Ibrutinib/Lenalidomide/Rituximab Yields Long-Term Efficacy in R/R MCL

Mantle Cell Lymphoma |
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Ibrutinib (Imbruvica) in combination with lenalidomide (Revlimid) and rituximab (Rituxan; IR2) produced durable responses in patients with relapsed/refractory mantle cell lymphoma (MCL), including initial activity in patients with TP53 mutations, according to long-term follow-up findings from the phase 2 Philemon trial (NCT02460276) published in Hemasphere.

At a median follow-up of 92 months (interquartile range [IQR], 88.2-96.9) in the single-arm trial, evaluable patients (n = 50) achieved a median progression-free survival (PFS) of 17.4 months (IQR, 5.3-80.5), and the longest PFS duration was 8.1 years. The 1-year PFS rate was 62% (95% CI, 61%-86%). Furthermore, the median overall survival (OS) was 45.3 months (IQR, 11.3-not applicable [NA]).

Survival outcomes from Philemon were compared with a matched patient cohort from MCLcomplete, a population-based cohort from Sweden that included patients with relapsed/refractory MCL who had primarily received treatment with chemotherapy. The analysis showed patients treated in Philemon had superior survival outcomes compared with those in MCLcomplete both before and after cohort matching.

“Our study demonstrates the long‐term outcomes of the IR2 regimen in [patients with] relapsed/refractory MCL and highlights that a lower global health status [GHS] is associated with worse OS,” lead study author Elin Forsgren, PhD, and coauthors wrote in the paper. “The superior survival observed for [the] IR2 cohort compared [with] a matched population‐based cohort, as well as durable responses, supports the efficacy of non‐chemotherapeutic agents in the treatment of [patients with] relapsed/refractory MCL.”

Forsgren is a member of the Department of Immunology, Genetics and Pathology at Uppsala University, as well as a member of the Department of Internal Medicine at Örnsköldsvik Hospital in Sweden.

Philemon Trial Design and Prior Findings

The multicenter Philemon trial conducted by the Nordic Lymphoma Group enrolled 50 patients with relapsed/refractory MCL across 10 centers in Denmark, Finland, Norway, and Sweden between January 1, 2015, and June 5, 2016. Patients were required to be at least 18 years of age with MCL who received prior treatment with 1 or more rituximab-containing regimens. An ECOG performance status of 0 to 3 was also required. Patients were excluded if they had central nervous system involvement, HIV infection, active hepatitis B or C infection, stroke, intracranial hemorrhage (within 6 months of enrollment), the need for anticoagulation with warfarin (or an equivalent vitamin K antagonist), or prior treatment with moderate or strong CYP3A inhibitors. Previous treatment with lenalidomide or ibrutinib was permitted.

Patients received IR2 during a 12-month induction phase, followed by ibrutinib plus rituximab in a maintenance phase until disease progression or unacceptable toxicity; treatment cycles lasted 28 days. Ibrutinib was administered orally at 560 mg per day. Lenalidomide was administered orally at 15 mg per day on days 1 through 21 of each cycle. Rituximab was administered once weekly for 4 weeks during cycle 1, then every 8 weeks thereafter.

PFS and OS served as the primary end points. Secondary end points included overall response rate (ORR) and late adverse effects (AEs).

Primary findings showed that ibrutinib plus lenalidomide and rituximab generated an ORR of 86% (95% CI, 73.3%-93.6%) and was active in patients with TP53-mutated disease.

A Note on MCLcomplete

MCLcomplete included patients who were diagnosed with relapsed/refractory MCL between 2006 and 2018 and were registered in the nationwide Swedish Lymphoma Register (SLR), which comprises approximately 95% of all cases of lymphoma in Sweden. This cohort consisted of 1418 patients, who had most commonly received MCL treatment with chemotherapy (92.7%). All patients in this cohort had received rituximab. To conduct an accurate comparison between the MCLcomplete cohort and the Philemon population, investigators excluded patients from MCLcomplete who experienced first relapse after the last inclusion date in Philemon (June 5, 2016; n = 1035). Sixty-three additional patients from MCLcomplete lacked information on the MCL International Prognostic Index (MIPI) category as a continuous variable and were also excluded from this analysis. Therefore, this comparison included 320 patients from MCLcomplete.

Four patients from Philemon had received prior ibrutinib vs 6 patients in MCLcomplete. Data on prior lines of treatment were missing for 2 patients in Philemon. Therefore, a total of 48 patients from Philemon were matched with 48 patients from MCLcomplete. Prior to matching, age and MIPI distribution were similar between the 2 cohorts, although high—but not prominent—absolute standard mean (ASM) differences were observed between the cohorts regarding sex and Ann Arbor stage. However, ASM differences decreased to acceptable match levels across all baseline characteristics after the 1:1 matching procedure between the 2 cohorts.

Additional Long-Term Efficacy Findings From Philemon

The median duration of response (DOR) was 39.9 months (IQR, 10.0-NA). Among the 4 patients who had previously received ibrutinib, 2 achieved partial response with the IR2 regimen, with respective DORs of 2.3 months and 3.2 years. The other 2 patients with prior ibrutinib exposure had progressive disease.

