The addition of the anti-CD20 monoclonal antibody rituximab (R) to the standard CHOP regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) was a major breakthrough in the front-line treatment for patients with DLBCL, resulting in dramatic improvements in progression-free survival (PFS) and overall survival (OS).1–3 However, despite these improvements approximately 40% of patients with DLBCL who are treated with R-CHOP or R-CHOP–like chemotherapy will relapse or develop refractory disease,4,5and the majority of patients with relapsed or refractory DLBCL will succumb to the disease.1–3 Various strategies have been implemented to improve the outcome of DLBCL, including intensification of chemotherapy and use of maintenance therapy. Regardless of molecular subtype, standard front-line treatment for DLBCL is a combination of R-CHOP or CHOP-like chemotherapy.
Additional regimens and immunochemotherapy combinations are under investigation as alternatives to front-line R-CHOP, including dose-dense R-CHOP14, dose-adjusted R-EPOCH (rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and R-CEOP90 (rituximab, cyclophosphamide, etoposide, vincristine, prednisone).6–8 In a phase III trial including 1,080 patients with previously untreated DLBCL, no additional clinical benefit was observed in patients treated with R-CHOP every 14 days (R-CHOP14) versus every 21 days (R-CHOP21).6 Although evaluation of some of these intensification strategies is still ongoing, recent insight into the biology of DLBCL allowed the development of strategies based on the addition of novel agents (X) to R-CHOP in so-called XR-CHOP combinations9 that target specific oncogenic pathways (Fig. 1). In the development of these strategies, molecular characterization of DLBCL and the development of biomarkers is a critical step to identify patients who might benefit from the addition of novel agent(s). Indeed, because of the molecular heterogeneity of DLBCL, addition of a novel agent may benefit only a subgroup of patients with DLBCL. In this regard, preclinical and clinical studies of novel agents as monotherapies in relapsed and refractory DLBCL often provide important initial indications regarding the subtype of DLBCL that might benefit from specific targeted therapy.
Pathways Targeted By Treatments Currently in Development for Patients with DLBCL
Abbreviations: AKT, protein kinase B; BAD, BCL2-associated death promoter; BAK, BCL2 antagonist killer; BAX, BCL2-associated X protein; BCL, B-cell lymphoma; BTK, Bruton's tyrosine kinase; CARD11, caspase recruitment domain family, member 11; CRBN, cereblon; DLBCL, diffuse large B-cell lymphoma; Me, methylation; DNMT, DNA methyltransferase; JAK1, Janus kinase 1; IL, interleukin; IRF-4, interferon regulatory factor 4; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MTOR, mammalian target of rapamycin; P, phosphorylation; NFκB, nuclear factor kappa B; PI3K, phosphoinositide 3-kinase; PKC-beta, protein kinase C beta; SFK, Src family kinase; STAT3, signal transducer and activator of transcription 3; SYK, spleen tyrosine kinase.
Gene expression profiling (GEP) of DLBCL resulted in the identification of two major and clinically distinct subtypes that are classified based on cell of origin (COO) and are associated with differences in clinical outcome: GCB and non-GCB, which is further comprised of ABC and primary mediastinal B-cell types.10,11 DLBCL subtypes have striking differences in clinical outcome, with the ABC DLBCL subtype being associated with poor outcome. Until recently, COO classification of DLBCL had little influence on clinical practice. However, COO classifications have become more clinically relevant as a result of two major factors: (1) the development of new real-time COO assessment methods, including immunohistochemistry (IHC) and Nanostrings technology and (2) the identification of novel agents with activity in a specific DLBCL subtype (particularly ABC DLBCL).
CLASSES OF AGENTS WITH MOLECULAR SUBTYPE-SPECIFIC ACTIVITY CURRENTLY IN DEVELOPMENT FOR THE TREATMENT OF DLBCL
Agents Predominantly Active in Non-GCB (ABC) DLBCL
The majority of novel agents in development as front-line treatment for DLBCL appear to specifically target the ABC subtype of DLBCL, through either the B-cell receptor (BCR) pathway or pathway(s) downstream of the BCR pathway. This review will include only agents that are already in advanced clinical trials.
