Evolving Treatment Patterns Lead to Improved Outcomes in Relapsed/Refractory MCL

Patients with relapsed/refractory mantle cell lymphoma (MCL) experienced event-free survival (EFS) and overall survival (OS) benefits due to advances in second-line treatment approaches over time, according to findings from a prospective cohort study published in Blood Cancer Journal.

Patients who received second-line treatment for relapsed/refractory MCL between 2003 to 2009 (Era 1; n = 61), 2010 to 2014 (Era 2; n = 73), and 2015 to 2021 (Era 3; n = 49) achieved estimated 2-year EFS rates of 21% (95% CI, 13%-35%), 40% (95% CI, 30%-53%), and 51% (95% CI, 37%-68%), respectively. Additionally, the respective 5-year OS rates were 31% (95% CI, 21%-45%), 37% (95% CI, 27%-50%), and 67% (95% CI, 54%-83%).

“These results provide real-world evidence on evolving treatment patterns of second-line therapy based on the era of relapse,” study authors wrote. “The changes in second-line treatment correlated with improved EFS and OS, suggesting that treatment advances are associated with improved outcomes in patients with relapsed/refractory MCL.”

To conduct their study, investigators identified patients with relapsed/refractory MCL diagnosed between 2002 to 2015 who initiated second-line therapy and were followed through 2021 from the Molecular Epidemiology Resource prospective cohort of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence. Frontline therapies were classified as high-dose cytarabine based; rituximab (Rituxan) plus bendamustine with or without ASCT; other systemic therapy (rituximab plus cladribine [Mavenclad] with and without temsirolimus [Torisel], fludarabine [Fludara] plus rituximab, or fludarabine plus rituximab and mitoxantrone); and non-systemic therapy (surgical resection or radiation). Second-line treatments were classified the same as frontline therapies, in addition to induction followed by allogeneic transplant, BTK inhibition, and other non–BTK targeted therapies.

Study authors subsequently evaluated patterns of second-line treatment in each year and defined the 3 treatment eras based on the compositions of second-line treatments and the changes over time. Era 1 was enriched for other systemic and non–BTK inhibitor targeted therapies, Era 2 was enriched for rituximab plus bendamustine, and Era 3 was enriched for BTK inhibitors.

Investigators noted that substantial heterogeneities were present in both frontline and second-line treatments across the 3 eras. Changes in second-line treatment patterns were present in different eras, which the study authors said were likely attributable to second-line agent availability and first-line treatment options.

In Era 1, the most common second-line treatment options included non–BTK inhibitor targeted therapies (26%) and other systemic therapies (43%), primarily consisting of rituximab and single-agent chemotherapy combinations. Patients treated in Era 2 most frequently received rituximab plus bendamustine (34%), other systemic therapies (18%) and non–BTK inhibitor targeted therapies (11%). Finally, in Era 3, the most common second-line treatment was BTK inhibition (47%) and other systemic therapies (12.2%).

At a median follow-up of 7.6 years, 86 patients were alive without progression, 60 patients died without progression, and 197 patients had disease relapse or progression after frontline therapy in the initial population (n = 343), leaving 183 patients who received second-line therapy and had complete treatment information available. At the time of second-line therapy most patients in this population were male (80.3%), were aged over 60 years (71.6%), and had stage III/IV disease (88.8%).

Patients treated in Era 1 were mostly older than 60 years (68.9%), male (82.0%), had stage III/IV disease (88.7%), an ECOG performance status of 0 or 1 (86.3%), no B symptoms (90%), and did not receive stem cell transplant in the second line (88.5%). In Era 2, most patients were also older than 60 years (74.0%), male (79.5%), had stage III/IV disease (92.6%), an ECOG performance status of 0 or 1 (86.9%), no B symptoms (85.1%), and did not receive stem cell transplant in the second line (84.9%). Similarly, patients in Era 3 were older than 60 years (71.4%), male (79.6%), had stage III/IV disease (82.1%), an ECOG performance status of 0 or 1 (100%), no B symptoms (79.5%), and did not receive stem cell transplant in the second line (85.7%).

Additional findings from the study demonstrated that at respective median follow-up times of 12.4, 8.7, and 4.2 years, the median EFS in Era 1, 2, and 3 was 0.5 years. 1.2 years, and 2.2 years, respectively. The median OS was 1.8 years, 3.6 years, and not yet reached, respectively. The objective response rates were 56% (95% CI, 42%-69%), 80% (95% CI, 68%-89%), and 88% (95% CI, 72%-95%), respectively, including respective complete response rates of 31% (95% CI, 20%-45%), 54% (95% CI, 41%-66%), and 53% (95% CI, 36%-68%).

Cross-Era comparisons revealed that, in terms of EFS Era 2 (HR, 0.61; 95% CI, 0.43-0.88; P = .008) and Era 3 (HR, 0.44; 95% CI, 0.28-0.70; P < .001) were both significantly superior compared with Era 1. Regarding OS, Era 3 was significantly superior compared with both Era 1 (HR, 0.33; 95% CI, 0.18-0.60; P < .001) and Era 2 (HR, 0.44; 95% CI, 0.24-0.80; P = .007).

Among patients who died, those in Era 1 (n = 56), Era 2 (n = 54), and Era 3 (n = 14), did so due to progressive disease at rates of 67.9%, 59.3%, and 50.0%, respectively. Other causes of death included therapy-related infections (5.4% vs 11.1% vs 14.3%), other therapy-related causes (3.6% vs 1.9% vs 0%), second malignancies (7.1% vs 7.4% vs 14.3%), causes unrelated to lymphoma (3.6% vs 16.7% vs 7.1%), and unknown causes (12.5% vs 3.7% vs 14.3%).

“In this study, we found that second-line therapy for MCL evolved with time and was likely affected by first-line treatment choice and the availability of treatment options at the time of relapse,” investigators wrote in conclusion. “While there has been a shift in the pattern of treatment, both first-line and second-line treatment choices across each era remain heterogeneous. Our data also demonstrate that a change in treatment patterns at the time of first relapse is associated with improved post-relapse outcomes. The improvement in EFS and OS is seen in both Era 2 and Era 3, emphasizing the impact of many recently approved therapies on improving survival outcomes for relapsed/refractory MCL.”

Reference

Bock AM, Gile JJ, Larson MC, et al. Evolving treatment patterns and improved outcomes in relapsed/refractory mantle cell lymphoma: a prospective cohort study. Blood Cancer J. 2023;13(1):169. doi:10.1038/s41408-023-00942-3