Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin’s, accounting for approximately 2% of B-cell malignancies [1, 2]. According to an understanding of the developmental etiology of MCL, deregulation of B-cell receptor (BCR) signaling and Bruton tyrosine kinase (BTK) permits continuous B-cell proliferation, leading to MCL development in the pre-germinal center. BTK inhibitors block BCR signaling propagation, related to B-cell proliferation, and allow cancer cell apoptosis by ultimately reducing nuclear factor-κB pathway activity [3]. Thus, BTK is a key factor in BCR signaling and a therapeutic target for MCL. Several covalent (ibrutinib, acalabrutinib, and zanubrutinib) and non-covalent (pirtobrutinib) BTK inhibitors have been developed [4].

Among the various BTK inhibitors, ibrutinib, the first oral selective BTK inhibitor, has a favorable objective response rate (ORR) of 65–70% with a complete response (CR) rate of 19% and progression-free survival (PFS) of 12–15 months for relapsed/refractory MCL (RR-MCL) patients, who received more than two treatments prior [5-15]. Previous studies suggested that the response to ibrutinib depended on the simplified Mantle Cell Lymphoma Inter-national Prognostic Index (sMIPI), which is calculated based on age, performance status, lactate dehydrogenase (LDH), and white blood cell (WBC) count. In addition to the sMIPI, other factors, predicting survival and therapeutic responses, have been suggested. However, their consistency has not been demonstrated across studies. Considering the various underlying conditions of non-selected patients, further retrospective studies, that accurately reflect real-world situations, are needed to identify clinical biomarkers, that directly predict the favorable outcomes of ibrutinib treatment, and treatment strategies need to be established accordingly.

The optimal timing of ibrutinib treatment is unknown due to the lack of consensus and the introduction of various novel agents. Owing to the limited efficacy of ibrutinib in achieving and maintaining disease remission, most patients experience disease progression, leading to poor survival. Chimeric Antigen Receptor (CAR)-T cell therapy is recommended for these patients [16, 17]. However, real-world constraints limit the accessibility of this cutting-edge treatment to a subset of patients. Thus, it is challenging to find definitive and palliative treatment schemes for patients with progressive disease due to the changing trends in the treatment of MCL treatment, caused by the development of various targeted agents and immune-cellular therapies.

Therefore, this retrospective study evaluated the clinical outcomes of 42 patients with RR-MCL, who received ibrutinib. This study presents the outcomes of ibrutinib treatment according to associated clinical variables and discusses subsequent therapeutic strategies for patients, who were refractory to ibrutinib treatment. In addition, the overall response and survival outcomes of patients, following the continuation and discontinuation of ibrutinib, were investigated.

Study overview

This retrospective study investigated the characteristics and survival outcomes of patients with RR-MCL, treated with ibrutinib after at least one prior systemic therapy. By analyzing this comprehensive dataset, this study aimed to determine the benefits and outcomes, associated with salvage ibrutinib therapy in patients with RR-MCL. The study population was drawn from two prospective cohort studies (Institutional Review Board numbers: 2016-11-040 and 2022-05-078). Following a meticulous review of all tissue samples by pathology experts at our institution (J.C. and Y.H.K.), the diagnosis of MCL was conclusively established according to the WHO 2016 classification [18].

Patients and data collection

The medical records of the patients were reviewed to collect the following clinical and laboratory data: age; sex; Eastern Cooperative Oncology Group Performance Status; Ann Arbor stage; presence of extra-nodal involvement; bone marrow (BM) involvement; splenomegaly, defined by a horizontal length greater than 11 cm; Ki-67 expression rate; sMIPI; complete blood count; LDH; and β-2 microglobulin (B2M). Unfortunately, TP53 mutation evaluation using next- generation sequencing (NGS) was not performed in all patients due to lack of consent.

The study registration of patients was concluded in December 2021, and the data analysis was based on information available up to April 2023, which served as the cut-off date for this study. The IRB of the Samsung Medical Center approved this study (approval number. 2016-11- 040-025), and all participants provided written informed consent before their enrollment. The study adhered to the ethical principles, outlined in the Declaration of Helsinki and the Korea Good Clinical Practice guidelines. Ethical considerations were strictly followed throughout this study.

