Effects of interleukin-5 on acute myeloid leukemias.

Because of the known activity of interleukin-5 (IL-5) as a growth factor for human eosinophils, we performed studies to ascertain whether M4Eo acute leukemia cells might be capable of responding to IL-5. Surprisingly, short term incubation of freshly isolated M4Eo blasts with rhIL-5 induced differentiation of the cells to macrophages. To determine whether other variants of acute myelogenous leukemia (AML) might also be capable of responding to IL-5, we studied cells from four additional unselected cases and found that one responded to IL-5 by vigorous proliferation. Using biotinylated rhIL-5, second labelling with streptavidin-fluorescein isothiocyanate (FITC) and flow cytometric analysis, specific binding of IL-5 to both responsive leukemias was demonstrated, suggesting the presence of specific IL-5 receptors. Additional study will be needed to assess the frequency of IL-5 responsiveness in AML and to determine the relationship of these phenomena to the physiologic role of IL-5 in the regulation of hematopoiesis.     

Serum beta 2 microglobulin in adult myeloid acute leukemias

Summary Serum ₂ microglobulin levels, measured by radioimmunoassay (Phadebas test), were found increased in acute myeloid leukemias at diagnosis. Serum ₂ microglobulin levels were significantly higher in patients with monocytic leukemias (13 patients, M4–M5 FAB classification) than in those with other cytological types (18 patients). ₂ microglobulin levels at diagnosis were correlated with serum lysozyme levels, but they were not correlated with blood blast counts, serum LDH and ferritin levels.195 serum ₂ microglobulin measurements were made serially in 30 patients with acute myeloid leukemias in first remission. Compared to values at diagnosis, ₂ microglobulin levels in remission were significantly decreased. Out of 30 patients in remission 12 had increased serum ₂ microglobulin levels (>3 mg/l). Serial measurements were not predictive for relapses.     

Clinical aspects of acute myeloid leukemias of the FAB types M3 and M4Eo

Summary Acute promyelocytic leukemia (AML FAB M3, APL) and acute myelomonocytic leukemia with abnormal eosinophils (AML M4Eo) are considered distinct entities with characteristic clinical, morphological, cytogenetic, and prognostic features. Promyelocytic leukemia is characterized by abnormal promyelocytes replacing normal hematopoiesis associated with a translocation between the long arms of chromosomes 15 and 17 t (15; 17), severe coagulopathy, and responsiveness to all-trans retinoic acid (tretinoin). Characteristic features of AML M4Eo are a myelomonocytic marrow infiltration, eosinophils with abnormal immature granules positive for chloroacetate esterase, an inversion or translocation of chromosome 16, and an increased risk of meningeal relapses. Prognosis of both types of AML has been reported to be better than prognosis of the other entities combined. Since most of the published data were collected from heterogeneous patient populations treated with various chemotherapeutic regimens, we have analyzed treatment outcome of AML M3 and M4Eo in the AMLCG-85 study for patients younger than 60 years. For the total population of 594 patients of this study, CR rate was 68.89%, early death rate 11.60%, and no or partial remission was achieved in 19.51% of the cases. Of 40 patients with AML M3 or M3v complete remission was attained in 62.5%. Nine patients died within 42 days after the start of antileukemic therapy (22.5%). Of these nine, four died because of infection, five because of bleeding. Relapse-free survival rate was 59% after 3 years, significantly better than the respective curve of the other FAB types combined (35% after 3 years). In AML M4Eo, 91.7% of the 24 patients reached complete remission. The early death rate was 8.3%. No case of nonresponse was seen. Relapse-free survival rate was 49% after 3 years compared with 35% for the other types combined.     

Graft-versus-host Disease Confined Solely to Intestine after Allogeneic Peripheral Blood Stem Cells Transplantation in a Patient with Chronic Myelogenous Leukemia

We describe a patient with chronic myelogenous leukemia who developing severe intestinal bleeding after allogeneic peripheral blood stem cells transplantation (allo-PBSCT). PBSC were obtained from an HLA one-locus mismatch sibling donor. On day 26 after PBSCT, although there was no sign of graft-versus-host disease (GVHD) in either the skin or the liver, diarrhea and severe intestinal bleeding occurred. The histopathological examination of the colon revealed complete denudation of the epithelial cells of the mucosa and no obvious apoptosis. Neither red cell fragments nor hemorrhagic diathesis was seen during this episode and the patient was diagnosed as having GVHD. Methylpredonisolone followed by FK506 may be effective in controlling intestinal bleeding and was used in our patient. Acute GVHD involving only the intestine has rarely been described but when using HLA-mismatched PBSCs, acute GVHD may occur severely and atypically.     

