- Email: [email protected]
Managing large cell lymphoma
Annals of Oncology 17 (Supplement 4): iv8–iv11, 2006 doi:10.1093/annonc/mdj991
symposium article Managing large cell lymphoma C. Gisselbrecht* & N. Mounier Institute for Hematology, Hoˆpital Saint Louis, Paris, France
Rituximab has greatly improved standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, but prospects remain poor in patients with adverse risk factors. We need to know whether the addition of rituximab also improves the efficacy of more intensive treatments and how to use molecular profiling to guide us in introducing other novel agents. Key words: large cell lymphoma, risk factors, rituximab, chemotherapy, autologous stem cell transplantation
symposium article
Understanding and treatment of aggressive lymphomas have undergone continuous progress. The permanent change in classification has been solved by a recognized histological WHO classification [1] which will evolve with molecular biology findings. The classical chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) has been challenged by several randomized studies, either by increasing dose or dose intensity or by the addition of monoclonal antibodies such as rituximab. The definition of clinical prognostic factors through the international prognostic index (IPI) has been efficient in tailoring therapy for poor prognosis patients.
how to define a poor prognosis lymphoma? These patients have generally two or more IPI prognostic factors where the complete response rate does not exceed 65% with a 5-year probability of survival of less than 50%. Within this group sharing the same adverse factors, it has been showed that several parameters will influence the outcome. A clear distinction that is useful for the treatment has been made between the T non-anaplastic lymphoma of worst prognosis, T anaplastic lymphoma and B large cells lymphomas (DLBCL) [2]. More recently using micro arrays, it has been possible to demonstrate in diffuse large B cell lymphoma that within a clinical group defined by IPI, the distinction between germinal center B cells (GCB) and the activated peripheral blood peripheral B cells (ABC) could further stratify the patients for overall survival [3]. All prognostic markers in lymphoma are subject to the influence of therapy. The prognostic importance of Bcl-2 protein expression as a predictor of inferior survival in patients with DLBCL has been reported. When patients were treated with rituximab and CHOP the negative impact *Correspondence to: C. Gisselbrecht, Institut d’He´matologie, INSERM U728, Hoˆpital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris. France. Tel: +33-1-42-49-92-96; Fax: +33-1 42-49-96-41; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
of Bcl-2 expression was overcome [4]. The introduction of novel biomarker assessment in DLBCL may soon be at the level of routine immunohistochemistry. The definition of poor prognosis lymphoma will be described further in the future and more targeted treatment will emerge from this research work.
progress in treatment before the rituximab era The results of CHOP established this regimen as a standard for several decades. However, with a projected disease-free survival rate of 36%, it is not an ideal treatment and there is a need for better treatment approaches especially in poor prognosis lymphoma. Before the rituximab era, three European randomized studies demonstrated the superiority of intensive chemotherapy when compared with CHOP. In localized stage without adverse prognostic factor [5], the intensive regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) [6] was compared with three cycles of CHOP chemotherapy followed by involved field irradiation. In patients less than 60 years of age with a median follow-up of 7.7 years, there was superiority in survival (90%) and event-free survival (82%) for the 318 patients treated with ACVBP when compared with the survival (81%) and event-free survival (74%) of the 329 patients treated with CHOP and radiotherapy. In multivariate analysis, survival rates were affected by treatment arm but not by the presence of bulky disease. The place of radiotherapy has been considerably reduced with this intensive regimen associated, nevertheless, with severe but manageable toxicities. This was also true for patients with adverse prognostic factors as demonstrated in a randomized trial in which we compared the ACVBP chemotherapy regimen with standard CHOP [7]. Patients aged 61–69 years who had aggressive non-Hodgkin’s lymphoma with at least one adverse prognostic factor (advanced stage, poor performance status or elevated LDH level) were randomly assigned to receive ACVBP or
