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Adding Targeted Agent to Treatment Shows Significant Benefits in Pediatric Patients With High-Risk Hodgkin Lymphoma


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Integrating the antibody-drug conjugate brentuximab vedotin into the front-line treatment of pediatric patients with high-risk Hodgkin lymphoma “facilitated significant reduction in radiation exposure and yielded excellent outcomes,” Monika Metzger, MD, MSc, Director for the Central and South America Region, Global Pediatric Medicine Department, St. Jude Children’s Research Hospital, Memphis, and colleagues reported in the Journal of Clinical Oncology.1 Event-free survival was 97.4% at a median follow-up of 3.4 years, and overall survival was 98.7%.


“We are no longer giving the steroid after two cycles for those who have a good response, because we don’t see any use for steroids after that.”
— Monika Metzger, MD, MSc

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Early response assessment by positron-emission tomography (PET)/computed tomography (CT) after two cycles of chemotherapy found that 27 of the 77 patients in the trial (35%) achieved complete remission. These patients were spared any radiation. Those who had not achieved complete remission received residual node radiotherapy following the completion of all chemotherapy.

Reduced Radiation Exposure

The trial was specifically designed to reduce radiation exposure by using a response-adapted strategy to irradiate only those nodal sites that had not achieved complete remission at the time of the early response assessment, rather than all of the originally involved nodal sites, Dr. Metzger explained in an interview with The ASCO Post. “It is very targeted radiation, and I am very happy about that because radiation therapy can put survivors of Hodgkin lymphoma at risk for secondary cancers,” she said.

One of the most common secondary cancers is breast cancer among women. “Historically, women with Hodgkin lymphoma who received radiation to the mediastinum were just as likely to get breast cancer as if they were BRCA1- or BRCA2-positive,” Dr. Metzger noted.

In addition, “radiation to the lungs can cause fibrosis, and radiation to the heart can cause vascular problems,” Dr. Metzger said. “Radiation to the neck can cause atherosclerosis of the coronary artery. There have been studies of survivors showing that they can have cognitive deficits secondary to radiation to the neck.”

‘A Smart Drug’

The open-label, single-arm study (ClinicalTrials.gov identifier NCT01920932) enrolled 77 patients—51% female and 65% White—with previously untreated high-risk (stage IIB, IIIB, or IV) classical (CD30-positive) Hodgkin lymphoma. Patient demographics did not differ significantly between the enrolled patients and a historical control group, although the current trial had higher percentages of patients with stage IIIB or IV disease.

In addition to St. Jude, patients were enrolled at Stanford University Medical Center, Stanford, California; Dana-Farber Cancer Institute and Massachusetts General Hospital Cancer Center, Boston; Maine Children’s Cancer Program, Scarborough; and Children’s Hospital of Illinois, Peoria. The study was sponsored by Seattle Genetics.

“In this trial, to maintain excellent outcomes without intensifying chemotherapy and its associated toxicities, we substituted brentuximab vedotin for vincristine in the OEPA/COPDac (vincristine, etoposide, prednisone, and doxorubicin/cyclophosphamide, vincristine, prednisone, and dacarbazine) regimen followed by response-based residual node radiation,” the researchers wrote. Already approved to treat adults with Hodgkin lymphoma, brentuximab vedotin is specifically targeted to Hodgkin Reed-Sternberg cells, considered the hallmark cells of Hodgkin lymphoma.

“I think of brentuximab vedotin as a smart drug,” Dr. Metzger commented in a news release announcing the study findings.2 “Unlike conventional chemotherapy, which can have wide-ranging side effects on all cells of the body, this drug knows to go directly to the Hodgkin lymphoma cells—maximizing its effect while minimizing side effects.”

Trial participants received two cycles of the new AEPA regimen, with brentuximab vedotin substituting for the vincristine in the OEPA regimen, and four cycles of the new CAPDac regimen, with brentuximab substituting for the vincristine in the COPDac regimen. “After AEPA cycles, patients underwent an early response assessment with PET/CT and contrast-enhanced CT scan or [magnetic resonance imaging],” the researchers reported. Patients who had not achieved complete remission at that early response assessment received residual node radiotherapy after completion of four cycles of CAPDac.

Generally Well Tolerated

“Therapy was generally well tolerated and mostly limited to low-grade nausea, vomiting, and constipation. The most common adverse events were hematologic, particularly during the first two cycles,” the researchers reported.

