Ann Hematol (2014) 93:541–556 DOI 10.1007/s00277-013-1979-7
REVIEW ARTICLE
Accelerated therapeutic progress in diffuse large B cell lymphoma Qingqing Cai & Jason Westin & Kai Fu & Madhav Desai & Liang Zhang & Huiqiang Huang & Wenqi Jiang & Rong Liang & Zhengzi Qian & Richard E. Champlin & Michael Wang
Received: 21 August 2013 / Accepted: 27 November 2013 / Published online: 28 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in the world. Clinically, biologically, and pathologically, DLBCL is a heterogeneous entity with a range of potential outcomes. Immunochemotherapy regimens, consisting of the chimeric monoclonal anti-CD20 antibody rituximab in combination with chemotherapy, have improved the outcomes. Relapsed DLBCL is generally treated with salvage immunochemotherapy followed by high-dose therapy and autologous stem cell
Q. Cai : H. Huang : W. Jiang Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China Q. Cai : H. Huang : W. Jiang State Key Laboratory of Oncology in Southern China, Guangzhou, China Q. Cai : J. Westin : M. Desai : L. Zhang : M. Wang (*) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Unit 429, 1515 Holcombe Blvd, Houston, TX 77030, USA e-mail: [email protected] K. Fu Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA R. Liang Department of Leukemia, Xi’an The Fourth Military Medical University, Xi’an, China Z. Qian Department of Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China R. E. Champlin Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
transplantation; however, DLBCL is not yet curable in up to a third of patients. The real promise for cure lies in novel agents and their rational combinations. The improved understanding of DLBCL subtypes and gene expression profiling has led to the identification of targeted drugs that may allow for subtype specific therapy. We have summarized the existing data on the prognostic factors and the treatment of DLBCL, including the use of novel agents such as lenalidomide, carfilzomib, and ibrutinib. We also share our thoughts on the direction of future clinical trials. Keywords Diffuse large B cell lymphoma . Novel biological agents . Immunochemotherapy . Rituximab
Introduction Diffuse large B cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), accounting for 31 % of all NHL in Western countries [1]. In Asia, the proportion is more than 40 % [2]. The 2008 World Health Organization classification divided DLBCL into four categories: (1) DLBCL, not otherwise specified (NOS); (2) DLBCL with predominant extranodal location; (3) large cell lymphoma of terminally differentiated B cells; (4) borderline cases [3]. DLBCL, NOS, is the most common type, accounting for 20–30 % of DLBCL cases. The addition of the chimeric monoclonal anti-CD20 antibody rituximab to the standard chemotherapy protocol of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has significantly improved the survival of patients with DLBCL [4–6]. However, a substantial proportion of these patients (30–40 %) have disease that is refractory or eventually relapses after R-CHOP [7]. The optimal method to further improve outcomes of DLBCL based on biological factors has become an interesting and vital topic. This review will focus on recent
542
developments and future directions in treatment of patients with DLBCL.
Prognostic factors The International Prognostic Index (IPI) and age-adjusted IPI (aaIPI) were standards for DLBCL prognosis [8, 9]. Gene expression profiling (GEP), and to some degree immunohistochemistry, can stratify DLBCL patients into three biologic prognostic groups based on the cell of origin, the germinal center B cell-like (GCB), the activated B cell-like (ABC) subtypes, and primary mediastinal B cell lymphoma (PMBL) [10–12]. PMBL is often diagnosed as a unique disease entity based upon location and histology and lies outside the scope of this review. Historically, fresh frozen tissue was needed for genetic analysis which limited the clinical utility of GEP [13]. Recent advances in technology may now allow formalin-fixed paraffin-embedded (FFPE) tissue to be used for GEP [13, 14]. Various immunohistochemical algorithms have been developed to reproduce the GEP findings in FFPE tissue and predict the cell of origin in DLBCL. One of the most widely accepted methods is the Hans algorithm, which uses antibodies against CD10, BCL6, and MUM1 [15]. However, the prognostic benefit of DLBCL subtyping in the rituximab era has been questioned. Some investigators reported no difference in survival between GCB and ABC subtypes when rituximab was added to the chemotherapy regimen [16–19], whereas others have shown a persistent difference [20]. It is the opinion of the authors that there are significant biologic differences between the ABC and GCB subtypes which may be specifically targeted with rational clinical trials, whether or not there are true differences in outcomes with R-CHOP.
