Mitoxantrone as first-line chemotherapy in advanced breast cancer: results of a collaborative European study

Summary Mitoxantrone (Novantrone^®; dihydroxyanthracenedione) is a substituted anthraquinone with a spectrum of activity similar to doxorubicin in experimental tumors.One hundred and seventy three patients with advanced breast cancer and no prior cytotoxic therapy for advanced disease entered a phase II study of mitoxantrone, 14 mg/m² i.v. repeated every 3 weeks. At the time of this analysis 116 patients were evaluable. Eight patients achieved a complete response and 27 a partial response, the overall response rate being 30% (95% confidence limits: 22–39%). The median time until response was recorded was 15 weeks. The median duration of response was 74+ weeks and the median time to progression or death for all 116 patients was 22+ weeks.Mitoxantrone was well tolerated with myelosuppression as the dose-limiting toxicity. The most frequent non-haematological toxicities were nausea and vomiting (65%) but they were rarely severe. Total alopecia occurred in only 6% of the patients. Four patients developed clinically significant evidence of cardiotoxicity after cumulative mitoxantrone doses of 174–256 mg/m².Thus, mitoxantrone offers comparable efficacy and less acute toxicity than the most active single agents currently available in the treatment of advanced breast cancer.     

Mitoxantrone in the treatment of relapsed and refractory acute leukemia

Summary Twenty-four patients with acute leukemia or blast crisis (BC) of chronic myelocytic leukemia (CML) in relapse or refractory to standard chemotherapy, were eligible for treatment with mitoxantrone. Mitoxantrone (Novantrone®; dihydroxyanthracenedione) was administered in a dose of 8–13 mg/m² on five consecutive days. Five of 20 evaluable patients were induced into complete remission, one patient achieved a partial remission. Side-effects included moderate to severe bone marrow suppression, moderate mucositis and hair loss. No cardiotoxicity was observed. We believe that mitoxantrone is an active agent in the treatment of acute leukemia and suggest further studies in combination chemotherapy.     

Sequential studies on the role of mitoxantrone in the treatment of acute leukaemia

Summary Mitoxantrone (Novantrone®; 1, 4-dihydroxy-5, 8-bis [[2-[(2-hydroxyethyl) amino]ethyl]amino-] 9, 10 anthracenedione dihydrochloride (NSC 301739)) is a synthetic anthracenedione with intercalating properties. Activity has been shown in preclinical studies in mice bearing intraperitoneal P388 and L1210 leukaemias, ADJ-Pc6 plasmacytoma and a variety of solid tumours.In a phase I/II collaborative study (1) fourteen consecutive patients with relapsed or primarily refractory acute leukaemia received a single infusion of mitoxantrone (20–32 mg/m²) at fourteen-day intervals. Antileukaemic activity was seen but there were no complete remissions and toxicity was minimal. Mitoxantrone was subsequently given in a five-day schedule at a dose of 10mg/m² daily to twenty-one patients with relapsed or refractory acute leukaemia or chronic myeloid leukaemia in blast crisis (CML-BC). Four of five patients in first relapse of acute non-lymphoblastic leukaemia (ANLL) achieved a complete remission (CR). The overall response rate (CR + partial remission (PR)) was 48% (2). In an ongoing phase III study the same (5-day) mitoxantrone treatment has been given in conjunction with a 7-day continuous infusion of cytosine arabinoside (Ara-C) in a kinetically designed schedule based upon the preclinical studies of the Mount Sinai group (3).     

Mitoxantrone as a first-line treatment of advanced breast cancer

Summary Forty-two women with measurable or evaluable advanced breast cancer who had received neither prior chemotherapy for advanced disease nor any anthracycline-containing regimen as adjuvant were entered in a phase II study of mitoxantrone (Novantrone^®; dihydroxyanthracenedione). Patients were aged from 36 to 80 years, performance status was from 0 to 2. All patients had normal hematological status and normal renal and liver function tests. Cardiac scintigraphy and sonography techniques were used to monitor cardiac function. Mitoxantrone was administered at a dose of 14 mg/m² in 100 ml 5% dextrose solution over 30 minutes, repeated every three weeks.The number of courses per patient ranged from 2 to 12. Of 42 eligible patients 39 were fully evaluable for response and all for drug toxicity. Responses to treatment were: complete response four patients, partial response 10 patients, stable disease 18 patients and progressive disease seven patients. The overall response rate was 36% (95% confidence limits 20–52%). Three patients showed decreased left ventricular ejection fraction but no patient developed signs of overt left ventricular failure during the treatment period. Hematological and gastrointestinal toxicities were mild. Hair loss was minimal.The data indicate that mitoxantrone is an effective agent for the treatment of advanced breast cancer with mild side-effects, especially with respect to nausea/vomiting, hair loss and cardiotoxicity.     

