联合去甲氧柔红霉素治疗急性白血病的临床研究

采用以４－去甲氧基柔红霉素（ＩＤＡ）为主组成的联合化疗方案，治疗３３例初发和复发的急性白血病，其中急性淋巴细胞白血病（ＡＬＬ）７例，急性非淋巴细胞白血病（ＡＮＬＬ）２６例。结果：总有效率７０％。初治２３例ＡＮＬＬ患者，完全缓解（ＣＲ）１６例，部分缓解（ＰＲ）２例，有效率为７９％。５例初治ＡＬＬ患者，４例ＣＲ，１例ＰＲ。而复发的２例ＡＬＬ和３例ＡＮＬＬ患者均未缓解。ＩＤＡ主要副作用表现为骨髓抑制及心脏毒性。认为以ＩＤＡ组成联合化疗方案治疗初发的急性白血病具有较好的疗效     

Evaluation of 58 patients with acute leukemia]

We made a retrospective study of 44 patients with acute non-lymphocytic leukemia (ANLL) and 14 patients with acute lymphocytic leukemia (ALL) admitted to our hospital from September 1984 to May 1991. The complete remission (CR) rate of ANLL was 90.9%, against 85.7% for ALL. The 5-year survival of ANLL was 50.7%, and that of ANLL under age 60 years was 70.3%. The 2-year median survival of ALL was 35.1%. These results were obtained with response-oriented individualized therapy, and intensive chemotherapy with a view to eradication of residual leukemic cells. Eight elderly patients with ANLL were treated with cytosine arabinoside in low doses. Complete remission was achieved in 6 patients, but these cases relapsed. These treatments should be reconsidered for long CR duration. Our schedules of response-oriented individualized therapy were too flexible to apply at another institute so they should be arranged for general application.     

Immunodiagnosis of childhood ALL with monoclonal antibodies to myeloid and lymphoid associated antigens

Sixty-five cryopreserved leukemic samples from children diagnosed and treated as having acute lymphocytic leukemia (ALL) were retrospectively examined for the presence of lymphoid and myeloid associated antigens by indirect immunofluorescence using monoclonal antibodies. Expectedly, the majority of these specimens expressed antigens known to be expressed on lymphoid, and not myeloid malignancies. These included the common acute lymphoblastic leukemia antigen (CALLA), the p32 B-cell associated antigen, and T-cell associated antigens. Leukemic cells from the 8 remaining patients expressed antigens known to be present on both myeloid and lymphoid leukemias. These included HLA/DR, and the antigens identified by BA-1 and BA-2. Cells from 2 of these 8 patients reacted with antibodies that define antigens present on normal and malignant myeloid cells. Both specimens reacted with 1G10, an anti-granulocyte antibody, and one reacted with 5F1 which reacts with monocytes, nucleated red blood cells, megakaryocytes and platelets. One of these patients relapsed while receiving ALL therapy, and the morphology of her leukemic cells became characteristic of acute monocytic leukemia (AMoL). The second patient failed ALL therapy but responded to standard acute nonlymphocytic leukemia (ANLL) therapy, clearing her peripheral blasts. Thus these studies confirm that cell surface phenotyping with monoclonal antibodies can recognize ALL cells that express myeloid rather than lymphoid associated antigens and demonstrate that the malignant cells display a clinical behavior consistent with the diagnosis of ANLL.     

Sequential high-dose cytosine arabinoside-asparaginase treatment in advanced childhood leukemia

Sequential high-dose cytosine arabinoside (ara-C) and asparaginase were given to 41 children age six months to 21 years of age with advanced leukemia. Ten of 22 patients with acute lymphocytic leukemia (ALL) and eight of 19 patients with acute nonlymphocytic leukemia (ANLL) obtained complete remissions. The most significant toxicity seen was infection in 22 patients. In addition, patients given intrathecal chemotherapy within 24 hours of ara-C developed neurologic toxicity. The high response rate seen in these patients with advanced leukemia indicates that a trial of this regimen is warranted in children with less advanced ALL and ANLL.     