Proteasome inhibitors play a key role in suppression of the transcription factor nuclear factor kappa B (NFκB), a critical pathway downstream of the BCR pathway that is constitutively activated in ABC DLBCL.12 Use of the first-generation proteasome inhibitor bortezomib as monotherapy generated no responses in patients with relapsed/refractory DLBCL despite good preclinical evidence of possible activity. Bortezomib combined with DA-EPOCH (dose-adjusted etoposide, vincristine, doxorubicin, with cyclophosphamide and prednisone) chemotherapy yielded a complete response (CR) of 18% and a partial response (PR) of 16%,13 and demonstrated a significantly higher response (83% vs. 13%; p < 0.001) and median OS (10.8 vs. 3.4 months; p = 0.003) in ABC DLBCL compared to GCB DLBCL, respectively.
Immunomodulatory drugs (IMiDs) are structural and functional analogs of thalidomide that have immunomodulatory, antiangiogenic, and antitumor functions.14 Preclinical studies show that IMiDs modulate antibody synthesis; regulate the production of certain subsets of T cells (T-helper cells); inhibit the production of cytokines, including tumor necrosis factor alpha (TNFα); induce G0/G1 cell cycle arrest; and decrease angiogenesis through the suppression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF).15 In vivo and in vitro experiments have shown that the IMiD lenalidomide functions in DLBCL through multiple mechanisms, for example by enhancing antibody-dependent cell-mediated cytotoxicity (ADCC), inhibiting the production of proinflammatory cytokines such as TNFα, decreasing NFκB activity, and arresting DNA synthesis.16–18 The effect of single-agent lenalidomide was investigated in 217 patients with aggressive relapsed/refractory NHL as part of an international phase II study. Median PFS and response duration in the DLBCL subpopulation were 2.7 months and 4.6 months, respectively.19 In a retrospective analysis of two phase II trials (NHL-002 and NHL-003), patients with aggressive relapsed/refractory NHL who received single-agent lenalidomide and prior autologous stem cell transplantation (ASCT) were compared with those who did not receive ASCT. Thirty-four patients (39%) with relapsed or refractory NHL and prior ASCT therapy responded to lenalidomide (objective response rate [ORR] 39%), including patients with DLBCL (ORR 29%).20 In an ongoing, randomized, phase II/III clinical trial, the safety and efficacy of lenalidomide in relapsed/refractory DLBCL is being compared to the Investigator's choice (gemcitabine, oxaliplatin, rituximab, or etoposide) (NCT01197560).21
B-cell receptor signaling pathway inhibitors.
The BCR complex and associated protein tyrosine kinases are important for normal B-cell function and antibody production. Constitutively activated BCR signaling is linked to the initiation and maintenance of B-cell malignancies, including involvement in the pathogenesis of the ABC subtype of DLBCL.22 The BTK inhibitor ibrutinib was investigated in 70 patients with relapsed/refractory DLBCL as part of a multicenter, open-label, phase II trial. Among 60 patients who were evaluable for response, the ORR was 22% (5% CR) and PFS was 1.6 months.23 In a phase II study, 23 patients treated with the spleen tyrosine kinase (SYK) inhibitor fostamatinib demonstrated a median PFS of 2.7 months and achieved an ORR of 22%.24
AGENTS WITH POTENTIAL ACTIVITY IN GCB DLBCL
Although patients with GCB DLBCL have better outcomes than patients with the ABC subtype, approximately 20% of patients with the GCB subtype of DLBCL relapse following R-CHOP or R-CHOP—like chemotherapy and DLBCL relapse is associated with poor outcomes regardless of molecular subtype. Several agents show potential activity in the GCB subtype of DLBCL, among which BCL2 inhibitors are the best studied to date. Importantly, DLBCL with concurrent MYC and BCL2 or BCL6 translocation, known as double-hit DLBCL,25 is associated with very poor outcomes and is usually the GCB subtype by molecular profiling. Double-hit DLBCL represents approximately 5% of de novo cases of DLBCL, and is responsible for approximately a quarter of all relapses in GCB DLBCL. Treatment of this particularly high-risk lymphoma is discussed later.
