VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group

PURPOSE: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B). RESULTS: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed. CONCLUSION: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.     

Therapy of highly malignant non-Hodgkin lymphoma with high-dose chemotherapy and stem cell transplantation

Patients with intermediate or high-grade non-Hodgkin's lymphoma are rarely cured of their disease after the failure of conventional therapy. High-dose chemotherapy followed by transplantation of either autologous marrow (ABMT) or peripheral stem cells (PBSCT) offers such patients a new possibility of cure. To patients younger than 60 years and without contraindications high-dose chemotherapy should be offered in case of relapse and bad prognosis. The PARMA-study demonstrated, that high-dose chemotherapy with subsequent autologous stem cell transplants is superior to conventional chemotherapy for relapsing patients. However high-dose chemotherapy in first complete or partial remission followed by ABMT and PBSCT as post-remission therapy for adult NHL has yielded only similar results randomized to those achieved with conventional chemotherapy in several prospectively studies. This approach should be limited to patients with bad prognostic factors (high-intermediate or high-risk groups according to the International Prognostic Factor Project). The success of ABMT and PBSCT in treating these diseases mandates exploration of the best high-dose chemotherapy, the use of autologous or allogenic bone marrow resp. peripheral stem cell for haematopoietic reconstitution and technical aspects such as purging of tumor cells, the short- and long-term transplant-related mortality continues to be a major concern.     

BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors

In the present paper, we evaluate tolerability, outcome and prognostic factors in patients with poor prognosis non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) when uniformly treated with BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem cell transplant (ASCT). On hundred and forty-eight patients with NHL (n = 112) or HD (n = 36) received BEAM followed by infusion of bone marrow (n = 55), peripheral blood stem cells (n = 79) or both (n = 14). Twenty-eight patients had low-grade lymphoma (LGL), 68 intermediate- and 16 high-grade lymphoma (IGL). Within the NHL group, 21 patients were in 2nd or subsequent complete remission (CR) at transplant, 34 had sensitive disease and 11 resistant disease; 46 patients were transplanted in 1st CR due to the presence of > or = 2 adverse prognostic features at diagnosis or to a slow CR. Of the HD patients at transplant 17 had active disease, 16 were in > or = 2 CR and three in 1st CR. The overall percentage of toxic deaths was 5.4%, while in the group of patients transplanted with PBSC it was only 1.3%. NHL patients: 78% were in CR following ASCT, including 25 out of 45 patients (56%) who were transplanted with active disease. Only two of the 11 patients transplanted with resistant disease achieved CR. Incidence of overall survival (OS) and disease-free survival (DFS) at 3 years was 65 and 75%, respectively. As far as histology was concerned, OS was significantly better for patients with LGL in comparison with IGL (88 vs 56%) (P = 0.002). DFS was significantly higher for patients transplanted in first CR or first partial remission (PR) than it was for those transplanted in a later CR or PR (86 vs 53%) (P = 0.02). Multivariate analysis for OS showed that histology, bulky disease, poor performance status at transplant and achievement of CR were independent prognostic factors. In addition, a high number of infused MNC was associated with poor DFS. HD patients: 30 (83%) were in CR after transplantation, with 25 maintaining CR at the end of the study. Only one of the four patients transplanted with resistant disease reached CR. Incidence of OS and DFS at 3 years was 78 and 81%. DFS was similar for patients transplanted with early or late relapse (95 and 93%). With multivariate analysis, the only independent variable for OS was CR after transplant. In conclusion, the present results demonstrate the efficacy and low toxicity of the BEAM regimen in high-risk lymphoma patients with sensitive disease. Other strategies should be investigated for patients with refractory lymphoma.     