Treatment Front-line treatment for DLBCL What is the best choice of front-line treatment for DLBCL in the Rituximab era? The benefit of adding rituximab to CHOP has been demonstrated in numerous randomized trials [4–6]. Further confirming the significant efficacy of rituximab, a trial of dose-dense CHOP was conducted in patients with DLBCL over the age of 60 (RICOVER-60; Table 1) [21]. In this trial, 1,222 elderly patients were randomly assigned to receive six or eight cycles of CHOP-14 (CHOP every 14 days) with or without eight cycles of rituximab based on a bifactorial design. Radiotherapy was planned for patients with sites of initial bulky masses. Radiotherapy within RICOVER-60 trial was also planned for extra-lymphatic involvement. The rituximab arm, six cycles of R-CHOP-14 treatment followed by
Ann Hematol (2014) 93:541–556
two cycles of rituximab, resulted in a significant improvement in event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). However, the RICOVER-60 trial did not compare the dosedense R-CHOP regimen with R-CHOP-21 directly. Recently, Delarue et al. presented the final analysis of the LNH03-6B, a multicenter phase III randomized trial assessing the efficacy of R-CHOP given every 21 days compared with R-CHOP given 14 days. The results showed no significant difference in the length of survival between patients in the R-CHOP-14 and RCHOP-21 groups. The frequency of side effects was similar between the regimens, although R-CHOP-14 was associated with an increased need for red blood cell transfusion [22]. In another phase III randomized trial of 1,080 newly diagnosed elderly patients with DLBCL, Cunningham et al. also reported no evidence that R-CHOP-14 improved OS or PFS when compared with the standard R-CHOP-21 treatment [23]. Based upon the results of these trials, it does not appear that increasing the dose density of R-CHOP is a viable strategy to improve clinical outcomes. The intensive chemotherapy regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) has shown impressive efficacy, perhaps even superior to CHOP treatment for DLBCL in young patients [24–26]. However, Molina and colleague’s trial showed that there was no difference in survival between patients with GCB-type DLBCL being treated with rituximab and ACVBP (R-ACVBP) and those being treated with R-CHOP [27]. Interestingly, EFS, PFS, and OS were significantly improved among patients with non-GCB-type DLBCL who were being treated with R-ACVBP than those patients being treated with R-CHOP. This subgroup analysis suggests that the survival benefit related to R-ACVBP over R-CHOP in the LNH 03-2B is in large part linked to a survival improvement in the nonGCB population [28]. In conclusion, R-CHOP-21 for six or eight cycles is the standard treatment of front-line treatment for young patients with a good risk profile (low or low-intermediate IPI) with DLBCL. The standard management of elderly patients should be based on the general health status of patients (comorbidity). For fit patients, R-CHOP21×8 or R-CHOP 14×6+2R′ from the ESMO Guidelines should be considered too. The shorter time under chemotherapy for R-CHOP-14 in comparison to R-CHOP-21 is another important aspect, especially for young patients [29]. Role of radioimmunotherapy in the frontline consolidation treatment of DLBCL Is there any definite role of radioimmunotherapy (RIT) in the frontline consolidation treatment of DLBCL? Morschhauser et al. evaluated the utility of ibritumomab tiuxetan, a RIT, and found could be used as second-line therapy for patients with
Ann Hematol (2014) 93:541–556
543
Table 1 Randomized, phase III trials of dose-dense R-CHOP in frontline DLBCL Study
Design/regimen
Patient characteristics
Results
Pfreundschuh et al. [21] 6×R-CHOP-14 vs 8×R-CHOP-14 vs 1,222 patients; age, 61–80 years PFS, improved 6/8×R-CHOP-14; P =0.0001 [RICOVER-60] 6×CHOP-14 vs 8×CHOP-14 OS, improved only 6×R-CHOP-14; P =0.0031 Delarue et al. [22] 8×R-CHOP-21(A) vs 602 patients; age, 60–80 years; 3-year EFS: 60 (A) vs 56 % (B); P =0.7614 [LNH03-6B] 8×R-CHOP-14 (B) aaIPI, ≥1 3-year PFS, 62 (A) vs 60 % (B); P =0.8983 3-year OS, 72 (A) vs 69 % (B); P =0.7487 No survival differences between two arms R-CHOP-14 increased red blood cell transfusion Cunningham et al. [115] 8×R-CHOP-21 vs 1,080 patients; median age, Median follow-up, 37 m 6×R-CHOP-14 +2×R 61 years OS, HR=0.96; P =0.75 PFS, HR=1.0; P =0.98 No survival differences between two arms Récher et al. [26] RACVBP vs R-CHOP 380 patients; age, 15–59 years; 3-year EFS, 81 (RACVBP) vs 67 % (R-CHOP); [LNH03-2B] aaIPI=1 P =0.0035 3-year PFS: 87 (RACVBP) vs 73 % (R-CHOP); P =0.0015 3-year OS, 92 (RACVBP) vs 84 % (R-CHOP); P =0.007 Survival benefit in RACVBP arm aaIPI age-adjusted international prognostic index, DLBCL diffuse large B cell lymphoma, EFS event-free survival, HR hazard ratio, OS overall survival, PFS progression-free survival, RACVBP rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone, R-CHOP rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, RICOVER-60 rituximab with CHOP over age 60 years
relapsed or refractory DLBCL who were not candidates for autologous stem cell transplantation (ASCT) [30]. Several phase II studies have examined the role of RIT consolidation therapy in DLBCL patients in the rituximab era. Zinzani et al. evaluated the feasibility, efficacy, and safety of a regimen of four courses of R-CHOP-21 followed by yttrium-90ibritumomab tiuxetan in high-risk elderly DLBCL patients. The patients’ 2-year PFS and OS were estimated to be 85 and 86 %, respectively. The common grades 3–4 hematologic toxicities were neutropenia and thrombocytopenia [31]. Hamlin et al. showed similar results in a phase II study of RCHOP-21 and yttrium-90 ibritumomab tiuxetan for elderly patients with high-risk untreated DLBCL[32]. The complete response/unconfirmed complete response (CR/CRu) and partial response (PR) rates for patients who received RIT after RCHOP were 86 % and 2 %, respectively. Response improvement (PR≥CR or CRu≥CR) occurred in 7 points (16 %). After a median follow-up of 42 months, OS and PFS rates were 83.5 and 74.5 %, respectively. Southwest Oncology Group S0433 found that a consolidation strategy using iodine-131 tositumomab after eight cycles of CHOP chemotherapy (six with rituximab) for advanced stage DLBCL patients does not appear to be promising. The estimated 1-year PFS and 1-year OS rates were 75 and 83 %, respectively. Based on prior studies, the estimated historical 1-year PFS rate with R-CHOP treatment alone in this population was 74 % [33].
