Comparison of Autologous and Allogeneic Bone Marrow Transplantation in Children with Acute Leukemia

Thirty-one patients with acute non-lymphocytic leukemia (18 patients) or with high-risk refractory acute lymphocytic leukemia (13 patients) underwent bone marrow transplantation between March 1980 and March 1990. The high-dose conditioning regimen employed included cyclophosphamide followed by fractionated total body irradiation (12 GY). Fourteen patients who had an HLA-identical sibling donor received allogeneic bone marrow transplantation (ailo-BMT); the other 17 patients received autologous bone marrow transplantation (auto-BMT) purged with 4-hydroperoxycyclophosphamide (4HC). Four of the 14 allo-graft recipients died of leukemic relapse and 2 others died of graft-versus-host disease. Three of the 17 auto-graft recipients died of relapse and 1 suffered relapse in the testes. The actuarial risk of relapse was 29% for the allo-BMT patients and 24% for the auto-BMT patients (P<0.05). The event-free survival rate at five years was 57% and 74% respectively (P<0.05). Although there was no difference between them, a trend toward a higher survival rate and a lower mortality and morbidity was observed in the auto-BMT group. These results suggest that autologous bone marrow transplantation purged with 4HC is an effective and useful treatment for children with acute non-lymphocytic and lymphocytic leukemia who have no HLA-identical donor.     

Second Bone Marrow Transplantation in Eight Children

Between 1985 and 1989, eight children underwent two successive bone marrow transplantations. The initial disease was chronic myelomonocytic leukemia in three patients, chronic myelocytic leukemia in two, acute M7 nonlymphoblastic leukemia in one, sickle cell anemia in one, and thalassemia major in one. The preparation in view of the second grafting included high-dose chemotherapy in all patients, associated with antithymocytic globulin transfusion and total nodal irradiation in three patients. Hematological recovery was similar after both graftings. Infectious complications were not more common following the second graft than after the first one. On the other hand, the rates of rejection and graft-versus-host disease were lower, probably due to a more intensive immunosuppressive therapy. The prognosis of chronic leukemia relapsing after a first graft does not seem to be improved by a second attempt.     

Autologous Bone Marrow Transplantation in Pediatric Solid Tumors

During the last 5 years massive chemotherapy and autologous bone marrow transplantation have been increasingly explored in the treatment of pediatric solid tumors, mainly for neuroblastoma, Ewing's sarcoma, rhabdomyosarcoma, Wilms' tumor, germ cell tumors, osteosarcoma, and retinoblastoma. Although the disease course could be changed successfully in most instances, the long-term survival has not yet been improved much over the best available conventional treatments. Despite this, in responding relapsed patients this approach seems promising and may represent the only chance of cure. New and better induction regimens are needed.     

Antiinfective Prophylaxis with Ceftazidime and Teicoplanin in Children Undergoing High-Dose Chemotherapy and Bone Marrow Transplantation

Sixty children treated for solid tumors with high-dose chemotherapy followed by bone marrow transplantation were randomly assigned to one of two antibiotic protocols. Group A received prophylaxis consisting of ceftazidime plus teicoplanin beginning before the onset of aplasia and fiver; group B received exactly the same antibiotic regimen but beginning at the onset of fever. The two groups were compared in terns of the rate of septicemia, fever of unknown origin, the time-lapse before the appearance of septicemia, the sensitivity of the causative organisms to the antibiotics, the effect of the latter on the intestinal flora, and the rate of fungal infections. The incidence of septicemia was significantly lower in group A (6.6%) than in group B (24.0%), mainly due to the prevention of episodes of early onset. Similarly, the appearance of the first episode of fever was delayed in group A, and the overall duration was reduced. Amphotericin B was prescribed empirically with the same rule in both groups, but three children in group A did not require amphotericin B. The effect on the intestinal flora was similar in the two groups; it must, however, be closely monitored so that the presence of potential pathogens can be dealt with appropriately.     

