Mantle cell lymphoma (MCL) may be 1 of the few cancers for which multiple chemotherapy and nonchemotherapy regimens are considered as standard. Despite the significant activity of chemotherapy in the first-line setting and beyond, its limitations are reflected in the relatively poor ultimate outcomes of patients with MCL treated in the real world. Patients with highly proliferative MCL and those with TP53 mutations tend to respond poorly despite intensive cytotoxic therapies. Patients with comorbidities and those who are geographically isolated may not have access to the regimens that may appear most promising in clinical trials. Thoughtfully directed, nonchemotherapy agents might overcome some of the factors associated with a poor prognosis, such at TP53 mutation, and might resolve some of the challenges related to the toxicity and deliverability of standard chemotherapy regimens. Several clinical trials have already demonstrated that combinations of nonchemotherapy plus chemotherapy drugs can impact outcomes, whereas data with nonchemotherapy agents alone or in combination have suggested that some patients might be well suited to treatment without chemotherapy at all. However, challenges including chronic or unexpected toxicities, the rational vs practical development of combinations, and the financial acceptability of new strategies abound. The nonchemotherapy era is here: how it unfolds will depend on how we meet these challenges.

The goal of therapy in mantle cell lymphoma (MCL) is to extend overall survival (OS) with as few lymphoma-related symptoms and treatment-related side effects as possible. Historically, this has been accomplished through the sequential administration of chemotherapy or immunochemotherapy regimens, with drugs and doses individualized to best suit the specific scenario. Fortunately, immunochemotherapy is active in most patients. Unfortunately, immunochemotherapy is rarely if ever curative, and highly proliferative or TP53-mutated lymphomas tend to respond poorly regardless of treatment intensity.1,2  Moreover, chemotherapy comes with well-documented toxicities that can limit its use and detract from quality of life. Over the past decade, 4 nonchemotherapy options (bortezomib, temsirolimus, ibrutinib, lenalidomide; Table 1) have been approved by the US Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) for treatment of MCL, and several others are in development. In some cases, these nonchemotherapy drugs appear to be active where traditional cytotoxic chemotherapy might fail, and in many cases the side-effect profile is distinct from chemotherapy. Despite the failure of any of these drugs to improve OS in randomized trials, their introduction corresponds with better outcomes in population studies3-5  suggesting that the availability of new options that can be used sequentially may be extending survival. Increasingly, clinicians, patients, and other interested parties are raising the possibility of a future without chemotherapy.

Table 1.

Registrational trials of approved nonchemotherapy drugs

AgentPatient populationStudy designAdministrationNPrimary end pointSecondary end points
Bortezomib55  1-3 prior lines of therapy Phase 2 Bortezomib 1.3 mg/m2 days 1, 4, 8, 11 q21 d until progression 155 TTP, 6.2 mo
(95% CI, 4.0-6.9 mo) 
ORR, 33% 
CR + CRu, 8% 
Bortezomib14  Previously untreated Randomized phase 3 VR-CAP vs R-CHOP ×6-8 cycles 243 vs 244 Median PFS, 24.7 mo vs 14.4 mo; HR, 0.63
(95% CI, 0.50-0.79) 
Median OS, 56.3 mo vs NR; HR, 0.80
(95% CI, 0.59-1.10) 
Temsirolimus33  Previously treated Randomized phase 3 Temsirolimus 175/75 mg vs 175/25 mg vs investigator’s choice until progression 54 vs 54 vs 53 Median PFS, 4.8 mo vs 3.4 mo vs 1.9 mo ORR temsirolimus, 22% vs investigator’s choice 2%; P = .0019 
Ibrutinib56  1-5 prior lines of therapy, prior bortezomib in 48 of 111 Phase 2 Ibrutinib 560 mg daily until progression 111 ORR, 68% Median PFS, 13.9 mo
(95% CI, 7.0 vs NR) 
Lenalidomide57  Prior bortezomib, anthracycline, cyclophosphamide, rituximab Phase 2 Lenalidomide 25 mg days 1-21 q28 d until progression 134 ORR, 28% Median PFS, 4.0 mo
(95% CI, 3.6-5.6 mo) 
AgentPatient populationStudy designAdministrationNPrimary end pointSecondary end points
Bortezomib55  1-3 prior lines of therapy Phase 2 Bortezomib 1.3 mg/m2 days 1, 4, 8, 11 q21 d until progression 155 TTP, 6.2 mo
(95% CI, 4.0-6.9 mo) 
ORR, 33% 
CR + CRu, 8% 
Bortezomib14  Previously untreated Randomized phase 3 VR-CAP vs R-CHOP ×6-8 cycles 243 vs 244 Median PFS, 24.7 mo vs 14.4 mo; HR, 0.63
(95% CI, 0.50-0.79) 
Median OS, 56.3 mo vs NR; HR, 0.80
(95% CI, 0.59-1.10) 
Temsirolimus33  Previously treated Randomized phase 3 Temsirolimus 175/75 mg vs 175/25 mg vs investigator’s choice until progression 54 vs 54 vs 53 Median PFS, 4.8 mo vs 3.4 mo vs 1.9 mo ORR temsirolimus, 22% vs investigator’s choice 2%; P = .0019 
Ibrutinib56  1-5 prior lines of therapy, prior bortezomib in 48 of 111 Phase 2 Ibrutinib 560 mg daily until progression 111 ORR, 68% Median PFS, 13.9 mo
(95% CI, 7.0 vs NR) 
Lenalidomide57  Prior bortezomib, anthracycline, cyclophosphamide, rituximab Phase 2 Lenalidomide 25 mg days 1-21 q28 d until progression 134 ORR, 28% Median PFS, 4.0 mo
(95% CI, 3.6-5.6 mo) 

CI, confidence interval; CR, complete response rate; CRu, complete response rate unconfirmed; HR, hazard ratio; NR, not reported; ORR, overall response rate; PFS, progression-free survival; q21, every 21 days; q28, every 28 days; R-CHOP, rituximab, cyclophosphamide, adriamycin, vincristine, prednisone; TTP, time to progression; VR-CAP, bortezomib 1.3 mg/m2 days 1, 4, 8, 11 plus rituximab, cyclophosphamide, adriamycin, prednisone.

There is clearly value in more effective, better-tolerated treatments for people with MCL; whether these new treatments are chemotherapy or not is less important than whether they work. Indeed, many experts take issue with the term “nonchemotherapy,” questioning its provenance and, no doubt, concerned that it could be construed as a gimmick promoted by those looking to advance the use of new drugs to a group of patients anxious about their diagnosis and eager to believe that progress is at hand. “Nonchemotherapy” often implies, rightly or wrongly, “more effective” and “less toxic,” generally with a mechanism of action that preferentially targets tumor cells. Although there are clearly issues with the term, it is broadly understood because it simply describes what it is not: traditional cytotoxic chemotherapy. With roughly 20 years of experience with rituximab, 10 years since the approval of bortezomib and temsirolimus, and roughly 5 years of experience (including clinical trials) with lenalidomide and ibrutinib (Table 1), we are already in the nonchemotherapy era, and there are data that allow us to evaluate whether the sentiments attached to nonchemotherapeutic approaches are true.