Ibrutinib therapy and response evaluation

Patients with RR-MCL received a prescribed daily dose of 560 mg of oral ibrutinib until disease progression or the emergence of intolerable toxicity. Dose adjustments, delays, and treatment discontinuation were decided at the physician’s discretion, based on the severity of adverse events (AEs) or disease progression. According to the Lugano classification, treatment response was evaluated using computed tomography (CT) and/or ¹⁸F-fluorodeoxyglucose positron- emission tomography CT [19]. Patients, who achieved a CR or partial response (PR), were categorized as responders, while those with stable disease (SD) or disease progression were considered non-responders. The patients, who did not achieve disease control (CR, PR, or SD), were classified as primary non-responders. Moreover, those, with controlled diseases, that receded over time, were classified as secondary non-responders. Finally, those, whose controlled disease status was maintained until the last follow-up, were classified as consistent responders. Early relapse was defined as disease recurrence within 12 months of ibrutinib administration.

The administration of the following first-line treatment options was confirmed: bendamustine and rituximab (BR); rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP); and rituximab, cyclophosphamide, cytarabine, vincristine, and prednisolone (R-Hyper-CVAD). The regimens were classified as BR- or anthracycline-containing (R-CHOP or R-Hyper-CVAD) for analysis. None of the patients received cytarabine-containing first-line chemo-therapy. A few patients eligible for autologous stem cell transplantation (ASCT) underwent high-dose chemotherapy, including cytarabine, followed by ASCT. None of the patients underwent allogeneic SCT.

Statistical analysis

Descriptive statistics, including proportions and medians, were used to analyze the data. Intergroup comparisons of categorical variables were performed using the Fisher’s exact test. ORR was defined as the proportion of patients, who achieved CR or PR, with the best response obtained during ibrutinib treatment. PFS and OS were evaluated using the Kaplan-Meier method. The PFS was measured from the initiation of ibrutinib treatment to the date of disease progression or death. OS was measured from the date of ibrutinib initiation to the date of death due to any cause or last follow-up. Additionally, the OS of post-ibrutinib treatment patients was calculated from the starting date of next-line anti-cancer therapies after ibrutinib interruption to the date of death from any cause or last follow-up. The cumulative incidence of early relapse was estimated using the Kaplan- Meier method. The log-rank test was used for comparisons, and both univariate and multivariate analyses were performed to estimate the associations between the survival rate and variables, concerning the administration of salvage ibrutinib. Data were analyzed using the Statistical Package for Social Sciences software (version 24.0, IBM Corp., Armonk, NY, USA).

Patient characteristics at diagnosis and outcomes of front-line treatment

The baseline demographics of the 42 patients at the time of their diagnosis are presented in Table 1. The median age was 62 years (range, 38–78 yr), and 25 patients (59.5%) were more than 60 years old. Most patients were male (N=30, 71.4%). Leukocytosis and elevated LDH levels were observed in 20% (N=11) and 45.4% (N=19) of the patients, respectively. Based on the pathologic reviews, most cases were documented as the classic MCL type (N=41, 97.6%), and 21.4% (N=9) presented with Ki-67 overexpression (≥30%). Among 37 patients (88.1%) diagnosed with stage III or IV disease, five (11.9%) presented with high-risk sMIPI, and most patients (N=37, 88.1%) were classified under low/intermediate- risk sMIPI.

Table 1 . Baseline demographics and disease characteristics at diagnosis..

