TO THE EDITOR:
The recently published comprehensive retrospective multicenter study by Wang et al demonstrated improved event-free survival and overall survival (OS) for patients with mantle cell lymphoma (MCL) treated with first-line (1L) bendamustine-rituximab (BR), who received rituximab (R) maintenance as compared with nonmaintenance.1 The study included 703 US and Canadian patients diagnosed since 2010, who did not receive additional 1L therapy to BR, achieved at least a partial response, and survived without relapse or treatment 3 months after end of treatment (EoT). The authors additionally performed subgroup analysis adjusting for clinical response, demographics, and known clinical and disease-related prognostic factors. As MCL is mainly diagnosed in older patients, comorbidity is an important missing variable in the published study. Further, the authors highlight the limitation of missing data on adverse events such as infections. Importantly, the StiL NHL7-2008 MAINTAIN trial (R-maintenance vs observation after 1L BR, n = 120 patients) could not demonstrate improved progression-free survival in MCL; likely due to lack of power (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.36-1.14).2 Here, we assessed time to next treatment or death (TTNTD) and OS in a retrospective, external Danish nationwide cohort with adjustment for Charlson Comorbidity Index (CCI) scores (≤2 vs >2) and polypharmacy (<5 vs ≥5 prescription medications),3,4 as well as assessed the rate of severe infections for the subset of patients diagnosed in East Denmark after 2016, for whom electronic health records (EHR) were available.
From the Danish Lymphoid Cancer Research (DALY-CARE) data resource,5 we used the Danish National Lymphoma Registry (LYFO)6 to identify patients diagnosed with MCL since 2010, who were treated with 1L BR with and without R-maintenance. Information on response to 1L treatment, clinical stage, mantle cell lymphoma international prognostic index (MIPI)7 as well as date of EoT, 2L therapy, and death or end of follow-up, were likewise retrieved from LYFO. International Classification of Disease version 10 codes across all available datasets up until 3 months after EoT were used to calculate CCI scores.3,5 Prescriptions from the National Register of Pharmaceutical Sales,8 in the last year leading up to 3 months after EoT, were used to define polypharmacy (<5 vs ≥5 distinct prescription medications).4 In contrast to TTNTD defined by Wang et al, the TTNTD event in Danish data was restricted to the composite end point of treatment or death, but not including relapse or progression (for which data are not validated in DALY-CARE). TTNTD and OS were calculated from 3 months after EoT until event or end of follow-up. Severe infections were identified from EHR as ≥24 hours of IV antimicrobial therapy.4 We were unable to assess lower grade infections using prescribed antimicrobials as a proxy,9 because antimicrobial prescriptions would presumably differ between patients treated with and without R-maintenance.
Using the same inclusion and exclusion criteria as Wang et al,1 we identified 244 patients: 169 (69.3%) received R-maintenance and 75 (30.7%) did not. The 2 groups showed similar baseline characteristics, except for more bone marrow involvement and thus more advanced stage in the R-maintenance group as compared with the nonmaintenance group (Table 1). A complete response was achieved for 151 (89.3%) and 72 (96.0%) patients, whereas only 18 (10.7%) and 3 (4.0%) patients achieved a partial response in the R-maintenance and nonmaintenance groups, respectively. CCI scores were similar in the R-maintenance and nonmaintenance groups. Stratified based on CCI score (≤2 vs >2), patients had similar age (median 74 vs 75 years), bone marrow involvement (85.1% vs 80.2), advanced stage (92.1% vs 93.3%), and MIPI risk (4.0%, 34.4%, and 61.6% vs 4.3%, 29.1%, and 66.7% with low, intermediate, and high risk, respectively) for patients with a low CCI score as compared with a high CCI score, respectively (P > .41). Females, however, were more frequently CCI low as compared with CCI high (39% vs 24%; P = .014).
Table 1.
Patient characteristics
| Variable | R-maintenance (n = 169) | Nonmaintenance (n = 75) | Total (N = 244) | P value |
|---|---|---|---|---|
| Age, median (IQR) | 74 (70-79) | 74 (71-80) | 74 (71-79) | .39 |
| Sex, male | 114 (67.5) | 52 (69.3) | 166 (68.0) | .88 |
| Bone marrow involvement | ||||
| Yes | 140 (87.0) | 52 (73.2) | 192 (82.8) | .018 |
| Missing | 8 | 4 | 12 | |
| Ann Arbor stage | ||||
| I-II | 7 (4.1) | 11 (14.7) | 18 (7.4) | |
| III-IV | 162 (95.9) | 64 (85.3) | 226 (92.6) | .0083 |
| MIPI | ||||
| Low | 6 (3.6) | 4 (5.3) | 10 (4.1) | |
| Intermediate | 54 (32.3) | 23 (30.7) | 77 (31.8) | |
| High | 107 (64.1) | 48 (64.0) | 155 (64.0) | .81 |
| Missing | 2 | 0 | 2 | |
| Response to 1L | ||||
| PR | 18 (10.7) | 3 (4.0) | 21 (8.6) | |
| CR | 151 (89.3) | 72 (96.0) | 223 (91.4) | .14 |
| CCI score | ||||
| ≤2 | 84 (49.7) | 43 (57.3) | 127 (52.0) | |
| >2 | 85 (50.3) | 32 (42.7) | 117 (48.0) | .34 |
| Polypharmacy, yes | 136 (80.5) | 55 (73.3) | 191 (78.3) | .28 |
CR, complete remission; IQR, interquartile range; PR, partial remission.
