Management of mantle cell lymphoma in the era of novel oral agents

Abstract

Objectives:

To discuss (1) recent and emerging data for pharmacologic management of untreated and relapsed/refractory mantle cell lymphoma (MCL) with agents approved in the United States; (2) important considerations for toxicity monitoring and management; and (3) preliminary data and ongoing studies for agents in MCL-specific clinical trials.

Data Sources:

PubMed/MEDLINE, EMBASE, Google Scholar, product labeling, National Comprehensive Cancer Network, American Cancer Society, and ClinicalTrials.gov searched for studies published between January 1, 2017 and January 31, 2020 and key historical trials.

Study Selection and Data Extraction:

Relevant studies conducted in humans and selected supporting preclinical data were reviewed.

Data Synthesis:

MCL is a rare but usually aggressive non-Hodgkin lymphoma that most commonly affects the elder population. Traditionally, the treatment of MCL has been determined by patients being deemed “transplant-eligible” or “transplant-ineligible”. Newer data suggest more tolerable front-line therapy, including regimens incorporating novel agents, may produce similar outcomes to intensive historical induction regimens. This may in turn preclude fewer patients from autologous stem cell transplant and produce better long-term outcomes in transplant-ineligible patients. In the relapsed/refractory setting, novel agents and combination regimens are improving outcomes and changing the landscape of treatment.

Relevance to Patient Care and Clinical Practice:

This review summarizes and discusses recent and emerging data for management of newly-diagnosed and relapsed/refractory MCL, along with key supportive care considerations for agents discussed.

Conclusions:

Numerous recent studies have produced exciting results that are changing management of MCL. While these data have complicated the picture of regimen selection, the advent of increasingly effective and tolerable therapy and additional anticipated data point to a brighter future for patients with MCL.

Introduction

Mantle cell lymphoma (MCL) is a rare B-cell non-Hodgkin lymphoma (NHL) that represents approximately 3–8% of all NHLs.^{1, 2} MCL most often follows an aggressive course and patients nearly always present with advanced stage disease, with bone marrow and gastrointestinal (GI) tract being common extranodal sites of involvement. The median age at presentation of MCL is approximately 69 years and it is more common in men than women.³ MCL is classically characterized by aberrant cyclin D1 expression due to the reciprocal chromosomal translocation t(11;14) between the proto-oncogene CCND1 and the immunoglobulin heavy chain locus, although some unusual cases are cyclin D1-negative.^{4, 5}

Historically, treatment for advanced-stage MCL has split patients into two groups: transplant-eligible (or “younger”) versus transplant-ineligible (or “older”). Transplant-eligible patients have traditionally received multi-agent chemotherapy induction followed by high dose therapy with autologous stem cell transplant (HDT-ASCT). Conversely, transplant-ineligible patients are generally treated with less toxic chemotherapy combinations followed by maintenance therapy.⁶ However, the landscape of front-line MCL treatment is changing as novel therapies are introduced. While cure of MCL remains elusive and responses in the relapsed/refractory (R/R) setting are fewer and shorter-lived, management of R/R MCL is also changing with newer agents and data suggesting importance of sequence in which drugs are utilized.^{7, 8} Here, we review recent and emerging data for front-line and subsequent management of MCL and important clinical considerations and supportive care for these regimens.

Data Sources

Information sources searched for peer-reviewed publications included PubMed/MEDLINE, EMBASE, and Google Scholar using key term mantle cell lymphoma. Additional resources included product labeling, the National Comprehensive Cancer Network (NCCN), and ClinicalTrials.gov. Inclusion was limited to studies published between January 1, 2017 and January 31, 2020, except for key historical trials and selected studies influencing design or interpretation of newer studies.

Developments in Front-Line Therapy

Introduction of cytarabine to induction regimens

Front-line treatment of MCL in younger patients has evolved over time, with mounting evidence over the last two decades indicating cytarabine is important for maximizing response to induction. Recent and key historical front-line MCL trials are summarized in Table 1. The course of incorporation of cytarabine into induction helps to inform understanding of modern MCL regimens and trials. Cytarabine was first introduced as part of the HyperCVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine) regimen.^{9, 10} While clinical trials suggest significantly improved outcomes in MCL with this regimen relative to historical standard-of-care, it has been associated with poor tolerability and concern for transplant mobilization failure.^11–15 Alternative cytarabine-containing regimens have been evaluated in an effort to identify more tolerable treatment.

Table 1:

Summary of Front-Line MCL Trials^*

Study; Year	Regimen Name	No. of MCL Patients	Median Age (years)	Transplant Eligible	PFS	OS
Geisler CH, et al 200817	Nordic trial regimen	160	56	Yes	4-yr PFS: 73%	4-yr OS: 81%
Hermine O, et al 201620	MCL Younger	Control: 234 Cytarabine: 232	Control: 55 Cytarabine: 56	Yes	5-yr PFS: 65% cytarabine vs 44% control (p<0.0001)	5-yr OS: 76% cytarabine vs 69% control (p=0.12)
Le Gouill S, et al 201722	LyMa Trial	Observation: 120 Rituximab: 120	Observation: 56 Rituximab: 58	Yes	4-yr PFS: 83% rituximab vs 64% control (p<0.001)	4-yr OS: 89% rituximab vs 80% control (p=0.04)
Le Gouill S, et al 201726	Subgroup Analysis of LyMa	Carbo/Cis: NR Oxaliplatin: NR	NR	Yes	4-yr PFS: 65% carbo/cis vs 86.5% oxaliplatin	4-yr OS: 75.9% carbo/cis vs 92% oxaliplatin
Rummel MJ et al 201338	BR	BR: 46 RCHOP: 48	70	No	Median PFS: 35.4 months BR vs 22.1 months RCHOP (p=0.0044)	NR
Chen RW, et al 201714; Kahl BS, et al 201928	S1106 follow-up	BR: 35 R-HyperCVAD: 17	BR: 57 R-HyperCVAD: 59	Yes	5-yr PFS: 71% BR vs 62% R-HyperCVAD	5-yr OS: 71% BR vs 62% R-HyperCVAD
Visco C, et al 201742	RBAC500	57	71	No	2-yr PFS: 81%	2-yr OS: 86%
Merryman RW, et al 201846	BR to replace RCHOP in Nordic	86	57	Yes	4-yr PFS: 80%	4-yr OS: 92%
Ruan J, et al 201559	R2	38	65	No	4-yr PFS: 69.7%	4-yr OS: 82.6%
Robak T, et al 201576 & 201877	VR-CAP	VR-CAP: 140 RCHOP: 128	VR-CAP: 65 RCHP: 66	No	Median PFS: 24.7 months VR-CAP vs 14.4 months RCHOP (p<0.001)68	Median OS: 90.7 months VR-CAP vs 55.7 months RCHOP (p=0.001)
Jain P, et al 201990	IR	42	71	NR	Median PFS not reached	Median OS not reached
Wang M, et al 201993	IR + HyperCVAD	131**	56	NR	Median PFS not reached	Median OS not reached
Spurgeon SE, et al 201997	SCR	39	62	NR	Median PFS 84 months	Could not be estimated

^*In order of discussion in main text

^**Number of patients included in efficacy evaluation not specified

BR: bendamustine plus rituximab; Carbo: carboplatin; Cis: cisplatin; NR: not reported; OS: overall survival; PFS: progression free survival; R²: rituximab plus lenalidomide; RBAC: rituximab, bendamustine, and cytarabine; RCHOP: rituximab, cyclosphosphamide, vincristine, doxorubicin, and prednisone; R-HyperCVAD: rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high dose cytarabine and methotrexate; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; IR: ibrutinib and venetoclax; SCR: SAHA, cladribine, and rituximab