Characteristics		Total (N=42)	BR (N=16)	Anthracycline-based regimen (N=26)	P
Age (yr)	Median (range)	62 (38–78)	63 (50–78)	61 (39–70)
	<60	17 (40.5%)	2 (12.5%)	15 (57.7%)	0.004
	≥60	25 (59.5%)	14 (87.5%)	11 (42.3%)
Gender	Male	30 (71.4%)	11 (68.7%)	19 (73.0%)	0.763
	Female	12 (28.6%)	5 (31.2%)	7 (27.0%)
ECOG-PS	0–1	39 (92.9%)	14 (87.5%)	25 (96.2%)	0.290
	2–4	3 (7.1%)	2 (12.5%)	1 (3.8%)
B symptom	Absence	37 (88.1%)	13 (81.2%)	24 (92.3%)	0.283
	Present	5 (11.9%)	3 (18.7%)	2 (7.7%)
Leukocytosis	Absence	31 (73.8%)	8 (50.0%)	23 (88.5%)	0.006
	Present	11 (26.2%)	8 (50.0%)	3 (11.5%)
Anemia	Absence	33 (78.6%)	9 (56.2%)	24 (92.3%)	0.006
	Present	9 (21.4%)	7 (43.7%)	2 (7.7%)
Thrombocytopenia	Absence	36 (85.7%)	11 (68.7%)	25 (96.2%)	0.014
	Present	6 (14.3%)	5 (31.2%)	1 (3.8%)
Serum LDH	Absence	23 (54.8%)	7 (43.7%)	16 (61.5%)	0.261
	Elevated	19 (45.2%)	9 (56.2%)	10 (38.5%)
Serum β-2 microglobulin	Absence	23 (54.8%)	5 (31.2%)	18 (69.2%)	0.016
	Elevated	19 (45.2%)	11 (68.7%)	8 (30.8%)
Bone marrow involvement	Absence	13 (31.0%)	2 (12.5%)	11 (42.3%)	0.042
	Present	29 (69.0%)	14 (87.5%)	15 (57.7%)
Number of extra-nodal involvement	Less than one	11 (26.2%)	2 (12.5%)	9 (34.6%)	0.113
	More than two	31 (73.8%)	14 (87.5%)	17 (65.4%)
Bulky (≥7 cm) mass	Absence	33 (78.6%)	10 (62.5%)	23 (88.5%)	0.046
	Present	9 (21.4%)	6 (37.5%)	3 (11.5%)
Pathology	Classic type	41 (97.6%)	16 (100.0%)	25 (96.2%)	0.427
	Pleomorphic/blastoid type	1 (2.4%)	0 (0.0%)	1 (3.8%)
Ki-67	<30%	33 (78.6%)	12 (75.0%)	21 (80.8%)	0.658
	≥30%	9 (21.4%)	4 (25.0%)	5 (19.2%)
Ann Arbor stage	I/II	5 (11.9%)	1 (6.3%)	4 (15.4%)	0.375
	III/IV	37 (88.1%)	15 (93.7%)	22 (84.6%)
sMIPI score	Low (0–3)	19 (45.2%)	3 (18.7%)	16 (61.5%)	0.002
	Intermediate (4–5)	18 (42.9%)	8 (50.0%)	10 (38.5%)
	High (6–11)	5 (11.9%)	5 (31.3%)	0 (0.0%)

Abbreviations: ASCT, autologous stem cell transplantation; BR, bendamustine plus rituximab; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; LDH, lactate dehydrogenase; sMIPI, simplified mantle cell lymphoma international prognostic index..

Among the 42 patients, 16 (38.1%) received BR, and 26 (61.9%) were treated with an anthracycline-containing regimen as a front-line treatment. Patients older than 60 years (P=0.004) with leukocytosis (P=0.006), anemia (P=0.006), thrombocytopenia (P=0.014), elevated B2M (P=0.016), BM involvement (P=0.042), or low-/intermediate-risk sMIPI (P=0.002) mainly received BR regimens rather than anthracycline-containing regimens (Table 1).

Ibrutinib as a salvage treatment

The patient’s characteristics at the start of ibrutinib treatment are presented in Supplementary Table 1. The patients received a median of one other treatment (range, 1–5) before ibrutinib administration. The ORR was 69% (N=29), with 21 CR (50%) and eight PR (19%). Patients (N=29, 69.0%), who had previously received one line of treatment, were administered a median of 12 cycles of ibrutinib (range, 1–55), and they achieved an ORR of 72.4% (N=21), with 16 CR (55.1%) and five PR (17.2%). Furthermore, patients (N=13, 31.0%), previously treated with more than two lines of treatment, received a median of 14 cycles of ibrutinib (range, 3–23), and they achieved an ORR of 61.5% (N=8), with five CR (38.4%) and three PR (23%). The most common reasons for treatment discontinuation were disease progression (N=23, 54.8%) and severe AEs (N=5, 11.9%).

