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CHICAGO -- Replacing chemotherapy with a targeted agent resulted in a better tolerated regimen for advanced classical Hodgkin lymphoma (cHL) with no loss in efficacy, according to a randomized study reported.

The estimated 4-year progression-free survival (PFS) was 94.3% with brentuximab vedotin (Adcetris) versus 90.9% with the conventional regimen. The 4-year overall survival (OS) was 98% for patients treated with either regimen. Almost all patients who received the modified regimen (BrECADD) remained free of treatment-related morbidity (TRMB) at 1 year, and overall TRMB occurred significantly less often with BrECADD.

More than 95% of women treated with the regimen had recovery of gonadal function after BrECADD, similar to recovery after the low-intensity regimen, reported Peter Borchmann, MD, of University Hospital of Cologne in Germany, during a press briefing prior to the American Society of Clinical Oncology (ASCO) meeting.

"We see a [PFS] superiority [of BrECADD], which was not preplanned, over BEACOPP. It's 94.3% at 4 years which is unprecedented," said Borchmann. "This benefit was observed in all risk groups, and most patients [64%] achieved a very good response and PFS after only two cycles of therapy, allowing them to finish treatment in only 12 weeks [after four cycles]. The PFS in that subgroup was 96.8% at 4 years."

"The overall risk-benefit ratio of PET-guided individualized BrECADD is very good," he added. "We therefore recommend BrECADD as a standard treatment option for advanced stage cHL patients."

The results are "really important and striking" within the context of the cHL patient population, which has a median age of 31 at diagnosis, said ASCO expert Oreofe O. Odejide MD, of Dana-Farber Cancer Institute in Boston.

"In thinking about therapies, it's really important to align efficacy with tolerability and reducing the risk of long-term side effects," said Odejide. "The results showed that BrECADD, which has fewer drugs than escalated BEACOPP, has better tolerability and a striking outcome of a 4-year progression-free survival. Almost two-thirds of patients who received this regimen had good results on their interim PET scan and could finish treatment in just 12 weeks."

"I think this is really poised to impact the standard-of-care treatment for patients with advanced-stage classical Hodgkin lymphoma," she added.

The study offers "a perfect example" of a recent trend of achieving excellent outcomes with de-escalated therapy for patients who do not require intensive treatment, said ASCO chief medical officer Julie Gralow, MD.

"By replacing some pretty toxic chemotherapy with an antibody-drug conjugate and changing the regimen a bit, and using PET scans to determine the number of cycles received, the long-term outcomes were maintained, if not improved upon," said Gralow. "In this young group of patients we really need to make sure we're focusing on the survivorship bar, and this was very impressive."

"Using FSH [follicle-stimulating hormone] as a marker of gonadal function for these young people, who probably haven't started a family yet, we're increasing the odds that they will be able to do so after survival," she said. "We need to have some discussion on how this relates to ABVD, which is the more commonly used regimen in the United States right now."

Although combination chemotherapy cures most patients with advanced cHL, intensified regimens that provide better disease control also cause more toxicity. The escalated (e)BEACOPP regimen is the standard intensified regimen for the German Hodgkin Study Group (GHSG), said Borchmann.

Brentuximab vedotin (BV) targets CD30 and has a better risk-benefit ratio as compared with intensified chemotherapy. GHSG investigators modified the eBEACOPP regimen by replacing bleomycin and vincristine with BV. They also substituted dacarbazine and dexamethasone for procarbazine and prednisone. With the changes, investigators hoped to reduce generalized organ damage, bone marrow suppression, peripheral neuropathy, and gonadal toxicity and improve quality of life.

Borchmann reported primary findings from the GHSG HD21 trial involving 233 sites in nine countries. Patients had a median age of 31.1 and 44% were female.

The protocol included use of PET imaging at baseline and after two cycles of randomized therapy (PET2) to guide continued treatment. Patients who had PET2-negative imaging received two additional cycles of BrECADD or eBEACOPP and those with positive images received four more cycles of assigned treatment. Data analysis included about 1,500 randomized patients.

The results showed that 59% of patients treated with eBEACOPP had TRMB versus 42% of those treated with BrECADD (P<0.0001). Additionally, the rate of red-cell transfusion decreased from 52% to 24% and platelet transfusion from 34% to 17%. Severe sensory polyneuropathy was uncommon with BrECADD (1% grade 3, 0% grade 4), and more patients had full recovery of gonadal function with BrECADD (95.7% vs 73.4% of women and 86.6% vs 39.8% of men). Only two patients in the BrECADD group developed secondary myelodysplastic syndrome or acute myelogenous leukemia.

Patients treated with BrECADD had a 34% reduction in the PFS hazard at 4 years (95% CI 0.45-0.67, P=0.035). Borchmann said 64% of patients had negative PET2 scans, which was associated with better 4-year PFS (93.0% of the eBEACOPP arm and 98.6% of the BrECADD arm).

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