Abstract
Diffuse large B-cell lymphoma is the most common adult non-Hodgkin lymphoma and is potentially curable. Immunochemotherapy, R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) is the standard of care. This regimen has been incorporated in other approaches and reevaluated in different trials in different age groups. The duration of cycle therapy has varied from 14 to 21 days. In addition, R-ACVBP has been evaluated in randomized trials. Autologous stem cell transplantation (ASCT) has been evaluated in randomized clinical trials. Ongoing studies are evaluating new regimens such as EPOCH-R and novel maintenance therapy approaches in the upfront management of DLBCL. In the relapse and refractory setting, autologous stem cell transplantation remains the standard of care with treatment with R-ICE or R-DHAP followed by different conditioning regimens prior to ASCT. The outcomes of patients who relapse following ASCT are improving with the treatment of new agents targeting different pathways such as lenalidomide. New monoclonal antibodies are under evaluation. The Bruton s tyrosine kinase inhibitor is in early stages of development. Targeted therapy has changed the natural history of diffuse large B-cell lymphoma. Past microarray and new DLBCL hypersequencing data are revealing new pathways and targets to further explore therapeutically. This review will describe the contribution of immunochemotherapy and other interventions in diffuse large B-cell lymphoma evaluating past clinical trials, review early clinical trial observations, and discuss current future directions.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma.Citation1 The 2008 WHO classification includes 15 different DLBCL subentities.Citation2 We will review the present directions in therapeutic interventions, other DLBCL disorders, the molecular classification, and associated biology.
DLBCL is potentially curable. The identification of lymphoma-specific surface markers leads to the development of monoclonal antibodies targeted to specific antigens. Monoclonal antibodies, monoclonal antibodies conjugated to radioisotopes, and stem cell transplantation with these therapeutic modalities are incorporated into management strategies in DLBCL. New drugs with different mechanisms of action in different pathways are leading to new directions in DLBCL. Of even greater potential impact, different new oral agents are under development and evaluation in clinical trials.
The Current Standard of Care: R-CHOP21
Rituximab is a chimeric anti-CD20 human immunoglobulin antibody which was the first approved antibody in the treatment of DLBCL. Studies have demonstrated a consistent clinical benefit to the addition of rituximab to chemotherapy, immunochemotherapy. In a landmark phase 3 trial of R-CHOP versus CHOP in previously untreated patients at 60–80 years of age, the Groupe d’Etude des Lymphomes de I’Adulte (GELA) reported an improved progression-free survival (PFS) and overall survival (OS) that was further confirmed in long-term follow-up.Citation3–Citation5 The 10-year overall survival was 43·5% with R-CHOP compared with 27·6% with CHOP.Citation5 The US Intergroup Trial Eastern Cooperative Oncology Group 4494/Cancer and Leukemia Group B 9793 with participation from the Southwestern Oncology Group was a prospective randomized phase 3 trial designed to address the failure of induction therapy and failure to maintain a response comparing failure-free survival in patients 60 years of age or older with DLBCL assigned to either R-CHOP or CHOP followed by a second randomization in responders to either maintenance rituximab (MR) or observation.Citation6 The estimated 2-year failure-free survival rates after second randomization were 77% for R-CHOP followed by observation, 79% for R-CHOP and MR, 74% for CHOP+MR, and 45% for CHOP followed by observation (P<0·001). These findings suggested an additive rather than a synergistic effect of rituximab. A secondary analysis was undertaken to elucidate the effects of induction treatment without MR. In this analysis, R-CHOP alone significantly decreased the risk of treatment failure compared to CHOP alone [hazard ratio (HR) = 0·64; 95% confidence interval (CI): 0·47 to 0·85; P = 0·003) with an estimated 3-year OS rate of 67% for R-CHOP and 58% for CHOP. In comparing the GELA and US Intergroup trials, the 3-year PFS (R-CHOP, 53% and 52%; CHOP, 35% and 35%, respectively) OS (R-CHOP, 62% and 67%; CHOP 51% and 58%, respectively), and respective OS HR (0·72 and 0·72) were similar in the GELA and US Intergroup Trial, despite differences in the number of patients with high-risk International Prognostic Index (IPI) scores (R-CHOP, 12% versus 23%; CHOP 15% versus 27%, respectively). MR is under further evaluation in the GELA NHL-13 trial which incorporates rituximab every 2 months for 2 years in patients who achieved a complete remission (CR) or unconfirmed remission (Cru). The German High Grade Lymphoma Study Group randomized 413 young patients to rituximab CHOP-like regimen for six cycles versus a CHOP-like regimen alone in 410 patients with an IPI of 0 or 1 in the MInT Trial.Citation7,Citation8 Radiation therapy was administered to bulky disease and at physician discretion to primary extranodal disease. The median age was 47 years. The initial and 6-year outcomes were superior in the rituximab arm. There have been no randomized studies in young patients with poor risk patients, and these patients have not been adequately represented in registry studies. Registry data confirmed the randomized clinical trial observations. A Canadian population study confirmed the OS observation of R-CHOP.Citation9 A total of 292 patients with DLBCL treated in the province of British Columbia were retrospectively evaluated in a population-based analysis. Of these patients, 140 with a median follow-up of 42 months (range: 5–52 months) were treated in the pre-rituximab era with CHOP-like therapy, and 152 patients were treated with R-CHOP with a median follow-up of 24 months (range: 9–35 months) in the post-rituximab era. The risk ratio [relative risk (RR): 0·40; P<0·002) and the OS (RR: 0·40; P<0·001) were significantly improved in the post-rituximab group regardless of age.
There has been debate regarding the number of cycles of CHOP chemotherapy, six versus eight. In a randomized controlled trial in patients over the age 60 in the RICOVER-60 trial, there was no difference in patients treated with six versus eight cycles.Citation10 In patients with a CR/Cru, the German High Grade Lymphoma Study Group has reported that additional radiotherapy has no role with an OS in R-CHOP treated patients of 76% versus 80% in R-CHOP/RT-treated patients (P = 0·509).Citation11
R-CHOP21 is superior to CHOP and related regimens, but is not sufficient in approximately half of patients with stage III or IV disease. Alternative treatment strategies are needed.
Clinical Trials with R-CHOP21 and Other Approaches
Other regimens have been evaluated in DLBCL including R-CHOP14, DA-EPOCH-R in phase 2 studies predominantly at the NCI in more aggressive subtypes, R-MACOP-B, R-Mega-CHOEP in predominantly mediastinal lymphoma, and R-ACVBP.
R-CHOP14 Trials
Initial trials suggested an advantage of treatment with every 14 days versus 21 days.Citation12,Citation13 In the results of the LNH03-6B GELA study, there were no differences in the outcomes of patients treated with R-CHOP14 versus R-CHOP21 and the incidence of febrile neutropenia episodes and transfusion requirements were greater in the R-CHOP14 arm.Citation14 Cunningham and colleagues reported on a randomized study of 540 patients treated with R-CHOP21 for eight cycles versus R-CHOP14.Citation15 There was no difference in the OS rates of 81% and 83% (P = 0·70). In a randomized study of R-MegaCHOEP [cyclophosphamide (1500 mg/M2 cycle 1; 4500 mg/M2 cycles 2 and 3; 6000 mg/M2 cycle 4); doxorubicin (70 mg/M2 in all cycles), vincristine (2 mg, all cycles); etoposide (600 mg/M2 cycle 1, 960 mg/M2 cycles 2 and 3; 1480 mg/M2 cycle 4); prednisone (500 mg, all cycles); high-dose therapy cycles 2–4; rituximab (375 mg/M2×6)] (n = 132) versus R-CHOP-14 (n = 130) by the German High-Grade Lymphoma Study Group, there was no difference in the OS or PFS.Citation16 The 3-year event free survival was better in the conventional arm. The authors concluded that high-dose therapy has no role to play in first-line therapy for high-risk aggressive B-cell lymphoma.
