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Leukemia & Lymphoma

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/ilal20

Management of relapsed/refractory mantle cell

lymphoma

Musa Alzahrani & Diego Villa

To cite this article: Musa Alzahrani & Diego Villa (18 Apr 2024): Management

of relapsed/refractory mantle cell lymphoma, Leukemia & Lymphoma, DOI:

10.1080/10428194.2024.2338851

To link to this article: https://doi.org/10.1080/10428194.2024.2338851

Published online: 18 Apr 2024.

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Review Article

Leukemia & Lymphoma

Management of relapsed/refractory mantle cell lymphoma

Musa Alzahrania and Diego Villab,c

a

Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia; bCentre for Lymphoid Cancer, BC Cancer,

Vancouver, BC, Canada; c

Division of Medical Oncology, University of British Columbia, Vancouver, BC, Canada

ABSTRACT

In this review we summarize the current evidence describing the management of patients with

relapsed/refractory MCL and outline the various novel therapeutics that have been developed

over the past two decades. We also describe how overall response rates, complete response rates,

duration of responses, and life expectancy have dramatically increased with the introduction of

novel therapies, particularly covalent Bruton Tyrosine Kinase inhibitors (BTKi) and chimeric antigen

receptor T-cell (CAR-T) therapy. The most recent emerging options for patients with progressive

disease following BTKi or CAR-T, including non-covalent BTKi, antibody-drug conjugates, Bcl-2

inhibitors, and bispecific antibodies, may further improve response rates and outcomes. Future

directions should focus on identifying the best sequencing and/or combinations of the increasingly

available treatment options while prioritizing strategies with curative potential.

Introduction

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma that constitutes around 7% of all non-Hodgkin

lymphomas (NHL) [1]. Malignant cells usually harbor the

hallmark translocation t(11;14), which leads to overexpression of cyclin D1 which dysregulates the cell cycle

and promotes uncontrolled cell growth [2]. Its clinical

behavior at diagnosis and subsequent relapses is driven

by various prognostic factors, including the degree of

cellular proliferation as assessed with the Ki-67 proliferative index, blastoid or pleomorphic morphology, the

presence of TP53 mutations, and a high MCL

International Prognostic Index (MIPI) score [3–6].

Even though first-line therapy has significantly

improved outcomes over the past four decades with the

incorporation of rituximab to induction and maintenance

therapy, high-dose cytarabine-based induction regimens,

consolidative autologous stem cell transplantation (ASCT),

and more recently ibrutinib with induction and maintenance therapy, virtually all patients will eventually relapse

[7–12]. Historically, the prognosis of relapsed/refractory

(R/R) MCL has been poor with a short median overall

survival (OS) less than one year [13,14].

Various options for R/R MCL were approved by regulatory agencies such as United States Food and Drug

Administration (US FDA) and/or the European Medicines

Agency (EMA) prior to the advent of Bruton Tyrosine

Kinase inhibitors (BTKi) about a decade ago. These

agents included temsirolimus, bortezomib, and lenalidomide. Despite mechanisms of action that were non-cross

resistant with the cytotoxic chemotherapeutics available

at the time, overall response rates (ORR) were usually

only around 30% and the median progression free survival (PFS) rarely exceeded six months. Anti-CD20 monoclonal antibodies in combination with chemotherapy,

particularly bendamustine-based regimens, were associated with improved response rates, although these

were not consistently durable. Table 1 summarizes therapies for R/R MCL in the era prior to BTKi.

Allogeneic stem cell transplantation (alloSCT) with

either fully myeloablative or reduced-intensity/nonmyeloablative conditioning was frequently used based on

retrospective data showing that a modest proportion of

patients achieved durable long-term remissions, suggesting a possible curative potential. Challenges with

donor identification, the potential for serious short and

long-term toxicities, as well as significant non-relapse

mortality rates have limited the use of alloSCT (Table 2).

The role of alloSCT is diminishing over time with the

increasing availability of newer, more effective therapeutic options, particularly BTKi and chimeric antigen

receptor T-cell (CAR-T) therapy. For example, guidelines

from the American Society of Transplantation and

© 2024 Informa UK Limited, trading as Taylor & Francis Group

CONTACT Diego Villa dvilla@bccancer.bc.ca BC Cancer – Vancouver Cancer Centre, 600 West 10th Avenue, Vancouver, BC V5Z 4E6, Canada

https://doi.org/10.1080/10428194.2024.2338851

ARTICLE HISTORY

Received 26 December

2023

Revised 26 March 2024

Accepted 31 March 2024

KEYWORDS

Mantle cell lymphoma;

relapse; refractory; BTK;

CART; bispecific

2 M. ALZAHRANI AND D. VILLA

Cellular Therapy, Center of International Blood and

Marrow Transplant Research, and European Society for

Blood and Marrow Transplantation recommend that

CAR-T therapy should be considered before alloSCT,

although they recognized alloSCT could be a reasonable consolidative option in selected patients responding to second-line BTKi or in those who do not have

access to CAR-T therapy [15].

Several novel therapeutics have been introduced

into the management of R/R MCL over the past decade

including BTKi, both covalent and non-covalent types,

CAR-T therapy, Bcl-2 inhibitors, bispecific antibodies

(bsAbs), antibody-drug conjugates (ADC), and other

small molecule inhibitors. Collectively, these therapies

have markedly improved response rates and outcomes

in this patient population. The purpose of this review

is to summarize the current evidence informing the

management of R/R MCL.

Approved agents for R/R MCL

Covalent BTKi

Covalent BTKi form an irreversible bond with a cystine

residue (CYS-481) at the active site of BTK thereby

inhibiting its enzymatic activity. The introduction of

covalent BTKi changed the treatment landscape for

R/R MCL. BTKi were the first class of agents with a

novel mechanism of action translating into significantly greater activity and with reasonable safety compared the other options available at the time. These

agents are associated with ORR, CR, and median PFS

in the range of 67-84%, 19-59%, and 13-22months,

respectively, across the spectrum of patients with R/R

MCL in prospective trials [16].

Ibrutinib was the first covalent BTKi to be approved

by the FDA and EMA in 2013 for the treatment of

patients with MCL after at least one prior therapy

based on data from the phase 2 PCYC-1104 study and

the randomized phase 3 RAY study (Table 3) [17,19].

The ibrutinib clinical trials provided much of the early

and now long-term experience with covalent BTKi in

R/R MCL. In a pooled analysis of 370 patients from 3

clinical trials that included ibrutinib, most patients

responded within the first several months of continuous use, largely in the form of partial responses (PR)

(Table 3). Importantly, outcomes were improved when

ibrutinib was used as second-line therapy rather than

later in the course of therapy, or when patients

achieved a complete response (CR). In fact, many such

Table 1. Therapies for R/R MCL in the era prior to BTKi.