Without question, chemotherapy is active in MCL. Administered appropriately, combinations including high-dose cytarabine and autologous stem cell transplantation can result in remissions nearly a decade long in some younger patients.6  Less-intensive regimens have also been reported to produce durable remissions, with emerging evidence that patient-related factors and disease biology trump choice of therapy in impacting outcomes.1,7,8  Moreover, chemotherapy may have some desirable effects beyond simple cytotoxicity: cyclophosphamide may inhibit regulatory T cells (Tregs),9  doxorubicin may impair myeloid-derived suppressor cells,10  and low-dose metronomic therapy may impact tumor angiogenesis.11  Nonetheless, the most effective immunochemotherapy regimens are restricted to young, healthy patients who account for <25% of all patients.3  Cytotoxic chemotherapy is associated with well-documented toxicities. In addition to usually modest nuisance-type side effects that can sometimes be more significant, such as alopecia, nausea, and fatigue, chemotherapy can cause significant hematological toxicities, resulting in neutropenic fever and other opportunistic infections. Rarely, it can be associated with cardiac toxicity, renal toxicity, and peripheral nerve or central nervous system toxicity. Long-term side effects resulting from myelotoxicity include secondary malignancies and, more relevantly, impaired bone marrow function that can limit the ability to tolerate subsequent treatments. These factors likely contribute to the discordance between outcomes described in an optimized clinical trial population, which have improved significantly over the past decade, and real-world outcomes, which remain disappointing.3 

Front-line setting: combinations of chemotherapy with nonchemotherapy

Multiagent chemotherapy regimens are standard treatment of most cancers and are based on the concept that the combination of drugs with distinct mechanisms of action and toxicity profiles should be more able to eradicate a broader spectrum of subclones that might result in treatment resistance and disease recurrence. It is no surprise that incorporation of novel, nonchemotherapy drugs into standard chemotherapy regimens might be the most natural first step. Table 2 describes several trials where nonchemotherapy agents have been used in front-line treatment of MCL. Shortly after bortezomib was approved as a single agent for previously treated MCL, it was already being combined with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with diffuse large B-cell lymphoma and MCL, and results appeared worthy of further evaluation.12,13  In a subsequent phase 3 trial, substitution of vincristine in R-CHOP for bortezomib (VR-CAP) resulted in a significant improvement in progression-free survival (PFS; 24.7 vs 14.4 months; hazard ratio [HR], 0.63; P < .001) and subsequent approval of the drug in the setting.14 

Table 2.

Completed and ongoing trials including nonchemotherapy agents in patients with previously untreated MCL

Agents (Trial)Study designAdministrationNPrimary end pointSecondary end points of interest
Lenalidomide, bendamustine, rituximab, (Lena-Berit)15  Phase 1-2 Lenalidomide days 1-14, bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1 every 28 d ×6 cycles followed by single-agent lenalidomide days 1-21 cycles 7-13 51 MTD lenalidomide omitted in cycle 1 then 10 mg in cycles 2-6; median PFS, 42 mo (95% CI, 31-53 mo) CR/CRu, 64%; MRD-negative in blood, 42% 
Ibrutinib, bendamustine, rituximab16  Phase 1/1b Ibrutinib 280 mg or 560 mg daily, bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1, ×6 cycles 17 (including 5 previously untreated) MTD ibrutinib 560 mg daily ORR, 94%; CR, 76% 
Lenalidomide, rituximab24  Phase 2 Induction: Lenalidomide 20 mg days 1-21 ×12 cycles, rituximab 375 mg/m2 weekly ×4 then day 1 of cycles 4, 6, 8, 10, 12 38 ORR, 87% 2-y PFS, 85%
(95% CI, 67%-94%) 
  Maintenance: Lenalidomide 15 mg days 1-21 of each cycle, rituximab 375 mg/m2 q8 wk until progression    
Ibrutinib, rituximab23  Phase 2 Ibrutinib 560 mg daily, rituximab 375 mg/m2 weekly ×4 then day 1 of cycles 3-12 50 ORR, 100% (36 of 36 evaluable) CR, 100% (19 of 19 evaluable) 
Ibrutinib, bendamustine, rituximab (SHINE) NCT01776840 Randomized phase 3 Induction: Ibrutinib 560 mg vs placebo daily, plus bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1 q28 ×6 cycles ∼524 PFS (estimated 28 March 2018) OS 
  Maintenance: ibrutinib 560 mg vs placebo daily until progression, plus rituximab 375 mg/m2 q8 wk ×2 y    
Bortezomib, bendamustine, rituximab (E1411) NCT01415752 Randomized phase 2 Induction: Bortezomib 1.8 mg/m2 days 1, 8, 15 vs nothing, plus bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1 q28 d ×6 cycles ∼332 2-y PFS for RB vs RBV CR 
  Maintenance: Lenalidomide 20 mg days 1-21 q28 d vs nothing, plus rituximab 375 mg/m2 q8 wk ×2 y  PFS for R2 vs R  
Ibrutinib, rituximab (ENRICH) CRUK/14/026 Randomized phase 3 Ibrutinib 560 mg daily until progression, rituximab 375 mg/m2 q3-4 wk ×6 then q8 wk × 2 y vs R-CHOP or RB followed by rituximab q8 wk ×2 y    
Ibrutinib, R-CHOP/R-DHAP (Triangle) NCT02858258 Randomized phase 3 R-CHOP/R-DHAP/ASCT vs R-CHOP/R-DHAP + I/ASCT + I vs R-CHOP/R-DHAP + I ∼870 FFS (estimated May 2021) OS 
Agents (Trial)Study designAdministrationNPrimary end pointSecondary end points of interest
Lenalidomide, bendamustine, rituximab, (Lena-Berit)15  Phase 1-2 Lenalidomide days 1-14, bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1 every 28 d ×6 cycles followed by single-agent lenalidomide days 1-21 cycles 7-13 51 MTD lenalidomide omitted in cycle 1 then 10 mg in cycles 2-6; median PFS, 42 mo (95% CI, 31-53 mo) CR/CRu, 64%; MRD-negative in blood, 42% 
Ibrutinib, bendamustine, rituximab16  Phase 1/1b Ibrutinib 280 mg or 560 mg daily, bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1, ×6 cycles 17 (including 5 previously untreated) MTD ibrutinib 560 mg daily ORR, 94%; CR, 76% 
Lenalidomide, rituximab24  Phase 2 Induction: Lenalidomide 20 mg days 1-21 ×12 cycles, rituximab 375 mg/m2 weekly ×4 then day 1 of cycles 4, 6, 8, 10, 12 38 ORR, 87% 2-y PFS, 85%
(95% CI, 67%-94%) 
  Maintenance: Lenalidomide 15 mg days 1-21 of each cycle, rituximab 375 mg/m2 q8 wk until progression    
Ibrutinib, rituximab23  Phase 2 Ibrutinib 560 mg daily, rituximab 375 mg/m2 weekly ×4 then day 1 of cycles 3-12 50 ORR, 100% (36 of 36 evaluable) CR, 100% (19 of 19 evaluable) 
Ibrutinib, bendamustine, rituximab (SHINE) NCT01776840 Randomized phase 3 Induction: Ibrutinib 560 mg vs placebo daily, plus bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1 q28 ×6 cycles ∼524 PFS (estimated 28 March 2018) OS 
  Maintenance: ibrutinib 560 mg vs placebo daily until progression, plus rituximab 375 mg/m2 q8 wk ×2 y    
Bortezomib, bendamustine, rituximab (E1411) NCT01415752 Randomized phase 2 Induction: Bortezomib 1.8 mg/m2 days 1, 8, 15 vs nothing, plus bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1 q28 d ×6 cycles ∼332 2-y PFS for RB vs RBV CR 
  Maintenance: Lenalidomide 20 mg days 1-21 q28 d vs nothing, plus rituximab 375 mg/m2 q8 wk ×2 y  PFS for R2 vs R  
Ibrutinib, rituximab (ENRICH) CRUK/14/026 Randomized phase 3 Ibrutinib 560 mg daily until progression, rituximab 375 mg/m2 q3-4 wk ×6 then q8 wk × 2 y vs R-CHOP or RB followed by rituximab q8 wk ×2 y    
Ibrutinib, R-CHOP/R-DHAP (Triangle) NCT02858258 Randomized phase 3 R-CHOP/R-DHAP/ASCT vs R-CHOP/R-DHAP + I/ASCT + I vs R-CHOP/R-DHAP + I ∼870 FFS (estimated May 2021) OS 

