INTRODUCTION:

Indolent MCL (iMCL) is an infrequent presentation of the disease with variable incidence across different studies, and there is neither a formal definition nor a standard clinical management. Active observation (AO), deferring the start of first-line treatment (1L) until clinical progression occurs, is currently an accepted strategy in most guidelines.The aim of this study was to describe the characteristics and outcomes of patients with iMCL in clinical practice in Spain.

PATIENTS AND METHODS

The GELTAMO-MCL-2022 study retrospectively included 1162 MCL patients between 2000 and 2023 in 34 Spanish centers. Indolent MCL were identified by AO ≥ 3 months. We excluded from the analysis 12 non-evaluable patients (early deaths and lost to follow-up) and 34 iMCL patients treated in the IMCL2015 clinical trial under the study's specific criteria.Early and late progression/relapse (E-POD, L-POD) in iMCL treated after AO were calculated from the start of 1L. 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

Out of 1150 evaluable patients, 161 patients (14%) were considered iMCL and 989 (86%) conventional MCL (cMCL). After the first diagnosis, cMCL patients received 1L upfront and iMCL patients started AO, as indicated per local protocols. Median time on AO (M) was 24m (3-300) for 127 evaluable iMCL: 17 (13.5%) were lost after M=19m (3-106) (including 3 cases dying from MCL without treatment), 84 (66%) progressed and received 1L after M=20m (3-156) and 26 (20.5%) remained alive in AO after M= 61m (4-300) at data cut-off.

At diagnosis, iMCL patients were older than cMCL [M age 69 yrs (39-93) vs. 67 yrs (29-93), p=.019] and their disease biologically less aggressive (Ki67≥30% 15% vs. 55%; blastoid histology 1.9% vs. 20%, p<.001). Gender, MIPI, stage and extranodal involvement were similar, except for 23 cMCL with CNS involvement and none in iMCL. We did not observe significant differences between iMCL requiring treatment and iMCL in ongoing AO. Between treated patients (84 iMCL and 989 cMCL), iMCL received more non-HiDAC regimens in 1L (71% iMCL vs. 55% cMCL, p<.001), HiDAC was used in 23% vs. 39%, respectively, and BTKi in 1L was 6% in both groups (in CTs other than IMCL2015). More cMCL received ASCT (30% vs. 15.5%, p=.002) while the use of Rituximab Maintenance was similar (43% vs. 40.3%). After 1L, L-POD was more frequent than E-POD in both groups (69% and 31% in iMCL vs. 62% and 38% in cMCL, p=.3)). Regarding the number of lines received, most iMCL patients had received only 1 (66% vs. 43% cMCL, p<.001) and only 13% required ≥3 (vs. 32% cMCL). Management in 2L was comparable between iMCL and cMCL.

With median FU=90.2m (83.5-99.3), 58.4% iMCL patients were alive (vs. 45.7% cMCL) and 37.8% iMCL had died (vs. 51% cMCL), being MCL the main cause of death (51% vs. 55.2%). Median OS (mOS) was longer in iMCL vs. cMCL (8.58 yrs vs. 6.82 yrs, HR=0.71, p=.014), with no differences between iMCL receiving 1L and iMCL in ongoing AO. In the MVA, age>65 and HR-MIPI had a negative impact (HR=2.16, p<.001) whereas being eligible for AO and the use of BTKi in 1L were independent factors for longer OS (HR=0.64, p=.006; HR=0.49, p=.009). Median PFS was only numerically longer in treated iMCL vs. cMCL (HR=0.88, p=.409), being BTKi in 1L (HR=0.37, p<.001) and HiDAC (HR=0.81, p=05) independent factors for longer PFS.Regarding POD24, E-POD had a strong negative impact on OS in both iMCL and cMCL, with no OS advantage observed for iMCL (1.58 and 1.36 yrs, HR=1.12, p=.682). Similarly, the OS difference in L-POD between iMCL and cMCL was not statistically significant: 14.95 and 10.7 yrs for iMCL and cMCL, respectively; HR=0.74, p=.260).

CONCLUSIONS

In Spain, only 14% of the patients diagnosed with MCL are deemed eligible for AO, with 66% of them progressing and requiring treatment within less than 24 months.Their disease is biologically less aggressive at diagnosis (lower Ki67, rarely blastoid or pleomorphic) with a significant 29% OS advantage over cMCL, which remains even when the disease progresses and 1L is required, thus suggesting that the previous time on AO did not have a negative impact on OS in iMCL.However, this survival advantage for iMCL is no longer observed when E-POD occurs, with mOS dropping below 24m in both groups, which reinforces the need for more effective treatments from the 1L for all patients with MCL.

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2025
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