Interleukin 2 Immunotherapy in Children with Neuroblastoma after High-Dose Chemotherapy and Autologous Bone Marrow Transplantation

Four children with persistent neuroblastoma after marrow ablative chemoradiotherapy and autologous bone marrow transplantation received continuous infusion of recombinant interleukin 2, 75 to 120 days after the graft. Recombinant interleukin 2 therapy did not induce any major or nonreversible toxicity, hematological toxicity in particular. One patient entered complete remission for 9 months and a second patient had a long-lasting normalization of urinary catecholamine metabolites with more than 50% regression of bone marrow metastases (8 months). In three children, recombinant interleukin 2 and a second patient entered complete remission for 9 months therapy was followed by major increase and activation of circulating natural killer cells which amounted to 80% of the circulating mononuclear cells.     

Diarrhea and Weight Loss After Bone Marrow Transplantation in Children

To define the determinants of diarrhea after bone marrow transplantation (BMT) and its nutritional sequelae, the medical records of 20 consecutive children (median age, 9 years; 13 boys and 7 girls) undergoing BMT at Children's Hospital in Birmingham, UK were surveyed. All patients who received total body irradiation (TBI) required parenteral nutrition (PN). Seventy-eight percent of TBI patients and 73% of children who received allografts developed diarrhea compared with only 27% of non-TBI patients and 22% of those who received auto grafts (P < 0.05). Ninety percent of children with diarrhea required PN. Duration of PN in these children was longer than in those without diarrhea who requested PN (P < 0.05). Despite PN, weight loss at discharge was still greater in the study group (P < 0.05). Diarrhea was associated with a significant fall in serum albumin (P < 0.005). Diarrhea and weight loss occur in children after BMT despite active PN support. Pretransplant TBI and the we of all grafts are important determinants of these complications.     

Immunity to Polioviruses and Tetanus After Bone Marrow Transplantation in Children

Immunity to tetanus toxoid and polioviruses was studied in 34 (27 allografted, 7 autografted) children who underwent bone marrow transplantation (BMT). At a median time of 3 years after BMT, only one recipient was seronegative for tetanus toxoid. On the contrary 73 % of children were seronegative for at least one of the three poliovirus types and 30% for all vim types. Undetectable antibody titers were more frequently found against type 3 than the other two types. We recommend that reimmunizations of children after BMT be based on serologic tests for antibody titers.     

Immunity to Polioviruses and Tetanus After Bone Marrow Transplantation in Children

Immunity to tetanus toxoid and polioviruses was studied in 34 (27 allografted, 7 autografted) children who underwent bone marrow transplantation (BMT). At a median time of 3 years after BMT, only one recipient was seronegative for tetanus toxoid. On the contrary 73 % of children were seronegative for at least one of the three poliovirus types and 30% for all vim types. Undetectable antibody titers were more frequently found against type 3 than the other two types. We recommend that reimmunizations of children after BMT be based on serologic tests for antibody titers.     

Kidney Function in Long-Term Pediatric Survivors of Acute Lymphoblastic Leukemia Following Allogeneic Bone Marrow Transplantation

Renal dysfunction may occur in survivors of bone marrow transplantation (BMT). The renal function of children who have survived 5 to 10 years after BMT has not been reported. Bone marrow transplantation was performed in 55 children with acute lymphoblastic leukemia less than 18 years of age at the University of Florida between September 1983 and October 1992. All received a uniform conditioning regimen of high-dose cystosine arabinoside and fractionated total body irradiation. Twenty-three are currently surviving. The survival average period following transplantation is 79 ± 6.6 (SD) months. The longest survival is 129 months after BMT. We retrospectively examined data evaluating kidney function prior to transplantation, within 150 days after transplantation, and at each child's most recent clinic visit (1.7 to 10 years after transplantation). We were able to collect follow-up data regarding renal function for 17 survivors. Two children (11 %) have renal dysfunction in the form of hypertension, glucosuria, and hematuria. One of them had acute renal insufficiency during the first 100 days following BMT. An unexpected finding was the presence of hyperfiltration in 10 patients. In conclusion, in this homogeneous group of children, allogeneic BMT did not lead to significant long-term renal dysfunction.     