Mutation analysis of the N-ras proto-oncogene in active and remission phase of human acute leukemias

DNA isolated from blood or bone-marrow samples from 18 patients with acute non-lymphocytic leukemia (ANLL) and 14 patients with acute lymphocytic leukemia (ALL) was analyzed for the presence of mutations in the N-ras gene. Using synthetic oligonucleotide probes we detected mutations in 5 cases of ANLL; 4 GGT----GAT transitions in codon 12 and one CAA----AAA transversion in codon 61. One case exhibited homozygosity for the mutation. No mutations could be detected at these codons in the DNA of the 14 ALL patients. In a follow-up study with 3 of the above 5 patients, the mutation could no longer be detected in 2 cases following successful induction of clinical remission by chemotherapy. However, the mutated N-ras persisted in one patient who did not achieve remission. We show that oligonucleotide hybridization is a sensitive assay for the detection of N-ras point mutations, which in ANLL could be used to follow the fate of the leukemic clone during (and after) therapy.     

The clinical relevance of IgG subclasses in acute leukemias: low serum IgG as a risk factor for early death due to infection in acute myelogenous leukemia.

In order to investigate the clinical significance of IgG subclass levels in adult patients treated for acute lymphocytic (ALL) or myelogenous leukemias (AML), patients were tested before and in regular intervals during and after chemotherapy. Ten patients treated for acute lymphocytic leukemia had normal total IgG and IgG subclass levels that decreased under chemotherapy. This decrease was not associated with septic complications. In contrast, total IgG and subclass levels increased in most patients with acute myelogenous leukemia during chemotherapy and bone marrow aplasia. Those patients with newly diagnosed AML and low total serum IgG before treatment with intensive remission induction chemotherapy had, however, an increased risk of early death due to septic complications.     

改良FLAG方案治疗33例难治复发性急性白血病的初步分析

背景与目的:FLAG方案用于治疗难治复发性急性非淋巴细胞性白血病(acute non-lymphocytic leukemia,ANLL)已有多年,大多报道的CR率为50%～64%.本研究探讨改良FLAG方案(减少合并应用Ara-C剂量并在化疗前不用G-CSF)能否达到同样疗效,并减轻不良反应.方法:33例成人急性白血病中难治性ANLL 16例,难治性急性淋巴细胞白血病(ALL)12例,复发性ALL 5例.全部病例接受氟达拉宾30 mg@(m2@d)-1,静滴,第1～5天;其中合并Ara-C 200 mg@d-1有18例,Ara-C 500 mg@d-1有5例,Ara-C 1 000 mg@d-1有10例,全部静脉滴注5～7天为1疗程.应用Ara-C 200 mg@d-1组和ALL组化疗前不用G-CSF,ALL患者每周加用长春新碱2 mg,共2次;强的松60～80 mg@d-1,共14天.化疗后WBC＜1.0×10 9/L者加用G-CSF,剂量均为300μg@d-1,皮下注射至WBC 3.0×10 9/L以上.每疗程完成后复查骨髓.结果:16例难治性ANLL的CR率为56.3%,而12例难治性ALL的CR率为8.3%(P＜0.01);难治性ANLL患者中Ara-C 200 mg@d-1组的CR率高于500～1 000 mg@d-1组(70%:33%),但无统计学差异(P＞0.05).化疗后WBC 0.6×10 9/L和血小板15.6×10 9/L的平均持续时间分别为5天和4.3天,Ara-C 200 mg@d-1组感染发生率明显低于500～1 000 mg@d-1Ara-C组(58.0%:85.7%)(P＜0.05).结论:与经典的FLAG方案相比,改良FLAG方案的CR率有增高、感染发生率降低.     

Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia

The basis of intrinsic resistance of blasts from patients with acute non-lymphocytic leukemia (ANLL) to methotrexate was studied. MTX polyglutamate formation was measured in blast cells from 19 patients with ANLL and in 7 pediatric patients with acute lymphocytic leukemia (ALL), after in vitro incubation for 24 h with ³H-methotrexate. There were no significant differences seen in the total amount of MTX plus polyglutamates measured between ANLL and ALL blasts, indicating that transport defects do not account for intrinsic MTX resistance in ANLL. However, there were significant differences between the amounts of long chain MTX polyglutamates found in ANLL cells as compared to ALL cells. Most, but not all, ANLL blasts were unable to form long chain polyglutamates. In as much as the level of MTX polyglutamates found in blast cells after MTX administration allows for retention of this drug, this property may explain, at least in part, the refractoriness of most patients with ANLL to methotrexate.     

EB病毒在儿童白血病患者中的感染状况及其临床意义——附35例报告

背景与目的:Epstein-Barr病毒(EBV)与多种肿瘤的发生密切相关,为此我们探讨在儿童白血病中EBV的感染及其临床意义.方法:采用荧光定量聚合酶链反应(fluorescence quantitative-polymerase chin reaction,FQ-PCR)技术,检测35例儿童白血病[其中急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)26例(初治24例,复治2例);急性非淋巴细胞性白血病(acute nonlymphocytic leukemia,ANLL)8例;慢性淋巴细胞性白血病(chronic lymphocytic leukemia,CLL)1例]及14例正常儿童外周血单核细胞EBV-DNA的含量,并结合患儿的临床表现、泼尼松敏感试验、诱导治疗完全缓解率,分析在儿童白血病患者血中EBV的感染及其临床意义.结果:35例儿童白血病患儿中8例(22.86%)有EBV感染.其中26例ALL中7例(26.92%)EBV感染,EBV-DNA含量为(5.14±6.91)×105 copy/ml;8例ANLL中1例(12.5%)EBV感染,EBV-DNA含量为4.031×103 copy/ml;1例CLL及14例正常对照儿童未检测到EBV-DNA的含量.EBV感染的儿童白血病患儿白细胞数[(144.64±46.41)×109 /L]和肝脾肋下≥5 cm发生率87.5%均高于非EBV感染患儿[(31.04±60.27)×109 /L和7.4%,P＜0.001].感染EBV和非EBV感染的ALL患儿泼尼松疗效者分别为100%、26.32%(P=0.001);诱导治疗完全缓解率分别为28.57%、84.21%(P=0.003).ANLL患儿中,1例感染EBV者的诱导治疗完全缓解率(100%)和早期复发率(100%)较未感染EBV的7例(84.21%,28.57%)高,二者无显著性差异(P＞0.05).结论:EBV感染组儿童白血病患儿肝脾肿大明显,外周血白细胞数明显高于非EBV感染者,EBV感染ALL组对泼尼松敏感试验反应差,诱导治疗获得完全缓解率低.     

Mitoxantrone for refractory and relapsed acute leukemia

Seventy-seven patients with relapsed or refractory acute leukemia and three with acute blastic chronic myeloid leukemia (CML) were treated in an open Phase II study using mitoxantrone 12 mg/m2 intravenously daily X 5 days. Complete remission (CR) was achieved in 32 of 80 (40%), including 23/45 (52%) with relapsed acute nonlymmphocytic leukemia (ANLL), four of 12 (33%) with relapsed acute lymphocytic leukemia ALL, four of 17 (24%) with ANLL refractory to daunorubicin + cytosine arabinoside, and one of three (33%) with refractory ALL. None of the patients with acute blastic CML achieved CR. Median survival time for all patients was 121 days. Median duration of complete response was 303 days with ten of 32 patients in continuing CR for periods varying from 44+ to 1210+ days. Apart from moderately prolonged hematologic suppression toxicity was mild and subjective side effects were tolerable. Mitoxantrone is an active agent in the treatment of acute leukemia and demonstrates incomplete cross resistance with duanorubicin. Mitoxantrone should be considered for first-line therapy in ANLL.     

