Emerging Therapy for the Treatment of Mantle Cell Lymphoma

Authors: Saurabh Rajguru MD 1 and Brad S. Kahl MD 1
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  • 1 From the Department of Medicine, Division of Hematology/Oncology, University of Wisconsin School of Medicine and Public Health, and the UW Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin.

Mantle cell lymphoma (MCL) is a heterogenous disease with historically relative poor outcomes. However, new treatment strategies seem to be improving the prognosis for patients. Although no universally accepted standard of care exists, options for patients with newly diagnosed MCL include intensive and nonintensive strategies. Generally, intensive strategies produce more durable remissions and are selected for younger patients, whereas nonintensive strategies are most appropriate for older patients or patients with comorbidities. However, new options are closing the treatment gap between intensive and nonintensive strategies. Treatment options are also increasing for patients with relapsed/refractory MCL and include agents targeting the microenvironment and the B-cell receptor signaling pathway.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/52911; and 4) view/print certificate.

Release date: September 5, 2014; Expiration date: September 5, 2015

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Summarize the current and emerging treatment options for MCL in the frontline setting
  • Discuss the evidence from clinical trials supporting the use of maintenance therapy in patients with MCL
  • Review the mechanism action, safety, and efficacy of targeted therapies in the management of R/R MCL

Mantle cell lymphoma (MCL) is a distinct and unique subtype of non-Hodgkin lymphoma (NHL). It accounts for approximately 3% to 6% of all NHLs, with a median age at diagnosis of 68 years and a significant male predominance.1,2 Most patients present with an advanced stage and a high-intermediate or high International Prognostic Index (IPI) score. Diffuse lymphadenopathy, splenomegaly, and bone marrow involvement are often seen at presentation, with most patients having extranodal disease, with a predilection for the gastrointestinal tract.3 MCL is characterized by t(11,14)(q13;q32), leading to overexpression of cyclin D1, resulting in dysregulation of the cell cycle machinery.4

Prognosis for patients with MCL can be estimated using the MCL IPI (MIPI) score, which has been found to be a better predictor of overall survival (OS) than the IPI score. It uses 4 independent prognostic factors: age, performance status, lactate dehydrogenase, and WBC count. Based on these factors, patients are divided into low-risk (44% of patients; median OS, not reached), intermediate-risk (35% of patients; median OS, 51 months), and high-risk (21% of patients; median OS, 29 months) categories. The cell proliferative index (Ki-67) has also been shown to be of additional prognostic significance.5,6

No consensus exists regarding frontline therapy for MCL, although standards are emerging. The management of relapsed MCL is an area of intense study. This review discusses the current landscape and emerging therapies for MCL in both the front-line and relapsed/refractory (R/R) settings.

Therapy for Previously Untreated MCL

Treatment for patients with previously untreated MCL can be divided into 2 general strategies: intensive and nonintensive therapies. Most trials of intensive strategies have been limited to patients aged 65 years or younger without significant comorbidities (Table 1). Examples of intensive therapies include chemoimmunotherapy induction followed by autologous stem cell transplantation (ASCT) or the R-hyperCVAD (rituximab and hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone) with alternating rituximab and high-dose cytarabine/methotrexate (R-MA) regimen (Figure 1). Most studies of nonintensive strategies focus on older patients with MCL or include patients with significant comorbidities. Examples of nonintensive combination chemoimmunotherapy regimens include R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), FCR (fludarabine, cyclophosphamide, rituximab), modified R-hyperCVAD, and BR (bendamustine and rituximab) (Table 2).

Table 1

Comparison of Intensive Treatment Strategies for Newly Diagnosed MCL

Table 1

Intensive Treatment

Intensive Chemoimmunotherapy Without ASCT: Intensive induction therapies given without consolidative ASCT have been studied in MCL. A single-institution prospective study from MD Anderson examined the efficacy of R-hyperCVAD/R-MA in 97 patients with previously untreated MCL. The response rates were high, but the toxicity was substantial, and the authors did not recommend this treatment strategy in patients older than 65 years.7 After a median follow-up of 8 years, the median OS had not been reached, and the median time to failure for the entire study population was 4.6 years versus 5.9 years in patients aged 65 years or younger (P=.003).8 This was tested in a phase II cooperative group study (SWOG 0213), which treated 49 patients with advanced, untreated MCL (median age, 57 years) using R-hyperCVAD/R-MA. The 3-year progression-free survival (PFS) and OS rates were 66% and 81%, respectively, with poorer outcomes in patients older than 65 years; 39% of the patients could not complete therapy because of toxicity.9 The conventional R-hyper-CVAD regimen therefore produces durable remissions in younger patients, but is prohibitively toxic for many older patients.

