Therapeutic Options in Relapsed or Refractory Diffuse Large B-cell Lymphoma: Part 2

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) patients who are not eligible for high-dose chemotherapy may benefit from an increasing number of regimens integrating novel agents with promising activity and manageable toxicity. Advances in biotechnology have led to the development and validation of novel biomarkers used for categorization or risk stratification in patients with DLBCL. Simultaneously, novel agents are being developed to target cellular pathways that are important in the initiation, growth, and progression of DLBCL. These agents are undergoing clinical testing, and early data are encouraging. This two-part review, which begain in last month’s issue of ONCOLOGY, summarizes treatment options for patients with relapsed/refractory DLBCL and stresses the emerging therapeutic challenges for patients who were previously exposed to rituximab.

The addition of rituximab (Rituxan) 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. As noted in last month’s ONCOLOGY, in part 1 of this two-part article, it is becoming evident that the subset of patients with rituximab immunotherapy–relapsed/refractory DLBCL represents a different clinical entity with a higher degree of chemotherapy resistance compared to DLBCL patients receiving upfront chemotherapy alone.

Several novel agents are being evaluated in patients with relapsed/refractory DLBCL, and we have selected some of the most promising agents emerging from early phase I/II clinical trials to discuss here. Each of these agents represent a new class of drug or pathway targeted for the treatment of relapsed/refractory DLBCL: monoclonal antibodies, including drug conjugates and radioimmunoconjugates; immunomodulatory drugs (lenalidomide [Revlimid]); and small molecules targeting cellular pathways (eg, proteasome inhibitors and histone deacetylase inhibitors).

Monoclonal Antibodies, Drug Conjugates, and Radioimmunoconjugates

Advances in molecular biotechnology and tumor immunology have led to the development of chimeric and humanized monoclonal antibodies with longer half-lives and decreased immunogenicity.[1] In addition, improvements in the antibody structure design, large-scale production, and the development of stable linkers used for drug or radioisotope conjugation have resulted in the generation of novel and more potent biologically active agents. Moreover, a better understanding of the biology of B-cell differentiation and B-cell lymphoma has lead to the identification of novel targets for antibody development. These novel agents are being actively studied preclinically and in a large number of clinical trials.

Radioimmunoconjugates

Monoclonal antibodies carrying radioisotopes such as the humanized ⁹⁰Y-ibritumomab tiuxetan (Zevalin) and murine tositumomab/¹³¹I-tositumomab (Bexxar) target the CD20 antigen and deliver cytotoxic radiation into the tumor bed. The antitumor activity of radioimmunoconjugates has been demonstrated in patients with indolent lymphomas, and to a lesser degree, in patients with DLBCL. The major barrier for the use of radioimmunoconjugates in the treatment of DLBCL is myelosuppression, which is of significant concern in patients with rapidly growing and symptomatic disease requiring repeated bouts of chemotherapy. As a result, radioimmunoconjugates have been primarily used either as a palliative option for highly refractory DLBCL patients or evaluated in clinical trials as part of a bone marrow transplant conditioning regimen to replace total-body irradiation.[2-5]

⁹⁰Y-ibritumomab tiuxetan was evaluated in the palliative setting in 104 patients with relapsed/refractory DLBCL. The patients enrolled in this study were ineligible for high-dose chemotherapy with autologous stem cell support (HDC-ASCS). Response rates to ⁹⁰Y-ibritumomab tiuxetan were higher in patients without prior rituximab exposure (58%) than in patients with rituximab-treated relapsed/refractory lymphomas (19%).[2]

Several earlier clinical trials had evaluated myeloablative doses of ¹³¹I-tositumomab followed by ASCS in elderly DLBCL patients, or the incorporation of ⁹⁰Y-ibritumomab tiuxetan or ¹³¹I-tositumomab into various conditioning regimens in the ASCS or allogeneic bone marrow transplant setting-for example, CyVP16 (cyclophosphamide and etoposide) followed by ASCS, or BEAM (carmustine [BCNU], etoposide, cytarabine, melphalan [Alkeran]) followed by ASCS-in patients with DLBCL. The addition of either 90Y-ibritumomab tiuxetan or ¹³¹I-tositumomab to currently available conditioning regimens did not result in additional significant toxicity, and the relapse-free and overall survival at 2 or 3 years was 74% and 93% for ⁹⁰Y-ibritumomab tiuxetan plus CyVP16–treated patients, and 39% and 55% for patients receiving the ¹³¹I-tositumomab plus BEAM regimen, respectively.[3,5]

The results of radioimmunoconjugates are promising, and the benefits and toxicities are challenging clinicians to optimize the use of these novel agents as further data are obtained from clinical trials. Further studies are necessary to better define their role in the management of patients with DLBCL.