Therapeutic category Agents Study Design n

Number of prior

therapies (range) ORR CR Median PFS Median OS

mTOR inhibitors Temsirolimus Hess et  al. [55] Phase 3 RCT 162 2-7 22% 2% 4.8months 12.8months

Everolimus Renner et  al.

[56]

Phase 2 single

arm

36 1-3 20% 6% 5.5months NA

Proteasome inhibitors Bortezomib PINNACLE [57] Phase 2 single

arm

155 1-3 33% 8% NA, median

TTP 6.7

months

23.5months

Immune modulatory

drugs

Lenalidomide SPRINT [58] Phase 2 RCT 254 1-5 40% 5% 8.7months 27.9months

Lenalidomide EMERGE [59] Phase 2 single

arm

134 2-10 28% 8% 4months 20.9months

Rituximab-containing

chemotherapy

R-Bendamustine Czuczman

et  al. [60]

Phase 2 single

arm

45 1-4 82% 40% 17.2months 55% at 3 years

R-BAC MANTLE-FIRST

[61]

Retrospective

study

76/261 1 (only including

first-relapsed or

refractory

73% 63% 25months 43.4months (for

patients treated

with

bendamustine)

R-GemOx Obrador-Hevia

et  al. [62]

Retrospective

study

18 1-5 83% 60% 22months 20months

Abbreviations: n: number; ORR: overall response rate; CR: complete response; PFS: Progression free survival; OS, overall survival; mTOR: the mammalian

target of rapamycin; RCT: randomized controlled trial; NR: not reached; NA: not available; R: rituximab; R-BAC: ritixumab-bendamustine-cytarabine;

R-GEMOX: rituximab-gemcitabine-oxaliplatin; RCT: randomized clinical trial; TTP: time to progression.

Table 2. Examples of studies of allogeneic stem cell transplantation in R/R MCL.

Conditioning Study Design n

Number of

prior therapies

(range)

GVHD higher

grade acute/

chronic NRM PFS OS

Myeloablative CIBMTR [63] Retrospective study 74 2-5 36%/35% 47% at 3 years 20% at 3 years 25% at 3 years

Reduced intensity CIBMTR [63] Retrospective study 128 1-5 37%/43% 43% at 3 years 25% at 3 years 30% at 3 years

Reduced intensity Cook et  al.

[64]

Retrospective study 70 1-6 10%/61% 21% at 5 years 14% at 5 years 37% at 5 years

Abbreviations: n: number; GVHD: graft-versus-host disease; NRM: non-relapse mortality; PFS: Progression free survival; OS: overall survival; CIMBTR: Center

for International Blood and Marrow Transplant Research.

RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA 3

Table 3. Prospective clinical trials of BTKi in R/R MCL.

Study Design

Number of patients

Number of prior therapy median (range) Regimen Rates of atrial fibrillation, All Grades Rates of hypertension Grade ≥ 3 Rates of bleeding Grade ≥ 3 Rates of neutropenia/ thrombocytopenia, All Grades Rates of infection Grade ≥ 3 ORR CR Median PFS Median OS

Ibrutinib Wang et  al. (PCYC-1104) [17] Phase 2 111 3 (1-5) Ibrutinib 560mg daily 4.5% NA 5% 18%/18% 25% 68% 23% 13.9months NR (median f/u 15.3months)

Wang et  al. (SPARK)

[18]

Phase 2 120 2 (1-8) Ibrutinib 560mg

daily

10.8% NA 2.5% 20.8%/13.3% for high grades NA 62.7% 20.9% 10.3months 61% at 18months

Dreyling et  al. (RAY)

[65]

Phase 3 139/280 2 (1-9) Ibrutinib 560mg

daily vs IV temsirolimus

5% NA 9% 16%/18% NA 72% vs 40% 19% vs 1% 14.6 vs 6.2months Median f/u 20months: NR vs 21.3months

Pooled analysis from the 3 above studies [19] (Phase 2 PCYC-1104, Phase 2

SPARK, Phase

3 RAY)

370 2 (1-9) Ibrutinib 560mg

daily

6.8% 5.1% 7.3% 17%/12.4% for high grades 11.6% 69.7% 27% 12.5months 26.7months

Acalabrutinib Wang et  al. (ACE-LY-004) [66] Phase 2, single arm 124 2 (1-2) Acalabrutinib 100mg twice daily 0% 1% 1% 10%/NA 13% 81% 40% 72% at 1 year 87% at 1 year

Zanubrutinib Tam et  al. [67] Phase 1/2 32 1 (1-4) Zanubrutinib 160mg twice daily 6.3% 3.1% 9.4% 12.5%/12.5% 18.8% 91% 31% 21.1months 64.4% at 2 years

Song et  al. [20] Phase 2, single arm 86 2 (1-4) Zanubrutinib 160mg twice daily 0% 16% 3.5% 46.5%/32.6% 18.6% 83.7% 77.9% 33months 74.8% at 36months

Zhou et  al. [68] Pooled analysis of 2 phase 1/2 studies 112 2 (1-4) Zanubrutinib 160mg twice daily 1.8% 11.6% (all grades) 5.4% 32%/24% 10.8% 84.4% 62.5% 25.8 months 38.2months

Pirtobrutinib Wang et  al. (BRUIN)

[25]

Phase 1/2 90 3 (1-8) Pirtobrutinib 200mg once daily 3.7% 0% 3.7% 14%/14.6% 17.1% 58% 20% 7.4months NR (median f/u 16.6 months)

Abbreviations: ORR: overall response rate; CR: complete response; PFS: Progression free survival; OS: overall survival; NR: not reached; f/u: follow-up; NA: not available.

4 M. ALZAHRANI AND D. VILLA

patients have had ongoing disease control for >5 years

in the updated analysis with a median follow-up of

nearly 10 years. The long-term pooled analysis also

showed that the incidence of many severe toxicities,

including cardiovascular, bleeding, and cytopenias

was highest during the first year of treatment but

then diminished over time despite ongoing ibrutinib [19].

The FDA approval of ibrutinib in R/R MCL had been

contingent upon clinical benefit which the developer

aimed to confirm in the phase 3 trial SHINE trial. In

this study, the addition of ibrutinib to first-line BR and

maintenance rituximab improved PFS compared to

placebo (with BR and maintenance rituximab) in

transplant-ineligible patients, without a concomitant

difference in OS. There was increased toxicity in the

ibrutinib arm, particularly increased rates of fatal

adverse events during the treatment period which

may have been driven by COVID-19 [11]. Even though

SHINE met its primary endpoint, the accelerated FDA

approval for ibrutinib for R/R MCL was voluntarily

withdrawn in 2023 based on these data failing to confirm an overall benefit from ibrutinib in this setting.

