Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristine, BCNU, cyclophosphamide, melphalan, and prednisone)

The M-2 protocol (vincristine, cyclophosphamide, BCNU, melphalan, and prednisone) was administered monthly to 63 evaluable patients with advanced chronic lymphocytic leukemia. Complete remission (absence of all clinical and bone marrow evidence of leukemia) and partial response (greater than 50% decrease in organ enlargement and reduction of WBC count to below 15,000 x 10(6)/liter) were achieved in 17% and 44%, respectively, for a total response rate of 61%. The median survivals from therapy of patients achieving a CR, RR, or no response were 73+, 40, and 14 mo respectively. The median survival time from onset of treatment for stages II, III, and IV disease were 47, 20 and 19 mo, respectively, which was not statistically different from historical controls. However, when untreated patients are compared to this latter group, a significant survival advantage from diagnosis was found (p = 0.01), stressing the importance of prior therapy as the only unfavorable prognostic factor. Although complete remissions in CLL, as reflected in apparently normal bone marrow B-lymphocyte markers, can be induced wih acceptable morbidity, the majority of patients relapse after cessation of therapy. An alternative approach to the M-2 protocol will be needed to eradicate the disease.     

Improved survival times in multiple myeloma treated with melphalan, prednisone, cyclophosphamide, vincristine and BCNU: M-2 protocol

Seventy-three patients in whom multiple myeloma could be evaluated were treated with a combination drug protocol (M-2), consisting of melphalan, prednisone, cyclophosphamide, vincristine and BCNU (1,3-bis(2-chloroethyl 1)-1-nitrosourea). All patients were classified according to the clinical staging system of Salmon and Durie; 75 per cent of them were in stage III. Total tumor cell number was calculated according to the method of Salmon. A significant objective remission was obtained in 40 of 46 (87 per cent) previously untreated patients. The median duration of response for this group is presently 20+ months. Twenty-seven of these 40 responders are still in remission. Thirteen of 26 (50 per cent) previously treated patients responded. With eight of these still in remission, the median duration of response for the group is 22+ months. The median times between the first dose and an established response were two and three months for the previously untreated and treated groups, respectively. The duration of remission in the more rapid responders does not appear to be shorter. The response rate does not appear to correlate with the type of immunoglobulin or light chain secreted. One patient, without immunoglobulin secretion, has been in remission for 45+ months, and three with primary amyloid have failed to respond. At this point, it appears that survival time in patients treated with M-2 will be significantly longer than in the earlier group treated at this center with melphalan and prednisone alone.     

Multiple myeloma resistant to melphalan: treatment with cyclophosphamide, prednisone, and BCNU.

Eighty-nine patients with multiple myeloma resistant to melphalan were randomized to receive cyclophosphamide plus prednisone (CP) (47 patients) or cyclophosphamide plus BCNU plus prednisone (CBP) (42 patients). No differences were detected in the two groups prior to therapy. Objective responses occurred in three (7%) of the CP patients and in seven (17%) of the CBP patients. About 40% of the patients in each group achieved some response. Toxic reactions consisted mainly of leukopenia and thrombocytopenia. Median survival was not different in the two groups. The median survival time was 31 months among those patients with an objective response and 9.4 months among those without an objective response. The addition of BCNU to CP increased the frequency of objective response, but not significantly. This triple combination (CBP) cannot be recommended.     

BCNU with and without cyclophosphamide, vincristine, and prednisone (COP) and cycle-active therapy in non-Hodgkin's lymphoma.

Two hundred and ninety-eight evaluable patients with non-Hodgkin's lymphoma were stratified according to histology, treated with either BCNU, cyclophosphamide, Oncovin (vincristine), and prednisone (BCOP) or cyclophosphamide, Oncovin (vincristine), and prednisone (COP), and evaluated at 3 months. Those with a good partial (PR) or complete response (CR) were then separated and randomized to be treated with either cycle-active therapy (methotrexate, cytosine arabinoside, and 6-thioguanine) or more induction therapy with COP or BCOP. Patients not achieving a good PR at 3 months received cycle-active therapy. The results indicate (a) that there is a significant advantage for good over poor histologies with regard to good PRs at 3 months; (b) that the addition of cycle-active therapy (as administered in this study) is of advantage when the tumor has been significantly reduced only for patients receiving COP induction; and (c) that BCOP has an advantage over COP in diffuse histiocytic lymphoma where the percentage of CRs, their durability, and subsequent survival are superior for patients treated with BCOP. Since this lymphoma accounts for about 25% of all non-Hodgkin's lymphoma patients, this regimen represents a useful tool for the chemotherapist.     