Based upon historical treatment resembling that of large cell lymphomas with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like therapies and encouraging preliminary results of HDT-ASCT consolidation following chemotherapy, the Nordic Lymphoma Group conducted the NLG MCL-1 trial evaluating dose-intensified CHOP every 3 weeks (maxi-CHOP21) followed by consolidation with HDT-ASCT.¹⁶ Results were suboptimal with 85% of patients failing therapy. These disappointing results, juxtaposed with exciting concurrent experience with cytarabine-containing regimens, spurred modification of the Nordic regimen in NLG MCL-2 to include Maxi-CHOP21 alternating with high-dose cytarabine for 6 total cycles.^{17, 18} All induction chemotherapy cycles in NLG MCL-2 included rituximab and induction was followed by consolidation with HDT-ASCT. Outcomes were significantly improved compared to MCL-1, with 54% of patients achieving complete response/unconfirmed complete response (CR/CRu). Most notably, long-term follow-up in the recently-updated intent-to-treat analysis (median follow-up 11.4 years) showed median progression-free survival (PFS) of 8.5 years and median overall survival (OS) of 12.7 years, with 40% of patients remaining in first remission.¹⁹

Anthracycline- and alkylator-sparing intensive regimens

The above findings, along with meta-analyses indicating improved overall survival with addition of rituximab, prompted the MCL Younger trial which randomized patients to R-CHOP alternating with R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) or R-CHOP alone.^{20, 21} Both treatment arms received HDT-ASCT consolidation. Patients in the cytarabine arm had significantly longer PFS—the study was not powered to detect differences in OS and follow-up was limited. Patients that received R-DHAP experienced significantly more hematologic toxicity and nephrotoxicity compared with the control group, but this did not preclude proceeding to HDT-ASCT. This and other contemporary studies, as well as subsequent studies discussed below, led to the gradual phasing out of CHOP (and, later, R-CHOP) as standard-of-care therapy.

Given persistent lack of survival plateau in prospective MCL trials and OS benefit with maintenance rituximab with older regimens in MCL and other NHLs, the role of rituximab maintenance following HDT-ASCT was then evaluated in the phase 3 LyMa trial.^{20, 22, 23} Induction with R-DHAP—uniquely sparing responders anthracycline and alkylator exposure—was followed by HDT-ASCT. Salvage R-CHOP was utilized for patients not responding to induction. Choice of cisplatin, carboplatin, or oxaliplatin was left to the practice of the treating investigator. Following HDT-ASCT, patients were randomized to rituximab maintenance every 2 months for 3 years or observation. Compared to observation, maintenance rituximab significantly improved 4-year PFS (83% versus 64%; p < 0.001) and OS (89% versus 80%; p = 0.04). Notably, of 240 patients randomized, only 20 received R-CHOP due to insufficient response to R-DHAP.

These results established maintenance rituximab as a standard therapy following R-DHAP with HDT-ASCT consolidation and prompted its use with other induction regimens for both transplant-eligible and -ineligible patients. It is unclear whether patients benefit from maintenance rituximab regardless of induction regimen. A retrospective Czech Lymphoma Study Group analysis of patients who did (n = 277) or did not (n = 218) receive maintenance rituximab following various induction regimens found significantly improved 5-year OS with maintenance (73.1% versus 57.5%; p < 0.001).²⁴ However, this benefit was not found in patients who received maintenance rituximab after HDT-ASCT. Moreover, in a recent observational study of patients in the Czech NiHiL lymphoma cohort, maintenance rituximab given every 12 weeks for 3 years was found to improve PFS but not OS in front-line treatment of patients with MCL following induction with the modified Nordic regimen and HDT-ASCT consolidation.²⁵

While cisplatin-containing regimens have proven useful in front-line MCL treatment, nephrotoxicity with cisplatin makes use of alternative platinum agents appealing. A subgroup analysis of the LyMa trial compared R-DHA-Oxaliplatin (R-DHAOx or R-DHAX) to R-DHA-Carboplatin (R-DHACa) and R-DHA-Cisplatin (R-DHACis).²⁶ All reported cases of renal failure occurred in patients receiving cisplatin. After one cycle, 15% and 21% of patients receiving cisplatin were switched to carboplatin and oxaliplatin, respectively. There was no decrease in efficacy noted in these patients—indeed, results suggested improved outcomes with oxaliplatin versus other platinum agents. R-DHACa/Cis demonstrated 4-year PFS of 65% and OS of 75.9% compared to PFS of 86.5% and OS of 92% with R-DHAX. While the LyMa trial was not designed to compare between platinum analogues and additional data are needed, this retrospective study is nevertheless encouraging.

Transplant-sparing intensive induction

Importantly, front-line HDT-ASCT is based on older data showing survival benefit, and there are no prospective data to indicate that HDT-ASCT improves survival following modern chemoimmunotherapy regimens.²⁷ Thus, efforts to capitalize on cytarabine’s efficacy include transplant-sparing intensive regimens. Preliminary results were recently reported for a phase 2 trial of front-line sequential therapy with lenalidomide plus R-CHOP followed by R-high-dose cytarabine consolidation and R-lenalidomide maintenance. End-of-treatment objective response rate (ORR) for 20 patients who had completed therapy was 96%, with 95% achieving CR, and 18 patients had ongoing remission at median follow-up of 15 months.^{28, 29} Notably, these promising results were accompanied by substantial hematologic toxicity reported during R-high-dose cytarabine consolidation.

Additionally, two recently-reported phase 2 studies recruited transplant-eligible patients with newly-diagnosed MCL to receive R-MACLO-IVAM (doxorubicin, fractionated cyclophosphamide, vincristine, and methotrexate alternating with high-dose cytarabine, etoposide, and ifosfamide, both with rituximab) induction, with complete responders receiving thalidomide maintenance in the first study or rituximab maintenance in the second study.³⁰ Consolidative HDT-ASCT was not utilized. As PFS and OS analyses indicated no difference in these outcomes between maintenance therapies, results were pooled for analysis of overall safety and efficacy outcomes. Among 44 patients (22 per study), most had intermediate-high-risk disease and 54% had Ki-67 above 30%. Forty-three patients completed at least 2 cycles of chemotherapy, all of whom responded (95% CR). Median PFS and OS were 8 years and not reached (10-year PFS and OS 39% and 60%), respectively. These outcomes were significantly worse in patients with high-risk disease—5-year PFS and OS were 23% (versus 54% and 93% in and intermediate- and low-risk) and 60% (versus 100% and 92%), respectively. One patient died during the first cycle of chemotherapy. Toxicities were stated to be similar to the initial report with this regimen, in which the most common toxicities and complications during induction (all-grade 20% or higher) included neutropenia (50% grade 3 or 4), anemia (68% grade 3 or 4), thrombocytopenia (88% grade 3 or 4), febrile neutropenia, infection, bacteremia, hyperglycemia, hypokalemia, nausea, vomiting, rash, and mucositis.³¹ Notably, febrile neutropenia and bacteremia occurred in 71% and 35% of the chemotherapy cycles, respectively—primary prophylaxis with granulocyte colony stimulating factor was utilized for all patients.