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 18, 2015
introduction
Annals of Oncology
autologous stem cell transplantation Although major progress has been made since the introduction of rituximab in the treatment of lymphoma, progress should continue for poor prognosis patients as results are far from being satisfactory and lessons coming from autologous stem cell transplantation (ASCT) should be re-evaluated. It has a significant survival advantage over conventional treatment for those with relapsed disease. What is not clear is whether ASCT should be used up-front as part of first-line therapy in patients with poor prognoses. One of the greatest challenges is then to identify those patients who are unlikely to respond to standard therapy or whose response will be of short duration. However, the parameters corresponding to an increased risk of relapse are also associated with a decreased likelihood of obtaining complete remission. What we have learnt from the last 15 years is that the quality of response, before ASCT, and the type and duration of treatment before transplant are important. Selection of patients with adverse prognostic factors is crucial. Several investigators have reported impressive results on the use of
Volume 17 | Supplement 4 | May 2006
ASCT as consolidation therapy for DLBCL poor-prognosis patients. Four randomized trials [9–12] have provided positive information on the role of ASCT in patients with adverse prognostic factors. In the LNH87-2 study [9], 1043 patients with various adverse prognostic factors were enrolled. Complete remission was achieved in 614 patients, who were then randomized to receive either intensive consolidation with ASCT or sequential chemotherapy. There was no difference in overall survival or disease-free survival between the two consolidation arms. However, for the subgroup of 236 patients with at least two adverse IPI factors, ASCT had a significant advantage in terms of 8-year disease-free survival (55% versus 39%, P = 0.01) and in survival (64% versus 39%, respectively, P = 0.04). The absence of consensus on prognostic factors for patients treated with consolidate ASCT increases the difficulty of comparing studies or designing clinical trials on maintenance therapy. We aimed to estimate the prognostic effect of clinical and biological variables by pooling the data from GELA trials on up-front ASCT [13]. Patients less than 60 years old and in complete remission received ASCT after induction ACBVP regimen, as in the LNH87 study. Among 330 patients, the median age was 43 years. Age-adjusted IPI score was equal to 0 in 11%, 1 in 23%, 2 in 51% and 3 in 15%; 140 patients (43%) had more than one extra-nodal site and 69 had marrow involvement. The histological slides showed: B aggressive non-Hodgkin’s lymphoma (NHL) in 249 patients (75%), T NHL in 52 patients (including 23 T anaplastic) and nonclassified NHL in 29 cases. With a median follow-up of 6.5 years, the 5-year OS was 75% and EFS was 67%. The univariate analysis showed that age-adjusted IPI (0–1 versus 2–3) had no prognostic value (5-year OS 76 versus 74%, P = 0.48; EFS 65 versus 66%, P = 0.67). In multivariate analysis only the following parameters had a significant (P < 0.05) adverse effect: age >35 years old, marrow involvement, number of extra-nodal sites >1 and histology (non-anaplastic T versus others). A complementary pair-matched analysis from the same GELA database (on histology, phenotype, extranodal sites, marrow and anthracycline) with control patients treated with ACVBP induction and sequential consolidation chemotherapy confirmed the poor prognosis of non-anaplastic T NHL (5-year OS 44% (chemotherapy) versus 49% (ASCT), P = 0.87; EFS 38% versus 45%, P = 0.89). This cohort study confirms the high efficacy of upfront ASCT in NHL responding patients. Our results suggest that ASCT is able to prevent chemotherapy failure in patients with adverse age-adjusted IPI factors. However, patients presenting with T phenotype or more than one extranodal site still have a higher risk of relapse.
progress in the treatment with rituximab Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, is effective when given as a single agent in the treatment of relapsed or refractory indolent lymphomas and has activity in relapsed or refractory diffuse large-B-cell lymphoma (DLBCL).