Prevention of apoptosis is one mechanism through which cancer cells continue to survive. Unlike most oncogenes that promote proliferation, members of the antiapoptotic B-cell lymphoma-2 (BCL-2) family of proteins (BCL-2, BCL-XL, BCL-w, MCL-1, BFL1/A-1, and BCL-B) suppress apoptosis through interaction with, and inactivation of, proapoptotic proteins such as BH3.26 In contrast to most agents active in ABC DLBCL, which appear to have low activity in the GCB subtype, BCL2 inhibitors might be active in both ABC and GCB DLBCL. Whereas in the GCB subtype BCL2 is often overexpressed as a result of translocation, some patients with the ABC subtype appear to overexpress BCL2 at the protein level.27 ABT-737 and its oral equivalent ABT-263 target multiple antiapoptotic members of the BCL-2 family, including BCL-2, BCL-XL, and BCL-w, whereas ABT-199 potently and selectively inhibits BCL-2, thereby sequestering the proapoptotic proteins and facilitating death of malignant cells.26,28,29
FRONT-LINE TREATMENT: XR-CHOP
A combination of the proteasome inhibitor bortezomib and R-CHOP (VR-CHOP or Bor-RCHOP) was evaluated in patients with previously untreated DLBCL or mantle cell lymphoma. The evaluable ORR was 100%; 86% of patients exhibited CR or CR unconfirmed (CRu). In the intent-to-treat (ITT) population of 40 patients, ORR was 88%, and 75% had CR/CRu. The 2-year PFS was 64% and 2-year OS was 70%.30 A current randomized phase II trial is designed to compare the effect of VR-CHOP versus R-CHOP on PFS (NCT00931918),31 and an ongoing randomized phase III trial is investigating the efficacy of CHOP versus RV-CHOP in patients with DLBCL (REMoDL-B; NCT01324596).32
Patients treated with the immunomodulatory agent lenalidomide (R) in combination with R-CHOP (R2-CHOP) achieved ORRs and CRs of 90% to 100% and 77% to 86%, respectively, in phase I and phase II trials.33–36 In one phase II trial, the most frequent grade 3/4 hematologic adverse events (AEs) included neutropenia (31%), leukocytopenia (28%), and thrombocytopenia (13%); no grade 4 nonhematologic AEs were reported.36 Response to R2-CHOP in patients with GCB versus non-GCB DLBCL was similar in a phase II trial (32 tissue samples available), and the 2-year PFS was 71% and 81%, respectively.36 Interestingly, in a separate phase II trial involving patients with newly diagnosed DLBCL who were treated with R2-CHOP, the 2-year OS was 75% for patients with GCB DLBCL compared with 83% for non-GCB subtypes. In patients treated with R-CHOP alone, a 2-year OS of 78% and 46% was achieved in GCB and non-GCB subgroups, respectively, suggesting that the addition of lenalidomide can improve the poor prognosis usually reported in the non-GCB population in response to standard R-CHOP therapy (Fig. 2).37
Outcomes of Patients Treated with R-CHOP or R2-CHOP according to GCB versus Non-GCB DLBCL Subtype
Outcomes are shown for historic control patients treated with R-CHOP and study patients treated with R2CHOP based on germinal center B-cell (GCB) versus non-GCB diffuse large B-cell lymphoma (DLBCL) subtype. (A) Progression-free survival in patients treated with R-CHOP for non-GCB versus GCB DLBCL. (B) Progression-free survival in patients treated with R2CHOP for non-GCB versus GCB DLBCL. (C) Overall survival in patients treated with R2CHOP for non-GCB versus GCB DLBCL. (D) Overall survival in patients treated with R2CHOP for non-GCB versus GCB DLBCL.
