- Email: [email protected]
Rituximab in High-Grade Lymphoma
Rituximab in High-Grade Lymphoma Carsten Zwick, Niels Murawski, and Michael Pfreundschuh, for the German High-Grade Non-Hodgkin Lymphoma Study Group In 1997, the approval of the anti-CD20 antibody rituximab heralded a new era of combined immunochemotherapy for the treatment of malignant lymphoma. Until then, a combination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) had been the standard of treatment for aggressive B-cell lymphoma for more than 25 years. The addition of rituximab led to an impressive improvement of response rates and survival outcomes in patients with follicular and diffuse large B-cell lymphoma (DLBCL) that has been confirmed in several randomized trials. Remaining challenges in the rituximab era are the identification of the optimal chemotherapy partner with respect to synergistic effects, as well as to the lack of interference with its effector mechanisms. Finally, the question of the optimal dosage and schedule of rituximab has to be addressed in well-designed randomized trials. The outcome of patients relapsing after a rituximabcontaining induction regimen is dismal even with high-dose therapy and autologous stem cell transplantation (ASCT). For these patients new modalities of second-line therapy are urgently warranted. Semin Hematol 47:148 –155. © 2010 Published by Elsevier Inc.
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major goal in the treatment of aggressive B-cell lymphoma was the demonstration that a combination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) was able to induce remissions in about 50% of all patients.1 However, long-term freedom from disease or cure could only be achieved in approximately 30% of patients treated with CHOP. Since the publication of the CHOP regimen in 1976, numerous attempts to improve treatment results by using escalated doses or implementing additional or alternative drugs failed in randomized trials. As demonstrated by a large US intergroup study in 1993 in approximately 1,100 patients, CHOP showed a similar efficacy but significantly less toxicity compared to more intensive second- or third-generation regimens like m-BACOD, ProMACE-CytaBOM, or MACOP-B.2 With the availability of growth factors and the tool of autologous stem-cell support, dose escalation, dose densification (by interval reduction), or combinations thereof were pursued to increase dose intensity in the Innere Medizin I, Saarland University Medical School, Homburg, Germany. Financial disclosure: M.P. is on the Roche Mabthera Advisory Board and has received unrestricted grants from Roche. Address correspondence to Michael Pfreundschuh, MD, Klinik für Innere Medizin I, Saarland University Medical School, D-66421 Homburg (Saar), Germany. E-mail: [email protected] 0037-1963/10/$ - see front matter © 2010 Published by Elsevier Inc. doi:10.1053/j.seminhematol.2010.01.008
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1990s. While dose-escalation strategies including highdose approaches necessitating stem cell support have not convincingly proven to be superior to a baseline CHOP-21 regimen,3–14 dose-dense (biweekly) modifications improved the outcome of young and elderly patients with aggressive lymphoma compared to baseline CHOP.15 In 1997 the approval of rituximab heralded a new era of combined immunochemotherapy of B-cell lymphomas and within a few years the addition of rituximab to CHOP was established as the new standard in first-line treatment of aggressive B-cell non-Hodgkin lymphoma.
RITUXIMAB IN FIRST-LINE TREATMENT OF AGGRESSIVE B-CELL LYMPHOMA Rituximab as a Single Agent The first study demonstrating the efficacy of rituximab in the treatment of aggressive lymphoma was a phase I–II prospective multicenter trial of patients with refractory or relapsing intermediate- or high-grade B cell lymphoma. Fifty-four patients were randomized to receive eight weekly applications of rituximab at a dose of 375 mg/m2 or one infusion at a dose of 375 mg/m2 followed by seven infusions of 500 mg/m2. With an overall response rate of 31% and a median time to progression of 246 days for the 17 responding patients, this trial showed an unexpected high activity of rituximab.16 There were no major differences in response Seminars in Hematology, Vol 47, No 2, April 2010, pp 148 –155
Rituximab in high-grade lymphoma
After those encouraging results, several randomized trials combining rituximab with CHOP were performed in the first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL). In the pivotal LNH 98-5 trial of the French lymphoma study group (Groupe d’Etude des Lymphomes Adultes; GELA) comparing eight cycles of CHOP with eight cycles of rituximab plus CHOP (R-CHOP) as firstline treatment in 399 elderly (60 – 80 years) patients, the addition of rituximab (375 mg/m2) at day 1 of each cycle significantly increased the rate of complete responses (CR/CRu [unconfirmed CR]) compared to CHOP alone (76% v 63%; P ⫽ .005).17 After a median follow-up of 5 years, this translated into a significant improvement of event-free survival (EFS; 47% v 29%; P ⫽ .00002), progression-free survival (PFS; 54% v 30%; P ⬍.00001), disease-free survival (DFS; 66% v 45%; P ⬍.0003), and overall survival (OS; 58% v 45%; P ⬍.007) (Figure 1).18 In a subgroup analysis, patients with low-risk but not with high-risk lymphoma according to the International Prognostic Index (IPI), had a significantly longer survival if treated with the combination. Most importantly, the addition of rituximab did not result in increased toxicity and no long-term toxicity has been reported for the patients treated with R-CHOP. A second randomized trial was performed in young good-prognosis patients by the MabThera International Trial Group (MinT). Young patients (18 – 60 years) with no or one risk factor according to the IPI were randomized to receive six cycles of CHOP-like (CHOP or CHOEP [CHOP ⫹ etoposide]) chemotherapy with (413 patients) or without (410 patients) rituximab (375 mg/ m2) on day 1 of each cycle. The rates of CR/CRu (86% v 68%; P ⬍.0001), as well as the 3-year estimates for EFS (79% v 59%; P ⬍.0001) and OS (93% v 84%; P ⬍.0001), were significantly better for the combination of chemotherapy plus rituximab compared to chemotherapy alone (Figure 1).19 Moreover, a population-based analysis (246 patients) to assess the impact of rituximab in combination with CHOP revealed that 2-year OS significantly increased from 52% to 78% after the recommendation of combining CHOP with rituximab for all patients with newly diagnosed advanced-stage DLBCL in the province of British Columbia.20 After controlling for age and IPI score, era of treatment remained a strong independent
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rates between the two treatment groups and toxicity was mild with 19% of patients having a grade 3 and only one patient having a grade 4 related adverse event. As rituximab monotherapy is a well-tolerated regimen, it can be an option as a palliative treatment for patients not qualifying for more aggressive therapies due to comorbidities or age.
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Figure 1. Improvement of treatment results with the addition of rituximab to anthracycline-based chemotherapy. GELA LNH 9.8-5 trial (A) and MinT-trial (B). Overall survival.
predictor of PFS (risk ratio, 0.59; 95% confidence interval [CI], 0.41– 0.85; P ⫽ .005) and OS (risk ratio, 0.43; 95% CI, 0.29 – 0.66; P ⬍.001). The benefit of treatment in the post-rituximab era was present regardless of age. Based on these results, R-CHOP and equivalent rituximab-containing anthracycline-based regimens are now widely accepted as the standard of care for any stage DLBCL. Although not formally established in the young-high risk population, a clinical benefit of rituximab can be expected from the results in the other risk groups.
