Novel therapies under investigation for mantle cell lymphoma

1. Introduction

Mantle cell lymphoma (MCL) is an aggressive, type of B-cell non-Hodgkin lymphoma (NHL).[1] It accounts about 6% of all NHL and occurs more commonly in men than in women.[2] At the molecular level, the disease is characterized by the translocation t(11;14)(q13;32). More than 90% of MCL patients carry the IGH-CCND1 fusion gene, which leads to aberrant expression of the cell cycle regulator protein cyclin D1 (CCND1). However, a CCND1-negative variant of MCL without typical t(11;14)(q13;32) translocation, with splenomegaly, lymphadenopathy, and bone marrow and blood involvement, has been identified on occasion.[3] Instead, tumor cells express either cyclin D2 or cyclin D3. No significant difference has been observed in overall survival (OS) between the cyclin D1-positive and cyclin D1-negative patients. While a minority of MCL patients (10–15%) have indolent course and may not need therapy for several years, the majority of MCL patients are diagnosed at advanced stages with an aggressive course, and these patients require immediate therapy.

In recent years, significant progress in treatment outcome has been observed, mainly due to the introduction of more intensive treatment with high doses of cytotoxic drugs and rituximab with subsequent autologous stem cell transplantation (ASCT).[1] In consequence, median OS of MCL patients has increased to between 5 and 7 years. The addition of rituximab to chemotherapy prolongs OS in this disease as compared to chemotherapy alone.[1] Despite promising results of current therapies, MCL remains incurable in the vast majority of patients; however, substantial progress has recently been made in treating the disease. Most notably, new drugs have been designed with significant clinical activity, and new treatment strategies have been demonstrated.[1] The present article discusses new drugs in preclinical to phase II clinical development.

2. Recently approved drugs

In recent years, bortezomib, lenalidomide, ibrutinib, and temsirolimus have been approved for relapsed or refractory MCL, and some of them are used in combination with other agents in previously untreated patients (Table 1).

Table 1. Characteristics and clinical activity of recently approved and investigational drugs in mantle cell lymphoma.