Acalabrutinib and zanubrutinib are more selective

second generation covalent BTKi that are designed to

have less off-target kinase inhibition and therefore

potentially lower toxicity than ibrutinib. Both agents

were approved by regulatory agencies for the management of R/R MCL after at least one prior line of

therapy based on large, single arm phase 2 trials

[20,66]. In these studies, response rates, duration of

response, PFS, and OS rates appeared numerically similar to those previously reported for ibrutinib (Table 3).

It is unknown whether any of the second generation

BTKi is more effective than the others because head-tohead comparisons have not been performed in MCL.

The incidence of grade ≥3 toxicities including cardiovascular, infections, cytopenias, and rash with acalabrutinib or zanubrutinib appear numerically lower

than those reported for ibrutinib in cross-trial comparisons in MCL. In particular, rates of atrial fibrillation

(with acalabrutinib and zanubrutinib) and hypertension (with acalabrutinib) appear lower compared to

those with ibruitnib. Randomized comparisons in R/R

CLL confirm a lower incidence of adverse events, particularly cardiovascular, with the second generation

BTKi [21].

Based on these data, currently covalent BTKi are

most frequently used as second-line therapy for MCL.

BTKi are being evaluated as part of first-line therapy

also because they can be safely combined with other

agents, including chemoimmunotherapy [11,12]. BTKi

can be combined with other novel agents such as Bcl-2

inhibitors which may have a synergistic effect.

Therefore, it is possible that BTKi will be used as part

of combination regimens rather than as monotherapy

in the near future [22].

Noncovalent BTK inhibitors

Non-covalent BTKi (pirtobrutinib, nemtabrutinib) bind

reversibly to the BTK protein in its adenosine triphosphate pocket, inhibiting its enzymatic activity regardless of the presence of mutations in CYS-481 which

are typically associated with covalent BTKi resistance

[23]. This suggests that a noncovalent BTKi could overcome mechanisms of acquired drug resistance from

exposure to a covalent BTKi. Proof-of-concept was

demonstrated in the single-arm phase 1/2 BRUIN trial

which led to FDA approval of pirtobrutinib for the

treatment of adult patients with R/R MCL following at

least two lines of prior systemic therapies including a

covalent BTK inhibitor [24].

Notwithstanding that patients entering the BRUIN

trial had previously received a median of 3 lines

(range 1-8) of systemic therapy and that 82% had discontinued their previous covalent BTKi because of PD,

the ORR was 58% (20% CR), with a median duration

of response of almost 2 years (Table 3) [25]. Even

though <5% patients had received prior CAR-T therapy, results are considered clinically relevant to current practice given the very poor outcomes expected

for patients at this point in their disease course [26,27].

Pirtobrutinib and covalent BTKi share common class

toxicities such as infections, bleeding, and cardiovascular events, although these appear to be less frequent with pirtobrutinib. A head-to-head comparison

of pirtobrutinib versus investigator’s choice of covalent BTKi in the ongoing randomized phase 3 BRUIN

MCL-321 clinical trial (NCT04662255) will clarify how

the efficacy and toxicity of these two BTKi classes

compare against each other. Nemtabrutinib is currently being investigated in other clinical trials

(NCT03162536, NCT05458297) and has not received

regulatory approval.

CAR-T therapy

The success of BTKi came together with the new clinical challenge of managing patients with disease resistance [26,27]. Prior to CAR-T therapy, outcomes were

dismal in patients following BTKi failure, with median

OS consistently <1year, including those who received

subsequent therapies. This highlights the important

contribution anti-CD19 CAR-T therapy has made in this

challenging context.

RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA 5

Brexucabtagene autoleucel (brexu-cel) formerly

called KTE-X19, an autologous anti-CD19 CAR-T cell

therapy containing a CD3ζ and a CD28 co-stimulatory

domain, is approved by both the FDA and EMA for R/R

MCL based on the ZUMA-2 phase 2 trial (Table 4). All

68 patients treated with brexu-cel in this study had

previously received a BTKi, of which 62% entered the

study with disease refractory to BTKi therapy. About 2

in 3 patients achieved a CR, independent of high-risk

features such as high Ki-67, blastoid variant, TP53

mutation, or high MIPI score [28]. Despite the known

serious toxicities of CAR-T therapy, with 3-year

follow-up, 37% patients have remained in an ongoing

CR without the need for further therapy [29].

Real-world cohorts from the CIBMTR (n=272) and

the US Lymphoma CAR-T Consortium (n=189) have

shown similar response, outcome, and toxicity data in

patients receiving brexu-cel as standard of care.

Importantly, 79% patients in the US Lymphoma CAR-T

Consortium study would not have been eligible for

ZUMA-2 [30,31]. Real-world studies of brexu-cel from

other centers in US, UK and Europe show similar efficacy and toxicity results (Table 4).

The evidence for other CAR T-cell products in R/R

MCL is more limited. Lisocabtagene maraleucel

(liso-cel), an anti-CD19 CAR T-cell product with a

4-1BB co-stimulatory domain, was evaluated in a subgroup of 88 patients with R/R MCL in the phase 1

TRANSEND NHL 001 study. Patients had received at

least 2 prior lines of therapy, including a BTKi, an

alkylating agent, and a CD20-targeted antibody. With

the limitation of cross-trial comparisons, overall and

complete responses were comparable to the brexu-cel

studies, with possibly a lower incidence of grade ≥3

CRS and neurologic toxicity. This observation suggests liso-cel may have a more favorable risk/benefit

profile than brexu-cel, especially when considering

the older median age of patients with MCL [32].

Tisagenlecleucel (Tisa-cel), which also includes and

anti-CD19, 4-1BB co-stimulatory domain, was evaluated together with ibrutinib in 20 patients in the

phase 2 TARMAC trial. Response rates appear comparable to those documented for brexu-cel and liso-cel,

but potentially at the expense of a higher incidence

of CRS, although this prospective study has the smallest sample size [33]. Table 4 Summarizes CAR-T studies in R/R MCL.

The success of CAR-T came together with new clinical challenges. First, there are serious short and

long-term toxicities which are being better managed

as the experience with CAR-T delivery expands and

studies evaluating toxicity mitigation strategies are

conducted. Second, there are limited options for managing patients with disease progression after CAR-T,

many also with BTKi resistant-disease. Third, CAR-T is a

complex, expensive, and resource intensive therapy.

Multiple patient, disease, geography, healthcare system, and CAR-T manufacturing factors influence access

to CAR-T.

Fourth, patients with access to CAR-T therapy often

develop rapidly progressive disease which can be difficult to control with standard therapies while CAR-T is

being set up. For example, in the US Lymphoma CAR-T

Consortium real-world cohort, 2 in 3 patients with R/R

MCL required some form of bridging therapy prior to

the brexu-cel infusion. The choice of bridging therapy

Table 4. Studies of CART in R/R MCL.

