Combined therapy in the treatment of primary mediastinal B-cell lymphoma: conventional versus escalated chemotherapy.

Treatment of patients with primary mediastinal B-cell lymphoma (PMBCL) remains controversial. We started a controlled clinical trial to evaluate the efficacy and toxicity of a conventional versus more intensive regimen of combined chemotherapy followed by radiotherapy to the mediastinum with the mantle technique. From 1989 to 1997, 68 patients diagnosed with previously untreated PMBCL, aged 18-65 years and negative for immunodeficiency virus test, were considered candidates to receive either conventional chemotherapy with CEOP-Bleo (cyclophosphamide 750 mg/m(2), vincristine 1.4 mg/m(2), prednisone 40 mg/m(2), epirubicin 70 mg/m(2), and bleomycin 10 mg/m(2)) or mega CEOP-Bleo (cyclophosphamide 1000 mg/m(2), epirubicin 120 mg/m(2), vincristine, prednisone, and bleomycin at the same doses) every 21 days for six cycles, followed by radiotherapy to the mediastinum with the mantle technique (35-45 Gy, mean 38 Gy). Complete response (CR) rates were not statistically different: 64% [95 percent confidence interval (CI): 58 percent to 70 percent] for conventional arm vs 81 percent (95 CI: 77-86 percent) in the intensive group (p=0.2). However, failure-free survival (FFS) and overall survival (OS) had statistical differences. At 5 years, actuarial FFS for patients treated with conventional chemotherapy was 51 percent (95 percent CI: 44-59 percent) compared to 70 percent (95 percent CI: 65-76 percent) in the intensive arm (p>0.01). OS rates were also different: 54 percent (95 percent CI: 48-57 percent) vs 70 percent (95 percent CI: 65-76 percent), respectively (p<0.01). Toxicity was mild and no therapy-related deaths were observed. At a median follow-up of 7.3 years, no second neoplasia or acute leukemia has been observed. The international prognostic index was not useful to define clinical risk in this selected group of patients. Multivariate analysis identified pleural and pericardial effusion and chemotherapy regimen as prognostic factors influencing FFS and OS. We feel that patients with PMBCL should be treated with more intensive, but not myeloablative chemotherapy, followed by adjuvant radiotherapy to achieve an improvement in outcome in this setting of patients. Patients with pleural or pericardial effusion are considered at high risk for failure with the actual programs of treatment and probably will be considered for experimental therapeutic approaches.

Late lethal events in patients with diffuse large B cell lymphoma: a review of 714 patients treated in a single centre.

Presence of late lethal events has been recognized as a complication in patients with malignant lymphoma. We reviewed 714 cases of patients treated during 1975-1995 with a long term follow-up (>4 years) in an attempt to identify all late events secondary to malignant lymphoma, either to the treatment or those which are unrelated. Forty-three patients died, and of these 21 (2.8%) were secondary to relapse and tumor progression; deaths associated with second neoplasm and cardiac events were increased 9.6 fold and 26.4 fold respectively compared to the general population. The risk factors for these complications did not differ from those in previous reports and included alkylating agents and/or radiotherapy for second neoplasms and anthracycline therapy and radiotherapy for cardiac toxicity. Moreover, 10 patients died secondary to non-related events. Nevertheless, at 10 years overall survival was 94% (95% confidence interval (CI): 82% to 98%) and event free survival was 97.1% (95% CI: 81% to 98%), for these patients. Thus, second events, fatal in most cases, will be considered as an expected risk in the treatment of patients with malignant lymphoma. The proposed modifications of therapy many indeed be useful to avoid or diminish these complications in the future.

Chemotherapy plus interferon-alpha2b versus chemotherapy in the treatment of follicular lymphoma.