Drug	Mechanism of action	Clinical activity	Approval status for MCL
Bortezomib (Velcade®, Janssen Pharmaceutical and Takeda)	Proteasome inhibitor, reversible inhibitor of the ubiquitin-proteasome pathway, involved in protein degradation. Bortezomib decreases expression of NF-κB	Bortezomib alone induces 30–50% OR in relapsed/refractory MCL.[4] Bortezomib used instead of vincristine in the R-CHOP in 1st line improved PFS duration and CR rate in comparison with R-CHOP.[5] Bortezomib added to R-CHOP in 1st line, with bortezomib maintenance—at 5 years: PFS—28% and OS—68%) [6]	Approved for relapsed and refractory MCL and for 1st line, both in the United States and the European Union
Lenalidomide (Revlimid^®, Celgene)	Immunomodulatory drug, effects the microenvironment by disruption of tumor–stroma interactions, direct cell cycle-arresting effects which exert a proapoptotic influence	Phase II study (EMERGE) in relapsed/refractory MCL-OR—28%, median PFS −4.0 m and median OS −19.0 months.[7] Lenalidomide + rituximab in relapsed/refractory MCL-OR 56.5% with CR 34.8%, median PFS 14.1 m and OS 24.6 m	Approved by FDA for relapsed MCL
Ibrutinib (PCI-32765, Imbruvica®, Pharmacyclics, Inc.)	Selective inhibitor of BTK, a crucial enzyme in BCR signaling	In phase II study in 111 relapsed/refractory patients, OR–68%, CR 21%, PFS 14 m, and 58% OS at 18 m [8]	Approved by FDA for previously treated MCL
Temsirolimus (CCI-779, Torisel^®, Wyeth Pharmaceuticals)	Selective inhibitor of mTOR	For dose 175/75-mg OR 22% and PFS 4.8 months [9]	Approved be EMA for relapsed or refractory MCL
Obinutuzumab (Gazyva™, GA-101, RO5072759, Genetech/Roche)	Type II, glycoengineered, humanized anti-CD20 mAb with increased antibody-dependent cellular cytotoxicity	In the phase II GAUGUIN study in 15 pretreated patients OR 27%, CR 13%, median PFS 2.7 m [10]	Not approved for MCL
Ofatumumab (Arzerra™, Genmab/GSK/Novartis)	Fully human type I anti-CD20 mAb with increased ability to activate complement-dependent cytotoxicity and longer off-rate compared to rituximab	Phase II study in 12 pretreated patients OR rate −8.3% (1 PR) and median OS 11.2 months. SD was noted in 6 patients (50%)	Not approved for MCL
Idelalisib (Zydelig®, Gilead)	Selective inhibitor of the PI3K δ isoform	Phase I study in relapsed/refractory patients—OR 40%, CR 5%, median PFS 3.7 months, and PFS at 1 year 22%;[11] ongoing phase II study evaluating idelalisib + lenalidomide, in relapsed or refractory MCL (NCT01838434)	Not approved for MCL
Acalabrutinib (ACP-196, Acerta Pharma)	Second-generation, irreversible BTK inhibitor, and increased potency and selectivity compared with ibrutinib in preclinical models	Ongoing phase II study in relapsed/refractory MCL(NCT02213926)	Not approved for MCL
Fostamatinib disodium (R935788, R788, Rigel)	Syk inhibitor	Phase I/II study in 9 patients—1 PR and 4 stable disease [12]	Not approved for MCL
Venetoclax (GDC-0199, ABT-199, Genentech and AbbVie)	Selective inhibitor of BCL-2 anti-apoptotic protein without significant binding to Bcl-xL, Bcl-w, and Mcl-1	Phase I study on 28 patients with MCL, OR 75%, CR—21% and SD—18%; ongoing phase I/Ib study of venetoclax combined with ibrutinib in relapsed/refractory MCL (NCT02419560)	Not approved for MCL
Carfilzomib (Kyprolis®, Onyx Pharmaceuticals, Inc/Amgen)	Binds irreversibly to the CT-L catalytic subunits of proteasome	Ongoing phase I single-arm safety and dose-finding trial of ibrutinib and carfilzomib in refractory/relapsed MCL (NCT02269085)	Not approved for MCL

ASCT: autologous stem cell transplantation; BCR: B-cell receptor; BTK: Bruton’s tyrosine kinase; EMA: European Medicines Agency; FDA: Food and Drug Administration; mAb: monoclonal antibody; NF-κB: nuclear factor-κB; CR: complete response; m: months; mTOR: mammalian target of Rapamycin; mAb: monoclonal antibody; OR: overall response; PFS: progression free survival; PI3K: phosphoinositol-3 kinase; PR: partial response; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone; SD: stable disease; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, vincristin, prednisone.

Bortezomib (Velcade^®, Janssen Pharmaceutical and Takeda) is the first therapeutic proteasome inhibitor approved for the treatment of multiple myeloma (MM) and MCL. It is a reversible inhibitor of the ubiquitin-proteasome pathway, involved in protein degradation. Bortezomib decreases the expression of nuclear factor-κB, responsible for the upregulation of genes promoting cell growth. In phase II studies, overall response (OR) rates of 30–50% were noted when bortezomib was used as a single drug in relapsed or refractory disease.[4] In previously untreated patients, the addition of bortezomib to induction chemotherapy is also promising. In the phase III LYM-3002 study, bortezomib was used instead of vincristine in the R-CHOP chemoimmunotherapy (VR-CAP) for previously untreated patients with MCL who were not suitable for intensive treatment and ASCT.[5] The VR-CAP regimen improved progression free survival (PFS) duration and CR rate in comparison with R-CHOP. The combination of R-CHOP with bortezomib followed by maintenance bortezomib also seems to improve outcomes to a greater degree than R-CHOP alone in previously untreated MCL patients.[6] The combination of bortezomib with other new drugs, such as lenalidomide, ibrutinib, or idelalisib, may also be a useful approach. Bortezomib has been approved by the Food and Drug Administration (FDA) for MCL with relapsed and refractory disease, and more recently for first line treatment, both in the United States and the European Union.

