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.