The GIMEMA ALL 0183 trial: analysis of 10-year follow-up. GIMEMA Cooperative Group, Italy

We report the 10-year follow-up of the GIMEMA ALL 0183 trial. From 1983 to 1987, 358 adults with acute lymphoblastic leukaemia (ALL) were entered into this trial, which included a mild induction, an early intensive consolidation, a post-consolidation phase randomized in conventional maintenance (arm A) and in more intensive regimen (arm B). CNS prophylaxis did not include CNS irradiation. The overall complete remission (CR) rate was 79.3% (284/358); 212 patient were randomized (110 in arm A and 102 in arm B). The median overall CR duration was 20 months and the median overall survival (OS) 21 months; both curves reach a plateau after 6 years; at 10 years 25% of patients were projected to be in long-term remission and survivors. The median disease-free survival (DFS) was 17 months, at 10 years 27% and 28% of patients were DFSs in arm A and in arm B respectively. In multivariate analysis age, WBC count and L2 FAB subtype were found to significantly influence OS and DFS. With regard to our previous report OS appears to linearly correlate with initial WBC count and age (P = 0.0002 and P = 0.042 respectively). 195 (68.7%) patients relapsed (only 25 had isolated CNS). The overall second CR rate was 56.5%; 23 patients underwent transplantation (12 BMT and 11 ABMT). Post-relapse survival was found to be influenced by the duration of first CR.     

Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation

Intensive chemotherapy followed by autologous bone marrow transplantation (ABMT) may provide an alternative therapy for young patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS (sAML) lacking a suitable donor. We report the results for 79 patients with MDS/sAML transplanted with autologous marrow in first complete remission (CR). Within the total group of 79, a cohort of 55 patients for whom the duration of first CR was known were compared with a matched control group of 110 patients with de novo AML. The 2-year survival, disease-free survival (DFS), and relapse rates for the 79 patients transplanted in first CR were 39%, 34%, and 64%, respectively. The relapse risk was greater than 55% for all stages and all disease categories. Patients younger than 40 years had a significantly (P = .04) better DFS (39%) than patients older than 40 years (25%). The DFS at 2 years was 28% for the cohort of 55 patients transplanted for MDS/sAML and 51% for those transplanted for de novo AML (P = .025). Relapse rates were 69% for patients with MDS/sAML and 40% for those with de novo AML (P = .007). ABMT for MDS or secondary leukemia results in a lower DFS when compared with similarly treated patients with de novo AML due to a higher relapse rate. The DFS of 28% for these patients suggests that autotransplantation may be a valuable therapy for this disease. The low treatment-related mortality rate of less than 10% supports the view that sufficient numbers of hematopoietic stem cells are present in patients with MDS to allow adequate repopulation after autologous stem-cell transplantation.     

Passive immune globulin therapy in the SIV/macaque model: early intervention can alter disease profile

In this study, we investigated the impact of recombinant interleukin-2 (rIL-2) after high dose chemotherapy and autologous bone marrow transplantation (ABMT) in 25 patients with refractory or relapsed Hodgkin's disease (HD) (11 patients) and non Hodgkin's lymphoma (NHL) (14 patients). 48% of patients had resistant disease, 84% achieved complete remission after ABMT. rIL-2 was started at a median of 54 days post-transplant and consisted of a first cycle of 5 days followed by 4 cycles of 2 days every other week. Patients received a mean of 160 x 10(6) IU/m2 rIL-2 and hematological toxicity was moderate and transient. None of the 5 evaluable patients with measurable disease responded to rIL-2. After a 5 year median follow-up, the probability of survival and DFS is 72% (HD: 73% and NHL: 70%, p = NS) and 45% (HD: 36% and NHL: 48%, p = NS) respectively. These somewhat encouraging results warrant further evaluation of rIL-2 after ABMT in controlled studies, especially in NHL patients stratified for previous chemosensitivity.     

The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA. European Organization for Research and Treatment of Cancer. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto

To determine whether patients with a HLA-identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention-to-treat principles was performed within the framework of the EORTC-GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT), the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients <46 years old and alive >8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: five in resistant disease, 14 during relapse and 19 in CR2. ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six (2%) patients during relapse and in 38 (10%) patients during CR2. The disease-free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P=0.01, RR 0.78, 95% confidence interval 0.63-0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P=0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.     

