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BTK Inhibitors and BTK Degraders for the Treatment of Mantle Cell Lymphoma - Current Status and Perspectives

Submitted:

10 July 2026

Posted:

13 July 2026

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Abstract
The introduction of Bruton tyrosine kinase inhibitors (BTKis) has significantly improved prognosis in the treatment of MCL. BTK inhibitors have demonstrated strong activity in the treatment of relapsed/refractory patients with mantle cell lymphoma (MCL), and several trials indicate that they also have potential as first-line treatment. Furthermore, combining BTKis with immunochemotherapy has enabled time-limited therapy as an alternative for continuous treatment with BTK inhibitors alone. In 2013, ibrutinib became the first BTK inhibitor to be approved by the FDA for previously-treated MCL. The TRIANGLE study found ibrutinib to improve the efficacy of standard immunochemotherapy and reduce the need for autologous stem cell transplantation (ASCT) in younger patients; however, its findings do not conclusively confirm whether ASCT enhanced the activity of the ibrutinib-containing regimen in treatment-naïve patients. The next-generation covalent, irreversible BTK inhibitors acalabrutinib and zanubrutinib demonstrate greater selectivity and better pharmacological characteristics than ibrutinib. The FDA approved acalabrutinib and zanubrutinib as single drugs for the treatment of R/R patients with MCL who have received at least one prior therapy. Acalabrutinib combined with bendamustine and rituximab was also approved for TN MCL unsuitable for ASCT. Pirtobrutinib, a first-in-class noncovalent reversible BTK inhibitor, was approved for the treatment of R/R MCL patients, including those resistant to covalent BTK inhibitors. Several other covalent and non-covalent BTK inhibitors are currently under investigation in MCL. Finally, BTK degraders have entered early clinical trials in B-cell lymphoid malignancies, and some of them in MCL.
Keywords: 
BTK
;  
acalabrutinib
;  
degraders
;  
ibrutinib
;  
inhibitors
;  
mantle cell lymphoma
;  
pirtobrutinib
;  
zanubrutinib
Subject: 
Medicine and Pharmacology  -   Hematology

1. Introduction

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma (NHL) characterized by the malignant transformation of B lymphocytes; MCL is characterized by heterogeneous clinical behavior, variable morphologic characteristics. and generally poor prognosis [1]. The condition accounts for approximately 6% of all NHLs [2]. A diagnosis is confirmed by the presence of translocation t (11;14) (q13;q32), overexpression of cyclin D1 and a characteristic immunophenotype with expression of CD5, CD19, CD20 and lack of expression of CD23, CD10 and BCL6 [3,4].
The prognosis of MCL is variable, with median overall survival ranging from 1.8 to 9.4 years depending on various laboratory and clinical factors. The most important factors in stratifying patients into risk categories and choosing therapeutic option are the International Prognostic Index (MIPI) and Ki-67 [2]. Approximately 20% of patients with MCL present a more indolent course known as indolent non-nodal leukemia [5]. A worse prognosis is indicated by the presence of blastoid or pleomorphic variants, a high Ki-67 expression (≥30%), and presence of TP53 mutation or deletions. The choice of treatment for MCL patients depends on the aggressiveness of the disease, staging, MIPI, patient age and comorbidities [6,7,8].
Asymptomatic patients with a low burden of lymphadenopathy, no significant splenomegaly or cytopenias may benefit from a watchful waiting strategy until progression. In treatment-naïve (TN) younger patients, immunochemotherapy based on high-dose cytarabine followed by autologous stem cell transplantation (ASCT) is an acceptable treatment option. In older, unfit patients, the commonly-recommended therapy is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) or bendamustine and rituximab (BR) followed by maintenance with rituximab [8,9].
More recently, targeted drugs have been introduced for the treatment of TN and relapsed/refractory (R/R) patients with MCL. Bortezomib combined with rituximab, cyclophosphamide, doxorubicin and prednisone (VR-CAP) has been approved for older TN patients; the results of the LYM-3002 trial indicate that VR-CAP significantly prolonged OS compared to R-CHOP, with an acceptable safety profile [10,11].
Another targeted drug investigated in MCL is lenalidomide [12,13,14,15]. In patients with R/R MCL ineligible for intensive chemotherapy or stem-cell transplantation, lenalidomide monotherapy was found to have an acceptable safety profile and induce longer PFS compared with investigator’s choice, i.e. either rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine [12,15]. The combination of lenalidomide with rituximab (LR), used as initial treatment or in R/R patients, induces high overall response rate (ORR) and durable remissions [13,15]. Finally, lenalidomide combined with BR (LBR), is an active regimen in elderly patients with MCL [14]. However, these treatments are associated with an unfavorable safety profile including a high infection rate and second primary malignancies.
The introduction of Bruton tyrosine kinase inhibitors (BTKis) to the treatment of MCL significantly improved prognosis (Table 1) [16]. These drugs are divided into covalent irreversible BTKis (cBTKis), such as ibrutinib, acalabrutinib and zanubrutinib, and non-covalent, reversible BTK inhibitors (ncBTKis), such as pirtobrutinib and nemtabrutinib [17,18]. Covalent BTK inhibitors bind permanently to the C481 residue of the BTK active site. Noncovalent BTK inhibitors do not bind to the C481 residue, and are effective in patients with BTK C481 mutation. Acalabrutinib and zanubrutinib are more selective and better tolerated than ibrutinib and they are now more commonly used in the treatment of MCL [19]. Pirtobrutinib is the only ncBTKi approved for the treatment of MCL and is mainly used in patients with C481--mutated BTK [20].
BTK protein degraders are targeted drugs that degrade BTK by inducing its ubiquitination [21,22]. BTK degraders have demonstrated adequate oral bioavailability and sustained pharmacodynamic target suppression in practice, confirming that the pharmacological barriers appear manageable [23]. Tacabrutideg (BGB-16673), NX-2127 and bexobrutideg (NX-5948) have shown promising results in Phase 1/2 clinical trials for R/R B-cell malignancies. The aim of this review is to present the current status and future directions of BTK inhibitors in the treatment of MCL.