A randomized phase II trial designed to evaluate the effect of R-CHOP versus R2-CHOP in patients with newly diagnosed DLBCL (NCT01856192) is ongoing.38 A separate phase III study (ROBUST) evaluating R2-CHOP versus R-CHOP in patients with ABC DLBCL as defined by GEP is currently open. Real-time GEP with a turnaround time of 5 business days or less is used to assess patient eligibility for this trial.
The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been investigated in combination with R-CHOP (IR-CHOP) in a phase Ib, nonrandomized, open-label trial in 33 patients with newly diagnosed DLBCL, mantle cell lymphoma, or follicular lymphoma. At the interim evaluation, the ORR was 100% (CR 64% and PR 36%) in 22 patients with DLBCL. The most common all-grade AEs reported in all patients were neutropenia (67%), nausea (67%), thrombocytopenia (61%), vomiting (48%), and anemia (36%).39 Additionally, a randomized, double-blind, phase III study is currently comparing event-free survival in patients treated with IR-CHOP versus R-CHOP (NCT01855750).34
TREATMENT FOR RELAPSED/REFRACTORY DLBCL
In the Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) study, 396 patients with relapsed/refractory CD20+ DLBCL were randomly selected to receive either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE), or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Patients whose disease relapsed early (< 1 year) following front-line rituximab chemotherapy had a very poor prognosis, with a 3-year PFS of 20% compared with 45% for patients whose disesase relapsed after 1 year.40
MYC-POSITIVE AND DOUBLE-HIT DLBCL
MYC is a transcription factor associated with a number of cellular functions (e.g., cell growth and proliferation, angiogenesis, protein synthesis, metabolism, and DNA replication) with a strong oncogeneic potential.42 In human B-cell neoplasms, MYC rearrangements involving the t(8;14) is a hallmark in Burkitt lymphoma and present in the majority of cases. Typically, it is a primary genetic event and presents as a simple karyotype and the sole chromosomal abnormality in this aggressive subtype of B-cell lymphoma. MYC gene rearrangements have also been identified in other lymphoid neoplasms, including: DLBCL (7% to 14%), unclassifiable B-cell lymphoma (35%), plasmablastic lymphoma (50%), plasma cell myeloma (15% to 50%), and mantle cell lymphoma (26 patients). Of interest, in non-Burkitt lymphoma histologies, MYC rearrangements are found as part of a complex karyotype and typically represent secondary genetic events.42–43 MYC gene activation in DLBCL can occur via translocation (5% to 14%), copy gain (19% to 38%), amplication (2%), or mutation (32%).44–47 In general, MYC rearrangement predicts an inferior outcome in DLBCL, but it is not clear whether it is because of MYC rearrangement itself or because 58% to 83% of MYC-translocated DLBCL also have concurrent dual or triple translocation with BCL2 and/or BCL6 (less likely) identified as double-hit or triple-hit DLBCL.42,48–49 These patients often have 12 months or less OS when treated with R-CHOP.50
Of note, high MYC-protein expression (28% to 41%) of DLBCL without MYC gene abnormalities has been identified (suggesting alternate mechanisms of MYC induction). Patients with DLBCL with a high percentage of both MYC and BCL2 protein (20% to 44%) expression by IHC staining carry a poor prognosis; treatment with standard R-CHOP or CHOP-like immunochemotherapy results in inferior PFS and OS on retrospective analyses.51–54 Many studies have defined these patients as having double-expressor DLBCL, and most studies require that tumor cells express at least 40% MYC and at least 50% to 70% BCL2 positivity. Although patients with double-expressor DLBCL (DEL) have a worse prognosis than those without double expression of MYC plus BCL2, it should be noted that different studies utilize variable cutoff points to define positivity. Unlike the reproducibility of the fluorescent in situ hybridization (FISH) technique, the IHC technique is less robust and has more variability associated with it. Interestingly, the majority of double-hit DLBCL (DHL) (defined here as having MYC + BCL2 rearrangements) is primarily GCB-like, whereas DEL is primarily ABC-like. This unique observation leads us to question whether a successful therapeutic approach in DHL will be equally successful in DEL based on differences inherent within the COO and likely differences in cellular/molecular pathways, genetics, and variable-resistance pathways. Only large prospective clinical trials utilizing central path review of FISH, as well has IHC, and well-defined inclusion definitions of positivity will be able to answer this question.