The best treatment of follicular lymphoma remains to be determined because the long natural history of follicular lymphoma requires mature data for accurate analysis. Although the goal of primary treatment remains durable remission, the sequential application of effective treatments may also result in a prolongation of median survival time. The use of interferon (IFN) with doxorubicin-based chemotherapy has demonstrated an increase of event-free survival but not in overall survival; however, its acute and late cardiac toxicity limits its use. For this reason, we began a controlled clinical trial to assess the efficacy and toxicity of chemotherapy: COPP (cyclophosphamide, vincristine, prednisone, and procarbazine) + IFN alternating every month for six cycles compared to six cycles of chemotherapy. In an intent-to treat analysis, 55 patients were enrolled (median age 61 years). Most cases (91%) with advanced disease were randomly assigned to chemotherapy + IFN (28 cases) or chemotherapy (27 cases). Complete remission was observed in 16 patients: 59% (95% CI, 53-70%) in the chemotherapy arm compared to 20 patients 71% (95% CI, 58-79%) in the chemotherapy + IFN arm; total responses were 74% and 86%, respectively. At a median follow-up of 60 months, event-free survival was 100% for patients treated with chemotherapy + IFN, which was statistically different from patients treated with chemotherapy 70%. At 7 years, median survival has not yet been reached; 72% of patients chemotherapy + IFN remain alive without disease (95% CI, 59-81%), which is not statistically different from 72% (95%CI, 50-73%) in the chemotherapy arm. Non-hematological toxicity was most frequent and severe in the chemotherapy arm; hematological toxicity was similar in both groups. Thus, it appears that chemotherapy + IFN, as described herein, improves event-free survival but the overall survival rates remain unchanged. The use of COPP appears to be better that anthracycline-based chemotherapy because it avoids the presence of acute and late cardiac toxicity.

Evaluation on a six-dose treatment of anti CD 20 monoclonal antibody in patients with refractory follicular lymphoma.

Treatment of refractory follicular lymphoma with monoclonal antibody CD 20 has been proven to be a good therapeutic option. However, most studies used four weekly doses and time to treatment failure (TTF) and overall survival (OS) could be considered very short: 11.0 and 13.6 months respectively. We started a pilot study to evaluate if six infusions at the same doses and schedule could improve the outcome in these patients. Seventeen patients with refractory follicular lymphoma heavily treated with chemotherapy (> 2 regimens), radiotherapy and biological modifiers were enrolled in a pilot study. They received 6 weekly doses, at 375 mg/m2, of monoclonal anti CD 20. In an intent to treat analysis, overall response was 76%, of which 47% (8 patients) were complete response and 5 patients were partial response. With a median follow-up of 28.6 months, 7 complete responders remain alive, free of disease, and 2 partial responses remain stable without additional treatment. Median to TTF has not been reached; yet, actuarial curves showed that at 3 years, 53% of patients are alive. The four patients who were failure died secondary to tumor progression. Overall survival (OS) at 3-year was 76%. Toxicity was mild, all patients completed the schedule on time and doses. The addition of two doses of anti CD 20 clearly improved OS and TTF in a group of patients with refractory follicular lymphoma heavily treated and with poor prognostic factors. However, the number is too short to draw definitive conclusions; more clinical trials are necessary to determine if 4 or 6 doses of anti CD 20 therapy are better in this setting of patients.

Rituximab in the treatment of refractory follicular lymphoma -- six doses are better than four.

Seventeen patients with refractory follicular lymphoma heavily treated with chemotherapy (>2 regimens), radiotherapy, and biological modifiers were enrolled in a pilot study to receive six weekly doses, instead of the more frequent four doses, of monoclonal anti CD20, at a standard dose of 375 mg/m(2). In an intent-to-treat analysis, overall response was 76%, of which 47% (8 patients) were a complete response. With a median follow-up of 33.6 months, 7 complete responders remained alive and free of disease, and 2 partial-response patients remained stable without additional treatment. Actuarial curves showed that at 3 years, 53% of patients should be alive and free of disease. The 4 patients who were failures died secondary to tumor progression. Overall survival at 3 years was 76%. Toxicity was mild; all patients completed the schedule on time and doses. The addition of two doses of anti-CD 20 clearly improved the outcome in a group of patients with refractory follicular lymphoma heavily treated and poor prognostic factors. However, the number is too small to drawn definitive conclusions, and more clinical trials are necessary to determine if four of six doses of anti-CD20 therapy are better in this setting of patients.

Treatment of refractory Hodgkin's disease with modified Stanford V program.

