Salvage chemotherapy with mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in relapsing and refractory lymphoma.

PURPOSE: The aim of the study was to evaluate the feasibility and efficacy of the combination of mitoxantrone, fludarabine, cytarabine, and cisplatin (MIFAP) in patients with prognostically unfavorable recurrent and refractory Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). METHODS: Forty-six patients (median age 43 years, range 18-63) with relapsed (n = 15) or refractory (n = 31) malignant lymphoma were enrolled (HD, n = 13; low-grade/transformed NHL, n = 4; high-grade NHL, n = 29). A total of 39 patients (85%) showed multiply relapsed diseases with a duration of prior remission of < 12 months (n = 8) or had lymphoma being resistant to prior chemotherapy (n = 31). The MIFAP therapy consisted of fludarabine (15 mg/m2, q. 12 h, day 1-4), cytarabine (50 mg/m2 by continuous infusion (CI) over 22 h, day 1-4), cisplatin (25 or 30 mg/m2 by CI over 24 h, day 1-4), and mitoxantrone (4 mg/m2, day 2-5). RESULTS: Thirteen patients (28%) achieved complete remission (CR) and 15 patients (33%) partial remission (PR), for an overall response (OR) rate of 61%. Twenty-two patients responding to MIFAP (10 CR, 12 PR) have been consolidated by high-dose therapy (HDT) with hematopoietic stem cell transplantation (SCT). After a median follow-up of 12 months, 16 patients are in continuous CR (CCR) (n = 14) or CCRu (unconfirmed) (n = 2). The median duration of event-free survival (EFS) and overall survival (OS) were 6.5 and 19.3 months, respectively. Probabilities of EFS and OS after 3 years were 19% and 40%. Responders consolidated by subsequent HDT showed rates for 3-year EFS and OS of 40% and 66%, respectively. Unfavorable prognostic factors for EFS by univariate analysis were refractory lymphoma and the presence of B-symptoms. Significant prognostic factors for OS were NHL, refractory lymphoma, B-symptoms, and bone marrow involvement. The major toxicities were leukocytopenia and thrombocytopenia of the World Health Organization (WHO) grade IV in nearly all courses (median duration 10 and 11 days). In contrast, non-hematological side effects were moderate, predominantly of WHO grades I and II. Treatment-related mortality with MIFAP was 4% (two patients with septicemia by Aspergillus fumigatus). CONCLUSIONS: MIFAP is an effective salvage protocol for patients with poor-risk recurrent or refractory HD and NHL. The observed toxicity seems to be acceptable considering the unfavorable prognosis and intensive pretreatment. The results in patients responding to MIFAP and afterwards undergoing HDT with autologous stem cell support are even comparable to those published in patients with prognostically more favorable diseases.

2-Acetylaminofluorene-produced selective cytotoxic damage of a ductal compartment and its repair in the submandibular gland of rats.

Salivary glands of rodents are rarely affected with spontaneous and induced malignancies. This may be linked with low physiologic cell renewal and the infrequency of cytolethal actions by xenobiotics. The genotoxic 2-acetylaminofluorene, carcinogenic for other organs, causes acute damage in salivary ducts. In the submandibular glands the damage is limited to the granulated convoluted tubules. They produce and release regulatory peptides including epidermal growth factor and nerve growth factor. The partial chemical sialoadenectomy is repaired by sequential cell proliferation in the basal cell layer of interlobular ducts and in dilated intralobular ducts (day 4 and 6), in intermediate duct-like structures (day 6 and 8), and lastly in acini (day 8 and 12). This is associated with a transient loss of structural characteristics of striated ducts and acini (up to day 6) and of the immunoreactivity for S-100 protein (up to day 4). Actin immunoreactivity at the acinar base is increased from day 6 to 20. Analogous to the late postnatal differentiation of the granulated convoluted tubules, their structural characteristics and immunoreactivity for epidermal growth factor do not recover within 20 days. The acute lesion of the endocrine ductal segment is suggested to be causally involved with other systemic effects following treatment with 2-acetylaminofluorene. First, hypophagia with loss of body, liver and thymus weight may result from disturbed saliva production. Second, previous studies have shown a mitotic burst of the biliary epithelium and bloodborne lymphocyte-stimulating activities. Either effect could be brought about by regulatory peptides (see above), probably after elevated circulatory release from necrotic granulated convoluted tubules.

Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia.

BACKGROUND: This study was performed to examine the feasibility and toxicity of the combination of mitoxantrone, fludarabine, cytarabine as bolus (B) or continuous infusion (CI) and granulocyte- colony stimulating factor (G-CSF) in patients with recurrent and refractory acute myeloid leukemia (AML). PATIENTS AND METHODS: 29 patients with relapsed (n =17) or refractory (n =12) AML were treated with the Mito-FLAG protocol consisting of mitoxantrone (7 mg/m(2), days 1/3/5), fludarabine (15mg/m(2), every 12 h, days 1-5), cytarabine (Ara-C) as bolus infusion (1000 mg/m(2) over 1 h, every 12 h, days 1-5) (n =15) or as continuous infusion (100-150 mg/m(2) over 24 h, days 1-5) (n =14), and G-CSF (5 mgr;g/ kg/day, day 0 until a neutrophile count of 0.5 x10(9)/l). RESULTS: 17 patients (59%) and 1 patient (3%) achieved complete remission (CR) and partial remission (PR), respectively; thus the overall response rate was 62%. Following Mito-FLAG, 5 patients with CR underwent high-dose therapy (HDT) with allogeneic (n = 2) or autologous (n = 3) stem cell transplantation (SCT). With a median follow-up of 28 (range 6-54) months, 4 transplanted patients are alive in CR (n = 2) or in relapse (n = 2). The median duration of event-free survival (EFS) and overall survival (OS) was 3.2 and 6.8 months, and probabilities of EFS and OS after 1 year were 14 and 34%, respectively. The 1-year rates for EFS and OS in this group were 18 and 53%, respectively. Median duration of WHO grade 4 granulocytopenia and thrombocytopenia was 20 and 23 days, respectively. Nonhematological side effects were moderate, predominantly reaching WHO grades 1-2. Neutropenic fever was seen in 85% of courses, with a median duration of 4 (1-38) days. Four patients (14%) suffered an early death because of aplasia (n = 2), pneumonia (n =1) or progressive AML (1 nonresponding patient). CONCLUSIONS: Our data suggest that the Mito-FLAG protocol is feasible and can be safely performed with both schedules of Ara-C. In this study the regimens have shown high efficacy and acceptable toxicity in patients with relapsed or refractory AML. We currently examine the importance of bolus versus continuous infusion of Ara-C as part of the Mito-FLAG regimen in a prospective randomized multicenter trial.