R-ACVBP
The GELA has evaluated ACVBP since 1984. R-ACVBP (196) with sequential consolidation has recently been compared to R-CHOP21 (183) for 8 cycles in a randomized trial in patients age 18–59.Citation17 The respective overall response rates (ORRs) were 92% and 88%. The 3-year PFS was 87% (95% CI: 81–91 in the R-ACVBP arm) and 73% in the R-CHOP21 arm (HR = 0·482; 95% CI: 66–79) (P = 0·0015). The OS was 92% (HR = 0·439; 95% CI: 87–95%) and 84% (95% CI: 77–89) in the R-CHOP-21 arm (P = 0·0071). Vindesine is not widely approved for DLBCL. Febrile neuturopenia occurred in 39% of patients treated with R-ACVBP and 9% of patients treated with R-CHOP21. Fifty-one percent of patients treated with R-ACVBP were transfused with red blood cells versus 7% in the R-CHOP21 arm. The overall survival in ACVP and R-ACVP plus high-dose therapy demonstrated improved outcomes in the LNH03+39B study and the LNH98-3 study (P = 0·0494). This is the only study to demonstrate improved outcomes in younger patients with adverse risk factors.
At this time, ongoing studies include randomized trials of R-CHOP21 versus DA-R-EPOCH, R-CHOP21 followed by enzastaurin versus observation in patients in CR, and other studies with different therapeutic approaches. In addition,Citation18FDG-PET strategies may further influence therapeutic approaches.
Relapsed and Refractory DLBCL
Autologous stem cell transplantation is the standard of care in patients who relapse following standard induction therapy with DLBCL.Citation18,Citation19 Outcomes of 68 404 patients in the CIBMTR demonstrated improvements in 1-year OS in NHL in patients who had a complete remission to first treatment/sensitive relapse in remission at the time of transplant. There was a decline in OS between day 100 and 1 year in patients in second complete remission/sensitive relapse and primary induction failures.Citation20 Induction regimens before stem cell transplantation have been under study. The International Collaborative Trial in Relapsed Aggressive Lymphoma study randomized 202 patients to R-ICE (rituximab, ifosphamide, carboplatin, and etoposide) versus 194 to R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin) and found no difference in these two induction regimens in young patients with relapsed/refractory DLBCL in the 3-year EFS and 3-year OS.Citation21 The outcome has been reported to be influenced by the cell of origin.Citation22 An improved overall survival with Zevalin- BEAM (84%) versus total body irradiation (59%) (P<0·01) with 0% versus 13% toxic deaths.Citation23 The outcomes of patients with primary refractory or early relapse have been evaluated by the British Columbia Cancer Agency.Citation24 One hundred and sixty-six of 1126 (15%) had refractory or early relapse disease. Ninety-three patients were greater than 70 years of age, too frail, or had failed more than two treatments. The other 73 patients had a median OS of 10 months. Forty (55%) relapsed within 3 months of CR/partial response (PR) and 5/6 transplanted were long-term survivors. The Southwestern Oncology Group compared CHOP (n = 215) or R-CHOP (n = 182) for five cycles and then randomized if a PR or CR to three more cycles of chemotherapy versus one more cycle of chemotherapy and autotransplant in high–intermediate and high-risk diffuse aggressive lymphoma.Citation25 There was an improvement in the PFS, 69% versus 56% (P = 0·005) with a stronger outcome in high IPI score patients, 75% versus 41%. There was no improvement in the overall survival, 74% versus 71% (P = 0·32).
New Agents in Combination with Immunochemotherapy
Although outcomes have improved with stem cell transplantation, a significant number of patients are not transplanted or they relapse. New approaches are needed in DLBCL. New drugs with different mechanisms of action are under study. Agents have been studied and subsequently combined with R-CHOP chemotherapy in phase I and phase II studies.