This study analyzes the results using an Stanford V modified program in the treatment of refractory Hodgkin's disease (RHD). We used cyclophosphamide instead of mechloretamine, and epirubicin instead of doxorubicin to avoid the risk of acute and late side effects associated with this drugs. Seventy-one patients with RHD were treated. All were at an advanced stage at therapy and had associated adverse prognostic factors. The complete response (CR) rate was 84% (60 patients; 95% confidence interval [CI]: 72-91%). At 5 yr, actuarial overall survival (CS) is 71% (95% Cl: 59-78%) and event-free survival (EFS) is 70% (95% CI: 59-79%). Only the duration of the initial complete response (> 12 mo) influenced the duration of EFS and OS. Toxicity was mild. Granulocyte colony-stimulating factor to ameliorate the presence of severe myelosuppression was used only in a few patients. Cardiac function was not affected and, until now, late side effects has not been observed. Thus, the use of this modified Stanford program retains the usefulness of the original scheme both with less frequent and less severe acute and late side effects. A controlled clinical trial in untreated patients comparing the Stanford program with standard chemotherapy is warranted to define the role of this therapeutic option in patients with Hodgkin's disease.

Randomized Clinical Trial to Evaluate Maintenance Therapy in Diffuse Large Cell Lymphoma Treated with Intensive Chemotherapy.

Although complete response (CR) rate has been increased with the use of more intensive and in some cases myeloblative chemotherapy, long term follow-up has shown that relapse continues to be a major problem in patients with diffuse large cell lymphoma. Maintenance therapy is not considered as standard therapy in this group of patients. In our experience, the use of maintenance therapy either with low-doses of cyclophosphamide and prednisone (C/P) or interferon-α2b (IFN) improves the duration of event free survival (EFS) and overall survival (OS) in patients treated with conventional chemotherapy. The use of more intensive chemotherapy increases the CR rate, but does not effect EFS and OS. We therefore started a controlled clinical trial to assess the efficacy and toxicity of maintenance therapy with C/P or IFN in patients on CR after intensive, non myeloablative, chemotherapy. From January 1994 to December 1996; 269 patients with diffuse large cell lymphoma (defined as patients with high- or high-intermediate clinical risk) were allocated to receive C/P (200mg/m(2), po, daily, by 5 days and 50 mg/m(2), po, daily, by 5 days, respectively, every 6 weeks by 2 years) or IFN: 5 MU three times at week by 1 year compared to a control group. In an intent to treat analysis, 269 patients were eligible for study. All were evaluated for EFS and OS. The median follow-up is 49.6 months. A comparison of the three groups revealed no significant differences on EFS: 72% (95% CI: 60% to 77%) for IFN arm; 71% (95% CI: 62% to 82%) for C/P group and 74% (95% CI: 68% to 85%) in the control group (p =.8). Also OS was not different: 70% (95% CI: 59% to 79%); 68% (95% CI: 60% to 78%) and 72% (95% CI: 63% to 78%) respectively (p =.750). All patients completed the programmed schedule. Toxicity was mild. Previously we demonstrated that maintenance therapy is useful in patients with aggressive malignant lymphoma when they were treated with conventional chemotherapy. However, when more intensive chemotherapy was used to achieve CR, maintenance therapy was not useful. We do not have a convincing explanation. We believe that intensive chemotherapy may eradicate all sensitive cells to drugs, such as IFN or C/P, and for this reason improve survival was not observed. On the other hand, in patients treated with conventional chemotherapy, some residual and sensitive tumor cells must remain and maintenance therapy may eliminate this cells, with improvement in EFS and OS. Long term follow-up is necessary and for the controlled clinical trials to define the role of maintenance therapy in patients with aggressive malignant lymphoma are required.

High dose chemotherapy with G-CSF in refractory Hodgkin's disease.

