The shifting therapeutic paradigm for relapsed/refractory mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a heterogeneous subtype of non-Hodgkin lymphoma that has been historically associated with poor 5-year overall survival rates, especially for aggressive variants. Traditional cytotoxic chemotherapy had been a mainstay of therapy for relapsed/refractory (R/R) MCL for many years until the advent of molecularly targeted therapies and cell-based approaches. However, a significant concern is the lack of definitive consensus guidelines for management of R/R MCL. The managerial conundrum partly stems from the absence of head-to-head comparisons of novel therapies, with conclusions drawn from cross-trial comparisons. In this evidence-based review, we discuss the current therapeutic options for R/R MCL, including the most recent data from the BRUIN study that led to the approval of the first-in-class non-covalent reversible Bruton’s tyrosine kinase (BTK) inhibitor pirtobrutinib in 2023, as well as the recent removal of ibrutinib from the market. We discuss outlooks for targeted therapy and tolerability considerations for novel agents, including unique considerations for the elderly population. We highlight emerging data that support the curative potential of chimeric antigen receptor-T (CAR-T) therapy from ZUMA-2, relative to other promising investigational agents in the pipeline, including glofitamab, epcoritamab, and zilovertamab vedotin. We summarize management recommendations based upon the most rigorous clinical evidence to date.

1. Introduction

Mantle cell lymphoma (MCL) is a subset of non-Hodgkin lymphoma characterized by clonal proliferation of mature B cells, often due to the hallmark cyclin D1 translocation and sometimes cyclin D2 or D3 translocations [1]. It typically represents 5–10 % of all non-Hodgkin lymphomas worldwide. MCL is a clinically heterogeneous disease partly due to the cell of origin: MCL can arise from naïve-like cells or memory-like cells of the adaptive immune system. These have clinical relevance as tumors arising from naïve-like cells are known to harbor fewer somatic mutations with a high risk for progression. In contrast, tumors from memory-like cells harbor many somatic mutations but have an indolent course. Though MCL has two subtypes based on the cell of origin, the proliferation largely depends on B cell receptor signaling due to their restricted immunoglobulin gene repertoire [2]. In the past, MCL has been reported to have poor 5-year overall survival (OS) and 5-year failure-free survival [2,3]. R/R MCL is sometimes considered as an incurable disease, and the goal of management is often to prolong survival and reduce disease-related symptoms [4].

The therapeutic landscape of relapsed/refractory (R/R) MCL has been a topic of great interest in recent years as novel therapeutic modalities have arisen from molecular target validation. For more than two decades, the backbone of treatment for R/R MCL involved anthracycline-based chemotherapy or other types of cytotoxic antimetabolite chemotherapy. The addition of rituximab was a major molecular-based therapeutic breakthrough for treating CD20-positive disease. Autologous stem cell transplantation (ASCT) has also made its way into the standard of care. However, a significant unmet need in R/R MCL was the design of precision therapeutics based on disease biology and cell surface targets. Molecular target validation has led to critical translational insights into novel therapies for R/R MCL, and we now have highly selective Bruton’s tyrosine kinase (BTK) inhibitors and autologous cell-based therapeutics, which are discussed herein (Fig. 1).

Fig. 1.

Summary of novel FDA-approved and investigational therapies for R/R MCL, organized by class/mechanism of action. Clinical trial names for these agents are shown, if applicable.

2. FDA approvals for R/R mantle cell lymphoma

2.1. Ibrutinib

2.1.1. Development

In the 2010 s, a breakthrough in management options for aggressive MCL was the ‘need of the hour,’ given the highly myelosuppressive adverse effects of conventional chemotherapy regimens such as rituximab plus hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone), rituximab plus ICE (ifosfamide, carboplatin, etoposide), and ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) [5]. The first demonstration of molecularly targeted oral therapy in MCL was the first-in-class irreversible BTK inhibitor ibrutinib (PCI-32765). BTK is expressed in the cytoplasm of myeloid and B cells and plays a pivotal role in B cell proliferation, forming the basis for using ibrutinib as an oral targeted therapy for various B cell malignancies [6,7]. In vitro data showed the efficacy of ibrutinib in chronic lymphocytic leukemia (CLL) cells [7].