ASCT, autologous stem cell transplantation; CI, confidence interval; CR, complete response; CRu, complete response unconfirmed; FFS, failure-free survival; I, ibrutinib; MRD, minimal residual disease; MTD, maximum tolerated dose; ORR, overall response rate; PFS, progression-free survival; q3-4, every 3-4 weeks; q8, every 8 weeks; q28, every 28 days; R, rituximab; R2, lenalidomide, rituximab; RB, rituximab, bendamustine; RBV, rituximab, bendamustine, bortezomib; R-CHOP, rituximab, cyclophosphamide, adriamycin, vincristine, prednisone; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin.

The bendamustine-rituximab (BR) regimen has served as a backbone for multiple chemotherapy/nonchemotherapy combinations. The addition of bortezomib to BR is currently being evaluated in the randomized phase 2 US Intergroup E1411 trial (NCT01415752), which completed accrual in 2016. The Nordic MCL4 trial combined BR with lenalidomide (Lena-Berit).15  After early experience with the regimen resulted in unexpectedly high rates of cutaneous reactions and serious infections, the doses and timing of bendamustine and lenalidomide were modified, bringing the regimen in line with what might be clinically acceptable. The finding that 2 treatments that are relatively well tolerated when given separately (ie, BR and lenalidomide in this case) result in unexpected toxicities when combined is observed repeatedly and highlights the importance of prospective clinical trials. In a small study of patients with MCL, the combination of ibrutinib and BR demonstrated not only promising activity but also a surprisingly high rate of cutaneous reactions.16  The combination is being further evaluated in the double-blind, placebo-controlled, randomized phase 3 SHINE trial (NCT01776840), with PFS as the primary end point.

To date, there are no published data describing the combination of intensive front-line regimens with nonchemotherapy agents. The ongoing European MCL Network Triangle (NCT02858258) trial is evaluating the addition of ibrutinib to a high-dose cytarabine-based immunochemotherapy induction, and we are likely to see similar trials in the future.

Critical to the interpretation of chemotherapy/nonchemotherapy trials will be the assessment of whether the PFS benefit justifies the added toxicity if there is the absence of an OS benefit. Part of that question includes an estimate of whether the PFS benefit would be similar if the chemotherapy and nonchemotherapy regimens were given sequentially rather than concurrently. For example, if the addition of ibrutinib to BR results in a PFS benefit that is similar to what might be expected from ibrutinib administered as second-line therapy following BR failure (likely 18 months or more based on pooled data from 3 trials),17  it would likely be less toxic and less expensive to administer the drugs sequentially. Despite these issues, we are likely to see adoption of these combination regimens in the near future and should move quickly to try to understand which patients are most likely to benefit from this approach.

Front-line setting: nonchemotherapy alone

In the absence of true synergy arising from the combination of chemotherapy and nonchemotherapy, it may be rational to replace the chemotherapy component altogether. For example, a common criticism of the HELIOS trial,18  which evaluated BR with or without ibrutinib in patients with previously untreated chronic lymphocytic leukemia (CLL), is the question of whether patients who were randomized to the BR plus ibrutinib arm would have done equally well had they received ibrutinib without BR. Similarly, there may be specific scenarios where chemotherapy is unlikely to be effective and a nonchemotherapy approach might have a higher probability of benefit. Again, experience with CLL may provide clues to scenarios in MCL where standard chemotherapy should be avoided. Patients with CLL and a 17p deletion/TP53 mutation have poor outcomes with chemotherapy and appear to do significantly better when treated with ibrutinib alone in the front-line setting.

Patients with MCL and TP53 mutations have poor outcomes. In the Nordic MCL2 trial, which evaluated intensive induction therapy followed by autologous stem cell transplantation, patients with a TP53 mutation had a median PFS of 1 year compared with 9.9 years in patients without a TP53 mutation (P < .0001).19  Similar results were seen in an Italian trial using a similar treatment regimen.20  MCL, however, is not CLL, and the answer is likely to be considerably more nuanced. Other variables, including blastoid morphology, high Ki67, KMT2D mutations, a complex karyotype, among other high-risk features have also been associated with poor outcomes,1,2,20,21  and whether nonchemotherapy agents can overcome some, all, or any of these adverse factors is unclear. In previously treated MCL, the combination of ibrutinib, lenalidomide, and rituximab did not appear to be adversely impacted by the presence of a TP53 mutation.22  On the other hand, blastoid MCL has been associated with worse outcomes among patients treated with single-agent ibrutinib or temsirolimus.17  Whether specific combinations can control these highly proliferative tumors remains to be seen. It is likely that some patients with MCL might do well regardless of the choice of chemotherapy or nonchemotherapy, some patients might do better receiving nonchemotherapy alone, and some patients will continue to have poor outcomes despite the availability of new, nonchemotherapy agents. Without more informative data, omitting chemotherapy altogether in very-high risk, highly proliferative MCL patients cannot be recommended. There may, however, be a role of nonchemotherapy regimens in less proliferative tumors with TP53 mutations.