The role of maintenance in cytarabine-containing regimens remains an important question, particularly in the context of whether HDT-ASCT consolidation is required for transplant-eligible patients. Early data suggest some patients may experience similar outcomes with front-line maintenance rituximab following induction instead of HDT-ASCT. A front-line Eastern Cooperative Oncology Group (ECOG) phase 2 study of rituximab, bortezomib, modified hyper-fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone (VcR-CVAD) induction therapy included a maintenance phase with rituximab for 2 years.³² This study included 75 patients and those considered transplant-eligible had the option of HDT-ASCT consolidation instead of maintenance rituximab. ORR was 95% (68% CR) and at median follow-up of 4.5 years, 3-year PFS and OS were 72% and 88%, respectively. There were no differences in PFS or OS observed between patients treated with maintenance rituximab (n = 44) versus HDT-ASCT (n = 22). However, these results are tempered by the study’s size and relatively short follow-up; unknown comparability of VcR-CVAD to other, better-established induction regimens; and the possibility that post-transplant maintenance may have improved outcomes in the HDT-ASCT group. This concept is being explored more rigorously in two ongoing front-line phase 3 trials. The TRIANGLE study is combining ibrutinib (discussed below) with alternating R-CHOP/R-DHAP during induction followed by HDT-ASCT, ibrutinib maintenance, or both.³³ Ibrutinib maintenance safety and feasibility was demonstrated in a recently-reported ongoing phase 2 trial.³⁴ An ECOG study is incorporating minimal residual disease (MRD) status, which is not yet in widespread clinical use but has demonstrated utility for relapse risk stratification and success of induction therapy.³⁵ In this trial, patients who achieve CR and MRD negativity with standard-of-care chemotherapy are randomized to HDT-ASCT plus rituximab maintenance or rituximab maintenance alone.³⁶

Less intensive front-line therapy

BR and RBAC

Many patients with newly-diagnosed MCL are unable to undergo intensive induction with or without stem cell support due to age or comorbidities, or may elect for less intensive treatment. Since its approval in the United States the bifunctional alkylator bendamustine has quickly gained prominence in the management of B-cell NHL, including transplant-ineligible MCL.³⁷ A front-line phase 3 trial in indolent lymphomas and MCL established bendamustine and rituximab (BR) as a standard-of-care option in transplant-ineligible patients.³⁸ BR demonstrated superiority in PFS compared to R-CHOP in MCL (median 35.4 months versus 22.1 months; p = 0.0044). BR was better tolerated than R-CHOP, with no alopecia and fewer cases of neutropenia, paresthesias, stomatitis, and infection, while skin reactions were more frequent. CR rate was also superior in the subset of patients with MCL treated with BR (n = 36) compared to R-CHOP or R-CVP (rituximab, cyclophosphamide, vincristine, prednisone; n = 38) in the phase 3 BRIGHT study (CR rate ratio 1.95, p = 0.018). Updated analysis at median 5-year follow-up of the BRIGHT study supports the PFS benefit of BR (65.5% versus 55.8% at 5 years; p = 0.0025) without difference in OS, although the study was not powered for this analysis and increased secondary malignancies (primarily squamous and basal cell carcinomas) were noted with BR.^{39, 40} Interestingly, an ad hoc analysis indicated BR increased time to next line of therapy (HR 0.57; p = 0.0012), although this analysis was not specific to MCL patients.⁴⁰

BR has also demonstrated a role in front-line induction in transplant-eligible patients. The phase 2 S1106 study by the Southwestern Oncology Group randomized newly-diagnosed patients with MCL aged 65 or younger to receive BR or R-HyperCVAD induction, followed by HDT-ASCT for those achieving CR or PR.⁴¹ The R-HyperCVAD arm was closed early due to nearly one-third failing stem cell collection and an additional third failing to undergo HDT-ASCT due to delayed count recovery. Recently-updated results (n = 53, median 5-year follow-up) indicate ORR and CR/PR rates were similar between arms. Rates of grade 3 or 4 hematologic toxicities, febrile neutropenia, and non-hematologic toxicities were higher with R-HyperCVAD. Five-year PFS was 66% versus 62% for patients receiving BR versus R-HyperCVAD and 5-year OS was 80% versus 74%, respectively. While these results are encouraging, this study was small and BR in this setting requires further exploration in large trials, particularly with more thorough comparison to cytarabine-containing regimens.

Growing experience with BR raised the question of whether combining it with cytarabine improves outcomes. Based on high thrombocytopenia rates in a 2013 pilot study combining BR with higher doses of cytarabine, a recent phase 2 study in newly-diagnosed, transplant-ineligible patients with MCL combined cytarabine at a dose of 500mg/m² with BR (RBAC500).⁴² Among 57 patients enrolled, 52 (91%) achieved CR, with remaining patients refractory to treatment or discontinuing treatment early due to toxicity. At median follow-up of 35 months, PFS was 76%; median PFS and OS had not been reached. Hematologic toxicities were common, particularly neutropenia and thrombocytopenia (grade 3 or 4 in 49% and 52%, respectively), although febrile neutropenia was uncommon (5%). Non-hematologic toxicities were rarely grade 3 or 4—the most common included fatigue and nausea/vomiting (all-grade in 25% and 21%, respectively). ⁴³

In the same vein, given the evident superiority of BR to R-CHOP, two studies are investigating substitution of R-MaxiCHOP with BR in the modified Nordic regimen for newly-diagnosed transplant-eligible patients.^{44, 45} Recently-presented results from these ongoing trials and off-trial experience are promising, with 4-year PFS and OS of 80% and 92%, respectively.⁴⁶ A small study (n = 23) utilizing sequential BR followed by R-high-dose cytarabine in transplant-eligible patients noted an ORR of 96% (all CRs), with all but one responder undergoing HDT-ASCT; both PFS and OS were 96% at median 13-month follow-up.⁴³ At the time of this publication, longer-term follow-up is awaited.

It is unknown if patients receiving BR benefit from rituximab maintenance and data are conflicting, although prospective data suggest they do not. In a front-line MCL subgroup study of the StiL NHL7–2008 MAINTAIN trial with median 4.5-year follow-up, 59 patients randomized to maintenance rituximab every 8 weeks for 2 years following BR induction did not have longer PFS or OS compared to 61 patients randomized to observation.⁴⁷ In the BRIGHT study, an ad hoc analysis of patients who received maintenance rituximab following BR showed no difference in PFS compared to those who did not.⁴⁰ Conversely, two retrospective multicenter analyses of patients with MCL who received front-line BR identified OS benefit with versus without maintenance rituximab in patients who did not undergo consolidative HDT-ASCT (n = 114 and 135).^{48, 49} However, subgroup analyses in both studies indicated this benefit was confined to patients achieving PR, not CR, with BR induction.

Delayed neutrophil recovery and prolonged lymphopenia during and after completion of treatment are well-characterized effects of bendamustine-containing chemoimmunotherapy regimens.^50–52 Randomized clinical trials have reported variable incidence of infections with bendamustine-based regimens and additional studies have been undertaken to attempt to better characterize infection risk. In a retrospective analysis of our institutional experience with bendamustine-based chemoimmunotherapy regimens in B-cell NHL patients (n = 416; 15% with MCL), 2% of patients received Pneumocystis jiroveci pneumonia (PJP) prophylaxis and 1% developed PJP infection.⁵³ A systematic review with meta-analysis of pooled randomized clinical trial data for 2620 patients receiving bendamustine-containing regimens for hematologic malignancies did not indicate increased risk of grade 3 or 4 infection, including opportunistic infections, with the possible exception of patients receiving bendamustine doses greater than 180mg/m².⁵⁴ This analysis carries significant caveats, such as only including patients carefully selected for clinical trial participation and heterogeneity in treatment setting and regimens. A subsequent population-based study of 1791 Medicare beneficiaries aged 65 or older receiving BR, R-CHOP, or R-CVP identified increased risk of infection and pneumonia with BR during the second year following initiation of treatment, although the absolute increase in risk was small (0.9 and 0.6 cases per 100 person-months, respectively).⁵⁵ The largest population analysis to date examined 9395 Medicare beneficiaries aged 65 or older with indolent NHL receiving bendamustine or other specified chemotherapy regimens.⁵⁶ This study identified increased risk of infections, especially opportunistic infections (particularly Varicella zoster virus, VZV) and bacterial pneumonia with bendamustine exposure—for example, numbers needed to harm were 17 for any infection, 27 for bacterial pneumonia, and 19 for VZV. These risks were highest in patients receiving bendamustine as third-line therapy or later. It is important to note that this study did not include patients with MCL, and while it included the age group in which most MCL will occur, its results may not apply to younger patients. Additionally, the authors did not report concomitant therapeutic agents nor prophylaxis used with bendamustine.

