Allogeneic bone marrow transplantation in children: Tokai experience 1982 to 1984

Ten children between the ages of five and fifteen years old with leukemia (two with acute nonlymphocytic leukemia in first remission, four with acute lymphocytic leukemia in first or second remission, one with acute lymphocytic leukemia in relapse, and one with chronic myelocytic leukemia in chronic phase), malignant lymphoma (one) or severe aplastic anemia (one) were given transplants from HLA-matched or mismatched family members between March, 1982 and April, 1984. Two patients died of leukemia relapses on days 107 and 257 following transplantation. One patient died of cardiac failure on day 157. One patient who received HLA-mismatched marrow from his father died of pulmonary edema and acute graft versus host disease on day 32. Six are alive 268-843 days post transplantation. None of the ten patients developed interstitial pneumonia due to cytomegalovirus which is one of the major causes of death reported in other published studies.     

Drug interactions of tacrolimus

Allogeneic hematopoetic stem cell transplantations can be complicated by a graft-versus-host disease (GvHD), i.e., immunocompetent cells from the transplanted bone marrow act against solid organs of the recipient. A GvHD is treated with immunosuppressants. Consequently, further drugs are required, for example in order to prevent infections and result in in polymedication of those patients with a risk of drug interactions. In this case report, drug interactions between tacrolimus and concomitant therapy in a stem-cell-transplanted patient are discussed.     

Cyclosporin-A in allogeneic bone marrow transplantation for leukemia: Basle experience 1979 to 1984

Since July 1979 all patients transplanted in Basle have been treated with Cyclosporin-A (CyA) as prophylaxis against Graft-versus-Host-Disease (GvHD). Currently CyA is given as a continuous infusion for 3-4 weeks, followed by an oral once-daily-therapy for one year. The daily dose is adjusted depending on the serum creatinine. Patients with acute GvHD during CyA therapy are treated with high dose bolus-steroid therapy. 83 patients with leukemia were treated in these 5 years. All were conditioned with 2 X 60 mg/kg Cyclophosphamide and 10 Gy total body irradiation. 78 had an HLA-identical, 5 an HLA-haploidentical family donor. The median age is 28 years (5-42 y). 20 patients had AML in 1. CR, 9 patients AML not in 1. CR (2nd, 3rd CR or relapse), 11 ALL in 1. CR, 19 not in 1. CR, 20 CML in chronic and 4 CML in accelerated phase. 40 patients are actually alive, well and without any signs of their disease; 9 are living in relapse. Major cause of death is relapse and GvHD. CyA does not reduce the incidence, it does reduce the severity of GvHD. The only long-term side-effects of bone marrow transplantation seen are cataracts and sterility. The major factors influencing outcome is the time of transplant. 31/51 patients transplanted in 1. CR or in chronic phase of CML are alive compared to only 9/32 transplanted in later stages. We conclude that bone marrow transplantation should be performed early in the disease and that CyA eases the procedure.     

Reality check: the patient perspective

No discussion of the topic of oncology chemotherapy quality improvement is complete without the patient as the focus of health care provider efforts. To explore the patients' perspective in their wellness quest, we present an interview with a patient who was diagnosed with lymphoma and received autologous stem cell and allogenic bone marrow transplants. As health care providers, let us never forget that advances in the science of medicine will ultimately be judged by their lasting effects, either positive or negative, on real people.     

荧光标记STR-PCR技术用于外周血干细胞移植监测

目的建立骨髓移植后监测的荧光标记STR-PCR检测方法,为白血病患者骨髓移植疗效评价提供可靠依据。方法建立荧光标记STR-PCR检测方法。于移植前、移植后7d至3个月不同时间采集供、受者血液提取DNA利用荧光标记STR-PCR方法进行分析。结果所检测的受者和供者均具有不同的DNA分型图。例1为HLA半相合母子,移植后监测结果仍为受者基因型,例2、3为HLA全相合的同胞,监测结果为完全供者基因型。结论荧光标记STR-PCR技术是一种准确、可靠的骨髓移植后监测方法。     

