Multicenter phase II study of the CyclOBEAP (CHOP-like + etoposide and bleomycin) regimen for patients with poor-prognosis aggressive lymphoma

Our aim was to study the efficacy of the addition of etoposide and bleomycin to a [cyclophosphamide (CPA), doxorubicin (DXR), vincristine (VCR), and prednisone (PDN)] CHOP-like regimen for the treatment of aggressive lymphoma. The CyclOBEAP regimen was administered over a total period of 12 weeks. Doxorubicin, 50 mg/m², was given every 2 weeks in combination with either cyclophosphamide, 1,000 mg/m², (weeks 1, 5, 9) or etoposide, 70 mg/m² qd ×4 (weeks 3, 7, 11). During the alternate weeks, non-myelosuppressive vincristine, 1.4 mg/m² (maximum, 2.0 mg/body), was given either with bleomycin, 10 mg/m² (weeks 2, 6, 10), or alone (weeks 4,8,12). Prednisolone, 40 mg/m², was administered daily for 14 days during weeks 1–2, 5–6, and 9–10. There were 121 eligible patients and median age of 51 years. A complete response was achieved in 106 patients (88%) and a partial response in 11 patients. The 5-year overall survival (OS) rate was 72% and progression-free survival (PFS) rate was 62%. When the patients were divided according to the International Prognostic Index (IPI), the 5-year OS and PFS rates did not significantly differ among risk groups. When the patients with DLBCL were divided according to the IPI, the 5-year OS and PFS rates also did not significantly differ. World Health Organization (WHO) grade 4 neutropenia was observed in 91 patients and thrombocytopenia in 13 patients. No treatment-related deaths were observed. The addition of etoposide and bleomycin to CHOP therapy may enhance the effect of CHOP therapy for aggressive lymphoma. We will perform a prospective study of CyclOBEAP regimen combined with rituximab and test its safety and efficacy.     

Biweekly COP-BLAM (cyclophosphamide,vincristine, prednisone,bleomycin, doxorubicin and procarbazine) regimen combined with granulocyte colony-stimulating factor (G-CSF) for intermediate-grade non-Hodgkin's lymphoma

Abstract: We evaluated the efficacy and adverse effects of biweekly COP-BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin and procarbazine) therapy combined with granulocyte colony-stimulating factor (G-CSF) for treating non-Hodgkin's lymphoma (NHL). A complete remission was achieved in 65 (90.3%) of the 72 patients. The median follow-up period was 28 months, and 64 patients were alive at the time of writing. Treatment was delivered as scheduled to 61 patients. G-CSF made it possible to shorten the interval between courses of chemotherapy. One of the 72 patients died of granulocytopenia and pneumonia; no other severe infections were noted. Further studies regarding adverse effects on organs other than the bone marrow are required to improve the long-term results of combination therapy on NHL.     

Elevated serum levels of soluble CD44 variant 6 are correlated with shorter survival in aggressive non-Hodgkin's lymphoma

A variant form of CD44 that has additional amino acids in the common protein backbone (CD44-v6) seems to play a role in the metastasis of malignancies. We measured soluble CD44-v6 (sCD44-v6) by ELISA in 201 patients with malignant lymphoma. The sCD44-v6 level was significantly elevated in patients with non-Hodgkin's lymphoma (NHL) (n = 184). The sCD44-v6 level was correlated significantly with the standard sCD44 and soluble interleukin-2 receptor levels, but only weakly with serum lactate dehydrogenase (LDH). In 149 patients with aggressive NHL, the sCD44-v6 level was elevated in the subgroups with a high LDH level, stage III/IV disease, T-cell lymphoma, and high-intermediate or high risk group as identified by the International Prognostic Index (IPI). When the sCD44-v6 level was > or = 800 ng/ml the overall survival rate was significantly decreased (p = 0.0001). In the low + low-intermediate risk group (IPI) both overall survival rates (log-rank p = 0.0005, Wilcoxon p =0.002) were significantly decreased when the sCD44-v6 level was > or = 800 ng/ml. In multivariate analysis, sCD44-v6 was shown to be independent of the five prognostic factors in the IPI (age, performance status, number of extranodal sites, Ann Arbor stage and LDH level), so it may be useful for predicting the outcome of aggressive NHL.     

