ABSTRACT
We reviewed outcomes after allogeneic hematopoietic cell transplantation (HCT) in 35 children with Chediak-Higashi syndrome (CHS). Twenty-two patients had a history of the life-threatening accelerated phase of CHS before HCT and 11 were in accelerated phase at transplantation. Thirteen patients received their allograft from an human leukocyte antigen (HLA)-matched sibling, 10 from an alternative related donor and 12 from an unrelated donor. Eleven recipients of HLA-matched sibling donor, three recipients of alternative related donor and eight recipients of unrelated donor HCT are alive. With a median follow-up of 6.5 years, the 5-year probability of overall survival is 62%. Mortality was highest in those with accelerated phase disease at transplantation and after alternative related donor HCT. Only four of 11 patients with active disease at transplantation are alive. Seven recipients of alternative related donor HCT had active disease at transplantation and this may have influenced the poor outcome in this group. Although numbers are limited, HCT appears to be effective therapy for correcting and preventing hematologic and immunologic complications of CHS, and an unrelated donor may be a suitable alternative for patients without an HLA-matched sibling. Early referral and transplantation in remission after accelerated phase disease may improve disease-free survival.
Subject(s)
Chediak-Higashi Syndrome/therapy , Hematopoietic Stem Cell Transplantation/methods , Adolescent , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Graft vs Host Disease , HLA Antigens/biosynthesis , Hematopoietic Stem Cells/cytology , Humans , Male , Retrospective Studies , Transplantation, Homologous , Treatment OutcomeABSTRACT
PURPOSE: The ACE Inhibitor After Anthracycline (AAA) study is a randomized, double-blind, controlled clinical trial comparing enalapril with placebo to determine whether treatment can slow the progression of cardiac decline in patients who screen positive for anthracycline cardiotoxicity. METHODS: The primary outcome measure is the rate of decline, over time, in maximal cardiac index (in liters per minute per meters squared) at peak exercise; the secondary outcome measure is the rate of increase in left ventricular end systolic wall stress (in grams per centimeters squared). Patients >2 years off therapy and <4 years from diagnosis, aged 8 years and older, were eligible if they had received anthracyclines and had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: A total of 135 patients were randomized to enalapril or placebo. Baseline characteristics were similar across treatment groups. CONCLUSIONS: The AAA study will provide important information concerning the efficacy of using angiotensin-converting enzyme inhibitors to offset the effects of late anthracycline cardiotoxicity.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Anthracyclines/adverse effects , Enalapril/therapeutic use , Heart Diseases/chemically induced , Heart Diseases/prevention & control , Neoplasms/drug therapy , Adolescent , Adult , Age Factors , Algorithms , Anthracyclines/therapeutic use , Child , Child, Preschool , Disease Progression , Double-Blind Method , Enalapril/adverse effects , Female , Heart Diseases/diagnosis , Heart Function Tests , Humans , Infant , Male , Placebos , Research Design/standards , Statistics, NonparametricABSTRACT
PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and L-asparaginase (DECAL) for recurrent non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% +/- 9% and 23% +/- 5% in patients with HD and NHL, respectively. Five-year survival was 31% +/- 14% and 30% +/- 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P =.002; survival, P =.011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Hodgkin Disease/drug therapy , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asparaginase/administration & dosage , Child , Cytarabine/administration & dosage , Dexamethasone/administration & dosage , Etoposide/administration & dosage , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Hodgkin Disease/mortality , Humans , Lymphoma, Non-Hodgkin/mortality , Male , Survival RateABSTRACT
Hemophagocytic lymphohistiocytosis (HLH), also referred to as familial erythrophagocytic lymphohistiocytosis, is a rare disorder of infancy associated with proliferation of activated histiocytes and T cells, anemia, thrombocytopenia, and fevers. This disorder appears to be due to the uncontrolled activation of T cells producing IL-2, tumor necrosis factor-alpha, and interferon-gamma. Untreated, the disorder is universally fatal. Various deficits in immune function have been described during acute disease activity including impaired T cell function, impaired monocyte-mediated antibody-dependent cytotoxicity, impaired natural killer cell function, and impaired IL-1 production. We examined natural killer cell function in familial HLH patients to determine whether this finding was consistently associated with the disease. We also examined natural killer cell function in asymptomatic parents and siblings of patients. Impaired natural killer cell function was identified in all patients and in some family members, including obligate carrier parents. This implies that one potential genetic defect in HLH may result in depressed natural killer function, but that this may not be sufficient to reliably predict eventual progression to disease.
