Reduced‐intensity conditioning in unrelated donor cord blood transplantation for familial hemophagocytic lymphohistiocytosis

Abstract

Familial hemophagocytic lymphohistiocytosis (FHL) is a disorder of immune homeostasis characterized by fever, cytopenias, hepatosplenomegaly, and coagulopathy. We studied the outcomes of 13 FHL patients who underwent the first unrelated cord blood transplantation (UCBT) after non-myeloablative conditionings. The major regimen consisted of fludarabine (FLU; n 5 12) 1 melphalan (MEL; n 5 11) ± low-dose total body irradiation (TBI 2-4 Gy; n 5 6). The median age at presentation and period to UCBT were 6 and 5 months, respectively. Central nervous system (CNS) disease developed in one infant at diagnosis, and in two others until UCBT. HLH activity was controlled in all but one at the time of UCBT. Ten patients had early engraftment on median day 21 with no grade >2 treatment-related toxicity and two controllable grade >2 acute GVHD. Two patients with early rejection successfully underwent subsequent UCBT after myeloablative conditioning. Two others had late graft failure following mixed donor chimerism. Two deaths occurred from HLH; early liver failure and late CNS disease. Of 11 FLU1MEL-conditioned patients, the frequency of disease-free complete engraftment was higher for MEL ( 120 mg/m 2 )1TBI, or high-dose MEL (180 mg/m 2 ) than for others (83% vs. 25%, p 5 0.036). The FLU1MEL-based non-myeloablative regimen was acceptable for FHL infants undergoing UCBT, although further studies will be needed for confirmation.Hemophagocytic lymphohistiocytosis (HLH) is a disorder of immune homeostasis characterized by fever, cytopenias, hepatosplenomegaly, hyperferritinemia, and disseminated intravascular coagulopathy [1]. The lifethreatening condition arises from uncontrolled activation of proliferating lymphocytes, hemophagocytosing macrophages, and hypercytokinemia. The genetic basis of primary HLH resides in the defective cytotoxicity of Tcells and natural killer cells, although secondary HLH can occur in patients with infection, malignancy, or autoimmune disease. Familial HLH (FHL) is an autosomal recessive disease. Affected patients develop HLH mostly in childhood as the sole phenotype of the disease and require allogeneic hematopoietic stem cell transplantation (SCT) for a complete cure. The causal genes of FHL account for the structure, function, and metabolism of cytotoxic granules, such as PRF1 (FHL2), UNC13D (FHL3), STX11 (FHL4), and STXBP2 (FHL5) [2]. A potential risk of developing HLH is also a part of the clinical expressions of X-linked lymphoproliferative disease (XLP1 and XLP2), Chediak-Higashi syndrome, and Griscelli syndrome [3].Recent advances in SCT procedures have improved the survival rate of patients with FHL who undergo SCT after myeloablative conditioning, which now range from 45 to 65% [4][5][6][7][8][9][10][11]. However, there remain critical problems with SCT for FHL; early death from treatment-related events often associated with venoocclusive disease, and neurological sequelae in survivors. The early age at diagnosis also raises a clinical dilemma concerning the timing, preparative regimen, and al...

Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis

“…5 In a study on umbilical cord blood transplantation in HLH patients after RIC including melphalan and low-dose total body irradiation in some cases, overall survival was 91% (n=11). 6 A broad spectrum of underlying genetic defects is covered in the analysis, demonstrating the efficacy in various subtypes of hereditary HLH, includ-…”

“…1) Three potential risk factors (donor type, remission, and administraTreosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis Kai Lehmberg, 1 Michael H. Albert, 2 Rita Beier, 3 Karin Beutel, 4 Bernd Gruhn, 5 Nicolaus Kröger, 6 Roland Meisel, 7 Ansgar Schulz, 8 Daniel Stachel, 9 Wilhelm Woessmann, 10 Gritta Janka, 1 …”

“…1,2 Melphalan-based reduced intensity conditioning (RIC) regimens have substantially improved overall survival. [3][4][5][6] Remaining issues are a high rate of mixed chimerism requiring donor lymphocyte infusions (DLI) with a substantial rate of subsequent graft-versus-host disease (GvHD) and fatal infections due to prolonged immunosuppression. 5 We hypothesized that treosulfan (with addition of thiotepa in selected patients) might be more lymphotoxic and myelosuppressive than melphalan and still produce less adverse effects than myeloablative busulfan.…”

“…In a cohort with cord blood SCT after melphalan-based RIC, 2 of 10 (20%) surviving patients required second transplant and another 2 (20%) had mixed chimerism and late graft failure. 6 To date, the degree of donor chimerism required in humans to prevent recurrence of HLH is not entirely clear.…”

Down-regulation of CD5 expression on activated CD8+ T cells in familial hemophagocytic lymphohistiocytosis with perforin gene mutations

“…Patient P2 did not respond to the HLH-2004 treatment protocol [12], and died at 12 days of age. Patients P1, P3, P4 and P5 underwent stem cell transplantation at the ages of 5 mo, 2 yr, 5 mo and 5 mo, respectively [13].…”