Aplastic anaemia preceding acute lymphoblastic leukaemia in an adult with isolated deletion of chromosome 9q

Aplastic anaemia (AA) can precede acute lymphoblastic leukaemia (ALL) in 2% of children but this is rarely reported to occur in adults. A 21-year-old male presented with bone marrow failure and bone marrow biopsy showed a profoundly hypocellular marrow. He recovered spontaneously but represented 2 months later when he was diagnosed with pre-B acute lymphoblastic leukaemia. Chromosomal examination revealed 46,XY,del(9)(q13q34). To the best of our knowledge this is the first case to be reported of aplasia preceding ALL with 9q minus as the sole chromosomal abnormality.     

Single dose total lymphoid irradiation combined with cyclophosphamide as immunosuppression for human marrow transplantation in aplastic anemia.

Six patients with aplastic anemia underwent bone marrow transplantation following conditioning with high dose cyclophosphamide and single dose total lymphoid irradiation with 750 rad, 26 rad/min at the midplane of the patient. They all received bone marrow from human leukocyte antigens/mixed lymphocyte culture (HLA/MLC) matched siblings. Five of 6 patients were alive without complications at 12, 11, 7, 4 and 4 months respectively. The remaining patient died from sepsis which he had prior to transplantation. There were no graft rejection, graft-vs-Host Disease (GVHD) or interstitial pneumonitis among these patients. The procedure was well tolerated with minimal side effects. The results will be compared with those of groups whose bone marrow was previously transplanted with different immunosuppressive methods.     

非血缘造血干细胞移植中抗胸腺细胞球蛋白预防移植物抗宿主病的疗效分析

 【摘要】　  目的　探讨非血缘造血干细胞移植中应用抗胸腺细胞球蛋白（ATG）预防移植物抗宿主病（GVHD）的临床疗效。方法　回顾性分析1999年1月至2011年12月行非血缘造血干细胞移植患者治疗的恶性血液病（包括白血病、骨髓增生异常综合征、淋巴瘤）92例患者资料。分为ATG预防组（66例）和无ATG组（26例）。ATG剂量为1.5 mg／kg,移植前第4天至移植前第1天。比较两组急性GVHD（aGVHD）和慢性GVHD（cGVHD）发生率,分析aGVHD与cGVHD发生的危险因素,并比较ATG预防对移植后总生存（OS）、治疗相关死亡（TRM）率、复发率的影响。结果　Ⅱ～Ⅳ度aGVHD和Ⅲ～Ⅳ度aGVHD发生率差异无统计学意义[26.7 %（16／60）比44.0 %（11／25）,P＝0.12;13.3 %（8／60）比 8.0 %（2／25）,P＝0.74]。ATG组cGVHD及广泛型cGVHD发生率明显低于无ATG组[ 34.0 %（17／50）比 72.2 %（13／18）,P＝0.005;10.0 %（5／50）比44.4 %（8／18）,P＝0.005]。多因素分析显示ATG预防能降低cGVHD发生[相对危险度（RR）＝0.22,95 % CI 0.081～0.599;P＝0.003],人类白细胞抗原（HLA）不完全相合增加cGVDH发生率（RR＝3.25,95 % CI 1.39～7.61;P＝0.007）。并且ATG预防显著降低广泛型cGVHD发生（RR＝0.05,95 % CI 0.009～0.240;P＜0.001）。92例患者中位随访时间12个月（1～84个月）。ATG预防组和无ATG组间OS率（60.4 % 比43.1 %,P＝0.41）、TRM率（19.8 %比34.3 %,P＝0.43）、复发率（40.6 % 比33.6 %,P＝0.54）差异均无统计学意义。结论　总量6 mg／kg的ATG预防可显著降低非血缘造血干细胞移植患者cGVHD及广泛型cGVHD的发生率,不增加疾病复发,对OS及TRM亦无影响。     

Recommendation of the scientific societies on the treatment of anaemia in cancer patients

At present, anaemia in the patients with cancer remains a problem of the first magnitude and of increasing interest due to the high incidence, the major knowledge of its physiopathology, the negative impact on the quality of life of the patient, the influence on the evolution of the disease and its treatments and, finally to the progressive development of new alternatives of treatment, especially the erythropoietic agents. For all this, it becomes necessary to consider the treatment of the anemia of the patients with cancer as a basic part of their support treatment. The erythropoietic agents have demonstrated in the last years that constitute a therapeutic alternative to obtain an increase of the levels of hemoglobin in the patients with anticancer treatments, considering specially that the correction of the anemia not only represents the improvement of an analytical value but also has a significant impact on the quality of life of the patients and diminishes the transfusion requirements. Erythropoietic proteins available for the treatment of the anemia of the patients with cancer are Epoetin-alpha, Epoetin-beta and Darbepoetin-alpha. The existence of different drugs, different doses and intervals of administration, clinical different situations and heterogeneous studies, made necessary the development of documents of consensus and guides of clinical recommendations which provide information on the scientific evidence that supports the use of these agents in medical care. This paper summarizes the main recommendations from panels of experts and scientific societies published so far.     

