Maintenance Rituximab Shows Improved Duration of Response in Follicular Lymphoma in Retrospective Analysis

Brian T. Hill, MD, PhD

Brian T. Hill, MD, PhD

A new retrospective analysis of 640 newly diagnosed patients with follicular lymphoma found that patients who had achieved partial remission (PR) after 4 or more cycles of bendamustine plus rituximab (Rituxan) experienced improved duration of response (DOR) on maintenance rituximab compared with patients who received no maintenance treatment or who were in complete remission following induction with bendamustine plus rituximab.¹

According to the authors, led by Brian T. Hill, MD, PhD, of the Cleveland Clinic, the 3-year DOR for patients who achieved a PR after ≥4 cycles of bendamustine plus rituximab was significantly longer than those who received maintenance rituximab versus no maintenance (80% vs. 45%,P= 0.003).

“In the setting in which a randomized prospective trial is unlikely be conducted, retrospective analysis can offer important insights into real-world patient outcomes and potentially inform practice decisions as well as future clinical trial design,” Hill et al wrote in theBritish Journal of Hematology. “[Our] data suggest that maintenance rituximab after bendamustine plus rituximab is safe. Additionally, within the limitations of the study design, these data suggest that the benefit of maintenance rituximab may be limited to patients who achieve a PR after induction therapy with bendamustine plus rituximab. PET imaging appears to be more reliable than CT for response determinations.”

The investigators analyzed the records from 13 US academic medical centers of outcomes of 640 follicular lymphoma patients whose grade I/II & IIIA diagnoses were based on local pathologist interpretation between 2011 and 2015. Once induction therapy with bendamustine plus rituximab had been completed, the treating physician decided whether each patient should receive maintenance rituximab or rely on observation only.

Study outcomes included fatal adverse events (AEs) during or after induction and response rates at the conclusion of induction therapy as locally assessed. Additional endpoints were progression-free survival (PFS) and overall survival (OS) as calculated from the time induction therapy began, and DOR following successful completion of induction therapy for responding patients.

Of the 640 patients, an initial cohort was created of 410 patients from 12 centers that responded to induction therapy. This cohort was further narrowed to 376 patients who had achieved remission on the induction regimen (CR = 262, PR = 114). This study design was chosen to mimic the design of the PRIMA trial, which randomized patients who responded to induction therapy.^2,3

Additionally, the investigators created a validation cohort from 207 patients who had been treated with bendamustine plus rituximab at The University of Texas MD Anderson Cancer Center.

Baseline patient characteristics were comparable among groups with the exception of performance status. The 357 patients who received maintenance rituximab were more likely to have better ECOG performance status than the 283 patients in the observation group. This finding also held true when the investigators analyzed the population who had achieved any kind of remission on the induction regimen.

Among the 357 patients who received maintenance rituximab, 71% achieved CR and 29% achieved PR. Among the 283 observation-only patients, 58% experienced a CR, while 28% had a PR. The remaining 14% of patients had either stable disease (SD) or progressive disease (PD).

Patients received maintenance rituximab for a median of 18 months (range 3-24), with the treating physician determining the schedule. Two-thirds of patients (66%) received treatment every 2 months, while most of the remaining third (30%) received maintenance every 3 months. The final 4% of patients in this group received 4 doses of rituximab every 6 months.

In the cohort of 410 response-evaluable patients, 271 (66.0%) had CR, while 116 (28.3%) had PR and 23 (5.6%) had SD or PD.

The authors noted that PET was used to assess about half (56%, n = 231) of the responses, while CT was used to determine the response of 174 patients (42%). The use of these technologies yielded notably different response rates: in the PET-assessed group, 187 patients (81%) had CR, while only 84 patients (48%) in the CT-assessed group did. “The lack of benefit of maintenance rituximab was most clearly demonstrable in patients who achieved CR by PET whereas those who were assessed by CT may have benefited by MR,” they wrote.

Hill et al found significant differences in clinical outcomes among the maintenance rituximab group. Of the entire 640-patient cohort, PFS at 36 months was 84.2% for the rituximab group vs. 61.2% for the observation-only patients (P< 0.001). OS was 94.3% vs. 85.1%, respectively.

The median PFS for patients with CR, PR, and SD was not reached. The 3-year PFS for CR, PR, and SD patients was 84.5%, 69.8%, and 66.7%, respectively.

Similarly, the median OS for patients with CR, PR, and SD was not reached. Patients with PD had a median OS of 73.8 months. The authors reported 3-year OS for CR, PR, and SD patients as 95.4%, 92.8%, and 88.9%, respectively.

Hill et al also assessed how patients&rsquo; baseline FLIPI scores affected PFS and OS. They found that patients with low (0—2) FLIPI scores had a 3-year PFS of 86.4% and an OS of 96.4. Patients with a FLIPI score of 3 had a 3-year PFS of 68.1% and an OS of 88.3%. Patients with high (4-5) FLIPI scores had a 3-year PFS of 59.0% and OS of 83.3%.

At a median follow-up of 3 years, 63 patients of the original 640 (9.8%) had died. Lymphoma caused 26 of these deaths. Known fatal AEs were caused by infection or multi-organ system failure (n = 12), cardiovascular events (n = 2), myelodysplastic syndrome (n = 1), respiratory failure (n = 1) and progressive multifocal leucoencephalopathy (n = 1). &ldquo;This represents a known fatal AE rate of 2.5% if cases of unknown cause of death (COD, n = 10) and solid tumor (n = 10) are excluded or 4.1% if cases of unknown COD are included in determining fatal AE rate,&rdquo; Hill et al wrote.

The authors noted several study limitations. First, patient response rates were assigned by investigators and not by a central review board, which could have allowed for individual site biases. Additionally, the validation cohort, with all patients drawn from a single site, contained a higher number of patients with CR and a higher rate of PET scans as an assessment tool than did the primary cohorts.

They called for future studies examining the value of maintenance rituximab following bendamustine-based induction therapy to use PET imaging to restage all patients prior to beginning any maintenance regimen.

References:

1. Hill BT, Nastoupil L, Winter AM, et al. Maintenance rituximab or observation after frontline treatment with bendamustine-rituximab for follicular lymphoma.Br J Haematol2018. doi: 10.1111/bjh.15720.
2. Salles G, Seymour JF, Offner F et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.Lancet. 2011;377:42—51.
3. Salles G, Seymour J, Feugier P, et al. (2017) Long term followup of the PRIMA study: half of patients receiving rituximab maintenance remain progression free at 10 years.Blood. 2017;130:486.