A phase I/II study of oral etoposide and idarubicin in elderly patients with high-risk acute myeloid leukemia unable to undergo intensive chemotherapy

Acute myeloid leukemia (AML) is a disease of mostly elderly patients who are often unable to undergo intensive intravenous chemotherapy. In an attempt to provide an all-oral regimen suitable for palliative treatment, we assessed the antileukemic efficacy of combination therapy of idarubicin 20 mg/m² (days 1, 3, and 5) and etoposide (EI) in increasing doses (75–125 mg/m²) on days 1–5. Eleven patients were included (median age 69 years, range: 56–77) with prognostically unfavorable characteristics (myelodysplastic syndrome, relapse, or unfavorable karyotypes). No complete remission and five partial remissions were observed whereas four patients had persistent leukemia. There were two patients who succumbed to early death. Median overall survival was 100 days (range: 8–493 days). Nonhematological toxicities were acceptable with nausea/vomiting being the predominant side effect. Hematological toxicity with grade III/IV aplasia was seen in all patients. In this study EI did not show convincing antileukemic efficacy and was unable to induce clinically useful complete remissions, with a substantial risk profile. In contrast to the situation of elderly patients with standard-risk AML in which similar oral treatment has shown promising activity, EI cannot be recommended for elderly patients with high-risk AML.     

伊达比星在初治急性淋巴细胞白血病高危组患儿联合化疗中的使用和疗效观察

目的：观察长春新碱（VCR）和左旋门冬酰胺酶（L-asp）联合伊达比星（IDA）的VILD方案在治疗初治急性淋巴细胞白血病高危组患儿（HR-ALL）的效果。方法：回顾分析2005年2月-2013年4月在本院接受化疗的初治急性淋巴细胞白血病高危组患儿,33例使用VILD方案强化化疗,15例使用长春新碱和左旋门冬酰胺酶联合表柔比星（Epi）的VDLD方案强化化疗,比较两组的无事件生存期（EFS）和5年无事件生存率。结果：VILD方案治疗组和VDLD方案治疗组的EFS分别为（80.98±5.36）个月和（52.06±9.10）个月,5年无事件生存率为（83.3±7.0）%和（52.5±13.1）%（P=0.029）。结论：VILD方案治疗急性淋巴细胞白血病高危组患儿疗效优于VDLD方案。     

Etoposide, 6-thioguanine and idarubicin, an oral combination regimen (ETI) for the induction treatment of acute leukemia

Twenty patients with advanced acute leukemia (16 acute myeloid leukemia (AML), three myeloid blast crisis (BC) of chronic myeloid leukemia (CML), one acute lymphatic leukemia) were treated with a peroral regimen consisting of etoposide 80 mg/m2 and 6-thioguanine 100 mg/m2 twice daily for 5 days, and idarubicin 15 mg/m2 once daily for 3 days (ETI). Two AML patients were in first relapse. All the other patients with acute leukemia had a later relapse or were refractory to primary or salvage treatment. One to six ETI cycles were given. Four AML patients achieved remission and one patient with BC of CML entered the second chronic phase. Clearing of the blood of leukemic cells was seen in seven additional patients. Infection was the most common complication, gastrointestinal toxicity was not a major problem. In conclusion, peroral ETI treatment has a marked antileukemic effect even in an advanced disease, and the toxicity is moderate and well acceptable.     

Oral Idarubicin in Elderly Acute Leukemia and Myelodyplastic Syndromes

During the last five years, a new anthracycline 4:demethoxy daunorubicin or ldarubicin (IDR) has been found to be useful as an antileukemic agent. IDR is less cardiotoxic and has unequivocal biological activity when administered orally. Therefore, the choice of this oral agent to treat elderly acute non-lymphoid leukemias (ANLL) or myelodysplastic syndromes (MDS) on an out-patient basis is attractive for obvious reasons. In this review we summarize the pharmacological characteristics of IDR, its use in the treatment off acute leukemia, and results reported until now in the literature and our sown results using oral IDR in elderly ANLL and MDS patients. IDR given orally at a total dose of 30 mg/m² to 90 mg/m² induced complete and partial overall responses, in approximately 50% of elderly ANLL and MDS. These results are comparable to those obtained in the same age category using low dose ARA-C, but with less drug toxicity for the patients.