Management of anaemia in patients with breast cancer: role of epoetin

Many patients with breast cancer suffer from anaemia, as a consequenceof the disease itself or its treatment. Anaemia has a negativeimpact on treatment outcome and overall survival, and affectsthe quality of life (QoL) of patients with cancer. Previously,cancer-related anaemia was treated with blood transfusion, butthis is inconvenient, offers only temporary improvement in haemoglobin(Hb) level and is associated with several risks. Consequently,blood transfusion is usually reserved for patients with severeanaemia (Hb levels <8 g/dl). Recombinant human erythropoietin(epoetin) is an effective and convenient treatment for cancer-relatedanaemia without the risks associated with red blood cell transfusion.Epoetin therapy effectively increases Hb levels, thereby reducingthe need for emergency blood transfusion and improving the QoLof patients with anaemia and breast cancer. Epoetin beta isalso effective for the prevention of anaemia and reduction oftransfusion requirements in patients with a high risk of developinganaemia during chemotherapy. With the increased use of dose-intensifiedchemotherapy in an attempt to improve response rates, administrationof epoetin to prevent anaemia could potentially benefit manypatients with breast cancer. Key words: anaemia, anaemia prevention, breast cancer, dose-dense chemotherapy, erythropoietin     

Impaired liver function tests in patients treated with antithymocyte globulin: Implication for liver transplantation

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day — 1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 ± 37.7 U/l pre-treatment to 1394.4 ± 488.7 U/l 3 days post-treatment (n = 16;p < 0.029), and then declined to 561.4 ± 61.3 U/l 10 days post-treatment (n = 16;p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 ± 11.3 U to 184.6 ± 74.6 U (n = 16;p < 0.036), and then declined to 121.9 ± 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 ± 5.7 U to 152.0 ± 67.0 U (n = 16;p < 0.44) and then declined to 46.0 ± 14 (n = 16;p < 0.049). The mean r-glutamyltransferase (GTP) levels increased from 93.0 ± 34 to 188.0 ±36 (n = 16;p < 0.02), and were 168.0 ± 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 ± 1.9μM I^-1 to 22.7 ± 2.8 (n = 16); NS), at day +3 and to 31.9 ± 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.     

Treatment-induced anaemia and its potential clinical impact in patients receiving sequential high dose chemotherapy for metastatic testicular cancer

First-line sequential high dose chemotherapy is under investigation in patients with "poor prognosis" metastatic germ cell tumours in order to improve survival. Despite the use of autologous peripheral blood stem cell transplantation and granulocyte colony stimulating factor chemotherapy dose intensification is associated with severe haematotoxicity including anaemia, which may significantly affect quality of life and tolerability of chemotherapy. This study investigates the frequency and degree of anaemia in patients receiving first-line sequential high dose chemotherapy for metastatic testicular cancer and the impact of anaemia on treatment outcome. A total of 101 newly diagnosed patients with "poor prognosis" metastatic nonseminomatous germ cell tumours were treated with one cycle of standard VIP followed by three cycles of HD-VIP-chemotherapy (etoposide, ifosfamide, cisplatin) within a large phase I/II study. Differential blood cell counts were taken prior, during and after every cycle of chemotherapy. Additionally, the numbers of red blood cell and platelet transfusions were recorded. Kaplan-Meier analyses were performed to correlate pre-treatment and post-treatment haemoglobin values to response and overall survival. Forty-eight per cent of the patients were classified anaemic (haemoglobin <12 g dl(-1)) prior to the start of chemotherapy. The application of sequential HD-VIP resulted in median haemoglobin nadirs between 7.8 g dl(-1) (range 5.5-11.1 g dl(-1)) in the first cycle and 7.6 g dl(-1) (range 6.0-11.4 g dl(-1)) in the third cycle despite the frequent use of red blood cell transfusions. Almost all patients (99%) had haemoglobin levels <10 g dl(-1) at some timepoint during first-line sequential high dose chemotherapy. Overall, 97 patients received red blood cell transfusions with a median of 10 units (range 2-25) per patient during the four consecutive cycles of therapy. The time to first transfusion was shortest in patients with the lowest initial haemoglobin values. While there was no prediction of response or outcome by baseline haemoglobin-levels, a significant survival difference in favour of patients with a haemoglobin value >10.5 g dl(-1) after completion of four cycles of therapy (at leukocyte recovery after the last cycle) compared to those with haemoglobin values <10.5 g dl(-1) was found with 3-year overall survival rates of 87% vs 68%, respectively (P<0.05). Severe anaemia is a very frequent side effect of sequential dose intensive therapy in patients with germ cell cancer, with almost all patients becoming transfusion dependent. Despite the frequent use of red blood cell transfusions, median haemoglobin nadirs remained about 7.5-8 g dl(-1) during therapy. A correlation of haemoglobin-values after completion of therapy to overall treatment outcome was found.     

