Impact of first- and second-line treatment for Hodgkin's lymphoma on the incidence of AML/MDS and NHL--experience of the German Hodgkin's Lymphoma Study Group analyzed by a parametric model of carcinogenesis.

BACKGROUND: Using a parametric carcinogenesis model, we disentangle the superimposing effects of primary and relapse therapies of Hodgkin's disease on secondary neoplasias. PATIENTS AND METHODS: We analyze eight randomized trials of the German Hodgkin's lymphoma study group [5357 individuals, 67 secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) and 97 secondary non-Hodgkin's lymphoma (NHL)]. Primary therapies were divided into four groups: radiotherapy alone, moderately dosed COPP/ABVD-like chemotherapies for intermediate and advanced stages and BEACOPP escalated. RESULTS: For secondary AML/MDS, the hazards after primary therapies are proportional (maximum at 3.4 years), while the hazard after relapse therapy is more peaked (maximum at 1.8 years). Intermediate and advanced stage chemotherapy resulted in a cumulative risk of 1.5%, while the risk after BEACOPP escalated is higher (4.4%, P = 0.004) and comparable with that after relapse therapy (4.5%). For secondary NHL, there are no differences in cumulative risk between the primary therapies (2.9%), while the risk after relapse therapy is increased (6.6%, P = 0.002). CONCLUSIONS: BEACOPP escalated moderately increases the risk of secondary AML/MDS but not NHL. No differences were found between other chemotherapies of advanced stages and intermediate stages. Secondary AML/MDS occurs faster after relapse treatment than after primary treatment.

Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte.

PURPOSE: To evaluate prospectively in patients with follicular lymphoma and a low tumor burden three therapeutic options: delay of any treatment until clinically meaningful progression, immediate treatment with an oral alkylating agent, or treatment with a biologic response modifier, interferon alfa-2b. PATIENTS AND METHODS: Newly diagnosed follicular lymphoma patients with a low tumor burden (n = 193) were randomly assigned to one of three arms: arm 1, no initial treatment (n = 66); arm 2, prednimustine 200 mg/m2/d for 5 days per month for 18 months (n = 64); or arm 3, interferon alfa 5 MU/d for 3 months then 5 MU three times per week for 15 months (n = 63). Clinical characteristics were similar in the three arms. RESULTS: Overall response rates with prednimustine and interferon alfa were 78% and 70%, respectively. The overall response to therapy, when deferred, was similar at 70%. With a median follow-up duration of 45 months after randomization, the median freedom-from-treatment (FFT) interval was 24 months in arm 1 and the interval of freedom from treatment failure (FFTF) was 40 months in arm 2 and 35 months in arm 3. The median overall survival time was not reached and the overall survival rate at 5 years was 78% in arm 1, 70% in arm 2, and 84% in arm 3. Therefore, deferred treatment does not adversely influence survival at 5 years. Patients who progressed within 1 year had a significantly shorter survival duration (median, 48 months). CONCLUSION: Delayed treatment is feasible in patients with follicular lymphoma and a low tumor burden. For patients with early progression, more intensive therapy should be considered. For others, because delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment, the long-term toxicity of alkylating agents can be reduced.

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.

Treatment of patients with high-grade non-Hodgkin's lymphoma aged over 70 years with an all-oral regimen combining idarubicin, etoposide and alkylators.

In elderly patients age-specific comorbidity often reduces the possibility of administering intensive chemotherapy and of obtaining response to treatment. Therefore, chemotherapy must differ from that for non-elderly patients, while maintaining the primary goal of a complete clinical response. We treated 19 patients over the age of 70 years (median age 75 years, range 70-86) with stage II-IV high-grade non-Hodgkin's lymphoma (NHL) with a combination regimen including idarubicin plus etoposide and prednimustine (or chlorambucil+prednisone), all administered orally on an outpatient basis. The therapeutic schedule included six 5-day courses of idarubicin 20 mg/sqm on day 1 (or 10 mg/sqm on days 1 and 3 in the nine patients last treated), etoposide 60 mg/sqm/12 h days 2-5, prednimustine 60 mg/sqm days 2-5, G-CSF 300 microg/day from day+7 until PMN>1000/microl. In ten patients prednimustine was replaced by chlorambucil 10 mg/sqm, days 2-5, and prednisone 50 mg days 2-5, because of non-availability of the drug. Of the 19 patients submitted to this regimen 15 (79%) obtained a clinical response: eight reached a complete response (CR), and seven a partial response (PR). Hematologic toxicity was generally mild. Only three patients had to be hospitalised for infection. Except alopecia, non-hematologic toxicities were negligible. At a median follow-up of 16 months, five of eight patients who obtained CR relapsed (median CR duration 7 months). The actuarial median survival is 34 months (range 6-46). This study demonstrates the feasibility and efficacy of an all-oral regimen including idarubicin, plus etoposide and prednimustine (or chlorambucil+prednisone) in NHL patients aged over 70 years.