doi:10.1093/annonc/mdj991 | iv9
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standard CHOP. Of the 635 patients eligible, the rate of complete response (CR) was 58% in the ACVBP group and 56% in the CHOP group (P = 0.5). Treatment-related death occurred in 13% of the ACVBP group and 7% of the CHOP group (P = 0.014). The median follow-up was 46 months. At 3 years, the event-free survival (EFS) was 45% (95% CI 0.40–0.51) in the ACVBP group and 33% (95% CI 0.28–0.39) in the CHOP group (P = 0.004). The disease-free survival at 3 years was better in the ACVBP group (P = 0.0003). The difference in overall survival (OS) was in favour of the ACVBP arm mostly in patients under 65 years. The conclusion was that ACVBP is a more toxic regimen than CHOP but it prolongs survival and event-free survival in patients with poor-risk aggressive lymphoma. It should be restricted to patients with good performance status and under the age of 65 years. The CR rate was still insufficient. More recently [8], dose intensification was made by shortening the interval between cycles and to determine whether biweekly CHOP (CHOP-14) with or without etoposide (CHOEP) was more effective than the same regimens administered on a 21-day basis. The study included 689 patients aged 61–75 years who were randomized to six cycles of CHOP-21, CHOP-14, CHOEP-21 (CHOP plus etoposide 100 mg/m2 on days 1–3) or CHOEP-14. Complete remission rates were 60.1% (CHOP-21), 70.0% (CHOEP-21), 76.1% (CHOP-14), and 71.6% (CHOEP-14). Five-year event-free and overall survival rates were 32.5% and 40.6% for CHOP-21 and 43.8% and 53.3% for CHOP-14. In a multivariate analysis, the relative risk reduction was 0.66 (P = 0.003) for event-free and 0.58 (P < 0.001) for overall survival after CHOP-14 compared with CHOP-21. Toxicity of CHOP-14 and CHOP-21 was similar, but CHOEP-21 and in particular CHOEP-14 were more toxic. Due to its favourable efficacy and toxicity profile, CHOP-14 was proposed as a new standard chemotherapy regimen for patients aged 60 or older with aggressive lymphoma.
symposium article
symposium article
iv10 | Gisselbrecht & Mounier
response will depend not only on the quality of salvage regimen but on several factors: time to relapse, on/off therapy, prior treatment, secondary IPI. A further uncertainty is the way prior exposure to the antibody may compromise the chances of response to salvage following a relapse [14]. Results should be interpreted with these parameters. In NHL large prospective studies with new combination chemotherapy with rituximab are necessary to establish some standard for salvage chemotherapy. The increasing use of PET scanning during early chemotherapy allows one to assess the biological response and to predict risk of relapse. Patients who are PET-negative after two cycles have much better event-free survival at 2 years than patients who are PET-positive during early treatment [17]. PET scanning will join the list of clinical, immunohistochemical and molecular features of disease that enable us to target novel therapies most in need of them.
references 1. Harris N. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849. 2. Gisselbrecht C, Gaulard P, Lepage E et al. For the GELA. Prognostic significance of T-cell phenotype in aggressive non Hodgkin’s lymphomas. Blood 1998; 92: 76–82. 3. Alizadeh AA, Elsen MB, Davis RE et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11. 4. Mounier N, Brie`re J, Gisselbrecht C et al. For the Groupe d’Etude des Lymphomes de l’Adulte. Rituximab plus CHOP (R-CHOP) in the treatment of elderly patients with diffuse large B-cell lymphome (DLBCL) overcomes Bcl2 associated chemotherapy resistance. Blood 2003; 101: 4279–4284. 5. Reyes F, Lepage E, Ganem G et al. Groupe d’Etude des Lymphomes de l’Adulte (GELA) ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005; 352: 1197–1205. 6. Coiffier B, Gisselbrecht C, Herbrecht R et al. LNH84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma. J Clin Oncol 1989; 7: 1018–1026. 7. Tilly H, Lepage E, Coiffier B et al. Intensive conventional chemotherapy (ACVPB regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin’s lymphoma. Blood 2003; 102: 4284–4289. 8. Pfreundschuh M, Tru¨mper L, Kloess M et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–641. 9. Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high dose therapy in poor risk aggressive non-Hodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol—a Groupe d’Etude des Lymphomse de l’Adulte study. J Clin Oncol 2000; 18: 3025–3030. 10. Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290–1296. 11. Santini G, Salvagno L, Leoni P et al. 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 group. J Clin Oncol 1998; 16: 2796–2802. 12. Milpied N, Deconinck E, Gailllard F et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem cell support. N Engl J Med 2004; 350: 1287–1295. 13. Mounier N, Gisselbrecht C, Brie`re J et al. Prognostic factors in patients with aggressive non-Hodgkin’s lymphoma treated by front-line autotransplantation