CURRENT TREATMENT APPROACH: OVERVIEW
As mentioned previously, R-CHOP is an inadequate induction therapy for DHL (i.e., most patients die within 2 years of diagnosis). The malignant DHL neoplastic cell attains an amazing survival advantage. Concurrent MYC + BCL2 translocations confer increased cell growth, cell cycle transit, and metabolism and/angiogenesis via MYC, but at the same time increased antiapoptosis (i.e., drug resistance) via BCL2. In general, DHL patients often present with several poor prognostic characteristics: median age in the seventh decade (many unable to tolerate dose-intensive therapeutic approaches); stage III/IV disease; high-intermediate/high (HI/H) IPI; elevated LDH; high frequency of extranodal sites (including the central nervous system).55–56 Various multidrug therapy regimens with or without rituximab have been utilized to treat DHL, including dose-intensive therapies that have curative potential in BL, although published data from retrospective reviews do not indicate any single optimal induction therapy approach (Table 2). Patients achieving a complete remission with regimens more intensive than R-CHOP had better PFS, but consolidative SCT did not seem to improve OS in these patients. Of the regimens utilized, R-EPOCH: (1) has curative potential in BL, (2) is better tolerated than more dose-intensive (DI) regimens, and (3) appears to have at least similar efficacy compared to DI therapies. In addition to the data from Oki et al (Table 2), a meta-analysis of 401 DHL patients by Howlett et al57 presented at the 2014 American Society of Hematology (ASH) Annual Meeting demonstrated R-EPOCH (and more DI regimens) were associated with improvement in PFS (but not OS) compared to R-CHOP. Another presentation at ASH 2014 by Dunleavy et al58 utilizing R-EPOCH in a multicenter phase II study, which included DHL, demonstrated a promising early PFS (87% at 14 months).
Agents with Differential Single Agent and in Combination of XR-CHOP Activity in DLBCL Subtypes
DHL Induction Therapy and Outcome
Currently consolidative autologous SCT in chemotherapy-sensitive patients (especially CRs) does not appear to significantly change clinical outcomes. This may likely be a result of the inherent rapid tumor cell growth and inherent drug-resistant DHL cells that remain after induction therapy (i.e., minimal residual disease) that would likely not be cured with a high-dose, chemotherapy-based conditioning regimen typically utilized during autologous stem cell transplantation. Of interest, review of the literature identified two abstracts, which included a total of approximately 50 patients, that concluded that patients with DHL who undergo allogeneic SCT following dose-intensive induction therapy have prolonged OS.57,59 Unfortunately, several reasons make it unlikely that allogeneic SCT will make a major effect in the future treatment of a significant percentage of DHL patients: (1) limited data from a small number of selected patients, (2) the risk of relapsed disease while awaiting graft-versus-lymphoma to occur, (3) the need for a suitable HLA-compatible donor, and (4) the risk of chronic graft-versus-host disease.
The future holds promise that novel targeted agents, which either directly or indirectly inhibit MYC and BCL2, will lead to improved overall survival in patients with DHL (Table 3). Many agents have demonstrated in vitro and in vivo animal antitumor activity, and a limited number are in early human clinical trials. It is quite likely that DHL will require a rational combination of MYC/BCL2 inhibitors in combination with effective chemotherapeutic agents (e.g., BH3-mimetics will resensitize cells to drug toxicity, etc.) to optimize the killing of these highly resistant lymphoma cells and change DHL from one of the worst subtypes of DLBCL into a therapeutically responsive subtype (with a significant improvement in clinical outcomes). Based on the information provided above, all newly diagnosed DLBCL tumor biopsies should undergo FISH and IHC evaluation to identify DHL and DEL, respectively. These patients, whenever possible, should be referred to participation on clinical trials. Off study, the use of R-EPOCH induction (including central nervous system prophylaxis) is a reasonable approach while we await further testing and validation of effective novel targeted agents to be added to our current therapeutic armamentarium against DHL.
