Evolution of Treatment Patterns and Sequencing in Mantle Cell Lymphoma (MCL) in Spain and Their Impact on Survival. the Geltamo-MCL-2022 Study
Authors: Marin Niebla Ana , Bastos-Oreiro Mariana , Perez Amanda Isabel , Cabirta Touzón Alba , De la Cruz Vicente Fatima , Canelo Marta , Jiménez Ubieto Ana , González De Villambrosia Sonia , Muntañola Ana , Luzardo Henríquez Hugo Daniel , Rios Herranz Eduardo , Gómez Pilar , López Alberto , Saus Carreres Ana , Martín García-Sancho Alejandro , Garcia Noblejas Ana , Grande Carlos , Prieto Martinez Pablo , Nicolás Concepción , Gutierrez Antonio , Hernandez Rivas Jose-Angel , Sánchez González Blanca , Alonso Trillo Rosalia , Donato Eva , Villafuerte Gutiérrez Paola , García Belmonte Daniel , Verdesoto Cozzarelli Silvia Rocio , Suarez Ordoñez Sandra , Pardal De La Mano Emilia , Villalon Blanco Lucia , Roldán-Pérez Alicia , Gine Eva , Sancho Juan-Manuel , Cordoba Raul , De La Cruz Beatriz , Navarro Garces Victor , Abrisqueta Pau 
Published: December 2024

INTRODUCTION:
MCL remains incurable and its management widely heterogeneous in clinical practice. We analyzed how the patterns and sequencing of treatments have evolved in Spain over the years and their impact on the survival of patients with MCL.
PATIENTS AND METHODS:
We retrospectively analyzed the management, efficacy data and progression-free and overall survival (PFS and OS) of patients with MCL included in the GELTAMO-MCL-2022 study. First-line (1L) treatments were grouped as HiDAC (containing HD-AraC) or non-HiDAC, second-line (2L) as BTKi (BTK inhibitors in monotherapy or combinations), ICT (standard salvage immunochemotherapy) or others (regimens with other targeted agents). We considered early relapse/progression (E-POD) when occurred within 24 months (m) from diagnosis and late (L-POD) beyond 24 m, including patients dying from MCL before 24 months as E-POD and patients still in response after 1L ≥24m at data cut-off as L-POD. Kaplan-Meier was used to analyze survival and the COX model for HR (CI95%) and p value of factors associated with PFS and OS.
RESULTS:
This study included 1105 patients with MCL diagnosed from 2000-2023 in 32 GELTAMO centers. Clinical-biologic and demographic characteristics are comparable with other reported real-world cohorts. At data cut-off (july 2024), 553 patients (50%) had died, being the lymphoma the main cause of death (n= 295, 53%). Out of 1051 patients treated in 1L, 112 (10.6%) received treatment after a median (M) time in “watch and wait” of 19 m (2-156) and 939 (89%) immediately after diagnosis, with a M number of 1 treatment line (0-10) for the entire cohort. After 1L, 49% (N=515) had not received further lines: 331 were in ongoing response but 35.8% were lost before 2L (18 lost of follow-up and 166 exitus).
In patients treated at diagnosis (excluding indolent cases receiving 1L after observation), 1L with HiDAC had higher Overall and Complete Responses (OR, CR) (88% vs. 78%, p=.002 and 77% vs. 61%, p&lt;.001) while Non-HiDAC showed higher rates of E-POD (68% vs. 47%, p&lt;.001). In 53 patients receiving BTKis in 1L (2 monotherapy and 51 with rituximab or ICT), ORR was 92.4% and CR 85% (significantly higher than HiDAC, p=.02). In Spain, 1L regimens are mainly R-CHOP-based (93% of HiDAC and 56% of nonHiDAC) but the pattern shifted over the years, R-Bendamustine becoming the preferred option for older patients from 2016. Out of 757 achieving CR/PR after 1L, 277 patients (35.6%) underwent autologous transplant (ASCT) in 1L (79% after HiDAC) and 368 rituximab maintenance (RM): after ASCT in 111 (30%) and after induction in 216 (81% nonHiDAC). RM and ASCT were associated with longer PFS and OS (HR=0.34, (0.28, 0.42) and HR=0.39 (0.29, 0.52) for RM and HR=0.35 (0.27, 0.46) and HR=0.45 (0.30, 0.68) for ASCT).
In 405 evaluable patients for 2L from 2013 (first BTKi recorded in our database), 197 received BTKi, 183 ICT and 25 other targeted-based treatments. BTKi and ICT showed comparable efficacy (ORR 61%/65% p=.5 and CR 39%/47% p=.07) and impact on OS-2 (HR=0.98, p=.097). From its launch in Spain in 2016, ibrutinib progressively replaced ICT, becoming the first choice in 2L. Only 25.6% of patients treated in 1L received ≥3 lines, predominating targeted agents other than BTKis in the subsequent lines.
With M FU=90.2m (84.3-99.3), M OS is 6.8 years and M PFS 39m, PFS progressively decreasing with each subsequent treatment line. MR, ASCT and BTKi used in 1L were the only treatment-related factors associated with longer PFS and OS in the MVAs.
CONCLUSIONS: HiDAC regimens are associated with higher efficacy and late relapses vs. non-HiDAC in our cohort, although without impact on PFS or OS (in MVA). Both ASCT and RM after 1L are associated with longer PFS and OS but, while 79% of patients eligible for intensive treatment receive ASCT 1L, only 45% of eligible patients receive RM. In our patients, BTKis in 2L show efficacy and survival rates similar to ICT and, with a more convenient oral administration and manageable toxicity profile, has become the choice at first relapse in Spain from 2016. After 1L, PFS remains progressively shorter with each subsequent line and we lose up to 34.5% of patients before 2L, which highlights the need of using the most effective agents as soon as possible from the 1L, since patients with MCL might miss their only chance to improve survival.