Based on these clinical studies, an international phase III randomized trial is ongoing to determine the value of RIT consolidation following rituximab-containing chemotherapy for elderly DLBCL patients with aaIPI≥1. Southwest Oncology Group S1001 is a prospective trial designed to study the role of RIT in the treatment of patients with stage I or II DLBCL who achieve a PR after threecycles of R-CHOP chemotherapy. In conclusion, the role of RIT in the frontline consolidation treatment of DLBCL requires a randomized phase III clinical trials for further confirmation. The role of high-dose chemotherapy and ASCT in the frontline consolidation treatment of DLBCL The role of high-dose chemotherapy (HDC) and ASCT in the frontline consolidation treatment of patients with DLBCL has also been questioned. For young DLBCL patients with aaIPI of 2–3, there is no standard approach to improve upon RCHOP. The main treatment strategies are rituximab combined intensive chemotherapy (higher doses with shortened intervals between treatments) with growth factor support, or ASCT after remission, but these approaches remain controversial regarding their impact on survival outcomes in several randomized trials. In the pre-rituximab era, several randomized clinical trials reported that consolidation therapy with HDC/ASCT
544
Ann Hematol (2014) 93:541–556
following frontline treatment was controversial [34–38]. In addition, two meta-analyses of 26 randomized trials failed to demonstrate a survival benefit for frontline HDC/ASCT [39, 40]. In the rituximab era, the role of rituximab-HDC (R-HDC) needed to be re-examined (Table 2). Gouill et al. presented the preliminary results of the GOELAMS 075 prospective multicenter randomized trial and found no significant benefit of RHDC over R-CHOP-14 for newly diagnosed DLBCL in young adults, and that R-CHOP-14 was better tolerated [41]. The German High-Grade Non-Hodgkin Lymphoma Study Group 2002-1, another randomized phase III trial, identified similar results [42]. In this study, young patients with high-risk aggressive B cell lymphoma received a treatment combining rituxan with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (R-MegaCHOEP) followed by ASCT. It was found that the R-MegaCHOEP regimen was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. By contrast, a US/Canadian Intergroup Trial (Southwest Oncology Group S9704) presented different results. This phase III trial compared a regimen of eight cycles of CHOP with a regimen of six cycles of CHOP (rituximab became
available during the trial and was subsequently added) followed by ASCT for patients with high-intermediate- or high-IPIgrade, diffuse aggressive NHL. The results showed that early ASCT improves PFS for responders, with a better outcome seen for those with a high IPI grade. However, it is important to note that only 44 patients belonged to the high-risk group, that the patient enrollment lasted nearly 10 years, and that 54 % of the patients in the study did not receive rituximab [43]. Recently, Vitolo et al. presented the final results of the DLCL04 study from the Fondazione Italiana Linfomi. Rituximab-dose-dense chemotherapy followed by carmustine, etoposide, cytarabine, and melphalan (BEAM) and ASCT significantly reduced the risk of progression compared with standard dose-dense chemotherapy in young patients with high-risk DLBCL; however, the 3-year OS rate was not significantly higher than with the standard dose-dense chemotherapy [44]. In conclusion, the role of R-HDC is unclear and will prove challenging to evaluate in large, randomized trials fully. In accordance with the current National Comprehensive Cancer Network guidelines, upfront HDC/ASCT is recommended only in select high-risk circumstances or in the context of a clinical trial.