2.1.2. Pivotal clinical trial data

In 2013, the first clinical phase 1 study involving R/R B cell malignancies showed ibrutinib’s highest response rate (78 %) in MCL. This was a breakthrough as, at the time, bortezomib and lenalidomide were the only Food & Drug Administration (FDA)-approved agents for R/R MCL with a modest response (overall response rate (ORR) 31 % and 26 %, respectively) [8,9]. Catapulting from this was an international open-label phase 2 trial (PCYC-1104) with ibrutinib 560 mg daily for R/R MCL (median of three prior therapies). One hundred eleven patients with a median follow-up of 15.2 months achieved a response rate of 68 %, irrespective of bortezomib pre-treatment, with most side effects limited to grades 1 and 2 [10]. This led to the FDA approval of ibrutinib in 2013 for treating R/R MCL. Another open-label phase II trial, the SPARK trial, studied ibrutinib in patients with R/R MCL who progressed after the rituximab-containing regimens [11]. In 2016, the randomized open-label multicentric phase III RAY trial comparing ibrutinib and temsirolimus in R/R MCL showed improvement in median progression-free survival (PFS) (14.6 months vs. 6.2 months) with lower grade 3 or higher adverse events (AEs) (68 % vs. 87 %) in favor of ibrutinib [12]. Pooled analysis of PCYC-1104, SPARK, and RAY trials suggested better patient outcomes across all clinical endpoints (PFS, OS, ORR, and complete response (CR)) with ibrutinib as a second line of treatment compared to other investigational therapies for R/R MCL. With the same patient pool, a comprehensive study with a 3.5-year follow-up resonated similar findings [13,14].

2.1.3. FDA approval and usage

Ibrutinib was granted accelerated approval for adult patients with R/R MCL who have received at least one prior therapy at a dose of 560 mg daily until intolerable adverse effects or disease progression. It was then removed from the market in April 2023 after SHINE trial data emerged [15].

2.2. Acalabrutinib

2.2.1. Development

Though ibrutinib was considered a game-changing medication in R/R MCL, several AEs from its off-target inhibition were noted. These included bleeding manifestations (up to 50 %) from inhibiting tyrosine kinases, skin rashes and diarrhea from inhibiting epidermal growth factor receptor, and atrial fibrillation (up to 5 %) from inhibiting phosphatidylinositol 3-kinase in cardiac myocytes. In addition, there were also concerns about the development of resistance due to the over-dependence of the first-in-class BTK inhibitor ibrutinib in managing R/R MCL. There was a need for second-generation BTK inhibitors, which led to the introduction of acalabrutinib (ACP-196), an irreversible BTK inhibitor. Acalabrutinib is a potent agent with rapid oral absorption, a short half-life, and a wide therapeutic index [16].

2.2.2. Pivotal clinical trial data

Before its use in R/R MCL, acalabrutinib was first studied in phase 1/2 multicenter ACE-CL-001 involving R/R CLL, and ORRs were 95–100 % with no dose-limiting toxicities. This study standardized the dose of acalabrutinib to 100 mg twice daily for continuous 24-hour irreversible BTK inhibition [17,18]. The open-label, single-arm multicenter phase 2 ACE-LY-004 trial involving 124 patients with R/R MCL with a median follow-up of 15.2 months showed an ORR of 81 %, CR rate of 40 %, and treatment-related severe (grade 3 or higher) AE rate of only 10 % [19]. A follow-up study from the same patient cohort of the ACE-LY-004 study with a median 26-month follow-up showed a durable response with similar ORR, CR rate, and AEs as before. The median PFS was 20 months [20].

2.2.3. FDA approval and usage

Acalabrutinib was approved for patients with R/R MCL who have received at least one prior therapy at 100 mg twice daily until disease progression or unacceptable toxicity.

2.3. Zanubrutinib

2.3.1. Development

Following successful clinical studies from ibrutinib and acalabrutinib, novel second-generation targeted therapy was developed to improve the depth of response and further minimize AEs. One among them was zanubrutinib. Like ibrutinib and acalabrutinib, zanubrutinib is a covalent irreversible inhibitor with more selective BTK inhibition than prior-generation BTK inhibitors.