Volume 17 | Supplement 4 | May 2006
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Randomized studies demonstrated in DLBCL that CHOP plus rituximab increase CR rate, EFS and overall survival. Factors affecting response are low IPI, Bcl2 oncoprotein overexpression. The GELA completed the first study to compare CHOP plus rituximab with CHOP alone in elderly patients with DLBCL [14]. Previously untreated patients with DLBCL, 60–80 years old, were randomly assigned to receive either eight cycles of CHOP every 3 weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients). The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76% versus 63%, P = 0.005). Updated results with a 5-year median follow-up confirm this benefit [15]. The OS estimate for all patients was 52% ± 6%. OS was significantly longer for the 137 patients treated with R-CHOP than for the remaining 155 treated with CHOP alone (OS 57% ± 8% versus 45% ± 9%, P = 0.02; EFS 47% ± 9% versus 25 ± 8%, P < 0.0001). The OS curves confirmed that R-CHOP was significantly associated with a better OS than CHOP in 193 bcl-2-positive patients (56% ± 9% versus 42% ± 11%, P = 0.01), whereas in 99 bcl-2-negative patients there was no statistically significant difference (58% ± 14% versus 52% ± 15%, P = 0.6). The same results were found for EFS (bcl-2-positive, 46% ± 11% versus 21% ± 9%, P = 0.0001; bcl-2-negative, 49% ± 13% versus 31% ± 13%, P = 0.06). As in DLBCL patients, deaths during the first 2 years mostly reflect treatment failure, rituximab significantly decreases the risk of progression or relapse in both bcl-2-positive (RR = 2.6, P = 0.001) and bcl-2-negative (RR = 2.2, P = 0.01) patients. Results from the MINT study [16] demonstrated the benefit of R-CHEMO for all patients irrespective of these risk factors. However, 2-year TTF after R-CHEMO in patients with bulky disease and/or IPI = 1 was significantly worse (P < 0.001) than in patients with IPI = 0 and no bulk (71% versus 90%, respectively). While further improvement will be difficult to demonstrate for the favorable (IPI = 0, no bulk) subgroup, it is still warranted with regard to TTF for the less favorable subgroup (IPI = 1 and/or bulk). In this study, results with R-CHOP are similar to R-CHOEP. Several randomized studies are ongoing exploring the association of rituximab with other regimens: CHOP/14, ACVBP, DA-EPOCH. Nevertheless, improving the CR rate remains the major goal for these high-risk patients. It is not known if the addition of rituximab in a more intensive regimen for poor prognosis lymphoma will increase the CR rate. The long-term results of the R-CHOP regimen did not show a significant advantage of survival for this group of patients. It seems probable that a group of poor prognosis patients exists who would benefit from high-dose therapy in first remission. The incorporation of rituximab with ASCT may improve the results. The other use of rituximab could be as maintenance after transplantation in order to reduce the relapse rate. Since, at present, the evidence base is not sufficiently substantial, entry into ongoing trials should be encouraged, but patients in first remission should be offered the option of high-dose therapy. From these experiences, it is clear that NHL remain sensitive to chemotherapy after relapses. However, the duration of
Annals of Oncology
Annals of Oncology
after complete remission : a cohort study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2004; 22: 2826–2834. 14. Coiffier B, Lepage E, Brie`re J et al. CHOP plus Rituximab with CHOP chemotherapy in elderly patients with diffuse large B-cell lymphoma. A Groupe d’Etude des Lymphomes de l’Adulte study. N Engl J Med 2002; 346: 235–242. 15. Feugier P, Van Hoff A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117–4126.
symposium article 16. Pfreundschuh M, Truemper L, Gill D et al. First analysis of the completed Mabthera international (MinT) trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): Addition of Rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favourable subgroup with IPI = 0 and no bulky disease. Blood 2004; 104: Abstr 157. 17. Haioun C, Itti E, Rahmouni A et al. 18Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood 2005; 106: 1376–1381.
