Current and emerging treatment options for mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma with typically aggressive behavior. The genetic signature is the chromosomal translocation t(11;14)(q13;q32) resulting in overexpression of cyclin D1. Asymptomatic newly diagnosed MCL patients with low tumor burden can be closely observed, deferring therapy to the time of disease progression. Although MCL classically responds to upfront chemotherapy, it remains incurable with standard approaches. For patients in need of frontline therapy, the initial decision is whether to proceed with an intensive treatment strategy or a non-intensive treatment strategy. In general, given the unfavorable risk–benefit profile, older MCL patients should be spared intensive strategies, while younger and fit patients can be considered for intensive strategies. The bendamustine and rituximab (BR) regimen is becoming an increasingly popular treatment option among the elderly population, with improved progression-free survival (PFS) and acceptable side-effect profile. Although rituximab maintenance after R-CHOP improves survival outcomes in elderly patients, no clinical trial to date has shown statistical significance to support the use of rituximab maintenance after BR induction in older patients. In young and fit patients with MCL, an intensive strategy to maximize the length of first remission has emerged as a worldwide standard of care. With current high-dose cytarabine-containing immunochemotherapy regimens followed by autologous stem cell transplantation, the median PFS has exceeded 7 years. In the relapsed or refractory (R/R) setting, reduced intensity conditioning allogeneic hematopoietic stem cell transplantation may offer the highest likelihood of long-term survival in young R/R MCL patients, at the cost of increased risk of non-relapse mortality and chronic graft versus host disease. Novel agents targeting activated pathways in MCL cells, such as bortezomib, lenalidamide, ibrutinib and temsirolimus are now available for the management of R/R disease.

Introduction

Mantle cell lymphoma (MCL) comprises approximately 7% of all non-Hodgkin lymphoma (NHL) cases.^1–3 The median age at diagnosis is 68, with a 3:1 male predilection.^1–3 MCL has typically been considered an aggressive and incurable B-cell lymphoma. The 2016 WHO Classification of lymphoid malignancies has recognized two separate types of MCL:

• classical MCL, usually composed of IGHV-unmutated B-cells, and SOX11 expression;⁴ the classical variant of MCL has a tendency to involve lymph nodes and extranodal sites;

• leukemic non-nodal MCL, generally composed of IGHV-mutated genes without SOX11 expression. The leukemic non-nodal variant typically involves the bone marrow, peripheral blood and spleen, and mostly has an indolent presentation.⁴

Multiple studies in the past decade have elucidated the wide range of biological events contributing to MCL pathogenesis. The recognition of the translocation t(11;14)(q13;q32) resulting in cyclin D1 (CCND1) overexpression was an evolutionary event in improving our understanding of the clinical and biological diversity of this tumor.^5,6 In addition to CCND1 overexpression causing deregulation of the cell cycle at the G1/S phase transition, other mechanisms such as DNA damage response alterations (CHK1 and CHK2),⁶ and activation of cell survival pathways, such as overexpression of antiapoptotic genes (BCL2)⁷ are other known pathways described in MCL pathogenesis.⁸

In terms of clinical manifestations, one-third of MCL patients present with high levels of lactate dehydrogenase (LDH), 25% of patients present with B symptoms, and less than 5% of patients have CNS involvement at some point throughout their course of disease.^9–11

In this article we review the clinical and biologic risk factors that are currently applied in risk stratification of MCL, discuss the optimal initial therapeutic options in young/fit and elderly treatment-naïve patients, outline viable treatment choices in the relapsed or refractory (R/R) setting and summarize the current literature supporting novel agents and strategies.

Identification of clinical and biologic risk factors in MCL

In 2008, Hoster and colleagues reviewed data from 455 advanced-stage MCL patients treated within three clinical trials, and developed the MCL international prognostic index (MIPI) of overall survival (OS). The MIPI score was created based on four independent prognostic factors including age, performance status, LDH and leukocyte count. According to the MIPI score, patients were categorized into low risk [44% of patients, MIPI score <5.7, median OS not reached (NR)], intermediate risk (35%, 5.7 ⩽ MIPI score ⩽ 6.1, median OS 51 months) and high-risk groups (21%, score ⩾ 6.2, median OS 29 months). Hoster and colleagues also explored the prognostic relevance of cell proliferation index (Ki-67), and demonstrated that it is an important biologic marker with added prognostic value.¹²