During a median follow-up of 46.0 months (95% CI, 1.9–80.5), the median PFS was 16.4 months (95% CI, 0.0–41.5), and the median OS was 50.1 months (95% CI, 9.7–90.5; Fig. 1A, B). The responders showed superior PFS (46.0 mo; 95% CI, 26.2–65.7 vs. 7.9 mo; 95% CI, 2.8–12.9; P=0.001) and OS (63.5 mo; 95% CI, 42.9–67.3 vs. 13.6 mo; 95% CI, 7.3–19.9; P=0.002), compared to poorly responding patients (Fig. 1C, D). There was no difference in PFS (P=0.730) or OS (P=0.544) according to the line of treatment (Fig. 1E, F). However, patients, who experienced disease progression within 24 months of front-line treatment (POD 24), exhibited inferior PFS (10.5 mo; 95% CI, 4.4–16.6 vs. 53.8 mo; 95% CI, 27.9–79.6; P=0.005) and OS (12.6 mo; 95% CI, 4.5–20.7 vs. NR; P=0.015) upon receiving salvage ibrutinib treatment (Fig. 1G, H).

Figure 1. Kaplan-Meier curve of progression-free survival (PFS) (A) and overall survival (OS) for salvage ibrutinib therapy (B). Comparison of PFS and OS of ibrutinib treatment according to response (C, D), line of treatment (E, F), and progression of disease within 24 months of front-line treatment (G, H). Assessment of PFS according to age (I), presence of splenomegaly (J), and simplified mantle cell lymphoma international prognostic index (sMIPI) (K) and OS according to age (L), presence of splenomegaly (M), and sMIPI (N).

Patients, who were older than 70 years at the initiation of ibrutinib treatment (7.9 mo; 95% CI, 1.3–14.4 vs. 36.6 mo; 95% CI, 9.8–63.5; P=0.004), or those with splenomegaly (9.9 mo; 95% CI, 0.4–19.4 vs. 46.0 mo; 95% CI, 10.3–81.6; P=0.022) or a high-risk sMIPI (5.0 mo; 95% CI, 2.3–7.7 vs. 37.4 mo; 95% CI, 29.4–45.4 vs. 63.5 mo; 95% CI, 0.0–152.8; P<0.001) exhibited inferior PFS with ibrutinib treatment (Fig. 1I–K). Moreover, patients older than 70 years (13.6 mo; 95% CI, 6.7–20.5 vs. 63.5 mo; 95% CI, 9.8–63.5; P=0.006) or those with splenomegaly (12.6 mo; 95% CI, 0.0–34.0 vs. not reached [NR]; P=0.006) or a high-risk sMIPI (9.9 mo; 95% CI, 3.4–16.4 vs. NR vs. NR; P<0.001) displayed poorer OS (Fig. 1L–N). In the univariate and multivariate analyses, the duration of ibrutinib treatment and sMIPI were significant factors, influencing both OS and PFS (Table 2).

Table 2 . Univariate and multivariate analyses for progressiong-free survival and overall survival with salvage ibrutinib treatment..

