonata Jodele, Kasiani C Myers, Sharat Chandra, Tom Leemhuis, Parinda A Mehta, Jack J Bleesing, Stella M Davies, Michael B Jordan, Alexandra H Filipovich

Abstract

Reduced-intensity conditioning (RIC) improves the outcomes of hematopoietic cell transplantation (HCT) in patients with hemophagocytic lymphohistiocytosis (HLH). Proximal (ie, close to graft infusion) dosing of alemtuzumab is associated with a high incidence of mixed chimerism, whereas distal (ie, distant from graft infusion) dosing is associated with less mixed chimerism but more acute graft-versus-host disease (GVHD). The alemtuzumab dose per kilogram of body weight also influences these outcomes. We hypothesized that an intermediate alemtuzumab dosing schedule would reduce mixed chimerism and maintain a low incidence of acute GVHD. In this study, 24 consecutive HCTs were performed in patients with HLH or a related disorder using a novel intermediate alemtuzumab schedule of 1 mg/kg starting on day -14. The cumulative incidences (CIs) of mixed chimerism, upfront acute GVHD grades II-IV, and receipt of additional hematopoietic cell products after HCT were compared in patients treated with a distal alemtuzumab schedule (n = 15) and those treated with a proximal alemtuzumab schedule (n = 33). All patients received fludarabine and melphalan. The CI of mixed chimerism was 31% in the intermediate group, 72% in the proximal group (P < .01), and 75% in the distal group patients who received ≥2 mg/kg alemtuzumab (P = .03). The CI of acute GVHD grades II-IV before the development of mixed chimerism was 4% in the intermediate group, 0% in the proximal group, and 13% in the distal group (P = .04, proximal versus distal). The 1-year CI of administration of additional hematopoietic cell products for mixed chimerism (donor lymphocyte infusion ± hematopoietic stem cell boost ± repeat HCT) was 14% in the intermediate group, 53% in the proximal group (P = .01), and 38% in the distal ≥2 mg/kg alemtuzumab group (P = .02). Our findings indicate that intermediate RIC reduces the incidence of mixed chimerism, is associated with a low incidence of upfront acute GVHD, and decreases the need for additional hematopoietic cell products after HCT.

Keywords: Alemtuzumab; Bone marrow transplantation; Familial hemophagocytic lymphohistiocytosis; Hematopoietic cell transplantation; Hemophagocytic lymphohistiocytosis; Reduced-intensity conditioning; SAP deficiency; X-linked lymphoproliferative disease; XIAP deficiency.