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Volume 17 | Supplement 4 | May 2006
doi:10.1093/annonc/mdj991 | iv11
symposium article Managing large cell lymphoma C. Gisselbrecht* & N. Mounier Institute for Hematology, Hoˆpital Saint Louis, Paris, France
Rituximab has greatly improved standard cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, but prospects remain poor in patients with adverse risk factors. We need to know whether the addition of rituximab also improves the efficacy of more intensive treatments and how to use molecular profiling to guide us in introducing other novel agents. Key words: large cell lymphoma, risk factors, rituximab, chemotherapy, autologous stem cell transplantation
symposium article
Understanding and treatment of aggressive lymphomas have undergone continuous progress. The permanent change in classification has been solved by a recognized histological WHO classification [1] which will evolve with molecular biology findings. The classical chemotherapy regimen of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) has been challenged by several randomized studies, either by increasing dose or dose intensity or by the addition of monoclonal antibodies such as rituximab. The definition of clinical prognostic factors through the international prognostic index (IPI) has been efficient in tailoring therapy for poor prognosis patients.
how to define a poor prognosis lymphoma? These patients have generally two or more IPI prognostic factors where the complete response rate does not exceed 65% with a 5-year probability of survival of less than 50%. Within this group sharing the same adverse factors, it has been showed that several parameters will influence the outcome. A clear distinction that is useful for the treatment has been made between the T non-anaplastic lymphoma of worst prognosis, T anaplastic lymphoma and B large cells lymphomas (DLBCL) [2]. More recently using micro arrays, it has been possible to demonstrate in diffuse large B cell lymphoma that within a clinical group defined by IPI, the distinction between germinal center B cells (GCB) and the activated peripheral blood peripheral B cells (ABC) could further stratify the patients for overall survival [3]. All prognostic markers in lymphoma are subject to the influence of therapy. The prognostic importance of Bcl-2 protein expression as a predictor of inferior survival in patients with DLBCL has been reported. When patients were treated with rituximab and CHOP the negative impact *Correspondence to: C. Gisselbrecht, Institut d’He´matologie, INSERM U728, Hoˆpital Saint Louis, 1 avenue Claude Vellefaux, 75010 Paris. France. Tel: +33-1-42-49-92-96; Fax: +33-1 42-49-96-41; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
of Bcl-2 expression was overcome [4]. The introduction of novel biomarker assessment in DLBCL may soon be at the level of routine immunohistochemistry. The definition of poor prognosis lymphoma will be described further in the future and more targeted treatment will emerge from this research work.
progress in treatment before the rituximab era The results of CHOP established this regimen as a standard for several decades. However, with a projected disease-free survival rate of 36%, it is not an ideal treatment and there is a need for better treatment approaches especially in poor prognosis lymphoma. Before the rituximab era, three European randomized studies demonstrated the superiority of intensive chemotherapy when compared with CHOP. In localized stage without adverse prognostic factor [5], the intensive regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP) [6] was compared with three cycles of CHOP chemotherapy followed by involved field irradiation. In patients less than 60 years of age with a median follow-up of 7.7 years, there was superiority in survival (90%) and event-free survival (82%) for the 318 patients treated with ACVBP when compared with the survival (81%) and event-free survival (74%) of the 329 patients treated with CHOP and radiotherapy. In multivariate analysis, survival rates were affected by treatment arm but not by the presence of bulky disease. The place of radiotherapy has been considerably reduced with this intensive regimen associated, nevertheless, with severe but manageable toxicities. This was also true for patients with adverse prognostic factors as demonstrated in a randomized trial in which we compared the ACVBP chemotherapy regimen with standard CHOP [7]. Patients aged 61–69 years who had aggressive non-Hodgkin’s lymphoma with at least one adverse prognostic factor (advanced stage, poor performance status or elevated LDH level) were randomly assigned to receive ACVBP or