2.3.2. Pivotal clinical trial data

Zanubrutinib’s first-in-human, open-label, multicenter, phase 1 study involving 89 CLL patients showed ORR of 96 %, with an estimated PFS at 12 months of 100 %. These analyses were at a median follow-up of 13.7 months. Zanubrutinib has a longer half-life than acalabrutinib (4 h vs. 1 h, respectively), suggesting that zanubrutinib can achieve more profound and more durable sustained remissions. Continuous BTK inhibition at oral dosing of 160 mg twice daily accounts for some favorable results [21]. Subgroup analysis for R/R MCL at a median follow-up of 18.8 months showed ORR of 84 %, CR rate of 25 %, and median PFS of 21.1 months. In addition, zanubrutinib demonstrated favorable tolerability with a low incidence of grade 3 or higher AEs, such as diarrhea (3.1 %), thrombocytopenia (6.3 %), neutropenia (9.4 %), and anemia (12.5 %) [21,22]. A major trial for zanubrutinib was a phase 2 open-label trial involving 86 patients with R/R MCL with a median follow-up of 35.3 months [23]. Consistent with prior trials, single-agent zanubrutinib demonstrated deep and durable responses irrespective of blastoid histology or bulky disease (ORR 83.7 %, CR rate 77.9 %, median PFS 33.0 months) with essentially unchanged safety profile with extended follow-up [23].

2.3.3. FDA approval and usage

In 2019, zanubrutinib received accelerated approval for adult patients with MCL who have failed at least one prior therapy. Zanubrutinib can be administered with one of two dosing regimens, 160 mg orally twice daily or 320 mg orally once daily, until disease progression or unacceptable toxicity.

2.4. Brexucabtagene autoleucel

2.4.1. Development

Though BTK inhibitors changed the landscape of management of R/R MCL, the development of primary and secondary resistance posed a significant challenge [24]. BTK inhibitor treatment failure sparked interest in alternative targets for drug development for R/R MCL. Inadequate responses to subsequent treatment following ibrutinib’s failure conferred poor survival outcomes, with a median OS of 4 months in the R/R setting [25]. Another multicenter retrospective study reconfirmed a worse prognosis following ibrutinib failure with a median OS of 2.5 months, with no subsequent favorable therapy [26]. Similarly, poor outcomes were noted following acalabrutinib failure [27]. This led to research on the possible role of chimeric antigen receptor-T (CAR-T) cells in MCL, which emerged after molecular target validation of CD19.

2.4.2. Pivotal clinical trial data

Initial studies involving CD19-directed CAR-T therapy for a subgroup of patients with R/R MCL showed a CR duration of more than 17 months [28]. This led to further research of autologous CAR-T therapy, namely, brexucabtagene autoleucel (brexu-cel), for R/R MCL. The key trial was the phase 2, multicenter ZUMA-2 trial, in which brexu-cel (KTE-X19) was administered to patients with R/R MCL [29]. Results demonstrated an ORR of 85 % and CR rate of 59 %, consistent among all high-risk subgroups. The safety profile was similar to other CAR-T regimens from prior trials, with treatment-related grade 3 or higher AEs being cytopenia (94 %), neurotoxicity syndrome (31 %), and cytokine release syndrome (15 %) [29]. An extended follow-up analysis of 3 years showed durable responses (ORR of 91 %, CR rate of 68 %) with no new safety concerns [29].

2.4.3. FDA approval and usage

Brexu-cel was granted approval in 2020 for adult patients with R/R MCL. The recommended dose of brexu-cel is a single intravenous infusion of 2 × 10⁶ CAR-positive viable T cells per kg body weight (maximum 2 × 10⁸ CAR-positive viable T cells), preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.

2.5. Pirtobrutinib

2.5.1. Development

First and second-generation BTK inhibitors showed a great response in the initial management of R/R MCL. However, prolonged use led to treatment discontinuation/failure from unacceptable toxicities or acquired C481S mutation in the BTK enzyme. The C481S mutation prevents the formation of an irreversible covalent bond between drug and enzyme, reducing the efficacy of BTK inhibitors [30]. Hence a dire need for next-generation, highly selective, non-covalent, reversible inhibitors with activity against C481-mutated BTK led to the development of pirtobrutinib (LOXO-305).

2.5.2. Pivotal clinical trial data

The first-in-human multicenter phase 1/2 trial of pirtobrutinib enrolled 13 patients (9 CLL and 4 MCL) with advanced disease. Ten patients (7 with CLL, 3 with MCL) had progressed through ibrutinib, and two patients with CLL had developed C481 BTK mutation following ibrutinib exposure [31]. Among patients evaluated for an initial response, pirtobrutinib treatment showed 87.5 % response rate, including partial response (PR) in CLL patients with C481 BTK mutation. No dose-limiting toxicities or grade 3 AEs were noted with pirtobrutinib [31]. The open-label multicenter phase 1/2 BRUIN study of pirtobrutinib monotherapy included 61 patients with R/R MCL with several prior lines of therapy, including 52 patients with MCL exposed to prior BTK treatment. After six months, pirtobrutinib exhibited a wide therapeutic window on a 200 mg once-daily regimen with a commendable ORR of 52 % (CR of 25 %, PR of 27 %) in patients with R/R MCL pretreated with BTK inhibitors [32–34].