This study analyzed the long-term results in patients with Hodgkin's disease (HD) who were resistant or refractory to conventional chemotherapy and who were treated with intensive, non-myeloablative chemotherapy with granulocyte colony-stimulating factor (G-CSF) as hematological support. The study population included 86 patients who were treated with combination chemotherapy with high doses: BCNU, 300 mg/m2, on day 1, vincristine 1.4 mg/m2, and bleomycin 10 mg/m2 on days 1, 7, 14 and 21; etoposide 500 mg/m2, i.v., on days 14 and 15; and ifosfamide 4 g/m2, and epirubicin 180 mg/m2, on day 29. G-CSF 5 ug/kg/day, was used to ameliorate severe myelosuppression on days 3 to 13, 16 and 26 and 29 to 38. If a complete response was observed, two cycles of IOPP (ifosfamide 1.5 g/m2, i.v., on days 1 and 8; vincristine 1.4 mg/m2, i.v. on days 1 and 8; prednisone 60 mg/m2, p.o., daily, days 1 to 14 and procarbazine 100 ng/m2, p.o., daily, days 1 to 14 vere given as consolidation therapy. At 8-years, the overall survival rate vas 58% (50 out of 86 patients) being 38 and 76% in patients whose initial complete response was shorter or longer that 12 months, respectively or in 44% of induction failures. Hematological toxicity grade III or IV was observed in all cycles. However hematological recovery was already evident (median on day 13). Only transitory delay in continuing therapy was observed (median 3.9 days). Twenty-two patients developed infection-related granulocytopenia but no therapy related deaths were observed. G-CSF was well tolerated. This study indicates that the hematopoetic growth factor, G-CSF, was sufficient to act as hematological support in patients who received intensive, but non-myeloablative chemotherapy. In our opinion intensive chemotherapy without autologous transplant procedures can be considered in patients with refractory Hodgkin's disease because complete response rate and overall survival times are similar to more aggressive but more toxic regimens.

Maintenance therapy with interferon alfa 2b in Hodgkin's disease.

We performed a randomized clinical trial to assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with advanced Hodgkin's disease in complete remission (CR) after conventional chemotherapy. One hundred and thirty-five patients (stage IIIB-IV B) were initially treated with EBVD (epirubicin, bleomycin, vinblastine, dacarbazine). IF CR was achieved they were randomly assigned to receive either maintenance therapy with IFN 5.0 MU three times a week for one year or no further treatment (control group). Clinical and laboratory characteristics at diagnosis were quite similar in both groups. After a median follow-up of 74.3 months (range 49 to 108), 61 out of 68 patients (91%; 95% confidence interval (CI): 76% to 97%) remain in first complete remission in the IFN-treated group compared to 38 out of 67 (58%; 95% CI: 49% to 71%) in the control group (p<.01). Overall survival was also better in the IFN treated group: 62 patients (92%; 95% CI: 82% to 97%) are alive free of disease at 7-years compared to 40 patients (67%, 95%: 55% to 76%) in the control group (p<.01). Toxicity secondary to IFN administration was mild and no dose modification was necessary during treatment. All patients received the planned dose of IFN. This was not an intent-to treat analysis. IFN administration as maintenance therapy was appears to be the only cause of improvement in outcome in these patients. We feel that IFN should be considered as maintenance therapy in patients with advanced Hodgkin's disease because this treatment improves the final outcome without the excessive toxicities of more aggressive therapeutic approaches such as bone marrow transplantation during first CR. We hope that IFN will be considered in future randomized clinical trials in order to define it's role in the treatment of Hodgkin's disease.

Maintenance Therapy with Interferon Alfa 2b Improves Outcome in Aggressive Malignant Lymphoma.

To assess the efficacy and toxicity of interferon alfa 2b (IFN) as maintenance therapy in patients with malignant lymphoma on complete response after conventional chemotherapy we start a randomized clinical trial. One hundred and seventy patients were randomized to received either IFN 5.0 MU three time at week by one year or no further treatment, as control group. At a median follow-up of 9.0 years (range 4.3 to 11 years) median freedom from relapse (FFR) has not been reached in patients who received IFN, it is statistically significant to patients in control group with a median FFR of 60 months (p <.001). Actuarial curves show that at 10-years, 58 patients (66%, 95% confidence interval (CI) 53% to 79%) remain in first remission, statistical different to control group 33 patients (40%, 95% Cl: 33% to 57%) (p <.001). Event free survival (EFS) shown that a 10-years 63 patients (71%, 95% CI: 59% to 81%) are alive free of disease in the IFN arm compared to only 38 patients (45%, 95% CI: 37% to 57%) in the control group (p <.001). Toxicity was mild, 81 patients received the planned doses of IFN on time and 6 patients had transitory delay secondary to hematological toxicity (grade 1 or 2) and completed the treatment on 13 months. No late side effects has been observed. After a long term follow-up we confirm that IFN used as maintenance therapy improves outcome in patients with aggressive malignant lymphoma who were in complete remission after conventional chemotherapy without excessive toxicity. We feld that IFN will be consider in controlled clinical trials to define the role of this therapeutic option.