Women''s anger: relationship of suppression to blood pressure

Myeloablative therapy followed by allogeneic bone marrow transplantation (BMT) has proven to be curative therapy in patients with hematologic malignancies. Relapse, however, remains a major cause of treatment failure for patients with advanced disease. During the past 15 years, we have gained considerable experience with the combination of fractionated total-body irradiation (FTBI) and etoposide followed by allogeneic BMT for hematologic malignancies. In an attempt to decrease post-transplant relapse rates, 67 patients under the age of 50 years with high-risk or advanced-stage hematological malignancies received an intensified regimen of FTBI and etoposide plus cyclophosphamide followed by BMT from a genotypically-matched related donor. The regimen consisted of 1320 cGy of FTBI in 11 fractions, 60 mg/kg of etoposide (VP-16), and 60 mg/kg of cyclophosphamide (CY). Fifty-three patients received cyclosporine and prednisone for graft-vs.-host disease (GVHD) prophylaxis and 14 patients received cyclosporine, methotrexate, and prednisone. Diagnosis at BMT included 45 patients with acute leukemia, 7 patients with chronic leukemia, and 15 patients with high-grade non-Hodgkin's lymphoma (NHL). Actuarial disease-free survival (DFS) at 3 years was 42% +/- 12% for the entire group with a median follow-up of 50 months (range 20-74) for 28 patients who remain alive in continued complete remission (CR). Actuarial 3-year-DFS was 38% +/- 14% in 52 patients with acute or chronic leukemia and 60% +/- 25% in 15 patients with NHL with relapse rates of 45% +/- 16% and 21% +/- 11%, respectively. DFS at 3 years was 40% +/- 18% in 32 patients with acute leukemia in 1st relapse or 2nd CR or chronic myelogenous leukemia in accelerated phase, and was 32% +/- 22% in 20 patients with more advanced disease. Regimen related mortality occurred in 9 patients (4, veno-occlusive disease of the liver; 2, multi-organ failure; 1, diffuse alveolar hemorrhage; 1, central nervous system (CNS) hemorrhage; 1, adult respiratory distress syndrome (ARDS). The combination of FTBI, etoposide, and cyclophosphamide followed by allogeneic BMT is an effective and relatively well-tolerated regimen for patients with advanced hematologic malignancies. The role for this regimen should be further defined by prospective clinical trials.     

Prognostic factors for survival of non-Hodgkin's lymphoma patients treated with high-dose chemotherapy and autologous bone marrow transplantation

Prognostic factors to identify patients with high-risk non-Hodgkin's lymphoma (NHL) have recently been developed. We retrospectively investigated the relation between prognostic factors and treatment outcome after autologous bone marrow transplantation (ABMT). From 1984 to 1994, 80 consecutive patients with NHL responding slowly to or relapsing after front-line therapy were treated with high-dose chemotherapy and ABMT. Prognostic factors at the time of diagnosis and of ABMT were related to clinical outcome after ABMT. The cumulative 5-year overall survival (OS) was 51%, progression-free survival (PFS) 41%, and relapse-free survival (RFS) 53%. Absence of B symptoms and intermediate-grade malignancy at first presentation of disease were independently related to prolonged OS (P = 0.02 and P < 0.01, respectively) and prolonged PFS (P = 0.005 and P = 0.01, respectively). At the time of ABMT, first PR or CR, normal LDH levels and tumour stage I + II were associated with prolonged OS (P = 0.0005, P = 0.03 and P = 0.004, respectively). A Coiffier index of 0 or 1, first PR or CR and no extranodal disease involvement were related to prolonged PFS (P = 0.0002, P = 0.005 and P = 0.07, respectively). Treatment-related deaths occurred in 10% of patients. Assessment of disease status, LDH level, tumour stage, extranodal disease involvement and Coiffier index at the time of ABMT is respectively efficient in predicting treatment outcome after ABMT.     

Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T-cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.     