We believe that IDP given orally may be used as an additional tool in the conservative approach in elderly ANLL and MDS, which is a problematic category of patients to treat aggressively with combination intravenous chemotherapy.     

Transport Mechanisms of Idarubicin, an Anthracycline Derivative, in Human Leukemia HL60 Cells and Mononuclear Cells, and Comparison with Those of Its Analogs

Transport mechanisms of idaruhicin (IDA) in HL60 cells, as leukemia cells, and human mononuclear cells (MNCs), as normal cells, were investigated, and compared with those of its analogs. The uptake of IDA by both cell types was temperature- and concentration-dependent, was inhibited competitively by daunorubicin (DNR) and noncompetitively by adriamycin (ADR), and was stimulated by preloading of the cells with DNR and ADR, indicating the partial involvement of a carrier-mediated mechanism. On pretreatment of the cells with 2,4-dinitrophenol, IDA uptake by HL60 cells increased, but that by MNCs decreased, suggesting that IDA was partially taken up into HL60 cells via an energy-independent carrier system, and into MNCs via an energy-dependent one. We speculated that in HL60 cells the carrier concerned with IDA uptake was common to DNR and ADR, and that the binding site of IDA on the carrier was the same as that for DNR, but not that for ADR, while in MNCs the carrier system consisted of, at least in part, a carrier for DNR uptake and one for ADR uptake, and the binding site of IDA was identical to that for DNR in the former, but different from that for ADR in the latter. It appeared that the uptake of IDA was greater than those of pirarubicin, DNR and ADR in both HL60 cells and MNCs, and that IDA was incorporated into MNCs more efficiently than into HL60 cells because of the higher uptake efficacy of the carrier(s).     

Oligonucleotide Enhanced Cytotoxicity of Idarubicin for Lymphoma Cells

Oligonucleotides offer the potential to manipulate gene expression in targeted cells which might be exploitable for therapeutic benefit. The effects of combining a phosphorothioate oligonucleotide OL(1) p53, which transiently down-regulates p53 levels, with an anthracycline, Idarubicin, on the growth of wild-type p53 WMN gene-expressing lymphoma cells was evaluated. Fluorescent OL(1) p53, was used to demonstrate oligonucleotide uptake and retention by the WMN cells. Uptake was maximal at 24 hours and compared to baseline (0 hours) increasing apoptotic cells were evident in WMN cells treated with OL(1) (1 μM) alone and in combination with Idarubicin (0.2 nM) for 24 to 48 hours. In cells treated with OL(1) p53 and Idarubicin, truncated p53 message of a predicted 201 base pair length based on RNAase H cleavage of the OL(1) p53-p53 mRNA heteroduplex was detected after 7 hours of incubation. The message for p53 was transiently downregulated as detected by RT-PCR analysis at 24 hours, and protein levels transiently reduced at 36 hours, as shown by a quantitative Western blot. Corresponding to these events, the growth of WMN cells ceased after 48 hours in the concurrent presence of OL(1) p53 and Idarubicin and, the lymphoma cells were dead after 72 hours. No reduction in hematopoietic colony forming cell capacity of similarly treated hematopoietic progenitor cells harvested from cytokine-mobilized blood by apheresis was observed. Therefore, synergistic cytotoxicity of Idarubicin for lymphoma cells treated with an oligonucleotide targeting p53 message was demonstrated at oligonucleotide and Idarubicin concentrations which were minimally toxic to hematopoietic progenitor cells. This approach offers new opportunities for purging of lymphoma cells from hematopoietic harvests and systemic lymphoma therapy.     