Variables	Overall survival						Progression-free survival
	Univariate			Multivariate			Univariate			Multivariate
	HR (95% CI)	P		HR (95% CI)	P		HR (95% CI)	P		HR (95% CI)	P
Age (≥70 yr)	3.419 (1.340–8.726)	0.010		0.380 (0.106–1.358)	0.137		3.158 (1.395–7.146)	0.006		0.578 (0.201–1.661)	0.308
sMIPI score (high score)	5.325 (2.111–13.428)	<0.001		6.249 (2.067–18.892)	0.001		4.681 (2.086–10.501)	<0.001		2.874 (1.171–7.055)	0.021
Splenomegaly	3.303 (1.345–8.111)	0.009		1.983 (0.439–8.961)	0.374		2.338 (1.107–4.936)	0.026		1.373 (0.506–3.720)	0.534
Anthracycline-contai- ning front-line treatment	0.197 (0.075–0.516)	0.001		1.282 (0.354–4.647)	0.705		0.159 (0.063–0.402)	<0.001		0.273 (0.081–0.921)	0.036
POD 24 of front-line treatment	3.013 (1.190–7.625)	0.020		0.991 (0.242–4.070)	0.991		2.858 (1.336–6.117)	0.007		1.895 (0.737–4.876)	0.185
Previous number of treatments (≥2 lines )	0.730 (0.263–2.024)	0.546					1.230 (0.576–2.626)	0.593
Underwent ASCT before ibrutinib treatment	0.692 (0.230–2.086)	0.513					1.068 (0.468–2.439)	0.876
Duration of ibrutinib >12 months	0.023 (0.003–0.179)	<0.001		0.011 (0.001–0.110)	<0.001		0.041 (0.011–0.154)	<0.001		0.042 (0.010–0.180)	<0.001
Grade 3/4 adverse events	3.185 (1.203–8.433)	0.020		1.884 (0.612–5.798)	0.269		1.977 (0.789–4.953)	0.146

Abbreviations: ASCT, autologous stem cell transplantation; POD 24, disease progression within 24 months; sMIPI, simplified mantle cell lymphoma international prognostic index..

Characteristics of the patients who experienced early relapse

An analysis was conducted to confirm the clinical markers, affecting early relapse during ibrutinib treatment (N=13, 30.9%). According to the independent samples t-test, only a high-risk sMIPI was correlated with early relapse (P=0.033, Table 3). Patients with early relapse had significantly poorer survival outcomes than those, who did not experience early relapse (12.6 mo; 95% CI, 7.9–17.3 vs. NR; P<0.001, Fig. 2A). The primary non-responders had exceptionally poor survival compared to secondary non-responders and consistent responders (5.9 mo; 95% CI, 0.7–11.1 vs. 30.7 mo; 95% CI, 1.2–60.2 vs. NR; P=0.002, Fig. 2B). In terms of cumulative incidence, patients who received BR as front-line treatment (P=0.004), those with high-risk sMIPI (P=0.010), and those older than 70 years (P=0.011) were strongly correlated with an increased cumulative incidence of early relapse (Fig. 2C–E). However, there was a weak correlation between early relapse, splenomegaly (P=0.084), and prior lines of treatment (P=0.720) (Fig. 2F, G).

Figure 2. Kaplan-Meier curves of overall survival according to early relapse (A) and type of response to salvage ibrutinib (B). Comparison of cumulative incidence of early relapse according to front-line treatment (C), simplified mantle cell lymphoma international prognostic index (D), age (E), presence of splenomegaly (F), and line of treat-ment of ibrutinib (G).

Table 3 . Comparison of patients with and without early disease relapse..

Characteristics		Early relapse (N=13)	Late relapse or no relapse (N=29)	P
Age (yr)	Median (yr), range	67 (51–77)	67 (45–81)
	<70	6 (46.2%)	21 (72.4%)	0.101
	≥70	7 (53.8%)	8 (27.6%)
Gender	Male	10 (76.9%)	20 (69.0%)	0.598
	Female	3 (23.1%)	9 (31.0%)
ECOG-PS	0–1	12 (92.3%)	29 (100.0%)	0.131
	2–4	1 (7.7%)	0 (0.0%)
sMIPI score	Low (0–3)	0 (0.0%)	7 (24.1%)	0.033
	Intermediate (4–5)	6 (46.2%)	14 (48.3%)
	High (6–11)	7 (53.8%)	8 (27.6%)
Splenomegaly (≥11 cm)	Absence	7 (53.8%)	11 (37.9%)	0.335
	Present	6 (46.2%)	18 (62.1%)
Prior number of treatment	Prior 1 line	9 (69.2%)	20 (69.0%)	0.986
	Prior ≥2 lines	4 (30.8%)	9 (31.0%)
Front-line treatment	Anthracycline-based	6 (46.2%)	20 (69.0%)	0.159
	Bendamustine-based	7 (53.8%)	9 (31.0%)
ASCT	Received	3 (23.1%)	7 (24.1%)	0.941
	Not received	10 (76.9%)	22 (75.9%)
Ibrutinib dose adjustment	Dose reduction	1 (7.7%)	5 (17.2%)	0.414
	No dose reduction	12 (92.3%)	24 (82.8%)
Ibrutinib discontinuation	Discontinuation	13 (100.0%)	24 (82.8%)	0.111
	No discontinuation	0 (0.0%)	5 (17.2%)

