Etoposide in combination as first-line chemotherapy for advanced Hodgkin disease. A Cancer and Leukemia Group B study.

BACKGROUND: In a pilot study, Cancer and Leukemia Group B (CALGB) incorporated etoposide into primary combination therapy for advanced Hodgkin disease. METHODS: Thirty-six evaluable patients were treated with two or three courses of methotrexate, vincristine, prednisone, leucovorin, etoposide, and cyclophosphamide (MOPLEC), and then treated with five to seven additional courses of a known "curative" regimen: nitrogen mustard, vinblastine, prednisone, and procarbazine (MVPP). RESULTS: After treatment with MOPLEC, there were 16 complete responders (44%) and 18 partial responders (50%). One patient had progressive disease and one patient was taken off study after an anaphylactic reaction to etoposide. After completing the entire protocol, 32 patients achieved complete remission (CR) (89%) and 3 achieved partial remission (PR) (8%). Five CR patients have relapsed and three additional patients have died in CR without recurrence. At 36 months, the estimated failure-free survival is 61% and overall survival is 72%. CONCLUSIONS: This combination, which includes etoposide, is active for the primary treatment of advanced Hodgkin disease.

Hodgkin disease in patients 60 years of age or older. Histologic and clinical features of advanced-stage disease. The Cancer and Leukemia Group B.

BACKGROUND: This article reviews the salient pathologic and clinical features of 171 patients with Stage III-IV disease who were 60 years of age or older who were treated on four Hodgkin disease (HD) protocols from 1969 to 1988. METHODS: Pretherapy sections were reviewed centrally for correlation of the histologic classification with anatomic sites of involvement and survival. RESULTS: The diagnosis of HD was confirmed in 114 (66.7%) patients. Non-Hodgkin lymphomas (NHL) and a miscellaneous non-HD group accounted for 52 (30.4%) and 5 (2.9%) of the cases. The overall median survival times of patients with Stage III-IV HD and NHL who were 60 years of age or older in the four protocols were not significantly different (1.5 versus 1.3 years, respectively; P = 0.28). There also was no significant correlation between the survival of these patients with HD and either the Rye classification, 19 specific histologic parameters, or the British National Lymphoma Investigation grading system for HDNS. In the last protocol, the 5-year survival rate of patients with HD who were 60 years of age or older was lower than that of patients 40-59 years of age or that of those younger than 40 years of age (31% versus 63% versus 79%, respectively, P < 0.0001). Patients with HD entered into the two most recent protocols showed lower incidences of involvement of cervical and iliac-inguinal-femoral lymph nodes and skin-subcutaneous tissues than the patients with NHL who were misdiagnosed as HD. Moreover, patients with Stage III-IV HD in the most recent protocol who were 60 years of age or older had lower rates of involvement of the cervical and mediastinal-hilar lymph nodes and a higher rate of involvement of the gastrointestinal tract than younger patients. CONCLUSIONS: Patients with Stage III-IV HD and NHL who are 60 years of age or older differ with respect to the rates of involvement of specific anatomic sites but not in survival when treated with HD protocols. In contrast, patients of different age groups with Stage III-IV HD disease differ with regard to the rates of involvement of anatomic sites and survival.

AMOPLACE treatment of intermediate-grade and high-grade malignant lymphoma: a Cancer and Leukemia Group B study.

PURPOSE: In an attempt to improve the efficacy of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy for intermediate-grade and high-grade non-Hodgkin's lymphomas, a phase II evaluation of a regimen consisting of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), methotrexate, Oncovin (vincristine; Eli Lilly Co, Indianapolis, IN), prednisone, leucovorin, cytarabine (ara-c), cyclophosphamide, and etoposide (AMOPLACE) was conducted. This regimen includes three additional agents not found in CHOP, uses weekly doses of alternating myelosuppressive and nonmyelosuppressive drugs, and incorporates most single agents active against diffuse lymphomas. PATIENTS AND METHODS: Ninety-one previously untreated patients were enrolled and 60 patients were confirmed eligible after central pathology review. Fifty-eight percent of patients had diffuse large-cell lymphoma (DLCL), 83% had stage III or IV disease, and 45% had B symptoms. RESULTS: Patients were treated with six to eight cycles of AMOPLACE and analyzed for response and survival. With a median follow-up of 48 months, complete responses (CRs) were seen in 68% of all patients with failure-free survival (FFS) and overall survival (OS) estimates at 4 years of 45% and 54%. In the DLCL subset, the CR rate was 69% and FFS and OS estimates at 4 years were 49% and 60%, respectively. The major toxicity was myelosuppression, with 73% of patients having WBC nadirs less than 1,000/microL; two treatment-related deaths occurred. CONCLUSION: We conclude that AMOPLACE is associated with CR and OS rates comparable with those of other third-generation regimens.