Based on the promising efficacy/toxicity profile of ibrutinib plus rituximab in patients with previously treated MCL, the combination is being tested in the front-line setting prior to an abbreviated course of intensive chemotherapy (NCT02427620). Preliminary results suggest a high complete response rate (72%), although the addition of chemotherapy makes durability difficult to assess.23  The randomized, phase 3 ENRICH trial will compare ibrutinib plus rituximab to rituximab plus chemotherapy as front-line therapy in older patients with MCL (CRUK/14/026). The most mature data with a nonchemotherapy regimen in the front-line setting comes from a multicenter phase 2 trial of rituximab-lenalidomide.24  The treatment, which continued until progression or unacceptable toxicity, resulted in an overall response rate of 87%, including 61% complete responses, and a 2-year PFS of 85%, and results continue to appear promising beyond 5 years (J.R., unpublished data). Interestingly, neither the MCL International Prognostic Index (MIPI) score nor Ki67 had an impact on PFS, although only 21% of patients had a Ki67 of >30% at baseline and the study was not powered to detect a difference in this unplanned subgroup analysis. At this point, it is unclear whether novel regimens might have activity in patients expected to do poorly with chemotherapy; future trials with nonchemotherapy agents should pay particular attention to these patient subgroups.

Other interesting data to arise from the lenalidomide-rituximab study include an adverse event profile that is distinct from what might typically be seen with chemotherapy. Although 50% of patients experienced grade 3-4 neutropenia at any time during treatment, only 5% of patients experienced febrile neutropenia. However, low-grade infections were relatively common albeit over a long and frequent observation period, including 39% of patients with grade 1-2 upper respiratory tract infections. Unlike the relapsed/refractory setting, there was a high rate of adverse events that may have been immunologically mediated, including tumor flare in 34% and rash in 66%. These observations should be taken seriously. “Nonchemotherapy” is not synonymous with “no side effects.” Long-term exposure to lenalidomide has been associated with increased risk of secondary cancers.25,26  Ibrutinib, which has limited long-term follow-up thus far, has been associated with opportunistic infections, bleeding, and atrial fibrillation.27-29  In phase 2 and 3 trials with ibrutinib in patients with MCL and CLL, roughly 10% of patients stopped ibrutinib because of adverse events.30,31  Unlike chemotherapy, which is administered for a finite period of time followed by a treatment-free interval, nonchemotherapy drugs are frequently given until progression or unacceptable toxicity, and the duration is likely to increase with earlier use. New methodologies for reporting the chronicity as well as the severity of adverse events will be needed.32 

Previously treated setting: combinations of chemotherapy with nonchemotherapy

Currently, the primary approval and most common use of all nonchemotherapy agents in MCL is in patients who have received prior therapy (Table 1). Both temsirolimus and lenalidomide were superior to investigators’ choice (primarily chemotherapy drugs that would not commonly be used as single agents in standard practice) in heavily pretreated patients.33,34 Table 3 describes several recent and ongoing studies evaluating nonchemotherapy agents in the previously treated setting. The addition of temsirolimus to bendamustine and rituximab resulted in an overall response rate of 88%, including 39% complete responses among 29 patients with previously treated MCL.35  The addition of lenalidomide to bendamustine and rituximab (the R2B regimen) yielded a median PFS of 20 months.36  In the absence of randomized data, it is difficult to know whether the apparent improvement in response outweighs the apparent increase in toxicity of these regimens. Interestingly, the rate of cutaneous reactions with the combination of lenalidomide and bendamustine appears to be significantly lower in the relapsed setting compared with the front-line setting, suggesting that context is as important as the treatment regimen itself.

Table 3.

