PET-Based Response after 2 Cycles of Brentuximab Vedotin in Combination with AVD for First-Line Treatment of Unfavorable Early-Stage Hodgkin Lymphoma: First Analysis of the Primary Endpoint of Breach, a Randomized Phase II Trial of Lysa-FIL-EORTC Intergroup

Background: About 15-20% of patients with early-stage unfavorable Hodgkin lymphoma (HL) relapse or are refractory to first-line treatment with combined modality therapies. Early assessment of metabolic response after 2 cycles of ABVD has been shown to be an accurate predictor of progression-free survival and overall survival. Brentuximab vedotin (BV) in combination with AVD chemotherapy (BV-AVD) has demonstrated a promising efficacy with a favorable safety profile in a phase I trial for treatment-naive patients (Younes A. et al, Lancet Oncol 2013). Based on these results, we conducted a randomized, multicentric, phase II trial in order to improve the PET response rate after 2 cycles with BV-AVD regimen for previously untreated, early-stage unfavorable Hodgkin lymphoma.

Methods: Patients with previously untreated, stage I/II, HL and unfavorable EORTC/LYSA criteria (defined with at least one of the following: age ≥ 50 y, bulky mediastinal mass with mediastinum / thorax ratio ≥ 0.35, number of involved nodal areas ≥ 4, ESR ≥ 50mm/h or ≥ 30mm/h with B symptoms) were enrolled at the time of diagnosis. Patients were randomly assigned in a 2:1 ratio to receive 4 cycles of BV-AVD (experimental arm) or ABVD (standard arm), followed by 30Gy involved node radiation therapy (INRT). The primary objective was to evaluate the efficacy of the BV-AVD regimen, as measured by negative-PET rate after 2 cycles based on central review. PET was interpreted according to the Deauville 5-point scale with negative PET defined as Deauville 1-3. Patients with missing PET evaluation, whatever the reason, were considered as non-responders. The statistical hypothesis was based on an increase of 10% (from 75% to 85%) of the PET negativity rate after 2 cycles in the experimental arm. The standard arm was added in order to ensure that the hypothesis taken in the sample size evaluation (negative-PET rate after 2 cycles of ABVD ≤ 75%) was verified. If ≥ 93 patients out of 113 evaluable patients had negative-PET, the hypothesis that the negative-PET rate ≤ 75% in the experimental arm would be rejected. This planned analysis of the primary endpoint was performed by intention to treat (ClinicalTrials.gov registration: NCT02292979).

Results: From March 2015 to October 2016, 170 patients were included, 113 were randomized in the BV-AVD arm and 57 in the ABVD arm. Median age at randomization was 29 y (range 18-60) and 51% were female. The median number of involved nodal areas was 3 and 92% of the patients were Ann Arbor stage II, 57% had a bulky disease and 40% had B symptoms. After 2 cycles of treatment, 93/113 patients (82.3%, 95% CI 75.3-88.0) and 43/57 (75.4%, 95% CI 64.3-84.5) achieved a negative-PET based on central review in the experimental and standard arms, respectively. With the lower bound of the 95% confidence interval superior to 75% in the experimental arm, the primary objective can be considered to be met. During the first 2 cycles, grade 3-4 adverse events (AEs) were documented in 74% of the patients in the BV-AVD arm and 56% in the ABVD arm. The most frequent grade 3-4 AEs in the experimental arm were neutropenia (64%), leucopenia (31%), gastro-intestinal disorders (8%), febrile neutropenia (7%), transaminases increased (4%) and infections (4%). Only 2 patients (2%) have developed a grade 3-4 peripheral neuropathy after the first 2 cycles of BV-AVD. No pulmonary toxicity has been observed. Grade 3-4 serious AEs (SAEs) were documented in 19% of the patients in the experimental arm (treatment-related SAEs in 17%) and 7% in the standard arm. SAEs have led to permanent BV discontinuation in 7/113 (6%) patients during the first 2 cycles. Reasons for permanent BV discontinuation were loss of weight, hyponatremia, febrile neutropenia, epileptic seizure, peripheral neuropathy, hepatitis and cutaneous rash.

Conclusion: This randomized, multicentric, open-label phase II trial aimed to evaluate the efficacy of BV in combination with AVD chemotherapy based on PET response after 2 cycles for previously untreated, unfavorable early-stage HL. The primary objective was met with an improvement of the negative-PET rate with BV-AVD regimen. This first analysis highlighted an increased toxicity with BV-AVD regimen compared to ABVD, with a higher rate of grade 3-4 AEs and SAEs during the first 2 cycles of treatment.