Phase II trial of etoposide and cisplatin in patients with refractory and relapsed non-Hodgkin's lymphoma: Cancer and Leukemia Group B study 8351.

A phase-II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed non-Hodgkin's lymphoma (NHL) to assess the activity of the combination of etoposide and cisplatin. Sixty-five patients were entered on study, and 51 patients were evaluated for this report. The treatment regimen consisted of etoposide, 80 mg/m2 IV daily times 5 and cisplatin 20 mg/m2 IV daily times 5, repeated every 21 days. All patients had failed 1-3 prior chemotherapeutic regimens, had measurable disease, and had a performance status of 0-2. In the 51 evaluable patients, there were 4 complete responses (8%) and 12 partial responses (23%), for an overall response rate of 31% (95% Cl: 19%, 46%). In addition, 15 patients (29%) had some improvement in disease and 6 (12%) had stable disease. Failure-free survival for the 51 eligible patients was 40% at 3 months, 23% at 6 months, and 15% at 1 year. Significant toxicity was observed with this regimen. Severe neutropenia occurred in 20 patients (39%), severe anemia in 8 patients (16%), and severe thrombocytopenia in 18 patients (35%). One patient died of infection. Severe neurotoxicity (1) and hemorrhage (3) were also seen. The etoposide, cisplatin combination is active in NHL; however, in this dose and schedule their combined activity is only minimally better than published reports of etoposide alone. Further studies of related combinations are under evaluation by the CALGB.

Immunophenotypic subclassification of chronic lymphocytic leukaemia (CLL).

To determine the significance of the immunophenotypic heterogeneity of B-cell chronic lymphocytic leukaemia (CLL), surface immunoglobulins (SIgs), mouse rosette assays (MR), and a panel of monoclonal antibodies for B cells, T cells and myeloid cells were performed on peripheral blood samples from 61 newly diagnosed cases. Four groups were observed: group I (SIg+, MR+, CD19/20+, CD5+, T antigen (Ag)-; 27 cases); group II (SIg+, MR+, CD19/20+, CD5+, T Ag+; 17 cases); group III (SIg+, MR+ CD19/20+, CD5-, T AG-; 12 cases); and group IV (SIg-, MR+, CD19/20+, Cd5+, T Ag-; 5 cases). Groups were compared according to French-American-British Cooperative Group subtypes, clinical and laboratory features, Rai staging, and survival. Typical CLL morphology (greater than 90% small lymphocytes) was present in 20/20 (100%) of group I cases and 23/27 (85%) group II, III and IV cases (P = 0.09). Expression of a myeloid antigen was seen in 5/27 group I cases (18%) and 1/16 group II cases (6%), but was not predictive of survival (P = 0.36). The CD5- group III had a lower haemoglobin level (P less than 0.0001), higher Rai stage (P less than 0.002), and poorer survival at 5 years (P less than 0.02) than the other groups. We conclude that at least four distinct immunophenotypic subgroups of B-cell CLL can be determined. Expression of myeloid or T-cell antigens does not appear to predict for patient survival; however, lack of CD5 antigen may be associated with more advanced stage of disease and poor patient survival.

A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B.

Between 1982 and 1986, 326 evaluable patients with acute myeloid leukemia (AML) were randomized to receive cytarabine (Ara-C) at 200 mg/m2 (A200) or 100 mg/m2 (A100) for induction and maintenance therapy. Cycle 1 of induction therapy consisted of 7 days of continuous intravenous (IV) Ara-C and 3 days of i.v. daunorubicin (DNR); cycle 2, if needed, consisted of 5 days of Ara-C and 2 days of DNR. Complete responders (CR) then received monthly subcutaneous (SC) Ara-C at the respective doses (A100 or A200) with 6-thioquanine (6TG) at months 1 and 5, with vincristine (VCR) and prednisone at months 2, 4, 6, and 8, and with DNR at months 3 and 7. Complete response rates were 58% (A100) and 64% (A200) (P = .29). Median survival was 46 weeks (A100) and 38 weeks (A200) (P = .64); 5-year survival was 10% (A200) and 8% (A100). Median time to remission was 6.7 weeks (A200) and 8.1 weeks (A100) (P = .18). Median disease-free survival was 41 weeks (A200) and 44 weeks (A100) (P = .86). Deaths were attributed to therapy-related toxicities in 21% (A200) and 13% (A100) (P = .05). The 5-year survival was 15% for patients with performance status (PS) 0, 8% for PS 1 to 2, and 2% for PS 3 to 4, 18% for patients less than 40 years, 8% for ages 40 to 59, and 3% for age 60 or greater. Stratification of data by age and PS suggested that A200 may improve survival in patients less than 60 years with a good PS 0 (P = .05). This trial does not support the superiority of A200 over A100 in the treatment of AML.