Karyotypic changes from initial diagnosis to relapse in childhood acute leukemia

Cytogenetic study was performed at both diagnosis and relapse in 31 children with acute leukemia who had initially abnormal karyotypes, 21 with acute lymphocytic leukemia (ALL) and 10 with acute nonlymphocytic leukemia (ANLL). Seventy percent of the patients showed karyotypic changes between diagnosis and relapse. The ALL patients showed karyotypic changes more often than the ANLL patients (76 vs. 40%)(chi-square test, p less than 0.05). All the initially abnormal patients with karyotypic changes exhibited structural changes, most frequently chromosome 1 abnormalities, especially in ANLL, and 6q-, 7p-, 9p- in ALL. Half of the patients, with structural karyotypic change had two or more clonally related cell lines at relapse. On the other hand, only 20% of the patients with karyotypic changes showed numerical changes. All but one of the initially abnormal patients showed karyotypic changes involving the original cytogenetically abnormal clone. Our study demonstrated that sequential cytogenetic studies may provide a better understanding of the nature of leukemia relapse.     

Prognostic significance of general immune competence in acute leukemia

The prognostic significance of lymphocyte transformation rate, E-RFC%, 29 degrees C E-RFC%, serum IgG, IgA, IgM and C3 levels were studied in 286 patients with acute leukemia. In acute lymphoblastic leukemia (ALL), the pretreatment immunological parameters were not related to whether the patients could achieve complete remission (CR), but the patients with E-RFC% greater than 30% before treatment or E-RFC% restored to normal after treatment had a significantly longer survival time. In acute nonlymphocytic leukemia (ANLL), pretreatment LTR and E-RFC% were significantly higher in patients who could achieve CR subsequently, the patients with higher pretreatment levels of LTR, E-RFC% or 29 degrees C E-RFC% survived significantly longer than patients with lower levels of these parameters, and the patients whose LTR could return to normal after treatment had a significantly higher CR rate and longer survival times. Except that the pretreatment IgM level was related to the survival of ANLL patients, serum levels of immunoglobulins and C3 had no prognostic value for both ALL and ANLL. In both ALL and ANLL, the immunological parameters changed significantly when relapse occurred.     

血清免疫抑制酸性蛋白和免疫球蛋白亚类在白血病和骨髓瘤患者中改变

目的观察白血病和骨髓瘤患者血清免疫抑制酸性蛋白（ＩＡＰ）,可溶性白介素２受体（ｓＩＬ－２Ｒ）和免疫球蛋白亚类的变化。方法 应用单向免疫扩散法邮患者血清免疫抑制酸性蛋白和ＩｇＡ亚类含量,双抗夹心酶联免疫吸附法检测了ｓＩＬ－２Ｒ和ＩｇＧ亚类含量,结果 ＭＭ,ＡＬＬ,ＡＮＬＬ,ＣＬＬ和ＣＭＬ患者血清ＩＡＰ含量均明显高于正常姐（Ｐ〈０．００１）。ＭＭ,ＡＬＬ,ＡＮＬＬ和ＣＭＬ未见明显异常。结论 ＩＡＰ和ｓ     

Expression of the non-T ALL-associated p24 antigen on leukaemic blasts from patients with ANLL

Leukaemic cells from the peripheral blood of 90 patients with acute leukaemia (54 non-lymphocytic (ANLL) 36 lymphocytic (ALL)) have been examined for the presence of the platelet/ALL-associated p24 membrane antigen by indirect immunofluorescence and flow cytometry using monoclonal antibody FMC8. Cells from 28 of the ANLL patients and 24 of the ALL patients expressed the antigen. In many specimens, both ANLL and ALL, blast cell populations were heterogeneous with respect to FMC8 binding. In ANLL, FMC8-positive cells were observed in specimens from a range of morphological subtypes. Proteolytic stripping/resynthesis experiments demonstrated that the antigen was synthesized by ANLL cells, not passively acquired. Immunoprecipitation and electrophoretic analysis of the antigen from NP40 lysates of 125I surface labelled cells from a patient with acute monoblastic leukaemia confirmed that the epitope identified by FMC8 was present on a peptide of the same molecular weight (p24) as that observed on ALL cells.     