Choice of the Optimal Chemotherapy Partner Upon ligation of CD20, rituximab triggers different effector mechanisms. In vitro, three main modes of action of rituximab (direct induction of apoptosis, complement-dependent cytotoxicity [CDC], and antibodydependent cytotoxicity [ADCC]) have been identified.21–26 However, there is no agreement about the contribution of each of these effector mechanisms in vivo. If, indeed, ADCC turns out to be the most important effector mechanism, then effector cells such as natural killer (NK) cells, granulocytes, and macro-
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phages are essential to recognize the Fc portion of rituximab and to mediate cytotoxicity. The combination of rituximab with a more myelosuppressive chemotherapy regimen might therefore compromise the efficacy of rituximab by diminishing the effector cells of ADCC. In this respect, it is of interest that although CHOEP confirmed to be superior to CHOP in the MinTtrial,19 R-CHOP was at least as good as R-CHOEP or even better in some subpopulations. Furthermore, the addition of rituximab to the triple high-dose regimen MegaCHOEP did not improve treatment results when compared to Mega-CHOEP alone.27 In summary, these observations caution against combining rituximab with chemotherapy regimens other than CHOP outside of clinical trials. Another yet unanswered question is whether CHOP combined with rituximab should be given as a biweekly (R-CHOP-14) or every-3-week regimen (RCHOP-21). In the NHL-B2 trial performed by the German High-Grade Lymphoma Study Group (Deutsche Studiengruppe für hochmaligne Non-Hodgkin Lymphome; DSHNHL) dose densification by shortening treatment intervals from 21 (CHOP-21) to 14 days with growth factor support (CHOP-14) in elderly patients resulted in a significant improvement of outcome without increased toxicity.28 Five-year EFS and OS rates were 32.5% and 40.6%, respectively, for CHOP-21 and 43.8% and 53.3%, respectively, for CHOP-14. In a multivariate analysis, the relative risk reduction was 0.66 (P ⫽ .003) for EFS and 0.58 (P ⬍.001) for OS after CHOP-14 compared with CHOP-21. In the subsequent RICOVER-60 trial,29 patients (60 – 80 years of age) were randomized to receive six or eight cycles of CHOP-14 with or without eight applications of rituximab in a 2 ⫻ 2 factorial design. There was no difference in EFS between six and eight cycles, but EFS after R-CHOP was significantly better than after CHOP (P ⫽ .000025). In a multivariate analysis using 6x CHOP-14 as the reference, PFS improved after 6x R-CHOP-14 and 8x R-CHOP-14, but OS only improved after 6x R-CHOP 14 (relative risk, 0.63 [0.46 – 0.85]; P ⫽ .0031) (Figure 2). As the results of this largest randomized trial (826 evaluable patients) with an OS of 78% after 3 years are the best ever reported for elderly patients, six cycles of R-CHOP-14 with growth factor support and two additional applications of rituximab should be considered as the standard treatment for this population. Ongoing trials of the French GELA and the British National Cancer Research Institute comparing R-CHOP-21 and R-CHOP-14 are addressing the question of biweekly or every-3-week application of R-CHOP in a randomized fashion. In a preliminary report of the National Cancer Research Institute (NCRI) study in DLBCL patients of all ages, no major differences in efficacy and toxicity between R-CHOP-14 and R-CHOP-21 have been observed.30
C. Zwick, N. Murawski, and M. Pfreundschuh
0.6 0.5 1: 6 x CHOP -14 (n=307) 2: 8 x CHOP -14 (n=305) 3: 6 x R-CHOP- 14 (n=306) 4: 8 x R-CHOP- 14 (n=304)
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Figure 2. Superiority of 6x R-CHOP 14 over 8x R-CHOP 14. Overall survival. RICOVER-trial.
Intensifying Rituximab Pharmacokinetic data in humans have only been obtained from patients with indolent lymphoma but not from DLBCL patients. Information regarding minimal serum levels and areas under the curve necessary to achieve tissue levels that are sufficient to kill the malignant DLBCL clone in situ is lacking. The commonly used dosage of rituximab (375 mg/m2) and the schedule of giving rituximab with each cycle of chemotherapy are mainly based on practicability and economic considerations. Rituximab has proven its efficacy when given every 3 weeks (R-CHOP 21),17,18,31 as well as when given biweekly (R-CHOP-14).29 However, the addition of rituximab to the biweekly regimen in the German trial resulted in a more pronounced improvement compared to the every-3-weeks regimen in the French trial, where the addition of rituximab even failed to reach significance with respect to survival in elderly poorprognosis patients. Analyzing rituximab trough serum levels in patients with biweekly applications32 showed an increase of preinfusion levels over the first four cycles. From the fifth to the eighth cycle rituximab levels reach a plateau and decrease slowly after the end of therapy with detectable levels of rituximab even after 9 months (Figure 3). For the every-3-weeks regimen, the decrease of serum levels between the cycles can be expected to be even more pronounced, possibly falling below a threshold that is needed to maintain efficacy. An explanation for the decrease of serum levels might be that during the first cycles a major portion of the antibody binds to and eliminates normal B cells and a vast amount of tumor cells. Based on these considerations, dose intensification at the beginning of therapy with a faster saturation might increase the benefit of rituximab application. This could also be
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concluded from the results of the GELA LNH 98 –517,18 and the Eastern Cooperative Oncology Group (ECOG) trial31: in the GELA trial eight applications of rituximab were given, whereas in the ECOG trial only five applications with two “dose-dense” applications before the first chemotherapy cycle (day –7 and –3) were administered (Figure 4). As the therapeutic gain that has been achieved in both trials by the addition of rituximab was very similar, it could be speculated that the dose-dense application of rituximab at the beginning of immunochemotherapy might be more relevant than the absolute number of rituximab cycles. A phase II study to evaluate the efficacy and pharmacokinetics of dosedense rituximab with four additional rituximab applications within the first 2 weeks is currently ongoing in Germany.33
RITUXIMAB IN THE SALVAGE TREATMENT OF AGGRESSIVE B-CELL LYMPHOMA Patients who fail to achieve a remission or relapse following first-line treatment have a poor prognosis with a life expectancy of 3 to 4 months. As less than 10% of these patients obtain long-term DFS with conventional chemotherapy alone, it is widely accepted that a remission should—whenever possible— be consolidated with high-dose therapy and autologous stem cell transplantation (ASCT). In the PARMA trial 109, chemotherapy-sensitive relapsed DLCBL patients were randomized to salvage chemotherapy with platinumand cytarabine-based chemotherapy alone or in combination with ASCT.34,35 Both EFS (46% v 12 % after 5 years; P ⫽ .001) and OS (53% v 32% after 5 years; P ⫽ .038) were significantly superior in the transplant group compared to the conventional DHAP (cisplatin, cytarabine, and dexamethasone). Based on these results, high-dose therapy with ASCT following induction chemotherapy has become the standard of care in patients with relapsed or primary refractory lymphoma in the pre-rituximab era.
In recent years, a number of chemotherapy combinations have been investigated in the salvage setting, mainly in nonrandomized phase II trials.36 – 48 Platinumbased salvage regimens like DHAP, ICE (ifosfamide, carboplatin, etoposide), or ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) are currently widely used and produced overall response rates rarely exceeding 50% with 2-year survival rates ranging from 7% to 35%. In a single-arm study, combining rituximab with ICE in patients with refractory or relapsed DLBCL following an anthracycline-based first-line regimen resulted in overall response and complete response rates of 78% and 53%, respectively. Compared to historical controls with similar IPI scores, this CR rate is nearly twice as high as with ICE alone. Patients with relapsed disease had a significantly higher overall response rate than those with primary refractory disease (96% v 46%; P ⬍.001).49 Similar results have been obtained for the combination of rituximab with DHAP in 53 patients with refractory or relapsed aggressive B-cell lymphoma with an overall response rate of 62% in the overall cohort and of 81% for the cohort of patients who were treated at first relapse. In a matched-pair analysis of 23 patient pairs, R-DHAP produced a higher CR rate than DHAP, although statistical significance was not reached.50 In an ongoing trial of the HOVON (HematoOncologie voor Volwassenen Nederland) group, 239 patients were randomized to receive a salvage regimen consisting of DHAP-VIM (etoposide, ifosfamide, methotrexate)-DHAP with or without rituximab.51 Overall response rates after two cycles and post-transplantation were 75% versus 54% (P ⬍.1) and 73% versus 50% (P ⫽ .003) in favor of the R-DHAP arm. After 24 months, a significant increase in failure-free survival (FFS; 50% v 24%; P ⬍.001) but not in OS (52% v 59%) could be demonstrated with combined immunochemotherapy. In a Cox regression analysis, rituximab treatment had a significant effect on FFS and OS when adjusted for time since upfront randomization, age, performance status, and secondary IPI. Taken together, these trials suggest that the inclusion of rituximab into salvage regimens
Figure 4. Schedule of rituximab application in the GELA and the ECOG trial.