Assessing the risks and benefits of prophylaxis against infection—and how long to administer it—for patients receiving BR and other bendamustine-based regimens remains complicated, with prospective data needed. Given the apparent risk of VZV infection and tolerability of acyclovir and valacyclovir, we suggest strong consideration be given to VZV prophylaxis.⁵⁷ Conversely, ideal prophylaxis against PJP with sulfamethoxazole/trimethoprim may be associated with tolerability issues, and the number needed to treat in the 2019 Medicare analysis was 252.⁵³ We do not routinely recommend PJP prophylaxis in the absence of other risk factors.^{56, 58}

R²

The R² regimen, consisting of lenalidomide (Revlimid) and rituximab, has also demonstrated viability as an alternative front-line therapy for transplant-ineligible patients.⁵⁹ Lenalidomide is a thalidomide derivative with various mechanisms ultimately producing direct cytotoxic effects as well as modulation of immune cell activity in the tumor microenvironment, with promotion of NK cell-mediated cytotoxicity being a primary mechanism of activity against MCL.^60–62

When first studied in R/R MCL, R² demonstrated activity with a reasonable toxicity profile.⁶³ Given unmet need for more tolerable front-line therapies in transplant-ineligible patients, a phase 2, multicenter study of R² induction and maintenance in previously untreated MCL was performed.⁵⁹ The results further support the utility of R², with an ORR of 81% and CR rate of 61%. Notably, the rate of CR increased over time providing support for maintenance therapy. At recently-reported 5-year follow-up, 4-year PFS and OS rates were 69.7% and 82.6%, respectively, showing the potential for R² to induce durable remissions.⁶⁴ It should be noted that this study was small (n = 38) and most patients had excellent performance status and Ki-67 less than 30%. Intriguingly, in a recent single-center retrospective analysis, a small subset of patients with MCL who had TP53 mutations—typically conferring lower response rates to chemoimmunotherapy and poor prognosis—and received front-line R² had 100% OS and event-free survival at median 15-month follow-up, suggesting a possible front-line niche for this regimen.^{65, 66} Prospective data with larger samples and longer follow-up are needed to further investigate this possibility.

R² comes with a unique set of adverse effects that must be considered. The most common grade 3 or 4 adverse effects associated with this regimen include cytopenias (most often neutropenia), rash, tumor flare, and fatigue.⁵⁹ Notable among all-grade toxicities was diarrhea, occurring in 55% of patients. In the absence of contraindications, thromboprophylaxis with aspirin or low molecular weight heparin is required with lenalidomide to reduce risk of venous thromboembolism (VTE). Recent systematic review and meta-analysis indicated similar rates of VTE in B-cell NHL patients receiving lenalidomide-containing regimens (including monotherapy) compared indirectly to patients with multiple myeloma receiving lenalidomide-containing regimens, although it should be noted that analysis by lymphoma subtype was not possible.⁶⁷ Consideration must also be given to hepatitis B reactivation prophylaxis with rituximab-containing regimens—this risk may be compounded by lenalidomide.⁶⁸ Lenalidomide-induced diarrhea is caused by bile acid malabsorption and manageable with the use of bile acid sequestrants.⁶⁹

The R² regimen is an effective and safe first-line treatment option for transplant-ineligible patients with MCL, although its associated toxicities are significant. There is also preliminary evidence indicating the addition of other active agents such as bortezomib and dexamethasone or bendamustine to R² may produce high response rates, but the apparently compounded risk of infectious complications jeopardizes long-term safety of such combinations.^70–72 It should also be noted that immunomodulatory agents may compromise hematopoietic cell collection—in instances where HDT-ASCT is being considered for a previously transplant-ineligible patient following treatment with R², this possibility must be taken into consideration.^{73, 74}

VR-CAP

In the era of standard-of-care R-CHOP treatment for MCL, the proteasome inhibitor bortezomib demonstrated single-agent activity in relapsed/refractory disease, garnering its approval in the United States and other countries for this indication.⁷⁵ In the phase 3 LYM-3002 trial, Robak and colleagues compared VR-CAP, a modified R-CHOP regimen substituting twice-weekly intravenous bortezomib for vincristine, against R-CHOP in front-line treatment of patients (n = 487) with transplant-ineligible MCL.⁷⁶ In a recently-reported final survival analysis (median follow-up 82 months), median OS was 90.7 months with VR-CAP versus 55.7 months with R-CHOP (HR 0.66; p = 0.001).⁷⁷ The most common adverse events were hematologic, with grade 3 or higher neutropenia and thrombocytopenia occurring more frequently with VR-CAP.⁷⁶ Rates of febrile neutropenia and peripheral neuropathy were similar.

These data support VR-CAP as a front-line option in transplant-ineligible patients and identify opportunities for optimization. LYM-3002 did not include maintenance rituximab in either treatment arm. Additionally, once-weekly and subcutaneous administration of bortezomib have shown non-inferior outcomes with improved tolerability in patients with multiple myeloma, although a post hoc analysis of LYM-3002 indicated bortezomib exposure was important for OS.^78–80 Bortezomib’s efficacy in MCL has prompted front-line trials incorporating it into regimens with cytarabine, lenalidomide, and other active agents, as well as exploring its use in maintenance therapy.^81–83 Finally, there is a question of whether other proteasome inhibitors are useful in MCL. A recently-reported phase 2 study of carfilzomib in relapsed/refractory MCL was closed due to slow accrual, with only 4 patients receiving treatment.⁸⁴ The oral proteasome inhibitor ixazomib, which may be more convenient than the other two approved agents, is being tested in combination with ibrutinib in a phase 1/2 study in relapsed/refractory patients.⁸⁵ Proteasome inhibitors are known to impair cell-mediated immunity, putting patients at risk of VZV reactivation; as proteasome inhibition continues to gain traction in MCL, it is important to ensure that patients receive VZV prophylaxis.^{86, 87}

IR with or without chemotherapy

Ibrutinib (PCI-32765, CRA-032765) is an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the TEC kinase family, currently approved by the United States Food and Drug Administration (FDA) for R/R MCL.⁸⁸ The B-cell receptor (BCR) signaling pathway is crucial to survival of many B-cell leukemias and lymphomas, including MCL, and inhibition of downstream signal transduction enzymes including BTK impairs malignant cell proliferation.⁸⁹ The first report of clinical trial experience with ibrutinib for MCL in the front-line setting was recently presented.⁹⁰ Preclinical evidence suggests that ibrutinib may reduce inflammatory cytokine-mediated T-cell exhaustion and produce a shift in T-cell differentiation toward cytotoxic subsets, altering the tumor microenvironment.⁹¹ Additionally, ibrutinib is known to mobilize MCL cells from bone marrow and other tissue compartments, potentially sensitizing malignant cells to immune-mediated cytotoxicity facilitated by monoclonal antibodies.⁹² Based on this anticipated synergy and clinical experience in the R/R setting (discussed below), Jain and colleagues enrolled 42 elderly patients with untreated MCL to receive ibrutinib and rituximab (IR). Median age was 71 years and most patients had low Ki-67 (notably, patients with Ki-67 50% and above or blastoid morphology excluded). ORR was 98% (60% CR), with PFS and OS not reached at median 28-month follow-up. The most frequent grade 3 or 4 toxicities were myalgias, fatigue, shortness of breath, and neutropenia. Five percent of patients experienced grade 3 or higher atrial fibrillation. Ibrutinib toxicity and management have been best characterized in the R/R setting and are further discussed below. Although longer follow-up and comparative data are needed, particularly in higher-risk patients, these results are exciting and frequent front-line use of this combination is anticipated in clinical practice.