Intensive Chemoimmunotherapy With ASCT: Several trials have studied the addition of a consolidative ASCT to frontline chemoimmunotherapy. The Nordic Lymphoma Group performed a phase II study of 3 cycles of dose-intensified CHOP (maxi-CHOP) alternating with 3 cycles of high-dose cytarabine with rituximab, followed by consolidation with an ASCT in 160 patients with MCL (145 patients went on to receive ASCT). Toxicity was not insignificant, with 17% and 12% of patients hospitalized for grade 3 and 4 adverse events (AEs), respectively—mostly neutropenic fever. The 4-year PFS and OS rates were 73% and 81%, respectively.10 An update after 6 years of follow-up revealed that the median OS was still not reached, whereas the median event-free survival was 7.4 years, with a distinct pattern of late relapses noted, especially in those with high-risk disease based on MIPI score and Ki-67 index.11

Figure 1
Figure 1

Treatment approach to patients with newly diagnosed mantle cell lymphoma.

Abbreviations: ASCT, autologous stem cell transplant; BR, bendamustine, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; R-hyperCVAD/R-MA, rituximab, hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, cytarabine; VcR-CVAD, bortezomib, rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 9; 10.6004/jnccn.2014.0126

In a phase II GELA study in young patients (n=60) with previously untreated MCL, patients were given induction therapy with 3 cycles of CHOP followed by 3 cycles of DHAP (dexamethasone, cytarabine, cisplatin), with rituximab given on cycles 3 to 6, followed by consolidative ASCT. The 5-year event-free survival and OS rates were 64% and 75%, respectively.12

The results of the GELA study were confirmed in a randomized phase III study performed by the European MCL Network, in which 497 patients were randomized to induction therapy with R-CHOP for 6 cycles versus R-CHOP for 3 cycles alternating with R-DHAP for 3 cycles, followed by a myeloablative conditioning regimen (included cytarabine for the patients receiving R-DHAP) and ASCT. The compete response (CR)/unconfirmed CR (CRu) rate was significantly higher in the cytarabine-containing arm (40% vs 54%; P=.0003). OS was also borderline significant in the cytarabine arm (not reached vs 82 months; P=.045).13 A large multicenter cooperative group study (CALGB 59909) also revealed comparable outcomes with those of the European studies.14 Taken together, the Nordic and GELA/European MCL Network studies, and CALGB 59909, suggest a benefit for including high-dose cytarabine in the induction regimen.

Nonintensive Treatment

Watch-and-Wait: Given the generally unfavorable prognosis of MCL, most patients historically have been treated immediately on diagnosis, a strategy similar to that for patients with the more traditional aggressive lymphomas. MCL, however, is a clinically heterogeneous disease. Gene expression profiling has revealed several unique proliferation signatures that correlate to a wide range in survival.15 A single-institution retrospective study from Weill Cornell Medical College evaluated the “watch-and-wait” strategy in 97 patients with newly diagnosed MCL. Based on a time-to-treatment cut-off of greater than 3 months, patients were divided into 2 cohorts: observation (n=31) and early treatment (n=66). Of the 31 patients in the observation cohort, 71% were observed for at least 6 months and 45% for at least 1 year. OS was statistically superior in the observation cohort (likely because they had better disease characteristics and tended to be younger with lower MIPI scores).16 This study provides evidence that no harm is done by adapting a “watch-and-wait” strategy in selected patients with MCL.

Table 2

Comparison of Nonintensive Treatment Strategies for Newly Diagnosed Mantle Cell Lymphoma

Table 2

Nonintensive Chemoimmunotherapy: Relatively few comparative trials with sufficient power are available that allow for the conclusion that one nonintensive induction therapy is superior to another. The one exception is a trial performed by the European MCL Network in which elderly patients (age >60 years) with untreated MCL were randomized to receive induction therapy with either FCR or R-CHOP. Because of increases in toxicity and a significantly worse OS (4-year OS, 47% vs 62%; P=.005), the FCR arm was closed early, making R-CHOP the clearly superior induction strategy.17