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results in higher overall response and CR rates compared with chemotherapy alone, enabling more patients to proceed to ASCT. Whether this translates into improved survival outcomes will have to be analyzed when long term follow-up data are available. To define the optimal salvage regimen in combination with rituximab, the CORAL trial (Collaborative Trial in Relapsed Aggressive Lymphoma) compared R-DHAP with R-ICE as induction therapy before ASCT in patients with relapsed/refractory lymphoma. In an interim analysis of 396 patients, no significant difference between R-ICE and R-DHAP has been observed with respect to overall response rate (63.5 v 62.8%), 3-year EFS (26% v 35%; P ⫽ .6), and OS (47% v 51%; P ⫽ .5).52 As the majority of patients in earlier studies had not been previously exposed to rituximab, the role of rituximab re-treatment after a rituximab-containing induction regimen has still not been defined. In a retrospective analysis of the GELA LNH 98 –5 trial, relapsing patients treated with a rituximab-containing salvage regimen had a 2-year survival of 58% compared with 24% for those treated without rituximab (P ⫽ .00067).18 Importantly, in patients treated with CHOP alone as firstline treatment, the benefit of the addition of rituximab at the time of salvage therapy is statistically significant (P ⫽ .002), whereas it is not in patients initially treated with R-CHOP (P ⫽ .23). However, as only nine patients received a second-line regimen with rituximab following first-line R-CHOP, it is not possible to draw any conclusions from this trial regarding the benefit of rituximab re-treatment. Recently, the outcome of elderly patients treated within the RICOVER-60 trial and relapsing after or refractory to CHOP or R-CHOP has been analyzed retrospectively. Fifty-nine percent of 297 patients received rituximab as part of salvage therapy. Three-year OS was significantly better for patients receiving salvage chemotherapy with rituximab compared to chemotherapy alone (39% v 18%; P ⬍.001). Whereas this effect was most pronounced in patients receiving primary treatment without rituximab (OS 43% v 24%; P ⬍.001), it was still detectable in patients receiving primary R-CHOP.53 Taken together, the efficacy of re-treatment with rituximab in patients with relapses following rituximab-containing primary treatment remains to be proven. The observation that patients failing a rituximabcontaining primary treatment have a poor prognosis has been made in a number of trials. The GEL/TAMO group (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea) evaluated the influence of prior exposure to rituximab on response rates and survival in patients with relapsing DLBCL treated with rituximab plus etoposide, cytarabine, cisplatin, and methylprednisolone (R-ESHAP).54 Of the 163 patients analyzed, rituximab had been administered to 94 patients during induction treatment (R⫹ group), whereas 69 patients had not received rituximab (R⫺ group). With a median
C. Zwick, N. Murawski, and M. Pfreundschuh
follow-up of 29 months, patients in the R⫹ group had significantly worse PFS (17% v 57% at 3 years; P ⬍.0001) and OS (38% v 67% at 3 years; P ⫽ .0005) than patients in the R⫺ group. Prior exposure to rituximab was an independent adverse prognostic factor for both PFS (relative risk 2.0; 95% CI, 1.2–3.3; P ⫽ .008) and OS (relative risk 2.2; 95% CI, 1.3–3.9; P ⫽ .004). Response rates were significantly higher in the R⫺ group in the univariate but not in the multivariate analysis. In the analysis restricted to the R⫹ group, very low complete remission and overall response rates were observed in patients with primary refractory disease (8% and 33%, respectively), compared to those in patients who were in first partial remission (41% and 86%) or who had relapsed disease (50% and 75%) (P ⬍.01 in both cases). A recently reported interim analysis of the CORAL trial also confirms that the outcome of second line treatment is worse after a rituximab-containing induction therapy (EFS after 3 years, 21% v 47%; P ⬍.001), especially for patients with early relapse (⬍12 months) (EFS after 3 years, 20% v 45%; P ⬍.001).52 In a retrospective analysis of the RICOVER-60 trial, patients relapsing after R-CHOP had an impaired EFS compared to patients relapsing after CHOP alone (EFS after 3 years, 23% v 44%; P ⫽ .016). High-dose therapy with ASCT was effective only in patients receiving primary treatment without rituximab, whereas the rate of long-term survivors was in the range of only 10% after primary R-CHOP.53 In a study investigating the efficacy of R-GemOx (rituximab, gemcitabine, and oxaliplatin) in 46 patients with relapsed or refractory B-cell lymphoma, the probability of remaining relapse-free at 2 years was 81% for the 19 responders not previously treated with rituximab compared with 37% for the 19 patients previously treated with rituximab.55 The CR/Cru rate of this low-toxicity regimen was 72% after eight cycles of treatment. The 2-year EFS and OS rates were 43% and 66%, respectively, and the median time to progression was 22 months. In summary, patients refractory to or experiencing an early relapse (⬍12 months) after a rituximab-containing primary treatment represent a negative selection and have a poor prognosis. In contrast to patients without a rituximab-containing first-line regimen, highdose chemotherapy with autologous stem cell support has only limited activity in these patients. As nearly all patients relapsing in the rituximab era will have been exposed to rituximab in first-line, new modalities of second-line therapy are urgently warranted.
Rituximab as Maintenance Therapy In follicular lymphoma, maintenance therapy with rituximab after chemoimmunotherapy in patients with previously treated lymphoma has been reported to improve PFS.56 The optimal maintenance regimen has not yet been defined.57–59 In the ECOG trial, 632 elderly
Rituximab in high-grade lymphoma
patients with DLBCL were first randomized to receive CHOP or R-CHOP and underwent a second randomization after achieving a partial or complete remission into rituximab maintenance (375 mg/m2 weekly times 4, every 6 months times 4) or observation. Interestingly, patients who received rituximab maintenance had a significantly increased FFS (FFS after 2 years, 76% v 61%; P ⫽ .09), but this advantage was only observed in patients who had not received rituximab as part of their induction therapy.53 In the CORAL trial, patients after ASCT were randomized to receive rituximab maintenance over 1 year or observation. Results of the second randomization are not yet available.52 A longer follow-up is necessary to answer the question of whether rituximab maintenance may provide a benefit after ASCT in high-grade lymphoma patients.
Conclusions The inclusion of rituximab in first-line treatment of aggressive B-cell lymphoma has significantly improved overall response rates, EFS, PFS, and OS of patients with CD20⫹ aggressive lymphoma. A combination of rituximab and an anthracycline-based chemotherapy has been accepted as the standard of treatment for patients with any stage DLCBL. Although not formally proven in young high-risk patients, a clinical benefit of rituximab can be expected from the results in the other risk groups. Whether and to what extent an intensified application at the beginning of treatment might improve treatment results will be investigated in ongoing trials. In the salvage setting, the use of rituximab in rituximab-naive patients results in higher overall response rates. Whether this translates into improved survival outcomes will have to be analyzed when long-term follow-up data are available. In contrast, the efficacy of rituximab in re-treating patients with relapses following rituximab-containing primary treatment remains to be proven. Patients relapsing after or refractory to rituximab-containing induction treatment have a poor prognosis with high-dose chemotherapy and ASCT being less efficient than in patients pretreated with chemotherapy alone. For these patients new treatment strategies are urgently warranted. The role of maintenance treatment will be addressed in the CORAL trial in a randomized fashion. A longer follow-up is necessary to answer this question.