Foetal intracardiac transfusion for the treatment of severe anaemia due to human parvovirus B-19 infection

Intra-uterine parvovirus infection may result in severe foetal anaemia and death. Ultrasound diagnosis of foetal parvovirus is presented, together with ultrasound-guided foetal transfusion to treat the anaemia.     

骨髓增生异常综合征和再生障碍性贫血患者骨髓CD34+细胞测定

 目的 检测骨髓增生异常综合征（MDS）和再生障碍性贫血（AA）患者骨髓CD+34细胞占单个核细胞（MNC）的比率,以探讨二者可能的发病机制。方法 用流式细胞术（FCM）检测22例MDS患者、13例AA患者及12例非血液病患者骨髓CD+34细胞占MNC的比率。结果 AA组与对照组、AA组与MDS-RA组、AA组与MDS-RAEB组、MDS-RA组与MDS-RAEB组的骨髓MNC中CD+34细胞的比率的比较差异有统计学意义（P＜0.05）。大多数重型AA（SAA）患者（3／4）及很少慢性AA（CAA）患者（1／9）的骨髓MNC中的CD+34细胞的比率＜0.1 %。结论 骨髓CD+34细胞的检测有助于判断AA患者病情及MDS患者的预后,亦可用于鉴别AA和MDS。     

A dose- and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer

A multicentre study evaluated the efficacy and safety of darbepoetin alpha administered weekly (QW), every 3 weeks (Q3W), and every 4 weeks (Q4W) to anaemic patients with cancer not concurrently receiving chemotherapy or radiotherapy. The QW portion (n=102) was an open-label, sequential, dose-escalation design; cohorts received darbepoetin alpha QW by subcutaneous (s.c.) injection at 0.5, 1.0, 2.25, or 4.5 micro g kg(-1) week(-1) for 12 weeks. The 12-week placebo-controlled, double-blind Q3W (6.75 micro g kg(-1)) and Q4W (6.75 or 10.0 micro g kg(-1)) schedules (n=86), which enrolled different patients, took place after the QW schedule and were followed by a 12-week, open-label phase. Patients were evaluated for change in haemoglobin end points and red blood cell transfusions, serum darbepoetin alpha concentration, and safety. Selected domains of health-related quality of life (HRQOL) were measured. With QW dosing, at least 70% of each cohort had a haemoglobin increase from baseline of > or =2 g dl(-1) or a concentration > or =12 g dl(-1) (haematopoietic response). In the 4.5 micro g kg(-1) QW cohort, all patients achieved a haematopoietic response (100%; 95% confidence interval (CI)=100, 100). In the Q3W and Q4W schedules, all cohorts had at least 60% of patients who achieved a haematopoietic response. Darbepoetin alpha effectively increases haemoglobin concentration when given QW, Q3W, or Q4W. Less-frequent administration may benefit patients with chronic anaemia of cancer and their caregivers alike.     

A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes.