Combination of oral idarubicin and prednimustine in advanced breast cancer: a phase II study.

The aim of this study was to assess the efficacy and toxicity of an idarubicin-prednimustine combination in advanced breast cancer. 19 patients received idarubicin 35 mg/m2 day 1 and prednimustine 100 mg/m2 days 2-6, every 21 days. Three objective responses with a median duration of 7 months were observed. Tolerance was good. A further 23 patients were given idarubicin administered at 15 mg/m2 days 1, 2 and 3 and prednimustine at the aforementioned dosage. 8 (35%) showed an objective response (4 CRs, 4 PRs) with a median duration of 6 months. No severe toxicity was observed. Results suggest activity of idarubicin-prednimustine combinations in advanced breast cancer, and further studies are indicated since this regimen is easily administered, especially to elderly patients.

Prednimustine in refractory non-Hodgkin's lymphoma: a phase II study of the Northern California Oncology Group.

Fifty-six patients with advanced non-Hodgkin's lymphoma (NHL) were entered into a phase II study of prednimustine, an ester of chlorambucil and prednisolone. All patients were refractory to extensive prior combination chemotherapy. Therapy with prednimustine, 100 mg/m2/day orally, was given for three consecutive days every 2 weeks. The overall response rate in 43 evaluable patients was 30% (13/43), with 9% (4/43) achieving complete response (CR) and 21% (9/43) achieving partial response (PR). In the favorable histology subgroup (23 patients), the response rate was 39% (9/23), with 4% (1/23) achieving CR and 35% (8/23) achieving PR. In the unfavorable histology subgroup (20 patients), responses were seen in 20% (4/20) with 15% (3/20) achieving CR, all in heavily pretreated diffuse histiocytic lymphoma. Toxicity of this regimen was mild, with leukopenia below 3,000/mm3 in 22% and thrombocytopenia below 90,000/mm3 in 16% of patients. A positive correlation was observed between response and hematologic toxicity, indicating the potential for a dose-escalation schedule in future trials. These data confirm activity of prednimustine in NHL refractory to standard treatment. In view of its relatively mild toxicity, we conclude that prednimustine is an appropriate agent to test in combination chemotherapy regimens in this group of lymphomas.

Prednimustine in advanced breast cancer: a review.

This review summarizes the available data of phase II and phase III single-agent trials with predminustine and one phase II trial of prednimustine in combination with methotrexate, 5-fluorouracil, and tamoxifen in the treatment of advanced breast cancer. The data available so far indicate that the drug is more active than in combined treatment with the two components, chlorambucil and prednisolone. Future trials should be designed to analyze whether this could be ascribed to a sustained release of the components from the parent drug. The data also indicate that prednimustine is as active but less toxic than cyclophosphamide, but this needs to be confirmed in ongoing randomized comparisons. A number of phase II and phase III trials with prednimustine as a part of combinations are in progress. Mature results from these studies are needed to define the future role of prednimustine in the systemic therapy of breast cancer.

Prednimustine v cyclophosphamide-vincristine-prednisolone in the treatment of non-Hodgkin's lymphoma with favorable histopathology: results of a national cancer care program in Sweden.