Table 2 Randomized, phase III trials of induction therapy followed by HDC/ASCT consolidation in newly diagnosed previously untreated DLBCL in rituximab era Trial
Protocol
Patient characteristics
Results
Gouill et al. [41] [GOELAMS 075]
8×R-CHOP-14 (A) vs R-HDC (B)
340 patients; age, 18–60 years; aaIPI, >1; bulk, 56 %
Schmitz et al. [42] [DSHNHL2002-1]
R-CHOEP-14 (A) vs R-HDC (MegaCHOEP) (B)
262 patients (intention to treat); age, 18–60 years; aaIPI, 2–3
Stiff et al. [43] [SWOG S9704]
CHOP±R×8 (A) vs CHOP±R×6 followed by HDC/ASCT (B)
397 patients; age, ≤65 years; stages, II (bulky), III, and IV; IPI (high intermediate/high)
Vitolo et al. [44] [DLCL04/FIL]
R-CHOP14×8; RMegaCHOP14×6; R-CHOP14×4+R-HDC+ BEAM/ASCT; RMegaCHOP14×4+ R-HDC+BEAM/ASCT
399 patients; age, 18–65 years; aaIPI, 2–3; stages, II–IV
ORR, 83 (A) vs 81 % (B); P =0.8 3-year PFS: 81 (A) vs 79 % (B); P >0.05 3-year OS, 85 (A) vs 82 % (B); P >0.05 No survival differences between two arms R-CHOP-14 less toxic 3-year EFS, 69.5 (A) vs 61.4 % (B); P =0.14 No survival differences between two arms R-HDC more toxic effects 2-year PFS, 56 (A) vs 69 % (B); P =0.005 2-year OS, 71 (A) vs 74 % (B); P =0.32 High IPI: 2-year PFS, 41 (A) vs 75 % (B) 2-year OS, 64 (A) vs 82 % (B) Better outcome for high IPI 3-year PFS, 70 (R-HDC+ASCT) vs 59 % (R-dose-dense); P =0.010 3-year OS, 81 (R-HDC+ASCT) vs 78 % (R-dose dense); P =0.556 ASCT improves PFS
aaIPI age-adjusted international prognostic index, BEAM carmustine, etoposide, cytarabine, and melphalan, DLBCL diffuse large B cell lymphoma, EFS event-free survival, HDC/ASCT high-dose chemotherapy/autologous stem cell transplantation, MegaCHOP cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone, ORR overall response rate, OS overall survival, PFS progression-free survival, R-CHOEP rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone, RHDC rituximab plus high-dose chemotherapy, SWOG Southwest Oncology Group
Ann Hematol (2014) 93:541–556
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Treatment for relapsed or refractory DLBCL DLBCL patients who are refractory or who have relapsed after R-CHOP or R-CHOP-like therapy have a worse prognosis than similar patients from the pre-rituximab era. After finding a significant improvement survival outcomes in an international randomized phase III trial (PARMA study), HDC/ ASCT has become the standard therapy for patients with relapsed or refractory DLBCL [45]. In the rituximab era, a prospective randomized trial by the Dutch Belgian HematoOncology Cooperative Group demonstrated the benefits of combining rituximab with HDC/ASCT (Table 3) [46]. The results of these studies are clear, but it is unclear which salvage chemotherapy regimen is optimal. The result of the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) directly compared two of the most commonly utilized salvage therapy [47]: Patients with relapsed/refractory DLBCL (N = 396) were randomly assigned to treatment with rituximab and ifosfamide, carboplatin, and etoposide (R-ICE) or dexamethasone, cytarabine, and cisplatinum (R-DHAP). Responding
patients received HDC/ASCT. There were no significant differences between R-ICE and R-DHAP for ORR, 3-year EFS, or OS. A sub-group analysis suggested that R-DHAP may improve outcomes in the GCB subtype, although this would require prospective evaluation [48]. Multivariate analysis revealed that OS was affected by prior rituximab exposure, relapse less than 12 months after diagnosis, and secondary aaIPI of 2–3. The result of a second randomization in the CORAL trial suggests that rituximab maintenance has no defined role in patients with relapsed DLBCL after ASCT [49]. These data suggest that the use of rituximab in frontline therapy may have prevented relapse in patients who ultimately respond to secondline chemotherapy, thus shifting responses forward. RIT treatment is promising when used as consolidation therapy for relapsed or refractory DLBCL. Furthermore, when iodine-131 tositumomab RIT was added to the BEAM combination as a conditioning regimen, the new regimen produced survival rates for patients with chemotherapy-sensitive relapsed DLBCL that were similar to those with rituximabBEAM combination regimens [50].