“One irradiated patient experienced disease progression at the end of therapy and now remains disease-free more than 6 years following salvage therapy. One unexpected death occurred,” which the authors noted, “is concerning and warrants postmarketing toxicity monitoring” of brentuximab vedotin. “Only 4% of patients experienced grade 3 neuropathy,” they added.

Weight gain was relatively common, with 45% of patients gaining more than 20% over baseline. None of the patients required dose reduction or discontinuation of brentuximab vedotin, which, Dr. Metzger said, “seems to be unusual compared to the adults.”

A New Standard?

Asked whether the regimen could become a new standard for high-risk pediatric Hodgkin lymphoma, Dr. Metzger replied: “I certainly welcome that. I would love to see that be the case.” In the meantime, since the regimen is not depending on getting approval for any new drug, the regimen can and is being used in the clinic.

“Between the closure of this trial and the opening of our new trial, we have used it off-protocol with approval from the insurance companies, and they have provided the brentuximab vedotin,” Dr. Metzger said.

A possible obstacle to more extensive use of the study regimen could be cost. “Brentuximab vedotin is quite expensive, but that would be the only thing holding it back,” Dr. Metzger said.

Prompted New Trial

“We are obviously quite pleased with the results of the trial,” Dr. Metzger stated, “and have moved forward to our follow-up study, where we have made some small changes but are hoping to maintain the cure rate.” For example, “we are no longer giving the steroid after two cycles for those who have a good response, because we don’t see any use for steroids after that,” Dr. Metzger said.

“Steroids are very important. That is why we use them for the first two cycles,” she continued, “but steroids have many side effects. They are not good for your quality of life. They increase your appetite. They increase your gastritis. They put you at risk for vascular necrosis, and that is significant, particularly for obese adolescents, especially girls. Steroids also play with your moods and can cause difficulty sleeping.”

PET Negativity Is Most Important Predictor

Dr. Metzger pointed out that, in the original study, most patients (64 of 77) were PET-negative. Even though only 13 patients were PET-positive, “50 patients were prescribed radiation because 37 did not meet CT standards for remission,” she noted. “In our new trial, all these 64 PET-negative patients would not get radiation because, in the meantime, we have learned that the most important predictor of who will be okay without radiation is PET negativity.”

About 17% of patients were PET-positive in the first trial, and Dr. Metzger expects the percentage to be similar in the new trial. “I foresee, in our new trial, less than 20% of the patients would be getting radiation,” she said. “We are very excited about that because, in other trials of advanced-stage Hodgkin lymphoma, even based solely on PET scan, they are still irradiating 50% of the high-risk patients.”

The new study “will also include low-risk and intermediate-risk patients, but with a different strategy for those patients,” Dr. Metzger said. That treatment strategy is not based on OPEA/COPDac, she noted, but “on a different commonly used regimen for Hodgkin lymphoma, which is Stanford V [mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide and prednisone].”

Other Targeted Agents

Concerning other targeted agents being tested for use among pediatric patients with Hodgkin lymphoma, Dr. Metzger reported: “There are a couple of studies using PD-1 inhibitors, such as pembrolizumab, and that is certainly exciting. We are not currently running one of those trials in front-line therapy,” she noted. “Perhaps in the future, combining pembrolizumab with brentuximab vedotin could be used as front-line therapy, but we cannot jump to it. The way we move forward is by starting to make little adjustments and see what it is safe to do,” she cautioned.

“Maybe the next trial will be using the brentuximab vedotin in intermediate- and low-risk patients, where we can take out vincristine and bleomycin that is part of those regimens and substitute the brentuximab. Right now, we use only 8 weeks of chemotherapy for low-risk patients and 12 weeks for intermediate-risk patients. It is very limited chemotherapy,” Dr. Metzger said. “We are moving in the direction where we are giving less and less, while maintaining or improving survival.” 

DISCLOSURE: Dr. Metzger has received research funding from Seattle Genetics.

REFERENCES

1. Metzger ML, Link MP, Billett AL, et al: Excellent outcome for pediatric patients with high-risk Hodgkin lymphoma treated with brentuximab vedotin and risk-adapted residual node radiation. J Clin Oncol. April 7, 2021 (early release online).

2. Excellent outcomes reported for first targeted front-line therapy for high-risk pediatric Hodgkin lymphoma. St. Jude Children’s Research Hospital news release, April 7, 2021. Available at https://www.stjude.org/media-resources/news-releases/2021-medicine-science-news/excellent-outcomes-reported-for-first-targeted-frontline-therapy-for-high-risk-pediatric-hodgkin-lymphoma.html. Accessed May 20, 2021.


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