Additional work from Sarkozy and colleagues studied the prognostic role of genetic abnormalities in addition to t(11;14)(q13;q32). A high MIPI score, a complex karyotype – defined as ⩾3 additional abnormalities, and blastoid morphology were shown to be independently associated with worse survival outcomes. A score based on these factors allowed for the separation of ‘indolent’ patients [median treatment-free survival (TFS) 107 months] from other patients (median TFS 1 month).¹³

In a concerted effort to combine clinical and biologic prognostic factors, the European MCL Network used the cohort from the European MCL Younger and MCL Elderly trials to evaluate the additional prognostic impact of cytology and growth pattern to improve risk stratification with the Ki-67 index and MIPI. In the combined cohort, blastoid cytology was associated with inferior OS independent of MIPI, but not independent of the Ki-67 index. Growth pattern did not prove to be an independent prognostic factor. These results revealed a superior prognostic value for the Ki-67 index compared to cytology and growth pattern in MCL. This study also confirmed the prognostic value of the previously validated 30% cutoff for the Ki-67 index.¹² The combination of the Ki-67 index and MIPI score separated four groups of patients: low risk (32% of patients, 5-year OS 85%), low intermediate risk (34%, 5-year OS 72%), high intermediate risk (23%, 5-year OS 43%) and high risk (11%, 5-year OS 17%).¹⁴

The modified combined Ki-67 index and MIPI score has been increasingly applied in clinical practice. This refined risk stratification system has facilitated the interpretation of the results of single-arm studies, and alongside the clinical context inform treatment decisions in patients with MCL.

Management of treatment-naïve MCL patients

Some newly diagnosed MCL patients can be diligently observed, deferring therapy to a later date. Asymptomatic, low tumor burden patients are candidates for this strategy. Martin and colleagues studied the outcomes of deferred initial therapy in 97 patients with MCL in a retrospective analysis. Thirty-one of 97 patients (32%) were observed for 3+ months before initial systemic therapy, with median time to treatment of 12 months (range 4–128 months). The observation group had better performance status and lower MIPI scores compared to the treatment group. At a median follow up of 55 months, the survival outcomes of the observation group were statistically superior to those of the early treatment group (NR versus 64 months, p = 0.004).¹⁵ These results indicate that a proportion of newly diagnosed MCL patients may follow a more indolent course, and are candidates for close monitoring and deferred therapy.

For patients in need of frontline therapy, the initial decision is whether to pursue an intensive treatment strategy or a non-intensive treatment strategy. MIPI score by itself infrequently influences clinical decision-making, as young patients tend to have low MIPI scores whereas elderly patients are more likely to have high MIPI scores. In general, older MCL patients should be spared intensive strategies as the risk–benefit profile is not favorable, while younger, fit patients can be considered for intensive strategies. While there is no firm rule regarding what constitutes older and younger, many of the European studies have used an age cutoff of 65.

Management of older MCL patients

Induction strategies for elderly MCL patients

The University of Texas M. D. Anderson Cancer Center experience using R-hyper-CVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) alternating with high-dose methotrexate/cytarabine (R-MTX/Ara-C) in 97 patients with de novo MCL showed an overall response rate (ORR) of 97% [complete response (CR)/unconfirmed CR (CRu) rate, 87%]. The median failure-free survival (FFS) was 3 years in patients aged >65 years (n = 32) versus 5.5 years in patients aged ⩽65 years (n = 65), highlighting the inferior results obtained in the older patients.¹⁶ Another group investigating intensive strategies for older MCL patients reported the outcomes for 38 patients with MCL aged ⩾60 years who received R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone) (n = 19) or R-HyperCVAD (n = 19) with or without autologous stem cell transplantation (ASCT). After a median length of follow up of 2.7 years, the median progression-free survival (PFS) of R-CHOP + ASCT was 3.2 years versus 4 years in R-HyperCVAD alone. Both strategies provided longer PFS than that of R-CHOP alone, 1.6 years. Compared with R-CHOP alone, R-HyperCVAD induction resulted in an increased incidence of toxicity, including treatment discontinuation and transfusion requirement, although rates of adverse events were similar for R-HyperCVAD alone and R-CHOP + ASCT. These results showed R-CHOP alone is a less adequate strategy for fit older patients with MCL. Intensifying therapy with R-HyperCVAD induction or R-CHOP followed by ASCT consolidation is associated with prolonged PFS and similar rates of toxicity.¹⁷ While these two groups demonstrated that intensive strategies are superior to historical outcomes realized with R-CHOP, newer approaches appear to produce outcomes similar to intensive strategies and with substantially less toxicity.