Lenalidomide (Revlimid^®, Celgene), a newer immunomodulatory drug, is also active in MM and MCL. The precise mechanism of action of lenalidomide in MCL is not entirely understood. However, the agent is known to influence the microenvironment by the disruption of tumor–stroma interactions and possibly by the activation of immune effector mechanisms. In the MCL-001 (EMERGE) pivotal trial, lenalidomide demonstrated predictable safety and durable activity when used in monotherapy in earlier intensively treated patients with advanced-stage disease, who had previously received bortezomib.[13]

Single-agent lenalidomide has also been compared with other monotherapies based on choice of investigators (SPRINT study).[7] A longer PFS was observed with lenalidomide (median 8.7 months vs. 5.2 months; P = 0.004). Lenalidomide combined with rituximab has been also evaluated in relapsed/refractory and previously untreated patients.[14,15] In the relapsed/refractory patients, lenalidomide combined with rituximab has induced an OR rate of 56.5% including 34.8% CR. Median PFS was 14.1 months and OS 24.6 months. In previously untreated patients with a median age of 65 years, the OR rate was 92% and the CR rate was 64%. Two-year PFS was 85% and 2-year OS 97%.[15] Clinical trials for untreated MCL based on combinations of lenalidomide with other agents, including rituximab or rituximab and bendamustine, are ongoing (NCT01472562). In June 2013, lenalidomide was approved by the FDA for MCL patients with relapsed MCL or progression after two prior therapies following previous treatment with bortezomib.

Ibrutinib (PCI-32765, Imbruvica®, Pharmacyclics, Inc.) is an oral small-molecule selective inhibitor of Bruton’s tyrosine kinase (BTK), a component of the B-cell receptor (BCR) signaling pathway. The agent binds covalently to a noncatalytic cysteine residue (Cys-481) in the BTK active site, leading to irreversible inhibition of BTK enzymatic activity. Ibrutinib has shown impressive single-agent responses with excellent tolerability and a modest side-effect profile in previously treated MCL. In a pivotal phase II study conducted on patients with relapsed/refractory MCL, ibrutinib demonstrated significant and durable single agent response.[8] However, disease progression in patients treated with ibrutinib is a frequent event and clinical outcomes in these patients are poor. The results of the use of combined ibrutinib and rituximab for relapsed MCL seem to be an improvement on historical data concerning ibrutinib as a single agent.[16] The use of an ibrutinib–lenalidomide combination is currently under investigation in previously treated MCL patients (NCT02460276). A randomized, placebo-controlled Phase III study of ibrutinib, in combination with bendamustine and rituximab, in elderly patients with newly diagnosed MCL (SHINE trial) has been also undertaken (NCT01776840). In 2013, ibrutinib was approved by the FDA for MCL patients previously treated with one or more previous therapies.

Temsirolimus (CCI-779, Torisel^®, Wyeth Pharmaceuticals) is a selective inhibitor of the mammalian target of Rapamycin (mTOR). In a pivotal multicenter, randomized phase III trial performed in 162 patients with relapsed or refractory MCL, temsirolimus significantly prolonged median PFS (4.8 months) in comparison with standard treatment (1.9 months; P = 0.0009).[9] Temsirolimus has been approved by the European Medicines Agency for MCL patients with relapsed or refractory disease. Another mTOR inhibitor, everolimus (RAD001) is less active in previously treated MCL patients.