2. Ibrutinib

Ibrutinib (Imbruvica, PCI-32765) is the first-in-class cBTK inhibitor approved for the treatment of B-cell lymphoid malignancies, including MCL and chronic lymphocytic leukemia (CLL) (Table 1) [24,25]. In one Phase 2 registration trial, ibrutinib (560 mg) was evaluated in 111 MCL patients who had received one prior therapy (Table 2) [26]. The overall response rate (ORR) was 67% including 23% complete responses (CR), with a median response duration 17.5 months. The 24-month progression free survival (PFS) was 31% and overall survival (OS) 47%. The most common adverse events (AEs) were diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). In another Phase 2 study performed in 16 R/R Japanese patients with at least one prior treatment regimen, ibrutinib (560 mg) was given once daily until relapse, progression or unacceptable toxicity [27]. The ORR was 87.5% and CR 12.5%; however, 50% of the patents had at least one grade 3 AE, and 31.3% patients had serious adverse events (AEs), most commonly diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%).
The combination of ibrutinib with rituximab was evaluated by Wang et al. in R/R MCL patients at the MD Anderson Cancer Center (Table 2) [28]. In in this Phase 2 study, continuous oral ibrutinib (560 mg daily) was administered until progressive disease or unacceptable toxic effect in 50 patients with R/R MCL with a median of three previous treatments; rituximab was given at 375 mg/m² once per week for four weeks during cycle 1, then on day 1 of cycles 3-8, and thereafter once every other cycle for up to two years [28]. At a median follow-up of 16.5 months, ORR was 88% including 44% CR and 44% PR. Grade 3 AEs included atrial fibrillation (AF) (12%), grade 4 diarrhea in one patient and neutropenia in one patient. A subsequent four-year follow-up of this study was performed, with a 16-month median duration of treatment and median 17 cycles [29]. Of the 50 original patients, 29 (58%) achieved CR, 38 experienced treatment discontinuation and 12 continued the treatment.
Even better results were observed in TN patients. Ibrutinib combined with rituximab without chemotherapy was evaluated in two small Phase 2 studies performed in TN MCL older patients, mainly at low risk (Table 2). The first included 50 patients: ORR was achieved in 84% of the patients, with a CR of 80% [30]. Undetectable MRD in peripheral blood was noted in 87%, with ibrutinib being discontinued in 69% of them. Treatment was generally well tolerated, and one patient developed severe aplastic anemia. In the second study, 50 previously-untreated older patients with a median age of 71 years received ibrutinib plus rituximab [31]. Ibrutinib was administered with rituximab for two years, and then ibrutinib alone was continued until progression or unacceptable toxicity. The best ORR was 96% including 71% CR. The three-year PFS was 87% and OS 94%. The treatment was well tolerated, although grade 3 AF was observed in 11 (22%) patients.
A UK study evaluated ibrutinib, alone or in combination with rituximab, in 149 patients observed for a median of 15.6 months. ORR was 71.2% and CR 20.2%, and median PFS 26.0 months [32]. In the ENRICH study, ibrutinib combined with rituximab was compared with rituximab plus chemotherapy (RCHOP or BR) in 397 TN MCL patients 60 years old and older; the ibrutinib–rituximab (IR) group achieved superior PFS than the immunochemotherapy group [33]. Also, at the median follow-up point (47.9 months), disease progression was observed in 94 (47%) of the 199 patients treated with ibrutinib and rituximab, and in 121 (61%) of 198 in the control group, with some deaths. The median PFS was 65.3 months in the ibrutinib plus rituximab group and 42.4 months in the RCHOP or BR group. The two groups achieved similar CR rates, viz. 54% and 53%, respectively, and similar 5-year OS, viz. 58% and 55%, respectively. However, the ibrutinib and immunochemotherapy arms were characterized by different Grade 3 or higher AEs. Neutropenia was reported in 9%, of patients treated with ibrutinib plus rituximab arm, 21% in RCHOP arm and 19% in BR arm; grade 3 or higher hypertension was reported in 11% of IR, 4% of RCHOP and 1% of BR. Atrial fibrillation was noted in 7% of patients in the IR group, and 1% in the immunochemotherapy group. These results indicate that ibrutinib-rituximab should be considered as a treatment option in TN patients unsuitable for intensive treatment. Finally, ibrutinib combined with BR was compared with BR alone in TN MCL in a randomized Phase 3 study [34]. It was found that ibrutinib with BR prolonged PFS but not survival, and that combined treatment was more toxic than BR.
The efficacy and safety of ibrutinib monotherapy was compared with temsirolimus in a Phase 3 study including 280 patients with R/R MCL (Table 2) [35]. The ibrutinib arm demonstrated a longer median duration of OS (14.6 months) than the temsirolimus arm (6.2 months), and was better tolerated than temsirolimus. Grade 3 or higher treatment-emergent AEs were reported in 68% of patients in ibrutinib and 87% in temsirolimus, and treatment discontinuation due to AEs were noted in 6% and 26%, respectively.
Another Phase 2 study compared ibrutinib plus venetoclax with ibrutinib monotherapy in historical controls in 23 patients with R/R MCL and one TN patient [36]. At week 16, the combined therapy achieved a higher CR rate (42%) than the controls (9%; p<0.001). For R/R MCL, the estimated 7-year PFS was 30% and OS was 43%; the median PFS was 28 months [37]. Another Phase 1/2 trial evaluated ibrutinib, obinutuzumab and venetoclax in R/R and TN patients with MCL [38]. The 2-year PFS was 69.5% and OS 68.6% in R/R patients, while the 1-year PFS was 93.3% and OS 100% in TN patients.
In the PHILEMON Phase 2 study, Jerkeman et al. evaluated the combination of ibrutinib, lenalidomide and rituximab in 50 R/R MCL patients [39]. At a median follow-up of 17.8 months, the ORR was 76%, including CR 56%. The most common AEs were neutropenia (38% of patients), infections (22%) and skin changes (14%) (Table 2) [39,40].
The three-arm, randomized, open-label, Phase 3 TRIANGLE study compared ibrutinib plus immunochemotherapy, with or without autologous ASCT, with immunochemotherapy and ASCT in TN patients with MCL (Table 2) [41]. It was found that combining ibrutinib with standard immunochemotherapy improves the efficacy of treatment and reduces the need for ASCT in MCL patients aged 65 years or younger. However, it remains uncertain whether ASCT enhanced the effect of the ibrutinib-containing regimen. A pooled analysis of clinical trials comprising 370 MCL patients treated with ibrutinib found the drug to be more effective when used earlier during treatment [42]. Similar results were observed in patients with CLL [43].
Ibrutinib was approved by the Food and Drug Administration (FDA) for previously-treated MCL in 2013 and for R/R CLL in 2014 [44]. However, ibrutinib is frequently discontinued due to adverse events (AEs) including bleeding, cytopenias and cardiac complications, particularly AF [26,45,46].

