Summary
A new treatment approach tailored to risk for relapse and response to induction therapy is associated with high response rates in children and young adults with very high-risk classic Hodgkin lymphoma, according to the most recent results from the Checkmate 744 study presented at the 2020 ASCO Annual Meeting (Abstract 8013).
“This treatment regimen was highly active for both pediatric and young adult patients with early relapse or primary refractory disease that was highly resistant to conventional chemotherapy. Participants were able to achieve a very high response rate [using this approach],” first author Peter D. Cole, MD, told Oncology Times. He is Vice Chair of the Hodgkin Lymphoma Committee for the Children’s Oncology Group at Rutgers Cancer Institute in New Brunswick, N.J.
Original Article
New Treatment Approach in Pediatric Classical Hodgkin Lymphoma
Oncology Times
By Veronica Hackethal
A new treatment approach tailored to risk for relapse and response to induction therapy is associated with high response rates in children and young adults with very high-risk classic Hodgkin lymphoma, according to the most recent results from the Checkmate 744 study presented at the 2020 ASCO Annual Meeting (Abstract 8013).
“This treatment regimen was highly active for both pediatric and young adult patients with early relapse or primary refractory disease that was highly resistant to conventional chemotherapy. Participants were able to achieve a very high response rate [using this approach],” first author Peter D. Cole, MD, told Oncology Times. He is Vice Chair of the Hodgkin Lymphoma Committee for the Children’s Oncology Group at Rutgers Cancer Institute in New Brunswick, N.J.
On independent central review, nearly 88 percent of participants achieved the primary endpoint (complete metabolic response, or CMR, as determined by PET scan). And, nearly all had a measurable response, with an overall response rate (ORR) of 98 percent.
The approach used induction therapy with nivolumab plus brentuximab vedotin. Nivolumab is an anti-PD-1 immune checkpoint inhibitor and brentuximab vedotin is a chimeric monoclonal antibody targeted at the CD30 antigen on tumor cells.
Participants who did not achieve CMR with induction therapy received intensification with brentuximab vedotin plus the chemotherapy agent bendamustine. However, most patients in the study were able to continue to stem cell transplant without exposure to bendamustine.
For patients with high-risk relapsed or refractory disease classical Hodgkin lymphoma, the standard practice is to first get patients into complete remission then continue to consolidation with high-dose chemotherapy and stem cell transplant. The success of this approach depends on being able to achieve complete remission with minimal toxicity so that consolidation can be successful. But current salvage therapies have high toxicity and are variably effective in getting patients to complete remission.
“In this study, we showed that targeted agents with less toxicity than conventional chemotherapy were able to get most of this very high risk population into a complete metabolic response so that they could then go on to consolidation,” Cole said.
Study Details
CheckMate 744 is a phase II, non-randomized, open-label clinical trial conducted in collaboration with pediatric cancer researchers in the U.S. and Europe. The study included 44 participants aged 5-30 years (median 16 years, range 9-30 years). Of these, 45 percent (n=20) had relapsed and 55 percent (n=24) had primary refractory classical Hodgkin lymphoma. Participants included in this arm of the study had relatively standard risk for relapse, based on refractory disease or early relapse criteria (Blood 2018;132(Supplement 1):927).
Forty-three participants received induction with 4 cycles of nivolumab plus brentuximab vedotin. Eleven participants did not achieve CMR with induction therapy and continued to intensification with 2-4 cycles of brentuximab vedotin plus bendamustine.
Response was determined using Lugano 2014 criteria and judged both by investigators (INV) and blinded independent central review (BICR). Those who achieved the primary endpoint at any time (CMR, or Deauville ≤3 by BICR) continued to consolidation off study. Those who did not achieve CMR after induction or intensification discontinued the study treatment and proceeded to high-dose chemotherapy and stem cell transplant. Median follow up was 20.9 months.
Results showed that the majority of participants (59% by BICR) reached the primary endpoint with induction alone, and almost all (98% by BICR) reached the primary endpoint anytime before consolidation. See Tables 1 and 2 for details.
At 1 year, the progression free survival rate was 91 percent (90% CI 77–96) by BICR.
| BICR | INV | |
|---|---|---|
| n | 43 | 44 |
| CMR, n (%[90%CI]) | 38 (88[77-95) | 39 (89 [78-95]) |
| ORR, n (%) | 42 (98) | 43 (98) |
| BICR | INV | |
|---|---|---|
| n | 44 | 44 |
| CMR, n | 26 (59) | 29 (66) |
| ORR, n (%[90% CI]]) | 36 (82 [70-91]) | 39 (89 [78-95]) |
No new safety signals were noted. The most common treatment-related adverse events were nausea (20%) and hypersensitivity (20%).
During induction, 18 percent (n=8) of patients experienced severe grade 3-4 treatment related adverse events. One case of grade 3 treatment-related anaphylaxis led to treatment discontinuation. However, most immune-related treatment-emergent adverse effects were mild to moderate (grade 1 or 2). One patient experienced two grade 3 infusion-related reactions.
This trial is ongoing. Another arm of the study is looking at whether this new approach is sufficient to cure patients with late relapses more than 1 year after completing primary therapy. Such patients are at lower risk for relapse than the patients in the study arm presented at ASCO 2020.
“We suspect that those lower risk patients don’t need high-dose chemotherapy and a stem cell transplant to be cured,” Cole said. “So we’re very excited to be asking whether this targeted approach—which has low toxicity and can be used as outpatient therapy—might be sufficient by itself to cure those patients.”
The primary endpoint for the other arm of the study is 3-year event-free survival. So it will take at least 3 years before results are reported, and probably even longer to know if the strategy works.
“Three years is actually insufficient. If someone has a late relapse a year or two after initial therapy, it’s not enough to show that they have a short-term response,” Cole noted. “As a clinician, I want to see the 5- or 10-year survival to know that it’s really enough to cure these kids.”
Veronica Hackethal is a contributing writer.