Product Study

Number of

patients

Number of

prior lines

of therapies,

median

(range) ORR CR

ICANS

(grade 3

or higher)

CRS (Grade

3 or

higher) PFS OS

Prospective Studies

Brexucabtagene

autoleucel

ZUMA-2(27) 74 3 (1-5) 91% 68% 31% 15% 49% at 2 years,

median PFS =

25.8months

56% at 30-months,

median PFS =

46.6months

Lisocabtagene

maraleucel

TRANSCEND NHL

001 [32, 69]

88 3 (1-11) 83% 72% 9% 1% Median PFS =

15.3months

Median OS =

18.2months

Tisagenlecleucel TARMAC(32) 20 2 (1-5) 85% 80% 0% 20% 75% at 1 year 100% at 1 year

Retrospective Studies

Brexucabtagene

autoleucel

CIBMTR data [30] 397 4 (1-12) 89% 78% 27% 9% 61% at 1 year 74% at 1 year

US Lymphoma CAR

T Consortium

[31]

168 3 (1-10) 90% 82% 32% 8% 59% at 1 year 75% at 1 year

US Academic

centers [70]

52 3 (2-8) 88% 69% 31% 10% 83% at 6months 89% at 6months

UK group [71] 49 2 (2-7) 90% 83% 24% 12% 56% at 1 year 72% at 1 year

European group

by Lacoboni

et  al. [72]

39 2 (1-8) 91% 79% 36% 3% 51% at 1 year 61% at 1 year

Abbreviations: ORR: overall response rate; CR: complete response; ICANS: Immune effector cell-associated neurotoxicity syndrome; CRS: cytokine release

syndrome; PFS: Progression free survival.

6 M. ALZAHRANI AND D. VILLA

can influence efficacy and/or toxicity aspects of CAR-T

therapy. Bendamustine-containing regimens such as

BR or R-BAC may not be ideal prior to CAR-T because

bendamustine impairs T-cell functionality prior to leukapheresis [29,31]. On the other hand, emerging data

suggest that continuous BTKi before and after CAR-T

therapy reduces inflammatory cytokines associated

CRS while maintaining robust in vivo CAR-T expansion

and activity [34,35].

Finally, given the durability of responses and favorable outcomes after a single CAR-T infusion in patients

with heavily pretreated R/R MCL, CAR-T therapy may

be better positioned earlier in the course of disease.

Subgroups who may benefit from this strategy include

patients with high-risk biology such as TP53 mutations

or elevated Ki-67, those with disease progression

shortly after first-line therapy, and those with expected

limited duration of benefit from second-line BTKi-based

therapy [36]. It is possible that CAR-T as consolidation

while the high-risk MCL is under relative control with

first or second-line therapy may lead to a potentially

safer or effective approach rather than waiting for progressive disease to implement CAR-T as part of the

next line of therapy. This approach may be limited in

most countries outside of the US where regulatory

approval for CAR-T therapy requires two or more lines

of therapy including a BTKi.

Approved agents with off-label use in

R/R MCL

Venetoclax is an oral BH-3-mimetic that selectively

inhibits the anti-apoptotic B-cell lymphoma (Bcl-2) protein. Limited data support its single agent activity in

R/R MCL [37,38]. The development of venetoclax in

MCL has largely occurred in combination with BTKi

given their complementary mechanisms of action.

Responses and rates of MRD negativity with the combination appear greater than with each agent alone in

cross-study comparisons. The most common AEs are

hematologic and diarrhea, and tumor lysis syndrome

occurs in <5% patients [39,40,73].

These early phase studies provided the rationale for

the randomized phase 3 SYMPATICO trial which randomized BTKi-naïve patients to venetoclax (2-year

duration) plus ibrutinib (until progression or toxicity)

against placebo (2-year duration) plus ibrutinib (until

progression or toxicity). In the primary analysis, the

combination was associated with a statistically significant improvement in CR rates, PFS, and time to next

treatment, with no new safety concerns [22]. It is

unknown whether these data will lead to regulatory

approval of the combination.

Sonrotoclax (BGB-11417) is an oral Bcl-2 inhibitor

with greater potency and selectivity than venetoclax.

Sonrotoclax is currently being explored alone and in

combination with zanubrutinib in clinical trials in MCL

and other B-cell malignancies (NCT04277637,

NCT05471843). Preliminary data with the combination

of sonrotoclax and zanubrutinib in 16 patients with

R/R MCL shows high ORR of 78% and CR rates of

67% [41].

Investigational agents in R/R MCL

Bispecific antibodies (bsAbs)

CD20xCD3 bsAbs simultaneously bind to CD20 on

malignant B-cells and CD3 on nonmalignant T-cells,

leading to enhanced immune recognition and reaction against malignant cells, particularly through

cytotoxic T-cells. Glofitamab is a CD20xCD3 bispecific antibody which is administered intravenously

every 3 weeks for 12 doses. In the phase 1 trial,

which included 37 patients with R/R MCL who were

heavily pretreated with a median of 3 (range 1-5)

lines of therapy including prior BTKi use in n = 24

and CAR-T in n = 2, time-limited therapy with glofitamab was associated with 84% ORR and 73% CR.

About 3 in 4 patients developed CRS, but grade ≥3

CRS occurred in 16%. Neutropenia and infections

were common [42]. Longer follow-up will be required

to determine whether the CR will be durable.

Epcoritamab and mosunetuzumab are other

CD20xCD3 bsAbs being investigated in R/R MCL.

Limited data suggest these agents are also highly

active in R/R MCL [43,44].

Given the emerging data on single-agent and combination activity with bsAbs across B-cell NHL and the

similarities with CAR-T in terms of mechanisms of

action and toxicity, bsAbs may emerge as counterparts

to CAR-T therapy. Response rates with glofitamab are

numerically similar to those documented with CAR-T,

and time-limited therapy is feasible with glofitamab

(12 cycles) or mosunetuzumab (8 cycles if CR, continue

for up to 17 cycles if PR/SD). bsAbs have been

described as ‘off the shelf’ because they do not require

the individual manufacturing process of CAR-T, which

means these agents can be readily administered to

patients, eliminating the need for holding/bridging

therapy. bsAbs could be ideal in certain scenarios such

as patients who decline or are ineligible for CAR-T,

with the added advantage that agents such as epcoritamab and mosunetuzumab can be administered subcutaneously. Even though bsAbs seem to have lower

rates of CRS and neurologic toxicity than CAR-T,

RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA 7

treatment initiation remains resource intensive with

the need for hospital admission and potentially supportive care with steroids and/or tocilizumab in many

patients. Finally, it is unknown whether either modality

is curative or at least achieves the longest treatment-free

remission.

