Reduced Cumulative Dosing of Alemtuzumab in Patients with Hemophagocytic Lymphohistiocytosis (HLH) Is Associated with Improved Long Term Survival

Background HLH is a syndrome characterized by an immune hyperactivation due either to an underlying genetic or inflammatory trigger. Relapsed/refractory HLH remains associated with dismal outcomes, prompting the need for novel therapies including hematopoietic stem cell transplant (HSCT). Novel agents for T cell depletion and cytokine blockade, such as alemtuzumab and emapalumab have been increasingly prevalent, but appropriate dosing and correlations with survival after HSCT are limited. Thus, we summarize our center's outcomes with treating relapsed/refractory HLH in the setting of alemtuzumab with the goal of proposing an optimized transplant regimen for these patients. Methods We reviewed 39 pediatric patients treated at Texas Children's Hospital from June 2008-January 2023 who had an underlying diagnosis of HLH. We performed outcome analysis of overall survival, and causes of death and correlate them with the dosing and use of cumulative alemtuzumab (both pre- and post-HSCT), as well as treatment with emapalumab. Results Thirty-nine patients with a diagnosis of HLH who underwent HSCT (median age 3.4 years; range 0.6-19.8). Twenty-nine received a matched unrelated donor transplant, three were matched related, eight were mismatched related. Nineteen patients received a reduced intensity conditioning with fludarabine, melphalan, and alemtuzumab while 16 patients received the same backbone but with thiotepa added. One patient received a myeloablative regimen with busulfan, fludarabine, melphalan, and alemtuzumab. 22 patients received alemtuzumab IV (dose range<15kg: 3 mg x 4 doses; 15-30 kg: 5 mg x 4 doses; >30 kg: 10 mg x 4 doses) compared to 18 subcutaneous (SQ) (dose: 1 mg/kg). Emapalumab was given to six patients prior to HSCT. 5-year overall survival (OS) for all patients was 59% with 18 patients dying at a median time of 118 days after transplant; (range: 9-894). Causes of death included: infections (9), organ failure (5), disease progression (2), and GVHD (1). Seven out of nine patients who died of infection had a cumulative alemtuzumab of 0.9 mg/kg or greater. Patients who died had a significantly higher median alemtuzumab dose/kg (M=1.49, SD=0.59) compared to survivors (M=1.15, SD=0.40), p=.02. Additionally, pre-conditioning alemtuzumab salvage therapy was associated with worse outcome with 5/8 patients dying following HSCT. When comparing the route of administration of alemtuzumab, patients receiving SQ dosing trended toward improved survival compared to IV treatment (66.6% vs. 50%; p=0.27). Conclusions HSCT is required for cure for patients with primary HLH. Optimizing conditioning therapy by adjusting overall dosing of alemtuzumab lead to improved long-term survival in patients with HLH.