Abstract
Addition of Bruton’s tyrosine kinase inhibitor (BTKi) to first-line (1 L) bendamustine-rituximab (BR) improved progression-free survival (PFS) in patients with mantle cell lymphoma (MCL) in the SHINE and ECHO trials. We investigated whether sequential treatment with 1 L BR and second-line (2 L) BTKi can result in similar cumulative PFS compared to BR-BTKi combination therapy, using a multicenter cohort of 755 patients treated with 1 L BR between 2014 and 2020. Event-free survival (EFS), EFS2, and overall survival (OS) were analyzed. By intention-to-treat (ITT), EFS2 was defined as time from 1 L BR start to progression/relapse or retreatment following 2 L BTKi or death. After a median follow-up of 61.4 (95% CI 56.4–65.9) months, the median EFS after 1 L BR was 34.2 (95% CI 31.5–38.4) months. The median EFS2 following 1 L BR and 2 L BTKi by ITT analysis was 64.8 (95% CI 56.7–82.8) months, and the 5-year OS rate after 1 L BR was 57.9% (95% CI 54.1–62.0%), close to SHINE and ECHO results. Patients without high-risk features (high simplified MIPI, high Ki-67, blastoid/pleomorphic morphology, TP53 mutation, or complex karyotype) had more favorable survival outcomes. These results suggest that sequential treatment with 1 L BR and 2 L BTKi remains reasonable for select patients with MCL, particularly those without high-risk features.
Subject terms: B-cell lymphoma, Epidemiology
Introduction
Mantle cell lymphoma (MCL) comprises 3-10% of non-Hodgkin lymphoma (NHL) and is generally considered to be incurable [1]. Historically, young and fit patients were often treated with high dose cytarabine (HiDAC)-containing immunochemotherapy induction followed by high dose chemotherapy and autologous stem cell transplant (ASCT) consolidation and rituximab maintenance [2–8], while older (e.g., ≥65 years old) or unfit patients usually received less intensive immunochemotherapy such as bendamustine plus rituximab (BR) [9–11] followed by optional maintenance therapy with rituximab [12–15].
Based on encouraging efficacy and tolerability of BTKi in the relapsed/refractory (R/R) setting [16–21], several studies have investigated the benefit of adding BTKi in the frontline therapy for MCL. For patients ≥65 years old, the randomized SHINE trial showed that addition of ibrutinib to BR and rituximab maintenance significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months, p = 0.01) but not overall survival (OS; 55.0% vs 56.8% at 7 years) [22]. In the randomized ECHO trial, the addition of acalabrutinib to BR and rituximab maintenance resulted in significant improvement of PFS (median 66.4 vs 49.6 months). There was no statistically significant improvement of OS, however (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.65–1.13, p = 0.27), although crossover to BTKi after progression occurred in 69% of patients in the placebo arm [23]. Results of the ECHO trial led to US FDA approval of acalabrutinib plus BR for patients with previously untreated MCL who are ineligible for ASCT in January 2025. Notably, in both SHINE and ECHO studies, the BTKi-containing arms had more grade 3 or above adverse events reported [22, 23]. Prolonged continuous BTKi therapy in 1 L may not be suitable for all patients with MCL.
SHINE and ECHO were not designed to determine whether BR and BTKi combination therapy in the frontline is better than sequential treatment with BR in the first-line (1 L) followed by a BTKi in the second-line (2 L), which has been a standard-of-care in routine practice prior to the recent FDA approval of acalabrutinib for frontline use. In addition, while rituximab maintenance was required in SHINE and ECHO, its use has been heterogeneous across different centers in routine practice, likely because of conflicting results of the small, randomized phase 2 MAINTAIN trial and several retrospective studies on the benefit of rituximab maintenance after BR induction in MCL [12–15]. Whether sequential treatment with BR in 1 L, with or without rituximab maintenance, followed by a BTKi in 2 L can result in similar cumulative PFS compared to 1 L BR and BTKi combination therapy is unknown. This seems possible considering that the differences in median PFS between BTKi and placebo arms in SHINE and ECHO (17–28 months) and the median PFS achieved with BTKi in R/R MCL (13–33 months) appeared similar [16–21]. To address this important gap of knowledge, we modeled observational data to evaluate MCL outcomes after sequential 1 L BR and 2 L BTKi therapy in the BTKi era. The results are expected to set benchmarks for MCL outcomes following sequential BR and BTKi treatment, provide important context for interpretation of the SHINE and ECHO results, and help inform clinical practice on whether and/or when to use a BTKi in the frontline setting.
Patients and methods
Patients
This retrospective multicenter study included patients from 27 US and Canadian centers. Main inclusion criteria included confirmed diagnosis of MCL with t(11;14)(q13;q32) translocation and/or cyclin D1 expression, age ≥18 years old at diagnosis, and started frontline BR treatment between January 1, 2014, and December 31, 2020. Main exclusion criteria included participation in the SHINE or ECHO trial, receipt of a BTKi in combination with BR in frontline, receipt of other therapy in combination with BR (e.g., venetoclax, bortezomib, cytarabine, etc.; pre-phase steroid was allowed), ASCT consolidation after BR, and receipt of maintenance therapy other than rituximab.