For example, Robak and colleagues investigated whether replacing vincristine in R-CHOP by bortezomib in frontline therapy could improve outcomes in patients with newly diagnosed MCL who were transplant ineligible. In this phase III trial, 487 patients were randomly assigned to receive 6–8 cycles of R-CHOP (n = 244) or VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) (n = 243). At a median follow up of 40 months, the median PFS was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group. This study showed superior outcomes for VR-CAP compared to R-CHOP at the cost of increased hematologic toxicity.¹⁸

Bendamustine–rituximab (BR) has been shown to be an effective induction strategy in older MCL patients. Rummel and colleagues conducted a prospective, multicenter, randomized trial to compare BR with R-CHOP as first-line treatment for patients with indolent and mantle cell lymphomas. Of a total of 549 patients, 94 (17%) carried a diagnosis of MCL. Of these 94 patients, 46 were assigned to the BR arm and the remaining 48 were assigned to the R-CHOP arm. The median age in both groups was 70. At a median follow up of 45 months, the median PFS was 35.4 months in the BR group versus 22.1 months in the R-CHOP group. Increased PFS, along with an acceptable side-effect profile, has made the BR regimen a popular first-line treatment option in treatment-naïve older MCL patients.¹⁹

To further improve the BR outcomes in the elderly patient population, an Italian group conducted a phase II study, combining cytarabine with rituximab and bendamustine (R-BAC) in treatment-naïve or R/R MCL patients older than 65 years of age. The maximum tolerated dose (MTD) for cytarabine in stage one of this phase II study was determined to be 800 mg/m². The ORR and 2-year PFS rate were 100% and 95% for previously untreated and 80% and 70% for R/R patients respectively.²⁰ To reduce the hematologic toxicity associated with the R-BAC800 regimen, the same group later performed another phase II study to investigate the efficacy and side-effect profile of the R-BAC500 regimen (cytarabine 500 mg/m²). The results in 57 patients enrolled in this phase II study were reported at the 2016 American Society of Hematology (ASH) annual meeting, and indicated a significant improvement in hematologic toxicity without compromising survival outcomes.²¹

Another innovative phase II study explored the combination of rituximab and lenalidomide (R² regimen) with induction and maintenance phases. The median age of 38 enrolled patients was 65 years. At the median follow up of 30 months, the ORR was reported to be 92%, with a CR rate of 64%. Median PFS was not reached. The 2-year PFS was estimated to be 85%, and the 2-year OS 97%.²² Although this combination biologic therapy provided a promising early signal, longer follow up and confirmation in a larger cohort is needed before this strategy can be endorsed.

In summary, based on the Stil trial,¹⁹ the BR regimen appears to be superior in terms of significant improvement in PFS in conjunction with a more tolerable side-effect profile. VR-CAP is a reasonable treatment strategy if bendamustine is not a viable option. Ongoing trials (SHINE and E1411) are testing novel agents (Shine – ibrutinib; E1411 – bortezomib) onto a BR backbone to determine if outcomes can be further improved in the elderly patient population with MCL.

Table 1 offers a summary.

Table 1.

The summary of induction strategies in treatment-naïve elderly patient population.

Author, year, study	Regimen	Patient Population	PFS	OS
Fayad and colleagues,16 phase III	R-hyperCVAD with alternating R-MTX/Ara-C	>65; (n = 32)	mFFS: 3 years	N/A
Frosch and colleagues,17 retrospective	R-CHOP	Median age 65 (61–74); (n = 5)	1.6 years	No difference among four groups
	R-CHOP+ASCT	Median age 65 (61–74); (n = 14)	3.2 years
	R-HyperCVAD	Median age 65 (61–70); (n = 12)	4 years
	R-HyperCVAD+ASCT	Median age 65 (61–70); (n = 7)	0.9 years
Robak and colleagues,18 phase III	R-CHOP	Median age 66 (34–82); (n = 244)	14.4 months (95% CI; 12–16.9)	56.3 months
	VR-CAP	Median age 65 (26–85); (n = 243)	24.7 months (95% CI; 19.8–31.8)	NR
Rummel and colleagues,19 phase III	R-CHOP	Median age 70 (IQR 64·5–74); (n = 48)	22.1 months (IQR 15.1–33.8)	NR
	BR	Median age 70 (IQR 64·5–74); (n = 46)	35.4 months (IQR 28.8–54.9)
Visco and colleagues,20 phase II	R-BAC800	Median age 70 (54–82); (n = 40)	2-year PFS 95% for untreated patients and 70% for R/R patients.	At a median follow up of 26 months, 78% (31/40)
Visco and colleagues,21 phase II	R-BAC500	Median age 71 (61–79); (n = 57)	2-year PFS 81% (95% CI; 76–86)	2-year OS 85% (95% CI; 81–89)
Ruan and colleagues,22 phase II	R2	Median age 65 (42–86); (n = 38)	NR Estimated 2-year PFS: 85% (95% CI; 67–94)	Estimated 2-year OS 97% (95% CI; 79–99)