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REFERENCES 1. McKelvey EM, Gottlieb JA, Wilson HE, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38:1484 –93. 2. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328:1002– 6. 3. Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation
15.
compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med. 1997;336:1290 –7. Haioun C, Lepage E, Gisselbrecht C, et al. Survival benefit of high-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: final analysis of the prospective LNH87–2 protocol—a Groupe d’Etude des Lymphomes de l’Adulte study. J Clin Oncol. 2000;18:3025–30. Verdonck LF, van Putten WL, Hagenbeek A, et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1995;332:1045–51. 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 Study Group. J Clin Oncol. 1998;16:2796 – 802. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin’s lymphoma: randomized phase III EORTC study. J Natl Cancer Inst. 2001;93:22–30. Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for “aggressive” lymphoma. J Clin Oncol. 2002;20:4413–9. Gisselbrecht C, Lepage E, Molina T, et al. Shortened first-line high-dose chemotherapy for patients with poorprognosis aggressive lymphoma. J Clin Oncol. 2002;20: 2472–9. Martelli M, Gherlinzoni F, De Renzo A, et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin’s lymphoma: an Italian multicenter randomized trial. J Clin Oncol. 2003;21:1255– 62. Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med. 2004;350:1287–95. Betticher DC, Martinelli G, Radford JA, et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol. 2006;17:1546 –52. Olivieri A, Santini G, Patti C, et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin’s lymphoma: longterm results by the NHLCSG. Ann Oncol. 2005;16: 1941– 8. Vitolo U, Liberati AM, Cabras MG, et al. High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an “Intergruppo Italiano Linfomi” randomized trial. Haematologica. 2005;90:793– 801. Pfreundschuh M, Trumper L, Kloess M, et al. Twoweekly 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 – 41.
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16. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (antiCD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998;92:1927–32. 17. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235– 42. 18. Feugier P, Van Hoof 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;23:4117–26. 19. Pfreundschuh M, Truemper L, Osterborg A, et al. CHOPlike chemotherapy plus rituximab compared with CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomized controlled trial by the Mabthera International Trial (MInT) Group. Lancet Oncol. 2006;7:379 –91. 20. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23:5027–33. 21. Manches O, Lui G, Chaperot L, et al. In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood. 2003;101:949 –54. 22. Van der Kolk LE, Evers LM Omene C, et al. CD20-induced B cell death can bypass mitochondria and caspase activation. Leukemia 2002;16:1735– 44. 23. Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol. 2000;51:634 – 41. 24. Dall’Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 2004;64:4664 –9. 25. Golay J, Cittera E, Di Gaetano N, et al. The role of complement in the therapeutic activity of rituximab in a murine B lymphoma model homing in lymph nodes. Haematologica. 2006;91:176 – 83. 26. Uchida J, Hamaguchi Y, Oliver JA, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptordependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004; 199:1659 – 69. 27. Schmitz R, Nickelsen M, Ziepert M, et al. Aggressive chemotherapy (CHOEP-14) and rituximab or high-dose therapy (MegaCHOEP) and rituximab for young high-risk patients with aggressive B-cell lymphoma: results of the MegaCHOEP trial of the German High-Grade NonHodgkin Lymphoma Study Group (DSHNHL) [abstract]. ASH Annual Meeting Abstracts. 2009;114;22:404. 28. Pfreundschuh M, Trumper L, Kloess M, et al. Twoweekly 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 – 41. 29. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20⫹ B-cell
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30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105–16. Cunningham D, Smith P, Mouncey P, et al. A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin‘s lymphoma [abstract 8506]. J Clin Oncol. 2009;27:15s. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121–7. Reiser M, Wenger M, Nickenig C, et al. Serum levels and pharmacokinetics of rituximab in bi-weekly R-CHOP in elderly patients with DLBCL treated in the RICOVER-60 trial [abstract]. J Clin Oncol 2006;24:430s. Poeschel V, Nickelsen M, Hänel M, et al. Dose-dense rituximab in combination with bi-weekly CHOP-14 for elderly patients with diffuse large B-cell lymphoma: results of phase I/II and pharmacokinetic study of the German High-grade Non-Hodgkin Lymphoma Study Group. Blood. 2006;108:774a–5a. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333: 1540 –5. Guglielmi C, Gomez F, Philip T, et al. Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol. 1998;16: 3264 –9. Cabanillas F, Hagemeister FB, Bodey GP, Freireich EJ. IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood. 1982;60:693–7. De Lord C, Newland AC, Linch DC, Vaughan HB, Vaughan HG. Failure of IMVP-16 as second-line treatment for relapsed or refractory high grade nonHodgkin’s lymphoma. Hematol Oncol. 1992;10:81– 6. Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988;71:117–22. Soussain C, Souleau B, Gabarre J, et al. Intensive chemotherapy with hematopoietic cell transplantation after ESHAP therapy for relapsed or refractory non-Hodgkin’s lymphoma. Results of a single-centre study of 65 patients. Leuk Lymphoma. 1999;33:543–50. Sweetenham JW, Johnson PW. ESHAP chemotherapy for relapsed/refractory non-Hodgkin’s lymphoma. J Clin Oncol. 1994;12:2766. Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994;12:1169 –76. Rodriguez MA, Cabanillas FC, Velasquez W, et al. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol. 1995;13: 1734 – 41. Wilson WH, Bryant G, Bates S, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory nonHodgkin’s lymphoma. J Clin Oncol. 1993;11:1573– 82.
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44. Chao NJ, Rosenberg SA, Horning SJ. CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin’s lymphoma. Blood. 1990;76:1293– 8. 45. Cortelazzo S, Rambaldi A, Rossi A, et al. Intensification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin’s lymphoma. Br J Haematol. 2001;114:333– 41. 46. Atta J, Chow KU, Weidmann E, et al. Dexa-BEAM as salvage therapy in patients with primary refractory aggressive non-Hodgkin lymphoma. Leuk Lymphoma. 2007;48:349 –56. 47. Reiser M, Josting A, Dias WP, et al. Dexa-BEAM is not effective in patients with relapsed or resistant aggressive high-grade non-Hodgkin’s lymphoma. Leuk Lymphoma. 1999;33:305–12. 48. Moskowitz C, Hamlin PA, Horwitz SM, et al. Phase II trial of dose-dense R-CHOP followed by risk-adapted consolidation with either ICE or ICE and ASCT, based upon the results of biopsy-confirmed abnormal interim restaging PET scan improves outcome of patients with advanced stage DLBCL [abstract]. Blood. 2006;108:161a. 49. Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103:3684 – 8. 50. Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine and cisplatin in combination wirh rituximab as salvage treatment patients with relapsed or refractory aggressive non-Hodgkin‘s lymphoma. Cancer Invest. 2006;24:593– 600. 51. Vellenga E, van Putten WL, ’t Veer MB, et al. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20⫹ NHL: a prospective randomized HOVON trial. Blood. 2008;111: 537– 43. 52. Gisselbrecht C, Glass B, Mounier N, et al. R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large
155
53.
54.
55.
56.
57.
58.
59.
B-cell lymphoma followed by autologous stem cell transplantation [abstract]. J Clin Oncol. 2009;27:436s. Glass B, Borgerding A, Ziepert M, et al. Outcome of elderly patients with DLBCL failing R-CHOP. The role of rituximab and high dose therapy in second line treatment. A retrospective analysis from the RICOVER 60 trial. [abstract]. ASH Annual Meeting Abstracts. 2009; 114;22:3714. Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008;93:1829 –36. El Gnaoui T, Dupuis J, Belhadj K, et al. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007;18: 1363– 8. Van Oers M, Van Glabekke M, Baila L, Giurgia L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin‘s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study [abstract]. Am Soc Hematol. 2008:836. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with R-FCM in patients with refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006;108:4003– 8. Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event free survival and response duration compared with the standard weekly ⫻ 4 schedule. Blood. 2004;103:4416 –23. Hainsworth JD, Litchy S, Burris HA, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin‘s lymphoma. J Clin Oncol. 2002;20: 4261–7.