High Dose Chemotherapy in the Treatment of Poor Prognosis Malignant Lymphoma.

UNLABELLED: The aim of the present study was to evaluate an intensive chemotherapy regimen in patients with poor prognosis malignant lymphoma. Sixty previously untreated patients with malignant lymphoma of high- or high-intermediate risk were treated with an intensive regimen. Patients received increasing doses of cyclophosphamide 1000 mg/m(2), and epirubicin 120 mg/m(2), in an CEOP-Bleo regimen with granulocyte-macrophage colony stimulating factor as hematological support. Moreover the high clinical risk patients had more adverse prognostic factors such as bulky disease, elevated levels of beta 2 microglobulin and multiple extranodal sites of involvement at diagnosis. Complete response was achieved in 49 out of 60 patients (81%) (95% confidence interval 63% to 89%). With a median follow-up of 43.6 months (ranged 31 to 61 months), only five patients have relapsed. Thus, at 5-years 72% of the patients remain in first complete response and 74% of the patients are alive free of disease. TOXICITY: severe granulocytopenia was observed in the 46% of the chemotherapy cycles; infection-related granulocytopenia was observed in 17%, but no fatality due therapy was observed. Granulocyte recovery was faster and delay on treatment was minimal (3.4 days). No thrombocytopenia, severe mucositis or cardiac abnormalities were observed. The CEOP-Bleo regimen with increasing doses of cyclophosphamide and epirubicin is an useful and well tolerated regimen for the treatment of poor prognosis malignant lymphoma.

Bone marrow protection with amifostine in the treatment of high-risk malignant lymphoma.

Based on preclinical and clinical studies which suggested that amifostine can protect against haematological toxicity of cyclophosphamide, we conducted a clinical trial of amifostine and intermediate doses of cyclophosphamide in patients with high-risk malignant lymphoma. 40 patients were enrolled to receive amifostine (910 mg/m2) before cyclophosphamide (1500 mg/m2) for two cycles (10 patients); 20 patients were allocated to receive amifostine/cyclophosphamide only on one cycle (patients were their own control) and 10 patients received cyclophosphamide alone without amifostine protection. Patients who received amifostine had fewer days of severe granulocytopenia (grade III or IV) and infectious episodes, and delay on treatment was minimal. Amifostine was well tolerated; only 2 patients developed transient and mild hypotension. The complete response rate was 72% (29/40). We conclude that amifostine is a good protector against haematological toxicity of cyclophosphamide and did not interfere with tumour response. Clinical trials with increasing doses of cytotoxic drugs or combination chemotherapy are needed to define the role of this myeloprotector agent in the treatment of patients with malignant lymphoma.

Dose escalation of epirubicin in the CEOP-BLEO regimen: a controlled clinical trial comparing standard doses for the treatment of diffuse large cell lymphoma.

One hundred and forty-seven consecutive patients with previously untreated high-intermedium and high clinical risk diffuse large cell lymphoma (DLCL) were included in a prospective clinical trial to evaluate the efficacy and toxicity of escalating doses of epirubicin compared to standard doses in the CEOP-Bleo (cyclophosphamide, epirubicin, vincristine and prednisone and bleomycin) regimen, 55% of the patients were > 60 years old and most patients had adverse prognostic factors at diagnosis. Complete response rates were similar in both groups (68% in the standard dose compared to 73% in the escalating arm, (p = 0.5). However, time to treatment failure (TFF) and overall survival were better after escalating doses. At 3-years TTF at a medial follow-up of 33.6 months was 76% in the patients whose received escalating dose statistical different to 37% of the patients whose received standard doses (p < .01). Overall survival was 81% in the escalated therapy arm which is statistical different to 40% of the patients treated with standard doses (p < .01). Toxicity was mild in both arms. Neutropenia, mucositis and cardiotoxicity were mild in the escalated dose arm and no severe complications were observed. All patients received the planned doses of all drugs. Patients > 60 years old had the same CR rate, TTF and overall survival as younger patients. In conclusion it seems that the dose of epirubicin can be increased in combination chemotherapy regimens with safety and only mild toxicity. The CR rate was not superior compared to the standard dose but the TTF and overall survival were better. Longer follow-up periods are required in order to determine if the cure rate can also be improved. Older patients can also benefit because they also tolerated the increase in epirubicin without severe side effects and also improved their outcome. The use of more aggressive regimens with increase in dose intensity may be the treatment of choice for more patients poor prognosis, with DLCL provided there is no increase in toxicity. In this respect the use of epirubicin in higher doses/appears to be useful.

