Fludarabine-based reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in primary hemophagocytic lymphohistiocytosis.

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition that clinically characterized by fever, hepatosplenomegaly, and cytopenia. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for patients diagnosed with primary HLH. In this prospective study, we analyzed the outcome of 10 pediatric patients with primary HLH who had received HSCT, using reduced-intensity conditioning (RIC) regimen from 2007 to 2012. The median age at transplantation was 22.6 months (range: 6-60). All of the patients received the same RIC regimen based on the use of fludarabine in combination with melphalan and horse antithymocyte globulin (ATG). Cyclosporine and methylprednisolone were used as graft-vs.-host disease (GvHD) prophylaxis. Hematopoietic engraftment occurred in all patients. At the present time, 8 patients with a median follow-up of 39 months are still alive and all of them are disease free. Acute and chronic GvHD developed in 6 and 2 patients, retrospectively. Two patients died of sepsis and chronic GvHD during the study. Because of pretransplant infections caused by underlying immunodeficiency in patients with primary HLH, the use of less toxic regimen with RIC seems to be highly effective in this regard. Recipients of RIC transplant, with either full or mixed chimerism, had a long-term survival rate with no manifestation of primary HLH symptoms.

Hamidieh AA ，Pourpak Z ，Hashemi S ，Yari K ，Fazlollahi MR ，Movahedi M ，Behfar M ，Moin M ，Ghavamzadeh A ... -  《-》

Successful engraftment and stable full donor chimerism after myeloablation with thiotepa, fludarabine, and melphalan and CD34-selected peripheral allogeneic stem cell transplantation in hemophagocytic lymphohistiocytosis.

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative option for primary hemophagocytic lymphohistiocytosis (HLH), a rare disease of infants and young children, characterized by recurrent fever, hepatosplenomegaly, and cytopenia. We report a case of successful engraftment and stable full-donor chimerism in a patient with HLH who underwent peripheral allogeneic CD34-selected HSCT. The donor was his 1-antigen-HLA-mismatched grandmother. After a conditioning regimen based on the combination of thiotepa, fludarabine, melphalan, and rabbit antilymphocyte serum, the patient received a megadose of 26.3 x 10(6)/kg of CD34(+) peripheral blood cells. Neutrophil (>0.5 x 10(9)/L) and platelet (>50 x 10(9)/L) engraftment was observed on days +16 and +12, respectively, and the patient was discharged home on day +24. No acute or chronic GVHD was observed. Infectious complications were the main causes of re-hospitalization in the first year after transplantation, but no significant morbidity was observed thereafter. Thirty-two months after HSCT, the patient is alive and well, still in complete clinical remission of his underlying disease with a durable engraftment, normal NK activity and full donor chimerism. This case suggests that a fludarabine-based conditioning regimen and CD34-selected peripheral allogeneic HSCT may be a feasible option in case of unavailability of a fully HLA-matched related or unrelated donor.

Cesaro S ，Gazzola MV ，Marson P ，Calore E ，Caenazzo L ，Destro R ，De Silvestro G ，Varotto S ，Pillon M ，Zanesco L ，Messina C ... -  《-》

Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 × 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.

Patel SA ，Allewelt HA ，Troy JD ，Martin PL ，Driscoll TA ，Prasad VK ，Kurtzberg J ，Page KM ，Parikh SH ... -  《-》

Successful father-to-son stem cell transplantation in a child with hemophagocytic lymphohistiocytosis using a reduced-intensity conditioning regimen.

Gonzalez-Llano O ，Jaime-Pérez J ，Cantu-Rodríguez O ，Mancias-Guerra C ，Gutierrez-Aguirre H ，Herrera-Garza J ，Gomez-Almaguer D ... -  《-》

Fludarabine/Melphalan 100 mg/m(2) Conditioning Therapy Followed by Allogeneic Hematopoietic Cell Transplantation for Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis.

Our previous research indicated that a reduced-intensity conditioning regimen (fludarabine and melphalan at 100 mg/m2) was useful in allogeneic hematopoietic cell transplantation (HCT) for patients with lymphoma. This retrospective study evaluated the reduced-intensity conditioning regimen in allogeneic HCT for adult patients with hemophagocytic lymphohistiocytosis (HLH). Sixteen patients with HLH were evaluated, including 6 patients who were enrolled in a prospective clinical trial (NCT00772811) and 10 patients who received the same conditioning regimen (fludarabine at 30 mg/m2/day on days -6 to -2 and melphalan at 100 mg/m2 on day -2). The median age was 42 years (range, 18 to 64), and 12 patients had Epstein-Barr virus (EBV)-associated HLH. Donors were an HLA matched sibling for 10 patients, an unrelated matched volunteer for 4 patients, and a mismatched family member for 2 patients. After excluding 3 patients who died soon after HCT, 12 patients achieved an engraftment (neutrophil median, day 12; platelet median, day 16). Five patients experienced acute graft-versus-host disease (GVHD), including 1 case of grade II and 4 cases of grades III to IV. Chronic GVHD occurred in 3 patients (moderate, 1 case; severe, 2 cases). After a median follow-up of 33.8 months 1 patient progressed, 3 patients relapsed, and 9 patients died. Five deaths were unrelated to relapse or progression and were caused by infection (n = 3), bleeding (n = 1), and GVHD (n = 1). No deaths or relapses were observed at >124 days post-transplant. The overall survival rate was 48.6%, and significant differences were observed according to pretransplant ferritin level (P = .007) and cytopenia lineage (P = .021). Before allogeneic HCT 10 of 12 patients still tested positive for EBV DNA: 6 patients tested negative for EBV DNA after HCT, 2 patients had persistent EBV DNA, and 2 patients were unassessable because of early death. Conditioning therapy using a lower dose of melphalan combined with fludarabine appears to be promising in allogeneic HCT for adults with HLH. However, strategies are needed to reduce the risk of early death.

Park HS ，Lee JH ，Lee JH ，Choi EJ ，Ko SH ，Seol M ，Lee YS ，Kang YA ，Jeon M ，Lee KH ... -  《-》