A
major goal in the treatment of aggressive B-cell lymphoma was the demonstration that a combination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) was able to induce remissions in about 50% of all patients.1 However, long-term freedom from disease or cure could only be achieved in approximately 30% of patients treated with CHOP. Since the publication of the CHOP regimen in 1976, numerous attempts to improve treatment results by using escalated doses or implementing additional or alternative drugs failed in randomized trials. As demonstrated by a large US intergroup study in 1993 in approximately 1,100 patients, CHOP showed a similar efficacy but significantly less toxicity compared to more intensive second- or third-generation regimens like m-BACOD, ProMACE-CytaBOM, or MACOP-B.2 With the availability of growth factors and the tool of autologous stem-cell support, dose escalation, dose densification (by interval reduction), or combinations thereof were pursued to increase dose intensity in the Innere Medizin I, Saarland University Medical School, Homburg, Germany. Financial disclosure: M.P. is on the Roche Mabthera Advisory Board and has received unrestricted grants from Roche. Address correspondence to Michael Pfreundschuh, MD, Klinik für Innere Medizin I, Saarland University Medical School, D-66421 Homburg (Saar), Germany. E-mail: [email protected] 0037-1963/10/$ - see front matter © 2010 Published by Elsevier Inc. doi:10.1053/j.seminhematol.2010.01.008
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1990s. While dose-escalation strategies including highdose approaches necessitating stem cell support have not convincingly proven to be superior to a baseline CHOP-21 regimen,3–14 dose-dense (biweekly) modifications improved the outcome of young and elderly patients with aggressive lymphoma compared to baseline CHOP.15 In 1997 the approval of rituximab heralded a new era of combined immunochemotherapy of B-cell lymphomas and within a few years the addition of rituximab to CHOP was established as the new standard in first-line treatment of aggressive B-cell non-Hodgkin lymphoma.
RITUXIMAB IN FIRST-LINE TREATMENT OF AGGRESSIVE B-CELL LYMPHOMA Rituximab as a Single Agent The first study demonstrating the efficacy of rituximab in the treatment of aggressive lymphoma was a phase I–II prospective multicenter trial of patients with refractory or relapsing intermediate- or high-grade B cell lymphoma. Fifty-four patients were randomized to receive eight weekly applications of rituximab at a dose of 375 mg/m2 or one infusion at a dose of 375 mg/m2 followed by seven infusions of 500 mg/m2. With an overall response rate of 31% and a median time to progression of 246 days for the 17 responding patients, this trial showed an unexpected high activity of rituximab.16 There were no major differences in response Seminars in Hematology, Vol 47, No 2, April 2010, pp 148 –155
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After those encouraging results, several randomized trials combining rituximab with CHOP were performed in the first-line treatment of patients with diffuse large B-cell lymphoma (DLBCL). In the pivotal LNH 98-5 trial of the French lymphoma study group (Groupe d’Etude des Lymphomes Adultes; GELA) comparing eight cycles of CHOP with eight cycles of rituximab plus CHOP (R-CHOP) as firstline treatment in 399 elderly (60 – 80 years) patients, the addition of rituximab (375 mg/m2) at day 1 of each cycle significantly increased the rate of complete responses (CR/CRu [unconfirmed CR]) compared to CHOP alone (76% v 63%; P ⫽ .005).17 After a median follow-up of 5 years, this translated into a significant improvement of event-free survival (EFS; 47% v 29%; P ⫽ .00002), progression-free survival (PFS; 54% v 30%; P ⬍.00001), disease-free survival (DFS; 66% v 45%; P ⬍.0003), and overall survival (OS; 58% v 45%; P ⬍.007) (Figure 1).18 In a subgroup analysis, patients with low-risk but not with high-risk lymphoma according to the International Prognostic Index (IPI), had a significantly longer survival if treated with the combination. Most importantly, the addition of rituximab did not result in increased toxicity and no long-term toxicity has been reported for the patients treated with R-CHOP. A second randomized trial was performed in young good-prognosis patients by the MabThera International Trial Group (MinT). Young patients (18 – 60 years) with no or one risk factor according to the IPI were randomized to receive six cycles of CHOP-like (CHOP or CHOEP [CHOP ⫹ etoposide]) chemotherapy with (413 patients) or without (410 patients) rituximab (375 mg/ m2) on day 1 of each cycle. The rates of CR/CRu (86% v 68%; P ⬍.0001), as well as the 3-year estimates for EFS (79% v 59%; P ⬍.0001) and OS (93% v 84%; P ⬍.0001), were significantly better for the combination of chemotherapy plus rituximab compared to chemotherapy alone (Figure 1).19 Moreover, a population-based analysis (246 patients) to assess the impact of rituximab in combination with CHOP revealed that 2-year OS significantly increased from 52% to 78% after the recommendation of combining CHOP with rituximab for all patients with newly diagnosed advanced-stage DLBCL in the province of British Columbia.20 After controlling for age and IPI score, era of treatment remained a strong independent
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rates between the two treatment groups and toxicity was mild with 19% of patients having a grade 3 and only one patient having a grade 4 related adverse event. As rituximab monotherapy is a well-tolerated regimen, it can be an option as a palliative treatment for patients not qualifying for more aggressive therapies due to comorbidities or age.
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Figure 1. Improvement of treatment results with the addition of rituximab to anthracycline-based chemotherapy. GELA LNH 9.8-5 trial (A) and MinT-trial (B). Overall survival.
predictor of PFS (risk ratio, 0.59; 95% confidence interval [CI], 0.41– 0.85; P ⫽ .005) and OS (risk ratio, 0.43; 95% CI, 0.29 – 0.66; P ⬍.001). The benefit of treatment in the post-rituximab era was present regardless of age. Based on these results, R-CHOP and equivalent rituximab-containing anthracycline-based regimens are now widely accepted as the standard of care for any stage DLBCL. Although not formally established in the young-high risk population, a clinical benefit of rituximab can be expected from the results in the other risk groups.
Choice of the Optimal Chemotherapy Partner Upon ligation of CD20, rituximab triggers different effector mechanisms. In vitro, three main modes of action of rituximab (direct induction of apoptosis, complement-dependent cytotoxicity [CDC], and antibodydependent cytotoxicity [ADCC]) have been identified.21–26 However, there is no agreement about the contribution of each of these effector mechanisms in vivo. If, indeed, ADCC turns out to be the most important effector mechanism, then effector cells such as natural killer (NK) cells, granulocytes, and macro-
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phages are essential to recognize the Fc portion of rituximab and to mediate cytotoxicity. The combination of rituximab with a more myelosuppressive chemotherapy regimen might therefore compromise the efficacy of rituximab by diminishing the effector cells of ADCC. In this respect, it is of interest that although CHOEP confirmed to be superior to CHOP in the MinTtrial,19 R-CHOP was at least as good as R-CHOEP or even better in some subpopulations. Furthermore, the addition of rituximab to the triple high-dose regimen MegaCHOEP did not improve treatment results when compared to Mega-CHOEP alone.27 In summary, these observations caution against combining rituximab with chemotherapy regimens other than CHOP outside of clinical trials. Another yet unanswered question is whether CHOP combined with rituximab should be given as a biweekly (R-CHOP-14) or every-3-week regimen (RCHOP-21). In the NHL-B2 trial performed by the German High-Grade Lymphoma Study Group (Deutsche Studiengruppe für hochmaligne Non-Hodgkin Lymphome; DSHNHL) dose densification by shortening treatment intervals from 21 (CHOP-21) to 14 days with growth factor support (CHOP-14) in elderly patients resulted in a significant improvement of outcome without increased toxicity.28 Five-year EFS and OS rates were 32.5% and 40.6%, respectively, for CHOP-21 and 43.8% and 53.3%, respectively, for CHOP-14. In a multivariate analysis, the relative risk reduction was 0.66 (P ⫽ .003) for EFS and 0.58 (P ⬍.001) for OS after CHOP-14 compared with CHOP-21. In the subsequent RICOVER-60 trial,29 patients (60 – 80 years of age) were randomized to receive six or eight cycles of CHOP-14 with or without eight applications of rituximab in a 2 ⫻ 2 factorial design. There was no difference in EFS between six and eight cycles, but EFS after R-CHOP was significantly better than after CHOP (P ⫽ .000025). In a multivariate analysis using 6x CHOP-14 as the reference, PFS improved after 6x R-CHOP-14 and 8x R-CHOP-14, but OS only improved after 6x R-CHOP 14 (relative risk, 0.63 [0.46 – 0.85]; P ⫽ .0031) (Figure 2). As the results of this largest randomized trial (826 evaluable patients) with an OS of 78% after 3 years are the best ever reported for elderly patients, six cycles of R-CHOP-14 with growth factor support and two additional applications of rituximab should be considered as the standard treatment for this population. Ongoing trials of the French GELA and the British National Cancer Research Institute comparing R-CHOP-21 and R-CHOP-14 are addressing the question of biweekly or every-3-week application of R-CHOP in a randomized fashion. In a preliminary report of the National Cancer Research Institute (NCRI) study in DLBCL patients of all ages, no major differences in efficacy and toxicity between R-CHOP-14 and R-CHOP-21 have been observed.30
C. Zwick, N. Murawski, and M. Pfreundschuh
0.6 0.5 1: 6 x CHOP -14 (n=307) 2: 8 x CHOP -14 (n=305) 3: 6 x R-CHOP- 14 (n=306) 4: 8 x R-CHOP- 14 (n=304)
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Figure 2. Superiority of 6x R-CHOP 14 over 8x R-CHOP 14. Overall survival. RICOVER-trial.
