CCNU (lomustine), idarubicin and dexamethasone (CIDEX): an effective oral regimen for the treatment of refractory or relapsed myeloma

We report the results of a non-randomized pilot study of an oral regimen comprising CCNU (lomustine; 25 or 50 mg/m2 on day 1), idarubicin (4-demethoxydaunorubicin) (10 mg/m2 on days 1-3) and dexamethasone (10 mg b.d. on days 1-4) in patients with relapsed or refractory myeloma. Treatment was given every 28 d for a maximum of six courses. Sixty patients were entered of whom 57 were evaluable. Overall response rate (partial or minor response) was 49% with 30% of patients achieving a partial response (50% tumour reduction). Response rates were higher in patients with untested relapse than in those with refractory disease (overall response rates 56% vs. 31%). The major toxicity was neutropenia and the regimen was otherwise well tolerated. The median survival from entry of all patients was 15 months, with 30% of patients alive at 2 years. This regimen represents a useful addition to available treatment options.     

Results of treatment with an intensive induction regimen using idarubicin in combination with cytarabine and etoposide in children with acute myeloblastic leukemia

We report results achieved in our institution with a study opened in July 1990 (similar to the German AML-BFM-87 in which daunorubicin was replaced by idarubicin in the induction phase and cranial preventive radiotherapy was omitted) and closed in December 1994, for the treatment of newly diagnosed acute myeloblastic leukemia (AML), without prior malignancies except for myelodysplasia.This evaluation included 68 patients, whose mean age was 6 years (range: 1 month–16 years). Thirty-nine were boys and 29 were girls. Complete remission rate was 80.9% (55/68), death on induction rate was 14.7% and induction failure rate was 4.4%. At median follow up of 38 months (range: 12–66 months), the 4-year event-free survival (EFS) estimate was 0.428 (S.E.: 0.062), event-free interval (EFI) estimate was 0.529 (S.E.: 0.07) and overall survival (OS) estimate was 0.44 (S.E.: 0.071).We conclude that idarubicin in combination with cytarabine and etoposide is a highly effective regimen for induction in children with AML. Although preventive cranial irradiation was not delivered, we have observed only one combined CNS relapse. Finally, we corroborate that in this setting two definite risk groups may be identified in children with AML.     

Idarubicinol myelotoxicity: a comparison of in vitro data with clinical outcome in patients treated with high-dose idarubicin

We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves. We treated 16 patients with poor prognosis lymphoma in a phase I-II trial of high-dose idarubicin and melphalan and investigated if idarubicinol persisting in patients' plasma at the time of transplantation (day 0), on day +1 and +2 could result in an inhibition of infused progenitors. Colony inhibition was correlated with pharmacokinetic data and with the time of patients' engraftment. Plasma samples obtained before idarubicin treatment demonstrated a colony-stimulating effect, increasing the cloning efficiency by 72%. The inhibitory activity on colony forming unit granulocyte-macrophage (CFU-GM) of patients' plasma collected on the day of transplantation was lower than expected from dose-response curves (21% measured vs 70% expected). The time to patients' WBC and PLT recovery correlated with the amount of CD34+ cells reinfused and, to a lesser extent, with the colony-inhibiting effect of patients' plasma. The correlation between idarubicinol concentration and CFU-GM inhibition was not significant. These data suggest that plasma drug concentration on the day of stem cell reinfusion may overestimate the toxicity of residual anthracyclines to the transplanted cells.     

Cost-Effectiveness Analysis of Induction Regimens Containing Anthracyclines in Adult Acute Myelogenous Leukemia

A cost-effectiveness analysis was performed to evaluate the impact on hospital costs of two alternative regimens, idarubicin + cytarabine and daunorubicin + cytarabine, in the induction treatment of newly-diagnosed patients with acute myeloid leukemia (AML). In evaluating the economic effects the perspectives of both hospital doctors and administrators were taken into account in order to achieve better value for money spent.

For this study, the comparative results from four recently published randomized clinical studies were used as the source of clinical data. Data on the duration of hospitalization, hospital procedures and AML treatment costs were obtained from the patient records of two haematological centers.

The idarubicin induction regimen appeared to be more cost-effective than that of daunorubicin in achieving complete remission, especially when costs are linked to response rate. Although several methodological issues in terms of economic evaluation still need to be solved, this type of study might offer a social contribution to the problem of the efficient allocation of resources in the health care sector.     