Table 3 Randomized, phase III trials in relapsed/refractory DLBCL in the Rituximab trial Trial
Design/regimen
Vellenga et al. [46] R-DHAP×2 (A) vs DHAP×2 (B) [HOVON trial] (PR/CR)→BEAM/ASCT
Gisselbrecht R-ICE (A) vs R-DHAP (B) et al. [47, 49] (Responding)→HDC/ASCT [CORAL study] (Second randomization) maintenance ® vs observation (O)
Vose et al. [50] [BMT CTN 0401 trial]
Iodine-131 tositumomab+BEAM HDC (B-BEAM) vs Rituximab+BEAM HDC (R-BEAM)→ASCT
Patient characteristics
Results
239 patients; age, 18–65 years; CD20+ aggressive NHL
RR, 75 (A) vs 54 % (B); P =0.01 2-year FFS, 50 (A) vs 24 % (B); P
REVIEW ARTICLE
Accelerated therapeutic progress in diffuse large B cell lymphoma Qingqing Cai & Jason Westin & Kai Fu & Madhav Desai & Liang Zhang & Huiqiang Huang & Wenqi Jiang & Rong Liang & Zhengzi Qian & Richard E. Champlin & Michael Wang
Received: 21 August 2013 / Accepted: 27 November 2013 / Published online: 28 December 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in the world. Clinically, biologically, and pathologically, DLBCL is a heterogeneous entity with a range of potential outcomes. Immunochemotherapy regimens, consisting of the chimeric monoclonal anti-CD20 antibody rituximab in combination with chemotherapy, have improved the outcomes. Relapsed DLBCL is generally treated with salvage immunochemotherapy followed by high-dose therapy and autologous stem cell
Q. Cai : H. Huang : W. Jiang Department of Medical Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, China Q. Cai : H. Huang : W. Jiang State Key Laboratory of Oncology in Southern China, Guangzhou, China Q. Cai : J. Westin : M. Desai : L. Zhang : M. Wang (*) Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Unit 429, 1515 Holcombe Blvd, Houston, TX 77030, USA e-mail: [email protected] K. Fu Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA R. Liang Department of Leukemia, Xi’an The Fourth Military Medical University, Xi’an, China Z. Qian Department of Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China R. E. Champlin Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
transplantation; however, DLBCL is not yet curable in up to a third of patients. The real promise for cure lies in novel agents and their rational combinations. The improved understanding of DLBCL subtypes and gene expression profiling has led to the identification of targeted drugs that may allow for subtype specific therapy. We have summarized the existing data on the prognostic factors and the treatment of DLBCL, including the use of novel agents such as lenalidomide, carfilzomib, and ibrutinib. We also share our thoughts on the direction of future clinical trials. Keywords Diffuse large B cell lymphoma . Novel biological agents . Immunochemotherapy . Rituximab
Introduction Diffuse large B cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL), accounting for 31 % of all NHL in Western countries [1]. In Asia, the proportion is more than 40 % [2]. The 2008 World Health Organization classification divided DLBCL into four categories: (1) DLBCL, not otherwise specified (NOS); (2) DLBCL with predominant extranodal location; (3) large cell lymphoma of terminally differentiated B cells; (4) borderline cases [3]. DLBCL, NOS, is the most common type, accounting for 20–30 % of DLBCL cases. The addition of the chimeric monoclonal anti-CD20 antibody rituximab to the standard chemotherapy protocol of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) has significantly improved the survival of patients with DLBCL [4–6]. However, a substantial proportion of these patients (30–40 %) have disease that is refractory or eventually relapses after R-CHOP [7]. The optimal method to further improve outcomes of DLBCL based on biological factors has become an interesting and vital topic. This review will focus on recent
542
developments and future directions in treatment of patients with DLBCL.
Prognostic factors The International Prognostic Index (IPI) and age-adjusted IPI (aaIPI) were standards for DLBCL prognosis [8, 9]. Gene expression profiling (GEP), and to some degree immunohistochemistry, can stratify DLBCL patients into three biologic prognostic groups based on the cell of origin, the germinal center B cell-like (GCB), the activated B cell-like (ABC) subtypes, and primary mediastinal B cell lymphoma (PMBL) [10–12]. PMBL is often diagnosed as a unique disease entity based upon location and histology and lies outside the scope of this review. Historically, fresh frozen tissue was needed for genetic analysis which limited the clinical utility of GEP [13]. Recent advances in technology may now allow formalin-fixed paraffin-embedded (FFPE) tissue to be used for GEP [13, 14]. Various immunohistochemical algorithms have been developed to reproduce the GEP findings in FFPE tissue and predict the cell of origin in DLBCL. One of the most widely accepted methods is the Hans algorithm, which uses antibodies against CD10, BCL6, and MUM1 [15]. However, the prognostic benefit of DLBCL subtyping in the rituximab era has been questioned. Some investigators reported no difference in survival between GCB and ABC subtypes when rituximab was added to the chemotherapy regimen [16–19], whereas others have shown a persistent difference [20]. It is the opinion of the authors that there are significant biologic differences between the ABC and GCB subtypes which may be specifically targeted with rational clinical trials, whether or not there are true differences in outcomes with R-CHOP.