Trials including nonchemotherapy agents in patients with previous MCL

Agents (Trial)Study designAdministrationNPrimary end pointSecondary end points
Temsirolimus, bendamustine, rituximab (BerT)35  Phase 1-2 Temsirolimus in doses from 25 to 75 mg added on days 1, 8, 15, bendamustine 90 mg/m2 day 1 + 2, and rituximab 375 mg/m2 day 1 q28 d 29 MCL Phase 1: temsirolimus 50 mg days 1, 8, 15 Median PFS, 33 mo 
Phase 2: ORR 92% 
Ibrutinib, bendamustine, ibrutinib16  Phase 1/1b Ibrutinib 280 mg or 560 mg daily, bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1, ×6 cycles 17 (including 5 previously untreated) MTD ibrutinib 560 mg daily ORR, 94%; CR, 76% 
Lenalidomide, bendamustine, rituximab (R2B)36  Phase 2 Induction: Lenalidomide 10 mg on days 1-14, bendamustine 70 mg/m2 on days 2 and 3, rituximab 375 mg/m2 on day 8 of cycle 1 and thereafter on day 1 q28 d ×4 cycles 42 CR, 55% Median PFS, 20 mo 
Consolidation: rituximab 375 mg/m2 on day 1, plus lenalidomide 15 mg daily on days 1-21 every 28 d 
Maintenance: Lenalidomide 15 mg daily on days 1-21 every 28 d for up to 18 cycles 
Lenalidomide, rituximab58  Phase 1-2 Rituximab 375 mg/m2 weekly ×4 plus 52 Phase 1: MTD lenalidomide 20 mg Median PFS, 11.1 mo 
Phase 1: escalating doses of lenalidomide days 1-21 Phase 2: ORR, 57% Median DoR, 18.9 mo 
Phase 2: lenalidomide 20 mg days 1-21 
Ibrutinib, rituximab38  Phase 2 Ibrutinib 560 mg daily, rituximab 375 mg/m2 weekly ×4 then day 1 of cycles 3-12 50 ORR, 88% CR, 44% 
Ibrutinib, lenalidomide, rituximab (PHELEMON)22  Phase 2 Lenalidomide 15 mg days 1-21, ibrutinib 560 mg daily, rituximab 375 mg/m2 days 1, 8, 15, 22 in cycle 1 then day 1 in cycles 3, 5, 7, 9, 11 for 12 cycles followed by ibrutinib 560 mg daily, rituximab 375 mg/m2 day 1 of each cycle until progression 50 ORR, 83% CR, 41% 
MRD, 7 of 12 in blood 
Ibrutinib, palbociclib43  Phase 1 Ibrutinib (escalating dose) daily, palbociclib (escalating dose) days 1-21 until progression 23 (preliminary) MTD ibrutinib 560 mg daily, palbociclib 100 mg days 1-21 ORR, 63%; CR, 41%; 1-y DoR, 100% 
Ibrutinib, venetoclax42  Phase 2 Ibrutinib 560 mg daily, venetoclax escalating doses (target 400 mg daily) 8 (preliminary) ORR, 4 of 5 evaluable  
Ibrutinib, venetoclax41  Phase 1/1b Ibrutinib escalating doses, venetoclax escalating doses 8 (preliminary) MTD: not yet reached  
Ibrutinib, venetoclax, obinutuzumab NCT Phase 1-2 Ibrutinib, obinutuzumab, venetoclax ∼33 MTD ORR; CR 
Agents (Trial)Study designAdministrationNPrimary end pointSecondary end points
Temsirolimus, bendamustine, rituximab (BerT)35  Phase 1-2 Temsirolimus in doses from 25 to 75 mg added on days 1, 8, 15, bendamustine 90 mg/m2 day 1 + 2, and rituximab 375 mg/m2 day 1 q28 d 29 MCL Phase 1: temsirolimus 50 mg days 1, 8, 15 Median PFS, 33 mo 
Phase 2: ORR 92% 
Ibrutinib, bendamustine, ibrutinib16  Phase 1/1b Ibrutinib 280 mg or 560 mg daily, bendamustine 90 mg/m2 days 1 + 2, rituximab 375 mg/m2 day 1, ×6 cycles 17 (including 5 previously untreated) MTD ibrutinib 560 mg daily ORR, 94%; CR, 76% 
Lenalidomide, bendamustine, rituximab (R2B)36  Phase 2 Induction: Lenalidomide 10 mg on days 1-14, bendamustine 70 mg/m2 on days 2 and 3, rituximab 375 mg/m2 on day 8 of cycle 1 and thereafter on day 1 q28 d ×4 cycles 42 CR, 55% Median PFS, 20 mo 
Consolidation: rituximab 375 mg/m2 on day 1, plus lenalidomide 15 mg daily on days 1-21 every 28 d 
Maintenance: Lenalidomide 15 mg daily on days 1-21 every 28 d for up to 18 cycles 
Lenalidomide, rituximab58  Phase 1-2 Rituximab 375 mg/m2 weekly ×4 plus 52 Phase 1: MTD lenalidomide 20 mg Median PFS, 11.1 mo 
Phase 1: escalating doses of lenalidomide days 1-21 Phase 2: ORR, 57% Median DoR, 18.9 mo 
Phase 2: lenalidomide 20 mg days 1-21 
Ibrutinib, rituximab38  Phase 2 Ibrutinib 560 mg daily, rituximab 375 mg/m2 weekly ×4 then day 1 of cycles 3-12 50 ORR, 88% CR, 44% 
Ibrutinib, lenalidomide, rituximab (PHELEMON)22  Phase 2 Lenalidomide 15 mg days 1-21, ibrutinib 560 mg daily, rituximab 375 mg/m2 days 1, 8, 15, 22 in cycle 1 then day 1 in cycles 3, 5, 7, 9, 11 for 12 cycles followed by ibrutinib 560 mg daily, rituximab 375 mg/m2 day 1 of each cycle until progression 50 ORR, 83% CR, 41% 
MRD, 7 of 12 in blood 
Ibrutinib, palbociclib43  Phase 1 Ibrutinib (escalating dose) daily, palbociclib (escalating dose) days 1-21 until progression 23 (preliminary) MTD ibrutinib 560 mg daily, palbociclib 100 mg days 1-21 ORR, 63%; CR, 41%; 1-y DoR, 100% 
Ibrutinib, venetoclax42  Phase 2 Ibrutinib 560 mg daily, venetoclax escalating doses (target 400 mg daily) 8 (preliminary) ORR, 4 of 5 evaluable  
Ibrutinib, venetoclax41  Phase 1/1b Ibrutinib escalating doses, venetoclax escalating doses 8 (preliminary) MTD: not yet reached  
Ibrutinib, venetoclax, obinutuzumab NCT Phase 1-2 Ibrutinib, obinutuzumab, venetoclax ∼33 MTD ORR; CR 

CR, complete response; DoR, duration of response; MRD, minimal residual disease; MTD, maximum tolerated dose; ORR, overall response rate; q28, every 28 days.

Previously treated setting: nonchemotherapy alone

With the possible exception of bendamustine (or bendamustine-based combinations), ibrutinib appears to have the highest response rate of all available options; it was significantly more effective and better tolerated than temsirolimus in a randomized phase 3 trial.37  Most patients currently receive bendamustine plus rituximab as front-line therapy in the United States, leaving ibrutinib as a de facto standard therapy in the relapsed/refractory setting. Despite its unprecedented single-agent activity, roughly one-third of patients do not respond to ibrutinib, and relapse appears to be universal, usually within the first 12 to 18 months. Depth of response and response duration can likely be improved by combining ibrutinib with rituximab, a regimen that yielded a 44% complete response rate with an apparent improvement in response duration in a single-center phase 2 trial.38  As is the case with chemotherapy/nonchemotherapy combinations, rational combinations of nonchemotherapy drugs with the potential for synergy, not just additive benefit, are particularly interesting, and preclinical data for several such ibrutinib-based regimens have been reported.39,40  Preliminary data from combination studies with lenalidomide/rituximab (the Nordic MCL6 PHILEMON study),22  the bcl2 inhibitor venetoclax,41,42  and the cdk4/6 inhibitor palbociclib43  all suggest that combinations are feasible. Among 50 patients treated on the PHILEMON study, 83% responded, including 41% with a complete response. Unlike the front-line setting in follicular lymphoma, where the same regimen resulted in grade 3-4 rash in 36%, only 10% of previously treated MCL patients developed grade 3 rash, consistent with the hypothesis that immune-mediated effects are more common in the front-line setting. Among 8 patients treated in the ibrutinib plus venetoclax (AIM) trial, 5 achieved a complete response with eradication of minimal residual disease and only 1 did not respond; promising responses have been observed in a second study of the same regimen.41  The OAsIs trial will evaluate the combination of ibrutinib, venetoclax, and obinutuzumab (NCT02558816). The combination of ibrutinib and palbociclib has been evaluated in 23 patients so far in a multicenter phase 1 trial.43  Grade 3 rash was experienced in 2 patients at the highest dose level and was considered dose limiting. The overall response rate was 64%, including 43% complete responses, and the estimated response duration at 1 year was 90%; that is, only 1 of 13 responding patients experienced progression. Notably, although these combinations have produced impressive results, not 1 appears to completely overcome ibrutinib resistance and none have reported identification of a biomarker to help target patients to the right therapy. Additionally, with small numbers, it is possible that patient selection is partially responsible for the apparent improvement. More work will be required to determine which patients are best treated by single-agent ibrutinib, a specific combination, or a nonibrutinib approach. These and other studies set the stage for a promising future, but it is worth noting that development of novel combinations may be negatively impacted by the widespread reliance on single-agent ibrutinib and the possible adoption of nonrational ibrutinib plus chemotherapy combinations in the front-line setting. Ideally, rational combinations will be based on cutting-edge science produced by laboratories around the world, but it is naive to believe that the complexity of MCL could be completely recreated in a laboratory environment. There is an urgent need for small, rapid combination studies with carefully designed, longitudinal laboratory correlates.