3. Acalabrutinib

Acalabrutinib (ACP-196, Acerta Pharma BV; Calquence, AstraZeneca) is a next-generation covalent, irreversible BTK inhibitor (Table 1). It has been found to demonstrate greater selectivity and better pharmacological characteristics than ibrutinib, with rapid oral absorption and a shorter plasma half-life. It is currently one of the most widely-used drugs for the treatment of B-cell malignancies including CLL/SLL, MCL, Waldenstrom macroglobulinemia (WM), and marginal zone lymphoma (MZL) [47].
Acalabrutinib showed high activity and good tolerability as both a single drug and in combination with others in R/R and TN MCL (Table 3) [48,49,50,51,52,53,54,55]. When used as a single drug in R/R MCL, it showed high efficacy and an acceptable safety profile. In a Phase 2 trial (ACE-LY-004), comprising 124 R/R patients with median age 68 years and a median of two previous lines of treatment, acalabrutinib was administered at 100 mg twice daily (BID), until disease progression or unacceptable toxicity (Table 3) [48,50]. The ORR was 81% and CR 40%. At a median 26-month follow-up, the median PFS was 20 months. The estimated 24-month PFS rate was 49.0% month, and OS rate was 72.4%. Treatment was well tolerated. The most common all-grade AEs included headache (8%), diarrhea (31%), fatigue (27%), and myalgia (21%); grade ≥ 3 AEs included neutropenia (10%), anemia (9%), and pneumonia (5%). Bleeding was reported in one patient and AF was not observed. Treatment discontinuation was reported due to progressive disease in 44% of cases, and due to AEs in 8%. In the final analysis, 43 (35%) patients had died: 29 (23%) due to progressive disease and six (5%) due to AEs. In October 2017, the FDA approved acalabrutinib as a single drug for the treatment of R/R patients with MCL who have received at least one prior therapy, based on the ACE-LY-004 trial [49]. In January 2025, the FDA approved acalabrutinib combined with bendamustine and rituximab for TN MCL patients who are unsuitable for ASCT [51].

4. Zanubrutinib

Zanubrutinib (BGB-3111, Brukinsa®, BeOne) is another next-generation irreversible BTK inhibitor. In contrast to ibrutinib, it demonstrates more selective BTK binding and has been found to be active in B-cell lymphoid malignancies (Table 1). It is also less toxic than ibrutinib, demonstrating lower activity against EGFR, FGR, FRK, HER2, HER4, ITK, JAK3, LCK, BLK and TEC kinases [56]. Zanubrutinib also exhibits higher bioavailability than ibrutinib and, unlike ibrutinib, enables therapeutic levels above the half-maximal inhibitory concentration (IC50), which can be maintained during daily and twice-daily administration [56,57].
Zanubrutinib has been compared head-to-head with ibrutinib in CLL and WM [58,59]. Both trials showed that zanubrutinib has better efficacy and tolerability, particularly a lower risk of AF and major bleeding events.
A Phase 1/2 study (NCT02343120) examined the effects of zanubrutinib 160 mg twice daily and 320 mg once daily in patients with R/R MCL [60,61]. At a median follow-up of 18.8 months, the ORR was 84%, including CR 25% and median PFS 21.1 months. OS at 24 months was 64.4%. In addition, 86 patients with R/R MCL were treated with zanubrutinib 160 mg twice daily as part of a multicenter, open-label, Phase 2 study [60]. At a median follow-up of 35.3 months, the ORR was 83.7%, including 77.9% CR with median PFS 33.0 months. The 36-month PFS was 47.6% and OS rate 47.6%. Most common grade ≥3 AEs were neutropenia (18.6%) and pneumonia (12.8%). No cases of AF or grade ≥3 cardiac were observed. The recommended dose of zanubrutinib in MCL is either 160 mg twice daily or 320 mg once daily.
A retrospective analysis by Philips et al. compared the efficacy of the cBTK inhibitors ibrutinib, zanubrutinib and acalabrutinib, used as single drugs, in 698 R/R MCL patients in second- or third-line scenarios [25]. The median time to next treatment (TTNT) was 14.5 months for second-line zanubrutinib, 12.8 months for acalabrutinib and 10.3 months for ibrutinib. Median PFS was 26.4, 23.2 and 29.3 months, respectively. Median OS was not reached for zanubrutinib, 27.4 months for acalabrutinib and 27.0 months for ibrutinib. Currently, a regimen based on zanubrutinib plus rituximab followed by zanubrutinib monotherapy, followed by observation, is under comparison with BR in an ongoing Phase 3 study (NCT04002297). The cohort comprises untreated MCL patients unsuitable for autologous SCT [62].
Finally, a Phase 2 study has evaluated zanubrutinib, obinutuzumab and venetoclax (BOVen) in 52 TN patients with TP53-mutated MCL (NCT03824483) [63]. Zanubrutinib was given at 160 mg twice daily, and obinutuzumab at 1000 mg on days 1, 8, and 15 on cycle 1, and on day 1 of cycles 2 to 8. Venetoclax was added after two cycles, with the dose increasing weekly to 400 mg daily. Treatment was discontinued after 24 cycles, if undetectable measurable residual disease (uMRD) was achieved in an immunosequencing assay. The results indicate ORR in 96% patients, including 88% CR (22/25). At cycle 13, uMRD was detected at a sensitivity level of 1 × 10-5 in 95% patients and of 1 × 10-6 in 84%. At a median follow-up of 28.2 months, the 2-year PFS was 72%, and OS 91%. Elsewhere, a Phase 1 study investigated the combination of zanubrutinib with zandelisib, a phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, in previously treated follicular lymphoma (n = 31) or MCL ( n = 19) [64]. Treatment was associated with high response rates, and no significant toxicity was noted for either agent. The overall response rate was 87% (CR = 33%) for FL and 74% (CR = 47%) for MCL. At a median follow-up of 16.5 months for FL and 10.9 months for MCL, the estimated 1-year PFS was 72.3% and 56.3%, respectively.