Novel Future Therapeutic Considerations
Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood
. 2010;116:2040-2045. PubMed
Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol
. 2006;24:3121-3127. PubMed
Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol
. 2005;23:5027-5033. PubMed
4. Sehn LH. Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma. Hematology Am Soc of Hematol Educ Program. 2012;2012;402-409.
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med
. 2002;346:235-242. PubMed
Cunningham D, Hawkes EA, Jack A, et al. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet
. 2013;381:1817-1826. PubMed
7. Purroy N, Lopez A, Vallespi T, et al. Dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor risk large B-cell lymphoma: a phase 2 study conducted by the Spanish PETHEMA group. Blood. 2009;114 (suppl; abstr 2701).
Cai QC, Gao Y, Wang XX, et al. Long-term results of the R-CEOP 90 in the treatment of young patients with chemotherapy-naive diffuse large B cell lymphoma: a phase II study. Leuk Lymphoma
. 2014;55:2387-2388. PubMed
Vaidya R, Witzig TE. Prognostic factors for diffuse large B-cell lymphoma in the R(X)CHOP era. Ann Oncol
. 2014;25:2124-2133. PubMed
Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med
. 2002;346:1937-1947. PubMed
Shipp MA, Ross KN, Tamayo P, et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med
. 2002;8:68-74. PubMed
Crawford LJ, Walker B, Irvine AE. Proteasome inhibitors in cancer therapy. J Cell Commun Signal
. 2011;5:101-110. PubMed
Dunleavy K, Pittaluga S, Czuczman MS, et al. Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. Blood
. 2009;113:6069-6076. PubMed
Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer
. 2004;4:314-322. PubMed
Aragon-Ching JB, Li H, Gardner ER, et al. Thalidomide analogues as anticancer drugs. Recent Pat Anticancer Drug Discov
. 2007;2:167-174. PubMed
Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, et al. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clin Cancer Res
. 2005;11:5984-5992. PubMed
17. Thieblemont C, Delfau-Larue MH, Coiffier B. Lenalidomide in diffuse large B-cell lymphoma. Adv Hematol. Epub 2012 Nov 20.
Wu L, Adams M, Carter T, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res
. 2008;14:4650-4657. PubMed
Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol
. 2011;22:1622-1627. PubMed
Vose JM, Habermann TM, Czuczman MS, et al. Single-agent lenalidomide is active in patients with relapsed or refractory aggressive non-Hodgkin lymphoma who received prior stem cell transplantation. Br J Haematol
. 2013;162:639-647. PubMed
Wilcox RA, Ristow K, Habermann TM, et al. The absolute monocyte and lymphocyte prognostic score predicts survival and identifies high-risk patients in diffuse large-B-cell lymphoma. Leukemia
. 2011;25:1502-1509. PubMed
Choi MY, Kipps TJ. Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. Cancer J
. 2012;18:404-410. PubMed
23. Wilson WH, Gerecitano JF, Goy A, et al. The Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, phase 2 study. Blood. 2012;120 (suppl; abstr 686).
Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood
. 2010;115:2578-2585. PubMed
Friedberg JW. Double-hit diffuse large B-cell lymphoma. J Clin Oncol
. 2012;30:3439-3443. PubMed
Kang MH, Reynolds CP. Bcl-2 inhibitors: Targeting mitochondrial apoptotic pathways in cancer therapy. Clin Cancer Res
. 2009;15:1126-1132. PubMed
Lossos IS, Morgensztern D. Prognostic biomarkers in diffuse large B-cell lymphoma. J Clin Oncol
. 2006;24:995-1007. PubMed
Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med
. 2013;19:202-208. PubMed
Vandenberg CJ, Cory S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood
. 2013;121:2285-2288. PubMed
Ruan J, Martin P, Furman RR, et al. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol
. 2011;29:690-697. PubMed
Witzig TE, Tang H, Micallef IN, et al. Multi-institutional phase II study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas. Blood
. 2011;118:4882-4889. PubMed
Mraz M, Zent CS, Church AK, et al. Bone marrow stromal cells protect lymphoma B-cells from rituximab-induced apoptosis and targeting integrin alpha-4-beta-1 (VLA-4) with natalizumab can overcome this resistance. Br J Haematol
. 2011;155:53-64. PubMed
Chiappella A, Tucci A, Castellino A, et al. Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: a phase I study by the Fondazione Italiana Linfomi. Haematologica
. 2013;98:1732-1738. PubMed
Nowakowski GS, LaPlant B, Habermann TM, et al. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia
. 2011;25:1877-1881. PubMed
35. Nowakowski GS, LaPlant BR, Reeder C, et al. Combination of lenalidomide with R-CHOP (R2CHOP) is well-tolerated and effective as initial therapy for aggressive B-cell lymphomas - a phase II study. Blood. 2012;120 (suppl; abstr 689).