Immunosuppression has recently been proposed for low-risk myelodysplastic syndromes (MDS) to reverse bone marrow failure by inhibiting intramedullary secretion of proapoptotic cytokines. We treated 35 MDS patients (24 refractory anaemia (RA), 10 RA with excess blasts and one chronic myelomonocytic leukaemia) with either horse antithymocyte globulin 15 mg/kg/day or rabbit antithymocyte globulin 3.75 mg/kg/day, each for 5 days. Median age was 63 years (range: 41-75). After 1 to 34+ months of follow-up (mean: 15+), four patients experienced complete haematological responses (CR), six good responses (GR) and two minor responses. All CRs and GRs occurred in patients with RA, in whom both horse and rabbit ATG yielded five responses out of 12 (42%). Time to response varied between 1 and 10 (mean: 3) months. The median duration of response was 9+ (1-17+) months; five patients are in continuing response. In all, 23 patients suffered side effects > degrees II WHO (the degree of toxicity encountered according to the internationally accepted WHO toxicity grading); one patient died 2 weeks after rabbit ATG from rhinocerebral mucormycosis. Parameters that correlated with response were duration of disease and RA subgroup. In our experience, immune-modulating therapy with either horse or rabbit ATG is feasible in patients with RA and short duration of disease.     

Low dose Ara-C for patients with myelodysplastic syndromes

Forty patients with high risk myelodysplastic syndromes--refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia--were treated with subcutaneous low dose cytosine arabinoside, 10 mg/m2 twice daily for up to 42 days. In 38 evaluable patients there were nine (24%) complete and four (11%) partial responses. Response was associated with symptomatic improvement and resolution of the need for red cell and platelet transfusions. The median duration of complete response was 9.8 months (range, 2.4-17.9); these patients had a median survival of 15.7 months (range, 6.0-22.7). Toxicities were predominantly those associated with pancytopenia, i.e., infection and hemorrhage.     

Once-weekly dose of epoetinum alfa in cancer patients with anemia receiving radiotherapy

Introduction Anaemia is present in 30%–90% of all patients with cancer, and its origin is multifactorial. Human recombinant erythropoietin has been shown to be useful in treating anemia in patients with cancer. The aim of this study was to evaluate the effectiveness of treatment of anaemia with epoetin alfa (EPO) given as a single weekly dose, and its repercussions on quality of life (QoL). Materials and methods From January to October 2002, a total of 139 patients referred to our service for radiotherapy (RT) had anemia and received treatment with EPO as a single weekly dose of 40,000 IU subcutaneously, with oral iron supplement. If haemoglobin (Hb) values after 1 month of treatment did not increase by≥1 g/dl, the dose was increased to 60,000 IU/week. Treatment with EPO ended when Hb values reached ≥14 g/dl or one month after the end of RT regardless of Hb values. QoL was evaluated with the Functional Assessment of Cancer Therapy-Anaemia subscale (FACT-An) and the Cancer Linear Analogue Scale (CLAS). Results Mean Hb at the start of treatment with EPO was 11.49±1.08 g/dl, and the mean value at the end of treatment was 14.52±1.41 g/dl (p<0.001). The mean increase in Hb was 2.97±2.91 weeks. In 11 patients (7.9%) the dose was increased after 4 weeks. In 84 patients (60.4%) EPO treatment was implemented before the commencing of RT. Mean Hb values in this group was 11.34±1.11 g/dl at the start of EPO treatment, 12.69±1.56 g/dl at the start of RT, 13.96±1.54 g/dl at the end of RT and 14.68±1.3 g/dl at the end of EPO treatment (p<0.001). In 55 patients (39.6%) anaemia developed during RT and, therefore, EPO treatment was implemented after commencing of RT. In this group the mean Hb values were 12.29±1.6 g/dl at the start of RT, 11.72±1.01 g/dl at the start of EPO treatment, 13.97±1.53 g/dl at the end of RT and 14.28±1.54 g/dl at the end of EPO treatment (p<0.001). Hemoglobin levels at the start of EPO were lower in patients who commenced EPO before RT (p<0.05). In 60 patients who received combined RT and chemotherapy, mean Hb values were 11.42±1.16 g/dl at the start of EPO and 13.98±1.55 g/dl at the end of EPO (p<0.005). In 75 patients who had received RT alone, the mean Hb values was 11.53±1.05 g/dl at the start of EPO and 14.98±1.17 g/dl at the end of treatment (p<0.001). Patients treated with RT alone had higher Hb levels at the end of RT and at the end of EPO treatment than did patients who had received combined treatment (p<0.005). The duration of EPO treatment was shorter in the group treated with RT alone than in the combined treated group (6.41±2.99 weeks versus 7.96±2.67 weeks; p<0.005). No significant differences were observed in FACT-An and CLAS scores at the beginning and the end of the study. Conclusions Treatment with epoetin alfa as a single weekly dose significantly increased Hb levels in patients with cancer who were undergoing radiotherapy. The response was greater in patients treated with radiotherapy alone than in those receiving combined therapy. The duration of EPO treatment was shorter in the group treated with radiotherapy alone than in the combined treatment group.     