Combination chemotherapy of advanced non-Hodgkin lymphoma with bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP).

Seventy-three patients with advanced non-Hodgkin lymphoma were treated with bleomycin, Adriamycin, cyclophosphamide, vincristine (Oncovin) and prednisone (BACOP), administered intensively during a 7-wk induction course followed by intermittent cycles every 3 wk for a total of 28 wk. The objective response in 44 evaluable nonleukemic patients with diffuse histology was 86%, with 66% achieving a complete remission (CR), varying from 80% for diffuse poorly differentiated lymphocytic (DPDL) to 56% for diffuse histiocytic (DH) lymphoma. In patients with nodular histology 89% (8/9) achieved a CR with a projected 75% of patiients in CR at 14 mo. Median follow-up from time of CR for nodular histology was 17 mo. The projected median duration of CR in diffuse histology was 14 mo. with median survival 14 mo. Patients with a partial response survived a median of 7 mo, compared to 3 mo for nonresponders. Of 29 patients with diffuse histology, 17 (59%) have remained disease free for 5-34 mo with a median follow-up of 12 mo. Survival beyond 20 mo has been projected for 42% of patients with diffuse histology (58% with DPDL and 32% with DH). The central nervous system (CNS) was involved in a total of 11/44 (25%) patients with diffuse histology, including 5 with primary CNS relapse. BACOP resulted in a higher CR rate and longer survival than a previous three-drug program (COP), especially in patients with diffuse histology.     

Comparison of vincristine, carmustine, melphalan, cyclophosphamide, prednisone (VBMCP) and interferon-alpha with melphalan and prednisone (MP) and interferon-alpha (IFN-alpha) in patients with good-prognosis multiple myeloma: a prospective randomized study. Greek Myeloma Study Group

OBJECTIVES: The purpose of the study was to evaluate, in a selected group of myeloma patients with favorable prognosis, the effect, on response and survival, of polychymotherapy compared with melphalan prednisone, plus interferon in both arms. METHODS: Eighty-nine previously untreated patients with multiple myeloma and prognostic factors indicating a good prognosis were randomized to either oral melphalan plus prednisone (MP) in combination with recombinant interferon-alpha (rIFN-alpha) or combination chemotherapy with vincristine, carmustine, melphalan, cyclophosphamide, and prednisone (VBMCP) alternating with rIFN-alpha. The two treatment groups were comparable in terms of pretreatment characteristics. RESULTS: The overall response rate was 67.4% (2.3% complete remission, 65.1% partial response) in the MP/IFN-alpha group and 69.1% (14.3% complete remission, 54.8% partial response) in the VBMCP/IFN-alpha group (p=0.59). There were no differences also in response duration and overall survival between the two treatment groups. The median response duration was 39.1 months in the MP/IFN-alpha group and was not reached in the VBMCP/IFN-alpha group (p = 0.6). Overall survival was long in both treatment groups. The estimated 5-yr survival was 66% and 62% in the MP/IFN-alpha and VBMCP/IFN-alpha group, respectively (p=0.8). Toxicity was modest and treatments were well tolerated. Neutropenia (WHO grade 3 or 4) was higher, but not statistically significant, in the VBMCP/IFN-alpha group. CONCLUSIONS: The results of the study show that in myeloma patients with good prognosis, combination chemotherapy alternating with interferon-alpha has no advantage over conventional MP plus interferon-alpha, in regard to response rate, response duration, and overall survival of patients.     

