Bendamustine/Obinutuzumab Induction Generates Responses and MRD Negativity in Treatment-Naive MCL

Induction therapy with bendamustine plus obinutuzumab (Gazyva) was tolerable and resulted in a higher complete response (CR) rate compared with historical data for bendamustine plus rituximab (Rituxan; BR) in patients with treatment-naive mantle cell lymphoma (MCL), according to findings from a phase 2 study (NCT03311126) published in Clinical Lymphoma, Myeloma & Leukemia.¹

At a median follow-up of 43.9 months (95% CI, 28.3-60.1), the median progression-free survival (PFS) was 46.5 months (95% CI, 35.1–not applicable [NA]). The respective 2- and 3-year PFS rates were 66.0% (95% CI, 41.6%-82.2%) and 58.7% (95% CI, 33.2%-77.3%).

Furthermore, the omission of maintenance obinutuzumab in patients who achieved minimal residual disease (MRD) negativity did not lead to worse outcomes vs those who received maintenance obinutuzumab. The 2-year PFS rates in patients receiving maintenance obinutuzumab vs observation were 42.9% (95% CI, 9.8%-73.4%) and 83.3% (95% CI, 48.2%-95.6%), respectively; the observed difference between these 2 rates was not statistically significant (HR, 0.45; 95% CI, 0.10-1.91; P = .28). Moreover, the 4-year PFS rates after consolidation were comparable between the MRD-negative vs persistent MRD-positive arms.

“These data support the notion that MRD assessment is a reasonable approach to identify patients with more favorable disease for whom maintenance may not be needed in order to preserve PFS and allow for minimization of treatment-related toxicity in an often older and less-fit population,” lead study author Julie E. Chang, MD, and coauthors, wrote in the paper. Chang is an associate professor in the Department of Medicine, Division of Hematology, Medical Oncology and Palliative Care at the University of Wisconsin (UW) School of Medicine and Public Health, as well as a hematologist at UW Health in Madison.

Trial Design

“Based on this prior experience with bendamustine plus obinutuzumab induction therapy, we hypothesized that bendamustine plus obinutuzumab induction with risk-adapted application of maintenance obinutuzumab based on MRD testing may also result in improved PFS in MCL,” the authors explained.

Between February 2018 and January 2022, this study enrolled 21 patients with MCL who were not eligible to receive intensive therapy. Patients needed to have histologically confirmed MCL with CD1 or t(11;14) that was previously untreated beyond rituximab monotherapy or involved-site radiotherapy for localized disease. Patients were required to be at least 60 years of age; younger patients with comorbidities that limited their tolerance to more intensive therapies were also permitted to enroll. Other enrollment criteria included an ECOG performance status (PS) of 0 to 2, adequate organ function, and adequate blood counts. Patients could not have had a prior malignancy within 2 years of enrollment, except in situ cancers of the cervix or breast, nonmelanoma skin cancers, or localized prostate carcinoma that was managed with definitive radiotherapy or surgery. Patients were also excluded if they were pregnant; breastfeeding; or had HIV, hepatitis B, or hepatitis C infections.

Patients received intravenous bendamustine at 90 mg/m² on days 1 and 2 of each 28-day cycle for 4 to 6 cycles. During cycle 1, patients also received intravenous obinutuzumab at 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15. Patients who achieved an objective response with induction therapy after 4 cycles but had toxicities that potentially limited their ability to receive 6 cycles were permitted to reduce their induction therapy to 4 cycles. Following completion of induction therapy, patients who achieved an objective response received consolidation intravenous obinutuzumab at 1000 mg weekly for 4 doses.

Subsequent restaging was conducted to determine each patient’s need for maintenance therapy; this involved MRD assessment via next-generation sequencing of bone marrow aspirate (BMA) and peripheral blood (PB). Maintenance obinutuzumab was omitted in patients who achieved CR and had MRD negativity in the PB/BMA. All other patients received 8 cycles of intravenous maintenance obinutuzumab at 1000 mg every 2 months.

PFS served as the primary end point. Secondary end points included response rates, overall survival (OS), and estimated MRD status.

Notably, the trial was closed prematurely because of slow enrollment.

Additional Efficacy Findings

Among enrolled patients, the median age was 70 years (range, 56-83), 76% were men, and 95% had stage IV disease. The median ECOG PS was 1. The median MCL International Prognostic Index (MIPI) score was 6.11 (range, 4.0-7.7), and 66.7% of patients had high-risk disease by MIPI. In total, 38.1% of patients had a Ki-67 proliferative index above 30%. Among 12 patients with available TP53/p53 mutation status by immunohistochemistry, 3 had p53 mutations.