3. Investigational agents

Preclinical data and early clinical trials suggest that several other agents may have clinical applications in the treatment of MCL in the near future (Table 1). These drugs are being explored in phase I and II studies and show exquisite promise in MCL. In particular, second-generation anti-CD20 monoclonal antibodies, including obinutuzumab (Gazyva™, GA-101, RO5072759, Genetech/Roche) and ofatumumab (Arzerra™, Genmab/GSK/Novartis), are more potent than the conventionally used rituximab and are currently being examined in MCL.[10,17]

Ofatumumab is a fully human, type 1 CD20, IgG1 mAb differs from rituximab in that it recognizes a different epitope and demonstrates higher cytotoxic potential. Ofatumumab is also more effective than rituximab at complement dependent cytotoxicity induction and killing target cells. In a phase II study, 12 MCL patients were enrolled but the trial was halted due to insufficient response.[17] An OR rate of 8.3% was obtained with a median OS of 11.2 months. Only one patient achieved a partial response (PR) and stable disease (SD) was noted in six patients (50%).

Obinutuzumab is a novel, type II, third generation, humanized anti-CD20 monoclonal antibody which is distinct from rituximab. The antibody is based on proprietary GlycoMAb^® technology, which incorporates glycoengineered antibodies that specifically increase antibody-dependent cellular cytotoxicity and thereby increase immune-mediated target cell death. Obinutuzumab was found to be superior to rituximab in experiments using whole-blood depletion assays and MCL-xenograft models. In the phase II GAUGUIN study, 15 previously treated MCL patients received eight cycles of obinutuzumab as a flat dose of 400/400 mg or 1600/800 mg.[10] The OR rate was 27% including 13% CR. However, median PFS was only 2.7 months in the 1600/800-mg group and 2.6 months in the 400/400-mg group.

Several other agents, including the BCL-2 inhibitor venetoclax (ABT-199) and the phosphatydilinosytol 3-kinase δ (PI3K δ) inhibitor idelalisib, were tested in a phase I study and showed promising activity in MCL.[11,18]

Venetoclax (GDC-0199, ABT-199, Genentech and AbbVie), is a selective inhibitor of BCL-2 anti-apoptotic protein without significant binding to Bcl-xL, Bcl-w, and Mcl-1. In a phase I clinical trial, venetoclax used as a single drug showed high activity in previously treated MCL patients. Among 28 patients, the OR rate was 75% including 21% CR and 54% PR.[18] In addition, 18% achieved SD. The drug is currently being tested in combination with ibrutinib in relapsed/refractory MCL (NCT02419560).

Idelalisib (Zydelig®, Gilead), is a selective inhibitor of the PI3K δ isoform, which has been implicated in the regulation of the activation, proliferation, migration, and survival of B-lymphocytes. The drug has shown promising activity during evaluation in a Phase I study in relapsed or refractory patients with MCL.[11] The efficacy analysis revealed the OR rate to be 40% and the CR rate 5%. Median PFS was 3.7 months, and PFS at 1 year was 22%. Diarrhea, nausea, pyrexia, fatigue, and rash were the most common adverse events. The ongoing study examines the effects of idelalisib in combination with lenalidomide in patients with relapsed or refractory MCL (NCT01838434).

Syk plays also an important role in the BCR signaling pathway, and Syk inhibitors are another therapeutic option in MCL. A novel Syk inhibitor, fostamatinib disodium (R935788, R788, Rigel), is an emerging new molecule with potential activity in B-cell lymphoid malignancies. The drug demonstrated some therapeutic activity in a phase I/II clinical trial of MCL comprising nine patients with relapsed or refractory B-cell lymphomas.[12] One of the nine patients achieved a PR and four patients showed SD after treatment. Diarrhea, fatigue, cytopenias, hypertension, and nausea were observed in some patients.

Several next-generation proteasome inhibitors (carfilzomib, oprozomib, ixazomib, NPI-0052) have been developed and some are undergoing clinical testing in MCL, both alone and in combination with other substances. These agents were active and demonstrated an acceptable safety profile in bortezomib-resistant MCL patients. Carfilzomib (Kyprolis®, Onyx Pharmaceuticals, Inc/Amgen) binds irreversibly to the CT-L catalytic subunits of proteasome. Carfilzomib has an established role in MM and in vitro studies have demonstrated it to have activity in MCL. Moreover, ibrutinib synergizes with carfilzomib and is cytotoxic to carfilzomib-resistant cell lines.[19] Currently, a Phase I single-arm safety and dose-finding trial of combined ibrutinib and carfilzomib administration in patients with refractory/relapsed MCL is ongoing (NCT02269085).