Abbreviations: ASCT, autologous stem cell transplantation; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; sMIPI, simplified mantle cell lymphoma international prognostic index..

Post-ibrutinib survival outcomes

The median OS for patients, who discontinued ibrutinib treatment (N=37, 88.1%), was 9.8 months (95% CI, 0.6–19.0) (Fig. 3A). The ibrutinib responders had a better post-ibrutinib OS than the non-responders, but the difference was not statistically significant (20.0 mo; 95% CI, 0.0–43.0 vs. 5.7 mo; 95% CI, 0.0–13.2; P=0.101). The primary non-responders, who did not achieve disease control, had a median OS of only 2.6 months (95% CI, 0.0–10.4) after ibrutinib treatment.

Figure 3. Kaplan-Meier curves of overall survival for post-ibrutinib treatment (A). Comparison of overall survival according to participation in clinical trials (B). Swimmer plot of patients who received post-ibrutinib treatment (C).

Twenty-three patients (62.1%) received additional anti-cancer therapies after ibrutinib discontinuation, and the estimated median OS after ibrutinib was 12.2 months (95% CI, 2.1–22.2). Sixty-five percent of patients (N=15) received bortezomib or novel agents, such as lenalidomide and venetoclax, and 21.7% (N=5) participated in clinical trials. Although statistical significance was not achieved, the patients assigned to clinical trials had improved survival outcomes, compared to those, who received conventional chemotherapy (P=0.458, Fig. 3B). In terms of post-ibrutinib survival, the patients, who experienced early relapse, generally had an inferior OS (5.4 mo; 95% CI, 0.0–12.7 vs. 24.8 mo; 95% CI, 15.7–37.2; P=0.012) (Fig. 3C).

Adverse events with ibrutinib treatment

During ibrutinib treatment, various hematologic and non-hematologic AEs were observed, but most were reported as grade 1 or 2 and were manageable. Six patients (14.3%) received a reduced ibrutinib dose, and five patients (11.9%) discontinued ibrutinib treatment due to toxicities (Supplementary Table 2). All grades of thrombocytopenia accounted for 11.9% of the hematologic AEs (N=5). In particular, grade ≥3 thrombocytopenia accounted for 7.1% (N=3). The incidence of all grades of anemia and neutropenia was 7.1%, and less than 5% had a grade ≥3. The most common non-hematologic AE was skin rash (N=20, 47.6%), and only four patients (9.5%) presented with a grade ≥3. Grade ≥3 fatigue and diarrhea were observed in approximately 9.5% (N=4) and 7.1% (N=3), respectively. Three patients (7.1%) had grade 1 or 2 atrial fibrillation, and all were adequately managed through medical intervention. Of the five patients who discontinued ibrutinib, one ceased treatment due to a hematologic AE (grade 3 thrombocytopenia), while the remaining four stopped due to non-hematologic AEs (two patients with grade 3 diarrhea, one with grade 3 rash, and one with grade 3 fatigue). Among the consistent responders older than 70 years, those who were maintained on ibrutinib treatment with well-managed severe AEs had a more favorable PFS (36.6 mo; 95% CI, 12.3–60.9 vs. 11.4 mo; 95% CI, 0.0–23.1; P=0.234) and OS (NR vs. 11.4 mo; 95% CI, 0.0–23.1; P=0.062) (Supplementary Fig. 1A).

This study evaluated the efficacy and survival outcomes of ibrutinib treatment, based on real-world clinical experience. According to previous studies (Table 4) [5-14],

Table 4 . Summary of previous studies on ibrutinib therapy in relapsed or refractory mantle cell lymphoma..

