Validation of POD24 As a Robust Early Clinical End Point of Poor Survival in Mantle Cell Lymphoma from 1280 Patients on Clinical Trials
Authors: Sarkozy Clementine , Chartier Loïc , Ribrag Vincent , Gressin Remy , Geisler Christian , Kluin-Nelemans Hanneke , Thieblemont Catherine , Morschhauser Franck , Haioun Corinne , Safar Violaine , Ghesquieres Herve , Klapper Wolframm , Burroni Barbara , Pott Christiane , Delfau Marie-Helene , Macintyre Elizabeth A. , Callanan Mary , Unterhalt Michael , Hoster Eva , Dreyling Martin , Le Gouill Steven , Hermine Olivier , Cheminant Morgane 
Published: December 2023

Background
The prognosis of mantle cell lymphoma (MCL) has largely improved in the past decade; however, the disease is characterized by a heterogeneous clinical course. Several retrospective studies identified early progression of disease (i.e. within two years, POD24) as a potential overall survival (OS) surrogate, but this has not been validated in cohorts of patients prospectively included in clinical trials in rituximab maintenance era.
Methods
We performed a pooled analysis of French patients with MCL included in six randomized clinical trials (EU-MCL younger NCT00209222, LyMA NCT00921414, LyMA101 NCT02896582, EU-MCL elderly NCT00209209, MCL-R2 NCT01865110 and RiBVD NCT01457144). Survival analysis using Landmark approach evaluated the association of POD24 status with post-event OS for all patients: starting from POD24 event or two years for patients without POD24 event. Logistic regression models were used to evaluate the association between POD24 status and (1) clinico-biological factors at diagnosis; (2) autologous stem cell transplantation at end-of-induction (ASCT) and anti-CD20 maintenance (RM) in responding patients after induction only.
Results
Among 1386 MCL patients, 106 censored for clinical follow-up before 24 months were excluded from the analysis, leading to 1280 patients evaluable for POD24 status: 299 with a POD24 event and 981 without. The 299 (23%) patients with a POD24 event had a post-event median OS of 9.3 months (95% CI 8.4-11.8) versus not reached in patients without POD24 event (95% CI 97.8-NR). Within the 981 non-POD24 patients, 314 presented a late relapse with a post-relapse median OS of 49.4 months (95% CI 30.4-56.8), significantly longer than OS of POD24 patients (HR=0.39; 95%CI 0.31-0.48; p&lt;0.001). Compared to patients without a POD24 event, POD24 patients were older, had more frequently a performance status &gt;1, elevated LDH and higher leucocytes leading to higher MIPI scores (high-risk MIPI 61% vs. 29%; p&lt;0.001), more frequent blastoid variant (24% vs. 9%; p&lt;0.001) and Ki67 &gt; 30% (45% vs. 23%, p&lt;0.001). Regarding treatment, POD24 patients had less frequently received high-dose cytarabine (21% vs. 39%, p&lt;0.001) as well as ASCT (26% vs. 47%, p&lt;0.001). In a final model, including baseline factors and treatment strategies, induction was not associated with risk of POD24, and only baseline variables (age, performance status, LDH, leucocytes and Ki67&gt;30%) remained significantly associated with POD24 status. Within responding patients only (CR/CRu/PR at end-of-induction, n=1000), 150 had a POD24 event, and ASCT or RM were not significantly associated with POD24 status whereas age, LDH and Ki67&gt;30% remained significant.
Conclusion
Using this large dataset of patients included in clinical trials, we confirm that POD24 can be used as a surrogate for OS in MCL. ASCT as well as RM have not a clear benefit to prevent early relapse within two years after the diagnosis in responding patients at end-of-induction.