In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission

PURPOSE: To evaluate in a prospective study the efficacy of autologous bone marrow transplantation (BMT) in adult patients with acute myelogenous leukemia (AML) in first remission, using a single course of high-dose Cytarabine (HD Ara-C) consolidation therapy as in vivo purging. PATIENTS AND METHODS: Sixty consecutive adult patients with AML in first complete remission (CR) were treated with HD Ara-C consolidation therapy as a method of in vivo purging before marrow collection. High-dose therapy consisted of fractionated total-body irradiation (FTBI) 12 Gy, intravenous etoposide 60 mg/kg, and cyclophosphamide 75 mg/kg, followed by reinfusion of cryopreserved marrow. RESULTS: Sixty patients underwent consolidation treatment with HD Ara-C with the intent to treat with autologous BMT. Sixteen patients were unable to proceed to autologous BMT (10 patients relapsed, one died of sepsis, one developed cerebellar toxicity, two had inadequate blood counts, and two refused). Forty-four patients underwent autologous BMT and have a median follow-up time of 37 months (range, 14.7 to 68.7) for patients who are alive with no relapse. The cumulative probability of disease-free survival (DFS) at 24 months in the intent-to-treat group is 49% (95% confidence interval [CI], 37% to 62%) and in those who actually underwent autologous BMT is 61% (95% CI, 46% to 74%). The probability of relapse was 44% (95% CI, 31% to 58%) and 33% (95% CI, 20% to 49%) for the intent-to-treat and autologous BMT patients, respectively. CONCLUSION: This approach offers a relatively high DFS rate to adult patients with AML in first CR. The results of this study are similar to those achieved with allogeneic BMT.     

In vitro evaluation of dissolution properties and degradation products of omeprazole in enteric-coated pellets

Between 1985 and 1990, 133 patients with advanced multiple myeloma (MM) (74% resistance; 41% resistant relapse, RR) were treated with five high-dose therapy (HDT) regimens including: melphalan < or =100 mg/m2 (MEL 100) (46 patients); MEL 100 plus GM-CSF (24 patients); MEL 140 plus autologous bone marrow transplantation (ABMT) (eight patients); MEL 140 plus TBI 850 cGy plus ABMT (37 patients); and thiotepa 750 mg/m2 (THIO 750) + TBI 850 cGy plus ABMT (18 patients). The median follow-up of alive patients as of December 1997 was 9 years. Overall, 17% experienced treatment-related mortality within 60 days (TRM) and 12% achieved stringently defined complete remission (CR) with a median duration of 16 months; four of 16 patients (25%) remain in CR at 10 years. The median durations of event-free survival (EFS)/overall survival (OS) were 6/15 months. Superior EFS/OS were noted with MEL 100 plus GM-CSF and the two TBI-containing regimens (9/24 months among 79 patients) compared to the remaining 54 patients receiving MEL < or =100 or MEL 140 plus ABMT (3/5 months) (P = 0.0001/0.0001, respectively). Multivariate regression analyses (MVA) were performed so that, despite patient heterogeneity among the five treatment groups, potentially relevant disease, host, treatment, and supportive care variables could be identified that were associated with TRM, CR, EFS and OS. TRM was higher with creatinine >2.0 mg/dl, absence of ABMT/GM-CSF support and age >50 years; CR was superior with TBI-containing regimens and < or =12 months of prior therapy; EFS and OS both were longer with B2M < or =2.5 mg/l, age < or =50 years, absence of RR and with ABMT/GM-CSF support. In the presence of >2 favorable variables (32 % of patients), median EFS/OS durations of 18/48 months were observed which progressively declined with 2 and <2 favorable parameters to 6/11 months (28% of patients) to 3/5 months (40% of patients) (P = 0.0001/0.0001). At 10 years, 10 and 20% of patients with >2 favorable variables were event-free and alive, which was also true for the 37 patients receiving MEL 140 plus TBI. To appreciate possible long-term contributions of supportive care or treatment intensity, landmark analyses performed at 1, 2, 4 and 6 months revealed virtually identical ranking orders of prognostically favorable variables to those seen pre-HDT; once supportive care was accounted for, regimen intensity with added TBI did not emerge as an independent favorable feature.     