In a nationwide multicenter study, single-agent treatment with prednimustine (PM) was compared with combination chemotherapy with CVP (cyclophosphamide, vincristine, and prednisolone) in patients with stage III-IV non-Hodgkin's lymphoma (NHL) with favorable histology (Rappaport groups nodular lymphocytic poorly differentiated, nodular mixed, and diffuse lymphocytic poorly and well-differentiated). From January 1979 to May 1982, 217 evaluable patients were randomized, and at present analysis, the median follow-up time is 42 months. Overall response rate in the PM group was 63% (complete, 40%; partial, 23%) compared with 66% in the CVP group (complete, 32%; partial, 34%). There was no significant difference in relapse-free survival (RFS) or survival between the two groups, median RFS being 30 months and median survival being 42 months, respectively. Reclassification of the lymphomas according to the Kiel system (possible in 80%) revealed high-grade malignant NHL in 22 patients (12 in PM group, 10 in CVP group). Within this small group, there was a marked difference in survival in favor of CVP-treated patients. However, treatment with PM was less toxic and better tolerated than the CVP regimen. It was concluded that for patients with low-grade malignant NHL treatment with PM is equally effective and less toxic than the CVP regimen.

Third-line salvage chemotherapy in Hodgkin's disease.

CEP (CCNU, etoposide, and prednimustine) was tested as third-line chemotherapy in 40 patients resistant to both MOPP and ABVD. The observed response rate (complete remission, 35%, and partial remission, 25%) is encouraging. Treatment was generally well tolerated and all acute side effects were reversible.

CCNU, etoposide, and prednimustine (CEP) in refractory Hodgkin's disease.

Starting in February 1980, 58 patients with Hodgkin's disease refractory to both MOPP and ABVD received as third-line chemotherapy a combination of CCNU or lomustine, etoposide, and prednimustine (CEP). Complete response (CR) was achieved in 40% of cases and partial response (PR) in 14%. The median duration of CR was greater than 15 months, and the median survival of complete responders was longer than 24 months. In addition, CEP alternating with ABVD was given to 21 patients refractory to MOPP chemotherapy. In this series, CR was documented in 67% of patients with a median duration of 24+ months and a median survival of 36+ months. Treatment was generally well tolerated, and all acute side effects were reversible. Present findings indicate that CEP is an effective regimen in patients refractory to MOPP and ABVD.

Combined cytotoxic and endocrine treatment of postmenopausal patients with advanced breast cancer: preliminary results of a phase II study of the combination of prednimustine, novantrone, methotrexate, 5-fluorouracil, and tamoxifen.

Postmenopausal patients with advanced measurable and/or evaluable breast cancer entered a phase II trial of multiple agent cytotoxic therapy combined with endocrine therapy. Cycles of PNMF (prednimustine, novantrone, methotrexate, and 5-fluorouracil) were repeated every 4 weeks as follows: P, 100 mg/m2 PO on days 1 to 5; M, 40 mg/m2 IV on day 1; F, 600 mg/m2 IV on day 1, and N, 14 mg/m2 IV on day 8. The endocrine therapy was tamoxifen given continuously, 10 mg three times daily. As of May 1985, 32 eligible patients had entered the study, 20 of whom had been treated for a sufficient time to enable evaluation of response. Ten patients responded (one complete, nine partial), five experienced no change, and five patients experienced progressive disease. The treatment regimen was fairly well tolerated, the dose-limiting factor being the hematologic toxicity. Conclusions from the trial must await the inclusion of more patients and longer time of follow-up.

Phase II trial of prednimustine (NSC-134087) in the treatment of small-cell anaplastic carcinoma of the lung.

In a phase II trial, the clinical activity of prednimustine, an ester of chlorambucil and prednisolone, was evaluated in 28 patients with small-cell anaplastic carcinoma of the lung. Prednimustine was given at dose levels ranging from 130 to 220 mg/m2/daily for 5 days every 3 weeks. Among 19 previously treated patients no responses were observed, while responses of 2, 2, and 3 months' duration were seen in three of nine previously untreated patients more than 70 years old. The toxicity took the form of mental disturbances in six patients, while the hematologic toxicity was mild. The therapeutic effectiveness of prednimustine in small-cell carcinoma of the lung is thus limited although some activity is observed in previously untreated patients.

Prednimustine in adult acute myeloid leukaemia.