IR with abbreviated R-HyperCVAD was also studied in patients aged 65 or younger, with early results recently presented.⁹³ One-hundred thirty-one patients received induction with IR until CR, followed by 4 cycles of consolidative R-HyperCVAD without HDT-ASCT or maintenance therapy. Most patients had low-risk disease, although half had Ki-67 30% or higher. At median 22-month follow-up, ORR to IR was 100% (88% CR), and at the last follow up for patients completing both components of treatment, CR rate was 94%—the number of patients in this follow-up analysis was not specified. Three-year PFS and OS were 85% and 97%, respectively, with median values not reached. The most common grade 3 or 4 toxicities with IR were fatigue, myalgia, and rash; toxicities were not reported for those patients who had completed R-HyperCVAD. These results present great promise for front-line use of ibrutinib in conjunction with established induction regimens, potentially sparing the need for consolidative transplant or maintenance therapy. However, safety and efficacy results for patients receiving the full study protocol are awaited, as are trials incorporating use of ibrutinib with other, less-toxic chemoimmunotherapy regimens. Further discussion of ibrutinib and management of its associated risks is presented below.

SCR

Aberrant DNA methylation is a well-known characteristic of MCL and other lymphomas.⁹⁴ Preclinical data indicate synergy of the combination of the histone deacetylase (HDAC) inhibitor vorinostat (suberanilohydroxamic acid, SAHA) with DNA hypomethylating agents.⁹⁵ Based on this information and known clinical activity of the combination of rituximab with the purine nucleoside analogue and hypomethylator cladribine, a recently-reported phase 1–2 trial combined vorinostat with cladribine and rituximab (SCR) for CD20⁺ NHL, including MCL.^{96, 97} The phase 2 component included a cohort of untreated patients with MCL (n = 39) and a cohort of relapsed/refractory NHL patients (including 10 patients with MCL) who received SCR for up to 6 cycles of SCR, followed by optional rituximab maintenance. In the untreated patients, ORR was 97% (80% CR), and median PFS was 84 months; median OS could not be estimated. In relapsed/refractory patients, ORR was 30%, all of which were CR, and median PFS and OS were 5.5 and 14.5 months, respectively. All-grade toxicity rates were not reported; the most frequently-encountered grade 3 or 4 toxicities included cytopenias, diarrhea, and infection. Additionally, the reported range of cycles completed was 1 to 5, indicating no patients completed the full induction course. While this small study does not identify a clear role for SCR, it suggests HDAC inhibitors have potential for clinical utility in MCL.

Developments in Management of Relapsed or Refractory Disease

R²

As noted previously, R² was initially studied in R/R MCL, and recently reported results from the phase 3 MAGNIFY study of R² with randomization to either R² maintenance or rituximab maintenance in indolent B-cell lymphomas have solidified this role.⁹⁸ In the subset of patients with MCL (n = 70) at median 14.6-month follow-up, ORR was 54% with 38% achieving CR; adverse events mirrored the profile of other R² studies discussed above, with the most common being cytopenias (particularly neutropenia; 39% grade 3 or 4), fatigue, constipation, dyspnea, diarrhea, and nausea.

Ibrutinib

Ibrutinib revolutionized management of R/R MCL at a time when only lenalidomide and bortezomib were FDA-approved for this indication; the course of its initial approval for MCL has been thoroughly reviewed.⁹⁹ Data for its use in this setting continue to develop. Ibrutinib was approved by the FDA for treatment of R/R MCL in patients who have received at least one prior therapy following the non-comparative phase 2 PCYC-1104 study which yielded an impressive median PFS of 13.9 months.¹⁰⁰ The subsequent phase 3 multicenter RAY trial comparing ibrutinib to temsirolimus (chosen as a comparator due to frequent use in the R/R setting in Europe, where most of the participating centers were located) helped to confirm ibrutinib’s role in R/R disease.¹⁰¹ At extended 3-year follow-up, ibrutinib exhibited an ORR of 77% with median PFS of 15.6 months compared to 40% ORR and median PFS of 6.2 months with temsirolimus (p < 0.0001 for each). Median OS trended toward improvement with ibrutinib (30.3 versus 23.5 months, p = 0.0621).¹⁰² Notable adverse effects associated with ibrutinib included diarrhea, fatigue, cough, atrial fibrillation (5% grade 3 or higher), and bleeding complications (serious bleeding in 9%) due to platelet dysfunction caused by off-target TEC kinase inhibition.^{102, 103}

Ibrutinib’s efficacy and role in R/R disease have been further elucidated in a recent pooled analysis of 370 patients enrolled in the above-described PCYC-1104 and RAY trials and the phase 2 SPARK trial.^{100, 101, 104, 105} At median follow-up of 41 months, median PFS and OS were 12.5 and 26.7 months. Of note, median PFS was 67.7 months and median OS was not reached in patients with best response of CR, compared to 12.6 and 23.6 months in patients achieving PR. In patients with only one prior line of therapy, median PFS and OS were 25.4 and 61.6 months, compared to 10.3 and 22.5 months, respectively, in patients with more than one prior line of therapy. Risk of serious adverse effects such as atrial fibrillation/flutter or bleeding did not appear to increase with longer duration of therapy. In patients who received ibrutinib as second-line therapy after CR to front-line therapy, ibrutinib appeared to perform especially well; median duration of response exceeded 4.5 years and was longer than median duration of response to front-line therapy. Conversely, in patients with TP53 mutations, response appeared to be less robust, with no patients achieving CR.⁶⁵ A retrospective analysis of 258 patients with R/R MCL receiving ibrutinib supports the notion of particularly good outcomes with use of ibrutinib in the second-line setting, although analysis was limited to a single institution.¹⁰⁶ Another retrospective analysis of patients who received ibrutinib as second-line therapy (n = 169) further demonstrated its utility in this setting in a sample with poor prognostic features (median age 72, 23% with ECOG performance status 2 or higher).¹⁰⁷ While PFS and OS appeared worse than those seen in clinical trials (median 16.5 and 23.9 months, respectively)—likely reflective of real-world experience in poorer-risk patients—PFS with ibrutinib nevertheless exceeded PFS with front-line therapy in nearly half of patients.

Assessment of risk of serious adverse events—namely, atrial fibrillation and bleeding—before initiating ibrutinib is important and should incorporate such factors as comorbidities and past medical history, end organ function, concomitant medications (particularly those affecting CYP3A4), modifiable risk factors for bleeding, and baseline electrocardiograph, among others. Guidance for assessing risk and managing these events is available.^{108, 109} There is also emerging evidence of association of bacterial and opportunistic fungal infections with ibrutinib use—often without classical opportunistic infection risk factors like neutropenia—likely due to ibrutinib-induced macrophage and T-cell dysfunction.^110–112 At present, however, we do not routinely recommend infectious prophylaxis with ibrutinib use due to a paucity of data for risk stratification or benefit from prophylaxis.