Epirubicin (CEOP-Bleo) versus idaurubicin (CIOP-Bleo) in the treatment of elderly patients with aggressive non-Hodgkin's lymphoma: dose escalation studies.

One hundred and sixty nine untreated elderly patients (median age 69 years old; range 60-89 years old) with high or high-intermediate clinical risk non-Hodgkin's lymphoma were enrolled in a controlled clinical trial to evaluate escalated doses of epirubicin in a CEOP-Bleo regimen (cyclophosphamide, vincristine, epirubicin, prednisone and bleomycin), compared to escalated doses of idaurubicin in an CIOP-Bleo regimen (idaurubicin instead of epirubicin). Overall, 71% of the patients in the CEOP-Bleo arm achieved a complete response compared to only 48% in the CIOP-Bleo regimen (p < 0.01). At actuarial 3 year, 72% of the patients treated with the CEOP-Bleo regimen remained alive and free of disease, compared to 34% in the CIOP-Bleo arm (p < 0.01). Dose intensity was 0.86 in the epirubicin regimen, similar to 0.82 in the idaurubicin arm. Toxicities were more frequent and severe in the CEOP-Bleo regimen; however, no death-related treatment was observed in either groups. Cardiac toxicity was also similar in both arms. We conclude that treatment of elderly paitents with aggressive non-Hodgkin's lymphoma should be considered a curative attempt and not only palliative. The use of full doses of chemotherapy should be contemplated in elderly patients. Epirubicin, in escalating doses, is a drug with mild toxicity and improvement in outcome in this setting is observed. We cannot confirm the usefulness of idaurubicin, including escalating doses, in the treatment of patients with aggressive malignant lymphoma, because the complete response rate and survival were worse than other chemotherapy regimens. We feel that the CEOP-Bleo regimen with escalated doses of epirubicin is a useful option in the treatment of elderly patients with aggressive non-Hodgkin's lymphoma.

Improved outcome in solitary bone plasmacytomata with combined therapy.

Solitary bone plasmacytoma (SBP) is a rare presentation of plasma cell dyscrasias. Radiotherapy has been considered the treatment of choice, however, most patients will develop multiple myeloma, 3 to 10 years after initial diagnosis and treatment. No innovations have been introduced in the treatment of SBP in the last 30 years. We began a prospective clinical trial to assess the efficacy and toxicity of adjuvant chemotherapy with low doses of melphalan and prednisone administered to patients with SBP after radiation therapy in an attempt to improve the disease-free survival and overall survival. Between 1982 and 1989, 53 patients with SBP were randomly assigned to be treated with either local radiotherapy with doses ranged from 4000 to 5000 cGy to achieve local control of disease (28 patients) or the same radiotherapy schedule followed by melphalan and prednisone given every 6 weeks for 3 years (25 patients). After a median follow-up of 8.9 years, disease-free survival and overall survival were improved in patients who were treated with combined therapy, 22 patients remain alive and free of disease in the combined treatment group compared to only 13 patients in the radiotherapy group (p < 0.01). Treatment was well tolerated; planned doses were administered in all cases; no delays in treatment or acute side-effects were observed during treatment. Long-term secondary toxicities including secondary neoplasms and acute leukaemia, have not been observed. We felt that the use of adjuvant chemotherapy after adequate doses of radiotherapy in patients with SBP improved duration of remission and survival without severe side-effects. However, as with other studies in SBP, the group was too small to draw definitive conclusions and more controlled clinical trials are necessary to define the role of this therapeutic approach in patients with SBP.