Statistical analysis
Patient and disease characteristics were summarized using descriptive analyses. Event-free survival (EFS) was defined as time from index line treatment start (or the 3-month post-1L BR end of treatment [EOT] landmark where specified) to the first event (progression, relapse, unplanned re-treatment, or death from any cause). OS was defined as time from index line treatment start (or the 3-month post-1L BR EOT landmark where specified) to death from any cause. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1 L BR start (or the 3-month post-1L BR EOT landmark where specified) to progression, relapse, or unplanned re-treatment following 2 L BTKi treatment or death from any cause. Living patients without progression, relapse, or retreatment following 1 L BR or 2 L BTKi were censored at last follow-up for EFS2 analysis; patients who received a non-BTKi treatment at 2 L were censored at 2 L treatment start; living patients who had progression or relapse after 1 L BR but no documented 2 L treatment were censored at 1 L progression or relapse date (Supplemental Fig. 1). Time-to-event data were analyzed using the Kaplan-Meier method. Survival outcomes among subgroups were compared using a Cox proportional hazards model, and Wald P values were reported. Statistical analyses were done in R, with survival_3.8-3 package used for survival analyses.
Ethics approval and consent to participate
This study was approved by the institutional review board at each participating center. The requirement for informed consent was waived due to the retrospective nature of the study. The study was conducted in accordance with the Declaration of Helsinki. Mayo Clinic (Rochester, MN) served as the principal research site for data assembly and analysis. A Data Use Agreement was executed between each external participating center and Mayo Clinic.
Results
Patient characteristics
A total of 755 patients with MCL from 27 centers who started 1 L BR between 2014 and 2020 were included (Supplemental Table 1). Baseline patient and disease characteristics are summarized in Table 1. The median age at 1 L BR start was 71 (interquartile range 65–76, range 35–91) years, and 580 (76.8%) were ≥65 years old; 539 (71.4%) were male. Excluding missing data, 94 (13.9%) had an ECOG performance status ≥2. Bone marrow involvement was present in 466 (73.4%) patients, 689 (92.9%) had stage III-IV disease, and 157 (27.3%) had bulky disease (≥ 5 cm). Simplified MIPI was low in 120 (19.0%), intermediate in 241 (38.2%), and high in 270 (42.8%) patients. Blastoid or pleomorphic morphology was present in 85 (13.0%) patients, and Ki-67 was ≥30% in 318 (58.3%) and ≥50% in 146 (26.8%) patients. TP53 aberration was detected in 74 (40.4%) of 183 patients, with TP53 mutation detected in 40 of 178 (22.5%) and 17p/TP53 deletion in 52 of 254 (20.5%). Complex karyotype was observed in 71 (20.9%) of 340 patients.
Table 1.
Baseline patient and disease characteristics.
| Variable | All patients (N = 755) | Age ≥ 65 (n = 580) |
|---|---|---|
| Age (at 1 L BR start) | ||
| Median | 71 | 73 |
| Range | 35–91 | 65–91 |
| IQR | 65–76 | 69–78 |
| ≥65 | 580 (76.8%) | 580 (100.0%) |
| Sex | ||
| Female | 216 (28.6%) | 174 (30.0%) |
| Male | 539 (71.4%) | 406 (70.0%) |
| Race | ||
| White | 572 (92.1%) | 436 (92.6%) |
| Black or African American | 27 (4.3%) | 17 (3.6%) |
| Asian or Pacific Islander | 12 (1.9%) | 11 (2.3%) |
| American Indian or Alaskan Native | 1 (0.2%) | 0 (0.0%) |
| Other | 9 (1.4%) | 7 (1.5%) |
| Missing | 134 | 109 |
| Ethnicity | ||
| Non-Hispanic | 583 (94.5%) | 446 (95.3%) |
| Hispanic/Latino | 34 (5.5%) | 22 (4.7%) |
| Missing | 138 | 112 |
| ECOG performance status | ||
| 0–1 | 584 (86.1%) | 449 (85.9%) |
| ≥2 | 94 (13.9%) | 74 (14.1%) |