Treatment Front-line treatment for DLBCL What is the best choice of front-line treatment for DLBCL in the Rituximab era? The benefit of adding rituximab to CHOP has been demonstrated in numerous randomized trials [4–6]. Further confirming the significant efficacy of rituximab, a trial of dose-dense CHOP was conducted in patients with DLBCL over the age of 60 (RICOVER-60; Table 1) [21]. In this trial, 1,222 elderly patients were randomly assigned to receive six or eight cycles of CHOP-14 (CHOP every 14 days) with or without eight cycles of rituximab based on a bifactorial design. Radiotherapy was planned for patients with sites of initial bulky masses. Radiotherapy within RICOVER-60 trial was also planned for extra-lymphatic involvement. The rituximab arm, six cycles of R-CHOP-14 treatment followed by
Ann Hematol (2014) 93:541–556
two cycles of rituximab, resulted in a significant improvement in event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). However, the RICOVER-60 trial did not compare the dosedense R-CHOP regimen with R-CHOP-21 directly. Recently, Delarue et al. presented the final analysis of the LNH03-6B, a multicenter phase III randomized trial assessing the efficacy of R-CHOP given every 21 days compared with R-CHOP given 14 days. The results showed no significant difference in the length of survival between patients in the R-CHOP-14 and RCHOP-21 groups. The frequency of side effects was similar between the regimens, although R-CHOP-14 was associated with an increased need for red blood cell transfusion [22]. In another phase III randomized trial of 1,080 newly diagnosed elderly patients with DLBCL, Cunningham et al. also reported no evidence that R-CHOP-14 improved OS or PFS when compared with the standard R-CHOP-21 treatment [23]. Based upon the results of these trials, it does not appear that increasing the dose density of R-CHOP is a viable strategy to improve clinical outcomes. The intensive chemotherapy regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) has shown impressive efficacy, perhaps even superior to CHOP treatment for DLBCL in young patients [24–26]. However, Molina and colleague’s trial showed that there was no difference in survival between patients with GCB-type DLBCL being treated with rituximab and ACVBP (R-ACVBP) and those being treated with R-CHOP [27]. Interestingly, EFS, PFS, and OS were significantly improved among patients with non-GCB-type DLBCL who were being treated with R-ACVBP than those patients being treated with R-CHOP. This subgroup analysis suggests that the survival benefit related to R-ACVBP over R-CHOP in the LNH 03-2B is in large part linked to a survival improvement in the nonGCB population [28]. In conclusion, R-CHOP-21 for six or eight cycles is the standard treatment of front-line treatment for young patients with a good risk profile (low or low-intermediate IPI) with DLBCL. The standard management of elderly patients should be based on the general health status of patients (comorbidity). For fit patients, R-CHOP21×8 or R-CHOP 14×6+2R′ from the ESMO Guidelines should be considered too. The shorter time under chemotherapy for R-CHOP-14 in comparison to R-CHOP-21 is another important aspect, especially for young patients [29]. Role of radioimmunotherapy in the frontline consolidation treatment of DLBCL Is there any definite role of radioimmunotherapy (RIT) in the frontline consolidation treatment of DLBCL? Morschhauser et al. evaluated the utility of ibritumomab tiuxetan, a RIT, and found could be used as second-line therapy for patients with
Ann Hematol (2014) 93:541–556
543
Table 1 Randomized, phase III trials of dose-dense R-CHOP in frontline DLBCL Study
Design/regimen
Patient characteristics
Results
Pfreundschuh et al. [21] 6×R-CHOP-14 vs 8×R-CHOP-14 vs 1,222 patients; age, 61–80 years PFS, improved 6/8×R-CHOP-14; P =0.0001 [RICOVER-60] 6×CHOP-14 vs 8×CHOP-14 OS, improved only 6×R-CHOP-14; P =0.0031 Delarue et al. [22] 8×R-CHOP-21(A) vs 602 patients; age, 60–80 years; 3-year EFS: 60 (A) vs 56 % (B); P =0.7614 [LNH03-6B] 8×R-CHOP-14 (B) aaIPI, ≥1 3-year PFS, 62 (A) vs 60 % (B); P =0.8983 3-year OS, 72 (A) vs 69 % (B); P =0.7487 No survival differences between two arms R-CHOP-14 increased red blood cell transfusion Cunningham et al. [115] 8×R-CHOP-21 vs 1,080 patients; median age, Median follow-up, 37 m 6×R-CHOP-14 +2×R 61 years OS, HR=0.96; P =0.75 PFS, HR=1.0; P =0.98 No survival differences between two arms Récher et al. [26] RACVBP vs R-CHOP 380 patients; age, 15–59 years; 3-year EFS, 81 (RACVBP) vs 67 % (R-CHOP); [LNH03-2B] aaIPI=1 P =0.0035 3-year PFS: 87 (RACVBP) vs 73 % (R-CHOP); P =0.0015 3-year OS, 92 (RACVBP) vs 84 % (R-CHOP); P =0.007 Survival benefit in RACVBP arm aaIPI age-adjusted international prognostic index, DLBCL diffuse large B cell lymphoma, EFS event-free survival, HR hazard ratio, OS overall survival, PFS progression-free survival, RACVBP rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone, R-CHOP rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, RICOVER-60 rituximab with CHOP over age 60 years
relapsed or refractory DLBCL who were not candidates for autologous stem cell transplantation (ASCT) [30]. Several phase II studies have examined the role of RIT consolidation therapy in DLBCL patients in the rituximab era. Zinzani et al. evaluated the feasibility, efficacy, and safety of a regimen of four courses of R-CHOP-21 followed by yttrium-90ibritumomab tiuxetan in high-risk elderly DLBCL patients. The patients’ 2-year PFS and OS were estimated to be 85 and 86 %, respectively. The common grades 3–4 hematologic toxicities were neutropenia and thrombocytopenia [31]. Hamlin et al. showed similar results in a phase II study of RCHOP-21 and yttrium-90 ibritumomab tiuxetan for elderly patients with high-risk untreated DLBCL[32]. The complete response/unconfirmed complete response (CR/CRu) and partial response (PR) rates for patients who received RIT after RCHOP were 86 % and 2 %, respectively. Response improvement (PR≥CR or CRu≥CR) occurred in 7 points (16 %). After a median follow-up of 42 months, OS and PFS rates were 83.5 and 74.5 %, respectively. Southwest Oncology Group S0433 found that a consolidation strategy using iodine-131 tositumomab after eight cycles of CHOP chemotherapy (six with rituximab) for advanced stage DLBCL patients does not appear to be promising. The estimated 1-year PFS and 1-year OS rates were 75 and 83 %, respectively. Based on prior studies, the estimated historical 1-year PFS rate with R-CHOP treatment alone in this population was 74 % [33].
