'Safe and Effective Therapies for Unfit Elderly Patients With DLBCL'

 The average age at onset of diffuse large B-cell lymphoma (DLBCL) is about 65 years, and a significant proportion of patients will be 80 or older and frail or unfit.

While chronologic age and tests to determine fitness or frailty, such as the Simplified Geriatric Assessment, can help guide treatment decisions, "we are realizing that as our population ages, this definition of elderly is also a moving number," said Pallawi Torka, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"Age is just a number, the chronological age," she told MedPage Today. "The other thing that we have to be mindful of is the biological age."

Patients 80 and older will fall into the category of unfit or frail -- "that is universal," she noted. "It's the people below 80 where we have to be cautious about whether we should treat them the same as younger patients, and if not, how do we separate out who needs how much?"

For decades, the standard of care for fit elderly patients with newly diagnosed DLBCL was R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Now, based on results from the POLARIX trial, the antibody-drug conjugate polatuzumab vedotin (Polivy) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone has also become an established frontline standard for these patients.

In the case of older, unfit or frail patients, treatments such as R-mini-CHOP (a standard dose of rituximab with reduced doses of the CHOP drugs) are used, "but toxicity and incomplete treatment remain concerns," said Dai Chihara, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

While the authors of a single-arm phase II study assessing R-mini-CHOP in older patients with DLBCL described the regimen as a "good compromise between efficacy and safety" in patients over 80, Chihara told MedPage Today that the 50% dose of standard chemotherapy "produces a suboptimal response and outcome."

"We would like to avoid toxicity from the chemotherapy, particularly in older patients, but, even for R-mini-CHOP, about one in four patients ... don't complete six cycles," he explained. "They get infections. They don't tolerate the treatment that well."

The Promise of Bispecific Antibodies

A promising development has been the impressive efficacy and safety demonstrated with bispecific antibodies in newly diagnosed older, unfit or frail patients, Torka said, pointing to a prospective phase II study evaluating rituximab, polatuzumab vedotin, and the bispecific antibody glofitamab (Columvi).

In that study, overall response rates with the combination in elderly and unfit or frail patients (median age 80, 19% over 85) with previously untreated DLBCL ranged from 90% to 96% depending on treatment cycle, with 1-year PFS and OS rates of 85% and 90%, respectively.

This regimen "was not palliative at all ... it was almost in the curative realm," observed Torka, who added that she is looking forward to seeing updated data, "because only time can differentiate between remission and cure. I think we'll have 2-year follow-up data this time, and if those remissions hold, that's really good news for our older patients."

Another promising combination is epcoritamab (Epkinly) with rituximab plus attenuated doses of cyclophosphamide, vincristine, and prednisone. In a phase II trial led by Chihara assessing older, unfit or frail patients or anthracycline-ineligible patients with newly diagnosed DLBCL, the complete response rate was 86% and the 1-year PFS rate was 94.7%.

Bispecifics are also showing good results as monotherapy for this patient population.

In a phase II study evaluating fixed-duration epcoritamab monotherapy in elderly patients (median age 82.5) with newly diagnosed DLBCL and comorbidities, the overall response rate was 70%, with a complete response rate of 58%.

Results from another phase II study showed that 73.5% of elderly patients (median age 82.5) with previously untreated DLBCL achieved a response with mosunetuzumab (Lunsumio) monotherapy, with complete responses in 59.2%.

"Even though bispecific antibodies have their own side effects -- including cytokine release syndrome, neurotoxicity, and increased risk of infections -- many of the side effects seem agnostic to age, especially the immune-related side effects like cytokine release syndrome, so age is no bar to these treatments," Torka said. "It doesn't help everybody, but we're seeing response rates  over 50%, and many of them are durable, meaning the cancer hasn't come back after 1 or 2 years of follow-up. So, we are on to something where ... we have a potent regimen which could really bridge that gap between age and fitness and cure."

"I'm really excited about bispecific antibodies," she added. "The unsolved problem with them is infection. They suppress B cells, and we do see a rise in viral infections in our older patients. In all the trials that have come so far, a majority of bad outcomes and deaths have been because of COVID or respiratory infections and such. So, if we could figure out a good way to mitigate that, that would really make these treatments truly safe for our frail patients."

Disclosures

Torka has reported relationships with AbbVie, Bristol Myers Squibb, Genentech, Genmab, Gilead, Lilly Oncology, Oramed, Perrigo, Pfizer, Seagen, Solventum, and Teladoc Health.

Chihara has reported relationships with AstraZeneca, Daiichi Sankyo, ADC Therapeutics, Genmab, Regeneron, Bristol Myers Squibb/Celgene, Genentech, and Ono Pharmaceutical.

https://www.medpagetoday.com/spotlight/dlbcl/123199