Clinical Challenges: Relapsed Hodgkin’s After Transplant

Roughly half of patients with Hodgkin’s lymphoma are cured with autologous stem cell transplant (auto-transplant), but the prognosis for those who then relapse remains poor.

Still, median survival over the past several decades has more than doubled among this group, increasing from 10.5 months for those transplanted in the years 1983-1990 to 26.1 months from 2000-2014, largely driven by the availability of novel agents, though some late relapsers may still respond to further chemotherapy.

Since 2011, the FDA has approved brentuximab vedotin (Adcetris), nivolumab (Opdivo), and pembrolizumab (Keytruda) for relapsed disease.

Increasingly, the treatment approach is dependent on what therapies a patient has already received, and how they responded to it, Anne Beaven, MD, of UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, told MedPage Today.

“Often in patients with higher-risk disease, you might have brentuximab vedotin as part of first-line therapy,” said Beaven, as the agent is now approved along with chemotherapy for stage III/IV disease and as post-transplant consolidation in patients with an increased risk of relapse.

If a patient relapsed 2 months into maintenance therapy, “you probably wouldn’t re-treat them with brentuximab vedotin, so maybe that’s one you’d take to a PD-1 inhibitor,” she said. With a relapsed patient from one of the placebo groups of the pivotal trials, on the other hand, “then you might say, ‘Oh, let’s do BV.'”

In some cases, durable remissions can be achieved with these agents alone. About 10% of patients from the initial post-transplant trial of brentuximab vedotin remained disease free at 5 years, and without need for further treatment. Long-term data on PD-1 inhibitors such as nivolumab and pembrolizumab are still awaited.

“In the past, if you relapsed after auto [transplant] and you were a young, healthy person, the goal of all therapy would be to get you to allo,” meaning allogeneic stem cell transplant, said Beaven. “But now a lot of times we’ll just keep a patient on a PD-1 inhibitor as long as it’s beneficial to them.”

In the recent head-to-head KEYNOTE-204 trial, involving relapsed or refractory patients who failed on or were ineligible for auto-transplant, PD-1 blockade with pembrolizumab improved progression-free survival over brentuximab vedotin, though this involved a patient population that was largely naive to the CD30-targeted antibody-drug conjugate.

“KEYNOTE-204 is pretty clear evidence that anti-PD-1 therapy is extremely effective,” Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai in New York City, told MedPage Today.

“PD-1 blockade is more effective in Hodgkin’s lymphoma than in any other cancer ever tested,” he added. “That’s a very big deal.”

As in diseases like melanoma where there’s much longer experience and follow-up with checkpoint inhibitors, he suggested that there may be a proportion of Hodgkin’s patients who experience long-term remission, or who are potentially cured, on PD-1-directed agents. “But we don’t clearly see that in the curves yet,” he cautioned.

Increasingly though, combinations may be the future for relapsed or refractory disease.

“We have some really beautiful data combining brentuximab with nivolumab,” said Brody, pointing to a study of 91 patients where 85% responded to treatment, including complete responses in two-thirds.

“That’s probably amongst the highest complete remission rates with any regimen for these relapsed and/or refractory patients,” said Brody. “Extremely exciting.”

While the combination is not FDA approved, it likely will be at some point, he suggested, and should be a consideration for appropriate patients.

Allo-Transplant

Allogeneic transplant can still be considered in select cases, said Brody, but the therapy only cures a minority of patients in Hodgkin’s and carries the potential risks for acute and chronic side effects.

Younger patients who can tolerate side effects could be good candidates if they have a matched donor, few other options, or are only showing a mild response to PD-1 blockade or brentuximab vedotin.

“If they have a good match, it’s the greater consideration, otherwise the lesser consideration,” he said, and noted that the timing of PD-1 blockade and allo-transplant is critical. “We don’t want, obviously, people to be getting PD-1 blockade too close to an allogeneic transplant because it can increase the risk of graft-versus-host disease.”

CAR T-Cell Therapy

At the American Society of Clinical Oncology meeting last year, Beaven shared her institution’s experience with 26 heavily pretreated patients, including 24 with classical Hodgkin’s lymphoma, who went on to receive CD30-directed CAR T-cell therapy. The vast majority had been exposed to brentuximab vedotin, a checkpoint inhibitor, and auto-transplant, with a median of eight prior lines of therapy in all.

“If they’ve gone through all those things and they still relapsed,” clinicians don’t have another proven “great drug” to follow, she said. “We’re hopeful that this CAR-T therapy will be that really great drug.”

In the UNC study, 11 of 18 patients that received bendamustine and fludarabine lymphodepletion achieved a complete response, three maintained an ongoing complete response from their prior treatment, and two had a partial response to therapy.

“The studies are small, but we’re seeing very encouraging results in that population,” said Beaven.

Brody also pointed to early but exciting data with anti-CD30 CAR T cells from Baylor, where seven of 12 patients had complete responses that lasted beyond 15 months, and one patient had a partial response.

One potential advantage of CAR T-cell therapy versus allo-transplant is the lower risk of post-treatment complications such as graft-versus-host disease and the need for long-term immunosuppression, said Beaven. “But we don’t yet have the same long-term data we have with CAR T that we have with allo.”

“Are there some patients who potentially could be cured with CAR-T therapy or do they just get into remission and eventually relapse?” she said. “It’s something that I don’t think we really know yet.”