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 18, 2015
introduction
Annals of Oncology
autologous stem cell transplantation Although major progress has been made since the introduction of rituximab in the treatment of lymphoma, progress should continue for poor prognosis patients as results are far from being satisfactory and lessons coming from autologous stem cell transplantation (ASCT) should be re-evaluated. It has a significant survival advantage over conventional treatment for those with relapsed disease. What is not clear is whether ASCT should be used up-front as part of first-line therapy in patients with poor prognoses. One of the greatest challenges is then to identify those patients who are unlikely to respond to standard therapy or whose response will be of short duration. However, the parameters corresponding to an increased risk of relapse are also associated with a decreased likelihood of obtaining complete remission. What we have learnt from the last 15 years is that the quality of response, before ASCT, and the type and duration of treatment before transplant are important. Selection of patients with adverse prognostic factors is crucial. Several investigators have reported impressive results on the use of
Volume 17 | Supplement 4 | May 2006
ASCT as consolidation therapy for DLBCL poor-prognosis patients. Four randomized trials [9–12] have provided positive information on the role of ASCT in patients with adverse prognostic factors. In the LNH87-2 study [9], 1043 patients with various adverse prognostic factors were enrolled. Complete remission was achieved in 614 patients, who were then randomized to receive either intensive consolidation with ASCT or sequential chemotherapy. There was no difference in overall survival or disease-free survival between the two consolidation arms. However, for the subgroup of 236 patients with at least two adverse IPI factors, ASCT had a significant advantage in terms of 8-year disease-free survival (55% versus 39%, P = 0.01) and in survival (64% versus 39%, respectively, P = 0.04). The absence of consensus on prognostic factors for patients treated with consolidate ASCT increases the difficulty of comparing studies or designing clinical trials on maintenance therapy. We aimed to estimate the prognostic effect of clinical and biological variables by pooling the data from GELA trials on up-front ASCT [13]. Patients less than 60 years old and in complete remission received ASCT after induction ACBVP regimen, as in the LNH87 study. Among 330 patients, the median age was 43 years. Age-adjusted IPI score was equal to 0 in 11%, 1 in 23%, 2 in 51% and 3 in 15%; 140 patients (43%) had more than one extra-nodal site and 69 had marrow involvement. The histological slides showed: B aggressive non-Hodgkin’s lymphoma (NHL) in 249 patients (75%), T NHL in 52 patients (including 23 T anaplastic) and nonclassified NHL in 29 cases. With a median follow-up of 6.5 years, the 5-year OS was 75% and EFS was 67%. The univariate analysis showed that age-adjusted IPI (0–1 versus 2–3) had no prognostic value (5-year OS 76 versus 74%, P = 0.48; EFS 65 versus 66%, P = 0.67). In multivariate analysis only the following parameters had a significant (P < 0.05) adverse effect: age >35 years old, marrow involvement, number of extra-nodal sites >1 and histology (non-anaplastic T versus others). A complementary pair-matched analysis from the same GELA database (on histology, phenotype, extranodal sites, marrow and anthracycline) with control patients treated with ACVBP induction and sequential consolidation chemotherapy confirmed the poor prognosis of non-anaplastic T NHL (5-year OS 44% (chemotherapy) versus 49% (ASCT), P = 0.87; EFS 38% versus 45%, P = 0.89). This cohort study confirms the high efficacy of upfront ASCT in NHL responding patients. Our results suggest that ASCT is able to prevent chemotherapy failure in patients with adverse age-adjusted IPI factors. However, patients presenting with T phenotype or more than one extranodal site still have a higher risk of relapse.
progress in the treatment with rituximab Rituximab, a chimeric anti-CD20 IgG1 monoclonal antibody, is effective when given as a single agent in the treatment of relapsed or refractory indolent lymphomas and has activity in relapsed or refractory diffuse large-B-cell lymphoma (DLBCL).