A randomized comparison of methotrexate dose and the addition of bleomycin to CHOP therapy for diffuse large cell lymphoma and other non-Hodgkin's lymphomas. Cancer and Leukemia Group B study 7851.

In 1978, Cancer and Leukemia Group B initiated a randomized study to determine the usefulness of the addition of bleomycin and/or high-dose methotrexate to standard therapy for the treatment of certain adult non-Hodgkin's lymphomas. Between 1978 and 1985, 177 patients with diffuse large cell lymphoma (DLCL) and 97 patients with other intermediate-grade non-Hodgkin's lymphoma were randomized to receive therapy with three courses of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) every 3 weeks with or without low-dose bleomycin by continuous IV infusion. Responders after three courses were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 gm/m2/week intravenously with leucovorin rescue) or standard-dose methotrexate (30 mg/m2/week orally without rescue). Therapy was concluded with three additional courses of CHOP. Neither the addition of low-dose infusion bleomycin nor the use of high-dose rather than low-dose methotrexate had significant effects on response for patients with DLCL; complete response rates for the four treatment programs ranged from 47% to 51%. Median failure-free survival (FFS) for the entire group of DLCL patients was 12 months; 5-year FFS was 27%. There was no significant effect on FFS from the addition of either low-dose bleomycin to CHOP (5-year FFS: CHOP, 28%; CHOP-B, 26%, P = 0.81), or from the use of different doses of methotrexate (5-year FFS: high-dose, 34%; standard-dose, 33%, P = 0.51). Patients with follicular large cell lymphoma, with or without diffuse areas, had a better FFS (5-year FFS, 47%) than patients with DLCL (5-year FFS, 27%), while the patients with the other histopathologic subtypes of diffuse lymphomas had the poorest FFS (5-year FFS, 16%).

Inducible lymphokine-activated killer (LAK) cell activity in the peripheral blood of patients with relapsed/refractory non-Hodgkin's lymphoma (NHL).

Therapy with recombinant interleukin-2 (rIL-2) induces clinical response in a significant number of patients with refractory malignant disease. Very few patients with non-Hodgkin's lymphoma (NHL) have been treated with rIL-2. The present study sought to determine if peripheral blood mononuclear cells (PBM) from patients with relapsed/refractory non-Hodgkin's lymphoma could be induced in vitro to generate LAK cell activity. PBM from 28 patients with relapsed/refractory NHL were incubated for 7 days in rIL-2 to determine their ability to lyse the LAK cell sensitive Daudi cell line. The PBM from all patients were able to generate LAK activity after in vitro incubation in rIL-2. Approximately one third of the patients' PBM samples generated less activity than activity generated in the PBM sample from normal control donors. However, two-thirds of patient samples were able to generate activity equal to or greater than that of the controls. The degree of LAK activity generated by the patients' PBM did not correlate either with histologic subtype or amount of prior chemotherapy. The amount of LAK activity an individual generated (control or patient) tended to remain stable over time.

Interferon therapy of relapsed and refractory Hodgkin's disease: Cancer and Leukemia Group B Study 8652.

A phase II trial of alpha 2b-interferon in patients with relapsed or refractory Hodgkin's disease was conducted by the Cancer and Leukemia Group B. Nineteen patients were eligible for study. These patients had received at least two (median of four) previous chemotherapeutic programs and 79% had received prior radiation therapy. Three patients had undergone intensive chemotherapy and autologous bone marrow transplantation. The treatment regimen consisted of interferon-alpha 2b 10 X 10(6) IU/m2 subcutaneously three times per week. Only limited antineoplastic activity was seen in this heavily pretreated group of patients. There was one partial response and four patients had reduction in measurable disease not meeting the criteria for partial response. The drug was well tolerated. Toxicity was predominantly myelosuppression. Thrombocytopenia was particularly severe in patients with bone marrow involvement. The observed antineoplastic activity, albeit limited, in this heavily pretreated group of patients suggests a potential role for this agent in combination regimens in patients with earlier disease.

Phase II trial of etoposide and cis-diaminodichloro-platinum in patients with refractory and relapsed Hodgkin's disease: Cancer and Leukemia Group B (CALGB) Study 8353.