Multidrug resistance gene expression in acute myeloid leukemia: Major prognosis significance for in vivo drug resistance to induction treatment

 The clinical significance of the multidrug resistance (MDR 1) gene phenotype was investigated in newly diagnosed AML and was compared with other clinical and biological prognostic factors in patients who received at least one course of induction therapy with intercalating agents and conventional doses of Ara-C. MDR 1 gene was overexpressed in 40% of the 110 cases of AML at presentation, MRP in 15% of the 48 patients tested for both markers. Both gene expressions were closely linked (p=0.008). Except for a lower frequency in the "good risk" cytogenetic group, MDR 1 overexpression was not associated with other prognostic factors. In univariate analysis, MDR 1 overexpression, age over 50 years, and cytogenetic were associated with a higher rate of resistance to induction treatment. The overall survival was shorter in the case of intermediate or poor cytogenetics, high leukocytosis, MDR 1 overexpression, age over 50 years, secondary AML, and poor cytologic differentiation. Using multivariate analysis on 64 patients receiving intensive treatment, MDR 1 overexpression was the first significant prognostic factor for resistance to the first course of induction treatment. Cytogenetic analysis maintained its prognostic value only in MDR 1-negative patients. These data underline the value of MDR 1 gene expression as a powerful prognostic factor in AML for response to the first induction treatment and overall survival, sustaining the use of MDR 1 modulators for firstline therapy in this disease. Received: 8 August 1996 / Accepted: 26 November 1996     

IL-2在老年急性髓细胞白血病治疗中的临床价值

目的　探讨在化疗基础上利用重组人白细胞介素 2 (IL 2 )治疗老年急性髓细胞白血病 (AML)的临床价值。　 方法　选择 1994～ 2 0 0 1年收住的老年人AML 41例分别作为观察组和对照组。观察组 2 1例在联合化疗基础上加用IL 2治疗 ,对照组 2 0例单用联合化疗 ,随访观察疗效。　 结果　患者对IL 2耐受性良好 ,观察组完全缓解 (CR)率、达CR所需时间与对照组无显著差异 [38 1%vs 35 0 % ,( 5 3 2± 2 1 3)dvs ( 5 5 8± 2 3 1)d ,P >0 0 5 ]。但缓解期和生存期长短优于对照组 [( 9 8± 4 8)月vs ( 5 3± 2 3)月 ,P <0 0 5 ;( 9 3± 2 8)月vs ( 6 1± 2 5 )月 ,P <0 0 0 1]。　 结论　对老年人AML在化疗的基础上给予IL 2治疗是延长缓解期和生存期的一种有效而可行的方法     

Rapid detection of chimeric bcr/abl mRNAs in acute lymphoblastic and chronic myeloid leukemia by the polymerase chain reaction

Summary We have developed a rapid method for the detection of bcr/abl mRNAs, the products of the BCR/ABL fusion genes. The method is based on the polymerasechain-reaction (PCR). Through the use of additional internal primers it is possible to detect directly a single Ph¹-positive cell among 10⁵ unaffected cells thus omitting time-consuming blotting procedures. The whole analytical procedure starting from RNA isolation to agarose gel electrophoresis including two rounds of PCR can be performed in less than six hours.Supported by the Wilhelm Sander-Stiftung, Neustadt/Donau and the Deutsche Krebsgesellschaft, Landesverband Berlin     

Mitoxantrone in the treatment of acute myelogenous leukemia: a review

Mitoxantrone is an intravenous anthracenedione structurally related to the anthracycline antibiotics. This drug has been used for several years in the treatment of acute myelogenous leukemia (AML). Its use has been based on its pharmacological properties, its incomplete cross-resistance with other intercalating agents, and its better tolerance as predicted by preclinical studies. Various treatment schedules, using mitoxantrone alone and in combination with other anti-leukemic agents, have been used in clinical trials. Complete remission (CR) rates ranged from 14 to 44% in refractory AML and from 46 to 79% in relapsed patients. Although a superiority of mitoxantrone over anthracyclines has not been clearly demonstrated in newly diagnosed patients, mitoxantrone is now recognized as a useful drug in first line therapy. The tolerability profile of mitoxantrone indicates that it offers patients an acceptable quality of life compared with standard treatment regimens, and could be a good alternative to the anthracyclines. The development of new therapeutic concepts aiming at an optimization of its use is now in process and first results are promising.     