In 23 patients with acute myeloid leukaemia (AML) and over the age of 64, four remissions (17%) were obtained with Prednimustine as a single drug. The daily dose was 24--60 mg orally. In 14 patients aged between 35 and 64 years who were treated with Prednimustine 60--80 mg daily and vincristine 2.25 mg i.v. every 7--10 days, six remissions were obtained (43%). Upon remission, patients were given ,0--40 mg of Prednimustine daily as maintenance therapy. Drug-induced pancytopenia preceding remission was not recorded in any patient. There were no side effects of major importance during maintenance therapy, and the median duration of remission was 8 months. It is concluded that the low toxicity of Prednimustine in normal bone marrow cells is of value, especially in elderly patients with AML.

A phase II study of prednimustine in acute non-lymphocytic leukemia, smouldering leukemia, and refractory anemia with excess blasts.

Prednimustine, an ester of chlorambucil and prednisolone, was evaluated for efficacy and toxicity in a selected group of leukemia patients with a poor prognosis. Disease subsets consisted of patients with acute non-lymphocytic leukemia (ANLL) over age 60; ANLL refractory to standard therapy; smouldering leukemia; and refractory anemia with excess blasts (RAEB). In agreement with previous studies, toxicity from Prednimustine was relatively mild, consisting primarily of infrequent myelosuppression, gastrointestinal side-effects, and mild hyperglycemia. This study did not, however, confirm previously reported remission rates in ANLL: in 41 evaluable patients only two complete remissions were achieved. Both occurred in the subset of patients with smouldering leukemia. We conclude that Prednimustine has limited activity in this patient population.

Mitozantrone and prednimustine in the treatment of advanced breast cancer--a toxic regimen with low activity.

The combination of mitozantrone and prednimustine has been reported to elicit response rates of around 50% in patients with advanced breast cancer. In the present trial, either three or nine courses of this combination were given to previously untreated patients with advanced breast cancer. Mitozantrone was given at 12 mg/m2 on day 1 and prednimustine was given orally at 130 mg/m2 on days 1-5; treatment was repeated every 4 weeks. A total of 34 patients were treated; the performance status was 0-1 in 29 subjects and 2 in 5 cases. Locoregional disease only was present in 13 patients; 9 showed lung involvement; 8, liver; 3, bone; and 1, stomach involvement. A total of 10 subjects had received no prior hormone therapy. The median disease-free interval from the time of initial diagnosis was 24 months (range, 0-144 months). In all 14/23 patients exhibited an oestrogen receptor level of greater than 20 fmol. Grade 1 nausea and vomiting occurred in 16 patients and that of grade 2-3, in 11 subjects; nausea was prolonged for greater than 10 days in 7 cases. Grade 4 neutropenia occurred in 2 patients. The response rate was 21% (95% confidence interval, 8%-38%). The combination of mitozantrone and oral prednimustine is toxic and displays low activity.

Prednimustine and vincristine compared with cytosine arabinoside and thioguanine for treatment of elderly patients with acute nonlymphoblastic leukemia.

Sixty-seven patients with acute nonlymphoblastic leukemia (ANLL) and above the age of 60 years were randomly allocated to treatment with either prednimustine + vincristine or cycles with cytosine arabinoside and thioguanine. Of the 67 patients, 13 (19%) entered a complete remission and four a partial remission. Of 33 patients randomized to prednimustine and vincristine (15 adequately treated), three entered a complete remission and one a partial remission. Four further patients went into complete remission after a switch to other treatment modalities. Of 34 patients randomized to cycles of ARA-C and thioguanine (22 adequately treated), four entered a complete remission and three a partial remission with the correct program. One patient entered a remission with intermittent cytosine arabinoside + thioguanine (wrong program) and one further patient entered a complete remission after a switch to prednimustine and vincristine. Prednimustine + vincristine did not appear to be superior to treatment with cytosine arabinoside thioguanine cycles for elderly patients with ANLL.

Randomised trial comparing prednimustine with combination chemotherapy in advanced ovarian carcinoma.