Immunodeficiencies better treated by transplantation

The correction of immunodeficiency requires T-cells, B-cells and antigen-presenting cells, all cooperating with each other in a balanced manner, and able to protect the tissues of the host from intracellular viral infections. Full B-cell function may require more than one genetic haplotype, and has only been achieved between host and donor cells when these are very well matched. Otherwise it has been necessary for the donor T- and B-cells to displace the host B-cells. In infants, displacement is better achieved using Busulphan rather than irradiation, (which also impairs the tolerising influence of the host thymus). Full correction has been achieved in 4 kinds of lymphopaenic SCID (+/- reticular dysgenesis or cartilage-hair dysplasia) without induction. For 16 other errors of lymphocyte function, displacement induction is preferred to ensure donor T-B-cell cooperation, although Cyclophosphamide alone has worked for matched sibling donors. For 9 other defects all expressed in phagocytes, which nevertheless occupy bone marrow space, displacement induction is essential. Elective transplants into fit hosts (e.g. no bronchiectasis) from matched sibling donors enabled 74 of 75 patients to leave hospital alive and well, with only 1 fatal acute GvHD. Currently, experienced teams can therefore consider another 20 diseases which might be better treated by bone marrow transplantation from matched siblings. In contrast, emergency transplants into unfit recipients produce only 60% survival. Transplants from donors sharing one genetic haplotype have reached 50% survival and there is room for improvement, but they are preferred to the use of unrelated donors or foetal tissues.     

Present status of bone marrow transplantation in Japan

One hundred and seventy three bone marrow transplantations (BMT) including 133 allogeneic, 17 syngeneic and 23 autologous BMT were recorded in Japan during the period between September, 1975 and March, 1984. The number of cases of BMT increased rapidly over the years, i.e., 16 cases in 1980, 27 in 1981, 39 in 1982 and 57 in 1983. All cases were treated in clean rooms, many of them receiving intensive gut decontamination containing vancomycin. In 110 cases with acute leukemia, the main causes of death were interstitial pneumonitis, relapse of leukemia, infection and GvHD. Favorable factors determined from 180-day survival were remission, no infection, low dose rate and fractionated total body irradiation (TBI), ABO minor mismatch and positive graft versus host reaction. Long-term survival of patients who received BMT during remission and were without infection amounted to 70% of acute lymphocytic leukemia (ALL) and 40% of acute myelogenous leukemia (AML) patients. Cyclosporin A (Cy-A) administered in 21 cases was compared with methotrexate (MTX) given in 20 cases. A statistically significant decrease of stomatitis was observed, while no difference in GvHD or survival was seen. There were seven cases giving a more than good response out of 11 cases treated with cyclosporin because methotrexate or immuran was ineffective or could not be administered due to toxicity. Such data suggest that allogeneic BMT is acceptable as a very promising form of treatment for acute leukemia in Japan.     

Use of donors sharing one genetic haplotype for bone marrow transplantation

Matched sibling transplants enjoy over 95% survival of the grafting procedure, but are only available for 1:5 patients. A sibling sharing one genetic haplotype is today our next choice of donor (67% survival) faring better than other relatives (50% survival), providing total body irradiation (of the thymus) has been avoided. The latter, without increasing the attack rate (64%) of GvHD more than doubles the deaths (57% as against 27%) attributable to it. Rejection is avoided by (a) suicide of host responders to donor buffy coat; (b) Cyclosporin-A; (c) displacement induction; (d) a higher dose of marrow. Prevention of GvHD is essential, using either Cyclosporin-A or removing donor T-cells from marrow prior to infusion or, probably better, both. Autoblast immunisation should be further explored. Tolerization seems an active process, easier in the very young, and nonirradiation of the thymus is believed important. An assay to assess tolerization (to guide cessation of immunosuppressive measures) is badly needed. Selection of a donor whose lymphocytes can deal with intracellular infections of the host's fibroblasts is now possible. The required increased immunosuppressive measures appear to increase the risk of leukemic relapse, and perhaps should be first improved in the more cost-effective fields of inborn error transplants.     

Biological significance of Ss (serum soluble) HLA-class I antigens in bone marrow transplantation

Ss (serum soluble) HLA-class I antigens were investigated in 10 cases of bone marrow transplantation and the relationships among Ss HLA antigens, lymphocyte counts, GvHD and the clinical course were compared. Cs (cell surface) HLA antigens were typed by the NIH standard microcytotoxicity test. Measurement of Ss HLA antigens was performed by both the lymphocytotoxicity inhibition test and solid phase RIA. A good correlation was found between the cytotoxicity inhibition test and solid phase RIA. No correlation was observed between lymphocyte counts and changes in the Ss HLA antigens in the presence of GvHD. In cases with GvHD, Ss HLA antigens were found to correlate with the GvHD. Ss HLA antigens also correlated with levels of lymphocyte counts in cases without GvHD. Ss HLA antigens are an important marker of biological significance in GvHD following bone marrow transplantation.     