Intensive brief chemotherapy with hematopoietic growth factors as hematological support and adjuvant radiotherapy improve the prognosis in aggressive malignant lymphoma.

An intensive brief chemotherapy and radiotherapy regimen including high doses of cyclo-phosphamide (5 g/m2), etoposide (1 g/m2), epirubicin (180 mg/m2), and ifosfamide (5 g/m2) administered in a period of 30 days followed by involved field radiotherapy to sites of initial bulky disease was administered to 46 untreated patients with high-intermedium and high-risk malignant lymphoma. G- or GM-CSF were used as hematological support instead of bone marrow transplantation. All patients had more than 3 adverse prognostic factors at diagnosis. Forty-one patients (89%) achieve complete response (33 after chemotherapy and 8 partial responses were converted to complete response after adjuvant radiotherapy). Acturial failure-free survival at 3 years is 83% and 37 of all patients started on therapy remain alive and in first remission at a median of 24.3 months from completion of treatment. Nearly all patients developed granulocytopenia grade IV; only 13 episodes of bacterial infection were documented. Because hematological recovery was very short (mean 13.6 days) no death related treatment and opportunistic infections were observed. Other non-hematological toxicities were scarce and well tolerated. No decrease > 10% was observed in the left ventricular ejection fraction. None have developed clinically evident congestion heart failure or other late side effects. These results showed that G- or GM-CSF can act as hematological support instead of bone marrow transplantation during intensive and brief chemotherapy. These regimens produce higher complete remission rate, and adjuvant radiotherapy will improve the outcome in patients with bulky disease.

Results of a randomized trial of granulocyte colony-stimulating factor in patients with infection and severe granulocytopenia.

A study was carried out to investigate the efficacy and toxicity of granulocyte colony-stimulating factor (G-CSF) in the treatment of infection in 119 severely granulocytopenic patients with hematological malignancies after intensive chemotherapy. Patients were assigned randomly to receive either antibiotics alone (ceftazidime, 2 g, i.v., every 8 h + amikacin 7.5 mg/kg, i.v., every 12 h) or the same antimicrobial regimen plus G-CSF (5 micrograms/kg/day, s.c.). Measurements were clinical improvement, eradication of infection and toxicity. Patients who received antibiotics plus G-CSF had more clinical responses (82 versus 60%), less superinfections (6 versus 20%), less mortality (5 versus 15 patients), less days in hospital (median 10 versus 27) and reduced antibiotic usage compared to patients who received only antibiotics. Hematological recovery (granulocytes > 1.0 x 10(9)/l) was also shorter in these patients (12 versus 23 days). Fungal infections occurred only in the group treated with antibiotics alone. Toxicity secondary to G-CSF was absent. We conclude that the addition of G-CSF to broad spectrum antibiotics is useful in selected patients with severe granulocyctopenia after intensive chemotherapy and infection, because if may prove the outcome in these patients.

Biological modifiers (etretinate (changed from etetrinate) and alfa 2a) in the treatment of refractory cutaneous T-cell lymphoma.

To assess the efficacy and toxicity of biological modifiers in combination etetrinate, 0.8 mg/kg/day, po and interferon alfa 2a 9.0 MU, three times at week) in the treatment of refractory cutaneous T-cell lymphoma (CTLC) we began a clinical study on 12 heavily treated patients. After 1 year on treatment 10/12 patients (83%) achieved complete response. Two patients were considered failures with disease progression. After a median follow-up of 3 years, seven patients (56%) remained in complete remission. Toxicity was mild. All patients received 93% of the planned dose of etetrinate and interferon. We feel that biological modifiers, as etetrinate and interferons, are agents with limited hematological toxicity even in higher doses. The combination of two agents, with different mechanisms of action, could improve the outcome in patients with refractory CTCL. Controlled trials are necessary to define the roles of this type of therapy as first line of treatment.

Long-term results of a multicentre randomised, comparative phase III trial of CHOP versus CNOP regimens in patients with intermediate- and high-grade non-Hodgkin's lymphomas. Novantrone International Study Group.