| Missing | 77 | 57 |
| Bone marrow involvement | ||
| Yes | 466 (73.4%) | 364 (74.9%) |
| No | 169 (26.6%) | 122 (25.1%) |
| Unknown | 120 | 94 |
| Stage | ||
| I-II | 53 (7.1%) | 39 (6.8%) |
| III-IV | 689 (92.9%) | 532 (93.2%) |
| Missing | 13 | 9 |
| Bulky disease (≥5 cm) | ||
| Yes | 157 (27.3%) | 132 (28.8%) |
| No | 418 (72.7%) | 327 (71.2%) |
| Unknown | 180 | 121 |
| Simplified MIPI | ||
| 0–3 (low) | 120 (19.0%) | 57 (11.6%) |
| 4–5 (intermediate) | 241 (38.2%) | 201 (40.9%) |
| 6–11 (high) | 270 (42.8%) | 234 (47.6%) |
| Missing | 124 | 88 |
| Ki-67 | ||
| <30% | 227 (41.7%) | 181 (41.8%) |
| 30–49% | 172 (31.6%) | 136 (31.4%) |
| ≥50% | 146 (26.8%) | 116 (26.8%) |
| Missing | 210 | 147 |
| Blastoid or pleomorphic morphology | ||
| Yes | 85 (13.0%) | 67 (13.0%) |
| No | 567 (87.0%) | 449 (87.0%) |
| Unknown | 103 | 64 |
| TP53 mutation | ||
| Yes | 40 (22.5%) | 32 (23.0%) |
| No | 138 (77.5%) | 107 (77.0%) |
| Unknown | 577 | 441 |
| 17p/TP53 deletion | ||
| Yes | 52 (20.5%) | 44 (21.8%) |
| No | 202 (79.5%) | 158 (78.2%) |
| Unknown | 501 | 378 |
| TP53 mutation or deletion | ||
| Yes | 74 (40.4%) | 59 (40.7%) |
| No | 109 (59.6%) | 86 (59.3%) |
| Unknown (if one unknown then counted as unknown) | 572 | 435 |
| Complex karyotype (≥3 abnormalities in addition to t(11;14)) | ||
| Yes | 71 (20.9%) | 57 (22.0%) |
| No | 269 (79.1%) | 202 (78.0%) |
| Unknown | 415 | 321 |
1 L first-line, BR bendamustine and rituximab, ECOG Eastern Cooperative Oncology Group, IQR interquartile range, MIPI mantle cell lymphoma international prognostic index.
Survival outcomes in the entire cohort
The median follow-up following 1 L BR start was 61.4 (95% CI 56.4–65.9) months. Data on response to 1 L BR was available in 711 patients, and the best objective response rate (ORR) was 88.3% (72.3% complete response [CR] and 16.0% partial response [PR]). Following BR induction, 337 (44.6%) patients received rituximab maintenance. As of last follow-up, 282 patients were alive without relapse or progression after 1 L BR ± rituximab maintenance, 383 patients had disease relapse or progression, and 90 patients died without relapse or progression (Fig. 1). The median EFS after 1 L BR was 34.2 (95% CI 31.5–38.4) months (Fig. 2A).
Fig. 1. Consort diagram.
1 L first-line, 2 L second-line, BR bendamustine and rituximab, BTKi Bruton’s tyrosine kinase inhibitor, R rituximab.
Fig. 2. Survival outcomes in the entire cohort.
A EFS after 1 L BR. B EFS after 2 L BTKi. C OS after 2 L BTKi. D EFS2 after 1 L BR and 2 L BTKi. E OS after 1 L BR. 1 L first-line, 2 L second-line, BR bendamustine and rituximab, BTKi Bruton’s tyrosine kinase inhibitor, EFS event-free survival, OS overall survival.
Among the 346 patients who started 2 L treatment, 263 (76.0%) received a BTKi at 2 L–149 (56.7%) with ibrutinib, 84 (31.9%) with acalabrutinib, and 30 (11.4%) with zanubrutinib. Progression of disease within 24 months (POD24) of 1 L BR start occurred in 170 (64.6%) of the 263 patients who received a BTKi at 2 L. The median time from 1 L BR start to 2 L BTKi start was 15.7 months (IQR 6.9–31.1 months). The median follow-up following 2 L BTKi start was 41.1 (95% CI 33.2–46.9) months. Data on response to 2 L BTKi was available in 184 patients, and the best ORR was 62.0% (34.8% CR, 27.2% PR). The median EFS after 2 L BTKi was 10.1 (95% CI 7.7–13.6) months (Fig. 2B), and the median OS was 21.4 (95% CI 14.9–29.0) months after 2 L BTKi therapy (Fig. 2C).
By ITT analysis, the median EFS2 following 1 L BR and 2 L BTKi was 64.8 (95% CI 56.7–82.8) months (Fig. 2D). The median OS after 1 L BR was 85.3 (95% CI 77.4–NE) months. The 5-year OS rate was 57.9% (95% CI 54.1–62.0%), and the 7-year OS rate was 50.6% (95% CI 46.1–55.6%) (Fig. 2E).
