The American journal of pediatric hematology/oncology最新文献

Purpose: We sought to determine the effect of disease and combination chemotherapy on the hemostatic system in children with acute lymphoid leukemia (ALL).

Patients and methods: We conducted a prospective study of children newly diagnosed with ALL. Plasma samples were obtained at four time points: at diagnosis before therapy, 5 days after administration of L-asparaginase alone, after the remission induction program, and at completion of the consolidation phase. Plasma levels of 21 hemostatic proteins were measured. The amount of thrombin generated following activation with an APTT reagent was quantitated.

Results: At diagnosis there were significant elevations in factors VIII, IX, von Willebrand, alpha 2-macroglobulin and protein S. In contrast, there were significant reductions in protein C, prekallikrein, and factors XIIIA and XIIIS. L-asparaginase treatment alone decreased concentrations of 11 proteins, with antithrombin III being affected to the greatest extent. After multiagent chemotherapy, not including L-asparaginase, concentrations of most proteins increased to or above baseline. At completion of consolidation therapy, which included weekly L-asparaginase administration, concentrations of most proteins were decreased compared with baseline values. The amount of thrombin generated following activation with an APTT reagent was similar to adults.

Conclusion: Plasma concentrations of coagulation proteins are affected by disease (ALL) alone and by combination chemotherapy with or without L-asparaginase. There is no impairment of in vitro capacity to generate thrombin. L-asparaginase alone caused a decrease in almost all proteins; however, ATIII was affected to the greatest extent.

Purpose: A retrospective analysis of Hodgkin's disease (HD) in children treated at the Northern Israel Cancer Center between 1971 and 1990 was conducted.

Patients and methods: Records of 102 patients < 18 years of age at diagnosis were reviewed. Patient characteristics were similar to those previously reported. There were 54 boys and 48 girls (1.1:1 boy:girl ratio), with more boys < 10 years of age. Forty-four patients were of Arab ancestry and 58 were Jewish; incidence rates were similar in both groups. The most common histological types were nodular sclerosing and mixed cellularity, the latter being more commonly diagnosed in the younger age group.

Results: The outcome of various treatment modalities in childhood HD were evaluated. Sixty-five patients (64%) had stage I or II and 37 (34%) had stage III or IV at diagnosis. Patients with stage I-II received radiotherapy alone (20 patients), chemotherapy alone (10 patients), or a combined approach of chemotherapy plus radiotherapy (35 patients). Survival rates and median disease-free intervals were statistically similar in all three modalities. However, relapse rates were higher among patients receiving radiotherapy alone or chemotherapy alone (35% and 38%, respectively) compared with patients receiving chemotherapy plus radiotherapy (14%).

Conclusions: We conclude that a combined approach of chemotherapy plus radiotherapy is advantageous over radiotherapy alone or chemotherapy alone.

Purpose: This article addresses some of the psychosocial issues of bone marrow transplantation for treatment of hemoglobinopathies. The central focus is on the importance of attending to the experiences of minority patients and their families. Findings of recent studies relative to issues of bone marrow donation provide some framework for this analysis.

Patients and methods: Unanswered questions are posed by hypothetical parents to raise critical questions and to highlight the importance of truly informed consent in shared decision making.

Conclusions: Recommendations for researchers and care-givers are for more personal contacts and dialogues with patients and families. There should also be involvement in grass roots activities, with attention to assessing the efficacy of bone marrow transplantation, as well as emphasizing minority representation in the process.

Purpose: Stimulating expression of the normal fetal globin genes is a preferred method of ameliorating sickle cell disease and beta-thalassemia for the majority of patients in North America who do not have appropriate bone marrow donors.

Patients and methods: Due to increased survival of red blood cells that contain both hemoglobin S and hemoglobin F, as little as 4-8% fetal globin synthesis in the bone marrow can produce levels of hemoglobin F of approximately 20% in the peripheral circulation. Some success has been achieved in stimulating hemoglobin F using chemotherapeutic agents (such as hydroxyurea and 5-azacytidine) and growth factors (erythropoietin) that alter erythroid growth kinetics. However, there is reluctance to treat children with chemotherapeutic agents because of possible undesirable long-term side effects.

