Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine.

The treatment of older patients with acute myeloid leukemia (AML) remains unsatisfactory, with complete remission (CR) achieved in only approximately 50% and long-term disease-free survival in 10% to 20%. Three hundred eighty-eight patients (60 years of age and older) with newly diagnosed de novo AML were randomly assigned to receive placebo (P) or granulocyte-macrophage colony-stimulating factor (GM-CSF) or GM in a double-blind manner, beginning 1 day after the completion of 3 days of daunorubicin and 7 days of cytarabine therapy. No differences were found in the rates of leukemic regrowth, CR, or infectious complications in either arm. Of 205 patients who achieved CR, 169 were medically well and were randomized to receive cytarabine alone or a combination of cytarabine and mitoxantrone. With a median follow-up of 7.7 years, the median disease-free survival times were 11 months and 10 months for those randomized to cytarabine or cytarabine/mitoxantrone, respectively. Rates of relapse, excluding deaths in CR, were 77% for cytarabine and 82% for cytarabine/mitoxantrone. Induction randomization had no effect on leukemic relapse rate or remission duration in either postremission arm. Because cytarabine/mitoxantrone was more toxic and no more effective than cytarabine, it was concluded that this higher-dose therapy had no benefit in the postremission management of older patients with de novo AML. These results suggest the need to develop novel therapeutic strategies for these patients. (Blood. 2001;98:548-553)

Cemp, a mitoxantrone containing combination, in the treatment of intermediate and high grade non-hodgkin's lymphoma: an effective and non toxic therapeutic alternative for adult and elderly patients.

Here we report the results of a randomised multicenter phase III clinical trial which assesses the therapeutic efficacy and tolerability of a chemotherapy protocol CEMP (cyclophosphamide, etoposide, mitoxantrone and prednisone) in adult and elderly patients with advanced intermediate and high-grade NHL. Between October 1991 and October 1995, 139 patients, aged 55 to 79 years, with diffuse intermediate and high-grade lymphoma, were enrolled. A considerable percentage of patients had clinically aggressive disease: 32.4% had systemic symptoms, 79% had stage III or IV disease, 33.8% had bone marrow involvement, 46% had splenic involvement and 42.5% had increased values of serum lactate dehydrogenate. Complete remission was achieved in 70 of the 139 patients (51.9%) and PR in 12 (16.6%) with an overall response of 68.5%. The overall response survival rate at 6 years was 39%, whereas DFS rate was 48.7% and PFS rate was 28.5%. At four years 49% of the patients were still in CR. Dividing the patients in two groups, under and over 65 years of age, we obtained the same results as far as overall response is concerned. No toxic deaths occurred, neither cardiac, renal nor liver complications happened. CEMP regimen is an effective and safe protocol with good results in elderly people, well comparable to those achieved in younger ones.

High remission rate in acute myeloblastic leukemia with only two days of chemotherapy.

Twenty five patients with AML who had neither a history of toxic exposure or myelodysplasia were treated with a remission induction regimen consisting of two pulses of chemotherapy separated by 96 hrs. Each pulse consisted of cytarabine 2gm/m(2) (at t=0 and t=12 hrs) with mitoxantrone [30mg/m(2) ] administered immediately after the second cytarabine administration. Amifostine was administered three times a week [on Monday, Wednesday, and Friday] until the outcome of therapy was known. This regimen induced complete remissions in 15 of 17 patients less than 70 years of age and in 5 of 8 patients older than 70 years.

Dose escalation of mitoxantrone given with thiotepa and autologous bone marrow transplantation for metastatic breast cancer.

High-dose chemotherapy given with autologous bone marrow support has resulted in significant tumor responses in the majority of patients with metastatic breast cancer, a minority of which are durable. To improve on these results, we are developing high-dose preparative regimens which may be given in successive cycles, each with autologous bone marrow transplantation (ABMT), over a short duration. In this report, 44 patients with metastatic breast cancer were treated with thiotepa (total dose: 900 mg/m2) and mitoxantrone (MT), administered in a dose-escalation fashion, with ABMT. The dose-limiting non-hematologic toxicity of mitoxantrone was cardiotoxicity, with the maximum tolerated dose being 50 mg/m2 Mucositis and pneumonia were also frequent treatment-related side-effects. The overall tumor response rate was 49% in this heavily pre-treated group of patients. We are currently evaluating the toxicity and efficacy of tandem non-cross-resistant transplant regimens, using the MT combination for the second cycle of therapy, in patients with metastatic breast cancer sensitive to standard dose chemotherapy.