Histone deacetylase (HDAC) inhibitors currently have been approved for cutaneous T-cell lymphoma. Two HDAC inhibitors, vorinostat and panobinostat, have been also investigated in MCL but the results are not promising.[20,21] Similarly, the results of cyclin D1 inhibitors in MCL patients are not encouraging.[22]

Recently, Kridel et al. using whole transcriptome shotgun sequencing (RNAseq) of 18 primary tissue samples and 2 cell lines found recurrent somatic mutations in NOTCH1, the majority of which truncate the PEST domain of NOTCH1.[23] NOTCH1 mutations were found to have a negative prognostic impact with significantly shorter PFS (P = 0.03) and OS (P = 0.003). Importantly, inhibition of the NOTCH pathway inhibited growth and induced apoptosis in a subset of MCL cell lines. It is possible that NOTCH inhibition by g-secretase inhibitors, or the use of antibodies against NOTCH1 will have implications for tailored therapy in MCL patients.[24]

Recently, the T-cell response checkpoint inhibitors, nivolumab and pembrolizumab demonstrated safe and durable responses in patients with relapsed and treatment-resistant lymphoid malignancies, particularly Hodgkin’s lymphoma.[25] These agents should be also explored in MCL. Pembrolizumab (MK-3475, lambrolizumab, Keytruda^®, Merck) is a humanized monoclonal IgG4 antibody that targets the human cell surface programed death-1 (PD-1) receptor with potential immune checkpoint inhibition. Nivolumab (Opdivo^®, Bristol-Myers Squibb) is an anti-PD-1 monoclonal antibody that has therapeutic activity in Hodgkin’s lymphoma and other lymphoid malignancies. This agent is currently under investigation in NHL, including DLBCL and follicular lymphoma (NCT02038933, NCT02038946).

Early studies have focused on the use of chimeric antigen receptor (CARs) T-cells transduced with the anti-CD19 (CART-19, CTL019) in MCL therapy. The production of CAR T-cells involves the adoptive transfer of autologous T-cells genetically modified via lentiviral transduction to express CARs designed to target CD19 or other antigens. Treatment with CAR T-cells has been found to be an effective form of therapy for treating NHL and MCL.[26] An ongoing clinical study will establish the potential of CART-19 therapy in patients with MCL (NCT02081937).

4. Conclusion

Four targeted drugs, bortezomib, lenalidomide, ibrutinib, and temsirolimus, have demonstrated promising results in treating MCL and significantly improved the prognosis. These agents have been approved in the European Union and/or the United States for the treatment of patients with relapsed/refractory MCL. In addition, bortezomib has been also approved for previously untreated patients. New drugs, particularly anti-CD-20 monoclonal antibodies, BTK, PI3K, and BCL-2 inhibitors, are currently being assessed in the treatment of MCL. Several Phase I/II trials with these new targeted drugs and their combinations are ongoing, particularly in relapsed and refractory patients, and new molecules are being integrated with existing therapies. The role of new, targeted drugs in MCL will doubtlessly be expanded in the coming years.

5. Expert opinion

MCL is a heterogeneous disorder that indicates a need for multiple therapeutic options. Patients with this disease can be distinguished from those with an indolent course not needing treatment to rapidly progressing aggressive cases. Despite significant progress and an impressive number of novel agents, MCL remains an incurable disease, even in younger, fit patients treated with high-dose therapy and ASCT. In the last 20 years, the median OS of the patients with MCL has improved from less than 2.5 years to more than 5 years, but for the overall population treated outside of clinical trials, median OS remains below 3 years.[27] However, it should be noted that the majority of patients with MCL treated with standard regimens demonstrate acquired resistance to these existing therapies, and this remains a challenge for researchers and clinicians.

