Maintenance Rituximab Prolongs Time to Next Treatment, OS in MCL

Peter Martin, MD

Maintenance rituximab (Rituxan) following first-line bendamustine plus rituximab (Rituxan; BR) or a combination of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) prolonged first-line treatment benefits and improved survival outcomes vs either induction regimen alone, according to data from a real-world retrospective analysis of patients with mantle cell lymphoma (MCL).

These findings were subsequently validated in an independent cohort. Additionally, investigators observed no clear first-line treatment prolongation or overall survival (OS) benefits in autologous stem cell transplant (ASCT)–eligible patients who received subsequent ASCT, regardless of the type of induction therapy they received.

Across the entire retrospective population, patients treated with BR (n = 1501) had a real-world time to next treatment (TTNT) of 34.4 months (95% CI, 31.1-37.9) and patients treated with cytarabine-containing regimens (n = 514) had a real-world TTNT of 31.0 months (95% CI, 24.2-41.7). Patients treated with R-CHOP (n = 636) had a median real-world TTNT of 16.0 months (95% CI, 13.2-19.0).

The 3-year OS rate in the entire retrospective population was 68% (95% CI, 66%-69%). Specifically, the 3-year OS rates were 68% (95% CI, 66%-71%) in patients treated with BR, 74% (95% CI, 70%-77%) in patients treated with R-CHOP, and 73% (95% CI, 68%-77%) in patients treated with cytarabine-containing regimens.

Maintenance rituximab after BR was associated with significantly longer real-world TTNT (HR, 1.96; 95% CI, 1.61-2.38; P < .001) and OS (HR, 1.51; 95% CI, 1.19-1.92; P < .001) compared with BR alone. The 3-year real-world TTNT rate for patients who received BR plus maintenance rituximab was 74.0% (95% CI, 69%-79%) vs 51.0% (95% CI, 46%-56%) in patients who received BR alone. Additionally, the 3-year OS rate for patients who received BR plus maintenance rituximab was 84.0% (95% CI, 80%-88%) vs 74.0% (95% CI, 70%-79%) in patients who received BR alone.

“The substantial survival benefit achieved with maintenance rituximab in patients responding to first-line BR, a frequently used chemoimmunotherapy regimen, should be considered routinely in patients with MCL,” lead study authors Peter Martin, MD, and Jonathon B. Cohen, MD, MS, wrote in a discussion of the data. Martin is an associate professor of medicine and chief of the Lymphoma Program at Weill Cornell Medicine. Cohen is an associate professor in the Department of Hematology and Medical Oncology, at Emory University School of Medicine and co-director of the Lymphoma Program at Winship Cancer Institute of Emory University.

Standard first-line treatment for patients with MCL younger than 65 years is high-dose cytarabine-based chemoimmunotherapy induction followed by ASCT and maintenance rituximab. The role of ASCT in this younger population is controversial, as is the role of maintenance rituximab after BR.

In patients aged 65 years or older who are ineligible for intensive regimens, standard treatments include BR, R-CHOP, and VR-CAP, a combination of bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone. Current treatment guidelines lack evidence to support the use of maintenance rituximab after BR.

Investigators conducted a retrospective analysis of 3614 adult patients with MCL diagnosed from January 2011 to January 2021 looking for treatment patterns and outcomes with first-line therapies using data from the Flatiron Health electronic record–derived deidentified database. Most patients were diagnosed in community oncology settings in the United States, defined as community clinics not associated with teaching institutions. Findings on the efficacy of ASCT and maintenance rituximab were evaluated in an independent validation cohort of 1168 patients from 12 academic centers.

Eligible patients in the Flatiron cohort included those with a confirmed MCL diagnosis and at least 2 clinic visit records on file.

From the Flatiron cohort, investigators defined 2 target study populations to study outcomes with maintenance rituximab after BR or R-CHOP followed by ASCT. The maintenance rituximab (MR)-eligible and ASCT-eligible cohorts included patients who experienced disease control after induction treatment. This group (n = 1461) included patients of any age who were alive and did not begin second-line treatment within 8 months of starting first-line BR or 6 months of starting first-line R-CHOP. Patients who received ASCT were excluded from this cohort.

The ASCT-eligible cohort (n = 962) included patients younger 65 years of age who were alive and did not begin subsequent lines of treatment within 6 months of their first-line treatment.

The validation cohort was further divided into 2 target study populations. The MR-eligible validation cohort (n = 298) included patients of any age who were alive with no disease progression within 8 months of beginning first-line BR or 6 months of beginning first-line R-CHOP. The ASCT-eligible validation cohort (n = 511) included patients younger than 65 years who were alive with no disease progression within 6 months of beginning their first-line treatment.

The median age of patients in the Flatiron cohort was 69.4 years (range, 27.7-84.6) vs 62 years in the validation cohort. Patients treated with BR were older than those treated with cytarabine-based regimens or R-CHOP, with the median ages being 73, 60, and 66 years, respectively.

In patients from the Flatiron cohort younger than 65 years (n = 1265), 30.5% received first-line cytarabine-based regimens, 28.0% received first-line BR, and 22.1% received first-line R-CHOP. Of these patients, 23.5% received ASCT and 20.9% received maintenance rituximab. Of the patients in this population who received ASCT (n = 287), 21.3% received induction R-CHOP, and 19.2% received induction BR.