COP-BLAM regimen combined with granulocyte colony-stimulating factor and high-grade non-Hodgkin's lymphoma

Abstract: The clinical efficacy of COP-BLAM chemotherapy combined with human recombinant granulocyte colony-stimulating factor (G-CSF) was evaluated in 104 previously untreated patients with non-Hodgkin's lymphoma (NHL). According to the method of Laurence et al., a modified COP-BLAM regimen was administered every 21 days. G-CSF was added when the granulocyte count fell below 1000 × 10⁹/l. Ninety-eight of 104 (94.2%) patients achieved a complete remission; the 4-year survival rate was 82.4% with a median duration of observation of 26 months. Survival was significantly longer in patients with low serum LDH levels, B-cell type or low CRP or in earlier clinical stages, than in patients with high serum LDH levels, T-cell type or higher CRP levels or in advanced clinical stages. The mean duration of administration of G-CSF was 5.4 days. Twelve patients developed infections during treatment. The adverse effects of G-CSF included interstitial pneumonia, bone pain and fever. Patients administered COP-BLAM combined with G-CSF achieved a high rate of remission and had a low incidence of infection. Nearly all the patients could be treated in 21-day cycles. The results suggest that G-CSF combined with COP-BLAM was effective in treating NHL, because the patients can tolerate a higher dose of the anticancer agents.     

Serum-soluble tumor necrosis factor receptor 2 (sTNF-R2) level determines clinical outcome in patients with aggressive non-Hodgkin's lymphoma

BACKGROUND: Recently investigators have worked to identify prognostic factors in non-Hodgkin's lymphoma (NHL) so an appropriate therapeutic plan can be put in action. The aim of the present study was to assess the prognostic significance of serum soluble tumor necrosis factor receptor (sTNF-R) 2 in aggressive NHL. METHODS: One hundred and ten consecutive patients with aggressive NHL who were previously untreated (diffuse large B-cell lymphoma; 94, peripheral T-cell lymphoma; 16) were prospectively enrolled in this study between 1997 and 2002. The patients were treated with 6-8 cycles of CHOP or THP-COP regimens. RESULTS: High serum sTNF-Rs level was associated with some poor prognostic factors and low complete remission rate. Patients with high sTNF-R1 (4 ng/mL and over) and sTNF-R2 (15 ng/mL and over) at onset had significantly lower survival rates (5 yr: 19%, 19%) than those with low sTNF-R1 (under 4 ng/mL) and sTNF-R2 (under 15 ng/mL) (62% and 69%), respectively (P < 0.0005 and 0.0001). Multivariate analysis employing sTNF-R2 and some conventional prognostic factors demonstrated that a combination of sTNF-R2 and performance status, and that of sTNF-R2, sIL-2R, and LDH were significant prognostic factors for poor overall survival and for poor event-free survival, respectively. In addition, we attempted to use sTNF-R2 in combination with the international prognostic index (IPI). The patients in the high risk group and those with high sTNF-R2 in the low-intermediate (LI)/high-intermediate (HI) risk group had significantly lower survival rates than the patients in the low risk group and those with low sTNF-R2 in LI/HI risk group (P < 0.0001). CONCLUSIONS: The results suggest that a high serum sTNF-R2 level predicts a poor prognosis in aggressive NHL and may be a useful biomarker for selecting appropriate treatment when used in combination with the IPI.     

Absence of mutations in the granulocyte colony-stimulating factor (G-CSF) receptor gene in patients with myelodysplastic syndrome/acute myeloblastic leukaemia occurring after treatment of aplastic anaemia with G-CSF

The development of myelodysplastic syndrome/acute myeloblastic leukaemia (MDS/AML) has been reported in patients with aplastic anaemia (AA) after administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). Similarly, patients with severe congenital neutropenia (SCN) have an increased risk of developing MDS/AML after treatment with rhG-CSF. Point mutations in the G-CSF receptor gene are found in about 20% of SCN patients who are predisposed to MDS/AML. We investigated the occurrence of mutations in the G-CSF receptor in eight patients with AA who developed MDS/AML. No mutations were detected around the cytoplasmic domain of the gene in our patients, indicating that the mechanisms of clonal evolution to MDS/AML in patients with AA might be different from those with SCN.     

Use of granulocyte colony-stimulating factor (G-CSF) for mobilizing peripheral blood stem cells: risk of mobilizing clonal myeloma cells in patients with bone marrow infiltration

Peripheral blood stem cells have been used for autologous reconstitution of haemopoiesis after high dose cytotoxic therapy and produce similar disease response rates as autologous bone marrow transplants. Peripheral blood stem cell transplants are an especially attractive option for patients in whom marrow harvest is not feasible due to bone marrow damage or infiltration. Recombinant growth factors mobilize adequate numbers of stem cells from the marrow but their effect on tumour cell circulation kinetics is not known. We report a patient with multiple myeloma and bone marrow infiltration in whom the use of G-CSF for stem cell mobilization led to release of plasma cells into the peripheral circulation and contamination of the stem cell harvest.     