Recombinant human granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer: an economic analysis of a randomised, double-blind, placebo-controlled trial

In a blinded retrospective economic evaluation of a double-blind, randomised, placebo-controlled clinical trial, total utilisation and charges for lymphoid cancer patients who received recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or placebo were compared following autologous bone marrow transplantation. The 40 patients enrolled (22 rhGM-CSF, 18 placebo) could have acute lymphoblastic leukaemia, non-Hodgkins lymphoma or Hodgkin's disease, be of any age, and were undergoing autologous bone marrow transplantation in a metropolitan cancer research centre. Main outcome measures consisted of initial hospital lengths of stay (LOS), total and department charges, rehospitalisation rates and charges, and outpatient charges, all inclusive of the first 100 days following bone marrow infusion. The perspective of the study is that of the third party payer. Initial hospitalisation charges were $US54 100 for patients who received rhGM-CSF and $US68 600 for patients who received placebo (p = 0.05). The difference of $US14 500 was 21% less in patients who received rhGM-CSF, mainly due to lower average LOS with rhGM-CSF (24.2 days) compared with placebo (30.8 days). Outpatient charges were $US9500 (rhGM-CSF) and $US6800 (placebo) {p = 0.18}. Total charges, including readmission (10 per group) were $US12 200 lower in the rhGM-CSF group ($US70 300 vs $US82 500, p = 0.19). The use of rhGM-CSF after autologous bone marrow transplantation was shown to result in substantial cost savings during the initial hospitalisation. When comparing total inpatient and outpatient medical charges within the first 100 days following bone marrow infusion, we found no evidence that these savings were negated.     

Aplastic anaemia in Christchurch Hospital 1979-89

We have reviewed the records of all patients referred to our departments with aplastic anaemia during the 11 years from 1979 to 1989. Of the 22 patients identified, 19 fulfilled the standard criteria for severe aplastic anaemia. There were 11 females and 11 males. Their mean age was 35 (range 2-85 years). Five cases followed exposure to drugs known to cause aplastic anaemia and one had a recent history of viral hepatitis. A variety of treatments were used. Four patients received an allogeneic bone marrow transplant (BMT) from matched sibling donors and two of these were alive and well 65 and 120 months post BMT. Antithymocyte globulin (ATG) treatment has been followed by lasting complete remission in two of the six patients treated and a partial response was seen in one other patient. Cyclosporin therapy was associated with unmaintained complete remission in one of the three patients given this drug after ATG had failed. The remaining 13 patients received only supportive care with or without androgens and six (46%) had early recovery of bone marrow function with lasting complete remission. These patients illustrate some of the therapeutic options available for aplastic anaemia.     

High dose chemotherapy with autologous bone marrow rescue in small cell lung cancer

Twenty five patients diagnosed as having small cell lung cancer (SCLC) were treated with etoposide and cisplatinum. After assessment for tumour response, autologous bone marrow (ABM) was collected from five patients in good clinical state who had shown a partial response (PR) and no bone marrow involvement with tumour. These patients were treated with high dose cisplatinum, etoposide and melphalan and then by ABM infusion. Although all patients (3 with extensive and 2 with limited disease) responded (4 CR and 1 PR), 3 patients with extensive disease relapsed and died of their disease. One patient with limited disease died of infection while pancytopaenic; one patient is alive but has relapsed at eighteen months. Although patient numbers are small, our data support the conclusion that high dose chemotherapy and autologous bone marrow rescue has a very small role or none at all in the management of patients with extensive or limited stage SCLC.     

