Primary mediastinal B-cell lymphoma (PMBL) is a rare type of aggressive lymphoma typically affecting young female patients. The first-line standard of care remains debated. We performed a large multicenter retrospective study in 25 centers in France and Belgium to describe PMBL patient outcomes after first-line treatment in real-life settings. Three hundred thirteen patients were enrolled and received rituximab (R) plus ACVBP (n=180) or CHOP delivered every 14 (R-CHOP14, n=76) or 21 days (R-CHOP21, n=57) and consolidation strategies in modalities that varied according to time and institution, mainly guided by positron emission tomography. Consolidation autologous stem cell transplantation was performed for 46 (25.6%), 24 (31.6%) and one (1.8%) patients in the R-ACVBP, R-CHOP14 and R-CHOP21 groups, respectively (p<0.001); only 17 (5.4%) patients received mediastinal radiotherapy. The end-of-treatment complete metabolic response rates were 86.3%, 86.8% and 76.6% (p=0.23) in the R-ACVBP, R-CHOP14 and R-CHOP21 groups, respectively. The median follow-up was 44 months, and the R-ACVBP, R-CHOP14 and R-CHOP21 3-year progression-free survival (PFS) probabilities were 89.4% [95% confidence interval: 84.8-94.2%], 89.4% [82.7-96.6%] and 74.7% [64-87.1%] (p=0.018), respectively. A baseline total metabolic tumor volume (TMTV) ≥360 cm3 was associated with a lower PFS (hazard ratio=2.18 [1.05-4.53]). Excess febrile neutropenia (24.4% vs 5.3% vs 5.3%, p<0.001) and mucositis (22.8% vs 3.9% vs 1.8%, p<0.001) were observed with R-ACVBP compared to R-CHOP regimens. PMBL patients treated with dose-dense immunochemotherapy without radiotherapy have excellent outcomes. R-ACVBP acute toxicity was higher than that of R-CHOP14. Our data confirmed the prognostic importance of baseline TMTV.

Introduction Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation are unknown. Methods We retrospectively analyzed patients with R/R HL who responded to anti-PD1 monotherapy and discontinued the treatment either because of unacceptable toxicity or prolonged remission. A machine learning algorithm based on 17 candidate variables was trained and validated to predict progression-free survival (PFS) landmarked at the time of discontinuation of anti-PD1 therapy. Results Forty patients from 14 centers were randomly assigned to training (n = 25) and validation (n = 15) sets. At the time of anti-PD1 discontinuation, patients had received treatment for a median duration of 11.2 (range, 0-time to best response was not statistically significant in discriminating patients with PFS lesser or greater than 12 months). Considering PFS status as a binary variable (alive or dead) at a specific time point (12 months) is convenient, intuitive and allows for comparing the value of potential predicting variables in these two groups of patients. Nonetheless, this approach has two drawbacks: first, it binarizes outcome; second, it excludes patients alive with a time to last follow up lesser 12 months. Therefore, it is less powerful to demonstrate statistically significant association with PFS even if it exists 5 months. Patients discontinued anti-PD1 treatment either because of prolonged remission (N = 27, 67.5%) or unacceptable toxicity (N = 13, 32.5%). Most patients were in CR (N = 35, 87.5%) at the time of anti-PD1 discontinuation. In the training set, the machine learning algorithm identified that the most important variables to predict PFS were patients' age, time to best response, and presence or absence of CR. The performance observed in the training set was validated in the validation set. Conclusion In this pilot, proof of concept study using a machine learning algorithm, we identified biomarkers capable of predicting the risk of relapse after anti-PD1 discontinuation (age, time to best response, quality of response). Once confirmed, these simple biomarkers will represent useful tools to guide the management of these patients.

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Introduction Patients with relapsed/refractory Hodgkin lymphoma (R/R HL) experience high response rates upon anti-PD1 therapy. In these patients, the optimal duration of treatment and the risk of relapse after anti-PD1 discontinuation are unknown. Furthermore, the efficacy of anti-PD1 re-treatment in patients who relapse after anti-PD1 discontinuation remains to be determined. Here, we investigated the risk of relapse in patients who responded to anti-PD1 therapy and discontinued the treatment, as well as the efficacy of anti-PD1 re-treatment in patients who relapsed after anti-PD1 discontinuation. Methods We retrospectively analyzed patients with R/R HL who responded to anti-PD1 monotherapy (concomitant radiotherapy was permitted) and discontinued the treatment either because of unacceptable toxicity or prolonged remission (based on the clinician's decision). Patients who discontinued because of relapse/progression or underwent consolidation with allogenic stem cell transplantation [alloSCT] were not included. A random forest machine-learning algorithm was trained to predict relapse using 14 candidate biomarkers. Finally, we analyzed the outcome of patients who relapsed after anti-PD1 discontinuation and their response to anti-PD1 re-treatment. Results We included 32 patients from 13 Centers in France, Portugal and Belgium. Patients' characteristics are summarized in Table 1. At the time of anti-PD1 discontinuation, patients had received either nivolumab (N=27, 84.4%) or pembrolizumab (N=5, 12.5%) for a median duration of 14.6 (range, 0-33.5) months. Patients discontinued anti-PD1 treatment either because of prolonged remission (N=23, 71.9%) or unacceptable toxicity (N=9, 28.1%). Most patients were in CR (N=29, 90.1%) at the time of anti-PD1 discontinuation. After a median follow-up of 20.8 months (range, 0.7-47.6) from anti-PD1 discontinuation, 21 (65.6%) patients had not relapsed/progressed. All 3 patients who were in PR at the time of anti-PD1 discontinuation had relapsed. Among the 29 patients who were in CR at the time of anti-PD1 discontinuation, the estimated disease-free survival was 64.3% (CI 95, 46.6-88.7%) at 24 months (Figure 1). Three patients died: two from disease progression and one from severe GVHD while in CR. Interestingly, 4 patients remain in CR more than 3 years after anti-PD1 discontinuation although these patients had received only short courses of anti-PD1 (<6 months). One of them received a single dose of nivolumab for a relapse post-alloSCT and remains disease-free 47.6 months later. Using a testing set of 25 patients, the machine-learning algorithm predicted an increased risk of relapse at 12 months based on three main patients characteristics: the absence of complete metabolic response at the end of anti-PD1 treatment, prolonged time to achieve best overall response, and older age. Among the 11 patients who relapsed, 7 were re-treated with (the same) anti-PD1 (Figure 2). Five achieved a CR, 1 achieved a PR and one patient has not been evaluated yet (but is in clinical response). Conclusion A significant proportion of patients experience prolonged remissions after anti-PD1 discontinuation and thus might be cured. Using a machine-learning algorithm, we identified biomarkers capable of predicting the risk of relapse after anti-PD1 discontinuation. These biomarkers are currently being validated in an independent set of patients. Finally, among patients who relapse after anti-PD1 discontinuation, re-treatment with anti-PD1 appears to be efficient. Disclosures Manson: Bristol Myers Squibb: Honoraria. Brice:Takeda France: Consultancy, Honoraria; Millennium Takeda: Research Funding; BMS: Honoraria. Herbaux:Janssen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Gilead: Honoraria. Silva:Abbvie Inc: Consultancy; Celgene: Consultancy; Gilead Sciences: Consultancy, Research Funding; Janssen Cilag: Consultancy; Roche: Consultancy. Stamatoulas Bastard:Celgene: Honoraria; Takeda: Consultancy. Houot:Bristol Myers Squibb: Honoraria; Merck Sharp Dohme: Honoraria.

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