2.5.3. FDA approval and usage

Pirtobrutinib was granted accelerated approval in 2023 for R/R MCL after at least two lines of systemic therapy, including a BTK inhibitor. The recommended dose is 200 mg once daily until disease progression or unacceptable toxicity.

3. Unanswered questions and ongoing debates

The emergence of targeted therapeutics has helped many patients suffering from MCL, but the availability of numerous options has left clinicians with a challenging landscape to navigate in the R/R setting. The optimal management paradigm is a matter of debate, and such decisions must weigh the curative potential, efficacy, safety, and logistics of administering these therapies in concert with individualized goals of care for each patient. The advent of cell-based therapies and molecularly targeted therapies have improved outcomes. However, this novel treatment paradigm has significant challenges compared to standard salvage options for R/R MCL. We herein discuss the most salient questions.

Firstly, are MCL-directed targeted agents curative, or do they serve as mere bridges to curative intent options?

Currently, the field does not have sufficient long-term follow-up data for novel therapies to conclude whether targeted agents will replace salvage cytotoxic chemotherapy followed by transplantation for R/R MCL. The curative potential for BTK inhibitors will be determined by the depth and durability of remission across all subgroups of patients with MCL, including high-risk subgroups. If the goal of salvage therapy is curative intent, then cell-based therapies can be considered. Brexu-cel has arguably been shown to lead to highly durable remissions with high-risk MCL, but additional long-term data is needed [35]. The curative potential for CAR-T therapies, in general, may depend on the ability to deliver high-dose therapy followed by autologous stem cell rescue. The curative potential of a specific novel agent may be limited by a unique biological phenotype, such as CD19 dependence for brexu-cel, constitutive BTK activation for BTK inhibitors, or ROR1 oncoprotein expression for zilovertamab vedotin. The immunophenotypic switch of surface antigens poses a barrier to durable responses.

Secondly, how does the unique toxicity profile for novel MCL-directed therapies compare with traditional chemotherapy?

Traditional therapy for physiologically fit patients with MCL includes high-dose chemotherapy (often araC-containing chemotherapy) followed by ASCT, then maintenance therapy with rituximab. However, mucosal barrier injury and other toxicities remain significant concerns with intense cytotoxic chemotherapy, especially since such therapies compromise one’s functional status and physiologic reserve. Novel agents confer less mucosal barrier toxicity but appear to have a higher risk for organ-specific toxicity, such as atrial fibrillation. In elderly patients with insufficient performance status, such novel agents may have limited tolerability. Comorbidities in the elderly may preclude the ability to deliver curative-intent treatments such as CAR-T cell therapy.

Thirdly, what are the financial implications of novel agents relative to traditional chemotherapy?

Medicare beneficiaries will likely comprise a significant portion of patients with R/R MCL receiving novel agents in the coming years. Cost and value considerations become important for novel agents in the R/R setting when determining the gain in quality-adjusted life-years (QALY). For example, the incremental cost-utility ratio has been studied in brexu-cel, and such studies have validated its use from a financial perspective [36]. QALY assessments for novel R/R MCL therapies can raise the bar for high-value care on a global scale. Novel BTK inhibitors like pirtobrutinib are likely to incur high individual and societal costs, and the risk-benefit ratio may need to be considered on an individualized basis. The societal costs of the various bispecific T cell engagers, such as glofitamab and epcoritamab, remain to be determined. It is worth weighing the institutional and out-of-pocket costs of such new modalities of therapies against an individual patient’s life expectancy (specifically, OS benefit) in the R/R setting.

4. Summary of current best evidence and emerging therapies

Management decisions for R/R MCL center on assessing disease risk alongside a patient’s physiologic well-being and therapy goals. Assessment of these variables often guides the treatment course of choice. For R/R MCL, we suggest evaluation of TP53 mutational status as well as eligibility for ASCT or CAR-T therapies. TP53 mutational status is especially worthy of consideration in the R/R setting. MCL with loss of function of TP53 tends to confer significantly worse outcomes, and these cells are often resistant to cytotoxic chemotherapy or BTK inhibitors due to impaired DNA damage response pathways. In some cases, an allogeneic stem cell transplant will be of benefit, or early deployment of CAR-T therapy may be appropriate [37]. Enrollment in a clinical trial is also a vital consideration (Table 1).