A pilot study of imatinib, low-dose cytarabine and idarubicin for patients with chronic myeloid leukemia in myeloid blast phase

Imatinib is the single most effective agent in chronic myelogenous leukemia (CML) in blast phase (BP), inducing hematologic responses in 30 - 50% of patients. However, only a few of these are complete (CHR) and durable. Imatinib is synergistic with idarubicin and cytarabine. We administered imatinib 600 mg/day, cytarabine 10 mg/day subcutaneous, and idarubicin 12 mg/m² intravenous every 14 days in 19 patients with CML in myeloid BP. Fourteen patients (74%) achieved a hematologic response: CHR in 9 (47%) (3 with complete and 1 with minor cytogenetic responses) and return to chronic phase (RTC) in 5 (26%). Median duration of response was 10 weeks (range, 2 - 89). Six patients received allogeneic stem cell transplantation: 4 CHR, 1 chronic phase and 1 BP. Median survival was 5 months (range, 2 - 20 months). This outpatient regimen is effective and well tolerated and perhaps superior to single-agent imatinib for patients in myeloid BP.     

Combination chemotherapy with oral idarubicin and cyclophosphamide for metastatic breast cancer

Summary A group of 40 women with objectively measurable metastatic breast cancer was treated with idarubicin, 35 mg/m² on day 1, and cyclophosphamide, 200 mg/ m² on days 2–5, both drugs being administered orally every 3 weeks. Of 37 evaluable patients, 4 (10.8%) achieved a complete response and 14 (37.8%) a partial response, for an overall response rate of 48.6% (95% confidence interval, 37.45%–59.75%). In previously untreated patients the response rate was 58.3%, whereas it was 44% in patients previously exposed to cytotoxic drugs. The median duration of response was 6.5 months, and the median survival of all patients was 10.5 months. Moderate nausea and vomiting were common. Diarrhoea, which occurred in 37% of the patients, was usually short-lived. Alopecia was generally mild, myelosuppression was the dose-limiting toxicity. Grade 3–4 leukopenia occurred only in pretreated patients. In previously untreated patients it was generally of grade 1–2. Laboratory evidence of cardiotoxicity (20% decrease in the left-ventricular ejection fraction from the baseline value) was observed in 3 out of 26 patients, who had at least two determinations of the left-ventricular ejection fraction, and was transient in nature. No cases of congestive heart failure were observed. These results indicate that the combination of idarubicin + cyclophosphamide represents a practical and effective regimen to be used in selected patients with advanced breast cancer.Abbreviations LVEF left-ventricular ejection fraction - CR complete response - PR partial response     

Early haemorrhagic morbidity and mortality during remission induction with or without all-trans retinoic acid in acute promyelocytic leukaemia

A total of 622 consecutive patients with acute promyelocytic leukaemia (APL) treated within the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group during 1989-97 have been reviewed to assess the clinical effectiveness of all-trans retinoic acid (ATRA) on the incidence of early haemorrhagic deaths and on APL-associated coagulopathy. Of them, 499 were treated with idarubicin plus ATRA (study A) and 123 with Idarubicin alone (study B). In both studies, similar guidelines for supportive treatment were used. Haemorrhagic symptoms were evaluated according to a reproducible score system. Deaths occurring within 10 d of starting treatment were 19 (3.8%) in study A and nine (7.3%) in study B (P = 0.09), with 15 (3%) and five (4.1%) (P not significant) due to haemorrhage. Overall, induction mortality was 7.6% and 16.2% respectively (P < 0.003). In study A, days with platelet counts 30 x 109/l (P < 0.001) in both studies, and by a haemorrhagic score of 3 in study A (P < 0.001). Although the reduction of early fatal haemorrhages was not significant, a substantial clinical improvement was evident in terms of reduction of the severity of bleeding symptoms, blood product consumption and overall induction mortality when ATRA was combined with idarubicin.     