Incubation Of Autolocous Bone Marrow Graft with Asta Z 7557: Comparative Studies of Hematological Reconstitution After Purged or Nonpurged Bone Marrow Transplantation

Thirty-three patients with advanced solid tumors were treated by high-dose chemotherapy (combined high-dose melphalan), followed by cryopreserved autologous bone marrow transplantation (ABMT). Thirteen of them had bone marrow (BM) tumor involvement at diagnosis, and BM harvest was purged with 50 μglml ASTA Z 7557 before cryopreservation. Following incubation, in vitro growth of granulomonocytic colony-forming cells (GM-CFC) was regularly inhibited (>99%). Hemopoietic reconstitution after purged and nonpurged ABMT was studied. All patients experienced engraftment. However, peripheral leukocyte and granulocyte recoveries were delayed significantly in patients receiving purged BM (mean 27 and 26 days) compared with those observed in patients receiving nonpurged BM (mean 18 and 18 days). These results confirm that purged BM, despite GM-CFC depletion after in vitro treatment, ensures engraftment after high-dose chemotherapy, but prolonged pancytopenia is observed and postgraft hemopoietic recovery is delayed. A clinical trial is necessary to evaluate the efficiency of the purging technique in eradicating residual tumor cells.     

Sensory-Motor and Cognitive Functioning in Children Who Have Undergone Bone Marrow Transplantation

ABSTRACT. Sensory-motor and cognitive functioning was investigated in a group of 32 children treated with bone marrow transplantation (BMT), 1–6 years after treatment. Twenty-five of the patients had suffered from leukemia. The BMT procedure had involved a regimen of cytostatic drugs and, for leukemia patients, total body irradiation at a dose of 10 Gy, administered in one session. Cytostatic drugs and irradiation are known to be potentially neurotoxic, particularly when combined. The examination involved four neuropsychological tests of sensory-motor and cognitive functioning, as well as an age-appropriate intelligence test. For control the bone marrow donors (n=32), siblings of the patients, were also investigated. A pronounced delay in motor development was found in four children, who had been treated with BMT including total body irradiation before 3 years of age. Patients between 3 and 11 years of age at BMT were at a slight disadvantage, compared to donors, on tasks involving perceptual and fine motor speed. In older patients no deficits were observed.     

骨化三醇及复方丹参对大鼠异基因骨髓移植后急性移植物抗宿主病和细胞因子的影响

目的观察骨化三醇及复方丹参对异基因骨髓移植(Allo-BMT)后aGVHD和细胞因子的影响。方法以雄性SD大鼠为供鼠,雌性Wistar大鼠为受鼠,受鼠随机分成aGVHD组及干预组,即骨化三醇组、复方丹参组、两药联合组。观察各组aGVHD和细胞因子(IL-2、IFN-γ、IL-4、IL-10)的变化。结果干预组与aGVHD组相比,其aGVHD的发病时间延迟,aGVHD评分降低,平均生存时间明显延长,差异有统计学意义(P<0.05);动态监测显示与Th1相关的细胞因子IL-2、IFN-γ在各干预组的总体走势呈下降趋势,与Th2相关的细胞因子IL-10总体走势呈上升趋势,均在第21天变化较为明显,与第0天相比有统计学差异(P<0.05);IL-4无显著性变化。结论骨化三醇及复方丹参在异基因骨髓移植后对减轻aGVHD、调节Th1/Th2平衡,抑制Th1的增殖及功能发挥,促进Th2细胞增殖有积极的作用。     

An Adolescent Case of Retroperitoneal Pure Choriocarcinoma: Successful Treatment with MCNU-Containing High-Dose Chemotherapy Followed by Autologous Bone Marrow Transplantation after Multiple Brain Metastases