Table 1.

Summary of actively recruiting phase II/III clinical trials of novel therapeutics for R/R MCL as of August 2023.

Study Title	Class/Mechanism of action	Phase	Study Design	Study Start Date	NCT Number
Study of Brexucabtagene Autoleucel (KTE-X19) in Participants with Relapsed/Refractory Mantle Cell Lymphoma (Cohort 3)	CD19-targeted CAR-T cells	II	Single group; open label	Apr. 27, 2021	NCT04880434
Consolidation With Loncastuximab Tesirine After a Short Course of Immunochemotherapy in BTKi-treated (or Intolerant) Relapsed/Refractory Mantle Cell Lymphoma Patients	CD19-specific ADC	II	Single group; open label	Apr. 21, 2022	NCT05249959
A Study of Ibrutinib With Rituximab in Relapsed/Refractory Mantle Cell Lymphoma	BTKi, anti-CD20 mAb	II/III	Randomized; parallel assignment; open label	Dec. 6, 2022	NCT05564052
Ultra Low Dose Radiation Delivered Before or After Chemotherapy-Free Targeted Therapy in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma	Low-dose radiation	II	Single group; open label	June 14, 2019	NCT04054167
Study of BGB-11417 Monotherapy in Participants With Relapsed or Refractory Mantle Cell Lymphoma	Bcl-2 inhibitor	II	Single group; open label	Sept. 5, 2022	NCT05471843
Modified Immune Cells (CD19 CAR T Cells) and Acalabrutinib for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma	CD19-targeted CAR-T cells, BTKi	II	Single group; open label	Dec. 31, 2020	NCT04484012
Venetoclax and Acalabrutinib in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma	Bcl-2 Inhibitor, BTKi	II	Single group; open label	Aug. 13, 2019	NCT03946878
Copanlisib and Venetoclax for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma	PI3K inhibitor, Bcl-2 inhibitor	II	Single group; open label	June 29, 2022	NCT04939272
Polatuzumab Vedotin, Venetoclax, and Rituximab and Hyaluronidase Human for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma	CD79b-specific ADC, Bcl-2 inhibitor, anti-CD20 mAb	II	Single group; open label	Apr. 1, 2021	NCT04659044
Avo (Acalabrutnib, Venetoclax, Obinutuzumab) In R/R And Previously Untreated MCL	BTKi, Bcl-2 inhibitor, anti-CD20 mAb	II	Single group; open label	July 2, 2021	NCT04855695
First-in-Human Study of NVG-111 in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma	Anti-ROR1/CD3 bispecific T-cell-engager	II	Non-Randomized; parallel assignment; open label	May 14, 2021	NCT04763083
CD19-targeted CAR T Cells for Relapsed and Refractory (R/R) Mantle Cell Lymphoma	CD19-targeted CAR-T Cells	II	Single group; open label	Jan. 13, 2021	NCT04718883
A Safety and Pharmacokinetic Study of IGM-2323 in Subjects With Relapsed/Refractory Non-Hodgkin Lymphoma	Anti-CD20/CD3 bispecific T cell engager	II	Randomized; sequential assignment; open label	Sept. 30, 2019	NCT04082936
Loncastuximab Tesirine for the Treatment of Relapsed or Refractory B-Cell Malignancies	CD19-specific ADC	II	Single group; open label	May 18, 2023	NCT05453396
A Study of Tafasitamab and Lenalidomide in People With Mantle Cell Lymphoma	Anti-CD19 mAb, IMiD	II	Single group; open label	Mar. 14, 2023	NCT05788289
Treatment by a Bispecific CD3xCD20 Antibody for Relapse/Refractory Lymphomas After CAR T-cells Therapy	Anti-CD20 mAb, anti-CD20/CD3 bispecific T cell engager	II	Single group; open label	Mar. 30, 2021	NCT04703686
Phase I/II, FIH, Dose Escalation Trial of TL-895 and Expansion of TL-895 Monotherapy and Combination Therapy With Navtemadlin in Tx-Naïve and R/R CLL/SLL Subjects	BTKi, MDM2 inhibitor	II	Randomized; sequential assignment; open label	Aug. 26, 2016	NCT02825836
Phase II Study of Pirtobrutinib With Venetoclax In Relapsed-Refractory MCL (Mantle Cell Lymphoma) Patients	BTKi, Bcl-2 Inhibitor	II	Single group; open label	Jan. 25, 2023	NCT05529069
A Phase I/II Study to Evaluate the Safety of Cellular Immunotherapy Using Autologous T Cells Engineered to Express a CD20-Specific Chimeric Antigen Receptor for Patients With Relapsed or Refractory B Cell Non-Hodgkin Lymphomas	CD20-targeted CAR-T cells	II	Single group; open label	Dec. 5, 2017	NCT03277729
Study to Assess Safety, Tolerability and Efficacy of MB-106 in Patients With Relapsed or Refractory B-Cell NHL or CLL	CD20-targeted CAR-T cells	II	Non-Randomized; sequential assignment; open label	May 24, 2022	NCT05360238
A Phase 1/2 Study of CYT-0851 in B-Cell Malignancies and Advanced Solid Tumors	RAD51 inhibitor	II	Non-Randomized; sequential assignment; open label	Oct. 9, 2019	NCT03997968