As ibrutinib and ibrutinib-based combinations become more widely used, an important emerging question is how best to treat patients who experience ibrutinib failure. Retrospectively collected data from a group of high-risk patients who had progressed while receiving ibrutinib suggested that outcomes were poor, although it was unclear whether that was due to the fact that most patients were heavily pretreated and tended to have short responses to ibrutinib, or whether ibrutinib might somehow promote the growth of more aggressive subclones.44  More importantly, the study failed to identify a specific treatment that might be most likely to produce responses following ibrutinib failure. A small, retrospective series evaluated responses to lenalidomide and lenalidomide-based combinations following ibrutinib failure and suggested that there was activity, albeit of short duration, in a sizeable minority of patients.23  As more effective ibrutinib combinations are developed, it is likely that patients who experience treatment failure will have even more aggressive disease courses, and the question of how to treat these patients will become more acute.

Allogeneic stem cell transplantation

Allotransplant has been reported to cure roughly 30% of patients with previously treated MCL in retrospective series.45-47  Despite its curative potential, allotransplant relies on donor availability, fails in most cases, and is associated with significant treatment-related morbidity and mortality, limiting its use to patients without significant comorbidities. Allotransplant should be considered in patients felt to be at high risk of treatment failure with few acceptable alternatives. Unfortunately, it is not always easy to identify these patients at a time when allotransplant might be most successful.

Chimeric antigen receptor–T cells

Although chimeric antigen receptor (CAR)-T cells have demonstrated activity in MCL,48,49  their future is still relatively unknown. In theory, MCL is the ideal setting for the implementation of CAR-T-cell therapies: it is incurable with a relatively short survival compared with other incurable lymphomas, but remissions of sufficient depth and duration can be obtained in most patients, allowing for manufacturing and administration of CAR-T cells. Possible exceptions include patients with chemorefractory MCL who experience explosive progression on ibrutinib, but hopefully this will change as we get better at predicting ibrutinib resistance and as we develop strategies to cope, at least transiently, with ibrutinib failure. That said, we already have an effective cellular/immunotherapy in MCL: allogeneic stem cell transplantation. In order for CAR-T cells to be more widely adopted in MCL, they will have to demonstrate either an ability to safely induce responses in patients who would not be eligible for allotransplant due to comorbid conditions or rapidly progressing disease, or they will need to be associated with a relatively superior efficacy and tolerability profile, that is, inducing durable remissions in at least a third of patients based on an intent-to-treat analysis with a treatment-related mortality of <15% to 20%. Additionally, the toxicities associated with CAR-T cells at present, including neurologic issues related to cytokine release syndrome, may limit applicability to MCL patients who are frequently older and have comorbid conditions.

Other immunotherapies

Existing data with immune checkpoint inhibitors in MCL are limited and unimpressive to date. In published trials that included MCL, there have been no reported responses.50  Reasons for resistance are likely multiple but may include limited expression of programmed death ligand 1 on MCL cells or tumor-derived immunosuppression. Nonetheless, given the remarkable promise these therapies have demonstrated in other cancers, it would be unfortunate to abandon further investigation at this early stage.

Vaccines have long been held out as a promising, if somewhat fantastic, strategy in B-cell lymphomas given the existence of a tumor-specific idiotype, but phase 3 trials in follicular lymphoma were mostly disappointing.51-53  Recently, T cells capable of recognizing tumor peptides derived from the idiotype and presented on the tumor cell major histocompatibility complex have been described, sparking renewed interest in vaccines.54  Perhaps the development of immune checkpoint inhibitors will prove serendipitous to the new generation of vaccine scientists.

Bendamustine or cytarabine-based therapies are clearly active in MCL. At a time when the novelty of chemotherapy has eroded, several recently published clinical trials have demonstrated the surprising activity of chemotherapy-based regimens, and we should not be too eager to discount these “old-fashioned” treatments. Unfortunately, no chemotherapy regimens have produced cures and the contributions of novel chemotherapeutic agents to improving survival rates is unclear. Thus far, no chemotherapy regimens have demonstrated any sign of overcoming the risks associated with highly proliferative and TP53-mutated/deleted tumors, and all chemotherapy regimens are associated with significant acute and cumulative toxicities.

The addition of nonchemotherapy to standard chemotherapy regimens has already demonstrated an ability to improve outcomes, and more studies are ongoing. Moreover, early results from trials testing regimens that consist of nonchemotherapy agents alone have suggested that the strategy may have some advantages. Patients with previously treated MCL are already standardly receiving nonchemotherapy. Despite the apparent progress of nonchemotherapy-based treatments, several challenges remain. Nonchemotherapy agents have distinctive toxicities, particularly when combined with chemotherapy or other agents with novel mechanisms of action. The duration of therapy, and therefore duration of toxicity, is clearly a factor that may impact quality of life. Importantly, the price of new drugs has real-world implications with respect to accessibility and sustainability. It remains unclear whether existing nonchemotherapy agents can overcome the highly proliferative, TP53-mutated lymphomas that are most in need of new drugs. Finally, patients who are refractory to novel agents like ibrutinib appear to have especially poor outcomes. Rational combinations are poised to improve duration of response to novel agents but it remains to be seen whether the differences will be synergistic vs additive and whether the benefits will outweigh the risks. CAR-T cells are attractive but may not be feasible in patients whose disease cannot be stabilized for a sufficient duration of time to produce and administer the treatment.

Currently, our approach is to prioritize clinical trials with nonchemotherapy agents and embedded correlative studies that include putative biomarkers for risk stratification. Existing data are either too limited or unconvincing to make recommendations regarding standard practice. Outside of clinical trials and the VR-CAP regimen (which we do not use), current data do not support the use of nonchemotherapy agents (other than rituximab) either alone or in combination with chemotherapy in the front-line setting, except for a small number of patients with TP53-mutated, leukemic, nonnodal MCL who we have treated with lenalidomide-rituximab. We expect that the evolving appreciation for the heterogeneous biology of MCL and the mechanisms of action of various novel agents are critical to the interpretation of ongoing trials and the design of future studies that incorporate nonchemotherapy agents. Our goal should be to cure MCL with treatments that are broadly available. To achieve that aim, we will need rational combinations of new drugs, regardless of how we call them.