Intensifying Rituximab Pharmacokinetic data in humans have only been obtained from patients with indolent lymphoma but not from DLBCL patients. Information regarding minimal serum levels and areas under the curve necessary to achieve tissue levels that are sufficient to kill the malignant DLBCL clone in situ is lacking. The commonly used dosage of rituximab (375 mg/m2) and the schedule of giving rituximab with each cycle of chemotherapy are mainly based on practicability and economic considerations. Rituximab has proven its efficacy when given every 3 weeks (R-CHOP 21),17,18,31 as well as when given biweekly (R-CHOP-14).29 However, the addition of rituximab to the biweekly regimen in the German trial resulted in a more pronounced improvement compared to the every-3-weeks regimen in the French trial, where the addition of rituximab even failed to reach significance with respect to survival in elderly poorprognosis patients. Analyzing rituximab trough serum levels in patients with biweekly applications32 showed an increase of preinfusion levels over the first four cycles. From the fifth to the eighth cycle rituximab levels reach a plateau and decrease slowly after the end of therapy with detectable levels of rituximab even after 9 months (Figure 3). For the every-3-weeks regimen, the decrease of serum levels between the cycles can be expected to be even more pronounced, possibly falling below a threshold that is needed to maintain efficacy. An explanation for the decrease of serum levels might be that during the first cycles a major portion of the antibody binds to and eliminates normal B cells and a vast amount of tumor cells. Based on these considerations, dose intensification at the beginning of therapy with a faster saturation might increase the benefit of rituximab application. This could also be
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Figure 3. Rituximab trough serum levels with dose dense and conventional application.
concluded from the results of the GELA LNH 98 –517,18 and the Eastern Cooperative Oncology Group (ECOG) trial31: in the GELA trial eight applications of rituximab were given, whereas in the ECOG trial only five applications with two “dose-dense” applications before the first chemotherapy cycle (day –7 and –3) were administered (Figure 4). As the therapeutic gain that has been achieved in both trials by the addition of rituximab was very similar, it could be speculated that the dose-dense application of rituximab at the beginning of immunochemotherapy might be more relevant than the absolute number of rituximab cycles. A phase II study to evaluate the efficacy and pharmacokinetics of dosedense rituximab with four additional rituximab applications within the first 2 weeks is currently ongoing in Germany.33
RITUXIMAB IN THE SALVAGE TREATMENT OF AGGRESSIVE B-CELL LYMPHOMA Patients who fail to achieve a remission or relapse following first-line treatment have a poor prognosis with a life expectancy of 3 to 4 months. As less than 10% of these patients obtain long-term DFS with conventional chemotherapy alone, it is widely accepted that a remission should—whenever possible— be consolidated with high-dose therapy and autologous stem cell transplantation (ASCT). In the PARMA trial 109, chemotherapy-sensitive relapsed DLCBL patients were randomized to salvage chemotherapy with platinumand cytarabine-based chemotherapy alone or in combination with ASCT.34,35 Both EFS (46% v 12 % after 5 years; P ⫽ .001) and OS (53% v 32% after 5 years; P ⫽ .038) were significantly superior in the transplant group compared to the conventional DHAP (cisplatin, cytarabine, and dexamethasone). Based on these results, high-dose therapy with ASCT following induction chemotherapy has become the standard of care in patients with relapsed or primary refractory lymphoma in the pre-rituximab era.
In recent years, a number of chemotherapy combinations have been investigated in the salvage setting, mainly in nonrandomized phase II trials.36 – 48 Platinumbased salvage regimens like DHAP, ICE (ifosfamide, carboplatin, etoposide), or ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) are currently widely used and produced overall response rates rarely exceeding 50% with 2-year survival rates ranging from 7% to 35%. In a single-arm study, combining rituximab with ICE in patients with refractory or relapsed DLBCL following an anthracycline-based first-line regimen resulted in overall response and complete response rates of 78% and 53%, respectively. Compared to historical controls with similar IPI scores, this CR rate is nearly twice as high as with ICE alone. Patients with relapsed disease had a significantly higher overall response rate than those with primary refractory disease (96% v 46%; P ⬍.001).49 Similar results have been obtained for the combination of rituximab with DHAP in 53 patients with refractory or relapsed aggressive B-cell lymphoma with an overall response rate of 62% in the overall cohort and of 81% for the cohort of patients who were treated at first relapse. In a matched-pair analysis of 23 patient pairs, R-DHAP produced a higher CR rate than DHAP, although statistical significance was not reached.50 In an ongoing trial of the HOVON (HematoOncologie voor Volwassenen Nederland) group, 239 patients were randomized to receive a salvage regimen consisting of DHAP-VIM (etoposide, ifosfamide, methotrexate)-DHAP with or without rituximab.51 Overall response rates after two cycles and post-transplantation were 75% versus 54% (P ⬍.1) and 73% versus 50% (P ⫽ .003) in favor of the R-DHAP arm. After 24 months, a significant increase in failure-free survival (FFS; 50% v 24%; P ⬍.001) but not in OS (52% v 59%) could be demonstrated with combined immunochemotherapy. In a Cox regression analysis, rituximab treatment had a significant effect on FFS and OS when adjusted for time since upfront randomization, age, performance status, and secondary IPI. Taken together, these trials suggest that the inclusion of rituximab into salvage regimens
Figure 4. Schedule of rituximab application in the GELA and the ECOG trial.