ASCT, autologous stem cell transplantation; BR, bendamustine, rituximab; CI, confidence interval; mFFS, median failure-free survival; IQR, interquartile range; N/A, not available; NR, not reached; OS, overall survival; PFS, progression-free survival; R², rituximab, lenalidomide; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-HyperCVAD, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R-MTX/Ara-C, high-dose methotrexate/cytarabine; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone.

Maintenance strategies for elderly MCL patients

Given the high response rates, but relatively brief remission duration to induction therapy, the notion of maintenance therapy has intuitive appeal in MCL. Multiple studies have explored the role of maintenance strategies upon the conclusion of induction therapy to improve the outcomes of older patients with MCL.

The European MCL Network conducted a study to compare rituximab, fludarabine and cyclophosphamide (R-FC) to R-CHOP. Patients who achieved a response underwent a second randomization to maintenance therapy with rituximab or interferon alpha, each continued until disease progression. This study enrolled 560 patients with a median age of 70 years. Mainly due to excess toxicity, the OS was significantly shorter with R-FC compared to R-CHOP, 4-year OS 47% versus 62% (p = 0.005), respectively. In total, 316 patients who responded to induction chemotherapy were randomly assigned to either rituximab maintenance (n = 155) or interferon alpha (n = 161). At a median follow up of 36 months, the median duration of remission (mDOR) was 23 months in the interferon alpha arm, while it was not reached in the rituximab maintenance arm. At a median follow up of 42 months, the median OS was 64 months in the interferon alpha group, whereas it was not reached in the rituximab maintenance group. These results indicated rituximab maintenance following R-CHOP induction regimen can improve response duration and potentially OS.²³

Based upon the promising results noted in the Stil trial, BR is growing as an increasingly popular induction strategy in the elderly MCL patients. To further improve the survival outcomes of BR induction, Rummel and colleagues investigated the role of rituximab maintenance versus observation after first-line treatment with BR in patients with previously untreated MCL. Following BR induction, responders to BR regimen were then randomized to either rituximab maintenance (375 mg/m² every 2 months for a total of 2 years) or observation only. Of 120 patients, 59 (49%) were randomized to rituximab maintenance and 61 (51%) to observation. Median patient age was 70 years. At a median follow up of 54.2 months, the median PFS was 54.7 in the observation arm, but not yet reached in the rituximab maintenance arm. The difference in PFS between the two study groups did not reach statistical significance.²⁴

In summary, the European MCL Network showed rituximab maintenance after R-CHOP improves survival outcomes. However, R-CHOP is a suboptimal induction strategy. BR, with good efficacy and acceptable toxicity profile, appears to be a better platform for older MCL patients. To this date, clinical trials have failed to demonstrate statistical evidence supporting the benefit of rituximab maintenance after BR in the treatment of older patients with MCL. More study is needed to conclusively answer this question.

Management of young and fit MCL patients

In general, intensive strategies produce more durable remissions in MCL. The impact of intensive treatment on OS is less clear. For the purposes of this review, intensive treatment encompasses any strategy that includes ASCT as consolidation or intensive chemotherapy such as conventional R-HyperCVAD with alternating R-MTX/Ara-C. If patients are young (age <65), fit and appropriate candidates for intensive therapy, this is a very reasonable approach.

Induction strategies for young and fit MCL patients

As mentioned in the elderly section, the University of Texas M. D. Anderson Cancer Center group experience with hyper-CVAD alternating with R-MTX/Ara-C included 97 patients with de novo MCL. Among patients aged ⩽65 years (n = 65), the 5-year FFS was 60%, with a median FFS of 5.5 years.¹⁶

The Cancer and Leukemia Group B (CALGB) 59909 trial explored the feasibility, safety and effectiveness of an aggressive immunochemotherapy regimen containing rituximab combined with methotrexate and augmented CHOP (RM-CHOP) followed by ASCT for patients up to age 69 years with a new diagnosis of MCL. Seventy-eight patients were enrolled, and the median age of patients was 57 years. At a median follow up of 4.7 years, the median event-free survival (EFS) was 4.4 years. The 2-year PFS was 76% (95% CI; 64–85%), and the 2-year OS was 87% (95% CI; 77–93%).²⁵