In total, 20 patients completed a course of bendamustine plus Obinutuzumab induction, 19 of whom received 6 cycles of treatment. The single patient who received 4 cycles had low-volume disease and was receiving concurrent immunomodulatory therapy for Crohn’s disease. All patients completed the weekly obinutuzumab consolidation therapy. All patients received granulocyte colony–stimulating factor (G-CSF) at the start of therapy, and 4 patients discontinued G-CSF at the physician’s discretion or because of toxicity.

Ten patients received maintenance obinutuzumab per protocol. Six patients did not complete maintenance obinutuzumab treatment because of disease progression (n = 4), newly diagnosed carcinoma (n = 1), and infection (n = 1). One patient died during induction therapy from cardiac issues unrelated to the study therapy or lymphoma.

The PB MRD test was positive in 7 patients after cycle 2 of induction therapy. Restaging PB MRD and BMA-MRD tests after induction and consolidation were both negative in 10 patients. The concordance rate for post-consolidation MRD test results in the PB and BMA was 70%. Four patients were positive for both tests, and 6 patients had positive BMA-MRD results with concurrent negative PB MRD results.

All 7 patients who underwent end-of-treatment (EOT) PB-MRD assessments had negative results. Six of these patients had previously confirmed positive BMA-MRD results but negative PB-MRD results following consolidation. One patient tested positive for both PB-MRD and BMA-MRD after consolidation and later tested negative for PB-MRD at EOT.

The overall response rate was 95%, including a 75% CR rate and a 20% partial response (PR) rate. Among the patients who received maintenance obinutuzumab, 5 achieved a confirmed PR, 4 of whom were MRD positive in the marrow only and 1 of whom was MRD positive in both the blood and marrow. An additional 5 patients had confirmed PR or stable disease, 2 of whom were MRD positive in the marrow only and 3 of whom were MRD positive in both the blood and marrow.

Nine patients died during the study from progressive disease (n = 3), infection (n = 4), and cardiac causes (n = 2). The 2- and 3-year OS rates were 75.4% (95% CI, 50.6%-89.0%) and 60.9% (95% CI, 33.9%-79.7%). There was no statistically significant difference in OS between patients who achieved MRD negativity post-consolidation and those who were persistently MRD positive (HR, 0.43; 95% CI, 0.10-1.92), nor between those who were MRD negative vs MRD positive following induction (HR, 0.43; 95% CI, 0.11-1.72).

Safety Profile and Next Steps

“The toxicity profiles observed in our study were overall consistent with [those] reported in previous clinical trials utilizing obinutuzumab-based regimens,” the authors noted.

The most common adverse effects included leukopenia (grade 1/2, 81.0%; grade 3/4, 28.6%), nausea (66.7%; 0%), neutropenia (61.9%; 47.6%), anemia (61.9%; 9.5%), dry skin/rash (57.1%; 0%), lymphopenia (38.1%; 52.4%), constipation (38.1%; 0%), fatigue (38.1%; 4.8%), infection not otherwise specified (33.3%; 0%), infusion reactions (28.6%; 14.3%), dysgeusia (28.6%; 0%), dyspepsia/GERD (28.6%; 0%), fever (23.8%; 0%), anorexia (23.8%; 0%), elevated transaminase levels (23.8%; 0%), hyperglycemia (23.8%; 0%), diarrhea (23.8%; 0%), hypokalemia (19.0%; 4.8%), weight loss (19.0%; 0%), thrombocytopenia (19.0%; 4.8%), hypertension (19.0%; 9.5%), pruritus (19.0%; 0%), nonmelanoma skin cancers (19.0%; 14.3%), pain (19.0%; 0%), neuropathy/paresthesia (19.0%; 0%), cough (19.0%; 0%), hypophosphatemia (14.3%; 0%), dyspnea (14.3%; 4.8%), edema (14.3%; 4.8%), urinary tract infection (14.2%; 0%), atrial fibrillation/flutter (9.5%; 4.8%), thrombophlebitis (9.5%; 0%), tumor lysis (4.8%; 0%), cardiac arrest (0%; 4.8%), abdominal infection/colitis (0%; 14.3%), and pneumonia (0%; 9.5%).

“Our results demonstrate that the combination of bendamustine with obinutuzumab is a reasonable alternative treatment option to BR in previously untreated MCL, with higher rates of CR and 50% rates of MRD negativity in the marrow and blood. Additionally, we found that MRD evaluation during early induction therapy may be a prognostic marker identifying patients with a more indolent disease course, and warrants further investigation,” the authors concluded.

Reference

Chang JE, McQuinn D, Hyun M, et al. Measurable residual disease testing following nonintensive chemoimmunotherapy is predictive of need for maintenance therapy in previously untreated mantle cell lymphoma: a Wisconsin Oncology Network study. Clin Lymphoma Myeloma Leuk. Published online October 8, 2024. doi:10.1016/j.clml.2024.09.014