甲氨喋呤单用及与其他化疗药物联合治疗原发中枢神经系统的弥漫大B细胞淋巴瘤的疗效比较

 目的 比较伊达比星(idarubicin,IDA)、替尼泊苷(teniposide,Vm26)、利妥昔单抗(rituximab,R)分别联合甲氨喋呤(methotrexate,MTX)及单用MTX作为一线化疗方案治疗原发中枢神经系统的弥漫大B细胞淋巴瘤的疗效。方法 对2007年1月至2012年12月的原发中枢神经系统淋巴瘤患者进行回顾性研究,共纳入68例的弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma of central nervous system,CNS DLBCL)患者,收集人口学资料和临床资料。使用χ2检验、Kaplan Meier法等统计学方法,比较MTX单用及分别联合IDA、Vm26或R 4个治疗组的缓解率、总体反应率、无失败生存期等预后指标。结果 单用MTX组共20例患者,4次化疗后,7例达到了完全缓解(complete response,CR),4例部分缓解(partial response,PR),无失败生存期(failure free survival,FFS)为15个月。MTX+IDA组共22例患者,15例达到CR,2例PR,FFS为30个月。MTX+Vm26组共20例患者,10例CR,7例PR,FFS为20个月。MTX+R组共6例患者,4例CR。FFS为12个月。结论 MTX+IDA治疗CNS DLBCL患者疗效明显优于单用MTX。     

Idarubicin plus Cytarabine versus Doxorubicin plus Cytarabine in Induction Therapy for Acute Non- Lymphoid Leukaemia: A Randomized Trial

A randomized trial comparing idarubicin plus cytarabine (IDA/Ara-C) with doxorubicin plus cytarabine (ADM/Ara-C) in induction therapy for ANL,L was carried out. The IDA/Ara-C regimen consisted of idarubicin 20 mg/m² p.o. given on days 1, 2 and 3 plus cytarabine 25 mg/m² as a loading dose followed by 100 mg/m² by continuous infusion daily × 7 days. The ADM/Ara-C regimen consisted of adriamycin 30 mg/m² on days 1, 2 and 3 and the same dose of cytarabine.

Patients who responded to the first cycle with at least 502, reduction of marrow blasts received a second treatment cycle followed by a consolidation cycle of the same treatment for those in CR at the end of 2 cycles. 35/52 (6770 receiving ADM/Ara-C achieved CR, with 25 (48%) patients in CR after a single treatment cycle. 28/48 (58%) receiving ADM/Ara-C achieved CR of whom 11 (23%) went into remission after the first treatment cycle. IDA/Ara-C caused less nausea and vomiting, less stomatitis, a shorter duration of neutropenia and less need for platelet support than ADM/Ara-C. The median duration of CR is 62 weeks for IDA/Ara-C and 48 weeks for ADM/Ara.-C. These differences are not statistically significant. Clinical cardiotoxicity occurred in 4/48 patients treated with ADM/Ara-C. No clinical cardiac toxicity was observed in those receiving IDA/Ara-C. The mean post-treatment ejection fraction was, in addition, lower for ADM/Ara-C than for IDA/Ara-C. It is concluded that IDA/Ara-C is an effective and safe induction therapy for ANLL.     

Phase I study of idarubicin administered orally on a daily × 3 schedule

Summary Twenty-one adult patients with refractory solid tumors were treated on a phase I study of idarubicin (4-demethoxydaunorubicin) administered daily for 3 days every 3 weeks. Nineteen of the patients had received previous chemotherapy (including 13 with prior anthracyclines), and 12 had received prior radiotherapy. Idarubicin dose levels of 10, 15, 17.5, 20, and 25 mg/m² were explored. Hematological toxicity was dose-related. Other toxicity was acceptable. Only one patient (treated with an idarubicin dose of 17.5 mg/m²/day) developed neutropenic fever, from which he recovered. Further dose escalations beyond 25 mg/m² were not carried out because of the increasing length of time required for recovery from granulocytopenia at higher doses. No patient experienced a major response, but minor responses were seen in 3 patients with carcinomas of the colon, breast, and kidney respectively. Further phase II studies of oral idarubicin at a starting dose of 20–25 mg/m² daily times 3 days in patients with good bone marrow reserves are recommended. Because of the degree of neutropenia expected, patients would have to be observed carefully.The Ontario Cancer Treatment and Research Foundation Ottawa Regional Cancer Centre, The Ottawa University Faculty of Health Sciences and Adria Laboratories Ltd.Presented in part at the 79th Annual Meeting of the American Association for Cancer Research, New Orleans, Louisianna, May 25–28, 1988 (1)