Twin-track studies of ifosfamide and mitoxantrone (I-M) in recurrent high grade non-Hodgkin's lymphoma and Hodgkin's disease. Yorkshire Regional Lymphoma and Central Lymphoma Groups.

Fifty-seven patients, initially diagnosed as having advanced high grade non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) refractory to first-line treatment or in relapse, were treated with ifosfamide 6 g/m2, infused over 48 h, followed by mitoxantrone 12 mg/m2. The regimen repeated at three-weekly intervals. Of 33 patients with NHL evaluable for response, 10 (30 per cent) achieved complete remission and six partial remission, giving an overall response rate of 48 per cent. Two patients subsequently went on to bone marrow transplant (BMT)--one allogeneic and the other autologous. Of 18 patients with HD evaluable for response, seven (39 per cent) achieved complete remission and six partial remission, giving an overall response rate of 72 per cent. Two of this group also went on to BMT (both autografts). The principal toxicity was neutropenia, though central nervous system changes were observed in 10 patients. The possibility of increasing the safety of the regimen by increasing the time of infusion to 72 h is discussed. Given the need to offer alternative treatment to patients in these categories, this combination (I-M) is of value in relapsed patients, especially where options are limited because of previous multi-drug treatment. Remissions may not be prolonged but allow the effective application of additional intensive treatment including bone marrow transplantation.

Phase I-II evaluation of intravesical novantrone (mitoxantrone) in superficial bladder cancer.

The objective of this study was to determine the safety and efficacy of intravesical novantrone in refractory superficial bladder cancer. The eligibility criteria included proven carcinoma in situ or superficial transitional cell carcinoma of the bladder at stage Ta or T1 that was proven refractory to or in relapse after the use of at least one other standard anti-cancer agent. The patient was to have received no prior radiotherapy or intravesical therapy for at least 4 weeks prior to entry. Patients also did not suffer significant cardiac dysfunction, such as angina, congestive heart failure, or uncompensated cardiomyopathy. All patients were given 4-6 doses of intravesical novantrone at the same dose level at weekly dosing interval. Patients were required to retain the drugs in the bladder for 2 h. Baseline study included history/physical, hematology, blood chemistry, cystoscopy, bladder barbotage, urine cytology, cystometrogram to assess the bladder capacity, and finally, chest X-ray, EKG, and MUGA scan, if indicated. Weekly assessment involved toxicity notation, blood chemistry, hematology and urinalysis. Monthly assessment included physical examination, toxicity notation, hematology, urinalysis and blood chemistry. Within 4 weeks of completion of the last dose, patients underwent repeat cystoscopy to assess disease status. Patients who responded to the 4-6 week induction phase were entered in a monthly dose regimen for up to 5 months. A total of 23 patients were enrolled: 22 males and 1 female. One patient dropped out before receiving medication because of a protocol violation for entry criteria. Twenty-two patients were eligible for assessment of safety and 20 were eligible for assessment of efficacy.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of a sensitive monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) for mitozantrone.

A mouse monoclonal antibody (NO-1) with specificity for the anti-cancer drug mitozantrone (MZ) (Novantrone) was produced by immunization of a BALB/c mouse with mitozantrone-keyhole limpet haemocyanin (MZ-KLH) conjugate. When used in an indirect competitive enzyme-linked immunosorbent assay (ELISA), NO-1 permitted the accurate and reproducible detection of between 0.25-50 ng/ml of MZ in pooled human serum, the standard curve obtained within this range being virtually linear. The assay demonstrated good reproducibility with intra-assay coefficients of variation (CV) of between 1.41% and 7.02% and an inter-assay CV of 3.45%. Regression analysis of levels of MZ detected by ELISA vs. the actual amounts added to pooled human serum gave a very good correlation coefficient of r = 0.995. NO-1 showed no cross-reactivity with either bisantrene or daunorubicin. A simple pharmacokinetic study was undertaken in rabbits given MZ intravenously at a dose of 0.5 mg/kg of body weight. Levels of MZ in rabbit serum measured with the assay ranged between 82 and 170 ng/ml for rabbits 1 and 2, respectively at 15 min falling to 1.25 ng/ml by 48 h for rabbit 1 and falling to undetectable levels by 120 h for rabbit 2.