Dacetuzumab

Dacetuzumab is a humanized monoclonal antibody that targets CD40, which is expressed on B-cell hematologic malignancies, as well as some solid tumors. CD40 ligand (CD40L), also known as CD154, is the natural ligand of CD40 and a member of the tumor necrosis factor (TNF) family of receptors. The interaction between CD40 and CD40L/CD154 plays an essential role in the contact interactions between antigen-presenting cells and T-cells.

In contrast, the role of CD40 and CD40L in cancer cells remains to be fully defined. There is considerable evidence to suggest that ligation of CD40 on malignant cells by CD154 or agonistic anti-CD40 monoclonal antibodies lead to growth inhibition and apoptosis.[6-9] However, the opposite effect has been demonstrated by other investigators. CD40 signaling may be antiapoptotic or proapoptotic on malignant B cells, depending on the type of malignancy studied and the specific monoclonal antibody or ligand used. In vitro exposure to CD40L of some low-grade B-cell neoplastic cells, such as chronic lymphocytic leukemia cells, promotes cell survival. On the other hand, high-grade lymphoma B-cell lines respond to CD40 signaling and undergo rapid growth arrest and apoptosis. The expression pattern of CD40 on a broad range of malignancies and the role of CD40-CD40L in vivo/in vitro make CD40 an important target for antibody immunotherapy. Preclinical studies demonstrate potential antitumor activity in multiple myeloma and other B-cell lymphoma histologies.[10,11]

The first phase I dose escalation clinical trial of dacetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) was led by Dr Advani et al. The primary objectives of this study were to assess the safety, pharmacokinetics, and antitumor activity of dacetuzumab.[12] Toxicity reported in the first 35 patients enrolled in this study were primarily infusion-related events; most of them were grade 1 or 2 and included fatigue (31%), headache (26%), chills (17%), pyrexia (17%), elevated hepatic transaminases (11%), and hypotension (11%). Antitumor activity was observed in this heavily pretreated group of patients. Responses were more evident in patients with DLBCL. At least eight patients with DLBCL completed one cycle and had received up to a 3-mg/kg dose of dacetuzumab. The response rate in this subgroup of patients was 37.5%, with one patient achieving a complete remission (CR) and two patients, a partial remission (PR).[12]

To further investigate the safety and efficacy of dacetuzumab, researchers conducted a phase II multi­center, open-label study in patients with relapsed CD40+ DLBCL (de novo or transformed histologies). Enrolled patients had failed prior rituximab/chemotherapy regimens or HDC-ASCS.[13] The first cycle of dacetuzumab was administered over a period of 5 weeks, and each patient underwent treatment according to the same dose-escalating schema. Dacetuzumab was given intravenously at 1 mg/kg on day +1, and then escalated to 2 mg/kg on day +4, and to 4 mg/kg on day +8. Subsequently, patients received the full dose of dacetuzumab at 8 mg/kg per weekly dose. Patients showing no evidence of progressive disease were continued on 28-day cycles of dacetuzumab at 8 mg/kg/wk until disease progression or up to 12 cycles.

Preliminary results from this study were presented at the 2008 annual meeting of the American Society of Hematology (ASH) and included 46 patients enrolled from 10 different centers in the United States. The overall response rate was 10%, half of them being CRs and the other half PRs. In addition, 24% of the remaining patients had stable disease on treatment.[13] Reductions in the tumor size of measurable lesions were seen in approximately one-third of patients. Dacetuzumab was well tolerated and the toxicity profile was very similar to what had been observed in phase I studies.[12,13]

Drug Conjugates

Further exploring the capacity of the CD22 antigen-antibody complex to internalize following antibody biding, the use of anti-CD22 to deliver toxins inside lymphoma cells has been investigated in preclinical models and clinical trials.[14,15] Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized CD22 antibody, conjugated to calicheamicin, a potent cytotoxic antitumor agent. The antitumor activity of inotuzumab was demonstrated in preclinical models.[14]

Fayad et al conducted a phase I clinical trial of inotuzumab in combination with rituximab in patients with follicular lymphoma and DLBCL. The study included patients with relapsed or refractory B-cell lymphomas who progressed after one or two therapies. Rituximab-resistant patients, defined as those with disease progression within 6 months of the first dose of rituximab, were excluded. Patients received rituximab at 375 mg/m² on day 1 of each 28-day cycle and inotuzumab on day 2 at doses of 0.8 mg/m² (n = 5), 1.3 mg/m2 (n = 3), and 1.8 mg/m² (n = 7) for a maximum of eight cycles. The maximum tolerated dose of inotuzumab was 1.8 mg/m²; additional patients were enrolled at this dose level. At the time of the preliminary analysis, 61 patients had been treated, 30 of whom were assessable for antitumor response.[15]