A phase II study of mitoxantrone in acute leukemia

Summary A phase II study of mitoxantrone (Novantrone®; dihydroxyanthracenedione) was conducted in 35 patients (22 male: 13 female) with acute leukemia. There were 35 evaluable cases with a mean age of 34 (range 8–61). Twenty-eight patients had acute non-lymphocytic leukemia (ANLL) and seven had acute lymphocytic leukemia (ALL). Mitoxantrone was administered intravenously 2–4 mg/m² daily for five days and after the nadir a further 2–3 doses were added if necessary. All previously treated cases (22 patients) had been treated with anthracyclines; 13 had no previous treatment. Out of the 13 untreated cases there were six complete remissions (CRs) (46.2%) and five partial remissions (PRs) (38.5%), while out of 22 pretreated cases, four CRs (18.2%) and five PRs (22.7%) were obtained. In seven of the untreated cases the decrease of leukemic cells and neutrophil leukocytes were analysed. Mitoxantrone showed a longer duration of decrease and higher log decrease of leukemic cells in the bone marrow than daunorubicin or cytosine arabinoside. Seventy-three percent of patients showed gastrointestinal disturbances such as nausea or loss of appetite. In 38.1% SGPT elevation and in 8.8% abnormal ECG findings were observed. All side-effects were mild and reversible. From this data mitoxantrone seems a very promising agent in the treatment of acute leukemia and a phase III study is now being carried out.     

Mitoxantrone,etoposide, mitoguazone and vinblastine chemotherapy (MV2) in relapsed and refractory lymphomas

Summary As part of a program to develop less leukemogenic chemotherapy regimens for the treatment of favorable prognosis Hodgkin's disease, a phase I–II trial of mitoxantrone, etoposide, mitoguazone, and vinblastine was used to treat patients with relapsed and refractory malignant lymphoma and Hodgkin's disease. An over-all partial response rate of 41% was observed. Although useful responses were seen, the absence of complete remissions is disappointing.Supported in part by a grant from the Mortimer Lacher Fellowship Fund.     

A phase II trial of oral etoposide with mitoxantrone and ifosfamide/mesna consolidated with intravenous etoposide,methylprednisolone, high-dose arabinoside,and cisplatin as salvage therapy for relapsing and/or refractory lymphomas

SummaryPurpose To evaluate the response to oral Etoposide when combined with mesna, ifosfamide, and mitoxantrone in patients with relapsed and/or refractory lymphoma. To evaluate response and its duration after administration of intravenous Etoposide, methylprednisolone, high-dose cytosine arabinoside, and cisplatin (ESHAP) as consolidation therapy after complete or partial responses (CR or PR, respectively) or after crossover therapy for progressive disease.Methods Patients received MINE(o) consisting of mesna, 1.33 g/m² infused over 1 hour daily × 3 followed 4 hours later by oral mesna at 500 mg; ifosfamide, 1.33 g/m² infused over 1 hour daily × 3; mitoxantrone, 8 mg/m² intravenously on day 1, and oral VP-16, 30 mg/m² daily × 13. The ESHAP regimen consisted of intravenous VP-16, 40 mg/m² infused over 2 hours daily × 4; methylprednisolone, 500 mg intravenously daily × 4; cytosine arabinoside, 1.5 g/m² infused over 3 hours on day 4; and cisplatin, 25 mg/m² given as a continuous 24-hour infusion daily × 4. Statistical analysis was performed using the 2-stage design described by Simon. For the oral VP-16 regimen to be of interest, at least 36% patients had to achieve a complete remission.Results The overall response rate achieved with MINE(o) was 40% (15% CR, 25% PR). Seven patients with prior exposure to cytosine arabinoside and cisplatin (AP) received MINE(o) alone of whom only one achieved a response (CR). Thirteen patients without prior exposure to AP received consolidation (2 patients) or crossover (11 patients) therapy with ESHAP. Crossover therapy with ESHAP further improved the response in only two of five patients with partial response to MINE(o) and none of six patients who failed MINE(o). Median response duration for the patients who received MINE(o)/ESHAP was 12 weeks (range, 4–55 weeks).Conclusions Oral VP-16 combined with ifosfamide/mesna and mitoxantrone at the doses and schedules indicated has little activity against relapsed and/or refractory lymphomas. Crossover therapy with ESHAP did not further improve the response rate. The duration of response after MINE(o)/ESHAP was short.     