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results in higher overall response and CR rates compared with chemotherapy alone, enabling more patients to proceed to ASCT. Whether this translates into improved survival outcomes will have to be analyzed when long term follow-up data are available. To define the optimal salvage regimen in combination with rituximab, the CORAL trial (Collaborative Trial in Relapsed Aggressive Lymphoma) compared R-DHAP with R-ICE as induction therapy before ASCT in patients with relapsed/refractory lymphoma. In an interim analysis of 396 patients, no significant difference between R-ICE and R-DHAP has been observed with respect to overall response rate (63.5 v 62.8%), 3-year EFS (26% v 35%; P ⫽ .6), and OS (47% v 51%; P ⫽ .5).52 As the majority of patients in earlier studies had not been previously exposed to rituximab, the role of rituximab re-treatment after a rituximab-containing induction regimen has still not been defined. In a retrospective analysis of the GELA LNH 98 –5 trial, relapsing patients treated with a rituximab-containing salvage regimen had a 2-year survival of 58% compared with 24% for those treated without rituximab (P ⫽ .00067).18 Importantly, in patients treated with CHOP alone as firstline treatment, the benefit of the addition of rituximab at the time of salvage therapy is statistically significant (P ⫽ .002), whereas it is not in patients initially treated with R-CHOP (P ⫽ .23). However, as only nine patients received a second-line regimen with rituximab following first-line R-CHOP, it is not possible to draw any conclusions from this trial regarding the benefit of rituximab re-treatment. Recently, the outcome of elderly patients treated within the RICOVER-60 trial and relapsing after or refractory to CHOP or R-CHOP has been analyzed retrospectively. Fifty-nine percent of 297 patients received rituximab as part of salvage therapy. Three-year OS was significantly better for patients receiving salvage chemotherapy with rituximab compared to chemotherapy alone (39% v 18%; P ⬍.001). Whereas this effect was most pronounced in patients receiving primary treatment without rituximab (OS 43% v 24%; P ⬍.001), it was still detectable in patients receiving primary R-CHOP.53 Taken together, the efficacy of re-treatment with rituximab in patients with relapses following rituximab-containing primary treatment remains to be proven. The observation that patients failing a rituximabcontaining primary treatment have a poor prognosis has been made in a number of trials. The GEL/TAMO group (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea) evaluated the influence of prior exposure to rituximab on response rates and survival in patients with relapsing DLBCL treated with rituximab plus etoposide, cytarabine, cisplatin, and methylprednisolone (R-ESHAP).54 Of the 163 patients analyzed, rituximab had been administered to 94 patients during induction treatment (R⫹ group), whereas 69 patients had not received rituximab (R⫺ group). With a median
C. Zwick, N. Murawski, and M. Pfreundschuh
follow-up of 29 months, patients in the R⫹ group had significantly worse PFS (17% v 57% at 3 years; P ⬍.0001) and OS (38% v 67% at 3 years; P ⫽ .0005) than patients in the R⫺ group. Prior exposure to rituximab was an independent adverse prognostic factor for both PFS (relative risk 2.0; 95% CI, 1.2–3.3; P ⫽ .008) and OS (relative risk 2.2; 95% CI, 1.3–3.9; P ⫽ .004). Response rates were significantly higher in the R⫺ group in the univariate but not in the multivariate analysis. In the analysis restricted to the R⫹ group, very low complete remission and overall response rates were observed in patients with primary refractory disease (8% and 33%, respectively), compared to those in patients who were in first partial remission (41% and 86%) or who had relapsed disease (50% and 75%) (P ⬍.01 in both cases). A recently reported interim analysis of the CORAL trial also confirms that the outcome of second line treatment is worse after a rituximab-containing induction therapy (EFS after 3 years, 21% v 47%; P ⬍.001), especially for patients with early relapse (⬍12 months) (EFS after 3 years, 20% v 45%; P ⬍.001).52 In a retrospective analysis of the RICOVER-60 trial, patients relapsing after R-CHOP had an impaired EFS compared to patients relapsing after CHOP alone (EFS after 3 years, 23% v 44%; P ⫽ .016). High-dose therapy with ASCT was effective only in patients receiving primary treatment without rituximab, whereas the rate of long-term survivors was in the range of only 10% after primary R-CHOP.53 In a study investigating the efficacy of R-GemOx (rituximab, gemcitabine, and oxaliplatin) in 46 patients with relapsed or refractory B-cell lymphoma, the probability of remaining relapse-free at 2 years was 81% for the 19 responders not previously treated with rituximab compared with 37% for the 19 patients previously treated with rituximab.55 The CR/Cru rate of this low-toxicity regimen was 72% after eight cycles of treatment. The 2-year EFS and OS rates were 43% and 66%, respectively, and the median time to progression was 22 months. In summary, patients refractory to or experiencing an early relapse (⬍12 months) after a rituximab-containing primary treatment represent a negative selection and have a poor prognosis. In contrast to patients without a rituximab-containing first-line regimen, highdose chemotherapy with autologous stem cell support has only limited activity in these patients. As nearly all patients relapsing in the rituximab era will have been exposed to rituximab in first-line, new modalities of second-line therapy are urgently warranted.
Rituximab as Maintenance Therapy In follicular lymphoma, maintenance therapy with rituximab after chemoimmunotherapy in patients with previously treated lymphoma has been reported to improve PFS.56 The optimal maintenance regimen has not yet been defined.57–59 In the ECOG trial, 632 elderly
Rituximab in high-grade lymphoma
patients with DLBCL were first randomized to receive CHOP or R-CHOP and underwent a second randomization after achieving a partial or complete remission into rituximab maintenance (375 mg/m2 weekly times 4, every 6 months times 4) or observation. Interestingly, patients who received rituximab maintenance had a significantly increased FFS (FFS after 2 years, 76% v 61%; P ⫽ .09), but this advantage was only observed in patients who had not received rituximab as part of their induction therapy.53 In the CORAL trial, patients after ASCT were randomized to receive rituximab maintenance over 1 year or observation. Results of the second randomization are not yet available.52 A longer follow-up is necessary to answer the question of whether rituximab maintenance may provide a benefit after ASCT in high-grade lymphoma patients.
Conclusions The inclusion of rituximab in first-line treatment of aggressive B-cell lymphoma has significantly improved overall response rates, EFS, PFS, and OS of patients with CD20⫹ aggressive lymphoma. A combination of rituximab and an anthracycline-based chemotherapy has been accepted as the standard of treatment for patients with any stage DLCBL. Although not formally proven in young high-risk patients, a clinical benefit of rituximab can be expected from the results in the other risk groups. Whether and to what extent an intensified application at the beginning of treatment might improve treatment results will be investigated in ongoing trials. In the salvage setting, the use of rituximab in rituximab-naive patients results in higher overall response rates. Whether this translates into improved survival outcomes will have to be analyzed when long-term follow-up data are available. In contrast, the efficacy of rituximab in re-treating patients with relapses following rituximab-containing primary treatment remains to be proven. Patients relapsing after or refractory to rituximab-containing induction treatment have a poor prognosis with high-dose chemotherapy and ASCT being less efficient than in patients pretreated with chemotherapy alone. For these patients new treatment strategies are urgently warranted. The role of maintenance treatment will be addressed in the CORAL trial in a randomized fashion. A longer follow-up is necessary to answer this question.
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REFERENCES 1. McKelvey EM, Gottlieb JA, Wilson HE, et al. Hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38:1484 –93. 2. Fisher RI, Gaynor ER, Dahlberg S, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328:1002– 6. 3. Gianni AM, Bregni M, Siena S, et al. High-dose chemotherapy and autologous bone marrow transplantation
15.
compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med. 1997;336:1290 –7. Haioun C, Lepage E, Gisselbrecht C, et al. Survival benefit of high-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: final analysis of the prospective LNH87–2 protocol—a Groupe d’Etude des Lymphomes de l’Adulte study. J Clin Oncol. 2000;18:3025–30. Verdonck LF, van Putten WL, Hagenbeek A, et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding patients with aggressive non-Hodgkin’s lymphoma. N Engl J Med. 1995;332:1045–51. 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 Study Group. J Clin Oncol. 1998;16:2796 – 802. Kluin-Nelemans HC, Zagonel V, Anastasopoulou A, et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin’s lymphoma: randomized phase III EORTC study. J Natl Cancer Inst. 2001;93:22–30. Kaiser U, Uebelacker I, Abel U, et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for “aggressive” lymphoma. J Clin Oncol. 2002;20:4413–9. Gisselbrecht C, Lepage E, Molina T, et al. Shortened first-line high-dose chemotherapy for patients with poorprognosis aggressive lymphoma. J Clin Oncol. 2002;20: 2472–9. Martelli M, Gherlinzoni F, De Renzo A, et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin’s lymphoma: an Italian multicenter randomized trial. J Clin Oncol. 2003;21:1255– 62. Milpied N, Deconinck E, Gaillard F, et al. Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med. 2004;350:1287–95. Betticher DC, Martinelli G, Radford JA, et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Ann Oncol. 2006;17:1546 –52. Olivieri A, Santini G, Patti C, et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin’s lymphoma: longterm results by the NHLCSG. Ann Oncol. 2005;16: 1941– 8. Vitolo U, Liberati AM, Cabras MG, et al. High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an “Intergruppo Italiano Linfomi” randomized trial. Haematologica. 2005;90:793– 801. Pfreundschuh M, Trumper L, Kloess M, et al. Twoweekly 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 – 41.