Equitoxicity of bolus and infusional etoposide: results of a multicenter randomised trial of the German High-Grade Non-Hodgkins Lymphoma Study Group (DSHNHL) in elderly patients with refractory or relapsing aggressive non-Hodgkin lymphoma using the CEMP regimen (cisplatinum, etoposide, mitoxantrone and prednisone)

To compare toxicity of etoposide bolus with continuous infusion and to assess the efficacy of the CEMP (cisplatinum, etoposide, mitoxantrone, prednisone) regimen, 47 patients with refractory or relapsed aggressive non-Hodgkin's lymphoma older than 60 years (n=43) or not qualifying for high-dose chemotherapy (n=4) received five four-weekly CEMP cycles. Patients were randomised to start with bolus or continuous-infusion etoposide and then received bolus and infusional etoposide in an alternating fashion. The primary objective was the comparison of differences in the course of leukocytopenia and thrombocytopenia between the two application schedules. CEMP was well tolerated with little organ and moderate haematotoxicity. There was no difference in toxicity between bolus and continuous-infusion etoposide. Complete remission rate was 44% in patients relapsing >or=1 year, 27% in patients relapsing within the first year after achieving complete remission and 5% in primary refractory patients. Median event-free and overall survivals for all patients were 3 and 10 months, respectively. The observed equitoxicity and the more challenging logistics of a 60-h infusion make bolus injection the preferred application of etoposide. As the CEMP regimen is well tolerated and efficacious in elderly patients with relapsed or refractory aggressive non-Hodgkin's lymphoma for whom more aggressive therapies are not feasible, a three-weekly modification of CEMP should be tested in combination with rituximab.     

Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group

Phase 2 studies suggest that the monoclonal antibody rituximab may improve the prognosis of patients with follicular lymphoma (FL) when it is added to chemotherapy. In the current study, 428 patients with untreated, advanced-stage FL were randomly assigned for therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone (n = 205) or CHOP combined with rituximab (R-CHOP) (n = 223). R-CHOP reduced the relative risk for treatment failure by 60% and significantly prolonged the time to treatment failure (P < .001). In addition, a significantly higher overall response rate (96% vs 90%; P = .011) and a prolonged duration of remission (P = .001) were achieved. In spite of a relatively short observation time, these beneficial effects even translated to superior overall survival (P = .016), with 6 deaths in the R-CHOP group compared with 17 deaths in the CHOP group within the first 3 years. The predominant treatment-related adverse effect was myelosuppression. Severe granulocytopenia was more frequently observed after R-CHOP (63% vs 53%; P = .01). However, severe infections were rare and of similar frequency after R-CHOP and CHOP (5% and 7%). Hence, adding rituximab to CHOP significantly improves the outcome for patients with previously untreated advanced-stage FL and does not induce major adverse effects.     

Randomized placebo-controlled trial of granulocyte colony stimulating factor (G-CSF) as supportive care after induction chemotherapy in adult patients with acute myeloid leukaemia: a study of the United Kingdom Medical Research Council Adult Leukaemia Working Party

The role of granulocyte colony stimulating factor (G-CSF) as supportive therapy following intensive induction chemotherapy for acute myeloid leukaemia (AML) in adults was investigated in a randomized trial. G-CSF (Lenograstim, 263 μg/d) or placebo was administered from day 8 after the end of chemotherapy until neutrophil recovery to 0·5 × 10⁹/l (or for up to 10 d). Eight hundred and three patients were entered. Neutrophil recovery was quicker with G-CSF ( P  < 0·0001), but this did not lead to differences in the number, severity or duration of infections. There were no substantial supportive care savings, although G-CSF patients spent 2 d less in hospital ( P  = 0·01). Complete remission (CR) rates were similar between arms (73% G-CSF, 75% placebo, P  = 0·5), as were reasons for failure (induction death: P  = 0·7; resistant disease: P  = 0·5) and, for remitters, 5-year disease-free survival (34% vs. 38%, P  = 0·3). Overall survival at 5 years was 29% with G-CSF vs. 36% with placebo ( P  = 0·10). Both CR rate ( P  = 0·006) and overall survival ( P  = 0·006) were worse with G-CSF in patients aged <40 years, but this may be a chance effect. There is some evidence from this trial of an adverse effect of G-CSF but these data need to be viewed in the context of the evidence from the other trials.