Phase I study of liposomal daunorubicin in patients with acute leukemia

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxome® DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m² on each cycle, to a total dose of 225, 300, 450, and 600 mg/m², respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3–4) in 3 of 5 patients treated at 200 mg/m², 2 of 9 treated at 150 mg/m² and 1 of 6 at 100 mg/m². Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m² and has significant anti-leukemia activity.     

米托蒽醌为主联合化疗治疗急性白血病的临床研究

目的：观察米托蒽酯治疗初治、难治和复发急性白血病35例的临床疗效和不良反应,并通过检测^170P表达探讨米托蒽醌与^170P的关系。方法：急性非淋巴细胞白血病采用MA方案,急性淋巴细胞白血病采用VMP或VMLP方案;用免疫化学ABC技术检测化疗前后骨髓细胞^170P表达。结果：初治组14例,CR8例,PR3例,有效率78．56％;难治复发组21例中,CR7例,PR5例,有效率51．14％;^170P检测发现难治性复发组中阳性率高于初治组（P＜0．01）,^170P表达阳性的12例患者经化疗后有6例达CR且^170P表达转为阴性。结论：米托蒽醌为主的联合化疗治疗初治、复发和难治急性白血病有较好的疗效,米托蒽醌对^170P表达阳性的难治和复发白血病患者也有明显的疗效。     

Phase I–II trial of mitoxantrone in acute leukemia: an interim report

Summary We evaluated the effect of mitoxantrone (Novantrone®; dihydroxyanthracenedione) in the treatment of refractory acute leukemia and acute leukemia in relapse. In this study, 70 patients are currently evaluable. Of the 25 patients who received mitoxantrone 10 mg/m² × 5, two of 10 with ANLL in relapse, one of five with ALL in relapse achieved complete remission, and one of seven with blastic phase CML responded. At a dose of 12 mg/m² × 5, nine of 22 patients with ANLL in relapse, one of five patients with blastic phase CML and none of the nine patients with ALL responded. At this dose all remissions occurred after one course of treatment. None of the patients with ANLL or ALL refractory to primary therapy achieved a remission. Toxicities encountered with both dose levels were comparable. However, second courses at 12 mg/m² × 5 led to severe stomatitis and prolonged cytopenia. We conclude that mitoxantrone is effective therapy for ANLL in relapse and that 12 mg/m² per day × 5 is the optimal dose schedule. A randomized trial comparing daunorubicin with mitoxantrone in combination with cytarabine in untreated patients with ANLL should answer whether mitoxantrone is less toxic and whether it should replace daunorubicin in standard induction therapy in ANLL.See Table 1     

A phase II study of (2″ R)-4′ -0-tetrahydropyranyladriamycin (THP) in hematological malignancies

A phase II study of new anthracycline, THP, was conducted in 46 patients with hematological malignancies in a cooperative study. THP was given intravenously either at a dose of 13–34 mg/m² for 3–5 consecutive days or 35–50 mg/m² at 3–4 week intervals.Of 21 patients with acute leukemia, complete response (CR) was observed in 3 patients and partial response (PR) in 4. Of 22 patients with malignant lymphoma, CR was observed in 2 and PR in 6.The predominant toxicity was myelosuppression. Leukopenia was noted in 73% of patients and thrombocytopenia in 14%. Anorexia, nausea and vomiting were observed in 49%, 26% and 23%, respectively. Alopecia and acute cardiac toxicities were mild and recovered quickly on discontinuation of THP.Thus, THP was found to be effective for acute leukemia and malignant lymphoma.     