In vivo and in vitro expression of myeloid antigens on B-lineage acute lymphoblastic leukemia cells.

The expression of myeloid antigens has been extensively examined using two-color analysis in 43 children with B-lineage acute lymphoblastic leukemia (ALL). On pre-culture cells, CD33 expression was frequently observed in CD19+, CD10- B-precursor ALL, and CD14 was expressed only on the cells from B-precursor ALL expressing CD19, CD10 and CD20, and B-ALL. After 2 or 3 days of culture without TPA, CD13 emerged on the cells from 21 of 29 patients irrespective of the presence or the absence of fetal calf serum in the culture. Of four patients with CD10+ B-precursor ALL, which showed no expression of CD13 after culture, two had T-cell associated antigens. Whereas the addition of TPA to the culture enhanced the expression of CD13 on the cells from acute non-lymphocytic leukemia (ANLL), TPA reduced the expression of this antigen on B-precursor cells. These findings suggest that the regulatory mechanism of CD13 expression may be different between B-precursor ALL and ANLL. Co-culture with cycloheximide mostly abrogated the induction of CD13, suggesting that CD13 expression was mainly dependent on de novo protein synthesis.     

Antibodies to human herpes virus-6 in patients with acute lymphocytic leukemia.

Human herpesvirus-6 (HHV-6), a ubiquitous virus that causes exanthem subitum and occasional cases of infectious mononucleosis, hepatitis and other viral syndromes, has also been associated with acute lymphocytic leukemia (ALL) in children. To further investigate this association, we obtained sera from 50 patients with ALL and 50 age-sex matched controls. Antibodies to HHV-6 were determined using ELISA and indirect immunofluorescent antibody (IFA) tests. No significant difference between antibody titers in the cases and controls was observed. Since seroepidemiologic studies have demonstrated higher HHV-6 antibody titers in young children than in adults, this serologic study suggests that the previous association reported for HHV-6 and ALL was a result of the age of the population rather than a relationship between the virus and the disease.     

Clinical value of long-term maintenance chemotherapy in 5-year survivors of acute leukemia

We investigated whether long-term follow-up of 5-year or longer survivors of acute leukemia might provide some information concerning cure-oriented chemotherapeutic strategy. By sending a questionnaire form to major medical institutions throughout the country, data of 2202 5-year or longer survivors of acute leukemia was obtained as of 30 June 1988. There were 1607 children and 595 adults. In order to investigate the data further, they were divided into four periods according to the year of diagnosis: before 1969, 1970-1974, 1975-1979 and 1980-April 1983. As regards remission induction regimens, vincristine plus prednisolone (VP) was the most popular in childhood acute lymphoblastic leukemia (ALL) throughout these four periods. In adult acute non-lymphoblastic leukemia (ANLL), daunomycin (DM), cytosine arabinoside (ard-C), 6-mercaptopurine (6MP), prednisolone (STH) (DCMP) or behenoyl ara-C, DM, 6-MP, STH (BH-AC.DMP) was the most popular since the latter half of the 1970s. Both in childhood ANLL and adult ALL, there was no predominant regimen whatsoever. In an analysis of survival curves for the above four periods, each survival plateau for childhood ALL rose over time with statistical significance, reaching over 90% in the 1980s, whereas those for adult ANLL were not so, suggesting that newer ANLL regimens in the 1980s did not play a successful role in cure-oriented therapy. Whether duration of post-remission chemotherapy could be a prognostic factor for these survivors was studied by dividing the duration as follows: less than one year, 1-2, 2-3, 3-5 and more than 5 years. A therapeutic gain, with a cure rate of over 90%, was observed in childhood ALL patients treated with chemotherapy for 5 years or longer. In adult ANLL patients, results were similar with chemotherapy groups of both less than one year and 5 years or longer. This suggests that risk-adapted therapy is an optimal strategy for cure of adult ANLL as well as childhood ALL.     