国产去甲氧基柔红霉素治疗白血病的安全性

目的 探讨国产去甲氧基柔红霉素（IDA）治疗急性白血病的安全性。方法 采用随机、对照、单肓的方法,155例急性白血病患者随机分入国产IDA（试验组）和进口IDA组（对照组）,急性髓系白血病（AML）采用IDA8mg／m^2,d1～3;阿糖胞苷100mg／m^2,d1～7;急性淋巴细胞白血病（ALL）IDA8mg／m^2,d1～3;长春新碱2mg／m^2,d1;环磷酰胺750mg／m^2,d1;强的松60mg／m^2,d1～14,1～2个疗程。结果 试验组和对照组的总体有效率比较,差异无统计学意义（P〉0．05）。试验组和对照组出现Ⅲ～Ⅳ级骨髓抑制的发生率分别为74．0％和73．1％,两组差异无统计学意义（P=0．73）。试验组相关死亡率为3．9％（3／77）,死亡原因为脑出血和败血症。试验组和对照组的非血液学毒性发生率依次为恶心或呕吐84．4％和79.5％,感染70．1％和71.8％,口腔炎42.9％和41．0％,脱发33．8％和33.3％,转氨酶升高28.6％和28．2％,心脏毒性16．9％和10．3％,后者主要为轻度心律失常,两组差异无统计学意义（P〉0.05）,无因非血液学毒性停止化疗的患者。结论 国产IDA联合化疗治疗急性白血病的毒性反应主要为血液学毒性,应在治疗过程中对患者密切观察和积极治疗．非血液学毒性可耐受。     

去甲氧柔红霉素治疗急性白血病的临床疗效观察

目的 观察和比较去甲氧柔红霉素治疗急性的初治、复发以及难治性白血病的临床疗效.方法34例急性白血病应用去甲氧柔红霉素辅以其它药物的联合化疗,分为初治组、复发组和难治组三组进行疗效观察比较.结果总有效率达70.6%,初治组与复发组疗效比较有显著性差异(P<0.05),初治组与难治组比较疗效有显著性差异(P<0.01).结论 去甲氧柔红霉素是一种新型、有效的治疗急性白血病的药物.     

Idarubicin monotherapy in multiply pretreated leukemia patients: response in relation to P-glycoprotein expression

 The aim of the study was to test whether fractionated (weekly) idarubicin administration to multiply pretreated leukemia patients is effective and tolerable for outpatient treatment, and whether idarubicin alone can overcome P-glycoprotein (P-gp)-related resistance. P-gp was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. P-gp expression was characterized as a percentage of P-gp-positive blasts. Additionally, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test in combination with or without verapamil and expressed as the R123 accumulation ratio. Fractionated idarubicin (12 mg/m²/week) was given to 36 acute myelogenous leukemia (AML) patients, 12 acute lymphoblastic leukemia (ALL) patients, and eight chronic myelogenous leukemia (CML) patients in blast crisis. Furthermore, 11 AML and four ALL patients were treated with fractionated daunorubicin at a dose of 50 mg/m²/week. All patients had been pretreated with drugs inducing P-gp-related resistance including daunorubicin and/or doxorubicin or vindesine (CML patients). Of 71 pretreated patients, 51 (72%) had a P-gp value between 25 and 98%. Six of these patients with increased P-gp expression had a nonpumping P-gp; four of them were CD34 positive. Of 51 patients with increased P-gp expression, 30 (59%) were CD34 positive. With regard to idarubicin monotherapy, overall response was 33/56 (59%) patients, and 23/33 (70%) responding patients showed a P-gp expression between 25 and 95%. All idarubicin-responding patients with high P-gp expression before treatment showed a clear reduction of P-gp-positive blasts. No patients with P-gp expression between 34 and 85% treated with fractionated daunorubicin showed response or reduction of P-gp-positive blasts in bone marrow. This study demonstrates that P-gp-related resistance can be overcome in multiply pretreated leukemia patients with idarubicin alone, and that the protocol used here is tolerable for outpatient treatment. Received: 1 October 1996 / Accepted: 27 November 1996