Based on these clinical studies, an international phase III randomized trial is ongoing to determine the value of RIT consolidation following rituximab-containing chemotherapy for elderly DLBCL patients with aaIPI≥1. Southwest Oncology Group S1001 is a prospective trial designed to study the role of RIT in the treatment of patients with stage I or II DLBCL who achieve a PR after threecycles of R-CHOP chemotherapy. In conclusion, the role of RIT in the frontline consolidation treatment of DLBCL requires a randomized phase III clinical trials for further confirmation. The role of high-dose chemotherapy and ASCT in the frontline consolidation treatment of DLBCL The role of high-dose chemotherapy (HDC) and ASCT in the frontline consolidation treatment of patients with DLBCL has also been questioned. For young DLBCL patients with aaIPI of 2–3, there is no standard approach to improve upon RCHOP. The main treatment strategies are rituximab combined intensive chemotherapy (higher doses with shortened intervals between treatments) with growth factor support, or ASCT after remission, but these approaches remain controversial regarding their impact on survival outcomes in several randomized trials. In the pre-rituximab era, several randomized clinical trials reported that consolidation therapy with HDC/ASCT
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following frontline treatment was controversial [34–38]. In addition, two meta-analyses of 26 randomized trials failed to demonstrate a survival benefit for frontline HDC/ASCT [39, 40]. In the rituximab era, the role of rituximab-HDC (R-HDC) needed to be re-examined (Table 2). Gouill et al. presented the preliminary results of the GOELAMS 075 prospective multicenter randomized trial and found no significant benefit of RHDC over R-CHOP-14 for newly diagnosed DLBCL in young adults, and that R-CHOP-14 was better tolerated [41]. The German High-Grade Non-Hodgkin Lymphoma Study Group 2002-1, another randomized phase III trial, identified similar results [42]. In this study, young patients with high-risk aggressive B cell lymphoma received a treatment combining rituxan with cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (R-MegaCHOEP) followed by ASCT. It was found that the R-MegaCHOEP regimen was not superior to conventional R-CHOEP therapy and was associated with significantly more toxic effects. By contrast, a US/Canadian Intergroup Trial (Southwest Oncology Group S9704) presented different results. This phase III trial compared a regimen of eight cycles of CHOP with a regimen of six cycles of CHOP (rituximab became
available during the trial and was subsequently added) followed by ASCT for patients with high-intermediate- or high-IPIgrade, diffuse aggressive NHL. The results showed that early ASCT improves PFS for responders, with a better outcome seen for those with a high IPI grade. However, it is important to note that only 44 patients belonged to the high-risk group, that the patient enrollment lasted nearly 10 years, and that 54 % of the patients in the study did not receive rituximab [43]. Recently, Vitolo et al. presented the final results of the DLCL04 study from the Fondazione Italiana Linfomi. Rituximab-dose-dense chemotherapy followed by carmustine, etoposide, cytarabine, and melphalan (BEAM) and ASCT significantly reduced the risk of progression compared with standard dose-dense chemotherapy in young patients with high-risk DLBCL; however, the 3-year OS rate was not significantly higher than with the standard dose-dense chemotherapy [44]. In conclusion, the role of R-HDC is unclear and will prove challenging to evaluate in large, randomized trials fully. In accordance with the current National Comprehensive Cancer Network guidelines, upfront HDC/ASCT is recommended only in select high-risk circumstances or in the context of a clinical trial.