Antibody drug conjugates

Zilovertamab vedotin (ZV) is a novel ADC that is

comprised of a humanized monoclonal antibody

against Receptor Tyrosine Kinase-Like Orphan

Receptor 1(ROR1), as well as a tumor promoting factor and a proteolytically cleavable linker and the

anti-microtubule monomethyl auristatin E. In the

waveLINE-001 phase 1 trial, ZV demonstrated activity

against a broad range of R/R B-cell lymphomas

including MCL where the ORR was 53% mostly in the

form of partial responses. As expected for an ADC

containing vedotin, peripheral neuropathy is a common AE (Table 5) [45]. There are emerging combination data with ibrutinib [46] and a study of ZV as

monotherapy and in combination with nemtabrutinib

in R/R MCL (NCT05458297) is recruiting.

Polatuzumab vedotin is an anti-CD79B ADC. Single

agent data in R/R MCL are very limited (Table 5). [47]

Preliminary data with fixed-duration polatuzumab

vedotin and mosunetuzumab in 20 patients with R/R

MCL showed a 70% CR, including patients with

high-risk subgroups or prior CAR-T [43]. It is likely that

ADCs will be developed as part of combinations with

BTKi or other novel drugs given non-overlapping

mechanisms of action and the potential for time-limited

therapy.

Table 5. Emerging therapies in R/R MCL.

Therapy Study Number of patients ORR CR Median PFS

Venetoclax Davids et  al. [37] 28 75% 21% 14months

Eyre et  al. [38] 20 53% 18% 3.2months

Venetoclax plus ibrutinib Wang et  al. [22] 134 82% 54% 31.9months

Tam et  al. [73] 24 71% 62% NR, 57% at 18months

Glofitamab Philips et  al. [42] 29 81% 67% NA

Zilovertamab vedotin Wang et  al. [45] 17 53% 12% NA

Mosunetuzumab plus

polatuzumab

Wang et  al. [43] 20 75% 73% NA

Parsaclisib Mehta et  al. [48] 108 69% 18% 11.9months

Abbreviations: ORR: overall response rate; CR: complete response; PFS: Progression free survival; NR: not reached; f/u: follow-up; NA: not available.

Figure 1. A proposed treatment algorithm for the management of patients with R/R MCL.

Abbreviations: 1L: first line, 2L: second line, 3L: third line, R-CHEMO: rituximab plus chemotherapy, ASCT: autologous stem cell transplantation, MR: maintenance rituximab, M: maintenance, ncBTKi: non-covalent Bruton tyrosine inhibitor, CART: chimeric antigen receptor, AlloSCT: allogeneic stem cell transplantation., ven: venetoclax, PD: progressive disease, bs Abs: bi-specific antibodies, ADC: antibody-drug conjugate.

8 M. ALZAHRANI AND D. VILLA

Agents with limited clinical and/or

commercial interest

Parsaclisib, umbralisib and copanlisib are PI3K inhibitors that have been evaluated in R/R MCL [48–51].

Despite moderate clinical activity and the potential for

combinations with other small molecule inhibitors

such as BTKi, it is unknown whether they will move

forward in MCL given efficacy and toxicity concerns in

other NHL [49,50,52]. Cyclin dependent kinase 4/6

inhibitors such as abemaciclib and palbociclib also

have moderate clinical activity in R/R MCL and can be

combined with BTKi [53,54]. Despite the strong scientific rationale behind their use in MCL where cell cycle

disruption is a key biologic feature, these drugs have

not moved forward possibly because of lower than

expected response rates.

Conclusions and future directions

The management of R/R MCL has rapidly evolved over

the past decade. The introduction of BTKi, CAR-T and

other novel agents has improved disease control and

patient outcomes. We present a proposed treatment

algorithm approach to the treatment of R/R MCL

based on the data presented in this review. (Figure 1)

This algorithm recognizes the increasing role of BTKi

as part of front-line therapy of MCL, as well as emerging scenarios in the R/R setting where BTKi as monotherapy or in combination with venetoclax may not

achieve durable disease control and where CAR-T therapy may play an important role as part of second-line

therapy [36].

Over the next decades, we anticipate additional

data informing the single agent efficacy and toxicity

of the novel therapeutics described in this review.

We also anticipate these agents will be increasingly

evaluated as part of combinations that exploit potentially synergistic mechanisms of action, including

combinations targeting emerging mechanisms of

resistance to one or more agents. These agents will

be increasingly used in the frontline setting, particularly in patients with high-risk disease biology including the presence of TP53 mutations, where BTKi may

be preferred given the suboptimal outcomes with

standard chemoimmunotherapy (NCT03824483,

NCT05951959).

Similar to the experience with BTKi and CAR T-cell

therapy, these major advances will generate new challenges particularly the need for access to additional

therapies for the management of highly refractory disease. Unfortunately, most patients will not be cured

with these therapies. It will be crucial to evaluate

long-term outcomes in patients who achieve deep

remissions with time-limited therapies such as CAR-T

or bsAbs to determine whether there is a true potential for cure. If cure seems plausible, strategies will be

necessary to bring these therapies earlier in the course

of treatment, ideally with less toxicity, and importantly

with broader patient access.

Authors’ contributions

MA and DV wrote the manuscript.

Disclosure statement

DV: Advisory boards and honoraria from: Roche, BeiGene,

AstraZeneca, Janssen, Abbvie, Merck, Kite/Gilead, BMS/Celgene,

Incyte. Research funding (to the institution): Roche, Astra

Zeneca. MA: Advisory boards and honoraria from: Roche,

Takeda, AstraZeneca, Janssen, Abbvie, Amgen, Novartis.

Funding

The author(s) reported there is no funding associated with

the work featured in this article.

ORCID

Musa Alzahrani http://orcid.org/0000-0002-0895-5114

Diego Villa http://orcid.org/0000-0002-4625-3009

References

[1] Teras LR, DeSantis CE, Cerhan JR, et  al. 2016US lymphoid malignancy statistics by world health organization subtypes. CA Cancer J Clin. 2016;66(6):443–459.

doi:10.3322/caac.21357

[2] Shakir R, Ngo N, Naresh KN. Correlation of cyclin D1

transcript levels, transcript type and protein expression

with proliferation and histology among mantle cell lymphoma. J Clin Pathol. 2008;61(8):920–927. doi:10.1136/

jcp.2008.057455

[3] Schaffel R, Hedvat CV, Teruya-Feldstein J, et al. Prognostic

impact of proliferative index determined by quantitative

image analysis and the international prognostic index in

patients with mantle cell lymphoma. Ann Oncol.

2010;21(1):133–139. doi:10.1093/annonc/mdp495

[4] Determann O, Hoster E, Ott G, et  al. Ki-67 predicts outcome in advanced-stage mantle cell lymphoma patients

treated with anti-CD20 immunochemotherapy: results

from randomized trials of the european MCL network

and the german low grade lymphoma study group.