Study	Pt. number	Front-line Tx.	Refractory to front-line Tx.	Upfront ASCT	Prior Tx.	ORR	PFS (median)	OS (median)	Ref
Phase 2	111	R-containing therapy (N=99, 89%)	50 (45%)	8 (13%)	3 (1–5)	67% (CR, 23%)	13 mo	22.5 mo	[5, 6]
Phase 3	280	R-containing therapy (N=280, 100%)	36 (26%)	N/A	2 (1–9)	72% (CR, 19%)	14.6 mo	Not reached	[7]
Retrospective	97	Intensive induction therapy (N=52, 54%) (R±hyper-CVAD, R-maxi CHOP)	7 (7%)	38 (39%)	2 (1–8)	65% (CR, 33%)	15 mo	22 mo	[8]
Phase 2	16	R-containing therapy (N=16, 100%)	1 (6.2%)	N/A	2.5 (1–4)	87.5% (CR, 12.5%)	N/A	N/A	[9]
Retrospective	33	R-CHOP (N=33)	N/A	6 (18.1%)	1 (33.3%). 2 (36.4%). ≥3 (30.3%).	64% (CR, 15%)	27.4 mo	35.1 mo	[10]
Retrospective	65	R-CHOP, R-bendamustine and R-hyper-CVAD (87%)	N/A	N/A	2 (1–6)	N/A	12.0 mo	18.5 mo	[11]
Retrospective	88	R±CHOP (N=63). R±hyper-CVAD (N=13). BR (N=6). VR-CAP (N=3). CVP/bendamustine (N=3).	N/A	5 (5.6%)	1 (1–6)	64.8% (CR, N/A)	20.8 mo	2-yr OS rate 79.5%	[12]
Retrospective	211	R-CHOP/mini-CHOP (N=70, 33%). Cytarabine-based regimen (N=60, 28%). R-bendamustine (N=45, 21%). VR-CAP (N=5, 2%). Others (N=31, 15%).	38 (18%)	53 (25%)	1	69% (CR, 27%)	17.8 mo	23.9 mo	[13]
Retrospective	77	CHOP/CHOP-like (N=42, 54%). Cytarabine-based regimen (N=25, 33%). Non-anthracycline regimen (N=10, 13%).	15 (20%)	19 (25%)	1 (29%). 2 (30%). ≥3 (41%).	66%. (CR, 31%).	10.3 mo	23.1 mo	[14]
Retrospective	42	R-CHOP (N=18, 43%). R-hyper-CVAD (N=8, 19%). R-bendamustine (N=16, 38%).	20 (47.6%)	6 (14.3%)	1 (1–5)	69% (CR, 50%)	19.2 mo	50.1 mo	Current study

Abbreviations: ASCT, autologous stem cell transplantation; BR, rituximab, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; CVP, cyclophosphamide, vincristine, prednisone; Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin dexamethasone; LOT, line of therapy; N/A, non-available; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Pt., patient; R, rituximab; Tx., treatment; VR-CAP, bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisolone..

Based on the CAN3001 study, which reported the long-term outcomes of salvage ibrutinib treatment with 10 years of follow-up [20], severe treatment-related AEs (TRAEs) were generally observed within one year of ibrutinib initiation, but it decreased annually thereafter. The AEs reported in this study were comparable to those, documented in previous studies, in terms of the type, timing of occurrence, and severity. This underscores that the prompt and proactive management of AEs during ibrutinib treatment alleviates the patient’s symptoms and enhances survival outcomes. The patients, who received active toxicity management along with ibrutinib, had a stable treatment course and improved clinical outcomes despite AEs. Thus, to prevent treatment interruption and achieve favorable outcomes, acute and chronic AEs, associated with ibrutinib therapy, should be recognized, monitored, and managed.