5. Orelabrutinib

Orelabrutinib (ICP-022, HIBRUKA Biogen/Innocare Pharma), is a highly selective, irreversible cBTK inhibitor designed to increase selectivity and reduce off-target side effects (Table 1) [65]. In a Phase 2 study including 97 patients, regimen selection was performed for 100 mg BID and 150 mg QD. The 150 mg QD dose was selected for further evaluation: OR was 87.9%, including CR 27.4% and DOR of 73.7% at 12 months [66]. At 12 months, the PFS rate was 70.8% and OS rate 88.7%. Orelabrutinib was well tolerated, with the most common treatment-related AEs being thrombocytopenia, neutropenia, leukopenia, and gastrointestinal toxicity. In a longer Phase 1/2 study, orelabrutinib was evaluated in 106 patients [67]. Of these, 86 patients received 150 mg once daily and 20 received 100 mg twice daily. After a median follow-up duration of 23.8 months, the ORR was 81.1%, including CR in 27.4%. The median response duration was 22.9 months and median PFS 22.0 months; the OS at 24 months was 74.3%. The most common AEs were thrombocytopenia (34.0%), upper respiratory tract infection (27.4%), and neutropenia (24.5%). Orelabrutinib plus BR is currently being compared with BR alone in patients with treatment-naïve MCL as part of an ongoing Phase 3 trial (NCT06363994). In December 2020, orelabrutinib was approved in China for the treatment of patients with MCL and CLL/SLL after at least one prior treatment, and in June 2021, it was granted Breakthrough Therapy Designation for the treatment of R/R MCL by the FDA. In February 2021, Chinese regulators approved it for first-line MCL therapy in combination with R-CHOP chemotherapy.

6. Pirtobrutinib

Pirtobrutinib (LOXO-305, Jaypirca, Eli Lilly, Indianapolis, IN, USA) is a first-in-class reversible ncBTK inhibitor (Table 1) [20,68]. As the drug does not need to bind to the C481 residue, it can overcome resistance to cBTKi caused by the BTK C481S mutation. It has high oral bioavailability and a long half-life of approximately 19 hours; its low off-target activity also minimizes side effects [69].
As part of the Phase 1/2 BRUIN (NCT03740529) trial, pirtobrutinib was investigated against R/R lymphoid malignancies in 52 evaluable patients with MCL, previously treated with cBTK inhibitors [70]. The drug was given at doses ranging from 25 to 300 mg QD in 28-day cycles in Phase 1, and the recommended dose of 200 mg QD in Phase 2. The ORR among patients was found to be 52%. A subsequent study comprising 90 R/R MCL patients who had received a median of three prior lines of therapy achieved an OR rate of 57.8%, including CR in 20% and median PFS 7.4 months. Of these patients, 82.2% had discontinued prior cBTKi treatment because of disease progression.
Another study of 124 patients with non-blastoid MCL examined data based on patient-reported outcomes [71]. Of 52 patients previously treated with cBTK inhibitors, the ORR was 52%. In addition, over 70% of patients demonstrated improvement or remained stable through Cycle 20, and median time to worsening was not reached. At a median follow-up of 39.7 months, nine patients with MCL remained under observation.
A real-life observation performed as part of a retrospective multicenter analysis in an Italian population (42 R/R patients) evaluated the use of pirtobrutinib at the approved dose (200 mg once a day; QD) as part of a compassionate use program [72]. The OR rate was found to be 47.6% and CR 23.8%. After a median observation of seven months, median PFS was 4.7 months and median OS 15.3 months. A similar European study evaluated 10 patients who had previously received three lines of systemic therapy [73]. The OR rate was 67% and neither mean duration PFS nor OS were reached at a median follow-up of 8.6 months.
The effects of pirtobrutinib treatment on R/R, but BTKi-naïve, MCL patients are currently under investigation in the BRUIN MCL-321 Phase 3 study (NCT04662255) [74]. The participants have been randomized to pirtobrutinib or investigator’s choice of covalent BTKi. The results are not yet available. In January 2023, pirtobrutinib was approved by the US FDA for the treatment of R/R MCL patients, including those resistant to cBTK inhibitors [68].

7. Currently Unapproved BTK Inhibitors Under Investigation in MCL

Several unapproved cBTK and ncBTK inhibitors are currently under investigation in MCL to improve the safety and efficacy of approved drugs such as ibrutinib.

7.1. Tirabrutinib

Tirabrutinib (Velexbru®, ONO/GS-4059, Ono Pharmaceutical, Gilead Sciences) targets BTK C481 more specifically and selectively than ibrutinib and has demonstrated potent activity in patients with CLL/SLL (Table 1) [75]. The drug has been evaluated in an initial Phase 1 study (#NCT01659255) involving 90 R/R patients with various B-cell lymphomas, including 16 patients with MCL [76]. Responses were observed in five (31%) patients with MCL, with an estimated mean PFS of 874 days. In a longer follow-up, with a median treatment duration of 97.3 weeks, ORR was found to be 68.8% with CR 55%. Of the 16 MCL patients, 11 discontinued treatment, including nine for disease progression.
One meta-analysis examined tirabrutinib data from seven studies including patients with CLL, primary central nervous system lymphoma (PCNSL), MCL and WM [77]. The pooled ORR was 72.5%, and CR rate 18.6%. Monotherapy was found to achieve a manageable safety profile and promising efficacy in patients with B-cell lymphoma. The most common all-grade AEs in patients with MCL were thrombocytopenia (44.0%), diarrhea (44.0%), and coughing (44.0%); the most common grade ≥3 AE was thrombocytopenia (19.0%). Patients with MCL achieved the highest CR (37.5%).