Two randomized trials have compared R-CHOP versus BR as frontline treatment of MCL. However, in both trials, the patients with MCL were a subset of the total population, limiting the strength of the conclusions. Bendamustine has a relatively favorable toxicity profile and does not have the cardiotoxicity associated with anthracycline-based chemotherapy regimens, making it an attractive treatment option in older patients. The Study Group Indolent Lymphomas (StiL) performed a randomized phase III noninferiority study of BR compared with R-CHOP in 549 previously untreated patients with advanced indolent lymphoma or MCL, of which 94 had MCL. The primary end point of PFS was statistically superior in the BR arm for almost all subtypes, including MCL (35.4 vs 22.1 months; P=.0044). Significantly fewer grade 3/4 leukopenia (P<.0001), alopecia (P<.0001), and infectious episodes (P=.0025) were also seen among others in the BR arm.18 The North American BRIGHT study compared BR versus R-CHOP/R-CVP in previously untreated patients with indolent NHL or MCL. Of 447 randomized patients, 74 had MCL. The primary end point was to demonstrate noninferiority of the CR rate of BR compared with R-CHOP/R-CVP. In the cohort of patients with MCL, the CR rate for BR was statistically superior to that for R-CHOP/R-CVP (51% vs 24%; P=.0180). BR did seem to be associated with a higher incidence of gastrointestinal side effects, including nausea, than in the StiL trial. Time-to-event data are still immature and have not yet been reported.19 The StiL and BRIGHT studies show that BR may be a superior chemoimmunotherapy backbone compared with R-CHOP in patients with MCL. Looking to expand on the BR backbone, a recent phase I/II study added cytarabine to BR. Forty patients were enrolled, 20 with previously untreated disease. The overall response rate (ORR) was 100% for the untreated group and 80% for the R/R group, with a 2-year PFS of 95% and 70% in the untreated and R/R groups, respectively.20

Several studies have investigated the addition of the proteasome inhibitor bortezomib to standard chemoimmunotherapy, with the rationale that constitutive activation of the NF-κB pathway plays an important role in the pathogenesis of MCL. In a recent phase I/II study exploring the combination of bortezomib plus R-CHOP, 36 patients with previously untreated MCL received R-CHOP plus escalating doses of bortezomib (0.7, 1.0, or 1.3 mg/m2). The ORR was 81% in the intent-to-treat population, with a 64% CR/CRu rate. The 2-year PFS rate was 44% (95% CI, 27%-60%) and the 2-year OS rate was 86% (95% CI, 70%-94%). These results suggest an improvement in the CR/CRu rate when bortezomib is combined with R-CHOP.21 Bortezomib was also tested in the modified R-hyperCVAD regimen (VcR-CVAD). In a phase II study (ECOG E1405), 75 patients with previously untreated MCL received VcR-CVAD for 6 cycles. The ORR was 95% (95% CI, 87%-99%), with a CR rate of 68% (95% CI 57%-79%). The 3-year PFS and OS rates were 72% and 88%, respectively. These response rates were comparable to those associated with the intensive strategies mentioned earlier. No grade 3/4 peripheral neuropathy was noted in this study, which used somewhat lower dosing of bortezomib and vincristine (1.3 mg/m2 and 1.0 mg, respectively).22 A current US Intergroup randomized phase II clinical trial (E1411) is testing whether bortezomib added to the BR regimen can improve CR rates compared with BR alone (Figure 2).

Maintenance Rituximab: Maintenance strategies are particularly attractive in MCL because of high initial response rates, but remission durability can be disappointingly short. Strategies involving maintenance rituximab (MR) have suggested a PFS benefit similar to that seen with other incurable lymphomas.23,24

The European MCL Network study, comparing FCR versus an R-CHOP induction, included a second randomization for patients experiencing response.17 Patients in the interferon arm could receive either standard interferon alpha (3 million units 3 times per week) or pegylated interferon alfa (1 mcg/kg/wk), and patients in the rituximab arm received rituximab at 375 mg/m2 every 2 months until disease progression. When analyzing the cohort of patients that received induction therapy with R-CHOP who went on to receive maintenance treatment, a significant difference was seen in the 4-year OS rate, favoring MR (87% vs 63%; P=.005).17 These results suggest that MR should be considered standard of care for older patients with MCL who experienced disease response to induction therapy. The E1405 study evaluated 2 years of MR after VcR-CVAD induction therapy. The decision whether to pursue MR or ASCT was left to the discretion of the treating physician. With a median follow-up of 4.5 years, the 3-year PFS and OS rates for the entire study population were 72% (95% CI, 62%-84%) and 88% (95% CI, 81%-96%), respectively. After adjusting for MIPI risk score and quality of response to induction therapy (partial response vs CR), no statistically significant difference in PFS or survival outcomes was found between the MR and ASCT groups.22 The data for MR support the notion that it could be compared with ASCT in a randomized clinical trial for younger patients with MCL.

