Page 184 - 2022_03-Haematologica-web

Letters to the Editor
Survival in mantle cell lymphoma after frontline treatment with R-bendamustine, R-CHOP and the Nordic MCL2 regimen – a real world study on patients diagnosed in Sweden 2007-2017
The optimal frontline treatment of mantle cell lym- phoma (MCL) with respect to long-term survival remains undefined. Intensified immunochemotherapy including rituximab (R), cytarabine and autologous hematopoetic cell transplant (HD-AHCT) upfront, such as the Nordic MCL2 protocol, has demonstrated improved disease control.1-3 Elderly patients may benefit from R-CHOP or R-bendamustine (BR), albeit the regi- mens have not been robustly evaluated in a randomized setting or in observational studies.1,4,5 Here, we used the Swedish Lymphoma Register (SLR), a nationwide regis- ter initiated in 2000 with a reported coverage of ∼95%, 6 in order to investigate overall and relative survival in a population-based cohort of patients diagnosed with MCL between Jan 2007 and Sept 2017. Particularly, we report outcome by given treatment with specific focus on the currently recommended treatment strategies upfront: BR, R-CHOP, the Nordic MCL2 protocol and curative radiotherapy to limited stage disease.
Data on patient characteristics and frontline treatment administered was retrieved from the SLR. Survival status was obtained from the national population register. Cases fulfilling all of the following criteria were catego- rized as having been treated with curative radiotherapy: stage I-II disease; treatment with single radiotherapy; reported curative intent and radiation dose of 30-40 Gy. Chemotherapy treatment subgroups (MCL2, BR and R- CHOP) were compared using t-test or chi2-test (continu- ous or categorical variables). Follow-up began 90 days after diagnosis to allow for treatment completion and ended on date of death (from any cause) or on 20 October 2018, whichever occurred first. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) comparing all-cause mor- tality rates between treatment groups. Both uni- and multivariable models were considered, allowing for adjustments for age at diagnosis, calendar year of diag- nosis, sex, WHO performance status (PS), white blood cell count (WBC), lactate dehydrogenase (LDH) and the MCL International Prognostic Index (MIPI). Interaction models were fitted with age at diagnosis (dichotomized into <70/≥70 years) as an effect modifier. Non-paramet- ric estimates of overall survival (OS) were calculated by age group using the Kaplan-Meier method. Marginal (standardized) OS was estimated using predictions from a flexible parametric survival model. 7 As a measure of net (cause-specific) survival, non-parametric relative sur- vival (RS) estimates were calculated using the actuarial method and standardized estimates were predicted from a flexible parametric relative survival model correspon- ding to that in the OS analysis. All statistical analyses were performed using Stata (StatCorp, 2017. Stata Statistical Software: Release 16. College station, TX: StataCorp LLC). The study was approved by the Regional Board of the Ethical Committee in Lund, Sweden (2018/739).
In total, 1277 patients were included in the study. The median age at diagnosis was 71 years, the majority were male (70%) and Ann Arbor stage III-IV (80%) (Table 1). Frontline systemic treatment was reported in 818 patients (63%). Among systemic treatments, MCL2 (n=268, 33%), BR (n=231, 29%) and R-CHOP (n=93, 12%) were the regimens most frequently applied. The
number of patients receiving maintenance rituximab was 10 (11%) after R-CHOP, 18 (8%) after BR and 14 (5%) after MCL2. In total, 218 patients received HD- AHCT after MCL2 (82%) and one (<1%) after BR (Online Supplementary Table S1). Patients who received BR and R-CHOP were comparable in terms of mean age (75.5 and 73.5, P=0.39) at diagnosis, performance status (WHO PS 0-1 87% vs. 82%, P=0.32) and high risk MIPI (55% vs. 49%, P=0.36). Patients who were treated with MCL2 had a lower mean age (60 years, P<0.0001), lower PS (WHO PS 0-1 n=251; 94%, P=0.01 (vs. BR, P<0.0001; vs. R-CHOP, P<0.0001)) and were less likely to score a high-risk MIPI (26%, (vs. R-CHOP, P=0.02; vs. BR, P<0.0001)) compared to R-CHOP and BR, respectively. A total of 1182 patients were included in the survival analyses (95 were excluded due to lack of follow-up (FU) within 90 days after diagnosis). In patients receiving any systemic therapy, median OS was 4.9 years (IQR 1.5- NR) at a median FU time of 3.5 years (IQR 1.4-5.8). Among patients of all ages, treatment with MCL2 was associated with a lower all-cause mortality than BR in univariable models (HR=0.49 (95% CI 0.37-0.66)) or when adjusting for MIPI (HR=0.66 (95% CI 0.48-0.91)) but not when adjusting for the individual prognostic fac- tors included in MIPI (HR=1.06 (95% CI 0.71-1.56)). By age stratification (<70/≥70), no differences in all-cause mortality were observed in patients receiving MCL2 and BR. Patients treated with R-CHOP demonstrated higher all-cause mortality rates compared to BR-treated patients in univariable analysis, either including all patients or by age stratification. In multivariable models, no differences in all-cause mortality were observed. Survival propor- tions by age and treatment groups are presented in Figure 1 and Online supplementary Table S2. In patients <70 years, the unadjusted three-year OS was 0.80 (95% CI 0.75-0.85) for MCL2, 0.79 (95% CI 0.62-0.89) for BR, and 0.62 (95% CI 0.39-0.78) for R-CHOP. The corre- sponding marginal three-year OS was 0.78 (95% CI 0.74-0.82), 0.75 (95% CI 0.67-0.84) and 0.62 (95% CI 0.51-0.76). In patients aged ≥70 years, the unadjusted three-year OS was 0.68 (95% CI 0.60-0.74) for BR and 0.49 (95% CI 0.36-0.61) for R-CHOP and the correspon- ding marginal three-year OS was 0.55 (95% CI 0.45- 0.67) and 0.40 (95% CI 0.22-0.71). Analysis of RS demonstrated very similar results as the analysis of OS (Online Supplemenetary Figure S1). In patients given cura- tive radiotherapy (n=26 (2%), median age was 64 years; all had WHO PS 0-1) and five-year OS was 0.75 (95% CI 0.51-0.88).
This study reports overall and relative survival in an unselected cohort of patients diagnosed with MCL in 2007-2017, receiving frontline treatment with R-CHOP, BR, or the Nordic MCL2 protocol. The results demon- strate no significant difference in overall or relative sur- vival by intensified MCL2 protocol or R-CHOP com- pared to BR, by adjustment for prognostic factors or in age-stratified analysis. Furthermore, our analysis demon- strates long-term survival with curative radiotherapy in limited stage MCL. R-CHOP and BR patients were com- parable whereas MCL2 patients were younger, had bet- ter performance status and less frequent MIPI high-risk score, thus the adjusted models were relevant. The lower all-cause mortality after MCL2 compared to BR in a univariable model or by adjustment for MIPI, but not when adjusting for individual prognostic factors or by age stratification, could be explained by the fact that MIPI is largely driven by age and WHO PS. Moreover, MCL2 is seldom considered in patients ≥70 years, thus the results from age stratification are expected to be
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haematologica | 2022; 107(3)