With a median follow-up of 6.1 years (interquartile range, 2.6-8.3), we performed landmark analyses of TTNTD and OS from 3 months after EoT. Both TTNTD and OS were significantly longer among patients who had received R-maintenance as compared with those who did not (Figure 1A-B). The median TTNTD (mTTNTD) was 6.1 vs 4.2 years in the R-maintenance and nonmaintenance groups, respectively, and the median OS (mOS) was 7.0 vs 5.1 years, respectively. Similar results were demonstrated for patients achieving a complete response (supplemental Figure 1). Adjusting TTNTD and OS for a CCI score of ≤2 vs >2, R-maintenance only demonstrated statistically significant improvement of TTNTD and OS for patients with a low CCI score (mTTNTD 7.0 vs 4.8 years, P = .0029; mOS 10.4 vs 5.5 years, P = .020), whereas R-maintenance did not impact TTNTD or OS for patients with a high CCI score (Figure 1C-D; mTTNTD 4.9 vs 3.6 years, P = .47; mOS 5.9 vs 5.1 years, P = .43). Similarly, R-maintenance demonstrated statistically significant improvement of TTNTD and OS for patients with polypharmacy (<5 vs ≥5: mTTNTD 6.3 vs 4.2 years, P = .037; mOS not reached vs 5.1, P = .039), whereas R-maintenance was likely underpowered to clearly stratify TTNTD and OS for patients without polypharmacy (mTTNTD 6.1 vs 4.7 years, P = .098; mOS not reached vs 5.1 years, P = .039; supplemental Figure 2). In an overlap-weighted propensity score-matched Cox model including age, sex, polypharmacy, CCI, and MIPI, R-maintenance was associated with a lower hazard of death (HR, 0.62; 95% CI, 0.41-0.93) and TTNTD (HR, 0.59; 95% CI, 0.40-0.86; supplemental Figure 3). In short, a CCI score >2 was independently predictive, whereas polypharmacy was only prognostic for the benefit of R-maintenance.10
Figure 1.
TTNTD and OS analyses. (A) TTNTD and (B) OS from 3 months after end of BR stratified by R-main vs non-main. (C) TTNTD and (D) OS further stratified by CCI score of 2 vs >2. Non-main, nonmaintenance; R-main, R-maintenance.
Among patients who died, the cause of death was established in 101 of 103 patients11,12: 48, 20, 14, 7, 6, and 6 patients died due to MCL, infections, other causes, other hematological malignancies, solid cancer, and cardiovascular disease, respectively. MCL-specific mortality continued to demonstrate benefit for patients receiving R-maintenance (P = .013), whereas CCI was no longer predictive of R-maintenance (supplemental Figure 4).
Among the 244 patients, we identified 139 patients with available EHR data: 103 (74.1%) with R-maintenance and 36 (25.9%) patients without. After 15 and 27 months from EoT (ie, landmark analysis 1 and 2 years), severe infections had occurred in 22 (23.6% [95% CI, 14.5-31.8]) and 27 (29.8% [95% CI, 19.6-38.6]) patients in the R-maintenance group and 5 (12.0% [95% CI, 0.2-22.4]) and 15 (39.0% [95% CI, 17.5-54.9]) patients in the nonmaintenance group (supplemental Figure 5). The total number of severe infections was 64 among 52 of the 103 (1.2 infections per infected) patients in the R-maintenance group and 32 among 21 of the 36 (1.5 infections per infected) in the nonmaintenance group. The mean number of infections was 0.6 (standard deviation 0.7) in the R-maintenance group and 0.9 (standard deviation 1.3) in the nonmaintenance group (P = .13). Thus, we find no evidence that R-maintenance was associated with a higher risk of severe infections.
Although this study benefits from well-validated clinical data from various registries,13,14 information on progression and biological markers such as Ki67 and TP53 mutations was missing. Although treatment is a clinically meaningful proxy for progression, 2L treatment does not capture asymptomatic progression or end of life palliation. Further, it is important to stress that International Classification of Disease version 10 diagnoses used to calculate CCI originate from hospital visits and may thus represent higher comorbid severity compared with prescriptions mostly filled by general practitioners.4
We here externally validate the findings of Wang et al1 in a different (free and publicly funded) health care system, confirming that R-maintenance after 1L BR among patients with MCL improves TTNTD and OS in a nationwide consecutive cohort. Further, these data suggest that the TTNTD and OS advantage may likely only benefit patients without significant comorbidity in terms of a low CCI score ≤2, although numbers were small. These data thus retrospectively confirm the conclusions of Wang et al, that R-maintenance should be offered after 1L treatment with BR for patients with MCL and possibly benefits patients without significant comorbidity.
Conflict-of-interest disclosure: C.B. reports travel grants from AstraZeneca outside this study. P.B. reports honoraria from Allogene, Amgen, Bristol Myers Squibb (BMS), Kite/Gilead, Janssen, Jazz Pharmaceuticals, Miltenyi, Novartis, and Nektar outside this study. M.H. reports consultancy fees and honoraria from AbbVie, AstraZeneca, Genmab, Johnson & Johnson (J&J), Merck, Roche, and Takeda; and research support (to institution) from AbbVie, Arvinas, AstraZeneca, BMS, Celgene, Genentech, Genmab, Incyte, J&J, Merck, Novartis, Pfizer, Roche, and Takeda outside this study. C.N. reports research funding and/or consultancy fees from AstraZeneca, J&J, AbbVie, BeOne, Genmab, CSL Behring, Octapharma, Takeda, Eli Lilly, Merck Sharp & Dohme, and Novo Nordisk Foundation. M.W. declares no competing financial interests.
Acknowledgments
Contribution: C.B. conceived the study and wrote the draft manuscript; C.B. and M.W. performed analyses; C.N. and C.B. gathered the data; C.B., P.B., M.H., and C.N. interpreted the data; and all authors contributed to and approved the final manuscript.
Footnotes
The full-text version of this article contains a data supplement.
Supplementary Material
References
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