7.2. DTRMWXHS-12

The pyrazolo-pyrimidine derivative DTRMWXHS-12 (DTRM-12) was investigated as part of a Phase 1–2 study in patients with lymphoid malignancies (CLL and NHL), including three (9%) with MCL (Table 1). In the first-in-human Phase 1 part of the study, DTRMWXHS-12 was investigated in patients with R/R CLL and lymphomas as three regimens: monotherapy, in combination with everolimus, and with everolimus plus pomalidomide [78]. DTRM-12 monotherapy was well tolerated in B-cell malignancies and CLL, and no dose-limiting toxicity was observed. Pharmacokinetic (PK) studies demonstrated adequate target drug exposures at all doses (50 mg, 100 mg, 200 mg, and 300 mg). ORR for all patients and doses was 13/31 (41.9%) including two patients (25%) treated with DTRM-12 only.
DTRMWXHS-12 is also under evaluation as part of an ongoing Phase 1b study in patients with R/R MCL (NCT03836768). The primary objective of the study is to evaluate the safety and tolerability of DTRMWXHS-12 and recommend the dosing method used in a later Phase 2 study. A single-arm, multicenter, open-label Phase 2 study was initiated in 2022 in China (NCT03836768, ChiCTR2200058983), with the aim being to evaluate the efficacy and safety of DTRMWXHS at doses of 150 mg and 300 mg in R/R MCL.

7.3. Spebrutinib

The cBTKi spebrutinib (CC-292, AVL-292, Avila Therapeutics/Celgene) also binds covalently with cysteine 481 in BTK and shows higher selectivity than ibrutinib against BTK [79]. In a human study, the drug showed near-complete BTK occupancy for eight to 24 hours (Table 1) [80]. It has also been found to inhibit other kinases, including JAK3 and Tec. A study of its anti-tumor effects in five MCL cell lines (REC-1, MINO, UPN-1, MAVER-1 and Z138) confirmed cytostatic effects in three: REC-1, MINO and UPN-1 [81]. In these lines, the antitumor cytotoxicity of spebrutinib was significantly increased by lenalidomide at both low and high doses. Spebrutinib has been investigated in DLBCL and CLL but not in MCL.

7.4. Nemtabrutinib

Nemtabrutinib (MK-1026, ARQ-531, Merck, Rahway, NJ, USA), like the ncBTKi pirtobrutinib, reversibly inhibits both wild-type and C481S-mutated BTK (Table 1). The drug was investigated in a Phase 1/2 dose escalation study encompassing 112 patients with R/R hematologic malignancies (NCT03162536, ARQ 531-101/MK-1026-001) [82]. The most common treatment-related AEs were dysgeusia (21%) and neutropenia (20%). A Phase 2 study evaluating the safety and efficacy of nemtabrutinib in participants with hematologic malignancies, including CLL/SLL and MCL, is ongoing, and the results are expected in 2029 (NCT04728893). The drug is also currently under evaluation as combined therapy in two Phase 2 studies. In the first, the Waveline-006 study (NCT05458297), it achieved an OR of 64% in combination with zilovertamab vedotin in patients with R/R MCL [83]. In the second (NCT06572618), in combination with rituximab in patients with TN MCL, results are still anticipated.

7.5. Rocbrutinib

Rocbrutinib (LP-168, HS-10561; NWP-775; Hansoh Pharma) is a highly selective fourth-generation dual BTK inhibitor demonstrating both covalent (irreversible) and non-covalent (reversible) binding (Table 1) [84]. The ROCK-1 Phase 2 trial evaluated its safety and efficacy in 61 heavily pre-treated patients with R/R MCL. The patients had previously been treated with cBTK inhibitors and received a median of three previous therapies (NCT05716087, LP-168-CN201). The results indicate ORR in 63.9% of patients, including CR in 23.0%, median PFS of 7.39 months and 12-month estimated duration of response (DOR) of 61.2%. The most common treatment emergent AEs (TEAEs) were thrombocytopenia (43.5%), anemia (30.6%), neutropenia (29.0%), increased blood creatinine (21.0%) and hyperuricemia (21.0%), mainly Grade 1 or 2. Among special interest AEs related to BTKi, major bleeding was noted in 3.2% of cases; no AF was observed. Rocbrutinib is currently under evaluation versus investigator’s choice of BTK inhibitor (ibrutinib, acalabrutinib, zanubrutinib, or orelabrutinib) in R/R MCL as part of a Phase 3 study.

7.6. Fenebrutinib

Fenebrutinib (GDC-0853) is a selective, reversible, and non-covalent BTK inhibitor that does not require binding with Cys481 (Table 1). In a phase 1 study 14 patients with CLL and 10 patients with NHL including two patients with MCL were analyzed [85]. Generally, fenebrutinib was found to be well tolerated with some antitumor activity. In the NHL group, only one patient with MCL responded, achieving a CR; however, the drug is not under further investigation in MCL

7.7. Vecabrutinib

Vecabrutinib (SNS-062) is a selective, reversible, non-covalent BTK inhibitor that demonstrates antitumor activity, irrespective of Cys481Ser mutation [86]. The drug is being investigated in a Phase 1b/2 study in patients with various B cell malignancies including CLL (NCT03037645). In a Phase Ib dose-escalation study, vecabrutinib was well-tolerated up to 410 mg twice daily (BID) [87]. However, clinical benefit was limited, and clinical trials were discontinued due to lack of efficacy.