Ibrutinib’s clear utility in R/R MCL—particularly in the second-line setting and in patients who respond well to front-line treatment—is tempered by primary and near-ubiquitous acquired resistance, both of which may portend poor prognosis.¹¹³ Although newer therapies may produce better outcomes post-ibrutinib than traditional chemoimmunotherapeutic approaches, there is nevertheless a need for strategies to overcome ibrutinib resistance. This need, alongside ibrutinib’s strong performance in the clinical setting and improving understanding of ibrutinib resistance, has prompted studies of ibrutinib combination regimens for both untreated and R/R disease, including use with rituximab, venetoclax, and other agents.¹¹⁴

Venetoclax

Venetoclax (ABT-199, GDC-0199) is an orally bioavailable inhibitor of the B-cell lymphoma-2 (BCL-2) protein, preventing activity of pro-survival proteins and facilitating apoptosis.¹¹⁵ While venetoclax is currently FDA-approved for treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, it has been used off-label in numerous disease states including R/R MCL.⁶ Venetoclax was studied as monotherapy in a phase 1 dose escalation trial including multiple subtypes of NHL.¹¹⁶ Of 28 patients with MCL relapsed after median 3 prior lines of treatment, 21 (75%) achieved at least PR and the median PFS was approximately 14 months. Adverse effects associated with venetoclax included fatigue, neutropenia, diarrhea, and nausea/vomiting. Tumor lysis syndrome (TLS) is an important adverse event associated with venetoclax. Based on predicted risk of TLS due to tumor burden in MCL and experience in patients with CLL, this study utilized a dose titration schedule in a 3+3 sequential escalation, with no cases of clinical TLS and 3 cases of laboratory TLS in patients with bulky disease reported.^{117, 118} Given these encouraging outcomes in this heavily-pretreated sample, venetoclax has become a frequently-used agent in R/R MCL, and is being studied in several combination regimens in both front-line and R/R settings.^119–128

Ibrutinib plus venetoclax

Preclinical data suggest that co-targeting the BTK and BCL-2 oncogenic pathways may have a synergistic effect.¹²⁹ The BCL-2 family of proteins has been associated with development of resistance in numerous tumor types, including those treated with BTK inhibitors. In MCL cell lines, the combination of ibrutinib with venetoclax has been found to be synergistic, likely due to inhibition of separate key survival pathways and possibly through activity against clones that circumvent BTK inhibition via BCL-2 amplification or defects in BCL-2 degradation.^130–132 The phase 2 AIM trial with recently-updated efficacy results combined ibrutinib with venetoclax for treatment of 24 R/R and 1 untreated patient with MCL.¹³³ To minimize risk of TLS, patients received ibrutinib alone for 4 weeks, followed by initiation of venetoclax weekly dose titration. Notably, 50% of patients had TP53 mutations or deletions. ORR was 71% with 62% of patients achieving CR and 8% achieving PR. At median follow-up of 37.5 months, median PFS and OS were 29 and 32 months, respectively. Among patients with TP53 alterations, ORR was 58% (50% CR), with duration of response ranging from 12 to 38+ months.

In the initial AIM study report, dose adjustments of either ibrutinib or venetoclax were required in 15 patients, with mean relative dose intensity of 87% for ibrutinib and 96% for venetoclax.¹³⁴ The most frequent all-grade adverse effects were gastrointestinal in nature, with diarrhea occurring in 83%, nausea/vomiting in 71%, and gastroesophageal reflux in 38% of patients. Low-grade bleeding or bruising events were common, but only one patient experienced serious bleeding. TLS occurred in 2 patients early in the protocol which prompted reduction in the initial dose of venetoclax from 50 to 20 mg, with no further patients developing TLS. Additional common adverse effects included fatigue, musculoskeletal pain, and neutropenia. All cases of neutropenia were grade 3 or higher, with one patient experiencing febrile neutropenia and 7 requiring granulocyte colony stimulating factor. Ten patients developed upper respiratory infections and 10 developed soft tissue infections (one of which was fatal). Atrial fibrillation occurred in 2 patients.

While this regimen predictably demonstrated additive toxicity, particularly GI- and infection-related events, most were grade 2 or lower, and only three patients discontinued one or both agents due to toxicity.¹³⁴ Given the promising efficacy of this combination, a phase 3 trial comparing ibrutinib plus venetoclax to ibrutinib alone is underway to further elucidate place in therapy in the R/R setting and confirm optimal dose titration of venetoclax, with early safety results indicating a low rate of dose-limiting toxicity.¹²⁷ With ongoing study of this regimen it will be important to continually assess its additive toxicity and appropriately select patients for its use.

Other ibrutinib combination regimens

Three other combination regimens with ibrutinib have recently been reported. Based on anticipated synergy discussed above, a phase 2 trial was conducted by Wang and colleagues to assess the utility of ibrutinib with rituximab in R/R MCL.¹³⁵ In 50 heavily-pretreated patients (median 3 prior lines of therapy) at median follow-up of 16.5 months, ORR was 88%, with 44% achieving CR and 44% achieving PR. Fifteen-month PFS and OS were 69% and 83%, respectively; median values had not been reached for either. The most common adverse events were fatigue, diarrhea, myalgia, nausea, mucositis, dyspnea, thrombocytopenia, and peripheral neuropathy. Grade 3 or 4 adverse events were uncommon—excluding atrial fibrillation (12%), rates were less than 10% for all reported toxicities. Three grade 3 bleeding events occurred, one of which led to treatment discontinuation.

The above-described potential for ibrutinib-mediated tumor microenvironment alteration indicates possible synergy with immunomodulatory agents. In the phase 2 PHILEMON study of 50 patients with R/R MCL, ibrutinib was used in conjunction with lenalidomide and rituximab in 4-week cycles for a 12-cycle induction phase, followed by maintenance with ibrutinib and rituximab.¹³⁶ At median follow-up of 17.8 months, ORR was 76%, with 56% achieving CR and 20% achieving PR. Median PFS and OS were 16 and 22 months, respectively. Of note, there was no discernible difference in ORR or PFS for the 11 patients with TP53 mutations. Most adverse events were grade 1 or 2. GI events were reported in 68% of patients, with 12% grade 3 or 4. Infections occurred in 62% of patients, 2 of which were fatal. Other common adverse events included cutaneous toxicity, fatigue, neurologic toxicity, respiratory events, muscle cramps, and neutropenia. Atrial fibrillation occurred in one patient. Vascular events were reported in 32% of patients, but bleeding events were not specified.

Hallmark abnormal cyclin D1 expression and resultant cell cycle dysregulation in the large majority of MCL cases suggests sensitivity to cell cycle arrest by cyclin-dependent kinase (CDK) inhibitors, particularly those targeting CDK4.¹³⁵ A phase 1b study of the CDK4/6 inhibitor palbociclib (PD0332991) as monotherapy in R/R MCL produced disappointingly low ORR (18%), but responders remained on therapy for prolonged periods.¹³⁷ Similar results were seen in a recent study of the combination of palbociclib and bortezomib.¹³⁸ The pilot study prompted a phase 1 trial combining several dose levels of palbociclib and ibrutinib.¹³⁹ Twenty-seven patients were enrolled, most of whom had received only one prior line of therapy. ORR was 67%, with 37% achieving CR. At median follow-up of 25.6 months, 2-year PFS and OS were 59% and 61%, respectively. The most common grade 3 or 4 toxicities were neutropenia and thrombocytopenia, with 15% of patients experiencing febrile neutropenia. Grade 3 atrial fibrillation and grade 4 bleeding were each reported in one patient. While response rates appear similar to ibrutinib’s activity as monotherapy in this setting, response duration may be longer, and a phase 2 trial is underway to clarify the efficacy of this combination and identify patient subsets who may derive additional benefit from CDK inhibition.¹⁴⁰ The mechanism of neutropenia induced by CDK inhibitors is categorically different from cytotoxic agents—conferring lower risk of infectious complications when used as monotherapy—but coupling this effect with ibrutinib may substantially increase this risk, as evidenced by the incidence of febrile neutropenia in the phase 1 trial.^{139, 141} This will be an important consideration when evaluating the utility of this regimen.