Blood. 2008;111(4):2385–2387. doi:10.1182/blood-2007-

10-117010

[5] Hoster E, Dreyling M, Klapper W, et  al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558–565.

doi:10.1182/blood-2007-06-095331

RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA 9

[6] Obr A, Klener P, Furst T, et  al. A high TP53 mutation

burden is a strong predictor of primary refractory mantle cell lymphoma. Br J Haematol. 2020;191(5):e103–e6.

doi:10.1111/bjh.17063

[7] Hermine O, Hoster E, Walewski J, et al. Addition of high-dose

cytarabine to immunochemotherapy before autologous

stem-cell transplantation in patients aged 65 years or

younger with mantle cell lymphoma (MCL younger): a randomised, open-label, phase 3 trial of the european mantle

cell lymphoma network. Lancet. 2016;388(10044):565–575.

doi:10.1016/S0140-6736(16)00739-X

[8] Kumar A. What is the role of up-front autologous stem cell

transplantation in mantle cell lymphoma? Hematology Am

Soc Hematol Educ Program. 2022;2022(1):155–162.

doi:10.1182/hematology.2022000333

[9] Le Gouill S, Thieblemont C, Oberic L, et  al. Rituximab

after autologous stem-cell transplantation in Mantle-Cell

lymphoma. N Engl J Med. 2017;377(13):1250–1260.

doi:10.1056/NEJMoa1701769

[10] Rummel M, Kaiser U, Balser C, et  al. Bendamustine plus

rituximab versus fludarabine plus rituximab for patients

with relapsed indolent and mantle-cell lymphomas: a

multicentre, randomised, open-label, non-inferiority

phase 3 trial. Lancet Oncol. 2016;17(1):57–66.

doi:10.1016/S1470-2045(15)00447-7

[11] Wang ML, Jurczak W, Jerkeman M, et  al. Ibrutinib plus

bendamustine and rituximab in untreated Mantle-Cell lymphoma. N Engl J Med. 2022;386(26):2482–2494. doi:10.1056/

NEJMoa2201817

[12] Dreyling M, Doorduijn J, Gine E, et  al. Efficacy and safety

of ibrutinib combined with standard first-line treatment

or as substitute for autologous stem cell transplantation

in younger patients with mantle cell lymphoma: results

from the randomized triangle trial by the European MCL

network. USA: American Society Of Hematology; 2022. p.

1–3. doi:10.1182/blood-2022-163018

[13] Kumar A, Eyre TA, Lewis KL, et  al. New directions for

mantle cell lymphoma in 2022. Am Soc Clin Oncol Educ

Book. 2022;42:1–15. doi:10.1200/EDBK_349509

[14] Kumar A, Sha F, Toure A, et  al. Patterns of survival in

patients with recurrent mantle cell lymphoma in the

modern era: progressive shortening in response duration and survival after each relapse. Blood Cancer J.

2019;9(6):50. doi:10.1038/s41408-019-0209-5

[15] Munshi PN, Hamadani M, Kumar A, et  al. American society of transplantation and cellular therapy, center of international blood and marrow transplant research, and european society for blood and marrow transplantation clinical

practice recommendations for transplantation and cellular

therapies in mantle cell lymphoma. Transplant Cell Ther.

2021;27(9):720–728. doi:10.1016/j.jtct.2021.03.001

[16] Burkart M, Karmali R. Relapsed/refractory mantle cell

lymphoma: beyond BTK inhibitors. J Pers Med.

2022;12(3):376. doi:10.3390/jpm12030376

[17] Wang ML, Rule S, Martin P, et  al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl

J Med. 2013;369(6):507–516. doi:10.1056/NEJMoa1306220

[18] Wang M, Goy M, Martin P, et al. Efficacy and safety of single

agent ibrutinib in patients with mantle cell lymphoma who

progressed after bortezomib therapy. Blood (2014) 124 (21):

4471. https://doi.org/10.1182/blood.V124.21.4471.4471

[19] Dreyling M, Goy A, Hess G, et al. Long-term outcomes with

ibrutinib treatment for patients with relapsed/refractory

mantle cell lymphoma: a pooled analysis of 3 clinical trials

with nearly 10 years of follow-up. Hemasphere.

2022;6(5):e712. doi:10.1097/HS9.0000000000000712

[20] Song Y, Zhou K, Zou D, et  al. Zanubrutinib in relapsed/

refractory mantle cell lymphoma: long-term efficacy

and safety results from a phase 2 study. Blood.

2022;139(21):3148–3158. doi:10.1182/blood.2021014162

[21] Byrd JC, Hillmen P, Ghia P, et  al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia:

results of the first randomized phase III trial. J Clin Oncol.

2021;39(31):3441–3452. doi:10.1200/JCO.21.01210

[22] Wang M, Jurczak W, Trněný M, et  al. Ibrutinib combined

with venetoclax in patients with relapsed/refractory

mantle cell lymphoma: Primary analysis results from

the randomized phase 3 sympatico study. Blood. 2024

Feb 22;143(8):673–684. doi: 10.1182/blood.2023021306.

[23] Burger JA. Bruton tyrosine kinase inhibitors: present

and future. Cancer J. 2019;25(6):386–393. doi:10.1097/

PPO.0000000000000412

[24] Mato AR, Shah NN, Jurczak W, et  al. Pirtobrutinib in

relapsed or refractory B-cell malignancies (BRUIN):

a phase 1/2 study. Lancet. 2021;397(10277):892–901.

doi:10.1016/S0140-6736(21)00224-5

[25] Wang ML, Jurczak W, Zinzani PL, et  al. Pirtobrutinib in

covalent bruton tyrosine kinase inhibitor pretreated

Mantle-Cell lymphoma. J Clin Oncol. 2023;41(24):3988–

3997. doi:10.1200/JCO.23.00562

[26] Martin P, Maddocks K, Leonard JP, et  al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood.

2016;127(12):1559–1563. doi:10.1182/blood-2015-10-673145

[27] Cheah CY, Chihara D, Romaguera JE, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to

salvage chemotherapy and have poor outcomes. Ann Oncol.

2015;26(6):1175–1179. doi:10.1093/annonc/mdv111

[28] Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell

therapy in relapsed or refractory mantle cell lymphoma.

NEJM 2020; 382:1331–1342.

[29] Wang M, Munoz J, Goy A, et  al. Three-Year follow-up of

KTE-X19 in patients with relapsed/refractory mantle cell

lymphoma, including high-risk subgroups, in the

ZUMA-2 study. J Clin Oncol. 2023;41(3):555–567.

doi:10.1200/JClinOncol.21.02370

[30] Kambhampati S, Ahmed N, Hamadani M, et  al.