Subsequent efforts focused on exploring the role of high-dose cytarabine (HiDAC) as part of the induction regimen prior to ASCT in young, newly diagnosed MCL patients. In a study by Delarue and colleagues, 60 patients with a median age of 57 years were enrolled, and treated with three cycles of R-CHOP (rituximab only received in the third cycle) followed by three cycles of R-DHAP (rituximab plus dexamethasone, HiDAC and cisplatin). Responding patients were considered for an ASCT. At a median follow up of 67 months, median EFS was 83.9 months (range 71.5–NR), median PFS was 84 months and median OS was not reached. Five-year OS rate was 75%.²⁶

Following the aforementioned phase II trial,²⁶ in an elaborate effort the European MCL Network aimed to further investigate whether the introduction of HiDAC to immunochemotherapy prior to ASCT results in better outcomes. In a randomized phase III trial, patients 65 years of age or younger were assigned to either six cycles of R-CHOP followed by ASCT (n = 234) versus six cycles of alternating R-CHOP and R-DHAP followed by ASCT (cytarabine group, n = 232). After a median follow up of 6.1 years, the median PFS was 4.3 years (95% CI; 3.8–5) in the R-CHOP + ASCT group, compared to 9.1 years (95% CI; 6.5–NR) in the cytarabine group. Given the outstanding results, this study suggested immunochemotherapy containing HiDAC followed by ASCT to be considered as the standard of care in younger patients with MCL.²⁷

Other groups have also investigated the role of further intensification of induction regimen in MCL to improve survival outcomes. In 2008, at that time based on a median follow-up time of 4 years, the Nordic MCL group published the early results of the second Nordic MCL trial of frontline intensive induction immunochemotherapy consisting of dose-intensified R-CHOP (maxi-CHOP), alternating with R + HiDAC for a total of six cycles followed by ASCT. The early results indicated the 6-year OS, EFS, and PFS to be 70%, 56%, and 66%, respectively, and no relapses reported after 5 years in 160 patients aged ⩽66 years enrolled on this phase II trial.²⁸ A 6-year follow up was later published in 2012, and showed continued superb overall results, as evidenced by the median EFS of 7.4 years. The follow-up results indicated progression in 6 out of 160 patients later than 5 years after the conclusion of treatment.²⁹ Finally the 15-year updated results of the Nordic MCL2 study after a median follow up of 11.4 years reported a median OS and PFS of 12.7 and 8.5 years, respectively.³⁰

More recent studies continue to investigate less toxic, but seemingly equally effective, induction regimens. As an example, a recent phase II study by the Dana-Farber Cancer Institute group examined a novel induction regimen consisting of three cycles of BR followed by three cycles of rituximab, high-dose cytarabine (RC) in 23 transplant-eligible patients ranging from 42 to 69 years of age. The primary endpoint of this study was the CR rate after six cycles of therapy, which was met in 96% of patients. After a median follow up of 13 months, the PFS rate was 96%. These promising results warrant further investigation and validation in larger randomized controlled trials.³¹

In brief, when treating a young and fit patient with MCL, an intensive strategy to maximize the length of first remission has emerged as a worldwide standard of care. With the current intensive approaches, the median PFS has surpassed 7 years. More studies are currently being conducted aiming to reduce the toxicity of intense induction regimens without compromising survival outcomes.

Table 2 offers a summary.

Table 2.

The summary of induction strategies in treatment-naïve young and fit patient population.

