Therapeutic Options in Relapsed or Refractory Diffuse Large B-cell Lymphoma: Part 1

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.[1] 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.[2]

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

PARMA Study

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.[5] 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.[5]

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.

GEL/TAMO Study

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.[9] 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.[9]

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.

GELA Study

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.[12] 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.

CORAL Study

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).[13] 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.

Salvage Chemotherapy

A vast number of regimens are used in the treatment of patients with relapsed/refractory DLBCL, primarily based on studies of non–cross-resistant chemotherapy agents compared to those used in the front-line setting (with or without rituximab). The goal of salvage regimens is to achieve maximum tumor cytoreduction prior to HDC-ASCS. The current salvage regimens used in the treatment of refractory/relapsed DLBCL that have been evaluated in phase II studies are delineated in Tables 1 and 2. Investigators have also tested the efficacy of adding rituximab to established salvage regimens and compared them to pre-rituximab historical controls.[9]

The only prospectively randomized phase III trial comparing established salvage regimens in relapsed DLBCL is the ongoing CORAL study.[13] While the results of this international study will serve as a guide to selecting the better of two salvage regimens, the optimal second-line therapy for relapsed/refractory DLBCL will require additional research. In general, when currently selecting an optimal salvage regimen for individual patients, we consider regimens associated with higher response rates (ie, especially higher CR rates), low hematologic and nonhematologic toxicity, and limited damage to stem cells (in attempting to collect adequate numbers of peripheral blood stem cells), as well as the patient’s performance status and comorbidities.

Depending on the agents used, and outside of a clinical trial, salvage chemotherapy can be divided into two groups: platinum-based and non–platinum-based. In general, platinum-based salvage regimens yield higher response rates, but at the price of higher hematologic and/or nonhematologic toxicity than non–platinum-based regimens. In general, platinum-based regimens are preferred in patients who are candidates for HDC-ASCS, and non–platinum-based regimens are used in a higher percentage of patients with poor bone marrow reserve (ie, relapsed after HDC-ASCS) or elderly patients who are ineligible for HDC-ASCS due to advanced age and/or concurrent comorbid conditions.

Platinum-Based Regimens in Relapsed DLBCL

TABLE 1

Cisplatin-Based Salvage Regimens Studied in Patients With Aggressive Lymphomas Including DLBCL

The antitumor effects of cisplatin, carboplatin, and most recently oxaliplatin (Eloxatin) against B-cell lymphomas have been demonstrated in preclinical and clinical studies (see Table 1). Cisplatin has been extensively studied in combination with high-dose cytarabine- or gemcitabine (Gemzar)-based regimens, such: as rituximab with or without DHAP, ESHAP, or GDP (gemcitabine, dexamethasone, cisplatin) in patients with refractory/relapsed DLBCL.[5,9-11,13-24] In addition, carboplatin has been combined with ifosfamide and etoposide (ICE) with or without rituximab.[9,13]

In general, platinum-based regimens yield OR rates ranging from 43% to 82% and CR rates of 16% to 61%. Successful peripheral blood stem cell mobilization has been documented in the majority of patients eligible for autologous stem cell transplantation treated on these regimens. However, these salvage regimens are associated with significant grade 3/4 hematologic, and a lesser degree (typically grade 1/2) of nonhematologic toxicity. Grade 3/4 neutropenia occurs in 50% to 70% of cases, grade 3/4 thrombocytopenia is observed in 30% to 90%, and between 40% and 70% of patients require at least one unit of packed red blood cell transfusions following therapy. Hospitalization for febrile neutropenia has been reported in 10% to 20% of relapsed/refractory DLBCL patients receiving platinum-based salvage regimens.[5,9-11,13-24] In addition, nonhematologic toxicities seen with these regimens include renal dysfunction, cardiac toxicity (ifosfamide-containing regimens only), neurotoxicity in the form of confusion (ifosfamide-containing regimens), and cerebellar toxicity (high-dose cytarabine-containing regimens, < 5% of cases).

Recently, several investigators have evaluated the possibility of replacing cisplatin/carboplatin with oxaliplatin given its more favorable toxicity profile. However, to date, no significant changes in the antitumor activity or toxicity profile of currently available salvage regimens has been demonstrated with this strategy.[21]

Non–Platinum-Containing Salvage Regimens

TABLE 2

Non-Cisplatin-Based Salvage Regimens Studied in Patients With Aggressive-Lymphoma Including DLBCL

In the past, four non–platinum-containing regimens were primarily used in the salvage regimen in preparation for high-dose chemotherapy and ASCS (Table 2). The antitumor activity of regimens such as MINE (methylprednisolone, ifosfamide, mitoxantrone, etoposide), IVAD (ifosfamide, etoposide, cytarabine, dexamethasone), IEV (ifosfamide, epirubicin, etoposide), and Mini-BEAM (busulfan [Busulfex, Myleran], etoposide, cytarabine, melphalan) was found to be comparable to that observed with platinum-based regimens.[25-28] Response rates to any of these four regimens in rituximab-naive relapsed/refractory DLBCL varies from 64% to 75%, with safety profiles similar to those of platinum-containing regimens.[25-28]

The use of these regimens has declined over time for several reasons, including: (1) to restrict the use of anthracyclines in salvage regimens for patients who have received prior CHOP/R-CHOP, to limit cumulative cardiotoxicity; (2) to “protect” stem cells by restricting the use of melphalan or busulfan in the salvage regimen prior to autologous stem cell collection; and (3) to decrease nonhematologic and hematologic toxicity from high-dose ifosfamide-containing regimens by combining them with platinum compounds.