Real-world outcomes of brexucabtagene autoleucel

(brexu-cel) for relapsed or refractory (R/R) mantle cell

lymphoma (MCL): a CIBMTR subgroup analysis by prior

treatment. J Clin Oncol. 2023;41(16_suppl):7507–7507.

doi:10.1200/JCO.2023.41.16_suppl.7507

[31] Wang Y, Jain P, Locke FL, et  al. Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in

standard-of-care practice: results from the US lymphoma CAR T consortium. J Clin Oncol. 2023;41(14):2594–

2606. doi:10.1200/JCO.22.01797

[32] Wang M, Siddiqi T, Gordon LI, et  al. Lisocabtagene

maraleucel in relapsed/refractory mantle cell lymphoma:

Primary analysis of the mantle cell lymphoma cohort

from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol. 2023;42(10):1146–1157.

doi:10.1200/JCO.23.02214

10 M. ALZAHRANI AND D. VILLA

[33] Minson A, Hamad N, Cheah CY. A phase II, Open-Label,

single arm trial to assess the efficacy and safety of the

combination of tisagenleucel and ibrutinib in mantle cell

lymphoma (TARMAC). Blood 2024; 143 (8): 673–684.

[34] Gauthier J, Hirayama AV, Purushe J, et  al. Feasibility and

efficacy of CD19-targeted CAR T cells with concurrent

ibrutinib for CLL after ibrutinib failure. Blood.

2020;135(19):1650–1660. doi:10.1182/blood.2019002936

[35] Ruella M, Kenderian SS, Shestova O, et  al. Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for

B-cell neoplasms. Leukemia. 2017;31(1):246–248.

doi:10.1038/leu.2016.262

[36] Villa D, Jiang A, Visco C, et  al. Time to progression of

disease and outcomes with second-line BTK inhibitors

in relapsed/refractory mantle cell lymphoma. Blood

Adv. 2023;7(16):4576–4585. doi:10.1182/bloodadvances.2023009804

[37] Davids MS, Roberts AW, Seymour JF, et  al. Phase I

first-in-Human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin

Oncol. 2017;35(8):826–833. doi:10.1200/JCO.2016.70.4320

[38] Eyre TA, Walter HS, Iyengar S, et  al. Efficacy of venetoclax monotherapy in patients with relapsed, refractory

mantle cell lymphoma after bruton tyrosine kinase inhibitor therapy. Haematologica. 2019;104(2):e68–e71.

doi:10.3324/haematol.2018.198812

[39] Portell CA, Wages NA, Kahl BS, et  al. Dose-finding study

of ibrutinib and venetoclax in relapsed or refractory

mantle cell lymphoma. Blood Adv. 2022;6(5):1490–1498.

doi:10.1182/bloodadvances.2021005357

[40] Le Gouill S, Morschhauser F, Chiron D, et  al. Ibrutinib,

obinutuzumab, and venetoclax in relapsed and untreated

patients with mantle cell lymphoma: a phase 1/2 trial.

Blood. 2021;137(7):877–887. doi:10.1182/blood.2020008727

[41] Frustaci AM, Soumerai JD, Lasica M, et  al. A phase 1 study

with the novel B-cell lymphoma 2 inhibitor sonrotoclax

(BGB-11417) as monotherapy or in combination with zanubrutinib in patients with non-Hodgkin lymphoma or

waldenstrom macroglobulinemia: Preliminary data.

Presented at the 50th italian society of hematology national congress, October 2023. Rome, Italy. https://www.

beigenemedical.com/CongressDocuments/Frustaci_BGB11417-101_SIE_Poster_2023.pdf

[42] Phillips T, Dickinson M, Morschhauser F, et  al. Glofitamab

step-up dosing induced high response rates in patients

(its) with relapsed or refractory (R/R) mantle cell lymphoma (MCL), most of whom had failed prior bruton’s tyrosine

kinase inhibitor (BTKi) therapy. Blood. 2021;138(Supplement

1):130–130. doi:10.1182/blood-2021-148949

[43] Wang M, Assouline S, Kamdar M, et  al. Fixed duration

mosunetuzumab plus polatuzumab vedotin has promising

efficacy and a manageable safety profile in patients with

BTKi relapsed/refractory mantle cell lymphoma: initial results from a phase Ib/II study. Blood (2023) 142 (Supplement

1): 734. https://doi.org/10.1182/blood-2023-174956.

[44] van der Horst HJ, de Jonge AV, Hiemstra IH, et  al.

Epcoritamab induces potent anti-tumor activity against

malignant B-cells from patients with DLBCL, FL and

MCL, irrespective of prior CD20 monoclonal antibody

treatment. Blood Cancer J. 2021;11(2):38. doi:10.1038/

s41408-021-00430-6

[45] Wang M, Mei M, Barr PM, et  al. Zilovertamab vedotin

(MK-2140) for the treatment of non-hodgkin lymphoma:

the phase I dose escalation and cohort expansion

waveline-001 study of an anti-ror1 antibody-drug

congugate. HemaSphere. 2022;6:1116–1117. doi:10.1097/01.

HS9.0000847788.96420.63

[46] Lee H, Choi M, Siddiqi T, et  al. Phase 1/2 study of zilovertamab and ibrutinib in mantle cell lymphoma

(MCL), chronic lymphocytic leukemia (CLL), or marginal

zone lymphoma (MZL). Blood. 2022;140(Supplement

1):566–568. doi:10.1182/blood-2022-167153

[47] Palanca-Wessels MCA, Czuczman M, Salles G, et al. Safety

and activity of the anti-CD79B antibody-drug conjugate

polatuzumab vedotin in relapsed or refractory B-cell

non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16(6):704–

715. doi:10.1016/S1470-2045(15)70128-2

[48] Mehta A, Trněný M, Walewski J, et  al. Efficacy and safety of parsaclisib in patients with relapsed or refractory

mantle cell lymphoma not previously treated with a

BTK inhibitor: Primary analysis from a phase 2 study

(CITADEL-205). Blood. 2021;138(Supplement 1):382–382.

doi:10.1182/blood-2021-147867

[49] Song Y, Li J, Zhou K, et  al. Umbralisib in combination

with ibrutinib in patients with relapsed or refractory

chronic lymphocytic leukaemia or mantle cell lymphoma: a multicentre phase 1-1b study. Leuk Lymphoma.

2019;6(1):e38–e47. doi:10.1016/S2352-3026(18)30196-0

[50] Qualls D, Lam HY, Whiting K, et  al. A phase 1 trial of

copanlisib plus ibrutinib in relapsed/refractory mantle

cell lymphoma. Blood Adv. 2022;6(18):5262–5266.

doi:10.1182/bloodadvances.2021006555

[51] Dreyling M, Santoro A, Mollica L, et  al.

