Primary hemophagocytic lymphohistiocytosis (HLH) is a disease characterized by hypercytokinaemia and T cell dysregulation, due to mutations of the perforin, SAP and other so far uncharacterized genes. Patients may achieve a remission with immunomodulation consisting of epipodophyllin/steroids +/− cyclosporin A, but the only curative option is allogeneic stem cell transplant (SCT). Patients often have significant pre-transplant morbidity with lung, liver and central nervous system disease and are hence at high risk of transplant related morbidity and mortality. Because HLH is caused by immune dysregulation, we hypothesized that a non-myeloablative conditioning regime might be sufficient for cure, by restoring normal immune regulation, while decreasing the transplant related morbidity and mortality.

We report the outcome of 11 children with HLH transplanted with a reduced intensity regime (RI) from an unrelated (fully matched, n=4, 1 antigen-mismatched, n=2) or haploidentical (n=5) donor. Of 7 patients assessed, 1 patient had absent SAP expression and 2 had a perforin gene mutation. 8 patients had significant morbidity of at least one other organ (including lung, cardiac, liver and CNS) pre-SCT. All had previously received HLH 94 protocol: 7/11 were in CR at the time of SCT and 4/11 in good PR. The median age at transplant was 16 months (range 3 –151 months). SCT was performed at a median of 7 months from diagnosis (3–14 months). Patients were conditioned with fludarabine 30mg/kg x 5 and melphalan 125 to 140mg/m2. Unrelated donor transplants received serotherapy with Campath 1H 0.2mg/kg x 5 and haplos received busulphan 4mg/kg x 2 and ATG 5mg/kg x 5. One unrelated donor recipient received TBI 2Gy single fraction with fludarabine.

Results: All patients engrafted at a median of 13 days post SCT. 8 of 11 (73%) children are alive and in CR a median of 19 months from transplant (range 5 to 61 months). There were 3 transplant related mortalities (2 UD, 1 Haplo) between 3 and 4 months post-SCT from CMV pneumonitis (n=1), multifactorial pneumonitis following previous HLH lung disease (n=1), and hepatic rupture post- transjugular liver biopsy (n=1). 4 patients had CMV reactivation and 2 EBV reactivation. 3 patients developed acute GVHD (2 Grade 2 skin/gut, 1 Grade 1 gut/liver) and 1 had an engraftment syndrome with T-cell sequestration in the lungs. 3/8 evaluable patients have developed limited chronic skin GVHD 6– 15 months post-SCT. 3 patients had early and continuing mixed chimerism with 20%, 84% and 82% donor cells in the peripheral blood at 61, 52 and 24 months respectively from transplant. At a median follow-up of 19 months, no patient has relapsed, including the 3 patients with mixed chimerism.

In summary, mixed chimerism appears curative for HLH and our results with SCT using reduced intensity conditioning compare favourably to those seen with conventional BMT, where a 3 year EFS of 62% has been reported in the HLH94 study. We believe this approach may be of major benefit in those patients with severe pre-SCT organ toxicity and merits further study in standard risk patients.

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