Subject(s)
Cytotoxicity, Immunologic , Histiocytosis, Langerhans-Cell/genetics , Histiocytosis, Langerhans-Cell/immunology , Killer Cells, Natural/immunology , Adult , Child, Preschool , Disease Progression , Family , Female , Histiocytosis, Langerhans-Cell/physiopathology , Humans , Infant , K562 Cells , Male , Nuclear Family , Predictive Value of TestsABSTRACT
This report describes a child with a severe phenotype of autoimmune lymphoproliferative syndrome (ALPS) who developed progressive disease requiring stem cell transplantation. This severe form of ALPS was associated with a novel Fas gene splice site mutation that resulted in functional deletion of exons 8 and 9. While this child shared many clinical features with previously described ALPS cases, including massive lymphadenopathy and circulating alphabeta+ CD3+CD4-CD8-T cells, his disease progressed despite immunosuppressive therapy to a clinically aggressive oligoclonal lymphoproliferation which resembled a diffuse large cell non-Hodgkin's lymphoma. After partial remission was achieved with cytotoxic therapy the patient underwent BMT from an unrelated donor. This is the first reported case of ALPS in which BMT was successfully attempted for correction of a Fas deficiency.
Subject(s)
Autoimmune Diseases/therapy , Bone Marrow Transplantation , Lymphoproliferative Disorders/therapy , Alternative Splicing/genetics , Amino Acid Sequence , Autoimmune Diseases/genetics , Base Sequence , Child, Preschool , Humans , Lymphoproliferative Disorders/genetics , Male , Molecular Sequence Data , Mutation , Treatment Outcome , fas Receptor/chemistry , fas Receptor/geneticsABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation leading to widespread lymphocytic and hemophagocytic infiltration of vital organs. Apparent cure has only been achieved with allogeneic bone marrow transplantation (BMT). This report describes 20 consecutive patients, who underwent either matched sibling donor (n = 4) or unrelated donor (URD; n = 16) BMT. Age at the time of BMT was 0.4 to 5.3 years (median, 0.8 years). Central nervous system disease was present at diagnosis in 13 patients. At BMT, 14 patients were in a clinical remission, whereas 6 patients had active HLH. All patients were engrafted after cytoreduction with busulfan, cyclophosphamide, and etoposide. The probability of grade II-III acute graft-versus-host disease (GVHD) for all patients was 57% (95% confidence limit [CL], 0.28, 0.86), and 73% (95% CL, 0.44, 1.0) in URD patients. The overall probability of survival at 3 years was 45% (95% CL, 0.23, 0.67) and 44% (95% CL, 0.19, 0.68) when URD BMT was evaluated separately. Favorable BMT outcome was associated with clinical remission status at the time of BMT. The preparative regimen was well tolerated, and in the 9 surviving patients it provided durable engraftment and was effective at eradicating the underlying disease.
Subject(s)
Bone Marrow Transplantation , Histiocytosis, Non-Langerhans-Cell/therapy , Adrenal Cortex Hormones/therapeutic use , Bone Marrow Transplantation/adverse effects , Child, Preschool , Combined Modality Therapy , Cyclosporine/therapeutic use , Etoposide/therapeutic use , Female , Graft vs Host Disease/epidemiology , Graft vs Host Disease/etiology , Histiocytosis, Non-Langerhans-Cell/cerebrospinal fluid , Histiocytosis, Non-Langerhans-Cell/drug therapy , Histiocytosis, Non-Langerhans-Cell/mortality , Humans , Immunosuppressive Agents/therapeutic use , Infant , Injections, Spinal , Killer Cells, Natural/immunology , Male , Methotrexate/therapeutic use , Remission Induction , Survival Analysis , Transplantation Conditioning , Transplantation, Autologous , Transplantation, Homologous/adverse effects , Treatment OutcomeABSTRACT
To assess the cardiotoxicity of moderate doses of anthracyclines and to control for possible contributions of other drugs, cardiac function in 12 patients 1 year 11 months to 9 years 4 months off treatment for Wilms' tumor whose therapy had included vincristine, dactinomycin, and the anthracycline doxorubicin (270 to 300 mg/m2 cumulative dose) was compared with that of 9 patients (controls) whose therapy had included vincristine and dactinomycin but not doxorubicin. The small numbers of patients studied suggest that a a medium of 6 years off therapy only small numbers of patients will have cardiac function values below age-related normal values. To confirm these results and to determine whether abnormalities are progressive or are clinically important, large cohorts of patients such as those available to the National Wilms' Tumor Study need to be studied.
Subject(s)
Doxorubicin/adverse effects , Heart/drug effects , Kidney Neoplasms/drug therapy , Wilms Tumor/drug therapy , Child , Child, Preschool , Electrocardiography , Humans , Infant , Pilot Projects , Ventricular Function, Left/drug effectsABSTRACT
Eighteen patients with Fanconi anemia (FA) with evidence of bone marrow (BM) aplasia underwent allogenic BM transplants (BMT) from matched sibling donors (MSD). Median age at BMT was 7.6 years. Conditioning consisted of low-dose cyclophosphamide (CY; 5 mg/kg x 4 days) and thoracoabdominal irradiation (TAI; 400 cGy). Graft-versus-host disease (GVHD) prophylaxis included cyclosporin A and prednisone. In addition antithymocyte globulin (ATG) was administered in the pretransplant period to promote engraftment and in the posttransplant period for additional GVHD prophylaxis. Engraftment occurred rapidly (median, 12 days for an absolute neutrophil count > or = 0.5 x 10(9)/L; median, 22 days for platelet count > or = 50 x 10(9)/L). Seventeen patients have sustained engraftment and are transfusion-independent, with Lansky scores of 100% at median follow-up of 27 months. One patient developed graft failure 4 months after initial engraftment and required a second BM infusion. None of the patients developed acute GVHD; 3 patients (16%) developed chronic GVHD. BMT is a feasible option for FA patients having an MSD and should be performed at a young age and early in the course of the disease, before the development of complications. We believe the addition of ATG to the transplant regimen of low-dose CY, TAI, and cyclosporin was responsible for improvement in the survival of FA patients undergoing BMT. The regimen was well tolerated and was associated with a low incidence of complications including GVHD.
