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Brentuximab vedotin plus gemcitabine safe, active for young patients with Hodgkin lymphoma
Salvage treatment with the combination of brentuximab vedotin and gemcitabine showed antitumor activity among children and young adults with relapsed/refractory Hodgkin lymphoma, according a multicenter, single-arm phase 1/phase2 study.
The regimen also had a tolerable toxicity profile.
“Looking at all the treatment options for children or young adults with relapsed or refractory disease, there are many reinduction regimens that are active. However, they have a lot of short-term and long-term toxicity,” Peter D. Cole, MD, division chief of pediatric hematology/oncology, Embrace Kids’ chair for pediatric hematology/oncology and professor of pediatrics at the Rutgers Cancer Institute of New Jersey, told HemOnc Today. “We were interested in developing a retrieval regimen that would be highly active but less toxic than other regimens that are out there.”
Cole and colleagues from Children’s Oncology Group assessed 45 patients (median age, 17.6 years; 53% female; 69% white) with primary refractory or high-risk relapsed Hodgkin lymphoma aged younger than 30 years to assess the safety and efficacy of brentuximab vedotin (Adcetris, Seattle Genetics) in combination with gemcitabine.
“Seeing very high activity of brentuximab vedotin as a single agent with a favorable safety profile in a previous study, we thought that that would be a good drug to include in a reinduction regimen,” Cole said.
“Other people have combined brentuximab with chemotherapy agents. We combined it with gemcitabine, a drug that we had used in an earlier retrieval regimen that we found to be both safe and effective,” he added. “We thought that this particular combination would take advantage of the high activity of the two agents without adding the toxicity that’s associated with alkylating agents, anthracyclines or epipodophyllotoxins, drugs that have long-term toxicity.”
Researchers excluded patients with previous brentuximab vedotin exposure.
In the phase 1 dose escalation, patients underwent treatment with 21-day cycles of 1,000 mg/m2 IV gemcitabine on days 1 and 8 and 1.4 mg/kg or 1.8 mg/kg IV brentuximab vedotin on day 1 to determine the recommended dose for phase 2.
Researchers determined the recommended dose as 1.8 mg/kg of brentuximab vedotin with 1,000 mg/m2 gemcitabine.
Among 42 evaluable patients given this dose, 57% (95% CI, 41-72) achieved complete response within the first four treatment cycles.
Among the 13 patients with a partial response or stable disease, 31% had all target lesions with Deauville scores of 3 or less after four treatment cycles, which under modern response criteria could be considered complete responses.
The overall response rate was 74% (95% CI, 56-86).
The most common grade 3 or grade 4 adverse events included neutropenia
(36%), rash (36%), transaminitis (21%) and pruritus (10%). Researchers observed no treatment-related deaths.
“There are certain caveats that clinicians should be aware of,” Cole said. “First of all, this was not a randomized trial. So, while we’re excited about the results, we didn’t prove that our regimen is superior in any way to any other regimen. All we can comment on is the high activity we saw and the favorable safety profile.”
Cole also cited the exclusion of patients with previous brentuximab vedotin exposure as a further caution.
“Brentuximab is becoming more and more integrated in frontline regimens for newly diagnosed patients,” he said. “It’s possible that this combination of brentuximab-gemcitabine will not be an appropriate reinduction regimen for someone who relapses or has refractory disease after initial treatment with brentuximab.”
Among 33 patients with serum thymus and activation-regulated chemokine (TARC) biomarker measurements at baseline and after one cycle, researchers observed significant decrease of median serum TARC concentrations (5,700 pg/mL vs. 680 pg/mL; P < .0001).
Patients who achieved a complete response appeared more likely to have 90% or greater reduction in serum TARC after two cycles (n = 8 of 12) compared with those without a complete response (n = 1 of 7; P = .04).
Among 41 patients with data on FcRIIIa polymorphism, 54% were homozygous for the
wild-type phenylalanine allele, 12% were homozygous for the variant valine allele and the remaining 34% were heterozygous.
Participants who were homozygous for the wild-type allele appeared more likely to achieve a radiographic complete response within four cycles of treatment than those who carried at least one variant allele (80% vs. 47%; P = .04).
“We’re continuing to look at biomarkers that will help us predict who is likely to have a good response,” Cole said. “We showed some data about gene variants that might be associated with a better or worse chance of response and we need to validate that prospectively. We’re also continuing to look at biomarkers in blood that changed with therapy to determine whether or not they’ll be good predictors of response.”
In an accompanying editorial, Umberto Vitolo, MD, and Annalisa Chiappella, MD, of Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino in Italy, discussed how this combination compares with other regimens.
“These results compare favorably with brentuximab vedotin monotherapy and are superimposable to brentuximab vedotin plus bendamustine or plus cisplatin,” they wrote. “However, the choice of gemcitabine instead of bendamustine as a companion drug to brentuximab vedotin might offer the following advantages for children and young adults: avoidance of late toxicities and the risk of second cancers recently reported with bendamustine; allowance of a short course of treatment before autologous stem cell transplantation; and the improvement of adverse events during treatment when compared with cisplatin-based regimens.” – by Cassie Homer
For more information:
Peter D. Cole, MD, can be reached at Robert Wood Johnson Medical School, Rutgers Cancer Institute of New Jersey, 195 Little Albany St., New Brunswick, NJ 08901; email: peter.cole@rutgers.edu.
Disclosures: The authors report no relevant financial disclosures. Vitolo reports advisory board roles with Celgene, Janssen and Roche, and speaking fees from Celgene, Gilead, Janssen, Roche and Takeda. Chiappella reports advisory board roles with Celgene and Janssen, and speaking fees from Amgen, Celgene, Janssen, Nanostring, Roche and Teva.