Phase II trial of mitoxantrone in acute lymphocytic leukemia of childhood

Summary Thirty children with refractory acute lymphocytic leukemia (ALL) were treated with mitoxantrone, 8 mg/m²/day, for 5 days. Three children received a second course of the drug 3 to 4 weeks later. All but two patients had received prior anthracycline therapy. There were 2 complete responses, 4 early deaths, and 24 patients with persistent leukemia. Of the 21 patients with circulating blasts at the start of mitoxantrone who did not achieve remission, 16 (76%) had complete clearance of their peripheral blood blasts. Although all patients developed profound neutropenia (< 100 per mm³), mucosal and hepatic toxicities were uncommon and mild. Mitoxantrone has moderate activity in childhood ALL and should be considered for further trials in less heavily pretreated patients.     

Phase I–II trial of acivicin in adult acute leukemia

Summary Six patients with relapsed or refractory acute leukemia were treated with 9 mg/m² or 11 mg/m² of acivicin daily for seven days in a phase I–II trial. No responses were attained and further dose escalation was prohibited by neurotoxicity in 2 of 3 patients who received 11 mg/m²/day. Although acivicin appears to have limited potential as a single agent, laboratory evaluation of leukemic blasts in one patient revealed cell cycle (S-phase accumulation) and metabolic effects which suggest that acivicin may be effective as a modulator of other antileukemia agents such as cytosine arabinoside.     

Phase II study of elsamitrucin (BMY-28090) for the treatment of patients with refractory/relapsed non-Hodgkin's lymphoma

Summary Purpose: To determine the response rate of patients withrefractory/relapsed non-Hodgkin's lymphoma to treatment with elsamitrucin and to further characterize the toxic effects of elsamitrucin in this group of patients. Patients and methods: Eligibility required pathologically verified relapsed or refractory non-Hodgkin's lymphoma with no more than two prior chemotherapy regimens for patients with tumors classified by the International Working Formulation (IWF) as A-C and no more than one prior chemotherapy for those with IWF grades D-G. Patients were entered with either normal or impaired bone marrow function, but normal liver function tests were required unless clearly related to lymphomatous involvement of the liver. Elsamitrucin 25 mg/m² was administered intravenously over 5–10 minutes weekly. Results: Thirty-one patients entered the study and were treated for a median of six weeks (range 1–42). All patients were évaluable for toxicity and 30 for response. Mild nausea and/or vomiting and asthenia were the most frequently reported adverse events. Four (13%, 95% CI 4.4–31.6%) partial responses were seen along with two (7%) minor responses while 9 (30%) patients had stable disease. Conclusion: Elsamitrucin showed modest activity in patients with relapsed or refractory non-Hodgkin's lymphoma. Toxicity was relatively mild, consisted mainly of asthenia, nausea and vomiting and did not include myelosuppression. The activity of elsamitrucin in this group of patients and its lack of myelosuppression suggest utility in this disease especially when combined with other proven agents.Presented in part at the 8th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands, March 1994.     

Phase II trial of trimetrexate in untreated advanced gastric carcinoma

Summary Twenty-three evaluable patients with advanced gastric adenocarcinoma were treated with trimetrexate at doses of 8–12 mg/m² intravenously daily for five days, with cycles repeated every 21 days. One complete response was seen for an overall response rate of 4% (95% confidence interval 0–22%). Hematologie toxicities of grade 3 were seen in 10/23 patients, and overall any grade 3 or greater toxicity was seen in 14/ 23 patients. Trimetrexate has minimal activity against gastric adenocarcinoma in this study, and no further investigation of this agent at this dose and schedule is recommended in this disease.     

Phase II evaluation of didemnin B in hormonally refractory metastatic prostate cancer

Summary Didemnin B, a dipsipeptide isolated from the Caribbean tunicate Trididemnum with antitumor and antiviral activity was evaluated in a phase II trial in the treatment of metastatic, hormonally refractory adenocarcinoma of the prostate. Thirteen patients were treated with didemnin B at 3.5 mg/m² and 20 patients were treated at 6.3 mg/m² intravenously every 28 days. Response was assessed every 8 weeks. Of 32 evaluable patients there was one partial response for an overall response rate of 3% (95% confidence interval of 0.1–16%). The most common toxicities were nausea, vomiting, and diarrhea. Serious cardiac and pulmonary toxicities were also noted. This drug does not appear to warrant further evaluation in this disease as a single agent.     

