Chemo-Free Regimen Highly Active in Older Mantle Cell Lymphoma Patients

Almost 100% of older patients with untreated mantle cell lymphoma (MCL) responded to the combination of ibrutinib (Imbruvica) and rituximab (Rituxan), a small prospective study showed.

All but two of 48 evaluable patients had objective responses with the combination, including complete responses in 34 patients. During a median follow-up of 45 months, a majority of patients discontinued treatment, but only four patients discontinued because of disease progression.

Almost 20% of patients developed atrial fibrillation (Afib), and screening for cardiovascular risks is recommended before starting the therapy, reported Preetesh Jain, MD, PhD, of the MD Anderson Cancer Center in Houston, and colleagues, in the Journal of Clinical Oncology.

"Our study excluded patients with Ki-67 ≥50% and/or blastoid/pleomorphic histology because we were not confident that this combination would be effective in patients with high-risk MCL," the authors said. "Our data demonstrated a lower rate of grade 3/4 myelosuppression and a lower risk of hospitalization for infections than previously published chemoimmunotherapy results. These were the major advantage of IR [ibrutinib and rituximab] combination in elderly patients with MCL, compared with other treatment modalities with chemoimmunotherapy or lenalidomide [Revlimid]-rituximab."

"Long-term follow-up and randomized studies with standard treatments are needed to further evaluate the efficacy, safety, and pattern of relapse with IR combination," they stated.

Treatment for older patients with newly diagnosed MCL remains challenging because of frequent coexisting comorbidities and age-related complications, the authors noted. Historically, older patients have received chemoimmunotherapy, which can adversely affect quality of life.

The advent of oral, well-tolerated, chemotherapy-free therapies, such as ibrutinib, represented a major advance for older patients with MCL, they continued. Following FDA approval of Bruton tyrosine kinase inhibitors for relapsed MCL, evaluation of ibrutinib and rituximab in combination as initial treatment was a logical next step in the evolution of frontline therapy for MCL.

Jain and colleagues at MD Anderson enrolled 50 consecutive older patients with untreated MCL. Each patient received ibrutinib and rituximab for a maximum of 2 years, followed by single-agent ibrutinib. The primary objectives were overall response rate (ORR) and safety.

The patients had a median age of 71 and a range of ages 69-76. Baseline values for the Ki-67 proliferation marker were <30% in 38 patients and 30%-50% in the remaining 12. Bone marrow involvement was detected in 94% of the patients and gastrointestinal tract involvement in 79%. Three of 18 evaluable patients had TP53 aberrations in bone marrow and four of 45 had complex karyotype. Eleven patients had a history of Afib.

The results showed an ORR of 96% and complete responses in 71% of evaluable patients. At last follow-up, five patients had died and 45 remained alive. Four patients developed disease progression. A total of 28 (56%) patients discontinued treatment, attributable to toxicity in 21 cases. At the time of discontinuation, 16 of 28 patients were still in complete remission.

Despite recent therapeutic advances, frontline treatment for MCL continues to evolve, as the optimal therapy remains unclear, said Jonathon Cohen, MD, of Emory University's Winship Cancer Institute in Atlanta, in a recent review.

"So do all patients, for example, require a stem cell transplant just because they're able to receive one?" he said. "For the past 15 years or so, based on a fairly old randomized trial, we've been offering stem cell transplantation and first complete remission for most patients who are fit with mantle cell lymphoma. But there are now studies ongoing using modern regimens, trying to identify whether or not this is something that is still required. So that's something that we hope to learn in the next couple of years."

"Along those lines, we're learning more about minimal residual disease [MRD] and its role in the management of patients with mantle cell lymphoma," he stated. "There are commercially available assays to help determine whether or not somebody is MRD positive or negative. And while we recognize that being MRD negative is preferable to being MRD positive, I would say it still is not clear how to act on those data."

If the IR regimen attracts a following among MCL specialists, other chemotherapy-free regimens can make a legitimate case for frontline therapy. A report from the 2020 American Society of Hematology meeting showed "remarkable" survival data with the combination of lenalidomide and rituximab, noted Jia Ruan, MD, PhD, of Weill Cornell Medical College in New York City.

"The 7-year overall survival now was measured at 73% and a 7-year progression-free survival with 60%, which is quite remarkable," said Ruan. "We have patients now the longest on treatment for 10 years, and doing well with good quality of life."

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