Ibrutinib has rapidly become a mainstay of treatment in the R/R MCL setting, and several other ibrutinib-based combination regimens are under investigation.^{85, 120, 121, 142} The looming threat of ibrutinib resistance and tolerability issues remain, however. While circumvention of primary and acquired resistance to BTK inhibitor monotherapy has not yet been achieved in the clinical setting, efforts have been made to identify small molecule BTK inhibitors that improve tolerability over ibrutinib.

Acalabrutinib

Acalabrutinib (ACP-196) is a second generation oral BTK inhibitor recently FDA-approved for the treatment of MCL in patients who have received at least one prior therapy.¹⁴³ Acalabrutinib and its active metabolite ACP-5862 form a covalent bond with Cys481 in the BTK active binding site with greater affinity than ibrutinib, leading to inhibition of BTK. In vitro data and in vivo CLL models also indicate that acalabrutinib exposure reduces cell-surface expression of CD69 and CD86, corresponding to reduced B-cell receptor (BCR) activation.¹⁴⁴ Importantly, acalabrutinib also has significantly improved target specificity compared to ibrutinib, with virtually no activity against other TEC kinases or EGFR, indicating potential for an improved toxicity profile.¹⁴⁵

Acalabrutinib was FDA-approved through the accelerated approval pathway following the phase 2 ACE-LY-004 trial, with updated results recently reported.¹⁴⁶ This international, multicenter trial of acalabrutinib included 124 patients with MCL who had relapsed after at least 1 prior therapy. Most patients previously received rituximab, and none had been exposed to ibrutinib. At median follow-up of 26 months, ORR was 81% (43% CR). Notably, response did not appear to differ in heavily pre-treated patients (having received at least 3 prior lines of therapy). Median PFS was 20 months and median OS had not been reached.

In pharmacokinetic studies, the area under the concentration-time curve was reduced by 43% when acalabrutinib was co-administered with a proton pump inhibitor, so these agents should be avoided during acalabrutinib therapy.¹⁴³ According to the manufacturer, H₂-receptor antagonists and other antacids may be considered but acalabrutinib should be administered at least two hours prior to minimize this interaction—however, if an H₂ receptor antagonist is being used twice daily, we suggest against concomitant use.¹⁴³

Although no comparative data are available, the adverse effect profile of acalabrutinib appears to differ from ibrutinib. In ACE-LY-004, the safety profile of acalabrutinib was favorable, with a low rate of adverse event-related discontinuation (6%), no cases of atrial fibrillation, and rare serious bleeding (2%).¹⁴⁶ Common adverse events included infection, headache, diarrhea, and fatigue. The most common grade 3 or 4 events were infection, anemia and neutropenia. A pooled safety analysis of 7 trials testing acalabrutinib in several hematologic malignancies (610 patients) appears to confirm these results—most notably, grade 3 atrial fibrillation and serious bleeding were rare (1% and 2.5%, respectively).¹⁴⁷ However, many patients included in this analysis received acalabrutinib once daily, which may have influenced toxicity rates. Compared to standard twice-daily dosing, once-daily dosing of acalabrutinib produces significant interpatient variability in BTK binding.¹⁴⁸

Based on efficacy in R/R MCL and an ostensibly improved safety profile compared indirectly with ibrutinib, acalabrutinib may be an attractive option in this setting, particularly in select patients at high risk of atrial fibrillation or bleeding complications. Acalabrutinib remains susceptible to BTK inhibitor resistance, however, and unless comparative data confirm similar efficacy and improved toxicity profile with acalabrutinib versus ibrutinib, ibrutinib will likely maintain its dominant role in the R/R setting. As with ibrutinib, acalabrutinib-based combination regimens are under investigation in both the R/R and front-line settings.^{124, 149, 150}

Zanubrutinib

Newer-generation BTK inhibitors continue to be developed, including the newly-approved second-generation BTK inhibitor zanubrutinib (BGB-3111). Zanubrutinib is a selective, irreversible oral BTK inhibitor possessing minimal off-target activity. Notably, unlike ibrutinib, zanubrutinib has little activity against IL-2-inducible kinase (ITK); inhibition of ITK has been shown to reduce NK cell-mediated cytotoxicity in vitro.¹⁵¹ Zanubrutinib received FDA breakthrough designation based on initial results from a recently-updated multicenter Chinese phase II trial in patients with R/R MCL.¹⁵² In 86 patients (most with intermediate-to-high-risk disease, median 2 prior lines of therapy) with median follow-up of 13.9 months, ORR to zanubrutinib was 84.7% (76.5% CR) and median PFS was 16.7 months. Response was reported to be similar among sub-groups including those with intermediate/high-risk disease and more heavily-pretreated patients. The most frequent toxicities included neutropenia, rash, upper respiratory tract infection, thrombocytopenia, hypokalemia, and diarrhea; 9.3% of patients discontinued treatment due to adverse effects. The only grade 3 or 4 toxicity reported in more than 10% of patients was neutropenia (16%). Major bleeding was reported in 2.3% and there were no cases of atrial fibrillation. A global phase 2 expansion cohort of patients with both treatment-naïve (n = 11) and R/R (n = 37) MCL appears to have similar response rates.¹⁵³ Based on these updated results, FDA granted accelerated approval for zanubrutinib for MCL following at least one prior line of therapy.

Zanubrutinib’s high response rate in pretreated patients shows promise, although mature and expanded efficacy data and better characterization of its toxicity profile relative to ibrutinib and acalabrutinib are needed. Resistance to BTK inhibition is nearly inevitable, and issues with tolerability remain. Therefore, it is imperative to continue exploring further treatment options.

RBAC

Data for regimen selection in patients who progress on novel oral agents are lacking, particularly with regard to cytotoxic chemotherapy use in this setting. A recent multicenter retrospective analysis of patients with MCL who received RBAC500 (discussed above) after exposure to a BTK inhibitor as a prior line of therapy included 35 patients (median of 2 prior lines of therapy), nearly all of whom received RBAC500 immediately following BTK inhibitor failure.¹⁵⁴ Most patients had received high-dose cytarabine-based front-line therapy and 40% were consolidated with HDT-ASCT. Half of patients had high-risk disease and 21% had blastoid histology, conferring worse prognosis.¹⁵⁵ ORR to RBAC500 was 82% (56% CR/unconfirmed CR). Median follow-up was reported to be short but was not specified. Median PFS and OS were 9.3 and 12.2 months, respectively. Interestingly, 54% of patients had longer duration of response to RBAC500 than to BTK inhibition. These intriguing data in a high-risk sample clearly highlight the need for prospective data in this setting.