Autologous bone marrow transplantation with monoclonal antibody purged marrow for children with acute lymphoblastic leukemia in second remission. Spanish Working Party for BMT in Children

The purpose of this study was to evaluate the outcome of children with acute lymphoid leukemia (ALL) in second remission who have undergone high-dose chemotherapy and radiotherapy and autologous bone marrow transplantation (ABMT) with monoclonal antibody purged marrow, and to determine the main prognostic factors. From 1987 to 1992, 55 children with ALL in second remission underwent ABMT. The conditioning regimen consisted of total body irradiation (TBI) plus cyclophosphamide in 21 patients and TBI plus cyclophosphamide plus cytarabine or VP-16 in 28 patients; the remaining six patients were treated with chemotherapy alone (cyclophosphamide and busulfan, and/or VP-16). The marrow was purged using monoclonal antibodies and complement or magnetic microspheres in all cases. All patients engrafted. Three patients (5%) died early post transplant from infections. Twenty-six patients (47%) relapsed (median 150 days); 26 patients (47%) are alive and in complete remission (CR) at a median of 36 months. The Kaplan-Meier estimation showed a probability of event-free survival (EFS) of 46 +/- 0.007%. In the univariate analysis, first CR length and conditioning with TBI plus two or more cytotoxic drugs were found to be the most significant predictors of EFS. ABMT with purged marrow is a treatment modality which offers a chance of cure in children with ALL after relapse, including children who relapse early.     

A radioreceptor assay for mass measurement of inositol (1,4,5)-trisphosphate using saponin-permeabilized outdated human platelets

PURPOSE: To evaluate the therapeutic efficacy of moderate-dose total abdominopelvic irradiation (TAI) in a retrospective series of pretreated non-Hodgkin's lymphomas (NHL). METHODS AND MATERIALS: From 1977 to 1994, 45 patients received TAI after failure of chemotherapy (CT). According to the Working Formulation, 10 patients were diagnosed with class A (group I), 19 with class B, C, or D (follicular) (group II), and 16 with class E or more severe (group III) NHL. Irradiation consisted of two daily fractions of 0.80 Gy each for a total dose of 20 Gy. RESULTS: Mean follow-up after TAI was 102 months (range 8-156). For the entire group, the complete response (CR) rate was 66%, the partial response (PR) rate 29%, 10-year overall survival (OS) 35%, 10-year disease-free survival (DFS) 29%, and median survival 32 months. When results between subgroups were compared, CR was 70% in group I, 84% in group II, and 44% in group III; and survival was statistically higher in group II than in groups I and III: 10-year OS 52% vs. 10% (p < 0.01) and 31% (p < 0.05), respectively, 10-year DFS 37% vs. 10% (p < 0.03) and 19% (p < 0.05), respectively. Grade III or IV complications were gastrointestinal in 27% of patients and hematologic in 25%. CONCLUSION: Large-field irradiation in moderate doses could provide an alternative to bone marrow transplantation in refractory NHL, especially in cases showing a follicular growth pattern.     

Phase II trial of paclitaxel by 24-hour continuous infusion for relapsed non-Hodgkin's lymphomas: Southwest Oncology Group trial 9246