Vitolo U, Chiappella A, Franceschetti S, et al. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol
. 2014;15:730-737. PubMed
Nowakowski GS, LaPlant B, Macon WR. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol
. 2015;33:251-257. PubMed
Tsujimoto Y, Finger LR, Yunis J, et al. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science
. 1984;226:1097-1099. PubMed
39. Younes A, Flinn I, Berdeja J, et al. Combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP): updated results from a phase 1b study in treatment-naïve patients with CD20-positive B-cell non-Hodgkin's lymphoma (NHL). Blood. 2013;122 (suppl; abstr 852).
Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol
. 2010;28:4184-4190. PubMed
Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, et al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer
. 2011;117:5058-5066. PubMed
Ott G, Rosenwald A, Campo E. Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification. Blood
. 2013;122:3884-3891. PubMed
43. Sewastianik T, Prochorec-Sobieszek M, Chapuy B, et al. MYC deregulation in lymphoid tumors: Molecular mechanisms, clinical consequences and therapeutic implications. Biochim Biochim Biophys Acta. 2014;1846;457-467.
44. Karube K, Campo E. MYC Alterations in Diffuse Large B-Cell Lymphomas. Seminars in Hematology. In press.
Pedersen MO, Gang AO, Poulsen TS, et al. MYC translocation partner gene determines survival of patients with large B-cell lymphoma with MYC- or double-hit MYC/BCL2 translocations. Eur J Haematol
. 2014;92:42-48. PubMed
Pasqualucci L, Neumeister P, Goossens T, et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature
. 2001;412:341-346. PubMed
Stasik CJ, Nitta H, Zhang W, et al. Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma. Haematologica
. 2010;95:597-603. PubMed
48 Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28:3360-3365.
Valera A, Lopez-Guillermo A, Cardesa-Salzmann T, et al. MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy. Haematologica
. 2013;98:1554-1562. PubMed
Petrich AM, Gandhi M, Jovanovic B, et al. Impact of induction regimen and stem cell transplantation on outcomes in double-hit lymphoma: A multicenter retrospective analysis. Blood
. 2014;124:2354-2361. PubMed
Green TM, Young KH, Visco C, et al. Immunohistochemical double-hit score is a strong predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol
. 2012;30:3460-3467. PubMed
Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood
. 2013;121:4021-4031;4250. PubMed
Johnson NA, Slack GW, Savage KJ, et al. Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol
. 2012;30:3452-3459. PubMed
Perry AM, Alvarado-Bernal Y, Laurini JA, et al. MYC and BCL2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with rituximab. Br J Haematol
. 2014;165:382-391. PubMed
55. Cheah CY, Oki Y, Westin JR, et al. A clinician's guide to double hit lymphomas. Br J Haematol. Epub 2014 Dec 22.
Lindsley RC, LaCasce AS. Biology of double-hit B-cell lymphomas. Curr Opin Hematol
. 2012;19:299-304. PubMed
57. Howlett C, Landsburg DJ, Chang EA, et al. Front-line, dose-escalated immunochemotherapy is associated with a significant PFS (but not OS) advantage in 401 patients (pts) with double-hit lymphomas (DHL): A SYSTEMIC REVIEW AND META-ANALYSis. Blood. 2014;124: (suppl; abstr 3056).
