melphalan and Severe-Combined-Immunodeficiency

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

Human Severe Combined Immunodeficiency (SCID) is a prenatal disorder of T lymphocyte development that depends on the expression of numerous genes. Juvenile myelomonocytic leukemia (JMML), previously known as juvenile chronic myeloid leukemia (JCML), is a rare, myelodysplastic/myeloproliferative disease typically presenting in early childhood.. Two cases are described of immunodeficiency disorders, both treated with chemotherapeutic drugs (Busulfan plus cyclophosphamide) before bone marrow transplantation. After treatment, these two different cases showed several similar oral lesions: microdontia, root alterations, numerous tooth ageneses, incomplete calcification, enamel hypoplasia, premature apexification and hypodontia. Both subjects underwent dental and orthodontic treatment. The first phase comprised orthopaedic treatment using a removable appliance (Interim-G®) followed by rapid palatal expansion; in the second phase patients underwent tooth extraction and were treated using fixed appliances for 19 and 26 months, respectively (mean 2 years) to obtain final alignment and maximum intercuspation. In the third and final phase, reconstruction of malformed teeth was completed, and implant-supported protheses were applied.. The difficulties of managing and treating these diseases are discussed, with particular focus on tooth anomalies and malocclusion disorders. Collaboration between dentist and paediatrician in dealing with patients with a variety of oral lesions and tooth anomalies is important in order to prevent any other possible tooth lesions and ensure correct jaw development.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Bone Marrow Transplantation; Busulfan; Child; Cyclophosphamide; Humans; Leukemia, Myelomonocytic, Juvenile; Male; Malocclusion; Melphalan; Severe Combined Immunodeficiency; Tooth Abnormalities

Unrelated cord blood (UCB) hematopoietic stem cells were serially transplanted into two human leukocyte antigen (HLA)-identical siblings with T cell, B cell, natural killer cell severe combined immunodeficiency. Brother A received a 4/6-matched, HLA DRbeta1-identical but class I-disparate UCB graft after myeloablative dosages of busulfan, melphalan, and antithymocyte globulin. He experienced complete donor chimerism, severe acute gastrointestinal graft-versus-host disease (GVHD), and limited chronic skin GVHD that resolved with treatment. Two years later, brother B received unfractionated marrow from brother A after reduced-intensity conditioning with cyclophosphamide and antithymocyte globulin. Brother B experienced mixed-donor (i.e. original UCB) chimerism and no histologically documented GVHD. Both brothers are clinically well; brother A is in a fully immunologically reconstituted state. The uneventful course and progressive increase in donor chimerism after the second transplantation indicates that hematopoietic cells derived from the older brother's marrow engrafted without causing GVHD, suggesting that acquired tolerance to disparate unrelated HLA antigens was achieved.

Topics: Antilymphocyte Serum; B-Lymphocytes; Bone Marrow Transplantation; Busulfan; Chimerism; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Graft vs Host Disease; HLA Antigens; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Killer Cells, Natural; Male; Melphalan; Severe Combined Immunodeficiency; Siblings; T-Lymphocytes; Transplantation Tolerance

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.

Topics: Adolescent; Alkylating Agents; Area Under Curve; Bayes Theorem; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Genetic Diseases, Inborn; Graft Survival; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Life Tables; Male; Melphalan; Prospective Studies; Severe Combined Immunodeficiency; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Topics: Chlorambucil; Cyclophosphamide; Genetic Diseases, X-Linked; Hodgkin Disease; Humans; Leukemia, Hairy Cell; Lymphatic Diseases; Melphalan; Nitrogen Mustard Compounds; Peptide Nucleic Acids; Prednisolone; Prednisone; Severe Combined Immunodeficiency; Thiotepa

Topics: Antineoplastic Agents; Genetic Diseases, X-Linked; Humans; Leukemia; Leukemia, Erythroblastic, Acute; Leukemia, Hairy Cell; Lymphatic Diseases; Lymphoma; Melphalan; Nitrogen Mustard Compounds; Severe Combined Immunodeficiency