Survival outcomes in patients ≥65 years old
A subgroup analysis of patients aged ≥65 years (n = 580; age eligibility in SHINE and ECHO) showed similar results. Other than age and simplified MIPI score, baseline patient and disease characteristics were similar to the entire cohort (Table 1). In this subgroup, the median EFS with 1 L BR was 33.5 (95% CI 29.3–36.3) months (Supplemental Fig. 2A). 267 patients received a 2 L therapy, 210 (78.7%) with a BTKi. The median EFS after 2 L BTKi was 10.7 (95% CI 7.5–14.0) months (Supplemental Fig. 2B), and the median OS after 2 L BTKi was 20.3 (95% CI 14.1–29.0) months (Supplemental Fig. 2C). By ITT analysis, the median EFS2 following 1 L BR and 2 L BTKi was 61.0 (95% CI 53.0–72.7) months (Supplemental Fig. 2D). The median OS after 1 L BR was 81.2 (95% CI 65.0–100.2) months, the 5-year OS rate was 55.4% (95% CI 51.1–60.0%), and the 7-year OS rate was 47.5% (95% CI 42.5–53.1%) (Supplemental Fig. 2E). Survival outcomes for the entire cohort and the age ≥65 subgroup are also summarized in Table 2.
Table 2.
Summary of results from this study, SHINE and ECHO.
| This study | This study, Age ≥ 65 | Ibrutinib Arm in SHINE | Placebo Arm in SHINE | Acalabrutinib Arm in ECHO | Placebo Arm in ECHO | |
|---|---|---|---|---|---|---|
| Patient number | 755 | 580 | 261 | 262 | 299 | 299 |
| Age, median (range) | 71 (35–91) | 73 (65–91) | 71 (65–86) | 71 (65–87) | 71 (65–85) | 71 (65–86) |
| Age ≥ 65 | 580 (76.8%) | 581 (100%) | 261 (100%) | 262 (100%) | 299 (100%) | 299 (100%) |
| ECOG PS ≥ 2 | 94 (13.9%) | 74 (14.1%) | Not reported | Not reported | 12 (4.0%) | 25 (8.4%) |
| Stage III-IV | 689 (92.9%) | 532 (93.2%) | 252 (96.6%) | 248 (94.7%) | 282 (94.3%) | 287 (96.0%) |
| Bulky disease ≥ 5 cm | 157 (27.3%) | 132 (28.8%) | 95 (36.5%) | 98 (37.5%) | 112 (37.5%) | 113 (37.8%) |
| Simplified MIPI, intermediate risk | 241 (38.2%) | 201 (40.9%) | 124 (47.5%) | 129 (49.2%) | 128 (42.8%) | 125 (41.8%) |
| Simplified MIPI, high risk | 270 (42.8%) | 234 (47.6%) | 93 (35.6%) | 87 (33.2%) | 72 (24.1%) | 73 (24.4%) |
| Ki-67 ≥ 30% | 318 (58.3%) | 252 (58.2%) | Not reported | Not reported | 139 (51.1%) | 147 (53.8%) |
| Blastoid or pleomorphic morphology | 85 (13.0%) | 67 (13.0%) | 19 (8.3%) | 26 (11.5%) | 41 (13.7%) | 38 (12.7%) |
| TP53 mutation | 40 (22.5%) | 32 (23.0%) | 26 (18.6%) | 24 (18.6%) | 22 (18.5%) | 29 (25.9%) |
| Median follow-up | 61.4 months | 63.9 months | 84.7 months | 49.8 months | ||
| ORR to 1 L BR | 88.3% | 88.0% | 89.7% | 88.5% | 91.0% | 88.0% |
| CR rate to 1 L BR | 72.3% | 72.1% | 65.5% | 57.6% | 66.6% | 53.5% |
| Rituximab maintenance | 337 (44.6%) | 266 (45.9%) | 206 (78.9%) | 210 (80.2%) | Not reported (required by design) | Not reported (required by design) |
| BTKi use | At 2 L: 263 (76.0%) of 346 who had 2 L (34.8% of all 755) | At 2 L: 210 (78.7%) of 267 who had 2 L (36.2% of all 581) | 1 L: 100% by design | At 2 L: 41 (38.7%) of 106 who had 2 L (15.6% of all 262) | 1 L: 100% by design | 68 of 99 who had PD after 1 L received BTKi later (22.7% of all 299) |
| Median EFS/PFS (months) | EFS: 34.2 (95% CI 31.5–38.4), ITT EFS2: 64.8 (95% CI 56.7–82.8) | EFS: 33.5 (95% CI 29.3–36.3), ITT EFS2: 61.0 (95% CI 53.0–72.7) | PFS: 80.6 (95% CI 61.9–NE) | PFS: 52.9 (95% CI 43.7–71.0) | PFS: 66.4 (95% CI 55.1–NE) | PFS: 49.6 (95% CI 36.0–64.1) |
| OS | 57.9% at 5 years, 50.6% at 7 years | 55.4% at 5 years, 47.5% at 7 years | 55.0% at 7 years | 56.8% at 7 years | ~65% at 5 years | ~60% at 5 years |
1 L first-line, 2 L second-line, BR bendamustine and rituximab, BTKi Bruton tyrosine kinase inhibitor, CI confidence interval, CR complete response, ECOG PS Eastern Cooperative Oncology Group performance status, EFS event-free survival, ITT intention to treat, MIPI mantle cell lymphoma international prognostic index, NE not estimable, ORR objective response rate, PD progressive disease, PFS progression-free survival, OS overall survival.