In this study, ibrutinib monotherapy resulted in an ORR of approximately 70%, which was similar to or higher than the response rates, reported in other studies (Table 4). Ibrutinib was more efficacious in patients, older than 70 years, who received anthracycline-containing front-line treatment, than in those, who received bendamustin-based front-line treatment (Supplementary Fig. 1B). Patients, treated with a bendamustine-containing regimen, presented with unfavorable baseline characteristics, including age >70 years, elevated WBC count, BM involvement, and high-risk sMIPI at the time of diagnosis (Table 1). Based on this, less intensive chemotherapy is preferred as the front-line treatment for patients aged 70 or older as they have poor general health conditions or comorbidities. It was assumed that prior bendamustine exposure led to poor subsequent ibrutinib treatment outcomes, as observed in other studies [10]. In cases where POD 24 occurred, regardless of the front-line treatment, favorable survival outcomes were not guaranteed, even with ibrutinib treatment. In line with previous studies [20, 21], POD 24 persisted as an unfavorable prognostic indicator in the targeted agent era.

TP53 mutation is a well-known biomarker, that predicts poor outcomes with conventional treatments in both newly diagnosed and RR-MCL patients. According to several retrospective studies [15, 22], the incidence of TP53 mutations was approximately 14%, and patients with TP53 mutations had lower response rates (55% vs. 70%) as well as shorter PFS (4 mo vs. 12 mo) and OS (10 mo vs. 34 mo) than patients with wild-type TP53. Unfortunately, this study was unable to include data on TP53 mutation status due to limited tissue samples and the lack of patient consent. While the presence of TP53 mutations impacts the prognosis of MCL, performing NGS on all MCL patients was not cost-effective in a real-world setting since only 14% were found to have TP53 mutations. Instead, Eskelund et al. [23] suggested specific clinical factors, related to TP53 mutation. These include a blastoid morphology, high-risk MIPI, and Ki67 >30%. In cases, where determining the TP53 mutation status is challenging, establishing a treatment plan, based on the implied factors, and defining the clinical signs of TP53 mutations are essential.

In this study, early disease relapse was defined as disease relapse within 12 months of starting ibrutinib treatment since the reported median PFS of ibrutinib was 12.6 months (95% CI, 10.3–16.6). Patients with early relapse exhibited significantly shorter PFS than those, who did not experience early relapse (5.4 mo vs. 24.8 mo). High-risk sMIPI scores were correlated with early disease relapse. Unfortunately, these patients were unsuitable for any subsequent treatment due to rapid disease deterioration, and the post-ibrutinib survival outcomes were poor. Establishing optimal treatment strategies for patients, who were refractory to ibrutinib, remains challenging. Allogeneic SCT has demonstrated long-term disease control through the graft-to-host effect, but it is limited to patients with favorable general conditions for withstanding intensive induction therapy and life-threatening complications. Pirtobrutinib, a novel non-covalent BKT inhibitor, achieved an ORR of 58%. Patients with RR-MCL, who received a median of three prior treatment modalities, including ibrutinib, responded for 21.6 months [24]. Moreover, brexucabtagene autoleucel (brex-cel), an anti-CD19 CAR-T cell therapy, achieved an ORR of 93% and CR rate of 67% [16, 17]. After 12 months, 57% of patients remained in remission. The lisocaltagene maraleucel (liso-cel) was associated with a low incidence of grade ≥3 TRAEs, and it demonstrated promising clinical activity in a phase 1 study [25]. Thus, novel therapeutic approaches, including targeted agents and immunocellular therapies, should be utilized in the management of patients, experiencing early disease relapse. Additionally, the risk stratification system should be continuously validated and adjusted to improve treatment outcomes.

In conclusion, this study demonstrated the efficacy and safety of salvage ibrutinib in patients with RR-MCL, and the patients, who potentially benefit from salvage ibrutinib therapy, were identified by verifying prognostic factors. Favorable survival outcomes were more frequent among patients with an objective response or those, who remained in disease remission with continuous ibrutinib treatment. To maximize the benefits of ibrutinib treatment, the capacity of the patient to endure TRAEs and the specific characteristics of their disease should be considered. Since patients, who experience early disease relapse within 12 months, have poorer survival outcomes, groundbreaking treatment strategies should be identified.

No potential conflicts of interest relevant to this article were reported.