melphalan and Lymphohistiocytosis--Hemophagocytic

Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced-intensity conditioning with melphalan, fludarabine, and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary end point was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow-up of 20 months, the 1-year OS for transplanted patients was 80.4% (90% confidence interval [CI], 68.6%-88.2%). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI, 52.9%-77.3%). Two patients experienced primary graft failure, and 18 patients either experienced a secondary graft failure or required a second intervention (mostly donor lymphocyte infusion [DLI]). At 1 year, the proportion of patients alive with sustained engraftment without DLI or second HCT was 39.1% (95% CI, 25.2%-54.6%), and that of being alive and engrafted (with or without DLI) was 60.9% (95% CI, 45.4 %-74.9%). The day 100 incidence of grade II to IV acute GVHD was 17.4% (95% CI, 8.1%-29.7%), and 1-year incidence of chronic GVHD was 26.7% (95% CI, 14.6%-40.4%). Although the trial demonstrated low early mortality, the majority of surviving patients required DLI or second HCT. These results demonstrate a need for future approaches that maintain low early mortality with improved sustained engraftment. The trial was registered at Clinical Trials.gov (NCT 01998633).

Topics: Adolescent; Adult; Alemtuzumab; Antineoplastic Agents; Child; Child, Preschool; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Survival Analysis; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

A nationwide retrospective analysis was performed on patients who received allogeneic hematopoietic stem cell transplantation for primary or familial hemophagocytic lymphohistiocytosis (HLH) in Japan. The present analysis investigated whether reduced-intensity conditioning (RIC) followed by cord blood transplantation (CBT) (RIC-CBT) is feasible, compared to the outcomes of myeloablative conditioning and bone marrow transplantation. Based on the JSHCT data, 53 patients were analyzed. The overall survival rate (OS) was 65.4 ± 6.6 %. RIC-CBT (n = 13) was not inferior to other methods. Patients with a performance status of PS 4 (ECOG scale) with HLH-associated severe organ dysfunction during the initiation of conditioning had extremely poor outcomes. The OS rate in the RIC-CBT patients, excluding those with a performance status 4, was 80.0 ± 12.6 %. RIC may reduce treatment-related mortality; in addition, patients with engraftment failure, which is the main adverse event following RIC-CBT, were successfully rescued with secondary CBT. Unrelated cord blood may represent an alternative source if a patient has no related donor. As a RIC regimen for CBT, 140 mg/m(2) melphalan with fludarabine and anti-lymphocyte globulin or anti-thymocyte globulin may be feasible, but further dosage optimization should be performed in controlled clinical trials.

Topics: Adolescent; Allografts; Antilymphocyte Serum; Child; Child, Preschool; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Female; Humans; Immunosuppressive Agents; Infant; Japan; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Myeloablative Agonists; Survival Rate; Transplantation Conditioning; Unrelated Donors; Vidarabine

Allogeneic hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis (HLH) disorders is associated with substantial morbidity and mortality.. The effect of conditioning regimen groups of varying intensity on outcomes after transplantation was examined to identify an optimal regimen or regimens for HLH disorders.. We studied 261 patients with HLH disorders transplanted between 2005 and 2018. Risk factors for transplantation outcomes by conditioning regimen groups were studied by Cox regression models.. Four regimen groups were studied: (1) fludarabine (Flu) and melphalan (Mel) in 123 subjects; (2) Flu, Mel, and thiotepa (TT) in 28 subjects; (3) Flu and busulfan (Bu) in 14 subjects; and (4) Bu and cyclophosphamide (Cy) in 96 subjects. The day 100 incidence of veno-occlusive disease was lower with Flu/Mel (4%) and Flu/Mel/TT (0%) compared to Flu/Bu (14%) and Bu/Cy (22%) (P < .001). The 6-month incidence of viral infections was highest after Flu/Mel (72%) and Flu/Mel/TT (64%) compared to Flu/Bu (39%) and Bu/Cy (38%) (P < .001). Five-year event-free survival (alive and engrafted without additional cell product administration) was lower with Flu/Mel (44%) compared to Flu/Mel/TT (70%), Flu/Bu (79%), and Bu/Cy (61%) (P = .002). The corresponding 5-year overall survival values were 68%, 75%, 86%, and 64%, and did not differ by conditioning regimen (P = .19). Low event-free survival with Flu/Mel is attributed to high graft failure (42%) compared to Flu/Mel/TT (15%), Flu/Bu (7%), and Bu/Cy (18%) (P < .001).. Given the high rate of graft failure with Flu/Mel and the high rate of veno-occlusive disease with Bu/Cy and Flu/Bu, Flu/Mel/TT may be preferred for HLH disorders. Prospective studies are warranted.