59 previously untreated patients with intermediate- or high-grade, stage II-IV non-Hodgkin's lymphoma (NHL) were entered into an open-label, randomised, multicentre study to compare the efficacy and safety of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) with that of CNOP (cyclophosphamide, mitoxantrone, vincristine and prednisolone). 10 patients refused treatment following randomisation. The remaining 349 patients received either the CHOP or CNOP regimen every 3 weeks for a maximum of six to eight cycles. The randomisation procedure was violated for 34 patients treated at two study centres. Data from these 34 patients were analysed separately for efficacy and survival. Data from the remaining 325 patients, 164 assigned to CHOP and 161 to CNOP, were used in the major efficacy and survival analyses. Of these 325 patients, 263 (81%) met the eligibility criteria of the protocol. Supplementary analyses of data from these 263 patients, 132 assigned to CHOP and 131 to CNOP, were conducted for efficacy and survival. Data from all 349 treated patients were analysed for safety. In the 325 randomised patients, the overall objective response rate was not significantly different between the two groups (chi 2 test, P = 0.35). The CHOP regimen had a 51% (83/164) complete remission (CR) rate compared with 40% (64/161) for the CNOP regimen (P = 0.05). Among those with CR, the median time to response was 104 days with the CHOP regimen and 77 days with the CNOP regimen, and the median duration of CR was 667 and 1833 days, respectively. The median time to progression was 449 days for CHOP patients and 564 days for CNOP patients. The median survival time was 932 days for CHOP patients and 1801 days for CNOP patients, with a risk of death on CNOP relative to CHOP of 0.93% (95% confidence interval 0.68-1.27). After 5 years, 50% of patients in the CNOP arm and 40% of patients in the CHOP arm were still alive; these differences between treatment groups were not statistically significant. The median time to treatment failure (TTF) was 285 days for patients on the CHOP arm and 282 days for patients on the CNOP arm. Separate analyses of 263 eligible randomised patients, and 34 patients in whom the randomisation procedure was not followed, yielded similar results for remission rate, TTF, duration of CR and estimated overall survival. The incidence of non-haematological events, such as severe nausea and vomiting (P < 0.01), mucositis (P < 0.05) and alopecia (P < 0.001), were significantly lower in were significantly lower in patients treated with CNOP as compared with those who received the CHOP regimen. The incidence of cardiovascular toxicity of any severity was similar in the two groups. While severe and potentially life-threatening neutropenia occurred more frequently in patients treated with CNOP compared with CHOP (0.05 > P > 0.10), the incidence of infection of any severity was similar in both arms. We conclude that CHOP and CNOP regimens were both efficacious in patients with previously untreated aggressive NHL.

GM-CSF instead of hematological support during high-dose chemotherapy for refractory malignant lymphoma.

Patients with refractory malignant lymphoma (RML) have a poor prognosis when treated with conventional chemotherapy. The use of high-dose chemotherapy has been limited by secondary myelosuppression. We report the use of intensive and short-duration chemotherapy in patients with RML who received granulocyte-macrophage colony-stimulating factor (GM-CSF) instead of hematological support and salvage with bone marrow transplantation or infusion of peripheral blood stem cells. Thirty-one patients with RML were treated with cyclophosphamide: 7 g/m2, iv on day 1, followed by GM-CSF: 5 micrograms/kg/day, subcutaneously until hematological recovery (granulocytes > 1.8 x 10(9)/L) started on day 2. Methotrexate, 5 g/m2, was also given when the granulocytes and platelets counts were normal, followed by leucovorin rescue. Epirubicin, 180 mg/m2, iv, was given on day 29 if the granulocyte count was normal, and GM-CSF was started on day 30. Complete response was obtained in 21 out of 31 patients (67%) and partial response in 4 more, thus an overall response was achieved in 80% of the treated patients. Time to treatment failure was 24+ months, and the overall survival was 28+ months. Hematological toxicity grade IV, according to the WHO criteria was observed in all cycles, however hematological recovery was already evident on day 13 +/- 2. Eleven patients developed infection related to the treatment, but no therapy related death was observed. GM-CSF was well tolerated with minimal toxicity. Is evident that GM-CSF can act as hematological support after high-dose chemotherapy in patients who cannot undergo bone marrow transplantation programs.(ABSTRACT TRUNCATED AT 250 WORDS)