Addressing Special Challenges in Older Patients With Hodgkin Lymphoma

Jonathan W. Friedberg, MD

The prognosis for patients with Hodgkin lymphoma (HL) has improved dramatically over the last few years, but outcomes for patients 60 years and older continue to be worse than outcomes for younger patients.¹ In fact, Jonathan W. Friedberg, MD, MMSc, considers the treatment of older patients the biggest current challenge in HL. “If you look at survival curves for patients with advanced age, [they mimic] solid tumor survival curves. These patients do quite poorly due to poor tolerance as well as disease resistance to standard therapy. Fortunately, this is beginning to change with some of the modern treatments,” he said.

Friedberg, director of the James P. Wilmot Cancer Institute, and the Samuel Durand Professor of Medicine at the University of Rochester Medical Center in New York, presented the latest research on the management of HL in older patients at the 11th Annual Meeting of the Society of Hematologic Oncology in September 2023.

“Older patients with HL have markedly inferior outcomes compared [with] younger patients. In general, the upfront cure rate for HL approaches 80% or more for all comers. And then it’s a very salvageable disease with autologous stem cell transplantation and various additional approaches with drugs such as checkpoint inhibitors (pembrolizumab [Keytruda®; Merck] and nivolumab [Opdivo®; Bristol Myers Squibb] and brentuximab vedotin [BV; Adcetris®; Seagen]. Younger patients can live with the disease for a long time, even if they aren’t cured. In older patients, one of the problems that we have is that it’s very difficult to salvage patients if they don’t achieve initial disease control,” he said.

Friedberg explained that there is approximately 8% to 10% mortality during treatment for older patients. “That’s really led us to use much less chemotherapy. But when you do that, you might be sacrificing ultimate disease control rates as well,” he said.

The definition of older patients varies, with some studies including patients 60 years and older and others putting the cutoff at 70 years, Friedberg explained. One of the difficulties in making treatment decisions for older patients with HL is that many clinical trials do not include this demographic or include them in very small numbers. “More than 15% of patients with HL are over the age of 70 years, but if you look at clinical trial enrollment, it’s in the single digits or less. And some of the studies cut off at age 60. So the amount of data that we have to guide us on how to manage older patients is quite limited,” Friedberg said.

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Friedberg added that clinicians are getting away from chronological age and focusing more on patient fitness when making treatment decisions. “A strict cutoff age isn’t that useful. There’s very little difference between a 59- and a 61-year-old patient,” he said.

Frailty indices, which are starting to be used in lymphomas and classify patients as fit, unfit, or frail, are more useful for clinical decisions, according to Friedberg. “It might be that the fit patient, no matter what their age is, should be treated as a younger counterpart and may enjoy similar outcomes,” he said. Unfit patients should be treated but need some modifications to their regimens; for frail patients, “there may need to be conversations about whether any treatment is indicated,” he said. It is important for providers treating patients with HL to be familiar with these tools and to begin to use them, Friedberg emphasized.

“The most exciting thing is that we now have new agents that are clearly tolerated better and work incredibly well,” Friedberg said. “Both BV and checkpoint inhibitors have been studied in various ways in older patients, with some studies targeted specifically to the older-age population. These agents can be given either in sequence or in combination with standard chemotherapy approaches, as well as instead of standard chemotherapy. We’re seeing median progression-free survival [PFS] rates in the 2- to 3-year range with these novel agents. Overall survival [OS] is better than that.” However, most of the studies that target the older patient population are quite small, he noted.

For example, Friedberg highlighted the preliminary data from a phase 2 trial (NCT02758717) of the combination of BV and nivolumab (Opdivo), which eliminated chemotherapy and was tolerated reasonably well despite some neuropathy concerns.² Although this trial did not meet its prespecified activity criteria—its overall response rate was 61% instead of 80%²—the combination was active in older patients and is considered an interesting approach.³

“Another treatment strategy for unfit patients that is starting to be widely adopted is a sequenced approach where patients get BV alone, followed by AVD [doxorubicin, vinblastine, dacarbazine] chemotherapy, and then additional BV alone. This approach seems to be tolerated better than the combination of BV-AVD,” he said. This regimen was found to be highly effective in a phase 2 trial (NCT01476410), with a 2-year PFS rate of 84% and OS rate of 93%.⁴

The phase 3 SWOG S1826 trial (NCT03907488), which compared nivolumab plus AVD versus BV plus AVD, included approximately 100 patients over the age of 60.⁵ “We're still analyzing that specific subgroup. When we looked at the forest plot, it was clear that those patients derived some of the most benefit from the nivolumab in place of BV,” Friedberg said. “So, I expect based on the maturing of those data as well as some of the other studies I alluded to, we're going to see more checkpoint inhibition used upfront for older patients with HL.”

Friedberg added, “There have also been some attempts to modify chemotherapy regimens, but we don’t have a modified regimen that has been widely adopted.” Chemotherapy regimens recommended for older patients include AVD, ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Additionally, bendamustine can be used as a palliative option, according to National Comprehensive Cancer Network guidelines.⁶

“Practicing physicians have to realize that you can’t just follow the textbook on older patients with HL. They really need to be treated in an individualized way,” Friedberg said, adding that it is important to do a geriatric fitness assessment when deciding on a therapy regimen and to realize that patients are unlikely to tolerate full therapy doses.

“You have to decide whether curative intent is an appropriate goal. A final thing to mention is that radiation therapy remains an important tool in the management of HL,” Friedberg said. Radiation therapy has been avoided in the past because of concerns regarding late effects. However, with older patients these are not as relevant, he said. “If somebody is 70, you don’t have to worry about breast cancer 20 years later; they’re not as vulnerable to it,” he said.

References

1.Major A, Jackson MW, Smith DE, Kamdar M, Rabinovitch R. Inferior outcomes and treatment disparities in elderly patients with classical Hodgkin lymphoma: a national cancer data base analysis. Leuk Lymphoma. 2019;60(5):1234-1243. doi:10.1080/10428194.2018.1522435

2.Cheson BD, Bartlett NL, LaPlant B, et al. Brentuximab vedotin plus nivolumab as first-line therapy in older or chemotherapy-ineligible patients with Hodgkin lymphoma (ACCRU): a multicentre, single-arm, phase 2 trial. Lancet Haematol. 2020;7(11):e808-e815. doi:10.1016/S2352-3026(20)30275-1

3.Milunović V, Hude I, Rinčić G, et al. Clinical dilemmas in the treatment of elderly patients suffering from Hodgkin lymphoma: a review. Biomedicines. 2022;10(11):2917. doi:10.3390/biomedicines10112917

4.Evens AM, Advani RH, Helenowski IB, et al. Multicenter phase II study of sequential brentuximab vedotin and doxorubicin, vinblastine, and dacarbazine chemotherapy for older patients with untreated classical Hodgkin lymphoma. J Clin Oncol. 2018;36(30):3015-3022. doi:10.1200/JCO.2018.79.0139

5.Herrera AF, LeBlanc ML, Castellino SM, et al. SWOG S1826, a randomized study of nivolumab(N)-AVD versus brentuximab vedotin(BV)-AVD in advanced stage (AS) classic Hodgkin lymphoma (HL). J Clin Oncol. 2023;41(suppl 17):LBA4-LBA4. doi: 10.1200/JCO.2023.41.17_suppl.LBA4

6.NCCN. Clinical Practice Guidelines in Oncology. Hodgkin lymphoma, version 2.2023. Accessed July 17, 2023. https://www.nccn.org/professionals/physician_gls/pdf/hodgkins.pdf