Toxicities were manageable, and the most common were thrombocytopenia (41%), nausea (38%), fatigue (36%), elevation of liver function test (26%), and neutropenia (25%). Grade 3/4 hematologic toxicities were rare and occurred in 5% of patients. Tumor responses (including 6 CRs) were seen at all dose levels of inotuzumab, and the 6-month progression-free survival in patients with DLBCL was 66%.[15] These data support the continuing development of inotuzumab ozogamicin in combination with rituximab for the management of aggressive NHL. In addition, radiolabeled anti-CD22 monoclonal antibodies in development have significant potential for antitumor activity in CD22-positive B-cell neoplasms.

Small Molecules Targeting Signaling Pathways in Relapsed/Refractory DLBCL Proteasome Inhibition With Bortezomib

The discovery and functional characterization of the ubiquitin-proteasome pathway as the major system for extralysosomal protein degradation has delineated its importance for regulating the selective and temporal proteolysis of key regulatory proteins.[16] Over the past couple of years, investigators have discovered a significant number of proteins that regulate cell cycle, apoptosis, cell proliferation, and differentiation, and that undergo processing and functional limitation by entering the ubiquitin-proteasome pathway.[17-21] Several groups of investigators have reported data suggesting that deregulation of the ubiquitin-proteasome system contributes to the pathogenesis of several malignancies (eg, lymphoma, glioma, and colon and lung carcinomas).[22-24]

To date, bortezomib (Velcade) is the first and only proteasome inhibitor approved by the US Food and Drug Administration (FDA) for the treatment of certain hematologic malignancies. However, newer second-generation proteasome inhibitors are entering clinical trials.[25] Preclinical and clinical studies have demonstrated that bortezomib possesses significant antitumor activity against various subtypes of lymphoma (eg, mantle cell lymphoma) and is capable of enhancing the biologic activity of other target-specific therapies such as rituximab or chemotherapeutic agents.[26-29]

Goy et al evaluated the effects of bortezomib in a group of 40 patients with relapsed or refractory indolent or aggressive B-cell lymphoma. Of note, half of the patients had mantle cell lymphoma. Bortezomib was administered at 1.5 mg/m² twice a week for 2 weeks every 21 days, for up to a total of six cycles. An overall response rate of 50% (four CRs, six PRs) was observed among the 20 evaluable mantle cell lymphoma patients. To a lesser degree, responses were also observed in patients with DLBCL.[30] Adverse events consisted of grade 3 hypotension, neutropenia, nausea and vomiting, and grade 4 thrombocytopenia. One recently completed clinical trial evaluated targeting of the proteasome with bortezomib in combination with dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin HCl), and demonstrated antitumor activity in a significant subset of patients with refractory/relapsed DLBCL (personal communication, W. Wilson, National Cancer Institute).

Histone Deacetylase Inhibitors

Over the past decade, we have gained a better understanding of the mechanisms that govern gene transcription and its relationship with cancer, including lymphoma. Histone deacetylase (HDAC) plays an important role in gene expression, and aberrant expression/function of HDAC can be found in many types of cancers. HDAC inhibitors appear to promote B-cell lymphoma cell death via downstream effects of acetylation and possibly through inactivation of BCL-6, a proto-oncogene implicated in the pathogenesis of DLBCL.[31,32]

Vorinostat (Zolinza) is an HDAC inhibitor approved by the FDA for the treatment of cutaneous T-cell lymphomas. This agent has also been shown to induce cell-cycle arrest and apoptosis, and prolong survival in preclinical models of B-cell lymphoma.[31] In addition, vorinostat is known to downregulate the expression of Bcl-xl in B-cell lymphomas promoting apoptosis and synergizing with chemotherapy agents.[33] In a phase I trial evaluating the maximum tolerated dose of single-agent vorinostat in hematologic malignancies, activity in DLBCL was noted.[34] A phase II study of vorinostat in relapsed/refractory indolent NHL, reported at the 2008 annual ASH meeting, demonstrated a 29% overall response rate in 35 patients (which includes a 0/9 response rate in a mantle cell lymphoma subset).[35]