Sequentisl induction chemotherapy with vincristine,daunorubicin cyclophosphamide,and prednisone in adult acute lymphoblastic leukemia

Sequential chemotherapy with vincristine, daunorubicin, cyclophosphamide, and prednisone doses was administered to 57 adult patients with acute lymphoblastic leukemia (ALL). Complete remission (CR) was achieved in 51 (89%, 95% confidence intervals, [CI] 78–96%). Among patients achieving CR, 62% were in CR after one sequence of chemotherapy, 23% after two sequences, and 5% after three sequences. Six patients (11%) had resistant disease. All patients experienced profound myelosuppression. Median time to recovery of neutrophils > 0.5 × 10⁹/l was 22 days (range: 5–89 days), and of platelets >100×l0⁹/l 21 days (range: 0–45 days). Nonhematologic WHO grade 3 or more side effects consisted predominantly of hyperbilirubinemia (7%), mucositis (5%), nausea and vomiting (2%), and cutaneous toxicity (1%). Severe infectious complications occurred in only 14% of cases. One patient (2%, 95% CI 0–9%) died of therapy-related toxicity while in early CR. We concluded that sequential use of prednisone seemed at least as effective as continuous administration at the expense of a few adverse side effects.     

Bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP) combination chemotherapy in the treatment of advanced diffuse histiocytic lymphoma.

A new combination chemotherapy program for patients with diffuse histiocytic and mixed histiocytic-lymphocytic lymphoma was designed to prevent tumor recurrence during the recovery period of each treatment cycle. A myelosuppressive phase consisting of adriamycin, cyclophosphamide, and vincristine was followed by the nonmyelosuppressive agents bleomycin and prednisone to suppress regrowth of lymphoma while allowing for a return in bone marrow function. Twelve of 25 patients (48%) with advanced, previously untreated, diffuse histiocytic lymphoma achieved a complete remission as determined by restaging 1 month after discontinuation of treatment. The median duration of complete response after completion of therapy is in excess of 1 year (range, 5 to 30 months), and no patient has relapsed. Based on previous experience, it is anticipated that the majority of these patients will achieve an extended disease-free survival for what had previously been regarded as an invariably fatal disease.     

Treatment of recurrent lymphomas with vincristine, BCNU, doxorubicin, and prednisone (VBAP): a Southwest Oncology Group Study

Chemotherapy with vincristine, BCNU, doxorubicin, and prednisone (VBAP) was administered to 75 patients with malignant lymphoma, including both Hodgkin's disease and non-Hodgkin's lymphoma. All patients had prior chemotherapy with or without radiation therapy. Remissions were achieved in 41% of all patients, with only minor toxicity. The median duration of remission for Hodgkin's disease and non-Hodgkin's lymphoma was 51 and 22 weeks, respectively. The median survival for all patients was 34 weeks. The VBAP program is effective palliative chemotherapy for advanced malignant lymphoma.     

Effects of Mega-COMLA (cyclophosphamide, cytarabine, vincristine, and methotrexate followed by leucovorin and prednisone) plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in the treatment of lymphoid neoplasms with very poor prognosis

Treatment results remain very poor for some clinical and histopathologic subsets of patients with aggressive non-Hodgkin's lymphoma. We treated 21 such patients with a high-dose combination chemotherapy regimen [Mega-COMLA (cyclophosphamide, cytarabine, vincristine, and methotrexate followed by leucovorin and prednisone) + CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)] in an attempt to improve disease-free survival. Neoplasms were classified using the Lukes-Collins system. Eight patients had T-cell lymphomas (convoluted lymphocytic lymphoma, four patients; T-cell lymphoma/leukemia, one; and peripheral T-cell lymphoma, three), eight had B-cell lymphomas (immunoblastic sarcoma, five patients; small noncleaved follicular center cell, one; and large noncleaved follicular center cell, two), and five had nontypable large noncleaved cell lymphomas. All patients were previously untreated; 18 of 21 patients had clinical stage III or IV disease. Following induction therapy (4-8 weeks' duration), 16 patients (76%) achieved complete remission, while three had partial remission. Two patients died of sepsis during induction therapy. Eleven of 16 complete responders (69%) remain in complete remission after a median follow-up of 35 months. The actuarial 3-year survival rate is 51% for the entire group. Myelosuppression with this regimen was severe and prolonged, with a median duration of neutropenia (less than 500 cells/microliter) of 14 days. Seven patients (33%) developed severe neuropathy following induction treatment. High-dose induction therapy with this regimen resulted in a high complete remission rate with manageable toxicity. Survival results are encouraging when compared retrospectively to our patients with similar poor-prognosis histologies treated with standard combination chemotherapy. However, the value of this intensive therapy, relative to newer ("third-generation") regimens, can only be established by prospective randomized studies.     