再生障碍性贫血转骨髓异常增生综合征患者1例诊疗过程分析及文献复习

目的 探索再生障碍性贫血(AA)患者向骨髓增生异常综合征(MDS)转化的危险因素,并探讨诊疗过程.方法 收集1例由AA转化的MDS患者临床资料,并通过相关文献加以分析总结.结果 患者为45岁男性,6年前曾行血常规、骨髓细胞学及骨髓病理等检查明确诊断为AA.治疗上首先给予雄激素等促进造血但效果不佳,4个月后加用环孢素,治疗1年后患者就诊,此时血常规结果提示血红蛋白(Hb)及白细胞(WBC)较前已有所恢复,但由于血小板(PLT)一直无明显提升.为排除其他疾病可能,再次行骨髓细胞学检查但未发现异常.在随后的2年多随访时间里,虽然该患者定期检测环孢素浓度并规范调整治疗,但WBC和PLT始终未见好转,Hb甚至有下降趋势,而患者网织红细胞比例一直处于较高水平且逐渐升高.因此考虑患者的原发病可能已转化,故再次行骨髓细胞学检查,结果发现骨髓中三系均存在病态造血,最终患者诊断为MDS(AA继发).结论 对于长期口服免疫抑制剂治疗但效果不佳的AA患者,尤其是重度AA患者,应积极监测患者外周血及骨髓情况,若疾病转化则应尽早处理,有条件者也可考虑行造血干细胞移植治疗,避免其向其他克隆性疾病转化.同时,由于AA患者存在向MDS转化的风险,在做骨髓检查时可以通过MDS的流式细胞术(FCM)积分系统早期判断患者原发病是否已转化.     

Chronic graft-versus-host disease

Chronic graft-versus-host disease is the most common late, non-relapse complication of transplantation yet it is also one of the least studied. It is the primary cause of morbidity and mortality of long-term survivors of allogeneic bone marrow transplants. Like acute graft-versus-host disease, it does have a strong antitumor effect. The recent National Institutes of Health sponsored Chronic Graft-versus-Host Disease Consensus Conference has proposed new criteria for diagnosis and staging, pathology, biomarkers, response and supportive care. New understanding of the pathophysiology of chronic graft-versus-host disease (i.e. the role of B cells) is already having an impact on therapy. Novel agents such as pentostatin, mycophenolate mofetil, rituximab, extracorporeal photochemotherapy, etc. are improving the outcome of steroid refractory chronic graft-versus-host disease.     

Thalassaemia, iron, and pregnancy.

Haematological values of 35 pregnant women with beta-thalassaemia trait were followed during pregnancy. The discriminant function, calculated from haematological indices, was of no value in diagnosing beta-thalassaemia trait during pregnancy. Initially patients were given iron supplements only if the serum iron and total iron binding capacity levels indicated iron deficiency, but bone marrow biopsies performed in the first 22 patients at 32 weeks indicated deficient iron stores. These patients were therefore given iron irrespective of their serum iron level. All subsequent patients with beta-thalassaemia were also put on iron routinely at booking. Retrospectively the patients were divided into two groups. Patients in group 1 (18 patients) had received iron for less than 12 weeks, and their haemoglobin levels fell significantly during pregnancy (P less than 0-001). Haemoglobin levels in 16 patients who had received iron for more than 12 weeks (group 2), however, did not fall significantly during pregnancy (P less than 0-6). It is suggested (contrary to common practice) that patients with beta-thalassaemia trait should be given iron supplements during pregnancy. Serum folate and vitamin B12 levels did not change significantly in these patients and there was no increase in the incidence of maternal or fetal complications.     

Determination of sedative and amnestic doses of lorazepam in children

An open-label, dose-escalation study was conducted to determine doses of lorazepam required to induce anterograde amnesia and sedation in children without producing excessive toxicity. Oncology patients 4 to 17 years of age undergoing lumbar puncture or bone marrow aspiration were eligible; a patient could be entered in the study for a second procedure at a different lorazepam dose. A single oral dose of lorazepam was administered 45-60 minutes before the procedure. Starting with 0.02 mg/kg, the same dose was given to three patients; if no dose-limiting effects occurred, dose was increased by 0.01 mg/kg. Before the procedure the patient was shown a toy that he or she was later asked to identify. Immediately after the procedure (usually 60-75 minutes after the lorazepam dose), sedation was assessed on a scale of 0 (alert) to 4 (coma), and the clinician performing the procedure was asked to subjectively evaluate sedation. Patients were rated for amnesia 24 hours after the procedure; a scale of 0 (recalls procedure and toy without prompting) to 4 (recalls nothing since procedure) was used. Twenty patients received 28 doses of lorazepam. The study was terminated when two patients who received 0.10 mg/kg had excessive ataxia. Sedation was subjectively considered adequate for 24 of the procedures. Sedation and amnesia scores were not well correlated with increased dose. Amnesia occurred in some patients with doses as low as 0.03 mg/kg. In children undergoing lumbar puncture or bone marrow aspiration, premedication with oral lorazepam 0.02-0.09 mg/kg generally produced adequate sedation for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of an inadvertent dose of cytarabine in a child with Fanconi's anemia: reducing medication errors