Impact of pre-induction therapy leukapheresis on treatment outcome in adult acute myelogenous leukemia presenting with hyperleukocytosis

9 /l were scheduled to undergo leukapheresis. This represented 53 patients (median age 59 years, range 16–78 years) who underwent from 1 to 4 sets of leukapheresis (median 1). The median initial WBC count was 160×10⁹/l (range 100–480×10⁹/l). Morphologic subtypes, according to the French–American–British classification, showed 3 M0, 16 M1, 6 M2, 10 M4, 16 M5, and 2 unclassified cases of AML. In 21 patients (40%), leukapheresis did not reduce their WBC counts significantly, while 32 patients (60%) achieved a WBC count of less than 100×10⁹/l (median 71×10⁹/l) after leukapheresis. Analysis of cell cycle was performed on bone marrow (BM) and peripheral blood leukemic cells before and after leukapheresis in three cases. In two of those cases, a recruitment of BM leukemic cells in the S phase was observed after leukapheresis. The median WBC count at the time of starting chemotherapy was 85×10⁹/l (range 23–264×10⁹/l). Complete remission was achieved in 55% (95% confidence interval 40–68%). Early death occurred in two cases. Median disease-free survival was 10 months, while median overall survival was 8 months. In this study, early death rate is lower than data previously published in the literature and almost all patients could receive chemotherapy. This might suggest a benefit of initial leukapheresis in the treatment of AML presenting with hyperleukocytosis. Received: 23 November 1999 / Accepted: 8 March 2000     

老年急性髓系白血病个体化治疗探讨

目的:探讨老年急性髓系白血病(AML)个体化治疗方案。方法:对我院1994~2005年收治老年AML患者(≥60岁)77例进行回顾性分析。根据化疗剂量将患者分为A(亚标准剂量)、B(减量化疗)及C(支持化疗)3组,并对3组的临床特征和治疗效果进行比较。结果:可评价患者A组45例,B组9例,C组9例。A组CR率高于B组(P<0.05),分别为53.3%和44.4%;平均生存期显著延长(P<0.05),分别为258、195d。但白细胞化疗后最低值A组要明显低于B组(分别为0.8×109/L,4.5×109/L),骨髓抑制时间明显延长(分别为19,13d),不良反应发生率明显增高(分别为97.8%,77.8%)。C组患者平均生存期231d,生存期与其他2组均差异无统计学意义(均P>0.05),但平均住院日明显缩短(P<0.05)。结论:老年AML对化疗反应差,缓解率低,生存期短,治疗方案宜个体化。     

Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial

Following a dose-escalation study performed to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection combined with chemotherapy, a phase II trial (EMA 2000 regimen) was performed in patients with refractory or relapsed acute myelogenous leukemia (AML) between October 2000 and December 2003. Sixty-two patients entered the study and received mitoxantrone 45 mg/m² on day 1 in combination with cytarabine and etoposide. Overall, 39 patients (63%) achieved complete remission (CR). Four patients died during remission induction, and 19 patients had resistant disease. Median time to granulocyte and platelet recovery was 34 and 39 days, respectively. The predominant non-hematologic toxicity was infection, with 53% severe infections. Thirty-three of the 39 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 17 patients, allogeneic stem cell transplantation (SCT) in 7 patients, and autologous SCT in 9 patients. The median overall survival of the entire cohort was 8.1 months, with 18% at 2.5 years. EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of high-risk AML. CR proportion was significantly higher in patients with a first CR duration 6 months when compared with those from a control trial using standard-dose mitoxantrone (90 vs 70%, p=0.03).     