Table 2 Randomized, phase III trials of induction therapy followed by HDC/ASCT consolidation in newly diagnosed previously untreated DLBCL in rituximab era Trial
Protocol
Patient characteristics
Results
Gouill et al. [41] [GOELAMS 075]
8×R-CHOP-14 (A) vs R-HDC (B)
340 patients; age, 18–60 years; aaIPI, >1; bulk, 56 %
Schmitz et al. [42] [DSHNHL2002-1]
R-CHOEP-14 (A) vs R-HDC (MegaCHOEP) (B)
262 patients (intention to treat); age, 18–60 years; aaIPI, 2–3
Stiff et al. [43] [SWOG S9704]
CHOP±R×8 (A) vs CHOP±R×6 followed by HDC/ASCT (B)
397 patients; age, ≤65 years; stages, II (bulky), III, and IV; IPI (high intermediate/high)
Vitolo et al. [44] [DLCL04/FIL]
R-CHOP14×8; RMegaCHOP14×6; R-CHOP14×4+R-HDC+ BEAM/ASCT; RMegaCHOP14×4+ R-HDC+BEAM/ASCT
399 patients; age, 18–65 years; aaIPI, 2–3; stages, II–IV
ORR, 83 (A) vs 81 % (B); P =0.8 3-year PFS: 81 (A) vs 79 % (B); P >0.05 3-year OS, 85 (A) vs 82 % (B); P >0.05 No survival differences between two arms R-CHOP-14 less toxic 3-year EFS, 69.5 (A) vs 61.4 % (B); P =0.14 No survival differences between two arms R-HDC more toxic effects 2-year PFS, 56 (A) vs 69 % (B); P =0.005 2-year OS, 71 (A) vs 74 % (B); P =0.32 High IPI: 2-year PFS, 41 (A) vs 75 % (B) 2-year OS, 64 (A) vs 82 % (B) Better outcome for high IPI 3-year PFS, 70 (R-HDC+ASCT) vs 59 % (R-dose-dense); P =0.010 3-year OS, 81 (R-HDC+ASCT) vs 78 % (R-dose dense); P =0.556 ASCT improves PFS
aaIPI age-adjusted international prognostic index, BEAM carmustine, etoposide, cytarabine, and melphalan, DLBCL diffuse large B cell lymphoma, EFS event-free survival, HDC/ASCT high-dose chemotherapy/autologous stem cell transplantation, MegaCHOP cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone, ORR overall response rate, OS overall survival, PFS progression-free survival, R-CHOEP rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide, R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, andprednisone, RHDC rituximab plus high-dose chemotherapy, SWOG Southwest Oncology Group
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Treatment for relapsed or refractory DLBCL DLBCL patients who are refractory or who have relapsed after R-CHOP or R-CHOP-like therapy have a worse prognosis than similar patients from the pre-rituximab era. After finding a significant improvement survival outcomes in an international randomized phase III trial (PARMA study), HDC/ ASCT has become the standard therapy for patients with relapsed or refractory DLBCL [45]. In the rituximab era, a prospective randomized trial by the Dutch Belgian HematoOncology Cooperative Group demonstrated the benefits of combining rituximab with HDC/ASCT (Table 3) [46]. The results of these studies are clear, but it is unclear which salvage chemotherapy regimen is optimal. The result of the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) directly compared two of the most commonly utilized salvage therapy [47]: Patients with relapsed/refractory DLBCL (N = 396) were randomly assigned to treatment with rituximab and ifosfamide, carboplatin, and etoposide (R-ICE) or dexamethasone, cytarabine, and cisplatinum (R-DHAP). Responding
patients received HDC/ASCT. There were no significant differences between R-ICE and R-DHAP for ORR, 3-year EFS, or OS. A sub-group analysis suggested that R-DHAP may improve outcomes in the GCB subtype, although this would require prospective evaluation [48]. Multivariate analysis revealed that OS was affected by prior rituximab exposure, relapse less than 12 months after diagnosis, and secondary aaIPI of 2–3. The result of a second randomization in the CORAL trial suggests that rituximab maintenance has no defined role in patients with relapsed DLBCL after ASCT [49]. These data suggest that the use of rituximab in frontline therapy may have prevented relapse in patients who ultimately respond to secondline chemotherapy, thus shifting responses forward. RIT treatment is promising when used as consolidation therapy for relapsed or refractory DLBCL. Furthermore, when iodine-131 tositumomab RIT was added to the BEAM combination as a conditioning regimen, the new regimen produced survival rates for patients with chemotherapy-sensitive relapsed DLBCL that were similar to those with rituximabBEAM combination regimens [50].
Table 3 Randomized, phase III trials in relapsed/refractory DLBCL in the Rituximab trial Trial
Design/regimen
Vellenga et al. [46] R-DHAP×2 (A) vs DHAP×2 (B) [HOVON trial] (PR/CR)→BEAM/ASCT
Gisselbrecht R-ICE (A) vs R-DHAP (B) et al. [47, 49] (Responding)→HDC/ASCT [CORAL study] (Second randomization) maintenance ® vs observation (O)
Vose et al. [50] [BMT CTN 0401 trial]
Iodine-131 tositumomab+BEAM HDC (B-BEAM) vs Rituximab+BEAM HDC (R-BEAM)→ASCT
Patient characteristics
Results
239 patients; age, 18–65 years; CD20+ aggressive NHL
RR, 75 (A) vs 54 % (B); P =0.01 2-year FFS, 50 (A) vs 24 % (B); P