doi:10.1093/annonc/mdj991 | iv9
Downloaded from http://annonc.oxfordjournals.org/ by guest on August 18, 2015
standard CHOP. Of the 635 patients eligible, the rate of complete response (CR) was 58% in the ACVBP group and 56% in the CHOP group (P = 0.5). Treatment-related death occurred in 13% of the ACVBP group and 7% of the CHOP group (P = 0.014). The median follow-up was 46 months. At 3 years, the event-free survival (EFS) was 45% (95% CI 0.40–0.51) in the ACVBP group and 33% (95% CI 0.28–0.39) in the CHOP group (P = 0.004). The disease-free survival at 3 years was better in the ACVBP group (P = 0.0003). The difference in overall survival (OS) was in favour of the ACVBP arm mostly in patients under 65 years. The conclusion was that ACVBP is a more toxic regimen than CHOP but it prolongs survival and event-free survival in patients with poor-risk aggressive lymphoma. It should be restricted to patients with good performance status and under the age of 65 years. The CR rate was still insufficient. More recently [8], dose intensification was made by shortening the interval between cycles and to determine whether biweekly CHOP (CHOP-14) with or without etoposide (CHOEP) was more effective than the same regimens administered on a 21-day basis. The study included 689 patients aged 61–75 years who were randomized to six cycles of CHOP-21, CHOP-14, CHOEP-21 (CHOP plus etoposide 100 mg/m2 on days 1–3) or CHOEP-14. Complete remission rates were 60.1% (CHOP-21), 70.0% (CHOEP-21), 76.1% (CHOP-14), and 71.6% (CHOEP-14). Five-year event-free and overall survival rates were 32.5% and 40.6% for CHOP-21 and 43.8% and 53.3% for CHOP-14. In a multivariate analysis, the relative risk reduction was 0.66 (P = 0.003) for event-free and 0.58 (P < 0.001) for overall survival after CHOP-14 compared with CHOP-21. Toxicity of CHOP-14 and CHOP-21 was similar, but CHOEP-21 and in particular CHOEP-14 were more toxic. Due to its favourable efficacy and toxicity profile, CHOP-14 was proposed as a new standard chemotherapy regimen for patients aged 60 or older with aggressive lymphoma.
symposium article
symposium article
iv10 | Gisselbrecht & Mounier
response will depend not only on the quality of salvage regimen but on several factors: time to relapse, on/off therapy, prior treatment, secondary IPI. A further uncertainty is the way prior exposure to the antibody may compromise the chances of response to salvage following a relapse [14]. Results should be interpreted with these parameters. In NHL large prospective studies with new combination chemotherapy with rituximab are necessary to establish some standard for salvage chemotherapy. The increasing use of PET scanning during early chemotherapy allows one to assess the biological response and to predict risk of relapse. Patients who are PET-negative after two cycles have much better event-free survival at 2 years than patients who are PET-positive during early treatment [17]. PET scanning will join the list of clinical, immunohistochemical and molecular features of disease that enable us to target novel therapies most in need of them.
references 1. Harris N. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee Meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849. 2. Gisselbrecht C, Gaulard P, Lepage E et al. For the GELA. Prognostic significance of T-cell phenotype in aggressive non Hodgkin’s lymphomas. Blood 1998; 92: 76–82. 3. Alizadeh AA, Elsen MB, Davis RE et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403: 503–11. 4. Mounier N, Brie`re J, Gisselbrecht C et al. For the Groupe d’Etude des Lymphomes de l’Adulte. Rituximab plus CHOP (R-CHOP) in the treatment of elderly patients with diffuse large B-cell lymphome (DLBCL) overcomes Bcl2 associated chemotherapy resistance. Blood 2003; 101: 4279–4284. 5. Reyes F, Lepage E, Ganem G et al. Groupe d’Etude des Lymphomes de l’Adulte (GELA) ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005; 352: 1197–1205. 6. Coiffier B, Gisselbrecht C, Herbrecht R et al. LNH84 regimen: a multicenter study of intensive chemotherapy in 737 patients with aggressive malignant lymphoma. J Clin Oncol 1989; 7: 1018–1026. 7. Tilly H, Lepage E, Coiffier B et al. Intensive conventional chemotherapy (ACVPB regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin’s lymphoma. Blood 2003; 102: 4284–4289. 8. Pfreundschuh M, Tru¨mper L, Kloess M et al. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood 2004; 104: 634–641. 9. Haioun C, Lepage E, Gisselbrecht C et al. Survival benefit of high dose therapy in poor risk aggressive non-Hodgkin’s lymphoma: final analysis of the prospective LNH87-2 protocol—a Groupe d’Etude des Lymphomse de l’Adulte study. J Clin Oncol 2000; 18: 3025–3030. 10. Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290–1296. 11. Santini G, Salvagno L, Leoni P et al. 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 group. J Clin Oncol 1998; 16: 2796–2802. 12. Milpied N, Deconinck E, Gailllard F et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem cell support. N Engl J Med 2004; 350: 1287–1295. 13. Mounier N, Gisselbrecht C, Brie`re J et al. Prognostic factors in patients with aggressive non-Hodgkin’s lymphoma treated by front-line autotransplantation