154
16. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (antiCD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998;92:1927–32. 17. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235– 42. 18. Feugier P, Van Hoof 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;23:4117–26. 19. Pfreundschuh M, Truemper L, Osterborg A, et al. CHOPlike chemotherapy plus rituximab compared with CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large B-cell lymphoma: a randomized controlled trial by the Mabthera International Trial (MInT) Group. Lancet Oncol. 2006;7:379 –91. 20. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23:5027–33. 21. Manches O, Lui G, Chaperot L, et al. In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas. Blood. 2003;101:949 –54. 22. Van der Kolk LE, Evers LM Omene C, et al. CD20-induced B cell death can bypass mitochondria and caspase activation. Leukemia 2002;16:1735– 44. 23. Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms. Scand J Immunol. 2000;51:634 – 41. 24. Dall’Ozzo S, Tartas S, Paintaud G, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration-effect relationship. Cancer Res. 2004;64:4664 –9. 25. Golay J, Cittera E, Di Gaetano N, et al. The role of complement in the therapeutic activity of rituximab in a murine B lymphoma model homing in lymph nodes. Haematologica. 2006;91:176 – 83. 26. Uchida J, Hamaguchi Y, Oliver JA, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptordependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004; 199:1659 – 69. 27. Schmitz R, Nickelsen M, Ziepert M, et al. Aggressive chemotherapy (CHOEP-14) and rituximab or high-dose therapy (MegaCHOEP) and rituximab for young high-risk patients with aggressive B-cell lymphoma: results of the MegaCHOEP trial of the German High-Grade NonHodgkin Lymphoma Study Group (DSHNHL) [abstract]. ASH Annual Meeting Abstracts. 2009;114;22:404. 28. Pfreundschuh M, Trumper L, Kloess M, et al. Twoweekly 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 – 41. 29. Pfreundschuh M, Schubert J, Ziepert M, et al. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20⫹ B-cell
C. Zwick, N. Murawski, and M. Pfreundschuh
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9:105–16. Cunningham D, Smith P, Mouncey P, et al. A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin‘s lymphoma [abstract 8506]. J Clin Oncol. 2009;27:15s. Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006;24:3121–7. Reiser M, Wenger M, Nickenig C, et al. Serum levels and pharmacokinetics of rituximab in bi-weekly R-CHOP in elderly patients with DLBCL treated in the RICOVER-60 trial [abstract]. J Clin Oncol 2006;24:430s. Poeschel V, Nickelsen M, Hänel M, et al. Dose-dense rituximab in combination with bi-weekly CHOP-14 for elderly patients with diffuse large B-cell lymphoma: results of phase I/II and pharmacokinetic study of the German High-grade Non-Hodgkin Lymphoma Study Group. Blood. 2006;108:774a–5a. Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med. 1995;333: 1540 –5. Guglielmi C, Gomez F, Philip T, et al. Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial. J Clin Oncol. 1998;16: 3264 –9. Cabanillas F, Hagemeister FB, Bodey GP, Freireich EJ. IMVP-16: an effective regimen for patients with lymphoma who have relapsed after initial combination chemotherapy. Blood. 1982;60:693–7. De Lord C, Newland AC, Linch DC, Vaughan HB, Vaughan HG. Failure of IMVP-16 as second-line treatment for relapsed or refractory high grade nonHodgkin’s lymphoma. Hematol Oncol. 1992;10:81– 6. Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988;71:117–22. Soussain C, Souleau B, Gabarre J, et al. Intensive chemotherapy with hematopoietic cell transplantation after ESHAP therapy for relapsed or refractory non-Hodgkin’s lymphoma. Results of a single-centre study of 65 patients. Leuk Lymphoma. 1999;33:543–50. Sweetenham JW, Johnson PW. ESHAP chemotherapy for relapsed/refractory non-Hodgkin’s lymphoma. J Clin Oncol. 1994;12:2766. Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP—an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994;12:1169 –76. Rodriguez MA, Cabanillas FC, Velasquez W, et al. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol. 1995;13: 1734 – 41. Wilson WH, Bryant G, Bates S, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory nonHodgkin’s lymphoma. J Clin Oncol. 1993;11:1573– 82.
Rituximab in high-grade lymphoma
44. Chao NJ, Rosenberg SA, Horning SJ. CEPP(B): an effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin’s lymphoma. Blood. 1990;76:1293– 8. 45. Cortelazzo S, Rambaldi A, Rossi A, et al. Intensification of salvage treatment with high-dose sequential chemotherapy improves the outcome of patients with refractory or relapsed aggressive non-Hodgkin’s lymphoma. Br J Haematol. 2001;114:333– 41. 46. Atta J, Chow KU, Weidmann E, et al. Dexa-BEAM as salvage therapy in patients with primary refractory aggressive non-Hodgkin lymphoma. Leuk Lymphoma. 2007;48:349 –56. 47. Reiser M, Josting A, Dias WP, et al. Dexa-BEAM is not effective in patients with relapsed or resistant aggressive high-grade non-Hodgkin’s lymphoma. Leuk Lymphoma. 1999;33:305–12. 48. Moskowitz C, Hamlin PA, Horwitz SM, et al. Phase II trial of dose-dense R-CHOP followed by risk-adapted consolidation with either ICE or ICE and ASCT, based upon the results of biopsy-confirmed abnormal interim restaging PET scan improves outcome of patients with advanced stage DLBCL [abstract]. Blood. 2006;108:161a. 49. Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103:3684 – 8. 50. Mey UJ, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine and cisplatin in combination wirh rituximab as salvage treatment patients with relapsed or refractory aggressive non-Hodgkin‘s lymphoma. Cancer Invest. 2006;24:593– 600. 51. Vellenga E, van Putten WL, ’t Veer MB, et al. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20⫹ NHL: a prospective randomized HOVON trial. Blood. 2008;111: 537– 43. 52. Gisselbrecht C, Glass B, Mounier N, et al. R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large
155
53.
54.
55.
56.
57.
58.
59.
B-cell lymphoma followed by autologous stem cell transplantation [abstract]. J Clin Oncol. 2009;27:436s. Glass B, Borgerding A, Ziepert M, et al. Outcome of elderly patients with DLBCL failing R-CHOP. The role of rituximab and high dose therapy in second line treatment. A retrospective analysis from the RICOVER 60 trial. [abstract]. ASH Annual Meeting Abstracts. 2009; 114;22:3714. Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008;93:1829 –36. El Gnaoui T, Dupuis J, Belhadj K, et al. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007;18: 1363– 8. Van Oers M, Van Glabekke M, Baila L, Giurgia L, et al. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin‘s lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study [abstract]. Am Soc Hematol. 2008:836. Forstpointner R, Unterhalt M, Dreyling M, et al. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with R-FCM in patients with refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006;108:4003– 8. Ghielmini M, Schmitz SF, Cogliatti SB, et al. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event free survival and response duration compared with the standard weekly ⫻ 4 schedule. Blood. 2004;103:4416 –23. Hainsworth JD, Litchy S, Burris HA, et al. Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin‘s lymphoma. J Clin Oncol. 2002;20: 4261–7.