58. Dunleavy K, Fanale M, LaCasce AS, et al. Preliminary report of a multicenter prospective phase II study of DA-EPOCH-R in MYC-rearranged aggressive B-cell lymphoma. Blood. 2014;124: (suppl; abstr 395).
59. Greenwood M, Amytage T, Fay K, et al. Outcomes of allogeneic stem cell transplantation for non-Hodgkin lymphoma with concurrent MYC and BCL2 translocations: a single centre retrospective analysis. Hematol Oncol. 2013;31:96-150.
Oki Y, Noorani M, Lin P, et al. Double hit lymphoma: the MD Anderson Cancer Center clinical experience. Br J Haematol
. 2014;166:891-901. PubMed
Johnson NA, Savage KJ, Ludkovski O, et al. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood
. 2009;114:2273-2279. PubMed
Li S, Lin P, Fayad LE, et al. B-cell lymphomas with MYC/8q24 rearrangements and IGH@BCL2/t(14;18)(q32;q21): an aggressive disease with heterogeneous histology, germinal center B-cell immunophenotype and poor outcome. Mod Pathol
. 2012;25:145-156. PubMed
63. Davids MD, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol. 2014;32: (suppl, abstr 8522).
64. Thieblemont C, Stathis A, Inghirami G, et al. A Phase I study of the BET-Bromodomain inhibitor OTX015 in patients with non-Leukemic hematologic malignancies. Blood. 2014;124: (suppl, abstr 4417).
Trabucco SE, Gerstein RM, Evens AM, et al. Inhibition of bromodomain proteins for the treatment of human diffuse large B-cell lymphoma. Clin Cancer Res
. 2015;21:113-122. PubMed
Mirguet O, Lamotte Y, Donche F, et al. From ApoA1 upregulation to BET family bromodomain inhibition: Discovery of I-BET151. Bioorg Med Chem Lett
. 2012;22:2963-2967. PubMed
Kochenderfer JN, Dudley ME, Kassim SH, et al. Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol
. 2015;33:540-549. PubMed
68. Sauter CS, Riviere I, Bernal YJ, et al. Interim safety analysis: a phase I trial of high dose therapy and autologous stem cell transplantation followed by infusion of chimeric antigen receptor modified T-cells (19-28z CAR-T) directed against CD19+ B-cells for relapsed and refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2014;124: (suppl, abstr 677).
den Hollander J, Rimpi S, Doherty JR, et al. Aurora kinases A and B are up-regulated by Myc and are essential for maintenance of the malignant state. Blood
. 2010;116:1498-1505. PubMed
Mahadevan D, Morales C, Cooke LS, et al. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2. PLoS One
. 2014;9:e95184. PubMed
Pourdehnad M, Truitt ML, Siddiqi IN, et al. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc Natl Acad Sci U S A
. 2013;110:11988-11993. PubMed
Smith SM, van Besien K, Karrison T, et al. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: the University of Chicago phase II consortium. J Clin Oncol
. 2010;28:4740-4746. PubMed
73. Evens AM, Dashnamoothy R, Kandela I, et al. The novel 2nd generation proteasome inhibitor MLN99708 induces redox- and MAPK-related cell death in T-cell lymphoma (TCL) and Hodgkin lymphoma (HL) cell lines and human lymphoma xenograft models. Hematol Oncol. 2013;31:30.
Gopal AK, Kahl BS, de Vos S, et al. PI3Kdelta inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med
. 2014;370:1008-1018. PubMed
Sheth A, Escobar-Alvarez S, Gardner J, et al. Inhibition of human mitochondrial peptide deformylase causes apoptosis in c-myc-overexpressing hematopoietic cancers. Cell Death Dis
. 2014;5:e1152. PubMed
Jeong SM, Lee A, Lee J, et al. SIRT4 protein suppresses tumor formation in genetic models of Myc-induced B cell lymphoma. J Biol Chem
. 2014;289:4135-4144. PubMed