复发AL多药耐药基因的检测与预后关系

目的：探讨复发急性白血病多药耐药性（ＭＤＲ）的产生与化疗疗效及生存期的关系。方法：通过对３９例复发型急性白血病细胞膜上Ｐ－１７０糖蛋白含量的检测，运用ＰＣＲ技术，判断ＭＤＲ结果，观察结果与化疗疗效及生存期的关系。结果：ＭＤＲ阴性组ＣＲ率、平均生存期均明显优于阳性组。结论：该项检测结果对临床合理制订化疗方案有较好的参考价值，为预后的判断提供了重要依据。     

Neutropenic enterocolitis: a serious complication during the treatment of acute leukemias

Neutropenic enterocolitis (NE) is a severe gastrointestinal complication in patients who undergo aggressive chemotherapy. It is a necrotizing inflammation of the cecum, colon, and the terminal part of the ileum. The serious clinical state of NE patients requires very frequent surgical consultations; however, in a few particular cases of NE, e.g., perforation of the bowels, a surgical intervention is necessary. Here, we report on six cases of NE in patients with acute leukemias. The patients were all women aged 21–55 years. Two of them had acute myeloid leukemia and four had lymphoblastic leukemia. NE occurred 7–10 days after the completion of chemotherapy, during the neutropenic phase. They represented a typical picture of NE: two of them died because of septic shock; five patients had subileus with irritation of the peritoneum; and one had hepatosplenic abscesses confirmed 6 months later by post-mortem examination. In each case, a surgical opinion was required. None of these patients were operated on. We present a report summarizing our experience and problems with six patients who had a clinical picture of NE and offer a short review of the current literature on the subject.     

High-dose cytosine arabinoside and idarubicin treatment of chronic myeloid leukemia in myeloid blast crisis

Chronic myeloid leukemia in myeloid blast crisis (CML-MBC) is highly resistant to standard induction chemotherapy regimens. Anecdotal results from previous clinical trials support the concept of dose escalation in patients with CML-MBC. Eight patients with CML-MBC were treated with cytosine arabinoside (Ara-C) 1.5-3.0 g/m2 intravenously over 1 hr every 12 hr for 12 doses and idarubicin 12 mg/m2 intravenously daily for 3 days. Sixteen previous reports describing the use of Ara-C-based chemotherapy regimens in patients with CML-MBC were also reviewed. Our patients' median age was 62 years (range, 42-69 years). One patient achieved complete hematologic remission (95% confidence interval, 0.3%, 53%). The median survival for our patients was 7.3 months. These results were not different from previous published reports using Ara-C-based chemotherapy regimens to treat CML-MBC. In summary, the combination of high-dose Ara-C and idarubicin did not improve the overall prognosis of patients with CML-MBC. Innovative approaches need to be explored for this patient population.     

羟基脲加干扰素治疗原发性血小板增多症的临床疗效研究

目的 :观察羟基脲加干扰素治疗原发性血小板增多症 (PT)的临床疗效。方法 :根据有无临床症状 ,将 38例PT患者分为有临床症状组及无临床症状组 ,根据用药情况再将 38例PT患者分为单用化疗组 (羟基脲0 .5 qd～0 .5tid ,加高三尖杉 )、α干扰素组 (上述化疗加α干扰素 3× 10 6IU qod～biw)和γ干扰素组 (上述化疗加γ干扰素 (1～ 3)× 10 6IUqd～qod)。 结果 :有临床症状组的患者发病时外周血血小板计数明显高于无临床症状组 (P <0 .0 1)。单用化疗组、α干扰素组与γ干扰素组疗效相似 ,总有效率分别为 91.7%、80 .0 %和 10 0 % (P >0 .0 5 )。三组治疗前后血小板计数分别为 (1137.0 0± 5 5 6 .5 0 )vs(74 4 .5 0± 4 84 .4 3)× 10 9/L、(114 6 .0 0± 32 5 .5 0 )vs(44 3.81± 2 13.0 2 )× 10 9/L和 (10 6 9.0 0± 2 4 3.70 )vs(44 0 .6 4± 14 1.72 )× 10 9/L。本研究中给予α干扰素无效的 2例患者改用γ干扰素 ,结果 1例取得缓解 ,1例进步。结论 :对于高危患者 ,若经济条件有限 ,可给予羟基脲、高三尖杉并抗栓胶囊等治疗 ,该治疗方法疗效明确 ,费用较低 ,副作用较少。对于α干扰素疗效欠佳的患者 ,可以考虑改用γ干扰素     