PURPOSE: The Southwest Oncology Group (SWOG) recently conducted a multiinstitutional phase II trial to determine the complete response (CR) and partial response (PR) rates, toxicities, and progression-free and overall survivals of patients with relapsed non-Hodgkin's lymphomas (NHLs) treated with a 24-hour continuous infusion of paclitaxel at a dose of 175 mg/m2. PATIENTS AND METHODS: Sixty-six patients with relapsed NHL who had received minimal prior therapy (one prior chemotherapy regimen for intermediate- to high-grade NHL [44 patients] or one or two prior regimens for low-grade NHL [22 patients]) were premedicated with dexamethasone, diphenhydramine, and cimetidine and then treated with continuous intravenous infusion paclitaxel over 24 hours every 21 days. RESULTS: Eleven of 66 patients (17%) achieved rigorously documented objective remissions, including two CRs (3%) and nine PRs (14%). In addition, another five patients (8%) achieved apparent PRs on a single computed tomographic (CT) scan. Responses were brief, lasting a median of 3 months (5 months for indolent lymphomas and 3 months for intermediate- to high-grade lymphomas). Grade 4 or 5 granulocytopenia was the only common serious toxicity, and occurred in 42 of 66 patients (64%). CONCLUSION: Paclitaxel is generally well tolerated when given as a continuous infusion of 175 mg/m2 over 24 hours, despite predictable granulocytopenia. However, single-agent paclitaxel has modest clinical efficacy compared with other available treatments for relapsed NHL.     

Autologous bone marrow transplantation in acute myeloid leukemia: the University of Minnesota experience

PURPOSE: To report the outcome of autologous bone marrow transplantation for patients with acute myeloid leukemia (AML) in first or greater complete remission (CR) treated by autologous bone marrow transplantation using two different preparatory regimens. METHODS AND MATERIALS: Between September 1986 and August 1993, 75 patients with AML ranging in age from 6 months to 58 years underwent autologous bone marrow transplantation using previously harvested and frozen unpurged (n = 6) or 4-hydroperoxycyclophosphamide purged marrows (n = 69). Patients were in first CR (n = 44) or beyond first CR (n = 31). The preparative regimen consisted of 120 mg/kg of cyclophosphamide (CY) and 1320 cGy total body irradiation (TBI) in eight fractions over 4 days (CY/TBI) in 29 patients; and 16 mg/kg of Busulfan (BU) and 200 mg/kg of CY (BU/CY) in 46 patients. Thirty-five of these 75 patients (18 CY/TBI and 17 BU/CY) were part of a randomized trial comparing the two preparative regimens. RESULTS: At 2 years, overall survival and disease-free survival (DFS) were 49% [95% confidence interval (C.I.) 37-61%] and 43% (95% C.I. 32-55%), respectively. Patients in first CR had a significantly better outcome than patients beyond first CR with an estimated 2-year DFS of 59% (95% C.I. 44-74%) vs. 21% (95% C.I. 5-36%, log-rank p = 0.0001), respectively. For patients conditioned with CY/TBI, the estimated 2-year DFS was 52% compared to 39% for BU/CY (log-rank p = 0.35). Estimated 2-year relapse rates were 44% vs. 56% (log-rank p = 0.40), respectively. For patients in first CR, no differences in DFS were observed between the two regimens (2-year estimates 69% vs. 55% log-rank p = 0.52). Patients beyond first CR had a significantly improved DFS with the CY/TBI regimen (2-year estimates of 38% vs. 7%, log-rank p = 0.04). No differences were found between the two regimens in terms of time to WBC engraftment, absolute neutrophil count of > 500, incidence of bacteremias, or median time to hospital discharge. Interstitial pneumonitis developed in two patients (one BU/CY, one CY/TBI) and venoocclusive disease developed in seven BU/CY patients (Fishers exact test p = 0.04). CONCLUSIONS: For patients beyond first CR, the CY/TBI regiment provided a better outcome, with a significantly better disease-free survival and less venoocclusive disease. For patients in first CR, no significant difference between the two regimens was found. The high relapse rate, especially for patients with advanced disease, emphasizes the need for early transplantation and for new strategies to improve outcome.     