Of the 11 patients harboring TP53 mutations, the 1-year PFS rate was 55% (95% CI, 32%-94%), and the ORR was 79%. One of the patients with a TP53 mutation remained relapse free at the end of follow-up and had PFS lasting 7.3 years. Notably, this patient had undergone allogeneic stem cell transplant immediately following the IR2.

Survival outcomes were borderline significant in the TP53-mutated population vs the TP53 wild-type population (OS, P = .09; PFS, P = .13). Adjusted univariable and multivariable Cox regression analyses demonstrated that TP53 mutation status was not significantly associated with prognosis for PFS or OS. However, investigators observed a trend toward higher progression risk in patients with TP53 mutations (HR for PFS, 2.09; 95% CI, 0.95-4.62; P = .068).

“This suggests that the IR2 regimen had initial activity in [patients with] TP53-mutated [disease], but [the combination] was unable to fully overcome the poor prognostic outlook,” the authors noted.

Disease characteristics associated with inferior OS outcomes included high- and intermediate-risk MIPI score, a GHS/quality of life (QOL) score below the median, and receipt of more than 1 prior line of therapy. However, a log-rank test and univariable analyses showed only high- and intermediate-risk MIPI score vs low-risk MIPI score (P = .041) and QOL score below the median (P = .016) to be significant prognostic features. Adjusted univariable and multivariable Cox regression models also showed inferior QOL outcomes in patients with scores below the median (HR, 2.53; 95% CI, 2.53-5.80; P = .028). Notably, patients with QOL scores below the median tended to be slightly older, have a higher MIPI score, and have a lower Ann Arbor stage compared with patients with higher QOL scores; however, none of these differences were statistically significant.

Moreover, QOL was not significantly associated with PFS. However, univariable Cox regression analyses showed that patients with scores below the median for QOL, emotional functioning, cognitive functioning, fatigue, and pain had significantly worse OS outcomes compared with patients with higher scores, “suggesting that [QOL] is more correlated to OS rather than predicting PFS after treatment in a relapsed setting,” the authors emphasized.

When patients were stratified by prior lines of therapy, investigators observed no significant PFS differences between patients who had received more than 1 line of prior therapy and those who had received only 1 prior line of therapy (P = .18).

The 5-year relapse-free survival rate was 28%, and 1 of the patients who was relapse free at 5 years had a TP53 mutation.

In total, 31 patients experienced disease progression after receiving the IR2 regimen, and 23 patients received subsequent treatment, including bendamustine plus rituximab (BR; 21%), radiotherapy only (21%), and a venetoclax (Venclexta)-based regimen (21%). Among patients who received subsequent therapy, the median OS from the start of the first treatment after the IR2 regimen to the date of death or last follow-up was 9.3 months (95% CI, 5.9-NA).

Of the patients with TP53 mutations, 2 received subsequent treatment following IR2. One of these patients received venetoclax plus lenalidomide and rituximab 3 years after IR2, followed by CAR T-cell therapy. The other patient received multiple subsequent therapies, including acalabrutinib (Calquence) plus BR, as well as venetoclax plus obinutuzumab (Gazyva); this patient died 3 years after enrollment in Philemon.

Findings From the MCLcomplete Efficacy Comparison

In a comparison between 48 patients in Philemon and 48 matched patients in MCLcomplete, those in Philemon had superior survival outcomes vs those in MCLcomplete both before and after matching. In the unmatched analysis, the 5-year PFS restricted mean survival time (RMST) difference was 1.10 (95% CI, 0.49-1.72; P < .01) and favored the Philemon cohort. After matching, the 5-year PFS RMST difference continued to favor the Philemon cohort with a difference of 1.15 (95% CI, 0.36-1.91; P < .01).

Safety Outcomes in Philemon

In December 2023, 11 patients remained relapse free at the end of follow-up. In total, 32 patients had died, including 72% due to MCL. Follow-up data from 25 patients who were evaluable for late AEs showed that 11 patients had long-lasting severe AEs, the most common being polyneuropathy (n = 4) and hypogammaglobulinemia (n = 2). Six patients had second malignancies: 2 patients had prostate cancer, and 1 patient each had basal cell carcinoma, non–small cell lung cancer, rectal cancer, and carcinoma in situ not specified.

“[Although] the response and PFS rates align with recent studies, this regimen also demonstrated moderate activity in patients with TP53 mutations, although the number of patients [is] small. However, the high initial response rate, even in TP53-mutated disease, suggests that the IR2 regimen may serve as a bridge to allogeneic stem cell transplantation or CAR‐T cell therapy,” the authors concluded.

Reference

Forsgren E, Jørgensen RRK, Bentzen H, et al. Ibrutinib, lenalidomide, and rituximab in relapsed mantle cell lymphoma: long-term follow-up of the Nordic Lymphoma Group MCL6 Philemon trial. Hemasphere. 2025;9(3):e70101. doi:10.1002/hem3.70101