Author, year, study	Regimen	Patient population	PFS	OS
Fayad and colleagues16	R-hyperCVAD with alternating R-MTX/Ara-C	⩽65 (n = 65)	5.5 years	N/A
Damon and colleagues25	RM-CHOP + ASCT	Median age 57 (37–69); (n = 78)	Median PFS: NR Median EFS: 4.4 years 2-year PFS: 76% (95% CI; 64–85) 5-year PFS: 56% (95% CI; 43–68)	Median OS: NR 2-year OS 87% (95% CI; 77–93) 5-year OS 64% (95% CI; 50–75)
Delarue and colleagues,26 phase II	R-CHOP/R-DHAP + ASCT	Median age 57 (40–66); (n = 60)	Median PFS 84 months Median EFS 83.9 (range 71.5-NR)	Median OS NR 5-year OS: 75%
Hermine and colleagues,27 phase III	R-CHOP + ASCT	Median age 55 (48–60); (n = 234)	Median PFS 4.3 years (95% CI; 3.8–5)	Median OS NR (95% CI; 7.6-NR) 5-year OS rate 69% (95% CI; 62–74)
	R-CHOP/R-DHAP + ASCT	Median age 56 (50–60); (n = 232)	Median PFS 9.1 years (95% CI; 6.5-NR)	Median OS 9.8 years (95% CI; 8.6-NR) 5-year OS rate 76% (95% CI; 70–81)
Esklund and colleagues,30 (Nordic MCL2), phase II	R-CHOP/R-HiDAC + ASCT	Median age 56 (32–65); (n = 160)	Median PFS 8.5 years	Median OS 12.7 years
Armand and colleagues,31 phase II	BR RC + ASCT	Median age 57 (42–69); (n = 23)	At a follow-up time of 13 months: PFS rate: 96%	N/A

ASCT, autologous stem cell transplantation; BR, bendamustine, rituximab; CI, confidence interval; N/A, not available; NR, not reached; OS, overall survival; PFS, progression-free survival; RC, rituximab, high-dose cytarabine; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; R-DHAP, rituximab, dexamethasone, high-dose cytarabine, cisplatin; R-HiDAC, rituximab, high-dose cytarabine; R-HyperCVAD, rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; RM-CHOP, rituximab, methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone; R-MTX/Ara-C, high-dose methotrexate/cytarabine.

Maintenance strategies for young and fit MCL patients

Rituximab maintenance after R-CHOP has been shown to prolong OS in elderly MCL patients treated with R-CHOP.²³ However, until just recently no data existed supporting rituximab maintenance in younger patients receiving intensive therapy. The role of rituximab maintenance following ASCT in young treatment-naïve patients was investigated in the LyMa trial. The induction regimen on this trial consisted of four cycles of R-DHAP followed by ASCT consolidation. Non-responding patients after R-DHAP received four additional cycles of R-CHOP before ASCT. Responding patients after transplant were then assigned to either rituximab maintenance every 2 months for 3 years versus observation only. The results of the final analysis were presented at the 2016 ASH annual meeting. A total of 299 patients were enrolled on this study, with a median age of 57 years (range 27–65). Overall, 257 patients (including 12 patients who progressed on R-DHAP and received R-CHOP) underwent ASCT. After ASCT, 240 patients were randomized to each maintenance arm. At a median follow up of 54.4 months, the median EFS, PFS and OS were not reached in either arm. The 4-year EFS was 61.4% (95% CI; 51.3–69.9) in the observation arm versus 78.9% (95% CI; 69.6–85.6) in the rituximab maintenance arm (p = 0.0012). The 4-year PFS and OS were 82.2% (95% CI; 73.2–88.4) versus 64.6% (95% CI; 54.6–73) (p = 0.0005) and 88.7% (95% CI; 80.7–93.5) versus 81.4% (95% CI; 72.3–87.7) (p = 0.0413) in the rituximab maintenance arm versus observation arm, respectively. The superior EFS, PFS and OS in the rituximab maintenance arm compared with the observation arm supports the efficacy of rituximab maintenance, and potentially establishes a new standard of care for young MCL patients.³²

Management of relapsed/refractory MCL patients

In recent years, several novel therapeutic agents have been investigated in phase I/II clinical trials in the relapsed or refractory MCL setting.

Bortezomib

In 2006, Fisher and colleagues in a phase II, multicenter PINNACLE study investigated the safety and efficacy of single-agent bortezomib in relapsed or refractory MCL patients, which was shown to be associated with prolonged responses and promising survival outcomes.³³ In 2009, after a median follow up of 26.4 months, an updated report of the study indicated an mDOR of 9.2 months. The ORR was 32% (95% CI; 24–40), including 8% CR/CRu (95% CI; 4–14).³⁴

Temsirolimus

In a phase II study, the safety and efficacy of the single-agent low-dose (25 mg weekly) mammalian target of rapamycin (mTOR) kinase inhibitor temsirolimus was examined in patients with relapsed or refractory MCL. Of 29 enrolled patients, 27 were evaluable for efficacy. The ORR was 41% (11 of 27 patients; 90% CI; 22–61%) with 1 complete response (3.7%) and 10 partial responses (37%). The median DOR for the 11 responders was 6 months (range 1–26 months).³⁵