The most commonly used non–platinum-containing regimens are primarily gemcitabine-based (Table 2). These regimens are well tolerated in the elderly, in patients with limited bone marrow reserve, and in patients with multiple comorbid medical conditions. The hematologic toxicity observed in clinical trials evaluating the efficacy and toxicity of nonplatinum, gemcitabine-based regimens is significantly lower than in platinum-containing regimens. Grade 3/4 neutropenia and thrombocytopenia have been reported in only 20% and 10%–25% of patients, respectively.[29-31]

TABLE 3

Retrospective Studies Evaluating the Effect of Rituximab in the Salvage Regimen for Patients with DLBCL

Another strategy used by other investigators is to modify the schedule of administration of previously used agents. A good example of this approach is the development of the infusional dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) regimen, with or without rituximab. Wilson et al demonstrated that EPOCH was highly effective (74% OR, with 24% CR) in relapsed/refractory aggressive NHL, with an acceptable toxicity profile. The incidence of cardiac toxicity was extremely low (3%) despite the fact that 94% of the patients had prior anthracycline exposure.[31-33] Similar antitumor activity was reported by Jermann et al in patients with refractory/relapsed B-cell NHL treated with R-EPOCH.[34]

Rituximab in the Salvage Setting

The role of rituximab in combination with systemic chemotherapy in the salvage setting has not been as clearly defined as it is in the management of newly diagnosed DLBCL. Clinicians have assumed that adding rituximab to salvage chemotherapy may result in better disease control than chemotherapy alone in patients with relapsed/refractory DLBCL, without adding significant toxicity (Table 3). Two groups of investigators recently addressed this question-one team testing the efficacy of rituximab in combination with ICE (Memorial Sloan-Kettering Cancer Center, MSKCC), and the other, evaluating rituximab plus DHAP-VIM (etoposide, ifosfamide, methotrexate)-DHAP (Dutch-Belgian Hemato-Oncology Cooperative Group, HOVON) in patients with relapsed/refractory DLBCL. These combinatons were compared to the identical chemotherapy regimens minus rituximab.[10,11]

The HOVON study was a prospective randomized phase III study, whereas the MSKCC study compared the results of R-ICE in the salvage setting with historical ICE-treated controls. The results of these studies (Table 3) demonstrated that the addition of rituximab to salvage chemotherapy appears to improve various treatment outcomes without adding significant toxicity. Moreover, the use of rituximab in combination with salvage chemotherapy did not have a negative impact on peripheral blood stem cell collection. It is important to note that the majority of the patients enrolled in the MSKCC (R-ICE vs ICE) and HOVON (R-DHAP-VIM-DHAP vs DHAP-VIM-DHAP) studies had originally received CHOP or CHOP-like therapy (ie, without rituximab) and may have had different tumor sensitivity to their R+ salvage regimens if treated with upfront R-CHOP–like therapy.

Of interest, the data recently published by the GEL/TAMO group suggested that R-ESHAP appears to be more beneficial for rituximab-naive relapsed/refractory DLBCL. This retrospective study comparing the effect of prior rituximab therapy on responses to R-ESHAP suggested that relapsed DLBCL patients exposed to upfront R-CHOP/CHOP-like therapy are more resistant to salvage chemotherapy (Table 3) and may represent an important clinical challenge.[9] The results of the CORAL study are eagerly anticipated to further define the role of rituximab in the salvage setting.[13]

The emergence of rituximab resistance is being observed in patients with relapsed/refractory DLBCL. The evaluation of other biologically active monoclonal antibodies targeting CD20 (eg, ofatumumab) or directed against other key regulatory surface receptors (eg, CD40, CD22) in combination with standard and/or novel systemic chemotherapy combinations will be necessary to broaden the therapeutic armamentarium against relapsed/refractory DLBCL.

Next month, in part 2 of this two-part article, we will review novel therapeutic strategies in relapsed or refractory diffuse large B-cell lymphoma, including monoclonal antibodies, drug immunoconjugates, radioimmunoconjugates, proteasome inhibition with bortezomib (Velcade), histone deacetylase inhibitors, and immunomodulatory drugs.

Financial Disclosure:Dr. Czuczman is a consultant for and has received honoraria and/or research funding from Genentech and Biogen Idec.

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