成人急性白血病中CD117与CD34共表达的临床意义

背景与目的:c-kit受体(c-kitreceptor,c-kitR,CD117)是干细胞因子受体。CD117在急性非淋巴细胞白血病(acutenon-lymphoblasticleukemia,ANLL)中高表达,可作为髓系免疫学标记物,对诊断ANLL有一定参考价值。但是,CD117也可在部分急性淋巴细胞白血病(acutelymphoblasticleukemia,ALL)中表达。CD34为造血干(祖)细胞抗原标记物,在ANLL和ALL中均有高表达。本研究旨在探讨CD117和CD34在急性白血病中共表达的临床意义。方法:采用流式细胞术(flowcytometery,FCM)分别检测92例ALL和81例ANLL初诊患者骨髓单个核细胞(BMMNC)CD117的阳性率和阳性细胞水平;比较ALL和ANLL患者CD117/CD34共表达率的差异,并比较ALL患者中CD117和CD117/CD34共表达率的差异。设立20例健康成人为对照组。结果:在ALL和ANLL患者中CD117阳性率分别为15.2%和71.6%,CD117/CD34共表达率分别为5.4%和55.5%,差异有显著性(P<0.001)。ALL患者中CD117表达率和CD117/CD34共表达率分别为15.2%和5.4%,差异有显著性(P=0.029)。结论:CD117可作为急性白血病的MIC分型诊断之髓系免疫学标志,用以协助ANLL的临床诊断;较之CD117表达,CD117/CD34在ALL中的共表达率更低,可籍此协助排除ALL。     

Expression of a multidrug resistance gene in human cancers

Many cancers have been cured by chemotherapeutic agents. However, other cancers are intrinsically drug resistant, and some acquire resistance following chemotherapy. Cloning of the cDNA for the human MDR1 gene (also known as PGY1), which encodes the multidrug efflux protein P-glycoprotein, has made it possible to measure levels of MDR1 RNA in human cancers. We report the levels of MDR1 RNA in greater than 400 human cancers. MDR1 RNA levels were usually elevated in untreated, intrinsically drug-resistant tumors, including those derived from the colon, kidney, adrenal gland, liver, and pancreas, as well as in carcinoid tumors, chronic myelogenous leukemia in blast crisis, and cell lines of non-small cell carcinoma of the lung (NSCLC) with neuroendocrine properties. MDR1 RNA levels were occasionally elevated in other untreated cancers, including neuroblastoma, acute lymphocytic leukemia (ALL) in adults, acute nonlymphocytic leukemia (ANLL) in adults, and indolent non-Hodgkin's lymphoma. MDR1 RNA levels were also increased in some cancers at relapse after chemotherapy, including ALL, ANLL, breast cancer, neuroblastoma, pheochromocytoma, and nodular, poorly differentiated lymphoma. Many types of drug-sensitive and drug-resistant tumors, including NSCLC and melanoma, contained undetectable or low levels of MDR1 RNA. The consistent association of MDR1 expression with several intrinsically resistant cancers and the increased expression of the MDR1 gene in certain cancers with acquired drug resistance indicate that the MDR1 gene contributes to multidrug resistance in many human cancers. Thus, evaluation of MDR1 gene expression may prove to be a valuable tool in the identification of individuals whose cancers are resistant to specific agents. The information may be useful in designing or altering chemotherapeutic protocols in these patients.