Pooled Analysis Shows POD24 Strongly Predicts Poor Survival in Newly Diagnosed MCL

MCL | Image credit:
© Tatiana Shepeleva
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A retrospective pooled analysis of 6 multicenter, prospective clinical trials conducted in the rituximab (Rituxan) maintenance era demonstrated that disease progression or death within 24 months of treatment initiation (POD24) was strongly associated with inferior survival outcomes in patients with newly diagnosed mantle cell lymphoma (MCL).

Findings from the pooled analysis published in Blood Cancer Journal showed that patients who experienced POD24 (n = 299) experienced a median post-progression overall survival (OS) of 9.3 months (95% CI, 8.4-11.8) vs a median OS that was not reached (NR; 95% CI, 97.8-NR) in the non-POD24 group (n = 981; HR, 11.02; 95% CI, 8.98-13.51; P < .001).

At 2 years, 27% of patients in the POD24 cohort were still alive 2 years after experiencing disease progression; conversely, 79% of patients in the non-POD24 group remained alive 7 years after trial registration. Among the 406 total deaths reported, 68% (n = 277) were attributed to lymphoma-related causes, and 32% (n = 129) were due to other causes.

“Our study confirmed POD24 as a valid and robust prognostic factor of poor OS among a large dataset of patients [with MCL] included in clinical trials, suggesting that it could be used as a primary end point in future clinical trials, thus allowing earlier evaluation and more adaptable design,” lead study author Clémentine Sarkozy, MD, PhD, and colleagues. “[Although] maintenance with rituximab seems to protect against the risk of early relapse, autologous stem cell transplant [ASCT] does not appear to have any impact on this risk, highlighting the need for alternative strategies.”

Sarkozy is an assistant specialist practitioner at Institut Gustave Roussy in Villejuif, France.

Study Design

The study employed a retrospective, pooled analysis of individual patient-level data those with previously untreated MCL enrolled in 1 of 6 multicenter, first-line clinical trials, including the phase 3 EU-MCL younger (NCT00209222), phase 3 LyMA (NCT00921414), phase 2 LyMA101 (NCT02896582), phase 3 MCLelderly (NCT00209209), phase 2 RiBVD (NCT01457144), and phase 3 MCL R2 (NCT01865110) trials. The pooled analysis aimed to define the optimal time-dependent cutoff for predicting OS, assess whether clinical features at diagnosis could predict the risk of POD24, and determine whether treatment strategies could modify this risk. POD24 was defined as progression, relapse, or lymphoma-related death within 24 months of trial registration. Notably, the analysis did not include patients who were censored or experienced non–lymphoma-related death before 24 months.

Kaplan–Meier estimates were used for the OS analysis, and Cox proportional hazards modeling with natural cubic spline transformations was applied to identify the optimal time-to-progression cutoff predictive of OS. A landmark analysis was performed to account for immortal time bias, using either the effect time (for those with early progression) or 24 months from registration (for non-POD24 patients) as the survival analysis starting point.

To identify clinical predictors of POD24, logistic regression models stratified by study were used. Variables included MCL International Prognostic Index (MIPI) status, age, ECOG performance status, leukocyte count, lactate dehydrogenase (LDH) levels, sex, Ann Arbor stage, presence of B symptoms, lymphocyte count, and blastoid morphology. Missing data on Ki-67 and histologic variant (31% and 30% for the POD24 and non-POD24 groups, respectively) were addressed using multiple imputation.

Treatment strategies, including ASCT and anti-CD20 maintenance, were evaluated in responding patients to avoid bias from treatment eligibility. The association between ASCT and POD24 was further assessed in a subpopulation 60 to 70 years of age.

OS Findings Continued

Among the 981 patients without a POD24 effect, 32% experienced relapse after 24 months. In this subgroup, the median post-relapse OS was 49.4 months (95% CI, 30.4–56.8; HR vs POD24 group, 0.39; 95% CI, 0.31-0.48; P < .001).

In patients who had disease progression but were still alive 24 months after trial registration, the 3- and 5-year OS rates were 64.8% and 40.2%, respectively, in this group, compared with 96.2% and 87.8% in patients without POD24 effects (HR, 7.24; 95% CI, 5.5-9.5; P < .001).

Among 1105 patients with who achieved a response at the end of induction therapy, the POD24 rate was 16.3%. In this population, 66.1% of patients received anti-CD20 maintenance therapy.

Due to age-related selection bias, with ASCT being primarily reserved for patients younger than 65 years of age in the LYMA, LYMA-101, and EU-MCL younger trials, its effect on POD24 incidence could not be robustly assessed across this full cohort. To mitigate this limitation, an exploratory analysis was conducted among 451 patients 60 to 70 years of age, where 35% received ASCT. Within the ASCT group, 10% experienced a POD24 effect compared with 16% in the non-ASCT group (unadjusted odds ratio [OR], 0.46; 95% CI, 0.1-2.4). However, in a multivariable model adjusting for baseline prognostic factors, ASCT was not significantly associated with reduced risk of POD24 (OR, 0.64; 95% CI, 0.1-3.6). Only clinical features—including elevated LDH, presence of B symptoms, and high Ki-67 index—retained statistical significance.

In responders who experienced a POD24 event, 61% had received anti-CD20 maintenance, which was associated with a trend toward reduced risk of progression within 24 months (OR, 0.5; 95% CI, 0.2-1.1).

Among 875 patients with available MIPI combined scores at trial registration, 13% were classified as high-risk, and 87% were classified as low or intermediate risk. Patients with a high MIPI combined score were significantly more likely to experience early disease progression (53%) compared with the low or intermediate risk group (17%).

Among patients with POD24, those with high MIPI combined scores had a median OS of 8 months compared with 13 months for those with low or intermediate scores (HR, 1.80; 95% CI, 1.3–2.5; P = .0002). In the non-POD24 group, patients with high MIPI combined scores also experienced significantly inferior OS outcomes (HR, 2.52; 95% CI, 1.5-4.2; P = .0003).

Reference

Sarkozy C, Chartier L, Ribrag V, et al. Validation of POD24 as a robust early clinical indicator of poor survival in mantle cell lymphoma from 1280 patients on clinical trials, a LYSA study. Blood Cancer J. 2025;15(1):78. doi:10.1038/s41408-025-01241-9