melphalan and Immunologic-Deficiency-Syndromes

Reduced-intensity conditioning (RIC) has offered many primary immunodeficiency disorder (PID) patients who are ineligible for myeloablative regimens a chance of cure. However, the beneficial role of RIC was questioned following reports suggesting higher chance of rejection and lower symptom resolution rate in mixed chimerism settings. Forty-five children affected by PIDs with a median age of 21 months underwent allogeneic hematopoietic stem cell transplantation in our institute from 2007 to 2013. All patients received an identical RIC regimen. Forty-one patients had successful primary engraftment (91%). Of the successful engraftments, 80% (n=33) had stable full donor chimerism at last contact. Overall, eleven transplant-related mortalities were reported including five patients due to sepsis, three children due to grade IV acute GvHD, two due to chronic GvHD and one patient due to sepsis after primary graft failure. The median post-transplantation follow-up of deceased patients was 55 days. Five-year overall survival and disease-free survival was 75.6% and 68.89%, respectively. All surviving patients with successful engraftment became disease free, regardless of having full or mixed chimerism. Our study suggests that RIC regimen provides satisfactory rates of successful engraftment and full chimerism. Furthermore, patients with mixed chimerism were stable in long-term follow-up and this chimerism status offered the potential to resolve symptoms of immunodeficiency.

Topics: Adolescent; Adult; Allografts; Antilymphocyte Serum; Child; Disease-Free Survival; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Male; Melphalan; Prospective Studies; Survival Rate; Time Factors; Transplantation Conditioning; Vidarabine

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare, fatal autoimmune disorder caused by mutations in the FOXP3 gene leading to the disruption of signaling pathways involved in regulatory T-lymphocyte function. Lifelong multiagent immunosuppression is necessary to control debilitating autoimmune manifestations such as colitis and food allergies. Allogeneic hematopoietic stem cell transplantation (HSCT) can restore T-cell regulatory function but has been previously associated with poor outcome. We describe successful HSCT in 4 patients with IPEX syndrome using a novel reduced-intensity conditioning regimen that resulted in stable donor engraftment, reconstitution of FOXP3+ T regulatory CD4+ cells, and amelioration of gastrointestinal symptoms.

Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Bone Marrow Transplantation; Child; Child, Preschool; Colitis; Endocrine System Diseases; Food Hypersensitivity; Forkhead Transcription Factors; Genes, X-Linked; Graft Survival; Humans; Ichthyosis, X-Linked; Immunologic Deficiency Syndromes; Infant; Leukocyte Count; Melphalan; Postoperative Complications; Reoperation; Syndrome; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Reduced-intensity conditioning (RIC) regimens are increasingly being used in the transplantation of patients with primary immunodeficiency disorders (PIDs), but there are no large studies looking at long-term lineage-specific chimerism.. We sought to analyze long-term chimerism and event-free survival in children undergoing transplantation for PIDs using RIC with fludarabine and melphalan (Flu/Melph) and to study the effect of donor type and stem cell source.. One hundred forty-two children underwent transplantation with RIC by using Flu/Melph and for PIDs by using bone marrow (n = 93) or peripheral blood stem cells (PBSCs; n = 49). Donors were matched unrelated donors (n = 72), mismatched unrelated donors (n = 37), matched sibling donors (n = 14), matched family donors (n = 12), and mismatched family donors (n = 7).. Overall survival at a median follow-up of 7.5 years was 78%, irrespective of stem cell source or donor type. When bone marrow was used as the stem cell source, 26% of patients ended up with very low levels of donor chimerism (<10% donor), especially in the myeloid lineage. Event-free survival in this group was significantly lower compared with that in the rest of the group (25% vs 70%, P < .001). With the use of PBSCs, more than 90% of patients achieved complete donor chimerism or high-level mixed chimerism (>50% donor chimerism) in all lineages.. On the basis of our experience, we would suggest that PBSCs should be the stem cell source of choice in children with PIDs undergoing transplantation with Flu/Melph RIC from a matched donor source. This is most likely to ensure sustained high-level donor chimerism.

Topics: Cell Lineage; Chimerism; Disease-Free Survival; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunologic Deficiency Syndromes; Infant; Infant, Newborn; Melphalan; Stem Cell Transplantation; Stem Cells; Vidarabine

FOXP3 is critical for the development and function of CD4(+)CD25(bright) natural regulatory T cells (nTreg). Individuals harboring mutations in FOXP3 develop immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX). We describe a child diagnosed with IPEX who underwent a reduced intensity, T and B cell depleted, matched unrelated donor bone marrow transplant followed by clinical resolution. Using lineage-specific donor chimerism studies, we demonstrate that non-myeloablative HSCT resolves disease in the context of low level donor hematopoietic stem cell (HSC) engraftment. Despite low-levels of donor HSC, thymically-derived nTreg and to a lesser extent CD4(+) and CD8(+) T cells, exhibit a selective in vivo growth advantage for populations containing a functional FOXP3 gene. Moreover, nTreg from this patient show regulatory function directly ex vivo. These results have implications for improving clinical therapy for patients with IPEX and provide mechanistic insight into the in vivo development of human nTreg and unexpectedly, non-regulatory T cells.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Bone Marrow Transplantation; Cell Survival; Forkhead Transcription Factors; Genetic Diseases, X-Linked; Graft Enhancement, Immunologic; Graft Survival; Humans; Immunologic Deficiency Syndromes; Infant; Interleukin-2 Receptor alpha Subunit; Lymphocyte Depletion; Male; Melphalan; Point Mutation; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thiotepa; Thymus Gland; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

BALB/c mice cured of large MOPC-315 plasmacytomas by melphalan remain deficient in their spleen T-cell functions. This was manifested by impairment of the allogeneic and the antibody responses in vitro to SRBC and in decreased numbers of T-cells including their subsets CD4 and CD8. IL-2 production and specific cytotoxicity against MOPC-315 tumor cells were, on the other hand, maintained. Treatment of these cured mice by in-vivo administration of THF-gamma 2, an octapeptide from calf thymus, repaired these deficits. This was evidenced by in vitro tests with spleen cells which manifested an increased allogeneic response and elevated generation of primary antibody response, restoration of T-cell subpopulations to normal and an enhanced IL-2 production above normal levels. The potential use of THF-gamma 2 as supportive therapy in cancer treatment is suggested.

Topics: Animals; Cytotoxicity Tests, Immunologic; Drug Evaluation, Preclinical; Erythrocytes; Flow Cytometry; Fluorescent Antibody Technique; Immunologic Deficiency Syndromes; Interleukin-2; Lymphocyte Culture Test, Mixed; Male; Melphalan; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Transplantation; Oligopeptides; Plasmacytoma; Spleen; Thymus Hormones

Topics: Adolescent; Blood Coagulation Disorders; Blood Platelets; Chromosome Aberrations; Chromosome Disorders; Chromosomes, Human, 16-18; Disseminated Intravascular Coagulation; Humans; Immunoglobulin A; Immunologic Deficiency Syndromes; Karyotyping; Male; Melphalan; Polycythemia Vera