Bone marrow transplantation or chemotherapy as post-remission treatment of adult acute myelogenous leukemia

Summary We compared three consolidation regimens in patients with acute myelogenous leukemia in first remission. Thirty-four patients received only intensive consolidation chemotherapy (SIC); 28 patients were scheduled to undergo an autologous bone marrow transplant (auto-BMT) and 44 patients an allogeneic BMT (allo-BMT). Twenty-seven of them were referred in first remission for allo-BMT. Nineteen patients achieved a complete remission after salvage treatment. All other patients obtained a remission after one or two courses of a standard combination of cytosine arabinoside and daunorubicin. Except for the patients who were referred in remission, all patients received intermediate dose cytosine arabinoside and amsacrine as a first consolidation treatment. The median ages of the three groups were 48 (SIC), 39 (auto-BMT) and 33 years (allo-BMT). Two patients relapsed before auto-BMT and 1 before allo-BMT. The median interval from the date of complete remission to the auto- or allo-BMT was 3 months. In total, 80% of the patients of the SIC group relapsed, compared to 50% of the patients belonging to the auto-BMT group and 35% of the 44 patients who were scheduled to receive an allo-BMT. The overall median disease-free survival was 14 months, 30% of the patients being alive and disease-free at 3 years. The disease-free survival rate at three years was 25% for the SIC group, 30% for the allo-BMT group and 40% for the ABMT group (P=0.45). Our study shows no benefit for bone marrow transplantation over intensive consolidation treatment. However, large randomized trials are required to define the real value of these treatment modalities.     

High-dose recombinant interleukin-2 and acute myeloid leukemias in relapse

Interleukin-2 (IL-2) is able to induce the regression of metastatic cancers when administered in vivo. IL-2-activated natural killer cells and lymphocytes show, in vitro, activities against leukemic cells. To assess if in vitro observations could have significant clinical relevance, we evaluated the in vivo activity of high-dose recombinant IL-2 (6 to 8 x 10(6) IU/m2/8H intravenous bolus for 5 days) in 10 patients with acute myeloid leukemias (AML) in relapse after chemotherapy (n = 7) or autologous bone marrow transplantation (n = 3). Two patients achieved a complete remission and one had a minimal improvement in his marrow blast cells. Response was observed after one cycle of IL-2 in the two patients achieving a complete remission. These two patients relapsed at 3 and 4 months. These results showing clinical activity of high-dose recombinant IL-2 in AML invite further evaluation of this new form of immunotherapy in other clinical situations, like an adjuvant setting for selected groups of high-risk patients.     

A phase I/II study of recombinant interferon alpha 2a and hydroxyurea for chronic myelocytic leukemia

Summary Nine previously untreated patients with Philadelphia chromosome-positive chronic myelocytic leukemia (CML) were treated with recombinant interferon alpha 2a (rIFN-alpha 2a) and hydroxyurea. Patients received 6×10⁶ U rIFN-alpha 2a daily for the first week and 3×10⁶ U rIFN-alpha 2a daily for the second week. As maintenance treatment starting on day 15, patients received 3×10⁶ U rIFN-alpha 2 a 3 times a week. Simultaneously, hydroxyurea was given, starting at a dose of 40 mg/kg on day one. The maintenance dosage was adjusted to the white blood cell count. Two patients responded with complete hematological remissions but without cytogenetic and molecular-genetic improvements. Seven patients responded with partial hematological remissions. Response to therapy was rapid; normal white blood cell counts were reached after a median of 12 days. The doses of rIFN-alpha 2a and hydroxyurea needed to keep the leucocyte count in the normal range were low (3×10⁶ U rIFN-alpha 2a 3 times per week, 0.5–1.5 g hydroxyurea/day). Acute toxicity of the combination therapy consisted of fever (9 of 9 patients), flulike symptoms (7 of 9 patients), pruritus and/or rash (3 of 9 patients) and evidence of a tumor cell lysis syndrome (1 of 9 patients). The side effects were not dose-limiting. Combination therapy with rIFN-alpha 2a and hydroxyurea for CML is well tolerated and allows quick and effective hematological control of the disease.     

Randomized study on the treatment of chronic myeloid leukemia (CML) in chronic phase with busulfan versus hydroxyurea versus interferon-alpha

Summary For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.