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Frontline brentuximab vedotin improved Hodgkin lymphoma outcomes

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Eagerly anticipated advance in Hodgkin lymphoma

The incorporation of the CD30 immunotoxin brentuximab vedotin into frontline therapy for Hodgkin lymphoma “has been eagerly anticipated, and the wait is over,” Dan L. Longo, MD, and Vincent T. DeVita Jr., MD, wrote in an editorial.

Results of the randomized phase 3 trial by Dr. Connors and colleagues suggest that, with a relatively short follow-up, adding brentuximab vedotin to AVD combination chemotherapy “merits consideration” as a first-line treatment, according to Dr. Longo and Dr. DeVita.

“Although it is too early to rule out unanticipated late side effects … brentuximab vedotin + AVD appears to be more effective than ABVD (and is unlikely to be less effective) and is associated with fewer, more treatable toxicities,” they wrote.

Adverse effects of ABVD are generally modest, but the bleomycin in the regimen can result in serious pulmonary toxicity. While the rate of serious pulmonary toxicity is low, “clinicians have the impression that it is unpredictable,” the authors noted.

Beyond a significant improvement in modified progression-free survival with a follow-up of 25 months, brentuximab vedotin plus AVD was associated with lower pulmonary toxicity, they noted.

While the brentuximab vedotin had more neutropenia and neuropathy, neutropenia could be addressed with G-CSF between doses, and neuropathy was mainly low grade and completely resolved most of the time, the authors said.

Brentuximab had promising single-agent activity in previous Hodgkin lymphoma studies, so substituting it for bleomycin “had the potential to improve on ABVD. And it did,” Dr. Longo and Dr. DeVita wrote.

Dr. Longo is with Dana-Farber Cancer Institute, Boston, and Dr. DeVita is with the Yale Cancer Center, New Haven, Conn. These comments are based on their editorial appearing in the New England Journal of Medicine (2018 Jan 24. doi: 10.1056/NEJMe1715141). Dr. DeVita reported no disclosures, and Dr. Longo reported employment as Deputy Editor with the New England Journal of Medicine.



Replacing bleomycin with brentuximab vedotin in the classic ABVD regimen improved a measure of progression-free survival and reduced pulmonary toxicity in patients with previously untreated Hodgkin lymphoma, findings from a randomized, phase 3 trial suggest.

Patients receiving brentuximab plus chemotherapy had a “statistically significant and clinically meaningful improvement” in the rate of modified progression-free survival, according to results published in the New England Journal of Medicine.

Pulmonary toxicity also occurred at a lower rate with the regimen containing brentuximab, an anti-CD30 antibody–drug conjugate, wrote Joseph M. Connors, MD, of the British Columbia Cancer Agency, Vancouver, and his coauthors.

Taken together, these findings suggest brentuximab vedotin and chemotherapy had “substantially less pulmonary toxicity and appears to be more effective for frontline treatment of advanced-stage classic Hodgkin lymphoma,” the researchers wrote.

Bleomycin is often omitted from later cycles of chemotherapy for patients with Hodgkin lymphoma due to pulmonary symptoms, and is sometimes associated with unpredictable or even fatal pulmonary toxicity, the researchers noted.

The brentuximab vedotin arm of the trial did have more neurotoxicity, which was largely reversible, and more myelotoxicity, though that “can be ameliorated with prophylactic granulocyte colony-stimulating factor (G-CSF),” the researchers wrote.

The study by Dr. Connors and colleagues, known as ECHELON-1, was an open-label, multicenter, randomized phase 3 trial including patients with previously untreated stage III or IV classic Hodgkin lymphoma. Among enrolled patients, 664 received brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AVD), and 670 received standard doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

The study used a primary endpoint of progression-free survival augmented to include not only time to disease progression or death, but also “modified progression,” which the researchers defined as evidence of noncomplete response at the end of frontline chemotherapy.

It is accepted practice to give more chemotherapy or radiotherapy in Hodgkin lymphoma patients who have a positive PET scan at the end of frontline therapy, since metabolically detectable residual disease reliably predicts imminent progression, Dr. Connors and coauthors wrote.

“In this context, the conventional endpoint of progression-free survival does not accurately assess the curative intent of frontline chemotherapy,” they wrote.

With a median 24.9-month follow-up, modified 2-year progression-free survival in the trial was 82.1% for patients receiving brentuximab plus AVD, versus 77.2% for ABVD (P = .03), a 23% risk reduction.

Pulmonary toxicity of grade 3 or higher occurred in less than 1% of patients in the brentuximab vedotin plus AVD arm of the trial and in 3% of the ABVD arm.

Neutropenia was reported in 58% and 45% in the brentuximab vedotin plus AVD and ABVD arms, respectively, while febrile neutropenia was reported in 19% and 8%, respectively.

In the brentuximab plus AVD group, the rate of febrile neutropenia was 11% for those patients who received primary prophylaxis with G-CSF, and 21% for patients who did not, the researchers noted.

Peripheral neuropathy was seen in 67% and 43% of the brentuximab vedotin plus AVD and ABVD arms, respectively, and about two-thirds of the patients in the brentuximab vedotin plus AVD arm had improvement or resolution at the final follow-up visit.

The study was supported by Millennium Pharmaceuticals and Seattle Genetics. Researchers reported ties to Millennium Pharmaceuticals, Takeda Pharmaceuticals, Seattle Genetics, and other companies.

SOURCE: Connors JM et al. N Engl J Med. 2018;378:331-44.

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