ABSTRACT: The addition of rituximab to systemic chemotherapy has improved the response rates, progression-free survival, and overall survival of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) compared to chemotherapy alone. In the front-line setting, the use of rituximab is changing the biology and clinical behavior in DLBCL patients who fail to respond or relapse following chemoimmunotherapy. Based on retrospective studies, it is becoming evident that the subset of patients with rituximab/chemotherapy–relapsed/refractory DLBCL represents a different clinical entity with a higher degree of chemotherapy resistance compared to DLBCL patients receiving upfront chemotherapy alone. The backbone of treatment for “sensitive” patients with relapsed/refractory disease continues to be salvage chemotherapy with or without rituximab, followed by high-dose chemotherapy and autologous stem cell support. Patients who are not eligible for high-dose chemotherapy may benefit from a growing number of regimens integrating novel agents with promising activity and manageable toxicity. Advances in biotechnology have led to the development of novel biomarkers used for categorization or risk stratification in DLBCL patients. This two-part review summarizes treatment options for patients with relapsed/refractory DLBCL and stresses the emerging therapeutic challenges for patients who were previously exposed to rituximab.
According to published statistics, in 2008 approximately 66,120 new cases of non-Hodgkin lymphoma (NHL) were diagnosed and 19,160 lymphoma patients died from their disease despite currently available treatment. Diffuse large B-cell lymphoma (DLBCL), the most common type of B-cell NHL, has an aggressive clinical course and, as demonstrated by gene-profiling studies, can be further divided into subgroups with distinct biologic characteristics and prognoses.
Target-specific therapies such as monoclonal antibodies (ie, rituximab [Rituxan]) have been developed in response to the need for novel treatments with better efficacy and more tolerable toxicity than that associated with previously available “chemotherapy-alone” regimens. The incorporation of rituximab (R) to standard doses of cyclophosphamide, doxorubicin HCl, vincristine (Oncovin), and prednisone (CHOP) resulted in an improved response rate, progression-free survival, and overall survival compared to standard CHOP chemotherapy in patients with DLBCL. Results from randomized clinical trials evaluating the efficacy of adding rituximab to standard CHOP or CHOP-like regimens have demonstrated that R-CHOP chemoimmunotherapy results in complete response (CR) rates between 75% and 88%, and 5-year survival rates between 50% and 80%.[3,4]
While the clinical benefit of adding rituximab to CHOP or CHOP-like chemotherapy as front-line treatment of DLBCL is beyond dispute, it is now necessary to reevaluate previously accepted biomarkers of response (ie, Bcl-2 expression, International Prognostic Index [IPI], etc), and respond to the challenge of how to treat those patients who fail to respond or have relapsed after chemoimmunotherapy. In other words, R-CHOP has not only improved survival in patients with DLBCL but has also modified the biology and response to subsequent therapy for patients with refractory or relapsed DLBCL. There is a growing need to further characterize the mechanisms by which DLBCL develops resistance to rituximab and chemotherapy agents, in an attempt to better design salvage strategies to overcome that resistance.
Patients with resistant DLBCL represent a heterogeneous group with different molecular fingerprinting (ie, germinal center B-cell [GBC] lymphoma vs activated B-cell lymphoma) and/or responses to front-line therapy (ie, relapsed vs primary-refractory). Those with primary-refractory DLBCL are the most challenging patients in this group, and we have not been able to significantly improve their outcome despite the introduction of rituximab in the front-line or salvage setting. The differences in clinical behavior and therapeutic response of patients with GBC and non-GBC DLBCL are largely unknown. This two-part article, which will conclude in the next issue of ONCOLOGY, summarizes the historic and newer approaches in the management of DLBCL patients who have relapsed after initial response to or are refractory to R-CHOP.
High-Dose Chemotherapy and Autologous Stem Cell Support
The role of high-dose chemotherapy (HDC) and autologous stem cell support (ASCS) in the treatment of relapsed/refractory DLBCL was confirmed by the only international randomized phase III clinical trial in this setting, the PARMA study. In this protocol, patients with relapsed/refractory DLBCL underwent salvage chemotherapy for two cycles, and those with chemotherapy-sensitive DLBCL were randomized to further salvage chemotherapy with cytarabine/platinum-based chemotherapy alone or in combination with ASCS. The results of this study demonstrated that event-free and overall survival rates at 5 years in the transplant arm were 46% and 53%, compared with 12% and 32%, respectively, in the chemotherapy-alone arm. Moreover, subset analysis revealed that response to salvage chemotherapy was associated with a 5-year progression-free survival of 43%, in contrast to a 1-year overall survival of 22% in patients with chemotherapy-resistant disease.
Based on these results, salvage chemotherapy followed by HDC-ASCS was adopted as the standard of care for transplant-eligible DLBCL patients. Subsequent work has focused on developing tools to predict which patients are most likely to benefit from HDC-ASCS (eg, value of age-adjusted IPI score, or a positive vs negative positron-emission tomography scan after salvage chemotherapy).[6-8]
As rituximab changed the treatment paradigm of patients with DLBCL, it has been postulated that the current subset of patients with refractory or relapsed DLBCL represent a different patient population then the one studied in pre-rituximab clinical trials. Several investigators are questioning whether responsiveness to second-line chemotherapy or HDC-ASCS in patients with relapsing or primary-refractory DLBCL previously treated with R-CHOP has decreased, compared to historical controls.