Survival outcomes in subgroup analyses
Survival outcomes in subgroups of interest are summarized in Table 3. High-risk disease features were associated with less favorable EFS, EFS2 and OS outcomes. The observed EFS after 1 L BR (Supplemental Fig. 3), ITT EFS2 after 1 L BR and 2 L BTKi (Fig. 3), and OS after 1 L BR (Fig. 4) were longer in patients without high simplified MIPI, high Ki-67 ( ≥ 50%), blastoid or pleomorphic morphology, TP53 mutation, or complex karyotype (all P < 0.001). Patients without bulky disease (≥5 cm) had longer EFS (P = 0.039) and a trend towards longer EFS2 (P = 0.094) and OS (P = 0.103).
Table 3.
Median EFS, EFS2 and OS in subgroups.
| Variable | n | 1 L EFS, median (95% CI) | P value | 1 L BR and 2 L BTKi EFS2, median (95% CI) | P value | 1 L BR OS, median (95% CI) | P value |
|---|---|---|---|---|---|---|---|
| All patients | 755 | 34.2 (31.5–38.4) | 64.8 (56.7–82.8) | 85.3 (77.4–NE) | |||
| Simplified MIPI | <0.001 | <0.001 | <0.001 | ||||
| 0–3 (low) | 120 | 73.5 (44.4–NE) | NE (NE–NE) | 111.5 (106.0–NE) | |||
| 4–5 (intermediate) | 241 | 38.2 (31.9–46.8) | 77 (59.5–NE) | 100.2 (77.4–NE) | |||
| 6–11 (high) | 270 | 27.1 (19.7–31.6) | 44.6 (35.0–61.6) | 54.5 (42.4–81.2) | |||
| Bulky disease (≥5 cm) | 0.039 | 0.094 | 0.103 | ||||
| Yes | 157 | 31.5 (21.4–38.3) | 54.5 (43.5–77.4) | 67.9 (54.3–87.3) | |||
| No | 418 | 35.8 (30.8–41.4) | 68.1 (58.0–NE) | 100.2 (72.7–NE) | |||
| Ki-67 | <0.001 | <0.001 | <0.001 | ||||
| <30% | 227 | 43.7 (39.6–61.0) | 97.8 (72.7–NE) | 111.5 (81.5–NE) | |||
| 30-49% | 172 | 36.2 (32.9–48.1) | 73.5 (54.5–NE) | 87.3 (85.3–NE) | |||
| ≥50% | 146 | 20.7 (17.1–28.0) | 37.9 (29.8–59.6) | 42.6 (32.7–93.4) | |||
| Blastoid or pleomorphic morphology | <0.001 | <0.001 | <0.001 | ||||
| Yes | 85 | 11.8 (9.0–19.1) | 31.8 (17.2–NE) | 38.1 (25.9–62.6) | |||
| No | 567 | 37.7 (33.8–42.7) | 71.1 (57.7–88.1) | 97.8 (81.3–NE) | |||
| TP53 mutation | <0.001 | <0.001 | <0.001 | ||||
| Yes | 40 | 5.7 (3.6–12.4) | 23.2 (8.8–43) | 30.8 (25.9–57.9) | |||
| No | 138 | 31.5 (25.9–42.7) | 53.0 (44.6–64.8) | 81.2 (55–NE) | |||
| Complex karyotype (≥3 abnormalities in addition to t(11;14)) | 0.015 | <0.001 | 0.008 | ||||
| Yes | 71 | 22.3 (15.5–30.8) | 37.6 (21.9–54.5) | 52.8 (30.8–NE) | |||
| No | 269 | 35.4 (28.6–43.6) | 64.3 (55.0–NE) | 100.2 (67.9–NE) |
1 L first-line, 2 L second-line, BR bendamustine and rituximab, CI confidence interval, EFS event-free survival, MIPI mantle cell lymphoma international prognostic index, NE not estimable, OS overall survival.
Fig. 3. EFS2 by subgroups.
A EFS2 by sMIPI. B EFS2 by disease bulk. C EFS2 by Ki-67. D EFS2 by morphology. E EFS2 by TP53 mutation status. F EFS2 by cytogenetics. 1 L first-line, BR bendamustine and rituximab, EFS2 event-free survival 2, sMIPI simplified mantle cell lymphoma international prognostic index.
Fig. 4. OS by subgroups.
A OS by sMIPI. B OS by disease bulk. C OS by Ki-67. D OS by morphology. E OS by TP53 mutation status. F OS by cytogenetics. 1 L first-line, BR bendamustine and rituximab, OS overall survival, sMIPI simplified mantle cell lymphoma international prognostic index.
