Description of a Clinical Score to Identify PMBL Patients at High Risk of Early-Failure after Rituximab Doxorubicin Back-Bone Chemoimmunotherapy. a FIL Real-World Study

Introduction. Primary Mediastinal B Lymphoma (PMBL) is a rare and aggressive neoplasia that typically occurs in young women and is primarily located in the mediastinum. Although the combination of anthracycline and rituximab immunochemotherapy, and PET-guided consolidation radiotherapy, results in a high cure rate, approximately 10-20% of patients show refractoriness or early failure to front-line treatment with a rapid clinical deterioration and a dismal prognosis. These cases, if promptly identified, could benefit from early treatment shift. Therefore, we addressed the development of a clinical score aimed at estimating the risk of early failure of PMBL patients treated with anthracycline-rituximab-based chemoimmunotherapy in a real-world nationwide setting.

Material and Methods This is a retrospective cohort study of an unselected population of 931 adult PMBL patients treated in 37 FIL centers. To qualify for this research, patients had to have a confirmed diagnosis of PMBL, display typical symptoms and have been included in the local databases from 01/01/2007 to 31/12/2019. All patients received treatment with rituximab plus CHOP21 (n=98), CHOP14 (n=181), megaCHOP (n=31), MACOPB (225), VACOPB (n=179), DAEPOCH (n=179). Patients were excluded from this analysis if they received suboptimal treatment (22) or ASCT as consolidation of first-line therapy (12) or were censored within 365 days of treatment initiation (22). We defined early failure (EF) as any relapse or progression within 365 days of treatment initiation. Candidate predictors were clinical factors at the time of diagnosis, including: age, ECOG PS (a 4-level scale), LDH higher than Upper Limit of Normal, Ann Arbor Stage (a 4-level scale), systemic B symptoms, bulky mediastinum > 10 cm, number of Extra-Nodal sites (a 4-level scale: 0, 1, 2, or >=3), and pericardial or pleural effusion. Missing data in the evaluated predictors were multiple-imputed, and combined estimates were obtained from 20 imputed data sets. We used a multivariable logistic model with Backward Selection (level to stay p<0.1). Estimates were adjusted for front-line therapy. Standard errors were adjusted using the clustered sandwich estimator according to the patient's center. The model was internally validated with 1000 bootstrap samples from the original data. The optimism-corrected AUROC was estimated based on the results of the bootstrap process. We constructed a risk score by assigning each factor a weight proportional to the smallest coefficient, rounded to the nearest integer. The discrimination ability of the prognostic score was also evaluated considering the time to progression or relapse (Early Failure Survival) using the Kaplan-Meier method.

Results Among the 869 patients included in the present study, 109 (12.5%) were identified as early failures (EF). Four factors were selected after the backward selection process to construct the prognostic score (AUROC 0.744, optimism-corrected 0.710). These factors included Systemic B-symptoms (OR=1.76, p=0.007, weight=1), Bulky mediastinum > 10 cm (OR=2.12, p=0.017, weight=1), AA Stage II (OR=2.20, p=0.018, weight=1), AA Stage III-IV (OR=2.73, p=0.017, weight=2), and Number of Extra-Nodal sites >=2 (OR=2.88, p<0.001, weight=2) (Table 1). Based on the incidence of EF, the score was classified into 3 classes: low (0-1) with 216 patients and an EF incidence of 3.7% (95% CI: 1.6% - 7.2%), intermediate (2-3) with 408 patients and an EF incidence of 11.8% (95% CI: 9.0% - 15.0%), and high (> 4) with 122 patients and an EF incidence of 30.8% (95% CI: 22.3% - 39.3%). (Figure 1A). At 24 months, Early-Failure-Survival (EFS) rates were as follows: High - 63.7% (95% CI: 54.5% - 71.6%), Intermediate - 87.0% (95% CI: 83.6% - 89.7%), and Low - 95.4% (95% CI: 91.5% - 97.5%).

Conclusions Based on a large PMBL retrospective case series, we developed a simple and practical prognostic score subdividing patients into three clear-cut groups with different likelihoods of experiencing early failure. We acknowledge that the study has potential biases inherent in retrospective analysis, and further efforts aim to validate these results in external series of patients. If the predictive ability is confirmed, the score could be a valuable tool for treatment planning, interpretation, and comparison of clinical studies.