We report the case of a 7-year-old boy with Fanconi's anemia, who underwent a bone marrow transplant using an unrelated donor, and who received an inadvertent dose of cytarabine (cytosine arabinoside). The cytarabine was given by mistake 6 months following transplant. This caused excessive toxicity to many systems, including the pulmonary and renal systems. The patient recovered from the episode, but this article further highlights the acute adverse effects of cytarabine. Furthermore, it is the first report of excessive toxicity to cytarabine in a child with Fanconi's anemia. The article also highlights the problems of medication administration errors, particularly in those exquisitely sensitive to the effects of toxic drugs.     

Mitoxantrone in refractory acute leukemia in children: A phase I study

Summary Nine children with acute non-lymphocytic leukemia (ANLL), ages 16 months to 16 years (median 7 years), and 15 children with acute lymphocytic leukemia (ALL), ages 10 months to 18 years (median 5 years), were treated with 5-day courses of mitoxantrone (Novantrone®; dihydroxyanthracenedione) as induction therapy. All the children had leukemia which was resistant to conventional therapy and all but one patient had received anthracycline therapy prior to the initiation of this trial. Three patients (two with ANLL, one with ALL) received the drug at a dose of 6 mg/m²/day i.v. for 5 days. Both patients with ANLL achieved partial remissions (PR) (105 and 87 days duration). The child with ALL failed to respond to two courses of the drug, and died of progressive disease 45 days after the institution of therapy. Twenty-one patients (14 with ALL, seven with ANLL) were treated with 8 mg/m²/day i.v. mitoxantrone for 5 days. There were three early deaths (all ALL) which were not felt to be secondary to drug toxicity. Four of the 18 children achieved complete remission (CR) (one ANLL — 35 days; three ALL — 39, 31 and 13 days). One child with ANLL achieved a PR (13 days) and one child with ALL showed improvement in his bone marrow status. Twelve children failed to respond to this therapy.Dose-limiting toxicity was not seen among the patients who received 6 mg/m²/day for 5 days. There were five patients who had mucositis and one patient who had nausea and vomiting among those patients who received 8 mg/m²/day for 5 days. Four of these children had significant decreases in the myocardial shortening fraction as measured by echocardiography. None of these patients had clinical signs of cardiotoxicity.The CR plus PR rate for both dose levels is 33%. Mitoxantrone appears to be an effective agent for remission induction in children with late stage ALL and ANLL. Toxicity was not a significant problem at the doses used in this trial.     

Successful bone marrow transplant for Fanconi's anaemia.

A 15-year-old boy with Fanconi's anaemia, who required four units of blood each month, received a bone marrow graft from his 9-year-old brother, who has HLA identical and compatible on mixed lymphocyte reaction. Considerable immunosuppression was used and bacterial infection was prevented by vigorous decontamination in a Vickers-Trexler isolator. After the graft the patient's blood counts remained satisfactory for nine months, but it took six months before qualitative immune function was normal.     

阿米福汀滴注速度与恶心呕吐的相关性分析

目的研究阿米福汀滴注速度的快慢与恶心呕吐分级和骨髓保护作用的相关性。方法采用随机的分组方法将35例化疗患者分为A组17例和B组18例,均接受相同周期的化疗。2组Ⅰ周期（对照组）,化疗前用阿米福汀时间严格控制在15min内;Ⅱ周期（实验组）,化疗前用阿米福汀时间控制在60min内。2个周期后评价恶心呕吐分级和血液毒性。结果 A组和B组患者在Ⅰ周期（对照组）出现恶心呕吐的人次、程度均明显高于Ⅱ周期（实验组）（P〈0.01）;而A组和B组患者在Ⅰ周期和Ⅱ周期化疗后的外周血毒性无显著性差异（P〉0.05）。结论阿米福汀滴注速度的快慢,对骨髓保护作用无明显差异,但适当延长阿米福汀使用时间,可以明显减少恶心呕吐的发生率。