Survival outcomes stratified by rituximab maintenance
Rituximab maintenance was required in SHINE and ECHO trials but was at the discretion of treating physicians in our cohort. Therefore, we explored survival outcomes by rituximab maintenance in our study. Among patients who achieved CR or PR to 1 L BR, the median EFS from the 3-month post-1L BR EOT landmark was 47.1 (95% CI 40.1–61.1) months for those who received rituximab maintenance (n = 322) and 31.2 (95% CI 27.3–37.7) for those who did not (n = 250) (P = 0.001; Supplemental Table 2 and Fig. 5A). By ITT analysis, the median EFS2 from the 3-month post-1L BR EOT was 91.6 (95% CI 79.6–NE) and 63.5 (95% CI 48.9–NE) months, respectively (P = 0.038; Fig. 5B). The median OS from the 3-month post-1L BR EOT landmark was 105.7 (95% CI 97.7–NE) and 75.2 (95% CI 63.5–NE) months, respectively, and the 5-year and 7-year OS rates were 69.0% (63.6–74.8%) and 61.8% (55.1–69.3%) in the maintenance group and 57.6% (50.4–65.9%) and 44.8% (35.0–57.4%) in the no maintenance group (P = 0.008; Fig. 5C). The association between rituximab maintenance and improved outcomes remained significant in multivariable Cox regression analysis (Supplemental Table 3). Of note, rituximab maintenance was not associated with EFS after 2 L BTKi treatment (Supplemental Fig. 4).
Fig. 5. Survival outcomes stratified by rituximab maintenance.
A EFS, B ITT EFS2, and C OS after 1 L BR by rituximab maintenance in all patients who had an objective response to BR. 1 L first-line, BR bendamustine and rituximab, EFS event-free survival, EOT end of treatment, ITT intention to treat, OS overall survival, R rituximab.
Discussion
In this multicenter retrospective study in patients with MCL, the EFS2 and OS outcomes after sequential treatment with 1 L BR and 2 L BTKi appeared numerically close to the PFS and OS achieved with frontline BR plus BTKi combination therapy observed in the SHINE and ECHO trials. The survival outcomes were particularly favorable in those without high-risk disease features in our study. Within the constraints of retrospective observational data, our results suggest that sequential use of BR in 1 L and BTKi in 2 L may be reasonable for at least a subset of patients with MCL, i.e., those without high-risk features.
While the indication for MCL for ibrutinib was withdrawn from the US market in 2023, acalabrutinib now has FDA approval for frontline use in combination with BR for MCL. Results of the ECHO trial and the FDA approval support the use of acalabrutinib and BR combination therapy in patients with newly diagnosed MCL. Results of our retrospective study, and the lack of statistically significant OS benefit with acalabrutinib in the ECHO trial, however, suggest that sequential treatment with BR in 1 L and BTKi in 2 L is a reasonable alternative approach for select patients. In addition, the most recent update from the ECHO trial showed that the median PFS (72.5 months) after 1 L acalabrutinib-BR and the time to third-line treatment or death in the placebo-BR arm (73.6 months; where about 70% of patients received a BTKi in 2 L) were similar [24], further supporting that sequential treatment may still be reasonable. The sequential approach avoids continuous BTKi treatment at the start of frontline treatment and thereby substantially reduces cost and may limit the increased toxicity associated with the triplet and prolonged BTKi exposure, particularly in vulnerable patient populations. Treatment-free intervals will likely be very valuable from a quality-of-life standpoint as well. Selection between the combination and sequential treatment approaches may be considered based on patient and disease characteristics. In our study, high simplified MIPI, high Ki-67 (especially ≥ 50%), blastoid or pleomorphic morphology, complex karyotype, and to a lesser extent bulky disease, were associated with inferior survival outcomes with sequential BR and BTKi treatment. Blastoid or pleomorphic morphology, high Ki-67 ( ≥ 30%), and bulky disease (≥ 5 cm) appeared to be associated with more benefit from frontline acalabrutinib in the ECHO trial [23]. Therefore, combination therapy may be favored in patients with high-risk factors mentioned above. For patients without high-risk factors and those who are not ideal candidates for prolonged BTKi use (e.g., with atrial fibrillation, hypertension, bleeding risk, etc.), using BR in 1 L and reserving BTKi for 2 L may be appropriate. The number of patients with TP53 mutations was limited in both ECHO and our study. Clinical trials or chemotherapy-free approaches should be considered for these patients [25].
The median EFS after 1 L BR (with or without rituximab maintenance) was ~3 years in our study, similar to that observed in the StiL NHL1 trial (35.4 months, without maintenance) though numerically shorter than that in the BRIGHT trial (~4 years, maintenance allowed) [9–11]. Whether rituximab maintenance after BR improves outcomes is controversial. The randomized StiL NHL7-2008 MAINTAIN trial showed no PFS benefit of rituximab maintenance after BR [12], while several retrospective studies suggested potential PFS or OS benefits [13–15]. The SHINE and ECHO trials adopted rituximab maintenance after BR, but in our study, rituximab maintenance was only used in approximately 45% of patients, indicating the variable adoption of rituximab maintenance in routine practices. In our study, patients who received rituximab maintenance had more favorable survival outcomes, providing additional support for the use of rituximab maintenance after 1 L BR in MCL.