In addition, Hess and colleagues conducted a multicenter, phase III study with 162 patients with R/R MCL to evaluate two dose regimens of temsirolimus in comparison with investigator’s choice single-agent therapy in R/R disease. Patients were assigned to either one of the two doses of temsirolimus: 175 mg weekly for 3 weeks followed by either 75 mg (175/75-mg) or 25 mg (175/25-mg) weekly, or investigator’s choice from already approved options. Median PFS was 4.8, 3.4 and 1.9 months for the temsirolimus 175/75-mg, 175/25-mg, and the investigator’s choice groups, respectively. ORR was significantly higher in the 175/75-mg group (22%) compared with the investigator’s choice arm (2%; p = .0019). The median DOR was 7.1 months (95% CI; 4.1–NR) for the temsirolimus (175/75 mg) group.³⁶

Lenalidomide

Goy and colleagues through the phase II MCL-001 (EMERGE) trial explored the safety and efficacy of lenalidomide in heavily pretreated MCL patients who had relapsed after or were refractory to bortezomib. In 134 patients with a median age of 67 years, the ORR was 28% (7.5% CR/CRu), and the median DOR was 16.6 months (95% CI; 7.7–26.7 months). The MCL-001 study demonstrated durable efficacious response to lenalidomide in heavily pretreated MCL patients who had failed bortezomib.³⁷

Lenalidomide in combination with rituximab

Wang and colleagues studied the safety and efficacy of combined lenalidomide plus rituximab in a phase I/II trial of patients with R/R MCL. Fifty-two patients were enrolled in phase I, and 44 patients proceeded to phase II of the study. Among 44 patients in phase II, 25 (57%) had an overall response; 16 (36%) a complete response and 9 (20%) a partial response. The median response duration was 18.9 months (95% CI; 17–NR). This study suggested the combination of lenalidomide and rituximab as a viable treatment option in patients with R/R MCL.³⁸

Idelalisib

Kahl and colleagues examined the single-agent idelalisib, an oral inhibitor of PI3Kδ, in a phase I trial of 40 patients with R/R MCL. The ORR was 40% (16/40 patients), with a CR rate and a partial remission rate of 5% (2/40) and 35% (14/35), respectively. The mDOR was 2.7 months.³⁹

Ibrutinib

In 2015, Wang and colleagues reported the updated safety and efficacy results from the multicenter, open-label phase II registration trial of ibrutinib after a median follow up of 26.7 months. In this study 111 patients with a median age of 68 years, who were heavily pretreated, received oral ibrutinib 560 mg once daily. The ORR was 67% (23% CR), with a median DOR of 17.5 months. These results demonstrated durable responses with ibrutinib in patients with relapsed or refractory MCL.⁴⁰

Venetoclax (ABT-199)

Venetoclax is a selective, potent, oral Bcl-2 inhibitor that has emerged as a promising agent for the treatment of patients with NHL. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics and efficacy of venetoclax. Among 106 patients with relapsed or refractory NHL, 28 had a diagnosis of MCL and showed an ORR of 75% (21/28). The median DOR was not reported for MCL subtype.⁴¹

Another viable option for patients with R/R MCL is reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-SCT).^42–44 The decision to proceed with allo-SCT cannot be made lightly. The 2-year non-relapse mortality (NRM) rate with RIC allo-SCT is about 30%⁴⁵ and up to 50% of RIC allo-SCT patients can suffer from chronic extensive graft versus host disease (GVHD).⁴⁶ Despite these risks, the allo-SCT approach may offer the best chance for long-term survival in young R/R MCL patients, justifying the risk in selected patients. Novel agents can be utilized in an effort to gain disease control while a donor search is undertaken.

Table 3 offers a summary.

Table 3.

Summary of novel targeted therapies in relapsed and/or refractory MCL patients.

Author, year, study	Patient population	Targeted agent	ORR	mDOR
Goy and colleagues,34 phase II PINNACLE study	R/R MCL; (n = 155)	Bortezomib	32% (95% CI; 24–40)	9.2 months
Ansell and colleagues 35	R/R MCL; (n = 29)	Temsirolimus (25 mg weekly)	41% (90% CI; 22–61)	6 months
Hess and colleagues,36 phase III	R/R MCL; (n = 54)	Temsirolimus (175/75-mg)	22% (95% CI; 11–33)	7.1 months
Goy and colleagues,37 phase II EMERGE study	R/R MCL; (n = 134)	Lenalidomide	28% (95% CI; 20–36)	16.6 months
Wang and colleagues,38 phase I/II	R/R MCL; (n = 52)	Lenalidomide–Rituximab	57%	18.9 months
Kahl and colleagues, 39 phase I	R/R MCL; (n = 40)	Idelalisib	40%	2.7 months
Wang and colleagues,40 phase II	R/R MCL; (n = 111)	Ibrutinib	67% (95% CI; 57.1– 75.3)	17.5 months
Davids and colleagues,41 phase I	R/R MCL; (n = 28)	Venetoclax	75%	Not reported

CI, confidence interval; mDOR, median duration of response; ORR, overall response rate; R/R, relapsed and/or refractory.