On behalf of the Grupo Espaol de Linfomas/Transplante Autologo de Medula Osea (GEL/TAMO), Dr. Alejandro Martin reported results from a retrospective analysis of the outcome of patients with DLBCL evaluating the influence of rituximab on response rate to rituximab in combination with ESHAP (etoposide, methylprednisolone [SoluMedrol], cytarabine [high-dose Ara-C], and cisplatin [Platinol]) as salvage therapy. Martin and colleagues studied 163 consecutive patients with relapsed/refractory DLBCL who received R-ESHAP as second-line therapy; 94 of whom were previously treated with rituximab/chemotherapy (R+ group) vs 69 who received chemotherapy alone (R– group) for front-line therapy.
In a univariate analysis, response rates were higher among patients who were not previously exposed to rituximab, but this finding did not hold true in a multivariate analysis. R-ESHAP produced overall response (OR) and CR rates of 67% and 37% in DLBCL previously treated with R-CHOP vs 81% and 56% for patients previously treated with CHOP (P = .045, P = .015, respectively). In addition, the progression-free and overall survival rates at 3 years were significantly higher for patients in the R– group (57% and 64%), compared to those in the R+ group (38% and 17%; P < .0001 and P = .0005, respectively). The same percentage of patients in both groups underwent subsequent HDC-ASCS. In a multivariate analysis, prior exposure to rituximab was found to be a prognostic indicator of worse progression-free and overall survival.
The results of this retrospective study suggest that DLBCL patients who relapse or fail to respond to rituximab/chemotherapy in the front-line setting have more “therapy-resistant” residual disease. This observation represents an emerging clinical challenge for physicians treating relapsed/refractory DLBCL patients. It also stresses the need to further study and define the mechanisms by which DLBCL cells are developing resistance to chemoimmunotherapy at cellular and molecular levels.
On the other hand, it is uncertain whether rituximab can enhance the antitumor activity of systemic chemotherapy in the salvage setting or to what extent the use of HDC-ASCS improves cure rates in previously R-CHOP–treated relapsed/refractory DLBCL. Two groups of investigators have shown improved response rates by adding rituximab to salvage regimens such as ICE (ifosfamide, carboplatin, etoposide) or DHAP (dexamethasone, high-dose cytarabine, cisplatin), as compared to historical controls.[10,11] However, the majority of patients included in these trials had not been previously exposed to rituximab in the front-line setting.
The GELA group (Groupe d’Etude des Lymphomes de l’Adulte) reported a subset analysis with long-term follow-up of 202 DLBCL patients who had relapsed/progressed following front-line R-CHOP or CHOP chemotherapy in their landmark study. All 202 patients underwent salvage chemotherapy; 31 received a rituximab-containing salvage regimen (22 were previously treated with CHOP, and 9 with R-CHOP). Patients treated with rituximab-containing salvage chemotherapy had a 2-year overall survival of 58%, as opposed to 24% for those treated with salvage chemotherapy alone (P = .00067).
Although the numbers were small, it is interesting to observe that the benefit of adding rituximab to the salvage regimen was statistically significant only for those treated with CHOP in the front-line setting. Given the extremely small sample size of relapsed R-CHOP patients receiving rituximab-containing salvage chemotherapy (ie, 9 patients), no definite conclusions can be drawn from these data alone.
The choice of salvage chemotherapy after R-CHOP failures is being addressed by a prospective multicenter phase III study, the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL). In addition, this study is aimed at defining the role, if any, of rituximab maintenance after HDC-ASCS. In this study, patients with relapsed/refractory DLBCL following induction R-CHOP are being randomized to receive three cycles of R-ICE or R-DHAP, followed by high-dose chemotherapy with BEAM (carmustine [BCNU], etoposide, cytarabine, melphalan [Alkeran]) and ASCS. Subsequently, patients are randomized to rituximab maintenance or observation. The study will enroll a total of 400 patients who will be stratified by (1) prior exposure to rituximab; (2) time of relapse (ie, within 12 months or 12 months after front-line therapy); and (3) primary-refractory disease.
Recently, the investigators reported an interim analysis on 200 patients, which demonstrated that factors affecting 2-year event-free survival included second-line age-adjusted IPI of 0 or 1 vs higher (56% vs 39%, respectively; P = .0084); relapse < 12 months after completion of first-line therapy (36% vs 68%, respectively; P < .001); and prior rituximab exposure in the front-line setting (34% vs 66%, respectively; P < .001). The preliminary results of the CORAL study validate the predictive value of the age-adjusted IPI at the time of relapse and strongly suggest that relapsed/refractory DLBCL that has been exposed to upfront rituximab/chemotherapy induction therapy appears to have a “therapy-resistant” phenotype, which is more difficult to control with standard salvage regimens. The final results of this study are eagerly awaited, to determine the more efficacious salvage regimen and the potential role of rituximab maintenance following HDC-ASCS in relapsed/refractory DLBCL.
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