A phase II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed Hodgkin's disease (HD) to assess the activity of the combination of etoposide and cis-platin. Twenty-seven patients were entered; 22 were evaluated for this report. Treatment consisted of etoposide (VP-16), 80 mg/m2 IV over 1 hour and cis-platin, 20 mg/m2 IV over 1/2-1 hour; both agents were given daily for 5 days and repeated every 21 days. All patients had received at least 2 prior chemotherapy regimens, had measurable disease, and most (86%) had a performance status of 0-1. In the 22 evaluable patients, there were 4 complete responses (18%) and 4 partial responses, for an overall response rate of 36% (95% Cl: 17.2%, 59.3%). Response duration was from 2.1 to 31 months. Significant toxicity was observed with this regimen. Ten patients (45%) had leukopenia less than 1,000/microliters, and 11 patients (50%) had thrombocytopenia less than 25,000/microliters. Serum creatinine levels reached greater than 2.0 in 14% of patients. Seven patients (32%) had severe nausea and vomiting. VP-16, cis-platin appears to be an active combination in HD; however, their combined activity is only marginally better than reported single-agent activity for VP-16 in the doses and schedule used. Further studies of related combinations in HD are currently under evaluation by the CALGB.

2' Deoxycoformycin (pentostatin) for refractory non-Hodgkin's lymphoma: a CALGB phase II study.

Seventy-six eligible patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) were treated with 2'-deoxycoformycin (pentostatin) at a dose of 4 mg/m2 intravenously weekly for three weeks and then every other week for a minimum of five total treatments. All patients had measurable disease, near normal hematologic, renal, and hepatic function, and a performance status of 0 or 1. Severe hematologic toxicity was observed in 13% of patients; severe renal or neurologic toxicity was observed in less than 5% of patients. There were no treatment-related deaths. Objective therapeutic responses were seen in 16% of patients (five complete response [CR] and seven partial response [PR]). However, in three of the patients achieving CR and one patient achieving PR, dexamethasone was employed as an anti-emetic, making the response of these patients to pentostatin difficult to evaluate. There were eight responses (3 CR) in patients with diffuse histologies and four responses (2 CR) in patients with nodular or mixed histologies. Three responses were in patients with a T-cell phenotype. Three of five patients with diffuse well-differentiated lymphoma (IWF A) responded. We conclude that 2' deoxycoformycin is only minimally active at this dose and schedule against refractory or relapsed NHL. The possibility that low grade B- and T-cell malignancies are more sensitive to 2' deoxycoformycin deserves further investigation.

Phase II study of MOPLACE chemotherapy for patients with previously treated Hodgkin's disease: a CALGB study.

To further evaluate possible non-cross-resistant regimens in Hodgkin's disease, a phase II trial utilizing antimetabolites and etoposide was initiated by the Cancer and Leukemia Group B (CALGB). Etoposide was included because of its known efficacy in relapsed Hodgkin's disease and to evaluate for synergy with an alkylating agent and vincristine. Cytosine arabinoside and methotrexate were included to evaluate their effectiveness in rapidly growing resistant disease. Forty-two patients with previously treated Hodgkin's disease were entered, of which 37 are evaluable for response and toxicity. All patients had at least 2 prior regimens of chemotherapy and 59% had additional radiation therapy. Complete and partial response was observed in 61%; there were 32% complete responders. Duration of complete response was a median of 8 months (range 2-28+ months). Duration of partial response was 7 months (range 1-17 months). Three patients remain in complete remission at 19, 19, and 28 months. Major toxicity was hematologic with severe or life-threatening toxicity in 54%. There was one patient with a fatal infection. Non-hematologic toxicity, save for nausea and vomiting, was mild and uncommon. There were two fatal and one severe pulmonary toxicities reported in patients who had previous exposure to bleomycin and mediastinal radiation. Three had interstitial pneumonitis and one pulmonary emboli. The interstitial pneumonitis was thought to be drug related. Survival of the entire group is estimated at 61% at 12 months. We conclude that MOPLACE is an effective regimen with an appreciable complete response rate in this heavily pretreated group of patients. Hematologic and pulmonary toxicities are severe and may necessitate dose modifications. The use of etoposide containing combinations requires further study as primary therapy in untreated patients.

The immunophenotyping of extramedullary myeloid cell tumors in paraffin-embedded tissue sections.