Crump et al reported the results of a phase II clinical trial evaluating the efficacy and safety of vorinostat in patients with DLBCL. The study enrolled 18 patients with relapsed/refractory DLBCL who had undergone a median of two previous treatments including ritxuimab/chemotherapy, and 6 of 18 had undergone prior HDC-ASCS. Patients received oral vorinostat at 300 mg bid for 14 days every 21 days until disease progression. Although vorinostat was well tolerated, only limited activity was observed in DLBCL patients; one achieved a CR and another had disease stabilization. Moreover, the median duration of response was only 44 days. The investigators elected to close the trial earlier than planned. It is possible that several factors contributed to the negative results observed, including the dose and schedule used, as well as the highly refractory patient population selected.[36]

Novel HDAC inhibitors with promising preclinical activity (eg, LBH589 and MS-275) are entering phase I/II studies in patients with relapsed/refractory lymphomas. Results from these and similar studies will better define the role of HDAC inhibitors in the management of patients with aggressive lymphomas.

Immunomodulatory Drugs

Modulation of the immune response is an attractive strategy by which to enhance the biologic activity of monoclonal antibodies. Lenalidomide and pomalidomide, analogs of thalidomide (Thalomid), are best known as immunomodulatory drugs (IMiDs). In vitro and in vivo studies of these agents demonstrated not only a higher antitumor activity (compared to thalidomide) against myeloma or lymphoma cells, but also a unique ability to augment the innate immune system (eg, activation of natural killer [NK] cells and production of interleukin-2 [IL-2]); enhance the antitumor activity of rituximab; and inhibit angiogenesis.[37-40] Their exact mechanism(s) of action are yet to be defined, but the immunomodulatory effects are believed to be related to (1) inhibition of the proinflammatory cytokine TNF-α, (2) inhibition of factors that promote tumor growth such as vascular endothelial growth factor (VEGF), (3) inhibition of nuclear factor (NF)-κB activity in tumor cells, and (4) induction of apoptosis and/or augmentation of NK-cell cytotoxicity against multiple myeloma or B-cell lymphomas.[37-40]

Wiernik et al reported the first phase II clinical trial evaluating the safety and efficacy of lenalidomide in relapsed/refractory aggressive lymphomas. Patients received oral lenalidomide at 25 mg daily for 21 days every 28 days for 52 weeks or until disease progression. The study included 49 patients, 53% of whom had DLBCL, with a medium number of four previous treatments. Response rates were observed in 35%, including 12% CR/CRu (unconfirmed CRs). The median duration of response was 6.2 months and the median progression-free survival was 4 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%).[41]

A confirmatory international phase II trial (NHL-003) of single-agent lenalidomide was initiated for patients with relapsed/refractory aggressive NHL (n = 203) who had received at least one prior treatment and had measurable disease. On behalf of the group of the investigators, Dr. Czuczman presented data on 73 evaluable DLBCL patients (it was too early to evaluate 34 patients) at the annual ASH 2008 meeting.[42] Lenalidomide was associated with an overall response rate of 29% (21/73), with 4% CRs (3/73) and 25% PRs (18/73). Eleven patients (15%) had stable disease. The most common grade 3/4 adverse events were neutropenia (32%), thrombocytopenia (15%), asthenia (8%), and anemia (7%).[43] The results of these two clinical studies confirm the activity of lenalidomide in heavily pretreated patients with relapsed or refractory DLBCL, with manageable side effects. Ongoing studies are aimed at delineating biomarkers of response to lenalidomide in patients with DLBCL to guide future clinical trials.

Conclusions

In summary, parallel to the increased efficacy of front-line regimens for patients with DLBCL, the care of patients with relapsed/refractory disease is becoming increasingly challenging. What had been postulated in the past and has been evaluated in preclinical models is becoming more evident: that is, that more resistant forms of DLBCL are emerging in response to the selective pressure applied to them by upfront use of rituximab-based immunochemotherapy regimens. Scientific efforts should focus on determining the best salvage therapy for patients with relapsed/refractory DLBCL in the rituximab era as well as evaluating and integrating effective novel agents with promising antitumor activity into current treatment paradigms.

The results of the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL study) will provide insightful information regarding the more effective rituximab-containing salvage regimen and evaluate the value of rituximab maintenance in DLBCL following HDC-ASCS. Further studies are necessary to validate or discover new biomarkers, which might correlate the sensitivity of relapsed DLBCL cells to a specific salvage regimen and/or targeted agent. As therapeutic options for patients with relapsed/refractory DLBCL increase, tailoring of optimal treatment regimens based on an individual tumor’s genetic profile and associated microenvironment-which is believed to be prognostic and contributes to resistance or sensitivity-will ultimately improve the clinical course and increase the percentage of cures in this challenging group of patients.

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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