8. BTK Degraders

BTK degraders are orally available proteins that tag BTK for degradation through the cellular proteasome pathway, thus blocking BTK signaling and leading to tumor regression [21]. Three BTK degraders are under investigation in B-cell malignancies, viz. tacabrutideg (BGB-16673, BeOne Medicines), bexobrutideg (NX-5948, Nurix Therapeutics) and NX-2127 (Nurix Therapeutics) [88,89]. Tacabrutideg is under study in R/R CLL/SLL, WM, FL, MZL in a Phase 1 study and in CLL in a Phase 3 study [89]. Bexobrutideg is being investigated in R/R CLL/SLL in a Phase1a/1b study [90].
Preliminary safety and efficacy data for tacabrutideg were recently presented following the Chinese Phase 1/2 CaDAnCe-102 study; the participants comprised patients with R/R B-cell malignancies, including 15 with MCL [91]. Three MCL patients had previously been treated with BTK inhibitors, achieved a CR, including one patient who was heavily pretreated, with seven prior lines of therapy. The most common grade ≥3 TEAEs were neutropenia and pneumonia. However, AF was not observed. These data support further studies of tacabrutideg in patients with MCL.

9. Conclusions

Front-line chemoimmunotherapy and ASCT are well established in the management of younger, fit patients with MCL. The treatment of R/R MCL patients has been considerably improved by the development of covalent BTK inhibitors, which are now recommended for MCL patients at first relapse after chemoimmunotherapy. However, most patients treated with BTK inhibitors will also relapse, and some of them become refractory to BTK inhibitor therapy. The treatment of MCL resistance associated with BTK mutation is an emerging challenge in clinical practice. While clinical trials have yielded new therapeutic options including BTK degraders and BCL-2 inhibitors, mature results from clinical trials remain unavailable for now. However, hope is offered for these patients by the continual development of novel immunotherapeutic options, such as CAR T cells and T-cell-activating bispecific antibodies.

Author Contributions

All authors contributed equally to writing, reviewing the manuscript and provided their approval of the final version of the manuscript.

Funding

No funding.

Institutional Review Board Statement

Not applicable.

Data availability statement

Not applicable.

Acknowledgments

We thank Edward Lowczowski, a native English speaker from the Medical University of Lodz, Poland, for language assistance.

Conflicts of Interest

The authors declare no conflict of interest.

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Table 1. Characteristics of BTK inhibitors approved and in clinical trials in MCL.
Table 1. Characteristics of BTK inhibitors approved and in clinical trials in MCL.
BTK inhibitor Characteristics Selected clinical trials in MCL FDA approval for MCL References
Ibrutinib (PCYC-1102, Imbruvica®, Johnson&Johnson)
 First generation irreversible cBTKi Phase 2 trial PCYC-1104-CA: Ibrutinib has high efficacy and favorable safety profile in R/R MCL (NCT01236391).
Phase 3 TRIANGLE study: Adding ibrutinib to standard immunochemotherapy improves outcome in younger patients (NCT02858258)		 2013: approved after at least one prior therapy.
 [26,92
Acalabrutinib
(ACP-196, Calquence®, AstraZeneca)
 Next-generation irreversible cBTKi
is more selective and less toxic than ibrutinib		 Phase 2 ACE-LY-004, (NCT02213926) trial: Acalabrutinib induces high rate of durable responses and a favorable safety profile in R/R MCL patients.
Phase 3 ECHO trial (NCT02972840): ABR vs BR- Longer PFS for ABR.		 2017: approved in R/R MCL after at least one prior therapy;
2025: approved in combination with BR for TN MCL ineligible for ASCT.
 [49,51]
Zanubrutinib (BGB3111, Brukinsa®, BeOne Medicines) Next-generation covalent, irreversible C481 BTKi with greater specificity and better bioavailability compared with ibrutinib Phase 1/2 trial BGB-3111-AU-003 (NCT02343120): Zanubrutinib at 160 mg BID or 320 mg once daily in R/R MCL ORR 84%, CR 25% and median PFS 21.1 m.
 2019: approved in monotherapy for R/R MCL after at least one prior therapy [61]
Orelabrutinib (ICP-022, HIBRUKA Biogen/Innocare Pharma) Highly selective, covalent, irreversible BTKi. Greater specificity and better bioavailability compared with ibrutinib Phase 2 study: Orelabrutinib in R/R MCL - ORR 87.9%, at 12-month PFS 70.8% and OS 88.7%, no grade 3 or higher diarrhea, AF or severe bleeding 2021: FDA granted a breakthrough therapy designation for R/R MCL [67]
Pirtobrutinib (LOXO-305, Jaypirca, Eli Lilly) Highly selective, non-covalent, reversible next-generation BTKi, inhibiting diverse BTK C481 substitution mutations Phase 1/2 BRUIN (NCT03740529) trial: In patents with R/R MCL pretreated with cBTKi - ORR 57.8%, CR 20% median PFS 7.4 m.
2023: FDA granted accelerated approval for R/R MCL after at least two lines of therapy, including cBTKi [20]
Tirabrutinib (Velexbru®, ONO/GS-4059, Ono Pharmaceutical, Gilead Sciences) Second-generation, highly selective, irreversible cBTKi with the ability to cross the blood brain barrier Phase 1 study (NCT01659255): In R/R MCL - ORR 68.8%, CR 55%. Not approved [75]