Choriocarcinoma is a rare disease in pediatric neoplasms. The prognosis of the disease is extremely poor once when patients relapse or become refractory to cisplaiin (CDDP). A 17-year-old male who had retroperitoneal pure choriocarcinoma of advanced stage was treated with CDDP-based intensive chemotherapy. In spite of the initial good response to CDDP-based intensive chemotherapy, the tumor metastasized to multiple areas of the brain during chemotherapy. Since the brain in this case was thought to be a sanctuary, after radiotherapy to the whole cranium, the patient was treated with high-dose chemotherapy consisting of etoposide, carboplatin, and ranimustine (MCNU), which can penetrate the blood-brain barrier, followed by autologous bone marrow transplantation (ABMT). Twenty-four months after ABMT, the patient had no sign of disease recurrence. MCNU-containing high-dose chemotherapy with ABMT appears to be quite effective in cases that present with relapsing multiple brain metastases during CDDP-based chemotherapy.     

Value of Routine Bone Marrow Examination for Detection of Bone Marrow Relapse in Children with Standard Risk Acute Lymphoblastic Leukemia

The value of routine bone marrow examination (RBME) in children during and after treatment for standard risk acute lymphoblastic leukemia (SR-ALL) was Investigated. The clinical symptoms and peripheral blood findings at the time of bone marrow relapse of 28 children were reviewed and compared with those of 28 matched controls in continuous complete remission. Five (45%) children with bone marrow relapse during maintenance therapy and six (35%) after cessation of cytostatic treatment were asymptomatic at the time of relapse. Signs indicative of relapse duriny treatment were lymphoblast cells in the peripheral blood, thromhocytopenia, hepatomegaly, anemia, or leukopenia in decreasing order of frequency. Afer cessation of treatment these signs were lymphoblasts in the peripheral blood, hepatomegab, splenomegaly, thrombocytopenia, or leukocytosis. Except for one case with thrombocytopenia, no signs suspicious for relapse were found in the control groups. When each sign was evaluated separately only the presence of lymphoblasts in peripheral blood and hepatomegaly were significant symptoms for relapse after cessation of treatment. The mean percentage of lymphoblasts in the bone marrow at the time of relapse was significant& lower for patients with an unpredicted relapse (46.8%) than patients with clinical and/or laboratory evidence of relapse (79.5 %). When lymphoblasts were present in the peripheral blood the percentage of lymphoblasts in the bone marrow was always more than 40%, both during and after cessation of treatment. These data suggest a relation between clinical and laboratory symptom and progression of the disease. It is concluded that 467% of relapses are detected by RBME in the absence of clinical or laboratory symptoms. This early detection may have a positive prognostic influence with more effective treatment for relapsed ALL.     

Report on the International Workshop of the Kind Philipp Foundation on Late Effects After Bone Marrow Transplantation in Childhood Malignancies

This report is a short summary of an international workshop on late effects after bone marrow transplantation in pediatric patients. Main topics of the report are chronic GVHD and immune reconstitution and the late effects of this kind of treatment on growth, respiratory function, the endocrinological system, teeth, and eyes. The development of secondary tumors is discussed as well as the influences on the central nervous system and behavior of children.     

High-Dose Melphalan, Etoposide ± Carboplatin (Mec) Combined with 12-Gray Fractionated Total-Body Irradiation in Children with Generalized Solid Tumors

Long-term disease-free survival is poor in patients with primary generalized or relapsed solid tumors. High-dose chemoradiotherapy with stem cell rescue improved survival, but more effective protocols are needed. From January 1988 to November 1988, we treated 7 patients (median age, 9 years; range, 3-23years) with an intensified treatment program. They received 12-Gy fractionated, total-body irradiation (FTBI). High-dose chemotherapy (MEC) consisted of melphalan (120-140 mg/m² Mel) and eloposide (40-60 mg/kg VP-16) with or without carboplatin (1.5 g/m² CBDCA). Although we combined 12-Gy FTBI with Mel, VP-16, ± CBDCA in doses used previously for high-dose single-agent chemotherapy, the extramedullary toxicity of FTBI with ME(C) was tolerable. Two of the four patients who were grafted without delay after good initial chemotherapy response are still alive in continued complete remission 30 and 33 months, respectively, after initial diagnosis. Early application of FTBI and ME(C) during first chemotherapy response might improve outcome in patients with primarily generalized solid tumors.     