Recently, a better understanding of the pathogenesis of this disease has stimulated the development of targeted drugs and promoted greater progress in therapy. In addition to the ongoing evaluation of new monoclonal antibody-based therapies, several targeted biologic agents are undergoing preclinical and clinical evaluation and have shown early promise as effective therapeutic agents in MCL. The most advanced drug in clinical trials in patients with MCL is the proteasome inhibitor bortezomib. At the time of writing, only this agent among targeted drugs has been approved for previously untreated patients with MCL. Other particularly promising new targeted agents in MCL are ibrutinib and idelalisib, which disrupt BCR downstream signaling. Ibrutinib has shown single agent activity in patients with relapsed and refractory MCL. However, acquired resistance has been observed in several cases. A recent study by Chiron et al. reports the presence of the relapse-specific C481S mutation at the ibrutinib-binding site of BTK in lymphoma cells collected from patients in progression after long-lasting remission on ibrutinib.[28] The C481S BTK mutation has been also observed in relapsed CLL patients treated with this drug [29] but in MCL patients, response duration is shorter and disease progression more common than in CLL patients. Nevertheless, it is hoped that other targeted drugs will overcome acquired resistance by targeting other cellular pathways. For example, it has been shown that PI3Kδ-specific inhibitors inhibit MCL growth regardless of the presence of the C481S BTK mutation.[30] These observations suggest that the combined use of targeted drugs will be effective in decreasing drug resistance. In addition, a second generation of BTK inhibitors has been developed and entered clinical trials. One such inhibitor is acalabrutinib (ACP-196), selective irreversible inhibitor of BTK that has better pharmacologic properties, including favorable plasma exposure and quicker oral absorption than ibrutinib. Moreover, acalabrutinib is a more highly selective BTK inhibitor than ibrutinib and has recently shown promising efficacy and safety profiles in relapsed CLL.[31] An open-label, phase II study of ACP 196 in previously treated patients with MCL is ongoing (NCT02213926).

Second generation mTOR inhibitors and immunomodulating drugs could also play a role in the treatment of MCL. However, temsirolimus and lenalidomide have moderate activity as single agents in the relapsed/refractory setting and are currently being investigated in combination with established chemotherapeutic regimens. Notably, temsirolimus is less active and more toxic than ibrutinib in previously treated patients. A recent phase III study, compares the efficacy and safety of temsirolimus with that of ibrutinib in relapsed or refractory MCL.[32] Primary efficacy analysis showed significant improvement in PFS for patients treated with ibrutinib (14.6 months) than in temsirolimus (6.2 months) (P < 0.0001). Temsirolimus was also poorer tolerated than ibrutinib, with more treatment-emergent adverse events.

Compared to conventional chemotherapy, however, the data concerning new drugs is relatively immature, and the long-term consequences of these agents are unknown, both regarding the disease and their toxicity. In the future, the most effective therapy of MCL will most probably be based on combinations of targeted agents, either combined with each other or with chemoimmunotherapy. Several clinical studies are currently ongoing to establish the best combinations of new agents with existing therapies. Most importantly, maintenance and/or consolidation therapies with anti-CD 20 antibodies and/or BCR inhibitors should significantly improve PFS and OS. Ongoing trials evaluating the role of newer drugs, including bortezomib, ibrutinib, and lenalidomide, used after induction therapy should establish the best approach to prolonging PFS and OS. In addition, the elimination of minimal residual disease (MRD) in MCL patients should become a goal for future therapies. Several recent studies indicate that the achievement of molecular remission in peripheral blood and/or bone marrow is associated with a better clinical outcome.[33]

Finally, very little data is available on the economic impact of MCL management with new drugs. In addition, the budget for health care is limited, particularly in countries with lower revenues, and the cost of novel drugs may be prohibitive. Therefore, clinical decisions should be based on cost-effective use of new drugs to achieve maximum health gain.

Declaration of interest

This work was supported in part by a grant from the Medical University of Lodz, Poland (No. 503/1-1093-01/503-01). The author received research grants from Janssen Cilag and Pharmacyclics and travel grants from Janssen Cilag. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.