Results: Butyric acid and butyrate derivatives are generally safe compounds that stimulate the promoters of individual fetal and embryonic globin genes and thus provide a more specific therapy. An initial trial with the parent compound, given as arginine butyrate, has demonstrated rapid stimulation of fetal globin expression to levels that can ameliorate these conditions. Phase I trials of an oral butyrate derivative with a long plasma half-life have begun.

Conclusions: These agents may provide a new and specific approach for ameliorating the clinical manifestations of sickle cell disease and beta-thalassemia.

Purpose: The treatment of choice for many inherited diseases is bone marrow transplantation (BMT). Limitations to using marrow transplants for inherited diseases include (a) the toxicity associated with high doses of chemotherapy necessary to obtain engraftment; (b) the complications associated with graft-versus-host disease (GVHD); (c) the fact that only 20-25% of children will have a human leukocyte antigen (HLA)-matched donor; and (d) the concern that, at least for some inherited diseases, significant organ damage, especially to the nervous system, has occurred by the time the child is diagnosed and evaluated for possible BMT. In utero transplantation of hematopoietic stem cells (HSCs) offers the possibility of overcoming many of these limitations.

Patients and methods: One of the biggest hurdles to a successful transplant is the ability of the recipient to reject the donor marrow. Except in patients with severe combined immunodeficiency disease (SCID), overcoming this hurdle requires high doses of chemotherapy. Early in gestation, the fetus is significantly immunoincompetent. Before 14-15 weeks of gestation, the human fetus appears to be similar to a child with SCID in its inability to reject allogeneic cells. Potential sources for HSCs are HLA-matched sibling marrow, fetal liver, parental bone marrow, and cord blood.

Results: With fetal liver, only cells from fetuses < 10-12 weeks are acceptable because of the high risk of GVHD. With parental marrow, the cells must be T cell depleted in order to minimize the risk for GVHD. Problems in using fetal liver include the inability to obtain sufficient numbers of cells and inadequate supplies of donor tissue. The source and supply of parental bone marrow is almost unlimited, but, because of the need for T-cell depletion, bone marrow from a parent may have a lower engraftment rate in the child.

Conclusions: Studies in fetal murine and Rhesus models using fetal liver or T cell-depleted bone marrow from adult animals suggest that engraftment can be successfully obtained, providing the transplant is performed sufficiently early in gestation. To date, at least a dozen in utero human transplants have been attempted worldwide in fetuses diagnosed with a variety of inherited diseases. Because of the small number of transplanted fetuses and the variety of diseases and differing transplant conditions, it is difficult to draw any firm conclusions regarding ultimate efficacy of the procedure and its risk. However, it does appear that the age of gestation of the recipient, the dose of cells infused, and possibly the route of administration of the HSCs will be critical factors in determining success rates for this approach. The successful application of in utero transplantation would allow treatment of a variety of inherited diseases early in gestation while eliminating many of the risks associated with conventional BMT.

Purpose: The two major factors associated with lack of survival after allogeneic marrow transplant for severe aplastic anemia have been graft rejection and acute graft versus host disease (GVHD). As a result, survival for patients transplanted in the 1970s was approximately 68%. Improved survival during the 1980s was primarily related to the decrease in the incidence of acute GVHD with the use of combination methotrexate and cyclosporine for GVHD prophylaxis. Although the incidence of graft rejection has not changed, the time to graft rejection has been delayed.

Patients and methods: One hundred forty children < 18 years of age received a marrow transplant for severe aplastic anemia at the Fred Hutchinson Cancer Research Center between May, 1971 and June, 1991. Four recipients of syngeneic marrow received a simple marrow infusion, 119 recipients of HLA-identical family member marrow received cyclophosphamide (CY), 200 mg/kg; most recipients of alternative donor marrow received CY plus 12.0 Gy fractionated total body irradiation. GVHD prophylaxis was MTX only for 91 recipients of HLA-identical family member marrow, and was MTX plus CSP for all other allogeneic marrow patients. Estimates of graft rejection, acute and chronic GVHD, survival and event-free survival (EFS) were determined by the Kaplan-Meier method.