Therapy for R/R Disease

The treatment of patients with R/R MCL has been an area of significant advancement, with the emergence of several novel agents (Table 3) that act on unique intracellular targets (Figure 3).

The multicenter phase II PINNACLE study firmly established the role of the proteasome inhibitor bortezomib in R/R MCL and led to FDA approval in 2006. Patients (n=155) were treated with bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11 of a 21-day cycle, with 141 patients assessable for response. The median number of prior therapies was 1. The ORR was 33% (8% CR/CRu) and the median duration of response was 9.2 months. Grade 3 or higher peripheral neuropathy was seen in 13% of patients.25

Figure 2
Figure 2

Treatment schema for Intergroup E1411.

Abbreviations: B, bendamustine; R, rituximab; V, bortezomib.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 9; 10.6004/jnccn.2014.0126

Translation of cyclin D1, the main driver in the pathogenesis of MCL, is thought to be regulated by the mTOR kinase, which is a key component of the PI3K/Akt intracellular pathway. On this basis, the mTOR inhibitor temsirolimus was evaluated in R/R MCL. In a phase III study, 162 heavily pretreated patients underwent a 1:1:1 randomization to receive temsirolimus at 175 mg weekly for 3 weeks followed by either 75 or 25 mg weekly or a therapy of the investigator’s choice (most commonly gemcitabine [42%] or fludarabine [23%]). The primary end point of PFS was significantly longer in the temsirolimus 175/75-mg group compared with the investigator’s-choice group (median PFS, 4.8 vs 1.9 months; P=.0009).26 These results led to European Union approval of temsirolimus for R/R MCL in 2009.

Table 3

Summary of Treatments for Relapsed/Refractory Mantle Cell Lymphoma

Table 3
Figure 3
Figure 3

B-cell receptor complex and associated intracellular pathways.

*Protein regions affected by recurrent somatic alterations in human lymphomas.

Abbreviations: BLNK, B-cell linker protein; BTK, Bruton tyrosine kinase; CARD11, caspase recruitment domain-containing protein 11; CBM, CARD11-BCL-10-MALT1; CIN85, Cbl-interacting protein of 85 kDa; DAG, diacylglycerol; IKK, inhibitor of NF-κB kinase; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light chain; IP3, inositol trisphosphate; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKCβ, protein kinase Cβ; PLCγ, phospholipase Cγ; SFK, SRC family kinase.

Reproduced and modified from Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 2013;12:229-243.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 9; 10.6004/jnccn.2014.0126

Lenalidomide, an immunomodulatory drug, has also been studied in the R/R MCL population. The phase II EMERGE study enrolled 134 patients (median of 4 prior therapies) with R/R MCL for whom bortezomib failed. Lenalidomide was administered orally at 25 mg/d on days 1 through 21 of a 28-day cycle until disease progression or intolerance. The ORR was 28.0% with a 7.5% CR/CRu rate. The median PFS was just 4 months, but the median response duration was 16.6 months, suggesting substantial clinical benefit in patients responding to treatment. The most common grade 3/4 AEs were neutropenia (43%) and thrombocytopenia (27%), with 34% and 31% of patients experiencing fatigue and diarrhea of any grade, respectively. Treatment was discontinued in 19% of patients because of AEs.27

A particularly interesting, mechanistically based combination is lenalidomide administered with rituximab. Lenalidomide has pleotropic effects on the immune system, including reversing the defective ability of T cells and natural killer cells to form synapses with malignant B cells.28,29 A single-institution phase I/II study from The University of Texas MD Anderson Cancer Center studied the combination of lenalidomide plus rituximab (375 mg/m2 in 4 weekly doses during cycle 1) in 52 patients with R/R MCL (50 patients received lenalidomide at the maximum tolerated dose of 20 mg). The ORR among the phase II cohort was 57% (36% CR). The median duration of response was 18.9 months with a median PFS of 11.1 months. Grade 3/4 neutropenia and thrombocytopenia occurred in 66% and 23% of patients, respectively, with 52% of patients needing at least one dose reduction or interruption because of AEs.30 These results suggest the combination is at least additive and possibly synergistic.