A total of 76 patients with advanced epithelial ovarian carcinoma were randomised to receive 6 months of treatment with either a combination of hexamethylmelamine, 5-fluorouracil, cisplatin and prednimustine or prednimustine alone following initial surgery. Pathologically confirmed response rates were 35% for combination chemotherapy and 28% for prednimustine, and the overall survival was identical for the two groups. Seven patients achieved a pathologically defined complete response, one of whom relapsed at 8 months; the others remain disease-free 18-36 months (median, 23 months) after presentation. The extent of initial surgery significantly affected the survival of patients receiving prednimustine but not of those receiving combination chemotherapy. Prednimustine can produce durable responses in advanced ovarian cancer using a schedule that results in negligible toxicity.

Prednimustine combined with mitoxantrone and 5-fluorouracil for first and second-line chemotherapy in advanced breast cancer.

A total of 60 patients with advanced breast cancer were treated with a combination of prednimustine (P: 110 mg/m2, days 1-5), mitoxantrone (M: 12 mg/m2, day 1) and 5-fluorouracil (F: 500 mg/m2, day 1) (PMF). Treatment was repeated every 3 weeks. In all 53 patients were evaluable for response. A total of 12 subjects had failed prior chemotherapy for metastatic disease. In response to PMF treatment we observed 21 partial remissions and 3 complete remissions, amounting to a total response rate of 45%. The median duration of response was 39 weeks, and median survival was 56 weeks. Dose-limiting side effects were leukopenia (40 cases) and thrombocytopenia (11 patients). Nausea and vomiting was experienced by 93% of subjects; in 56% of cases it reached WHO stage II-III. Alopecia occurred in 18% of our patients. Our results suggest that PMF represents an active regimen in the treatment of advanced breast cancer and yields a response rate of 45%. Considering that the majority of our patients had not received prior chemotherapy, the question remains open as to whether a 45% response rate outweighs the observed toxicity.

Does long-term application of granulocyte colony-stimulating factor adversely influence overall survival in patients with ovarian cancer? A clinical study.

The purpose of this study was to investigate the effect of long-term administration of G-CSF with regard to its impact on overall survival of patients with ovarian cancer. We report the results of a non-randomized trial on 64 patients with advanced ovarian cancer treated with 6 cycles of conventional chemotherapy. Chemotherapy comprised carboplatin 400 mg/m2 and epirubicin 70 mg/m2 on day 1 of each cycle and prednimustine 100 mg/m2 on days 3 to 7, every 28 days. Thirty-three patients received CEP chemotherapy with G-CSF support whereas 31 women received CEP chemotherapy alone. The schedule of G-CSF was 5 mg/kg/day subcutanously on days 8 to 21 of each cycle. The severity of reduction in white cells and neutrophil count was significantly different in the two treatment groups (p<0.05), with more toxicity in the non- G-CSF group. G-CSF users had a non significant 0.88-fold lower risk of dying from ovarian cancer (95% CI, 0.48-1.60, p=0.678). In a survival analysis using a Cox proportional hazards model, residual tumor remained as an independent prognostic factor. The increasing amount of residual tumor resulted in a 1.767-fold higher risk (95% CI, 1.23-2.53, p=0.002) of death secondary to the underlying disease. In conclusion, this trial has failed to demonstrate any negative impact on patients' overall survival for the additional use of G-CSF with platinum-based chemotherapy; our results were consistent with the beneficial effects of G-CSF treatment on cytotoxic chemotherapy-induced myelosuppression.

[Treatment of advanced stage Hodgkin disease with CCNU, etoposide and prednimustine (CEP)]. / Elörehaladott stádiumú Hodgkin-kóros betegek kezelése CCNU, etoposide és prednimustine (CEP) terápiával.

The authors treated 21 advanced, pretreated Hodgkin's disease patients with CEP (CCNU, etoposide, prednimustine) polychemotherapy between March 1988 and February 1993. Complete remission was achieved in 4 patients, partial remission in 8 patients, while 9 patients were unresponsive to treatment. None of the complete responders relapsed during the follow-up period, and the median duration of remission was 24 months. The median survival for the unresponsive and partially responsive patients was less than half a year. Side-effects included gastrointestinal symptoms, myelosuppression and alopecia, but treatment-related deaths did not occur. The present data confirm the favourable impact of CEP polychemotherapy on pretreated, advanced Hodgkin's disease patients.