Nodular histiocytic lymphoma: factors influencing prognosis and implications for aggressive chemotherapy

Twenty-five patients with Stage III and IV nodular histiocytic lymphoma (NH), entered on three different Eastern Cooperative Oncology Group protocols from 1972-78, were analyzed for response and survival. A complete response (CR) rate of 44% was observed, with 40% partial responders (PR). Four of the 11 CRs are continuing in their original remission. Median survival for CRs was 52 months; for PRs it was 30 months. The six patients treated with cyclophosphamide-prednisone had a median survival of 18 months versus 51 months for the 19 patients treated with more aggressive combination chemotherapy programs. No significant difference in survival was noted between those patients with both nodular and diffuse histology and those with a pure nodular pattern. The median survival of the 25 NH patients was 47 months and is similar to a group of 101 patients with nodular mixed lymphoma (NM) entered on the same ECOG protocols during this time. This survival is intermediate between the nodular lymphocytic poorly differentiated subtype and diffuse histiocytic lymphoma. It suggests that patients with NH histologies be treated with aggressive combination chemotherapy programs designed to achieve complete remission and prolonged disease-free survival.     

Diagnostic and prognostic value of interleukin-6 in malignant non-Hodgkin's lymphomas

Sixty six patients with non-Hodgkin's lymphomas (NHL) were studied, interleukin-6 (IL-6) was revealed in the blood sera of 33 patients. IL-6 was revealed more frequently in patients with high-grade malignant (p < 0.05) than in those with low-grade malignancy. The largest group of IL-6 positive patients included NHL patients with diffuse large B-cell lymphoma and angioimmunoblastic lymphoma. The marked relationship was found between the serum IL-6 levels and the stage of disease: the serum IL-6 level was significantly lower in untreated patients with Stages II and III disease than in those with end-stage (IV) NHL. IL-6 significantly decreased upon remission, comparable with its level before the initiation of treatment. Analysing the association of prognosis of disease with the serum IL-6 showed that in the group of patients with good (The SNLG index < 2) and intermediate (2 < SNLG index < by 2.6) prognosis, the concentration of this cytokine was significantly lower than in those with poor prognosis (SNLG index > 2.6). There was a significant decrease of the total survival rates of NHL with serum IL-6 found. Therefore, IL-6 is a good prognostic marker in NHL and associated with the activity of a malignant process. Additionally, the increased serum IL-6 levels correlated with NK activities positively and with serum IL-4 levels negatively.     

High-dose multimodality therapy with autologous stem-cell support for stage IIIB breast carcinoma

PURPOSE: Women with locally unresectable and inflammatory breast carcinoma (IBC) have an approximately 30% 5-year disease-free survival (DFS) rate with conventional multimodality therapy. A short but dose-intensive multimodality phase II trial was designed in an attempt to improve outcome in stage IIIB disease. Mastectomy was performed after high-dose therapy to evaluate pathologic response to treatment. METHODS: Women with newly diagnosed disease received four 2-week cycles of doxorubicin 90 mg/m2 with granulocyte colony-stimulating factor (G-CSF), followed by cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 (CTCb) with marrow and peripheral-blood progenitor cell (PBPC) support. Local therapy consisted of mastectomy and radiotherapy. Tamoxifen (5 years) was begun if the patient was estrogen receptor-positive (ER+). RESULTS: Fifty women (46 stage IIIB [91% IBC], four stage IIIA) entered the study and 47 are assessable. Ten had mastectomy before any systemic therapy (seven with pathologic IBC, three with residual tumor after mastectomy). Eighty percent received full-dose doxorubicin with 60% on schedule. Clinical response rates to induction were 15% complete response (CR), 5% very good partial response (VGPR), 59% partial response (PR), and 21% minor response (MR)/stable disease (SD). Mastectomy after CTCb in 37 patients showed a 14% pathologic CR rate, 29% microscopic foci in breast and/or axilla, and 57% gross tumor. Fifteen (32%) patients have relapsed (median, 17 months post-CTCb). The 30-month DFS is estimated at 64%. For those in pathologic CR, with microscopic, or with gross disease remaining after CTCb, the 30-month DFS is estimated at 100%, 70%, and 38%, respectively. Those with zero, one to three, or > or = four positive nodes at axillary dissection had a median DFS of 31, 18, and 13 months, respectively. CONCLUSION: This short but dose-intensive multimodality approach for stage IIIB breast carcinoma is feasible with encouraging results to date.