Horizons and future directions in the treatment of MCL

Treatment-naïve elderly MCL patients

• SHINE trial (BR → rituximab maintenance versus BR + ibrutinib → rituximab maintenance + ibrutinib). The SHINE trial has been designed as a phase III double-blind study of ibrutinib in combination with BR versus BR for the treatment of patients with a new diagnosis of MCL. All patients are scheduled to receive BR for six cycles. Patients who achieve a CR or PR will proceed with rituximab maintenance every 2 months for a total of 12 doses. In addition to BR and rituximab maintenance, all patients will either receive an oral daily dose of 560 mg ibrutinib or placebo until disease progression. The primary endpoint is PFS. This study enrolled 524 patients aged 65 years or older who are not suited for intensive therapy. The SHINE trial has concluded recruitment. [ClinicalTrials.gov identifier: NCT01776840]

• Eastern Cooperative Oncology Group (ECOG) 1411. This randomized phase II trial investigates the role of bortezomib in the induction and lenalidomide in the maintenance settings. This study enrolled 372 patients, aged 60 years or older, and has concluded recruitment. The primary objective of this study is 2-year PFS. The results of the induction question are expected to be reported at the 2017 ASH annual meeting. The four arms of the study include: (1) BR followed by rituximab maintenance; (2) BR followed by lenalidomide + rituximab maintenance; (3) BR plus bortezomib followed by rituximab maintenance; and (4) BR plus bortezomib followed by lenalidomide plus rituximab maintenance. [ClinicalTrials.gov identifier: NCT01415752]

Treatment-naïve young and fit MCL patients

• Triangle trial. This phase III randomized trial, conducted by the European MCL consortium, aims to enroll patients with a new diagnosis of MCL, between 18 and 65 years of age. The primary objective of this study measures FFS. The study consists of three arms: (1) six cycles of R-CHOP alternating with R-DHAP followed by ASCT; (2) six cycles of R-CHOP alternating with R-DHAP plus ibrutinib followed by ASCT consolidation and 2 years of ibrutinib maintenance; and (3) six cycles of R-CHOP alternating with R-DHAP plus ibrutinib followed by 2 years of ibrutinib maintenance – without upfront ASCT. This study attempts to investigate whether adding ibrutinib to induction and as maintenance improves outcomes over R-CHOP/R-DHAP followed by ASCT alone. It is also designed to examine whether adding ibrutinib to induction and maintenance allows for deferral of upfront ASCT. [ClinicalTrials.gov identifier: NCT02858258]

• ECOG-ACRIN (EA4151). This is a randomized phase III trial of consolidation with ASCT followed by rituximab maintenance versus rituximab maintenance alone for patients with MCL who have achieved a negative minimal residual disease (MRD) status following induction chemotherapy. Patients, regardless of the induction regimen they have received, will be screened for MRD status. MRD-negative patients will be randomized to either ASCT + rituximab maintenance or rituximab maintenance alone without ASCT. This study aims to explore the benefit of upfront ASCT in patients who have already achieved a complete molecular remission.

Conclusion

MCL is a clinically heterogeneous disease with a highly variable clinical course, emphasizing a need for personalized approaches to optimize survival outcomes. In the past decade, multiple clinical trials factoring in the patient’s age, comorbidities and tempo of the disease have resulted in significant improvement in clinical outcomes. In addition, a more detailed understanding of disease biology and pathways involved in the pathogenesis of MCL has culminated in the development of targeted agents. These agents are being integrated in clinical trials in the upfront, maintenance and R/R settings. Ongoing and future work should focus on further individualizing treatment based on tumor biology through incorporating translational studies into clinical trials to improve survival outcomes while enhancing toxicity profile associated with each treatment strategy. This goal will only be achieved by encouraging patients to participate in well-designed clinical trials to improve the understanding of disease heterogeneity, identify predictive biomarkers for response and develop more sophisticated treatment strategies.