A Randomized Phase 2 Study Incorporating Nivolumab and Brentuximab Vedotin into Radiation-Free Treatment of Early Stage Classic Hodgkin Lymphoma
Authors: LaCasce Ann S. , Jagadeesh Deepa , Lee Hun Ju , Chen Lu , Bond David A. , Weinstock Matthew , Mei Matthew , Feldman Tatyana , Winter Allison M. , Barnes Jeffrey A. , Mehta Amitkumar N. , Goyal Gaurav , Ahmed Sairah , Roth Lisa Giulino , Borogovac Azra , Blum Kristie A. , Winter Jane N , Hamadani Mehdi , Smith Sonali M. , Armand Philippe , Flinn Ian W. , Abramson Jeremy S. , Herrera Alex F. 
Published: December 2024

A.S.L, D.J., and H.J.L. contributed equally

I.W.F., J.S.A., and A.F.H. contributed equally

Introduction: Maximizing treatment efficacy while minimizing late effects is critical in patients with early stage classic Hodgkin lymphoma (cHL). We hypothesized that the incorporation of brentuximab vedotin (BV) and nivolumab (nivo) in early stage cHL would improve progression-free survival and obviate the need for radiotherapy.

Methods: Patients aged 16 and older with stage IA-IIB cHL with adequate organ function without active autoimmune disease or significant neuropathy were eligible. All patients underwent PET/CT after 2 cycles of ABVD (PET2). Patients with non-bulky disease (bulky defined as &gt; 7.5 cm on baseline PET/CT) who were PET2 negative (Deauville 1-3) were randomized to 2 additional cycles of ABVD followed by 3 months of nivo consolidation (arm A) (administered every 2 weeks) versus 3 cycles of BV-nivo administered every 3 weeks (arm B1), in both cases without radiation. Patients were stratified for baseline factors of stage I vs II and A vs B symptoms. PET-2 negative patients with bulky disease received 2 additional cycles of ABVD followed by 3 months of nivo consolidation (arm B2). PET2 positive patients received BV-AVD for 4 cycles followed by PET-CT and, if in CR, went on to receive 3 months of nivo consolidation (arm C). The primary endpoint was 18-month progression free survival.

Results: 153 patients were evaluable with median age of 31 years (18-73). 78 (51%) were male, 117 (76%) were white, 8 (5%) were black, 10 (7%) were Asian, 4 (3%) were other or mixed race, and 14 (9%) were unknown/not-disclosed.19 (12%) were Hispanic. 142 (93%) patients had nodular sclerosis or NOS subtype. 23 (15%) had extranodal disease. 134 (88%) had stage II disease, and 50 (33%) had B symptoms. According to GHSG, 54 (35%) were favorable and 95 (62%) unfavorable (3% missing information). 52 (34%) patients had bulky disease. 75% of patients were PET2 negative after 2 cycles of ABVD. Assignment to arms was: Arm A 45 (29%), Arm B1 36 (24%), Arm B2 35 (23%) and Arm C 37 (24%). The median follow-up was 22 months across study arms. The 18m PFS for Arm A and Arm B1 (non-bulky PET2-negative) was 100%, 97% (95% CI 81%-99.6%) for Arm B2 (bulky PET2 negative), and 81% (62%-91%) for Arm C (PET2 positive). The 24m PFS for Arm A and Arm B1 was 100%, 86% (66%-94%) for Arm B2, and 76% (55%-88%) for Arm C. No deaths have been reported to date in any study arm.

The most common adverse events (AEs) of any grade in patients treated on Arm A (BV+Nivo) were: maculopapular rash (40%), infusion related reaction (24%), nausea (22%), and peripheral sensory neuropathy (20%). The most common AEs in Arm B1/B2 were: neutropenia (48%), nausea (35%), fatigue (35%), constipation (24%), ALT elevation (21%), anemia (20%), and peripheral sensory neuropathy (20%). The most common AEs in Arm C were: peripheral sensory neuropathy (70%), constipation (54%), nausea (49%), fatigue (49%), neutropenia (46%), anemia (38%), vomiting (35%), diarrhea (32%). Febrile neutropenia occurred in 0% of Arm A patients, 7% of Arm B patients, and 8% of Arm C patients. 4 patients in arm A, 7 in arm B and 1 in arm C discontinued therapy for toxicity.

Conclusion: Incorporating Nivo +/- BV without radiotherapy in PET2-negative cHL patients with non-bulky early stage cHL after 2 cycles of ABVD resulted in 24-month PFS of 100% with manageable toxicity. PET2-negative patients with bulky disease and PET2-positive patients experienced good disease control, although alternative approaches for bulky PET2-negative patients and continued use of radiation in PET2 positive patients may be warranted. These results support the ongoing PET-adapted US Children's Oncology Group led Intergroup study AHOD2131 comparing standard therapy to the incorporation of BV-nivo in early stage cHL.