Topics: Busulfan; Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Lymphohistiocytosis, Hemophagocytic; Melphalan; Thiotepa; Transplantation Conditioning; Vidarabine

Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined.. Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model.. Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3).. The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Chimerism; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child, Preschool; Ferritins; Hepatic Veno-Occlusive Disease; Humans; Immunotherapy; Immunotherapy, Adoptive; Infant; Killer Cells, Natural; Liver Failure; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Systemic Inflammatory Response Syndrome; Transplantation Conditioning

Mixed donor chimerism is increasingly common in the pediatric hematopoietic stem cell transplantation (HSCT) setting because of the increased use of reduced-intensity preparative regimens for nonmalignant diseases. Donor lymphocyte infusion (DLI) is potentially useful in the treatment of mixed donor chimerism, but little are data available on the use of DLI in this setting. We conducted a retrospective review of 27 pediatric patients who received DLI for mixed donor chimerism between January 2006 and December 2010 after receiving a preparative regimen of alemtuzumab, fludarabine, and melphalan. Twenty-one patients (78%) were alive at a median of 35 months post-transplant. Seven patients (26%) sustained full donor chimerism after DLI only at a median of 35 months post-HSCT. Nine patients (33%) continued with mixed donor chimerism (median, 38% [range, 18% to 70%]) at a median of 37 months after DLI only. Five patients underwent unconditioned stem cell boosts or second conditioned transplants after no improvement in donor chimerism was seen following DLI. Donor source appeared to contribute to outcomes after DLI; patients with mismatched unrelated donors had earlier first decline in chimerism and timing of first DLI, a higher response rate to DLI, and an increased rate of graft-versus-host disease (GVHD). There was no response to DLI in patients with matched sibling donors. Ten patients, all with improvement in chimerism after DLI, developed acute GVHD after DLI, with 3 having grade III GVHD. Three patients developed chronic GVHD after DLI. These data illustrate the potential efficacy of DLI in the treatment of mixed donor chimerism after a reduced-intensity preparative regimen.

Topics: Adolescent; Alemtuzumab; Antibodies, Monoclonal, Humanized; Child; Child, Preschool; Chimerism; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Lymphocyte Transfusion; Lymphohistiocytosis, Hemophagocytic; Lymphoproliferative Disorders; Male; Melphalan; Mucopolysaccharidoses; Myeloablative Agonists; Retrospective Studies; Severe Combined Immunodeficiency; Siblings; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors; Vidarabine

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 = 12)+melphalan (MEL; n = 11)± low-dose total body irradiation (TBI 2-4 Gy; n = 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 FLU+MEL-conditioned patients, the frequency of disease-free complete engraftment was higher for MEL (≥120 mg/m(2) )+TBI, or high-dose MEL (180 mg/m(2) ) than for others (83% vs. 25%, p = 0.036). The FLU+MEL-based non-myeloablative regimen was acceptable for FHL infants undergoing UCBT, although further studies will be needed for confirmation.

Topics: Blood Component Transfusion; Blood Donors; Child, Preschool; Combined Modality Therapy; Cord Blood Stem Cell Transplantation; Disease-Free Survival; Female; Graft Survival; Graft vs Host Disease; Humans; Infant; Infant, Newborn; Japan; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Reoperation; Retrospective Studies; Salvage Therapy; Transplantation Conditioning; Treatment Outcome; Vidarabine; Whole-Body Irradiation

Reduced intensity conditioning followed by allogeneic SCT (RIC-SCT) has recently emerged as promising new salvage option for children suffering from Langerhans cell histiocytosis (LCH) with risk organ involvement and failure to conventional therapy. We report on the posttransplant course of female toddler with high-risk LCH, who achieved complete remission after RIC-SCT, despite a posttransplant chimerism constellation, in which only the T-cell subset proved to be of donor origin in the long-term. We therefore suggest that allogeneic T-cells have played a crucial role in controlling disease activity in this patient and may exert the major curative effect after RIC-SCT for LCH.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Bone Marrow Transplantation; Combined Modality Therapy; Drug Therapy, Combination; Etoposide; Female; Graft Survival; Histiocytosis, Langerhans-Cell; Humans; Infant; Lymphocyte Transfusion; Lymphohistiocytosis, Hemophagocytic; Melphalan; Prednisone; Remission Induction; T-Lymphocyte Subsets; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Vinblastine

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon disorder, usually lethal without allogeneic stem cell transplantation (SCT).. We report a 9-month-old boy, the first child of consanguineous parents, diagnosed with HLH and neurological involvement demonstrated by magnetic resonance imaging (MRI), who received an allogeneic SCT from his HLA genetically matched father. Transplant was performed after a reduced-intensity conditioning (RIC) regimen consisting of cyclophosphamide, fludarabine, and melphalan. Graft vs. host disease (GVHD) prophylaxis included cyclosporine a and methotrexate.. An absolute neutrophil count of 0.5 x 10(9)/L was documented on day +20 and a platelet count >20 x 10(9)/L was shown by day 33. Full donor chimerism was showed on day +175. A follow-up brain MRI was reported normal. Twenty months after SCT, the child shows no evidence of HLH or GVHD activity, and has a normal psychomotor development.. Given the reduced toxicity of SCT with RIC, it could represent an attractive transplant method for children with HLH, in whom myeloablation plays no role in disease eradication, and in whom mixed chimerism may be enough to cure the disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Etoposide; Family; Graft vs Host Disease; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Magnetic Resonance Imaging; Male; Melphalan; Methotrexate; Stem Cell Transplantation; Transplantation Conditioning; Vidarabine