Legend: ADC; antibody-drug conjugate; BTKi, Bruton’s tyrosine kinase inhibitor; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; IMiD, immunomodulatory imide drug; mAb, monoclonal antibody; MDM2, murine double minute 2; NHL, non-Hodgkin lymphoma; PI3K, phosphatidylinositol 3-kinase; ROR1, tyrosine kinase-like orphan receptor 1; SLL, small lymphocytic lymphoma

Emerging front-line therapeutic options for MCL may also influence the choice of therapy in the R/R setting. The most convincing front-line clinical trial data comes from the recent TRIANGLE and SHINE trials for untreated MCL. Front-line BTK inhibitors have been recently explored in both trials in combination with traditional therapies. The TRIANGLE trial is an ongoing three-arm Phase III randomized trial with patients randomized 1:1:1 to standard chemotherapy plus transplant (A) vs. standard chemotherapy plus ibrutinib plus transplant (A+I) vs. standard chemotherapy plus ibrutinib plus maintenance therapy without transplant (I) [38]. Patients were aged 65 or under and had stage II to IV MCL. The OR and CR rates were higher in the I-arm compared to the A-arm (98 % and 45 % vs. 94 % and 36 %, respectively). The 3-year failure free-survival was also improved in the I-arm vs. the A-arm (86 % vs. 72 %, respectively). The 3-year failure free-survival was also improved for A+I compared to A (88 % vs. 72 %, respectively) [38]. The best OS was noted in the I-containing arms, attesting to the value of up-front BTK inhibition. The SHINE investigators showed the high clinical value of adding ibrutinib to bendamustine plus rituximab: median PFS was improved by adding ibrutinib (80.6 months vs. 52.9 months) [15]. However, such management choices remain a matter of debate, as the use of BTK inhibitors in the front-line setting may limit their use in the R/R setting, mainly if BTK resistance mutations arise. Furthermore, tolerability considerations of a three-drug regimen should be weighed against potential benefits, especially in patients with suboptimal performance status or physiologic age.

Promising investigational agents are summarized in Table 1 and include the anti-CD3 x anti-CD20 bispecific antibodies glofitamab and epcoritamab, as well as the ROR1-targeting antibody-drug conjugate zilovertamab vedotin. Glofitamab has shown an ORR of 81 % in R/R MCL [39]. The Phase 2 GOlDiLOX trial was just initiated in April 2023 and will assess the safety and efficacy of glofitamab and pirtobrutinib in R/R MCL, and this will begin to recruit soon (NCT05833763). Epicoritamab showed a 50 % ORR and 25 % CR rate in R/R MCL, albeit with a small sample size (NCT03625037) [40]. A significant asset of epcoritamab is its subcutaneous route of administration, which is logistically less challenging in elderly or frail patients. Zilovertamab vedotin was studied with ibrutinib for R/R MCL and showed ORR of 81 %, with a median PFS of 35.9 months [41]. These agents may be especially useful in the elderly, as these patients may be unable to undergo one-time, intense, curative-intent CAR-T therapy. Although longitudinal data will be needed to conclude the depth and durability of response with novel agents, the horizons are very bright for these targeted therapeutics in aggressive B cell lymphomas [42].