Induction of a graft-versus-leukemia reaction by cyclosporin A withdrawal as immunotherapy for leukemia relapsing after allogeneic bone marrow transplantation.

We studied the immunomodulating effect of withdrawal of immunosuppression with cyclosporin A (CsA) in 42 patients with leukemic relapse of chronic myelogenous leukemia (CML) (n = 24), acute myeloid leukemia (AML) (n = 13) and acute lymphoblastic leukemia (ALL) (n = 5) after allogeneic unmanipulated bone marrow (BMT) or peripheral blood stem cell transplantation (PBSCT). Response to CsA withdrawal was monitored molecularly by the polymerase chain reaction for elimination of CML cells containing the bcr-abl messenger RNA (mRNA) transcript (n = 24), or mll-af4 mRNA transcript characteristic of leukemic cells with a 11q23 chromosomal abnormality (n = 1). Rapid tapering of CsA resulted in subsequent achievement of cytogenetic remission in 11 of 14 CML patients (79%) who relapsed in early disease phase (n = 9 cytogenetic relapse, n = 2 hematological relapse) after a median of 57 days. Three of 13 AML patients and one of five ALL patients achieved complete remission. CsA withdrawal was accompanied by the development of acute graft-versus-host disease (GVHD) grade II in most of the 24 patients with CML. Two patients who achieved remission of AML or ALL died from severe GVHD grade III-IV. We calculated a probability of 84% for achieving and remaining in remission with early relapse of CML 4 years after relapse post BMT, whereas patients with AML have only a probability of about 10% of achieving and remaining in remission after 3 years. Patients with advanced CML and ALL had no chance of achieving and remaining in remission in the same time period.

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.

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.

alpha Interferon maintenance therapy in patients with low-grade non-Hodgkin's lymphomas after cytoreductive chemotherapy with prednimustine and mitoxantrone.

A combination of prednimustine 100 mg/m2/day orally, days 1-5, and mitoxantrone 8 mg/m2/day intravenously, days 1 and 2, was administered to 19 patients with advanced low-grade non-Hodgkin's lymphoma after failure on or relapse after standard chemotherapy. The prednimustine and mitoxantrone (PmM) regimen was repeated every 4-6 weeks to a maximum of six cycles. Thirteen patients, achieving a complete (4) or partial (9) remission (CR or PR), received two additional courses for consolidation followed by interferon alfa-2b 5 million units (MU) subcutaneously (s.c.) three times weekly until progression or relapse. At the present time, remission duration ranges from 4.5+ to 17.5+ months, with a median of 14.5 months. In a historical comparison to unmaintained first remission preceding the PmM/interferon trial, a tendency towards a longer period of freedom from progression was apparent in the 13 patients receiving interferon maintenance treatment during their second PR or CR. These data provided the basis for a currently ongoing multicentre study randomly comparing initial chemotherapy with PmM versus cyclophosphamide/vincristine (Oncovin)/prednisone (COP) in patients with advanced centroblastic-centrocytic and centrocytic non-Hodgkin's lymphomas, followed by a second randomization in CR and PR patients for maintenance with alpha interferon versus observation only.

Treatment of low-grade non-Hodgkin's lymphoma by cytoreductive chemotherapy with prednimustine/mitoxantrone followed by interferon alpha-2b maintenance: results of a clinical phase II study.

In a clinical phase II study, the antitumor activity of the recently introduced combination of prednimustine and mitoxantrone (PmM) was evaluated in 17 patients with advanced low-grade non-Hodgkin's lymphoma after failure with or relapse after standard chemotherapy. The PmM regimen consisted of prednimustine 100 mg/m2/d orally on days 1 to 5, and mitoxantrone 8 mg/m2/d intravenously on days 1 and 2, giving a total dose of 16 mg/m2. Treatment was repeated every 4 to 6 weeks to a maximum of 6 cycles. Patients achieving complete remission (CR) or partial remission (PR) received two additional courses for consolidation, followed by interferon (IFN) alpha-2b 5 x 10(6) U subcutaneously three times a week until progression or relapse. Twelve of the 17 patients (71%) responded (CR, 4 and PR, 8). Side effects consisted mainly of neutropenia, which required dose reduction in 48% of treatment cycles. All 12 responders subsequently received IFN alpha-2b maintenance treatment. At present, remission duration ranges from 4.5+ to 17.5+ months (median 14.5 months). In comparison to unmaintained first remission prior to receiving PmM/IFN alpha-2b, a clear tendency towards a longer period of freedom from progression emerged in the 12 patients receiving IFN alpha-2b maintenance treatment during a second PR or CR. These data indicate a high antitumor activity of PmM in low-grade non-Hodgkin's lymphoma and suggest a beneficial effect of IFN alpha-2b maintenance. Present findings, however, will require confirmation in future investigations.