Combination chemotherapy of advanced Hodgkin's disease with vincristine, cyclophosphamide, procarbazine, and prednisolone]

Thirty-three patients with advanced Hodgkin's disease were treated with a combination chemotherapy consisting of vincristine 1 mg/m2 iv on day 1, 8, cyclophosphamide 500 mg/m2 iv on day 1, procarbazine 100 mg/m2 p.o. day 1-7, and prednisolone 40 mg/m2 p.o. day 1-7. Twenty patients received this regimen every 4 weeks (VCPP II regimen). Furthermore, we conducted higher dose intensive VCPP II-2 regimen which was repeated every two weeks for thirteen patients. Complete response rate of both regimens was 63% (VCPP II 45%, VCPP II-2 85%). The median duration of CR was 37 + months. Leukopenia, neurotoxicity and gastrointestinal toxicity were commonly observed but were clinically manageable. These results indicate that high dose intensive chemotherapy is effective for achieving high CR rate for advanced Hodgkin's disease.     

Chemotherapy (cyclophosphamide, vincristine, and prednisone) versus radiotherapy (total body irradiation) for stage III-IV poorly differentiated lymphocytic lymphoma

Seventy-two patients with stage III-IV malignant lymphoma of the poorly differentiated lymphocytic (PDL) type were randomly assigned to initial chemotherapy with cyclophosphamide, vincristine, and prednisone (CVP) or to radiotherapy with total body irradiation (TBI). The response and survival rates were similar for CVP and TBI in patients with nodular PDL, with 66% and 67%, respectively, surviving at 7 years. Induction treatment with TBI yielded better response and early survival than CVP for patients with diffuse PDL but a survival advantage did not exist at 5 years, the survival rate being 28% and 25%, respectively. TBI was more easily tolerated than CVP as initial therapy, 19 (51%) of the 37 CVP patients had a complication which required hospitalization during the first six cycles as contrasted to only one of 35 patients receiving TBI who required hospitalization. Most chemotherapy complications were infectious in nature, secondary to relatively severe granulocytopenia, and one patient died from Candida sepsis following the first cycle of CVP. Late complications consisted of two TBI patients who developed a myeloproliferative disorder and two CVP patients who experienced persistent disabling neurotoxic reactions. Durable remissions were not achieved with significant frequency using either form of treatment, indicating a need to evaluate new therapeutic approaches for the management of PDL lymphoma.     

Third-line chemotherapy with CAVP (CCNU, melphalan, etoposide and prednisone) in refractory Hodgkin's disease

Thirty-one patients affected by recurrent Hodgkin's disease have been treated with an oral combination chemotherapy including lomustine (CCNU 90 mg/sqm, on day 1), melphalan (Alkeran, 7.5 mg/sqm on days 1-5), etoposide (VP-16, 100 mg/sqm on days 6-10) and prednisone (40 mg/sqm on days 1-10). MOPP and ABVD regimens administered sequentially or in alternating fashion had been employed as first choice treatment. The majority of patients had extranodal (80%) and a progressive disease resistant to previous chemotherapy (80%). Complete and partial remission were induced in 8 (26%) and 5 patients (16%), respectively, with an overall response rate of 42%. Median duration of complete remission was 10 months. Patients who did not respond to previous chemotherapies had a significantly lower complete response rate (16%). Myelosuppression was the most frequent complication, with one patient dying of a thrombocytopenic hemorrhage. The oral administration of drugs allowed good patients', compliance with treatment. CAVP is an effective regimen in the management of patients with refractory Hodgkin's disease and the results obtained are comparable with other third-line chemotherapies.