Phosphatidylinositol 3-kinase inhibition by copanlisib in

relapsed or refractory indolent lymphoma. J Clin Oncol.

2017;35(35):3898–3905. doi:10.1200/JCO.2017.75.4648

[52] Batlevi C, Hamlin P, Matasar M, et  al. Phase I/IB dose

escalation and expansion of ibrutinib and buparlisib in

relapsed/refractory diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma. Hematol

Oncol. 2017;35(S2):54–54. doi:10.1002/hon.2437_38

[53] Morschhauser F, Bouabdallah K, Stilgenbauer S, et  al.

Clinical activity of abemaciclib in patients with relapsed

or refractory mantle cell lymphoma - a phase II study.

Haematologica. 2021;106(3):859–862. doi:10.3324/haematol.2019.224535

[54] Martin P, Bartlett NL, Blum KA, et  al. A phase 1 trial of

ibrutinib plus palbociclib in previously treated mantle cell

lymphoma. Blood. 2019;133(11):1201–1204. doi:10.1182/

blood-2018-11-886457

[55] Hess G, Herbrecht R, Romaguera J, et  al. Phase III study

to evaluate temsirolimus compared with investigator’s

choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009;27(23):3822–

3829. doi:10.1200/JCO.2008.20.7977

[56] Renner C, Zinzani PL, Gressin R, et  al. A multicenter

phase II trial (SAKK 36/06) of single-agent everolimus

(RAD001) in patients with relapsed or refractory mantle

cell lymphoma. Haematologica. 2012;97(7):1085–1091.

doi:10.3324/haematol.2011.053173

[57] Goy A, Bernstein SH, Kahl BS, et al. Bortezomib in patients

with relapsed or refractory mantle cell lymphoma: updat-

RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA 11

ed time-to-event analyses of the multicenter phase 2

PINNACLE study. Ann Oncol. 2009 Mar;20(3):520-5. doi:

10.1093/annonc/mdn656.

[58] Trněný M, Lamy T, Walewski J, et  al. Lenalidomide

versus investigator’s choice in relapsed or refractory

mantle cell lymphoma (MCL-002; SPRINT): a phase 2,

randomised, multicentre trial. Lancet Oncol. 2016;

17(3):319–331. doi:10.1016/S1470-2045(15)00559-8

[59] Goy A, Kalayoglu Besisik S, Drach J, et  al. Longer-term

follow-up and outcome by tumour cell proliferation

rate (Ki-67) in patients with relapsed/refractory mantle

cell lymphoma treated with lenalidomide on

MCL-001(EMERGE) pivotal trial. Br J Haematol.

2015;170(4):496–503. doi:10.1111/bjh.13456

[60] Czuczman MS, Goy A, Lamonica D, et  al. Phase II study

of bendamustine combined with rituximab in relapsed/

refractory mantle cell lymphoma: efficacy, tolerability,

and safety findings. Ann Hematol. 2015;94(12):2025–

2032. doi:10.1007/s00277-015-2478-9

[61] Visco C, Di Rocco A, Evangelista A, et  al. Outcomes in first

relapsed-refractory younger patients with mantle cell lymphoma: results from the MANTLE-FIRST study. Leukemia.

2021;35(3):787–795. doi:10.1038/s41375-020-01013-3

[62] Obrador-Hevia A, Serra-Sitjar M, Rodríguez J, et  al.

Efficacy of the GemOx-R regimen leads to the identification of oxaliplatin as a highly effective drug against

mantle cell lymphoma. Br J Haematol. 2016;174(6):899–

910. doi:10.1111/bjh.14141

[63] Hamadani M, Saber W, Ahn KW, et  al. Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive

mantle cell lymphoma: a cohort analysis from the center

for international blood and marrow transplant research.

Biol Blood Marrow Transplant. 2013;19(4):625–631.

doi:10.1016/j.bbmt.2013.01.009

[64] Cook G, Smith GM, Kirkland K, et  al. Outcome following

Reduced-Intensity allogeneic stem cell transplantation

(RIC AlloSCT) for relapsed and refractory mantle cell lymphoma (MCL): a study of the british society for blood and

marrow transplantation. Biol Blood Marrow Transplant.

2010;16(10):1419–1427. doi:10.1016/j.bbmt.2010.04.006

[65] Dreyling M, Jurczak W, Jerkeman M, et  al. Ibrutinib versus temsirolimus in patients with relapsed or refractory

mantle-cell lymphoma: an international, randomised,

open-label, phase 3 study. Lancet. 2016;387(10020):770–

778. doi:10.1016/S0140-6736(15)00667-4

[66] Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a

single-arm, multicentre, phase 2 trial. The Lancet Volume

391, Issue 10121, 17–23 February 2018, Pages 659–667

[67] Tam CS, Lamanna N, O'Brien SM, et  al. Zanubrutinib for

the treatment of relapsed or refractory mantle cell lymphoma. Curr Med Res Opin. 2021;5(12):1–7. doi:10.1182/

bloodadvances.2020004074

[68] Zhou K, Zou D, Zhou J, et  al. Zanubrutinib monotherapy in relapsed/refractory mantle cell lymphoma: a

pooled analysis of two clinical trials. J Hematol Oncol.

2021;14(1):167. doi:10.1186/s13045-021-01174-3

[69] Palomba ML, Gordon LI, Siddiqi T, et  al. Safety and preliminary efficacy in patients with relapsed/refractory

mantle cell lymphoma receiving lisocabtagene maraleucel in transcend NHL-001. Blood. 2020;136(Supplement

1):10–11. doi:10.1182/blood-2020-136158

[70] Romancik JT, Goyal S, Gerson JN, et  al. Analysis of

outcomes and predictors of response in patients with

relapsed mantle cell lymphoma treated with brexucabtagene autoleucel. Blood. 2021;138(Supplement 1):

1756–1756. doi:10.1182/blood-2021-153277

[71] O'Reilly MA, Sanderson R, Wilson W, et al. Brexucabtagene

autoleucel for relapsed/refractory mantle cell lymphoma: real-World outcomes in the United Kingdom.

Blood. 2022;140(Supplement 1):7519–7521. doi:10.1182/

blood-2022-165031

[72] Iacoboni G, Rejeski K, Villacampa G, et  al. Real-world

evidence of brexucabtagene autoleucel for the treatment of relapsed or refractory mantle cell lymphoma.

Blood Adv. 2022;6(12):3606–3610. doi:10.1182/bloodadvances.2021006922

[73] Tam CS, Anderson MA, Pott C, et  al. Ibrutinib plus venetoclax for the treatment of Mantle-Cell lymphoma. N Engl J

Med. 2018;378(13):1211–1223. doi:10.1056/NEJMoa1715519