1. Fuerst, Mark L.

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ATLANTA-The addition of brentuximab vedotin (BV) to standard treatment in first-line therapy for advanced Hodgkin lymphoma improves patients' chances of a cure and avoids the need for additional, more intensive therapy.

Hodgkin lymphoma. Ho... - Click to enlarge in new windowHodgkin lymphoma. Hodgkin lymphoma

Patients with advanced Hodgkin lymphoma (HL) who were treated with a multi-drug regimen that included the targeted agent BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) had a 23 percent reduction in the risk of disease progression, death, or the need for additional therapy as compared with patients who received the standard four-drug, first-line regimen for treating advanced HL, according to the results of a new study.


"The study results represent the first successful effort in more than 30 years to improve outcomes of first-line treatment in patients with advanced HL without escalating the toxicity of the chemotherapy to unacceptable levels," said lead author Joseph M. Connors, MD, FRCPC, Clinical Director of the British Columbia Cancer Agency Resource Centre for Lymphoid Cancer in Vancouver, Canada.


Connors presented the results of the study at the 2017 American Society of Hematology Annual Meeting. The results of the ECHELON-1 were simultaneously published online in the New England Journal of Medicine (2018;378:331-344).


Standard treatment for HL with the drugs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) has not changed since the 1970s, Connors noted. Previous trials have failed to improve the outcomes achieved with ABVD without causing severe side effects.


"We expect ABVD to cure about three-quarters of patients-which means, of course, that one-quarter will not be cured," he said. "In this study, we've been able to significantly reduce that rate of treatment failure. If this new regimen is widely adopted, it will change first-line treatment of advanced HL."


This is the first time a drug designed to take advantage of a specific biologic characteristic of HL cells has been used in first-line treatment of the disease, Connors explained.


Study Details

The multinational, phase III clinical trial included 1,334 patients with previously untreated advanced HL and was conducted at 218 sites in 21 countries around the world. The patients were randomly assigned to receive A+AVD (664 patients) or ABVD (670 patients), with up to 50 months of follow-up. They received A+AVD (BV 1.2 mg/kg, doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2), or ABVD (doxorubicin 25 mg/m2, bleomycin 10 units/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2) intravenously on days 1 and 15 of up to six 28-day cycles. Patients were followed every 3 months for 36 months, then every 6 months until the end of the study.


At the end of chemotherapy, patients were reassessed with CT and PET scanning, and then followed for the success of the treatment. "The unique aspect of HL is that you can get an early look at how well the treatment is working with a PET scan at 2 months," Connors noted.


The primary endpoint was modified progression-free survival (PFS) as determined by independent review. This endpoint was defined as the time to disease progression, death, or modified progression. Modified progression was defined as evidence of non-complete response after completion of frontline therapy followed by subsequent anticancer therapy. Treatment was deemed to have failed if patients' lymphoma did not completely disappear or if its persistence prompted additional non-study treatment, he said.


The study met its primary endpoint. With a median follow-up of 25 months, there were 117 events in the A+AVD arm (90 patients experienced progression, 18 deaths occurred, and nine patients experienced modified progression) and 146 events in the AVBD arm (102 cases of progression, 22 deaths, and 22 cases of modified progression).


The 2-year modified PFS was 82.1 percent with A+AVD compared with 77.2 percent with ABVD. Overall survival was not significantly different in the two arms.


Response rates were similar. Overall response rates were 86 percent in the A+AVD arm and 83 percent in the ABVD arm. Complete responses were seen in 73 percent of patients taking A+AVD and in 71 percent of those taking ABVD.


One-third fewer patients taking A+AVD received subsequent chemotherapy or high-dose chemotherapy and transplant compared with patients treated with ABVD, Connors noted.


Safety profiles were consistent with known toxicities of the single agents. Grade 3 or higher infections were more common in the A+AVD arm (18%) than the ABVD arm (10%). Neutropenia was also higher (58%) in the A+AVD arm compared with ABVD arm (45%). Similarly, peripheral neuropathy occurred in 67 percent of patients receiving A+AVD and 43 percent receiving ABVD.


The rate of febrile neutropenia was lower in the A+AVD arm among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor (GCSF) than among those who did not. Connors recommended GCSF primary prophylaxis for all patients.


"The experimental combination with BV more frequently got rid of all of the disease, and this was achieved with acceptable levels of adverse effects," he noted. "Treatment with BV was modestly more toxic, but when we added simple measures to improve patients' blood counts, they were able to take it safely."


George P. Canellos, MD, of the Dana-Farber Cancer Institute in Boston, who introduced Connors at a Plenary Session, noted that other considerations need to be addressed, including overall survival, duration of follow-up, toxicity, and cost, which includes the cost of supportive care as well as the cost of the drug.


The combination of BV with chemotherapy for frontline advanced classical HL was granted breakthrough therapy designation by the FDA in October 2017.


Mark L. Fuerst is a contributing writer.