DTRMWXHS-12 (DTRM-12) 		Pyrazolo-pyrimidine derivative irreversible cBTK inhibitor Phase 1b study MCL initiated in 2022 in China: Doses 150 mg and 300 mg in R/R MCL (NCT03836768, ChiCTR2200058983). Not approved [78]
Nemtabrutinib (MK-1026, ARQ-531, Merck) Reversible ncBTKi of both the wild-type and the mutation C481S of BTK Phase 2 Waveline-006 study (NCT05458297): Nemtabrutinib + zilovertamab vedotin in patients with R/R MCL - ORR - 64%.
Phase 2 study (NCT06572618).: Nemtabrutinib + rituximab in TN MCL 		Not approved [82,83]
Rocbrutinib (LP-168, HS-10561; NWP-775; Hansoh Pharma Highly selective 4th-generation dual BTKi with both covalent and non-covalent binding Phase 2 trial (ROCK-1, NCT05716087: Rocbrutinib in R/R patents with MCL - ORR 63.9%, CR 23.0%, PFS 7.39 months Not approved [84]
Abbreviations: ABR-Acalabrutinib + BR, AEs - adverse events, BID - twice daily, BR- bendamustine plus rituximab, BTKi – Bruton tyrosine kinase inhibitor, cBTKi- covalent BTKi, CR – complete response, m – months, MCL – mantle cell lymphoma, ncBTKI - noncovalent BTKi, ORR – over all response rate, PFS – progression free survival, R/R – relapsed/refractory, TN – treatment naïve.
Table 2. A summary of key clinical trials evaluating ibrutinib as a single agent and in combination in MCL.
Table 2. A summary of key clinical trials evaluating ibrutinib as a single agent and in combination in MCL.
Study
[Reference] 		Patient characteristics Treatment Median FU Efficacy Safety Comments
Wang et al. 2015, Phase 2 [26] N= 111, R/R Ibrutinib 560 mg once daily, until progression or unacceptable toxicity 26m ORR 67% (CR23%), 24-m PFS 31%, 24-m OS 47% AEs: diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea 32%). Ibrutinib induces durable responses and favorable safety in R/R MCL.
Wang et al. 2016, Jain et al. 2018 Phase 2 [28,29] N=50, R/R Ibrutinib plus rituximab 47m ORR 88%, CR 58%, Median PFS 43 m Gr 1-2 toxicities: fatigue, diarrhea, nausea, arthralgias and myalgias. Gr 3 AF 12%, Ibrutinib plus rituximab is active and well tolerated in R/R MCL
Jain et al. 2022, Phase 2 [31] N=50, TN. Older, nonblastoid Ibrutinib plus rituximab 45 m ORR 96, CR 71%, 3-year PFS 87% and OS 94% Gr 3-4 AF 18%. fatigue 14%, diarrhea 14%, anemia 8% neutropenia 4% thrombocytopenia 4% Ibrutinib plus rituximab is an effective, easily administered, and safe option in elderly patients with non-blastoid MCL.
Tivey et al, 2024, real-word study [32] N=149,
TN, 		Ibrutinib +/- rituximab (IR - 39.0%) 15m ORR 71.2%, CR 20.2%, median PFS 26.0 m Gr ≥3 all-cause toxicity 20.3%, Gr≥3 bleding 4.0%, Gr≥3 nonneutropenic infection 7.4%, AF 6.6% IR is effective and well tolerated in TN MCL, PFS and OS were inferior in high-risk disease
Lewis et al. 2025, phase 2/3 ENRICH study [33] N=397,
phase 2/3,
TN ≥ 60 yrs 		Ibrutinib plus rituximab vs immunochemotherapy (RCHOP 27% or BR 73%)
 47m vs 9 m ORR 86% vs 85%, CR 54 vs 53%; 5-year PFS: IR – 52% vs RCHOP 19%, IR 51%vs BR 47%, Total AES during induction: IR – 42%, RCHOP 67%, BR 51%, All cardac events: IR – 11%, RCHOP 10%, BR 5%; All bleeding events: IR – 3%, RCHOP 6%, BR 1%; Ibrutinib–rituximab is suitable treatment for TN, older patients with MCL
Wang et al.2022, phase 3 SHINE tral, [34] N=523 TN, ≥ 65 yrs Ibrutinib plus BR vs BR 84 vs 7 m Median PFS: 80.6 m vs 52.9 m (P = 0.01), ORR: 89.7% vs 88.5%; CR 65.5% vs 57.6%,(P=0.06). Gr 3 or 4 AEs 81.5% vs 77.3% Ibrutinib combined with BR significantly prolonged PFS
Dreyling et al. 2016, phase 3 [35] N=280; R/R, Ibrutinib vs temsirolimus 20 m ORR: 72% vs 40%, Median PFS: 14,6 m vs 6,2 m Most common AEs: Ibrutinib: Darrhea 29%, ibrutinib cough 22%, fatigue 22%; Temsirolimus: thrombocytopenia, 56%,
anaemia 43%), diarrhoea 31%, neutropenia 26% 		Ibrutinib treatment showed improvement in PFS and better tolerability versus temsirolimus in R/R MCL lymphoma.
Tam et al, 2018, phase 2 [36]
Handunnetti et al 2024 [37]		 N=24, R/R Ibrtinib + venetclax until progression 7 yrs OR 71%, CR 62%, PFS at at 15 m 78%, at 7-yrs 30% Most common AEs: Diarrhea 83%, fatigue 75%, nausea vomiting 71% Ibrutinib plus venetoclax induces long-term durable responses and acceptable toxicity profile in R/R MCL
Le Gouill et al 2021, phase 1/2 [38] N=48
R/R and TN		 Cohort A – I + Ob R/R N=9
Cohort B - I + Ob + Ven R/R N=24
Cohort C I + Ob + Ven TN N=15
 R/R 17 m,
TN 14m 		R/R: ORR 84% CR 67%, 1-year PFS was 74.5%, OS 87.5%
TN: ORR 100%, CR 86.6%; 1-yr PFS 93.3% OS
100% 		Most frequent Gr 3/4 AEs in all cohorts -- thrombocytopenia and neutropenia. Obinutuzumab + ibrutinib + Ven induces high response rates with acceptable safety profile
Jerkeman et al 2018 PHILEMON tral, phase 2
[39], Forsgren et al, 2025 [40]		 N=50
R/R phase 2