Extramedullary tissue infiltrates of acute myeloid leukemia are rare and often difficult to recognize in routine paraffin-embedded tissue sections. Since appropriate therapy for these tumors depends on their precise identification, we have studied a series of tissues infiltrated with primitive myeloid cells using monoclonal and polyclonal antibodies capable of labeling cells of the myeloid/monocytic system in paraffin-embedded tissue sections. The current retrospective study involved tissues from 15 patients (eight men and seven women) with a mean age of 51 years (range, 23-77). A diagnosis of extramedullary myeloid cell tumors had been made on the basis of routine histology, chloroacetate esterase cytochemical stain, and--in some cases--electron microscopy. Paraffin-embedded tissue sections were cut and stained employing the alkaline phosphatase antialkaline phosphatase (APAAP) immunocytochemical procedure with monoclonal antibodies against leukocyte-common antigen (PD7/26-2B11), restricted components of the leukocyte-common antigen (UCHL1, 4KB5), granulocytes (Mac-387, Leu-M1), leukocytes (MT1, MT2, LN1, LN2), HLA-DR (LN3), and elastase (NP57), as well as polyclonal antibodies against lactoferrin, lysozyme, alpha-1-antitrypsin, and alpha-1-antichymotrypsin. Results indicate that antibodies against Mac-387, elastase, and lysozyme are most useful in the recognition of neoplastic myeloid cells. We conclude that tissues containing granulocytic tumors can be identified in paraffin-embedded tissue sections using a panel of antibodies and the APAAP procedure.

Treatment of refractory lymphoma with methotrexate, VM-26 (teniposide), procarbazine, and dexamethasone: Cancer and Leukemia Group B study 7902.

Seventy-eight individuals previously treated with chemotherapy for non-Hodgkin's lymphoma were enrolled in a phase II pilot study employing methotrexate 100 mg/M2 iv (day 1), calcium leucovorin 10 mg/M2 iv and/or po q6h (days 2-4), VM-26 (teniposide) 100 mg/M2 iv (days 2 and 9), procarbazine 100 mg/M2 po (days 2-15), and dexamethasone 15 mg/M2po (days 2-8) (MV26PD). Thirty percent of the 78 patients treated had a response to therapy (8% complete, 22% partial). Twenty-four percent of patients with diffuse histiocytic (large cell) lymphoma had a response (12% complete, 12% partial). The estimated failure-free survival was 41% at 3 months and the median survival (death from any cause) was 4.5 months for the entire cohort. Two individuals, including one individual with diffuse histiocytic lymphoma, remain in a complete response for over 900 days. Significant hematologic toxicity and infectious complications were seen in this heavily pretreated group of patients. MV26PD represents an active combination of agents for the treatment of non-Hodgkin's lymphoma. The optimal dosing for MV26PD remains to be determined.

Thrombotic thrombocytopenic purpura: treatment with plasmapheresis.

Twenty-one episodes of thrombotic thrombocytopenic purpura (TTP) were treated with plasmapheresis. Adjunctive agents included corticosteroids, aspirin, dipyridamole, and vincristine. There were 17 patients; 12 were female. The median age was 41 years. Most patients presented with neurologic symptoms. Thrombocytopenia was profound with a mean initial platelet count of 14,900/mm3. The mean hematocrit on presentation was 26.7% and the mean LDH 1300 IU/L. Eighteen episodes responded completely following plasmapheresis/plasma exchange (86%). Response was prompt, the initial rise in platelet count occurred after a mean of four exchanges, and complete response (a platelet count over 150,000/mm3) was obtained after a mean of nine exchanges. Four of the episodes treated were relapses that occurred in three patients. All responders are alive with a median duration of follow-up of 20 months. The three patients who failed to respond have died. This report extends recent observations that the addition of plasmapheresis/plasma exchange to the therapy of TTP has significantly improved the outlook for patients with this disorder.

A randomized trial of high-dose methotrexate versus standard-dose methotrexate following cyclophosphamide, doxorubicin (adriamycin), vincristine, and prednisone with or without bleomycin in the therapy of diffuse large cell lymphoma: preliminary report of Cancer and Leukemia Group B Study 7851.

Between 1979 and 1985, 166 patients with diffuse large cell (histiocytic) lymphoma were randomized to receive therapy with 3 courses of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone (CAVP), with or without low-dose bleomycin, by continuous iv infusion. Responders were further randomized to 3 weeks of therapy with either high-dose methotrexate (3 g/m2 iv weekly with leukovorin rescue) or low-dose methotrexate (30 mg/m2 orally weekly without rescue). Therapy was concluded with 3 additional courses of CAVP. No significant differences among the 4 treatment programs were observed in complete response rates (ranging from 46% to 51%) or in failure-free survival. Of the 38 relapses that have occurred in patients treated with low-dose methotrexate, 5 included relapse in the central nervous system in conjunction with systemic relapse. However, none of 31 relapses observed in patients receiving high-dose methotrexate have occurred with involvement of the central nervous system. Patients entering this study with "B" symptoms had significantly poorer treatment results than those patients entering study without "B" symptoms.