Prevention of Gram-Positive Infections in Patients Treated with High-Dose Chemotherapy and Bone Marrow Transplantation: A Randomized Controlled Trial of Vancomycin

Between January 1986 and June 1988, 155 patients (73 children and 82 adults), who were candidates for bone marrow transplantation, were included in a randomized controlled trial (75 patients in vancomycin group and 80 patients in the group without vancomycin) to evaluate the efficiency of a short course of vancomycin (10 mg/kg IV every 6 hours, day -5 to + 1) in decreasing the incidence of Gram-positive infections during aplasia after high-dose chemotherapy and bone marrow transplantation. There was no statistical difference in the occurrence of documented septicemia, documented coccus Gram-positive infections, or fever of unknown origins during aplasia in the 2 groups. Thus, short prophylactic treatment with vancomycin proved inefficient in reducing morbidity due to infection after high-dose chemotherapy and bone marrow transplantation.     

小儿骨髓坏死19例

目的对19例小儿骨髓坏死（BMN）进行总结分析,探讨其临床和实验室特点。方法回顾性分析1996年1月~2005年11月住院治疗19例BMN的临床资料、实验室检查、治疗方法、随访资料,并进行总结。结果引起骨髓坏死的原发病15例为恶性疾病,4例为感染所致。贫血、白细胞减少和血小板减少是最常见实验室检查特点,骨髓涂片可见到典型坏死改变。结论恶性肿瘤是骨髓坏死主要原因,对于疑诊患者应及时行骨髓检查。     

Phagocytic Macrophages in the Bone Marrow Biopsies of Children with Hodgkin's Disease

Phagocytic macrophages in bone marrow aspirates have been described as normal and are frequently observed in autoimmune disorders. They are rarely seen in bone marrow biopsies. We observed phagocytosis of leukocytes and nuclear debris by macrophages in the bone marrow biopsies in 20 of 26 children with Hodgkin's disease before therapy.

In contrast, phagocytic activity was present in only 1 of 16 children with solid tumors and 4 of 17 children receiving chemotherapy for neoplasia other than Hodgkin 's disease. In all groups the marrow was not directly involved by tumor. The presence of macrophage activity did not correlate with clinical stage or histological type of Hodgkin's disease or with the peripheral blood count. Its increased frequency in patients with Hodgkin's disease may reflect abnormal macrophage function in those patients.     

Generation and Function of αδ T Cells after Allogeneic Bone Marrow Transplantation in Humans: Comparison in Absence or Presence of HLA-Matched or Mismatched Thymus

We have observed two patients who exhibited an exclusive increase of δ TCS1₊ subset of αδ T cells in the peripheral blood after bone marrow transplantation (BMT). In one case with severe combined immunodeficiency (SCID) who received haploidentical BMT from his father, αδ T cells appeared only after thymus transplantation. However, his T cell-mediated immunity remained severely defective despite the generation of T cells of donor origin. In the other case with aplastic anemia, δ T CS1_-αδ T cells began to increase in the peripheral blood later. This indicates that the thymus is necessary for the generation of αδ T cells and that the δ TCS1₊ subset is dominant in the early stages of their ontogeny. δ TCS1₊ T cell lines were established from both patients, and allo-reactivity was investigated. The cell line from the latter case reacted to recipient cells in a mixed lymphocyte reaction, but did not show cytotoxity to the allogeneic cells including recipient cells. The other cell line, from the former case, did not react to either donor or recipient cells. This indicates that an intact thymus is needed for αδ T cells to acquire allo-reactivity. Both cell lines showed MHC non-restricted cytotoxity against NK-sensitive target cells.