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

• Published in: Blood advances 2020-05, Vol.4 (9), p.1998-2010
• Main Authors: Felber, Matthias, Steward, Colin G., Kentouche, Karim, Fasth, Anders, Wynn, Robert F., Zeilhofer, Ulrike, Haunerdinger, Veronika, Volkmer, Benjamin, Prader, Seraina, Gruhn, Bernd, Ehl, Stephan, Lehmberg, Kai, Müller, Daniel, Gennery, Andrew R., Albert, Michael H., Hauck, Fabian, Rao, Kanchan, Veys, Paul, Hassan, Moustapha, Lankester, Arjan C., Schmid, Jana Pachlopnik, Hauri-Hohl, Mathias M., Güngör, Tayfun
• Format: Article
• Language: English
• Subjects: Animals; Busulfan; Hematologi; Hematology; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic - therapy; Medicin och hälsovetenskap; Neoplasm Recurrence, Local; Rabbits; Transplantation; Transplantation Conditioning
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2020001748

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. •Targeted busulfan, fludarabine, serotherapy, and HLA-matched hematopoietic stem cell transplantation achieved 100% event-free survival in HLH.•After a median follow-up of 3 years, satisfactory DC on myeloid and T cells, no graft failures, and a low rate of chronic GHVD were observed. [Display omitted]