Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis

Abstract

Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation–approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti–T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.

EBMT/ESID inborn errors working party guidelines for hematopoietic stem cell transplantation for inborn errors of immunity

“…While until 15-20 years ago, myeloablative conditioning with (oral) busulfan and cyclophosphamide was the norm, over the years, extensive experience has been obtained with a number of different, and increasingly less toxic, conditioning regimens [9,[17][18][19]. Moreover, therapeutic drug monitoring has resulted in improved outcome in busulfan-based regimens [20].…”

“…Patients may present with a variety of clinical symptoms including a broad spectrum of infections, inflammatory manifestations, auto-immune phenomena and malignant diseases. Treatment by hematopoietic stem cell transplantation (HSCT) is increasingly successful [2][3][4][5][6][7][8][9][10] and the joint EBMT/ESID Inborn Errors Working Party (IEWP) has played a pivotal role designing and developing common HSCT guidelines, which have contributed to this success.…”

Clinical features, diagnosis and therapy of familial haemophagocytic lymphohistiocytosis

“…The protective effect of >20% donor cells for prevention of reactivations was confirmed in a large retrospective study from 23 bone marrow transplant centres 28 . Exceptionally good results with a three‐year event‐free survival of 100% were reported in 25 FHL patients who received reduced intensity conditioning with fludarabine and targeted busulfan 29 . Donor cells engrafted in all patients, and donor chimerism of CD3+ T cells and NK cells was over 90%.…”

Allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency

“…35 Most experience to date has been with fludarabine/busulfan (Flu/Bu), fludarabine/melphalan (Flu/Mel), or fludarabine/ treosulfan (Flu/Treo)-based reduced intensity conditioning incorporating serotherapy (alemtuzumab or ATG) for in vivo T-cell depletion. Recent improvements in conditioning regimens for nonmalignant diseases such as PID have primarily come from pediatric centers and include the introduction of treosulfan, 36,37 the use of targeted busulfan, 24,38 and personalized serotherapy dosing. 34,35,39 The use of PTCy or αβTCR depletion to remove alloreactive T cells has facilitated the use of haploidentical donors in older recipients with hematologic malignancies, without prohibitive risks of GVHD and/or graft rejection.…”