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].

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.

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.

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).

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.

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).

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).

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).

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).

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.

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).

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).