Subject(s)
Bone Marrow Transplantation , Fanconi Anemia/therapy , Abdomen/radiation effects , Child , Child, Preschool , Chronic Disease , Cyclophosphamide/therapeutic use , Cyclosporine/therapeutic use , Family , Fanconi Anemia/immunology , Female , Graft vs Host Disease/prevention & control , Histocompatibility , Humans , Infant , Male , Prednisone/therapeutic use , Thorax/radiation effects , Tissue DonorsABSTRACT
There have only been a few reports documenting the use of umbilical cord blood as a source of stem cells for haemopoietic reconstitution. We report our experience with a child with Fanconi anaemia (FA) who underwent a stem cell transplant using umbilical cord blood cells from his HLA matched sibling. Although the engraftment was somewhat slow, it was complete and comparable to other transplants performed in FA patients using HLA matched sibling marrow. There was no graft-versus-host disease. The post-transplant period was uncomplicated and, at a follow-up of 36 months, this child is well with normal blood counts and immune function.
Subject(s)
Fanconi Anemia/therapy , Fetal Blood/cytology , HLA Antigens/analysis , Hematopoietic Stem Cell Transplantation , Child, Preschool , Chromosome Fragility , Fanconi Anemia/genetics , Fanconi Anemia/immunology , Follow-Up Studies , Humans , MaleSubject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasms/therapy , Radiotherapy/adverse effects , Child , Combined Modality Therapy , Endocrine System Diseases/diagnosis , Endocrine System Diseases/etiology , Female , Follow-Up Studies , Humans , Male , Mass Screening , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/etiology , Risk Factors , Sex FactorsABSTRACT
The acute leukemias have been considered to represent a clonal expansion of a malignant transformed hematopoietic progenitor cell with adherence to either the myeloid or lymphoid lineage--"lineage fidelity." Lineage fidelity has been challenged by the demonstration of lineage switching or mixed-lineage leukemias. We describe a 7 year old male who presented with undifferentiated acute leukemia and nasopharyngeal and cervical masses. His blasts had the morphologic appearance of myeloblasts (FAB M1) and were positive solely for the myeloid antigen CD15. He entered a complete remission (CR) with acute nonlymphocytic leukemia therapy. At first relapse he had evidence of mixed-lineage leukemia with B-cell lymphoid and myeloid phenotypes. He again relapsed from a second CR with Burkitt-cell leukemia. Cytogenetic findings showed a consistent 14q+, 17p+ abnormality in the blasts and nasopharyngeal mass. The t(8;14) associated with Burkitt's lymphoma was found in the mass tissue only following passage in the nude mouse. Our patient demonstrates that limitations still exist in our ability to classify acute leukemia. That leukemic transformation occurred in a multipotential progenitor cell leading to undifferentiated leukemia at diagnosis and/or that chemotherapy can influence the genetic programs of leukemic cells leading to the evidence of mixed-lineage leukemia and lineage switching is supported.
Subject(s)
Leukemia, Biphenotypic, Acute/pathology , Leukemia, Myeloid, Acute/pathology , Burkitt Lymphoma/genetics , Burkitt Lymphoma/pathology , Child , Cytogenetics , Diagnosis, Differential , Humans , Leukemia, B-Cell/drug therapy , Leukemia, B-Cell/genetics , Leukemia, B-Cell/pathology , Leukemia, Biphenotypic, Acute/classification , Leukemia, Biphenotypic, Acute/drug therapy , Leukemia, Biphenotypic, Acute/genetics , Leukemia, Myeloid, Acute/classification , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Male , Neoplasm Recurrence, Local , Phenotype , Remission InductionABSTRACT
Mature and immature monocytes express the CD4 molecule similar to that expressed on lymphocytes. Since monocytes and cells of myeloid lineage are derived from a common progenitor, we studied a panel of nine myeloid leukemia cell lines for the expression of the CD4 molecule. We found that six of nine myeloid leukemia cell lines (U937, KG1-B, HL-60, THP-1, HEL 92.1.7, KMOE) expressed CD4, the exceptions being the erythroleukemia line K562, myeloblast line KG1-REV, and megakaryocytic line, CHRF-288. SDS-PAGE analysis of HL-60 cells immunoprecipitated with OKT4 showed the presence of a 55 kd molecule similar in weight to that seen on lymphocytes. These data suggest that some myeloid progenitor cells express the CD4 molecule and that the CD4 may have a broader distribution within hematopoietic cells.