Constitutive activation of the BCR signaling pathway plays a major role in the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is an important mediator of the BCR pathway. Ibrutinib is an oral BTK inhibitor that received accelerated FDA approval for the treatment of R/R MCL in late 2013. In a phase II study of 111 patients with R/R MCL, ibrutinib was given at a dosage of 560 mg/d until disease progression or unacceptable toxicities occurred. The median number of cycles received was 9 (range, 1-24). The ORR was 68% (21% CR), with a median duration of response of 17.5 months and median PFS of 13.9 months. The median PFS for patients who experienced a partial response or CR was 17.5 months and not reached, respectively. Treatment was well-tolerated, with only 16% and 11% experiencing grade 3/4 neutropenia and thrombocytopenia, respectively. Treatment was discontinued because of an AE in only 7% of patients.31 These results indicate that ibrutinib is the single most promising novel agent for the treatment of MCL.

Another important mediator of the BCR signaling pathway is PI3K. Idelalisib is a potent oral inhibitor of the delta isoform of PI3K. In a phase I study performed in 40 patients with heavily pretreated MCL, the ORR was 40% for the entire treatment population and 69% in those who received the chosen phase II dose of 150 mg twice daily or higher. The median duration of response was only 2.7 months, however, with a median PFS of 3.7 months, suggesting that resistance develops quickly. A small group of patients (22%), however, experienced durable responses lasting more than a year. The major toxicities were transaminitis and diarrhea of any grade in 60% and 40% of patients, respectively, with no significant myelosuppression or peripheral neuropathy noted.32

The duration of response tempers enthusiasm for the use of idelalisib as a single agent. However, the high ORR provides proof of concept that PI3K delta is a viable target in MCL, and future work should focus on mechanisms of resistance so that next-generation compounds and/or rational combinations can be developed.

The Future of MCL

Intensive strategies have produced impressive outcomes in younger patients with MCL. Although not curative, median PFS in most trials exceeds 5 years. However, whether intensive treatment is needed upfront is still unclear because of the lack of randomized trials, and substantial improvement in current outcomes with variations of intensive strategies is difficult to envision. With the development of promising new agents such as ibrutinib, and promising combinations such as lenalidomide-rituximab, future studies should investigate whether less-intensive novel strategies can produce comparable outcomes. Alternatively, the addition of novel agents to an intensive therapy backbone could be investigated. For older patients with MCL, for whom intensive strategies are not an option, the path forward is clearly novel agents, either added to conventional cytotoxics or attempting to replace them. Maintenance strategies seem to have found a role in the frontline management of MCL in older patients. For patients with R/R disease, future trials should test rational combinations of novel agents in an effort to increase response rates and delay the development of resistance.

Dr. Kahl has disclosed that he is a consultant for Genentech, Inc.; Millennium Pharmaceuticals, Inc.; Gilead Sciences, Inc.; and Celgene Corporation. He receives research support from Genentech, Inc.; Gilead Sciences, Inc.; and Infinity Pharmaceuticals. Dr. Rajguru has disclosed that he has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education & Grants, has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education & Grants, has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships.

Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships.

Hema Sundar, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.

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Correspondence: Brad S. Kahl, MD, University of Wisconsin School of Medicine, 1111 Highland Avenue, 4059 WIMR, Madison, WI 53705. E-mail: bsk@medicine.wisc.edu

Supplementary Materials

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    Treatment approach to patients with newly diagnosed mantle cell lymphoma.

    Abbreviations: ASCT, autologous stem cell transplant; BR, bendamustine, rituximab; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; R-hyperCVAD/R-MA, rituximab, hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, cytarabine; VcR-CVAD, bortezomib, rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone.

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    Treatment schema for Intergroup E1411.

    Abbreviations: B, bendamustine; R, rituximab; V, bortezomib.

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    B-cell receptor complex and associated intracellular pathways.

    *Protein regions affected by recurrent somatic alterations in human lymphomas.

    Abbreviations: BLNK, B-cell linker protein; BTK, Bruton tyrosine kinase; CARD11, caspase recruitment domain-containing protein 11; CBM, CARD11-BCL-10-MALT1; CIN85, Cbl-interacting protein of 85 kDa; DAG, diacylglycerol; IKK, inhibitor of NF-κB kinase; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light chain; IP3, inositol trisphosphate; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKCβ, protein kinase Cβ; PLCγ, phospholipase Cγ; SFK, SRC family kinase.

    Reproduced and modified from Young RM, Staudt LM. Targeting pathological B cell receptor signalling in lymphoid malignancies. Nat Rev Drug Discov 2013;12:229-243.

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