Contribution: P.M., J.R., and J.P.L. coauthored the paper.

Conflict-of-interest disclosure: P.M. has consulted for Janssen, Pharmacyclics, AstraZeneca, Celgene, Gilead, Bayer, Novartis, KiTE, and Verastem. J.R. has consulted for Celgene. J.P.L. has consulted for Celgene, Genentech, Gilead, and Bayer.

Correspondence: Peter Martin, Weill Cornell Medicine, 525 East 68th St, New York, NY 10065; e-mail: pem9019@med.cornell.edu.

1.
Hoster
E
,
Rosenwald
A
,
Berger
F
, et al
.
Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network
.
J Clin Oncol
.
2016
;
34
(
12
):
1386
-
1394
.
2.
Nordström
L
,
Sernbo
S
,
Eden
P
, et al
.
SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma--a Nordic Lymphoma Group study
.
Br J Haematol
.
2014
;
166
(
1
):
98
-
108
.
3.
Abrahamsson
A
,
Albertsson-Lindblad
A
,
Brown
PN
, et al
.
Real world data on primary treatment for mantle cell lymphoma: a Nordic Lymphoma Group observational study
.
Blood
.
2014
;
124
(
8
):
1288
-
1295
.
4.
Leux
C
,
Maynadié
M
,
Troussard
X
, et al
.
Mantle cell lymphoma epidemiology: a population-based study in France
.
Ann Hematol
.
2014
;
93
(
8
):
1327
-
1333
.
5.
Patmore
R
,
Smith
A
,
Appleton
S
, et al
.
Mantle cell lymphoma management and outcome in the U.K’s population-based Haematological Malignancy Research Network [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 1112.
6.
Hermine
O
,
Hoster
E
,
Walewski
J
, et al
;
European Mantle Cell Lymphoma Network
.
Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network
.
Lancet
.
2016
;
388
(
10044
):
565
-
575
.
7.
Smith
MR
,
Hong
F
,
Li
H
, et al
.
Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Y-ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499
.
Leukemia
.
2017
;
31
(
2
):
517
-
519
.
8.
Rummel
M
,
Maschmeyer
G
,
Ganser
A
, et al
.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study [abstract]
.
J Clin Oncol
.
2017
;35(suppl 15). Abstract 7501.
9.
Proietti
E
,
Greco
G
,
Garrone
B
, et al
.
Importance of cyclophosphamide-induced bystander effect on T cells for a successful tumor eradication in response to adoptive immunotherapy in mice
.
J Clin Invest
.
1998
;
101
(
2
):
429
-
441
.
10.
Obeid
M
,
Tesniere
A
,
Ghiringhelli
F
, et al
.
Calreticulin exposure dictates the immunogenicity of cancer cell death
.
Nat Med
.
2007
;
13
(
1
):
54
-
61
.
11.
Ruan
J
,
Martin
P
,
Coleman
M
, et al
.
Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma
.
Cancer
.
2010
;
116
(
11
):
2655
-
2664
.
12.
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
(
6
):
690
-
697
.
13.
Chang
JE
,
Li
H
,
Smith
MR
, et al
.
Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405)
.
Blood
.
2014
;
123
(
11
):
1665
-
1673
.
14.
Robak
T
,
Huang
H
,
Jin
J
, et al
;
LYM-3002 Investigators
.
Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma
.
N Engl J Med
.
2015
;
372
(
10
):
944
-
953
.
15.
Albertsson-Lindblad
A
,
Kolstad
A
,
Laurell
A
, et al
.
Lenalidomide-bendamustine-rituximab in patients older than 65 years with untreated mantle cell lymphoma
.
Blood
.
2016
;
128
(
14
):
1814
-
1820
.
16.
Maddocks
K
,
Christian
B
,
Jaglowski
S
, et al
.
A phase 1/1b study of rituximab, bendamustine, and ibrutinib in patients with untreated and relapsed/refractory non-Hodgkin lymphoma
.
Blood
.
2015
;
125
(
2
):
242
-
248
.
17.
Rule
S
,
Dreyling
M
,
Hess
G
, et al
. Overall survival outcomes in patients with mantle-cell lymphoma (MCL) treated with ibrutinib in a pooled analysis of 370 patients from 3 international open-label studies. In: 21st Congress of the European Hematology Association; 11 June 2016; Copenhagen, Denmark. Abstract S438.
18.
Chanan-Khan
A
,
Cramer
P
,
Demirkan
F
, et al
;
HELIOS investigators
.
Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study
.
Lancet Oncol
.
2016
;
17
(
2
):
200
-
211
.
19.
Eskelund
CW
,
Hansen
JW
,
Westman
MK
, et al
.
Targeted sequencing of diagnostic samples correlated to clinical outcome: data from the Nordic Mantle Cell Lymphoma (MCL2 and MCL3) studies with long-term follow-up [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 1095.
20.
Rossi
D
,
Ferrero
S
,
Bruscaggin
A
, et al
.
A molecular model for the prediction of progression free survival in young mantle cell lymphoma patients treated with cytarabine-based high dose sequential chemotherapy and autologous stem cell transplantation: results from the MCL0208 phase III trial from Fondazione Italiana Linfomi (FIL) [abstract]
.
Blood
.
2015
;
126
(
23
). Abstract 336.
21.
Cohen
JB
,
Ruppert
AS
,
Heerema
NA
, et al
.
Complex karyotype is associated with aggressive disease and shortened progression-free survival in patients with newly diagnosed mantle cell lymphoma
.
Clin Lymphoma Myeloma Leuk
.
2015
;
15
(
5
):
278
-
285.e1
.
22.
Jerkeman
M
,
Hutchings
M
,
Räty
R
, et al
.
Ibrutinib-lenalidomide-rituximab in patients with relapsed/refractory mantle cell lymphoma: first results from the Nordic Lymphoma Group MCL6 (PHILEMON) phase II trial [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 148.
23.
Wang
M
,
Lee
HJ
,
Thirumurthi
S
, et al
.
Chemotherapy-free induction with ibrutinib-rituximab followed by shortened cycles of chemo-immunotherapy consolidation in young, newly diagnosed mantle cell lymphoma patients: a phase II clinical trial [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 147.
24.
Ruan
J
,
Martin
P
,
Shah
B
, et al
.
Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma
.
N Engl J Med
.
2015
;
373
(
19
):
1835
-
1844
.
25.
Jones
JR
,
Cairns
DA
,
Gregory
WM
, et al
.
Second malignancies in the context of lenalidomide treatment: an analysis of 2732 myeloma patients enrolled to the Myeloma XI trial
.
Blood Cancer J
.
2016
;
6
(
12
):
e506
.
26.
Palumbo
A
,
Bringhen
S
,
Kumar
SK
, et al
.
Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data
.
Lancet Oncol
.
2014
;
15
(
3
):
333
-
342
.
27.
Arthurs
B
,
Wunderle
K
,
Hsu
M
,
Kim
S
.
Invasive aspergillosis related to ibrutinib therapy for chronic lymphocytic leukemia
.
Respir Med Case Rep
.
2017
;
21
:
27
-
29
.
28.
Leong
DP
,
Caron
F
,
Hillis
C
, et al
.
The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis
.
Blood
.
2016
;
128
(
1
):
138
-
140
.
29.
Caron
F
,
Leong
DP
,
Hillis
C
,
Fraser
G
,
Siegal
D
.
Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis
.
Blood Adv
.
2017
;
1
(
12
):
772
.
30.
Wang
ML
,
Blum
KA
,
Martin
P
, et al
.
Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results
.
Blood
.
2015
;
126
(
6
):
739
-
745
.
31.
Byrd
JC
,
Furman
RR
,
Coutre
SE
, et al
.
Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib
.
Blood
.
2015
;
125
(
16
):
2497
-
2506
.
32.
Thanarajasingam
G
,
Hubbard
JM
,
Sloan
JA
,
Grothey
A
.
The imperative for a new approach to toxicity analysis in oncology clinical trials
.
J Natl Cancer Inst
.
2015
;
107
(
10
).
33.
Hess
G
,
Herbrecht
R
,
Romaguera
J
, et al
.
Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma
.
J Clin Oncol
.
2009
;
27
(
23
):
3822
-
3829
.
34.
Trněný
M
,
Lamy
T
,
Walewski
J
, et al
;
SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network
.
Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial
.
Lancet Oncol
.
2016
;
17
(
3
):
319
-
331
.
35.
Hess
G
,
Karola
W
,
LaRosee
P
, et al
.
Temsirolimus in combination with bendamustine and rituximab (BeRT) for the treatment of relapsed mantle cell and follicular lymphoma: final phase I/II results [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 2977.
36.
Zaja
F
,
Ferrero
S
,
Stelitano
C
, et al
.
Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi
.
Haematologica
.
2017
;
102
(
5
):
e203
-
e206
.
37.
Dreyling
M
,
Jurczak
W
,
Jerkeman
M
, et al
.
Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study
.
Lancet
.
2016
;
387
(
10020
):
770
-
778
.
38.
Wang
ML
,
Lee
H
,
Chuang
H
, et al
.
Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial
.
Lancet Oncol
.
2016
;
17
(
1
):
48
-
56
.
39.
Chiron
D
,
Di Liberto
M
,
Martin
P
, et al
. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4(9):1022-1035.
40.
Pham
L
,
Zhang
L
,
Tao
W
, et al
.
Developing novel therapeutic strategies to overcome ibrutinib resistance in mantle cell lymphoma [abstract]
.
Blood
.
2015
;
126
(
23
). Abstract 707.
41.
Portell
CA
,
Chen
RW
,
Wages
N
, et al
.
Initial report of a multi-institution phase I/Ib study of ibrutinib with venetoclax in relapsed or refractory mantle cell lymphoma [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 2958.
42.
Tam
C
,
Roberts
A
,
Anderson
M
, et al
.
The combination of ibrutinib and venetoclax (ABT-199) to achieve complete remissions in patients with relapsed/refractory mantle cell lymphoma: preliminary results of the phase II AIM study [abstract]
.
J Clin Oncol
.
2016
;34(suppl 15). Abstract 7548.
43.
Martin
P
,
Blum
K
,
Bartlett
NL
, et al
.
A phase I trial of ibrutinib plus palbociclib in patients with previously treated mantle cell lymphoma [abstract]
.
Blood
.
2016
;
128
(
22
). Abstract 150.
44.
Martin
P
,
Maddocks
K
,
Leonard
JP
, et al
.
Postibrutinib outcomes in patients with mantle cell lymphoma
.
Blood
.
2016
;127(12):1559-1563.
45.
Tessoulin
B
,
Ceballos
P
,
Chevallier
P
, et al
.
Allogeneic stem cell transplantation for patients with mantle cell lymphoma who failed autologous stem cell transplantation: a national survey of the SFGM-TC
.
Bone Marrow Transplant
.
2016
;
51
(
9
):
1184
-
1190
.
46.
Fenske
TS
,
Zhang
M-J
,
Carreras
J
, et al
.
Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality
.
J Clin Oncol
.
2014
;
32
(
4
):
273
-
281
.
47.
Krüger
WH
,
Hirt
C
,
Basara
N
, et al
.
Allogeneic stem cell transplantation for mantle cell lymphoma--final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO)
.
Ann Hematol
.
2014
;
93
(
9
):
1587
-
1597
.
48.
Kochenderfer
JN
,
Somerville
RPT
,
Lu
T
, et al
.
Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels
.
J Clin Oncol
.
2017
;
35
(
16
):
1803
-
1813
.
49.
Turtle
CJ
,
Hanafi
LA
,
Berger
C
, et al
.
Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells
.
Sci Transl Med
.
2016
;
8
(
355
):
355ra116
.
50.
Lesokhin
AM
,
Ansell
SM
,
Armand
P
, et al
.
Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study
.
J Clin Oncol
.
2016
;
34
(
23
):
2698
-
2704
.
51.
Levy
R
,
Ganjoo
KN
,
Leonard
JP
, et al
.
Active idiotypic vaccination versus control immunotherapy for follicular lymphoma
.
J Clin Oncol
.
2014
;
32
(
17
):
1797
-
1803
.
52.
Freedman
A
,
Neelapu
SS
,
Nichols
C
, et al
.
Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma
.
J Clin Oncol
.
2009
;
27
(
18
):
3036
-
3043
.
53.
Schuster
SJ
,
Neelapu
SS
,
Gause
BL
, et al
.
Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: phase III clinical trial results [abstract]
.
J Clin Oncol
.
2009
;
27
(suppl 18). Abstract 2.
54.
Khodadoust
MS
,
Olsson
N
,
Wagar
LE
, et al
.
Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens
.
Nature
.
2017
;
543
(
7647
):
723
-
727
.
55.
Fisher
RI
,
Bernstein
SH
,
Kahl
BS
, et al
.
Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma
.
J Clin Oncol
.
2006
;
24
(
30
):
4867
-
4874
.
56.
Wang
ML
,
Rule
S
,
Martin
P
, et al
.
Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma
.
N Engl J Med
.
2013
;
369
(
6
):
507
-
516
.
57.
Goy
A
,
Sinha
R
,
Williams
ME
, et al
.
Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study
.
J Clin Oncol
.
2013
;
31
(
29
):
3688
-
3695
.
58.
Wang
M
,
Fayad
L
,
Wagner-Bartak
N
, et al
.
Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial
.
Lancet Oncol
.
2012
;
13
(
7
):
716
-
723
.

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