Ibrutinib + lenalidomide + rituximab		 92 m ORR 76%, CR 56%; median PFS 17.4 m, median OS of 45.3 m Most common Gr 3-4 AEs: neutropenia 38% infections (22%, cutaneous toxicity 14% Ibrutinib + lenalidomide + rituximab is active and well tolerated in R/R MCL
Dreyling et al 2024, phase 3
TRIANGLE [41]		 N=870
TN,
< 65 years 		Group A: Chemo + ASCT
Group B:
I + ASCT
Group C: I		 31 m 3 Yr PFS: Group A: 72%
Group B: 88%
Group C:86%		 No relevant differences in Gr 3-5 AEs during induction or ASCT Adding ibrutinib during induction and maintenance should be part of treatment in younger TN pts
Abbreviations: A acalabrutinib, AEs adverse events, AF – atrial fibrillation, ASCT – autologous stem cell transplantation, BID - twice daily, BR – bendamustine plus rituximab, BTKi – Bruton tyrosine kinase inhibitor, CR – complete response, i-ibrutinib, IR- ibrutinib plus rituximab, m – months, M – month, MCL – mantle cell lymphoma, Ob – obinutuzumab, ORR – over all response rate, OS – overall survival, PFS – progression free survival, Pts – patients, R-rituximab, RCHOP – rituximab, cyclophosphamide, adriamycin, vincristine, prednisone, R/R – relapsed/ refractory, TN – treatment naïve, Ven – venetoclax, Yr - year .
Table 3. A summary of key clinical trials evaluating acalabrutinib as a single agent and combination in MCL.
Table 3. A summary of key clinical trials evaluating acalabrutinib as a single agent and combination in MCL.
Study
[Reference]		 Patient characteristics Treatment Median FU Efficacy Safety Comments
Wang et al 2018 [49], Le Gouill et al 2024 ACE-LY-004 [48] Phase 2, N =124, R/R Acalabrutinib 100 mg x 2/d continuousely 38,1 m ORR 81.5%, CR 47.6%, median PFS 22,0 m , OS 59.2 m, 5-year OS 49.5% AE of clinical interest: AF 2.4%; hypertension 4.0%; major hemorrhage 4.0%, infections 67.7% Study supports the use of acalabrutinib in patients with R/R MCL
Wang et al 2019 [50] N=50, TN, ≥ 65 yrs, phase 2 Acalabrutinib + rituximab 17 m ORR 94%, CR 90%, 2 year PFS 92% 2 year OS 96% All-grade AEs: fatigue 82%, myalgia 64%, headache 38%, bruising 28%, Acalabrutinib + rituximab is highly effective and safe treatment in older pts with MCL.
Phillips et al.2025, (ACE-LY-106) [52] Phase 1b N=38
TN (N=18)
R/R (N=20), 		Acalabrutinib + BR
24 m TN: ORR 94.4%, CR 77.8%, median PFS not reached
R/R:ORR 85%, CR 70.0%, median PFS 28,6 m 		Gr ≥3 AEs TN 72.2% R/R 85.0% most commonly neutropenia TN: 38.9%; R/R: 50.0%. Acalabrutinib + BR
demonstrates high efficacy in patients with TN and R/R MCL
Wang et al 2025, ECHO trial [51] phase 3 N=598, TN, ≥ 65 years, Acalabrutinib + BR vs BR 49,8 m ORR 91.0% vs 88.0%; PFS PFS was 66.4 vs 49.6 m , OS HR 0.86 P = 0,27. Gr ≥ 3 AEs 88.9% vs 88.2%, Gr ≥ 3 serious AEs 64.3% vs 55.9% ABR improved PFS in older, OS was similar but the majority of patients crossed over to treatment with a BTKi.
Wang et al 2024, [53]
Phase 1b		 N=21, TN
 Acalabrutinib + venetoclax + rituximab 27,8 m ORR 100% CR 71.4%, MRD- 87.5%, PFS at 1yr 90.5%, PFS at 2 year 63.2% Any-grade AEs: diarrhea 71.4%, headache 52.4%, and fatigue 47.6%. Gr ≥ 3 AEs 61.9% most commonly neutropenia (33.3%). ART is a promising, highly effective, and well-tolerated chemotherapy-free treatment option for TN MCL
Kim et al.2025, MAVO, [54]
Phase 1/2		 N=55
Cohort A R/R, N=20
Cohort B (TN, ASCT not eligible) N=24,
Cohort C TN, ASCT not eligible)N=12		 Acalabrutinib + Venetoclax + Obinutuzumab Cohort A 24 m
Cohort B 20 m
Cohort C 9 m		 Cohort A: ORR 86%, CR 75%, 2yrs PFS75%, OS 86%
Cohort B: ORR 88% CR 83%, 2yrs PFS 78%, OS 96%,
Cohort C: ORR100%, CR 100%, 1yr PFS 100%, OS100%		 Most common all Gr AEs: bruising 41%; diarrhea 29%; nausea 25% AVO is a well-tolerated and effective regimen in pts with R/R and TN MCL, with high rates of MRD- CR in TN MCL,
Ruan et al 2026 [55] Phase 2 N=34
TN MCL 		ALR (N=24)
or ALO (N=10)		 ALR 53m
ALO 25m		 ALR:
ORR100%, CR83%.3 yrs PFS76%, OS 91%
ALO:
ORR90%, CR90%, 2yrs
PFS 100%, OS 100%		 Gr 3/4 toxicities: ALR - asymptomatic neutropenia 33%, anemia 4%, thrombocytopenia 4% ALO, asymptomatic neutropenia 40%, anemia 0%, thrombocytopenia 30%, ALR and ALO are safe and active regimen is feasible as a time-limited initial therapy for patients with MCL
Abbreviations: AEs adverse events, AF – atrial fibrillation, ALO - Acalabrutinib + lenalidomide + obinutuzumab, ALR -Acalabrutinib + lenalidomide + rituximab, ART - Acalabrutinib + venetoclax + rituximab, AVO - Acalabrutinib + Venetoclax + Obinutuzumab,ASCT. – autologous stem cell transplantation, BID - twice daily, BR – bendamustine plus rituximab, BTKi – Bruton tyrosine kinase inhibitor, CR – complete response, m – months, MCL – mantle cell lymphoma, MRD -measuarable residual disease, ORR – over all response rate, OS – overall survival, PFS – progression free survival, Pts – patients, R/R – relapsed/ refractory, TN – treatment naïve.
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