Therapies on the Horizon

Ongoing BTK inhibitor development focused on improving tolerability has yielded multiple new agents. Orelabrutinib (ICP-022) is a selective, irreversible inhibitor of BTK; results from a multicenter phase 2 trial of orelabrutinib in patients with R/R MCL were recently reported.¹⁵⁶ One-hundred and six patients were enrolled and evaluated for safety, with 97 evaluable for response; sample characteristics were not reported. ORR was 82.5%, with 24.7% achieving CR and 57.7% achieving PR. Median duration of response had not been reached at time of reporting. The most frequent toxicities (all-grade 15% or higher) included thrombocytopenia, neutropenia, respiratory tract infections, and rash. The only grade 3 or higher toxicity in more than 10% of patients was thrombocytopenia (12.3%). No grade 2 or higher hemorrhage was reported, nor was atrial fibrillation. Notably, no grade 3 or higher diarrhea was reported. Additionally, 3-year follow-up on a R/R MCL expansion cohort of a phase 1 study of the selective, irreversible BTK inhibitor tirabrutinib (GS/ONO-4059) were recently published.^{157, 158} Sixteen patients with R/R MCL (median age 64 years and 3 prior lines of therapy; 31% had previously received hematopoietic cell transplantation) were enrolled, with 5 remaining on treatment at updated analysis. ORR was 68.8% (38% CR) with median duration of response not reached. Twenty-four month PFS and OS were 56% and 67%, respectively. The most frequent all-grade toxicities included cough, diarrhea, thrombocytopenia, contusion, and nasopharyngitis; grade 3 or higher toxicities in more than 10% of patients included thrombocytopenia (19%), anemia (13%), and dyspnea (13%). No cases of atrial fibrillation were reported; one patient experienced a grade 3 bleeding event (gastrointestinal hemorrhage).

CD19-directed CAR-T cell therapy has had a transformative role in managing R/R leukemia and large B-cell lymphoma, and has shown promise in various other subtypes of NHL, including MCL.^159–161 Axicabtagene ciloleucel (KTE-X19, formerly KTE-C19) is being investigated in the phase 2 ZUMA-2 trial in patients with R/R MCL who have received chemoimmunotherapy and ibrutinib or acalabrutinib.¹⁶² Preliminary reports have shown durable responses, with potential to achieve CR at 6 months.¹⁶³ Additionally, lisocabtagene maraleucel (JCAR017), an anti-CD19 CAR-T product with a defined composition of CD4⁺ and CD8⁺ CAR-T cells, showed promise in preliminary analysis of a subset of R/R MCL patients (n = 9) in the phase 1 TRANSCEND NHL 001 trial; ORR was 78%, with 2 patients in the first dose level maintaining CR up to 1 year.¹⁶⁴ Finally, a ‘second-generation’ anti-CD19 CAR-T product utilizing a 4–1BB costimulatory domain—appearing to improve CAR-T cell persistence based on studies of tisagenlecleucel—was administered to patients with R/R MCL in a small (n = 6) recently-reported trial.^{165, 166} Four patients (67%) achieved objective response, with ongoing response in two patients for 7 and 36 months.

The phosphoinositide 3-kinase (PI3K) signaling pathway has been implicated downstream of the BCR as a player in the pathogenesis of MCL and identified as a possible resistance pathway against BTK inhibition.^{167, 168} The PI3Kδ-specific inhibitor parsaclisib (INCB050465) is under investigation as monotherapy in a phase 2 study of R/R MCL.¹⁶⁹ Early experience suggests activity—parsaclisib was studied as monotherapy or in combination with the Janus kinase 1 inhibitor itacitinib in a phase 2 trial of patients with R/R B-cell NHL (n = 10 with MCL; 9 receiving monotherapy, 1 receiving combination therapy), with updated results recently reported. Among patients with MCL, ORR was 67% (44% CR) for monotherapy; the patient receiving combination therapy achieved PR. The most common adverse events included diarrhea/colitis, nausea/vomiting, fatigue, rash, cough, pyrexia, and pruritus. Early results were also recently presented for the R/R MCL cohort in a phase 1/1b study of the pan-PI3K inhibitor buparlisib in combination with ibrutinib.^{28, 170} Among 15 evaluable patients, ORR was 100%, with 11 (73%) achieving CR and 4 (27%) achieving PR.

MCL’s predominant incidence in male patients indicates a possible pathophysiologic role of aberrant androgen signaling. Mostaghel and colleagues recently demonstrated a two million-fold increase in androgen receptor transcription in MCL cell lines compared to other NHL cell lines, with significant growth inhibition after exposure to the anti-androgen agent enzalutamide.¹⁷¹ Based on these results, a phase 2 study of enzalutamide in R/R MCL is ongoing.¹⁷²

Discussion

While novel agents are changing the landscape of MCL treatment, HDT-ASCT remains a staple of standard-of-care therapy and patients are still stratified at diagnosis based on their ability to tolerate transplantation. HDT-ASCT is traditionally reserved for patients with MCL who are under age 65. The less toxic front-line therapies discussed here may preclude fewer older patients from undergoing HDT-ASCT, but the ability to tolerate conditioning chemotherapy remains a challenging prerequisite. The outpouring of data in recent years has also provided clinicians with several options for cytarabine-based induction but has consequently complicated the picture of regimen selection. Based on the results of the LyMa trial and subgroup analysis, it is our opinion that R-DHAX is efficacious and likely produces outcomes comparable to those of other standard induction regimens, although head-to-head study of modern regimens is needed.^{22, 26} Sparing anthracycline-, alkylator-, and cisplatin-induced toxicity does not appear to compromise efficacy and may allow for more patients to ultimately proceed to transplant.²⁶ BR has also demonstrated a potential role as induction therapy prior to HDT-ASCT, and therefore may also preclude fewer patients from transplant compared to traditional intensive regimens. However, we are cautious in recommending BR for transplant-eligible patients due to lack of comparative data with robustly-studied modern induction regimens. In newly-diagnosed, transplant-ineligible patients, treatment is highly dependent on performance status, comorbidities, and patient preference, as comparative data are lacking. However, for both transplant-eligible and -ineligible patients, we are very excited by the results from the front-line IR trials and await further follow-up and use in combination with other cytotoxic regimens.

Maintenance options following front-line induction are still being investigated and whether application of maintenance therapy should be based on type of induction therapy remains to be seen. Additionally, incorporation of novel agents into maintenance regimens may further elucidate the utility of maintenance. Experience with lenalidomide in the R² regimen suggests that including novel agents may improve upon rituximab maintenance therapy without adding burdensome toxicity—such maintenance regimens are being investigated in a number of ongoing clinical trials. It is our practice to recommend rituximab maintenance following induction therapy for non-BR induction regimens, or maintenance R² if R² is used for induction.

Oral targeted agents have proven to be very effective in the R/R MCL setting, and unfolding results of ongoing trials will likely move these agents into the front-line setting regardless of transplant eligibility.²⁸ While these agents carry unique toxicity profiles, understanding of the mechanism and management of these toxicities will help to maximize their utility. Outside of the clinical trial setting, we consider ibrutinib monotherapy or ibrutinib in combination with venetoclax to be of priority for patients who experience their first relapse or primary refractory disease based on aforementioned data suggesting ibrutinib confers greatest benefit in the second-line setting for this population. In patients for whom ibrutinib is considered unsafe due to cardiac or bleeding concerns, we consider acalabrutinib or zanubrutinib, with the caveats that comparative data for toxicity profiles are unavailable and reported follow-up is limited. If BTK inhibition is not an option, our recommendations are based on patient-specific factors.

Conclusion and relevance to clinical practice

Recent years have seen an explosion of data for management of MCL, but comparative data are sorely needed and are anticipated with ongoing trials. Nevertheless, front-line data are promising for achieving heretofore elusive cure in MCL in the near future, as are prospects for managing R/R MCL with a chronic disease-like approach with increasingly effective and tolerable agents.