Additionally, 18.1% received rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternated with high-dose methotrexate and cytarabine, and 16.4% received dose-intensified rituximab plus cyclophosphamide, vincristine, doxorubicin, and prednisone alternated with rituximab and high-dose cytarabine.

In patients from the Flatiron cohort aged at least 65 years (n = 2329), 49.0% received first-line BR was used, 15.2% received first-line R-CHOP, and 1.8% received first-line VR-CAP. Additionally, 24.3% of patients received maintenance rituximab.

In the Flatiron cohort overall, 3.3% of patients (n = 120) received both ASCT and maintenance rituximab. In total, 80 of these patients were younger than 65 years and 40 were at least 65 years of age.

Furthermore, from 2011 to 2020, the use of R-CHOP decreased from 32.9% to 9.7%, and the use of BR increased from 19.7% to 52.9%. From 2011 to 2019, the use of maintenance rituximab increased from 14.3% to 27.2% in patients younger than 65 years.

In patients 65 years or older, the use of cytarabine, ASCT, and maintenance rituximab did not change notably over the study period. The use of ASCT in patients younger than 65 years was more frequent in the validation cohort (47% vs 23.5%).

In the Flatiron cohort, patient characteristics were evaluated based on real-world TTNT and OS. Real-world TTNT, an accepted real-world alternative to the clinical end point progression-free survival (PFS), was defined as time from the initiation of first-line treatment to subsequent treatment or death.

Investigators evaluated PFS and OS in the validation cohort. PFS was defined as the time from the initiation of first-line treatment to disease progression or death. OS was defined as the time from the initiation of first-line treatment to death in both the Flatiron and validation cohorts.

At a median follow-up of 45.5 months (range, 0.03-119.4), the median real-world TTNT in the Flatiron cohort was 24.0 months (95% CI, 21.9-26.2). The median real-world TTNT in patients younger than 65 years was 28.0 months (95% CI, 24.4-34.5) vs 22.3 months (95% CI, 20.7-24.5) in patients 65 years or older.

A multivariate analysis of the predictors of real-world TTNT and OS in the Flatiron cohort showed that older age, an ECOG performance status of 2 or higher, and high-risk disease features such as lactate dehydrogenase (LDH) at the upper limit of normal, white blood count of at least 10 x 10⁹/L, bulky disease, and pleomorphic and blastoid disease were associated with worse real-world outcomes.

In the maintenance rituximab–eligible population of the Flatiron cohort, the median duration of induction therapy was 4.7 months and the median duration of maintenance rituximab was 19.9 months. A multivariate analysis in this cohort showed that no maintenance rituximab use, older age, LDH at the upper limit of normal, bulky disease, and pleomorphic and blastoid morphology were associated with significantly shorter OS and real-world TTNT.

Findings from the validation cohort were consistent with those from the Flatiron cohort. In maintenance rituximab–eligible patients from the validation cohort (n = 258), the 3-year PFS rate was 74.2% (95% CI, 61.6%-83.2%) in patients treated with BR plus maintenance rituximab compared with 48.5% (95% CI, 30.5%-64.3%) in patients treated with BR alone. The 3-year OS rate in this population was 91.9% (95% CI, 81.6%-96.5%) in patients treated with BR plus maintenance rituximab vs 73.2% (95% CI, 53.7%-85.5%) in patients treated with BR alone.

In the ASCT-eligible population of the Flatiron cohort, investigators did not observe a significant association between ASCT receipt and real-world TTNT (HR, 0.84; 95% CI, 0.68-1.03; P = .10) or OS (HR, 0.86; 95% CI, 0.63-1.18; P = .4). Additionally, in the Flatiron cohort, the 3-year real-world TTNT and OS rates were similar between patients who received ASCT (real-world TTNT, 65% [95% CI, 59%-71%]; OS, 88% [95% CI, 83%-92%]) and patients who did not (real-world TTNT, 59% [95% CI, 55%-64%]; OS, 84% [95% CI, 81%-88%]).

In the validation cohort (n = 511), the 3-year PFS rate for patients who received ASCT (n = 328) was 69.6% (95% CI, 63.6%-74.8%) and the 3-year PFS rate for patients who did not receive ASCT (n = 183) was 69.0% (95% CI, 61.2%-75.6%). The 3-year OS rates were also comparable across ASCT statuses.

“Taken together, our findings from 2 large retrospective cohorts provide additional considerations for the design of future trials evaluating new treatment regimens in MCL. First, there should be a continuous focus on the development of treatments that can be effectively delivered and implemented in routine and community practices. Second, our data suggest that the risk-to-benefit ratio of ASCT should be carefully weighed for each patient, and that it may be reasonable to perform future trials without a requirement for ASCT in younger patients,” the study authors concluded.

Reference

Martin P, Cohen JB, Wang M, et al. Treatment outcomes and roles of transplantation and maintenance rituximab in patients with previously untreated mantle cell lymphoma: results from large real-world cohorts. J Clin Oncol. Published online June 28, 2022. doi:10.1200/JCO.21.02698