title: Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low-Grade Lymphoma Study Group.
abstract: The current study was initiated to compare the anti-lymphoma activity and side-effects of prednimustine/mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) in patients with advanced low-grade non-Hodgkin's lymphomas in way of a prospective randomized multicenter trial. Two hundred and forty-six patients with stage III or IV centroblastic-centrocytic (CB-CC (Kiel-classification)) or follicle center lymphoma (FCL (REAL classification)) and centrocytic (CC) or mantle-cell-lymphoma (MCL) were randomized for therapy with either PmM or COP and are fully evaluable for response and toxicity. PmM consisted of prednimustine 100 mg/m2/day on days 1-5 and mitoxantrone 8 mg/m2 /day days 1 and 2, while COP comprised cyclophosphamide 400 mg/m2/day on days 1-5, vincristine 1.4 mg/m2/day on day 1 and prednisone 100 mg/m2/day on days 1-5. Both regimens were repeated for a total of six cycles followed by an additional two courses for consolidation in responding cases and a subsequent second randomization for interferon alpha maintenance vs observation only. Overall response rates were comparable with 83% complete and partial remissions after COP and 84% remissions after PmM. PmM revealed a significantly higher rate of complete remissions (36 vs 18%, P < 0.006), the majority being achieved after four courses. The more rapid and possibly also more effective reduction of the lymphoma cell mass by PmM resulted in a tendency to a longer event-free interval for patients achieving remissions after PmM as compared to COP with estimated median event-free intervals of 31 vs 14 months, respectively (P=0.04). Separate analysis of lymphoma subtypes showed a tendency to a lower rate of complete remission in CC or MCL as compared to CB-CC or FCL (16 vs 30%, P=0.12, NS) while overall response rates were in a similar range (81 vs 85%). In both subtypes, PmM induced a higher rate of complete remission while overall response rates were comparable after PmM or COP. Treatment associated side-effects comprised predominantly myelosuppression and granulocytopenia in particular which was more frequently observed after PmM than COP (43 vs 31 %, P < 0.0001). This difference was clinically irrelevant, however, since serious infectious complications were encountered in less than 3% of cycles after both regimens. COP therapy was associated with a significantly higher incidence and degree of hair loss and complete alopecia (31 vs 2%) as well as of peripheral neurotoxicity (23 vs 2%). These data show that both PmM and COP reveal a high anti-lymphoma activity in patients with advanced stage non-Hodgkin's lymphoma. PmM appears advantageous with a higher rate of complete remissions and a better tolerability with regard to secondary side-effects. A longer follow-up is needed to assess the long-term effects of initial treatment on disease-free and overall survival and the impact on additional maintenance therapy with interferon alpha.
authors.affiliation: Dept of Hematology and Oncology, University of Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Unterhalt
authors.forename: R
authors.initials: R
authors.lastname: Herrmann
authors.forename: M
authors.initials: M
authors.lastname: Tiemann
authors.forename: R
authors.initials: R
authors.lastname: Parwaresch
authors.forename: H
authors.initials: H
authors.lastname: Stein
authors.forename: L
authors.initials: L
authors.lastname: Trümper
authors.forename: M
authors.initials: M
authors.lastname: Nahler
authors.forename: M
authors.initials: M
authors.lastname: Reuss-Borst
authors.forename: C
authors.initials: C
authors.lastname: Tirier
authors.forename: A
authors.initials: A
authors.lastname: Neubauer
authors.forename: M
authors.initials: M
authors.lastname: Freund
authors.forename: E D
authors.initials: ED
authors.lastname: Kreuser
authors.forename: H
authors.initials: H
authors.lastname: Dietzfelbinger
authors.forename: H
authors.initials: H
authors.lastname: Bodenstein
authors.forename: A
authors.initials: A
authors.lastname: Engert
authors.forename: R
authors.initials: R
authors.lastname: Stauder
authors.forename: H
authors.initials: H
authors.lastname: Eimermacher
authors.forename: K
authors.initials: K
authors.lastname: Landys
authors.forename: W
authors.initials: W
authors.lastname: Hiddemann
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage / Q000009:adverse effects; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects; D008775:Methylprednisolone / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D011238:Prednimustine / Q000008:administration & dosage / Q000009:adverse effects; D012074:Remission Induction; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D014750:Vincristine; D003520:Cyclophosphamide; D011238:Prednimustine; D008942:Mitoxantrone; D006854:Hydrocortisone; D008775:Methylprednisolone; D008727:Methotrexate