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Randomized studies demonstrated in DLBCL that CHOP plus rituximab increase CR rate, EFS and overall survival. Factors affecting response are low IPI, Bcl2 oncoprotein overexpression. The GELA completed the first study to compare CHOP plus rituximab with CHOP alone in elderly patients with DLBCL [14]. Previously untreated patients with DLBCL, 60–80 years old, were randomly assigned to receive either eight cycles of CHOP every 3 weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients). The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76% versus 63%, P = 0.005). Updated results with a 5-year median follow-up confirm this benefit [15]. The OS estimate for all patients was 52% ± 6%. OS was significantly longer for the 137 patients treated with R-CHOP than for the remaining 155 treated with CHOP alone (OS 57% ± 8% versus 45% ± 9%, P = 0.02; EFS 47% ± 9% versus 25 ± 8%, P < 0.0001). The OS curves confirmed that R-CHOP was significantly associated with a better OS than CHOP in 193 bcl-2-positive patients (56% ± 9% versus 42% ± 11%, P = 0.01), whereas in 99 bcl-2-negative patients there was no statistically significant difference (58% ± 14% versus 52% ± 15%, P = 0.6). The same results were found for EFS (bcl-2-positive, 46% ± 11% versus 21% ± 9%, P = 0.0001; bcl-2-negative, 49% ± 13% versus 31% ± 13%, P = 0.06). As in DLBCL patients, deaths during the first 2 years mostly reflect treatment failure, rituximab significantly decreases the risk of progression or relapse in both bcl-2-positive (RR = 2.6, P = 0.001) and bcl-2-negative (RR = 2.2, P = 0.01) patients. Results from the MINT study [16] demonstrated the benefit of R-CHEMO for all patients irrespective of these risk factors. However, 2-year TTF after R-CHEMO in patients with bulky disease and/or IPI = 1 was significantly worse (P < 0.001) than in patients with IPI = 0 and no bulk (71% versus 90%, respectively). While further improvement will be difficult to demonstrate for the favorable (IPI = 0, no bulk) subgroup, it is still warranted with regard to TTF for the less favorable subgroup (IPI = 1 and/or bulk). In this study, results with R-CHOP are similar to R-CHOEP. Several randomized studies are ongoing exploring the association of rituximab with other regimens: CHOP/14, ACVBP, DA-EPOCH. Nevertheless, improving the CR rate remains the major goal for these high-risk patients. It is not known if the addition of rituximab in a more intensive regimen for poor prognosis lymphoma will increase the CR rate. The long-term results of the R-CHOP regimen did not show a significant advantage of survival for this group of patients. It seems probable that a group of poor prognosis patients exists who would benefit from high-dose therapy in first remission. The incorporation of rituximab with ASCT may improve the results. The other use of rituximab could be as maintenance after transplantation in order to reduce the relapse rate. Since, at present, the evidence base is not sufficiently substantial, entry into ongoing trials should be encouraged, but patients in first remission should be offered the option of high-dose therapy. From these experiences, it is clear that NHL remain sensitive to chemotherapy after relapses. However, the duration of
Annals of Oncology
Annals of Oncology
after complete remission : a cohort study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2004; 22: 2826–2834. 14. Coiffier B, Lepage E, Brie`re J et al. CHOP plus Rituximab with CHOP chemotherapy in elderly patients with diffuse large B-cell lymphoma. A Groupe d’Etude des Lymphomes de l’Adulte study. N Engl J Med 2002; 346: 235–242. 15. Feugier P, Van Hoff A, Sebban C et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23: 4117–4126.
symposium article 16. Pfreundschuh M, Truemper L, Gill D et al. First analysis of the completed Mabthera international (MinT) trial in young patients with low-risk diffuse large B-cell lymphoma (DLBCL): Addition of Rituximab to a CHOP-like regimen significantly improves outcome of all patients with the identification of a very favourable subgroup with IPI = 0 and no bulky disease. Blood 2004; 104: Abstr 157. 17. Haioun C, Itti E, Rahmouni A et al. 18Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: an early prognostic tool for predicting patient outcome. Blood 2005; 106: 1376–1381.
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Volume 17 | Supplement 4 | May 2006
doi:10.1093/annonc/mdj991 | iv11