Epratuzumab has been combined with R-CHOP.Citation26 In the expanded NO489 study of 107 patients, the 12-, 24-, and 36-month OS were 89%, 81%, and 80%.Citation27 The respective event-free survival (EFS) were 79%, 72%, and 70%. Bortezomib has been evaluated in combination with DA-EPOCH. In a limited study, outcomes were superior in the activated B cell-like DLBCL patients.Citation28,Citation29 Lenalidomide is an oral agent with multiple mechanisms of action including immunodulatory, anti-angiogenesis, modulator of the microenvironment, and direct anti-tumor activity.Citation30 The ORR was 19% in relapsed and refractory patients.Citation31 In an expanded confirmatory study, the ORR was 30%.Citation32 In a phase 1 dose escalation study of lenalidomide combined with R-CHOP (R2CHOP), the 12-month EFS was 75·1% (95% CI: 60·3–93·7).Citation33 In a retrospective analyses of patients with relapsed/refractory DLBCL, non-germinal center type DLBCL was associated with a higher response rate and improved PFS. The GELA is evaluating the role of maintenance lenalidomide following R-CHOP21 in the ReMaRC study. Iodine-131 tositumomab consolidation administered 4–12 weeks after R-CHOP was studied in 86 patients with de novo DLBCL.Citation34 The 1-year PFS was 75% with a predicted 75% with R-CHOP alone.
Single Agents
A protein C kinase inhibitor, enzastaurin, has demonstrated activity in DLBCL in the phase II setting and has been brought forward in a randomized maintenance trial following R-CHOP that has completed accrual.Citation35 Tipifarnib, an oral farnesyltransferase inhibitor, was one of the earliest oral agents evaluated. The ORR and PR rates were 19%.Citation36 The PI3K/Akt pathway is constitutively activated in non-Hodgkin lymphoma, and mTOR is downstream controlling cell proliferation. mTOR inhibitors have been under evaluation in phase II trials. Treatment with the oral mTOR inhibitor, everolimus (RAD001), at a dose of 10 mg per day resulted in an ORR of 36% in 7 or 20 patients treated with a median with relapsed/refractory DLBCL.37 Everolimus is being evaluated with another oral agent, sorafenib.Citation38 Tonic B-cell receptor signaling requires SYK expression and phosphorylation. Fostamatinib, an oral inhibitor of Syk, at a dose of 200 mg orally twice a day, resulted in an ORR of 21% of patients with one CR and four PRs in patients with relapsed/refractory disease.Citation39
New anti-CD20 antibodies have been analyzed in DLBCL. Rituximab is composed of 15% mouse protein. These agents have different effects on complement-dependent cytotoxicity, apoptosis, and immunization effects.Citation40 The zumabs have 5–10% mouse protein and include AME-133, GA101, and PRO131921. The ORR was 29% in seven patients treated with the anti-CD20 monoclonal antibody GA101 at 400 or 1600/800 mg dosages.Citation41 The mumabs include HuMax-CD, ofatumomab, ozralamumab, and valtuzumab. In a series of 81 patients, 96% previously treated with rituximab and 31% with a prior autologous stem cell transplant, treatment was with a first dose of 300 mg ofatumumab followed by 1000 mg for doses 2–8; the ORR was 11% with 4% CRs.Citation42 Veltuzumab is administered subcutaneously with significant activity in other lymphomas.Citation43
The Bruton’s tyrosine kinase inhibitor agents are under evaluation in a broad array of B-cell malignancies. These agents appear more active in the CARD11 wild type and more active in activated B cell-like DLBCL subtypes.Citation44
Biological observations of the genome in DLBCL will probably alter therapeutic approaches in the future.Citation45
Whole-exome sequencing has identified recurrent mutations in genes that are functionally relevant in DLBCL, including MYD88, CARD11, EZH2, and CREBBP, in addition to genes for which a functional role in DLBCL has not been established, including MEF2B, MLL2, BTG1, GNA13, ACTB, P2RY8, PCLO and TNFRSF14, along with infrequent likely functionally mutations of KRAS, BRAF, and NOTCH1.Citation45
Conclusion
At this time, R-CHOP21 remains the standard of care for the majority of patients with DLBCL. R-ACVBP has been reported to improve OS in younger patients with aggressive disease. To date, microarray molecular profiling data have identified at least two new drugs that have been evaluated in DLBCL, fostamatinib and enzastaurin. Drugs from new molecular pathways are under evaluation, everolimus and Bruton’s tyrosine kinase inhibitors. Future hypersequencing of the DLBCL genome will probably aid in providing new directions to approach DLBCL.
Related Research Data
References
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