Incidence of anaemia in breast cancer patients receiving adjuvant chemotherapy

Anaemia is frequent in breast cancer patients but often remains undiagnosed and untreated. To determine the incidence of anaemia a prospective survey of primary non-metastatic breast cancer patients who received at least four cycles of adjuvant, non-platinum multi-agent chemotherapy was conducted at 47 centres in Austria. Two hundred and forty seven patients were prospectively included between October 1999 and December 1999. Haemoglobin (Hb) levels were determined after surgery and prior to each cycle of chemotherapy. Treatment of anaemia (blood transfusion or epoetin alfa) during the observation period was at the physician's discretion. For the purpose of this study, patients were considered to be anaemic if their Hb was below 12 g/dl. At baseline (after surgery and before the first cycle of chemotherapy), 28.7% of all patients were anaemic. The only significant differentiating factor was the type of surgery. 37.9% of patients who underwent mastectomy were anaemic, whereas only 22.8% of patients who underwent breast conserving surgery were anaemic. Forty two percent of 176 patients with a Hb level of 12 g/dl at baseline developed anaemia during adjuvant chemotherapy. The only factor that significantly influenced the development of anaemia during chemotherapy was the Hb level at baseline. The total incidence of anaemia in patients with primary breast cancer who underwent surgery followed by adjuvant multi-agent chemotherapy was 58.7%. Forty nine patients (20.2%), 48 patients (19.2%) and 48 patients (19.2%) showed a decrease in Hb levels by 1 g/dl, 1–2 g/dl and >2 g/dl, respectively. Only 18.6% of the patients who were found to be anaemic received anaemia treatment. The two most important factors for developing anaemia are the kind of surgery and the Hb level prior to chemotherapy.     

Unexpected case of aplastic anemia in a patient with glioblastoma multiforme treated with Temozolomide

Summary We report the case of a 30-year-old woman with glioblastoma multiforme (GBM) treated with surgery followed by concomitant Temozolomide (TMZ) and external beam radiation, which she tolerated well without any interruptions. However, when she was being evaluated for adjuvant Temozolomide, she developed progressive decline in leukocyte counts and platelet counts and subsequently, febrile neutropenia with bleeding manifestations. A bone marrow aspiration and biopsy done showed a gross hypocellular bone marrow with very few erythriod and myeloid cells and no suggestion of progenitor cells, consistent with aplastic anemia.     

Total body irradiation as preparation for bone marrow transplantation in treatment of acute leukemia and aplastic anemia

In an attempt to improve survival while minimizing toxicity, many bone marrow transplant centers are now studying the use of cytoreduction regimens with an increased amount of radiation in single-dose or fractionated-exposure schedules for patients with leukemia and aplastic anemia. In order to review the current results, the literature prior to September, 1982 was surveyed and data were tabulated for each transplant center regarding the number of patients receiving transplants, diagnoses, cytoreduction regimen, clinical status, remission duration, relapse rate, causes of death and incidence of interstitial pneumonia. The incidence and severity of cataracts, growth failure, hypothyroidism and second malignant neoplasms were noted, and the data obtained from the literature search were updated and expanded by telephone questionnaire when possible. Marked variation in the technique of transplantation was found among the participating institutions, making it difficult to determine the contribution of the various TBI doses, dose rates and fractionation schedules to the efficacy and toxicity of the combined regimen. In order to define the risk-benefit ratio of the various TBI regimens more clearly, prospective controlled, randomized studies will be required.     

中国胃癌患者贫血的多中心前瞻性临床研究

目的探讨贫血在中国胃癌人群中的患病率和严重程度,分析影响胃癌患者贫血的独立因素。方法收集1 285例胃癌患者的临床资料,分析患者的贫血患病率、严重程度和影响其发生的独立因素。结果 1 285例胃癌患者中,63.2%的胃癌患者发生了不同程度的贫血,轻度、中度和重度贫血患者所占比例分别为48.6%、13.5%和1.1%。多因素回归分析结果显示,带瘤生存和既往接受过手术治疗是影响重度贫血发生的独立因素。手术切除范围、消化道重建方式、既往接受过铂类药物化疗、放射治疗、存在并发症和血小板计数<125×109/L均为影响D2根治术后患者发生中重度贫血的独立因素。结论胃癌人群中贫血发生率较高,临床治疗时应高度关注发生贫血的风险,积极采取预防和治疗措施以改善患者的生活质量。