以托泊替康为主治疗难治/复发性急性白血病

目的 评估托泊替康（TPT）为基础的联合方案治疗难治／复发性急性白血病（AL）的疗效和毒性反应。方法 TPT联合阿糖胞苷、安吖啶、环磷酰胺或异环磷酰胺治疗难治／复发性AL17例,均为一个疗程的挽救性化疗。结果 一个疗程化疗后完全缓解（CR）6例（35．3％）,部分缓解（PR）4例（23．5％）,总有效率58．8％;无效7例（41．2％）。该方案非造血系统毒性反应较轻,仅表现为轻度胃肠道反应及粘膜炎等。但有严重的骨髓抑制,所有的患者均予成份输血支持,14例患者出现不同程度的感染。结论 该方案治疗难治／复发性AL疗效确切,非造血系统毒性反应较轻。     

Phase I clinical and pharmacokinetic study of menogaril (7-con-O-methylnogarol) in previously treated patients with acute leukemia

Summary Fifteen patients with relapsed or refractory acute leukemia were treated in this phase I study of menogaril (7-con-O-methylnogarol), a nogalamycin anthracycline derivative. Doses ranged from 50 mg/m²/day to 130 mg/m²/day, administered daily for 5 days. Pharmacokinetic studies were performed at each dose level and confirmed the findings of pharmacokinetic data derived from previous studies in patients with solid tumors. All patients experienced grade 4 hematologic toxicity and the dose limiting toxicity was mucositis. Two patients, one with acute myeloid leukemia and one with acute lymphoid leukemia, achieved complete responses. The AML complete response lasted 10 months and the ALL patient died in CR at 2 + months. Both patients were treated at a dose of 100 mg/m²/day for five days. At this dose, a second induction or consolidation course could be given without severe mucositis, and this is the dose recommended for further phase II studies in leukemia using this schedule.     

Trimetrexate in advanced carcinoma of the esophagus

Summary Twenty-four patients with advanced epidermoid carcinoma of the esophagus were treated with trimetrexate (TMTX), a lipid soluble non-classical antifol. Patients were given TMTX 8 mg/m² intravenously day 1–5 every 28 days. In nine of these patients the dose was escalated to 12 mg/m² day 1–5 every 28 days. Three patients had a partial response (95% confidence limit 3–32%) with a median response duration of 14 weeks. No hematologic toxicity was documented. Two patients developed moderate stomatitis and only 3 patients experienced any nausea or vomiting. The median survival of all patients is 12 weeks. It is concluded that a higher dose of TMTX should be studied in patients with esophageal cancer in order to assess the true therapeutic value of the agent at a dose closer to the median tolerated dose. A phase II ECOG study using TMTX 12 mg/m² intravenously day 1–5 every 21 days is currently being conducted.     

FLAG联合米托蒽醌治疗复发急性白血病

目的探讨FLAG＋MIT方案治疗难治复发急性白血病的疗效和不良反应。方法 12例患者,年龄16～78岁,中位年龄46岁,难治病例4例,复发病例8例,福达拉宾（Flu）30mg/m230min静脉滴注第1～5天,阿糖胞苷（Ara-C）0.5-1.0g/m24h静脉滴注第1～5天（福达拉宾开始输注4h后）,粒细胞集落刺激因子G-CSF300μg/d（WBC〈1.0×10^9/L开始直到中性粒细胞绝对值〉0.5×10^9/L）,米托蒽醌（MIT）6-10mg第1～3天。结果第一疗程完全缓解（CR）9例,部分缓解（PR）1例,未缓解（NR）2例。CR中8例为急性粒细胞白血病,1例为急性淋巴细胞白血病,PR1例为AML-M4,NR2例为急性淋巴细胞白血病。主要的不良反应是骨髓抑制,发热和感染是最常见。胃肠道反应较低,各例均可耐受,按WHO分级属1-2级;2例发生静脉炎;心脏损害1例,通过支持治疗可控制,无早期死亡。结论 FLAG＋MIT对难治复发急性髓系白血病疗效较好,对部分急性淋巴细胞白血病有效,毒副作用可以耐受。