Compared to SHINE and ECHO participants, our patient population had less favorable baseline characteristics, with more patients in our cohort having ECOG PS ≥ 2, high-risk simplified MIPI, or high Ki-67 ( ≥ 30%), though the prevalence of blastoid or pleomorphic morphology and TP53 mutation (albeit limited testing) were largely similar. Patients in our cohort might have had more comorbidities as well since clinical trials often have strict eligibility criteria. In this context, the survival outcomes with sequential 1 L BR and 2 L BTKi treatment, particularly with rituximab maintenance, are encouraging when benchmarked to combination therapy outcomes in clinical trials and further support adoption of the sequential treatment approach in select patients in real-world practice.
The EFS outcomes after 2 L BTKi in our cohort was inferior to PFS results from pivotal trials [16–21]. However, they are on par with results of similar endpoints (duration of treatment or time to next treatment) reported by several real-world studies [26, 27]. Importantly, among the patients who received a BTKi at 2 L in our study, 65% had POD24 after 1 L BR, indicating aggressive disease in these patients and at least partially explaining the poor outcomes with 2 L BTKi therapy in these patients. It is possible that 2 L BTKi treatment will have better outcomes in patients with late relapses after 1 L BR (e.g., >24 months) with longer follow-up of our cohort. Close to 60% of our patients received ibrutinib as the 2 L BTKi, which was associated with numerically shorter EFS compared with acalabrutinib and zanubrutinib (data not shown). When acalabrutinib or zanubrutinib is used as 2 L BTKi treatment in routine practice, the outcomes might be slightly better than observed in our cohort.
BTKi-based chemotherapy-free regimens have been studied in the frontline. In the ENRICH trial, ibrutinib-rituximab did not outperform BR for either PFS or OS [28]. Results of the MANGROVE trial comparing zanubrutinib-rituximab vs BR are still pending [29]. At this time, we believe BR remains an excellent backbone for 1 L treatment of MCL in older patients. Adding BTKi to BR in 1 L or reserving BTKi for 2 L after BR failure are both reasonable and can be selected based on patient and disease characteristics, as discussed above.
The strengths of this multicenter study include a large cohort size, confined time frame (BTKi era), availability of detailed treatment and follow-up data, and an ITT framework for EFS2 analysis. The main limitations are retrospective design, incomplete data on some baseline variables (such as Ki-67 and TP53 alteration), and lack of reliable adverse event data in the retrospective setting.
In conclusion, this multicenter retrospective study demonstrated that sequential treatment with BR (and rituximab maintenance) in 1 L and BTKi in 2 L resulted in similar cumulative EFS2 and OS, when benchmarked to BR and BTKi combination therapy outcomes in SHINE and ECHO trials, with more favorable outcomes observed in the absence of high-risk features. These results support sequencing BR (and rituximab maintenance) and BTKi in 1 L and 2 L, respectively, as an alternative to BR-BTKi combination therapy in the frontline for select patients with MCL without high-risk disease features.
Supplementary information
Acknowledgements
We thank the clinical teams who cared for the patients included in this study and thank the research coordinators who helped with data collection. Dr. Yucai Wang is a recipient of Lymphoma Research Foundation Clinical Investigator Career Development Award. Dr. Anita Kumar is a Scholar in Clinical Research supported by Blood Cancer United.
Author contributions
YW contributed to the study concept and design, participated in data interpretation, and drafted the manuscript; MCL and MJM contributed to the study concept and design, performed statistical analyses, and participated in data interpretation; JRC, JBC and PM contributed to the study concept and design and participated in data interpretation. SRH, DV, LK, AK, AJ, TRB, BTH, DAB, KJM, AD, CA, JR, IAN, BSK, NSG, NBK, GNP, ISL, EO, AMT, FB, MAM, ZIH, JLM, PRY, CAP, PMR, CER, RWM, AV, IBG, DGG, PJ, MLW, SRA, EM, LGB, PAP, ACS, MRM, MSN, AM, TKM, NG, RSB, SKB, MKK, JA, AVS, and RK contributed to data acquisition and participated in data interpretation. All authors critically revised the manuscript for important intellectual content, approved the final version of the manuscript, and agree to be accountable for all aspects of this study.
Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
YW: Research funding (to institution): Incyte, InnoCare, Loxo Oncology, Eli Lilly, MorphoSys, Novartis, Genentech, Genmab, AbbVie, BeiGene, Merck; Advisory board (compensation to institution): Eli Lilly, Loxo Oncology, TG Therapeutics, Incyte, InnoCare, Kite Pharma, Janssen, BeiGene, AstraZeneca, Genmab, AbbVie; Consultancy (compensation to institution): InnoCare, AbbVie; Honoraria (to institution): Kite Pharma. DV: Honoraria and advisory board: Roche, Janssen, BeOne Medicines, AstraZeneca, AbbVie, Merck, Bristol Myers Squibb, Kite Pharma/Gilead Sciences, Incyte, Kyowa Kirin, Eli Lilly, ONO Pharmaceutical. AK: Research support: AbbVie, Adaptive Biotechnologies, Celgene, Pharmacyclics, Loxo Oncology/Eli Lilly, Seagen, Genentech, Incyte; Honoraria: AstraZeneca, Kite Pharma, Janssen, Genentech, Loxo Oncology/Eli Lilly; Consulting: Genentech. DAB: Research funding: Incyte, Accutar Biotech, Nurix Therapeutics, Novartis, Kite Pharma/Gilead Sciences, Bristol Myers Squibb, Genmab, BeOne Medicines; Consulting: Nurix Therapeutics, Kite Pharma/Gilead Sciences, ADC Therapeutics, Novartis. KJM: Consulting/Honoraria: AstraZeneca, AbbVie, Acerta Pharma, ADC Therapeutics, Autolus Therapeutics, BeOne Medicines, Bristol Myers Squibb, Caribou Biosciences, Genmab, Genentech, Janssen, Incyte, MorphoSys, Kite Pharma/Gilead Sciences, Eli Lilly. AD: Consulting fees: AbbVie, AstraZeneca, BeOne Medicines, Genmab, Incyte, Janssen, Eli Lilly, Merck, Nurix Therapeutics, Regeneron; Research funding: BeOne Medicines, Genmab, Incyte, Eli Lilly, Merck, Nurix Therapeutics, Prelude Therapeutics, Regeneron. JR: Research support: AstraZeneca, Bristol Myers Squibb/Celgene, Genentech, Daiichi Sankyo; Honoraria for consulting: AstraZeneca, Bristol Myers Squibb/Celgene, Pfizer, Ipsen. BSK: Consulting: AbbVie, AstraZeneca, Bristol Myers Squibb, BeOne Medicines, Genentech, Roche, Incyte, Eli Lilly; Research support: BeOne Medicines, Roche, AstraZeneca. NSG: Research funding (to institution): Bristol Myers Squibb, Poseida Therapeutics, Cabaletta Bio, Merck, Regeneron; Honoraria: Bristol Myers Squibb, Novartis, Regeneron, Genentech, Incyte, ADC Therapeutics. GNP: Equity: Mevox Ltd.; Consulting fees/Honoraria: ADC Therapeutics, BeOne Medicines. ISL: Research support: Genentech, ADC Therapeutics, Genmab. AMT: Advisory board: ADC Therapeutics. MAM: Advisory board: Genentech; Research funding: AbbVie/Genmab. JLM: Consulting: Pharmacyclics/AbbVie, Bayer, Gilead Sciences/Kite Pharma, BeiGene, Pfizer, Janssen, Celgene/Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Seagen, Karyopharm Therapeutics, Aurobindo Pharma, Verastem, Genmab, Sanofi Genzyme, Genentech/Roche, ADC Therapeutics, Epizyme, Novartis, MorphoSys/Incyte, MEI Pharma, TG Therapeutics, AstraZeneca, Eli Lilly; Research funding: Bayer, Gilead Sciences/Kite Pharma, Celgene, Merck, Portola Pharmaceuticals, Incyte, Genentech, Pharmacyclics, Seagen, Janssen, Millennium Pharmaceuticals, Novartis, BeiGene, Bristol Myers Squibb; Honoraria: Targeted Oncology, OncLive, Curio Science, Aptitude Health, Physicians’ Education Resource. CAP: Consulting: AbbVie, AstraZeneca, BeiGene, Genentech, Pfizer; Research funding: BeOne Medicines, Merck, Genentech, Loxo Oncology/Eli Lilly, AstraZeneca/Acerta Pharma, Seagen/Pfizer. PMR: Research funding (to institution): Genentech, Pfizer. CER: Consulting fees: AstraZeneca, BeOne Medicines, Genentech, Incyte; Research funding (to institution): BeOne Medicines, Eli Lilly, Genentech. RWM: Advisory board: Genmab, Bristol Myers Squibb, AbbVie, Ipsen, Kite Pharma; Consulting: DG Medicines; Honoraria: Genmab, AbbVie; Research funding (to institution): Merck, Bristol Myers Squibb, Genmab, Genentech/Roche. EM: Consultancy: AbbVie. NG: Research funding (to institution): Genentech/Roche, AstraZeneca, Incyte/MorphoSys, AbbVie; Consulting/Honoraria: AbbVie, AstraZeneca, Pharmacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, BeiGene, Incyte, Roche/Genentech, Genmab, Merck, Galapagos, Pfizer. RK: Research funding (to institution): Bristol Myers Squibb, Kite Pharma/Gilead Sciences, Takeda, Genentech, Genmab, AbbVie, BeiGene, Merck; Advisory board: Kite Pharma/Gilead Sciences, BeiGene, Genmab, AbbVie, Bristol Myers Squibb, Genentech/Roche, AvenCell. JRC: No funding related to this research; unrelated research funding: Bristol Myers Squibb, Genentech, Genmab (to institution); personal compensation for data and safety monitoring committee service: Protagonist Therapeutics.
Footnotes
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Supplementary information
The online version contains supplementary material available at 10.1038/s41408-026-01507-w.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.