Results: Two recipients of syngeneic marrow achieved engraftment with donor marrow infusion only and two required immunosuppression with CY. Among the 119 recipients of HLA-identical family member marrow the type of GVHD prophylaxis did not influence graft rejection but non-transfused patients had 10% incidence of rejection compared to 22% for transfused patients (p = 0.1). All patients with late graft rejection survive whereas those with early rejection usually do not. The incidence of acute GVHD was 27% and 11% for MTX recipients and MTX plus CSP recipients, respectively (p = 0.11), and the probability of chronic GVHD was 30% and 26%, respectively. Survival is 64% for recipients of MTX and 96% for recipients of MTX plus CSP (p = 0.007), but EFS was 60% and 71%, respectively (p = 0.48). Recipients of partially matched family member or unrelated marrow donor grafts have transplants complicated by infections and GVHD. Growth and development of CY only recipients is normal and several children have been born to these former patients.

Conclusions: High dose CY is usually an effective preparative regimen for children with severe aplastic anemia and an HLA-identical family member marrow donor. Additional immunosuppression with anti-thymocyte globulin may result in a further decrease in graft rejection and improved EFS. Identification of a group of children who are unlikely to respond to immunosuppressive treatment could permit earlier transplantation for patients without HLA-identical family member donors available. Children who receive CY only have normal g

Purpose: Enhanced engraftment and reduced viral complications may be achieved in bone marrow transplantation (BMT) by limiting homologous transfusions. We report on limiting donor exposures before and after BMT in a newborn with severe combined immunodeficiency (SCID) using dedicated whole blood and plateletpheresis donors as well as a sterile connecting device (SCD).

Patients and methods: A 1-day-old neonate was admitted for an allogeneic, human leukocyte antigen-disparate, T-cell-depleted BMT performed on day 43 of hospitalization. All transfused red blood cells (RBCs) and platelets were cytomegalovirus negative, and were irradiated and leukodepleted (via a Pall filter). Using the SCD, tubing above the filter was connected to the product bag, and the distal tubing was connected to a transfer pack for collection of the filtered product. Additional transfer packs were connected to the filtered product using the SCD to separate small aliquots as needed. RBC aliquots were irradiated individually before each transfusion.

Results: During a total of 134 days of hospitalization, only four donor exposures occurred. Eleven RBC transfusions (mean volume 46.4 +/- 12.6 ml) from three donors and five plateletpheresis transfusions (mean volume 74.2 +/- 7.5 ml) from one donor constituted all the patients' transfusion requirements. Evidence of engraftment was seen on day 18 post-BMT with an absolute neutrophil count sustained at > 500 cells/mm3. The last transfusion was received on day 35 post-BMT.

Conclusions: Current blood transfusion technology enables patients undergoing bone marrow transplantation to have limited donor exposures. This practice should decrease viral complications without effecting bone marrow engraftment.

Purpose: We reviewed the results of transplanting allogeneic marrow from HLA-identical donors in patients with beta-thalassemia. Among the 484 consecutive patients who have received transplants since 1981, survival and disease-free survival rates leveled off at approximately 1 year after transplantation, at 82 and 75%, respectively.

Patients and methods: Clinical characteristics of patients before transplant have been studied to determine their impact on survival, disease-free survival, and graft rejection. By multivariate analysis, portal fibrosis, hepatomegaly, and a history of inadequate chelation therapy were identified as risk factors. The patients were then divided into three classes of risk.

Results: The rate of prolonged disease-free survival was 98% and 87% for class 1 and class 2 patients. This rate of disease-free survival is 70% with the use of our last conditioning protocol for class 3 patients. Older patients (17-32 years) have a 79% probability of prolonged disease-free survival.

Conclusions: We conclude that for patients with thalassemia major, transplantation of bone marrow from a human leukocyte antigen-identical donor offers a high probability of disease-free survival, particularly for those patients in early stages of their disease.

Purpose: In Belgium and France, 42 patients underwent bone marrow transplantation (BMT) for treatment of sickle cell disease.

Patients and methods: The patients were young and symptomatic, but without chronic organ damage. Engraftment occurred in all patients and was sustained in 36. These 36 patients became free of symptoms and had a change in electrophoresis of their hemoglobin toward the donor's pattern.

Results: In five patients, engraftment was followed by bone marrow rejection. Two of these five patients underwent a second transplant, one at 62 days and the other at 21 months after the first transplant, and they are both doing well. The other three patients had autologous recovery of their own bone marrow. One patient died 3 months after marrow transplant of complications of graft-versus-host disease (GVHD). All the other patients are alive, with follow-up ranging from 1 to 75 months.

Conclusions: Concerning the long-term side effects, six patients had chronic GVHD disease. So far, eight patients returned to Africa where they are continuing to do well.