Concurrent Pembrolizumab with AVD for Untreated Classical Hodgkin Lymphoma

Lynch, Ryan C.; Ujjani, Chaitra S.; Poh, Christina; Warren, Edus H.; Smith, Stephen D.; Shadman, Mazyar; Shustov, Andrei R.; Till, Brian G.; Tseng, Yolanda D.; Coye, Hilary; Shelby, Megan; Ottemiller, Susan; Du, Hongyan; Vandermeer, Jacquelin; Rasmussen, Heather; Alig, Stefan; Alizadeh, Ash A.; Gulhane, Avanti; Chen, Delphine L.; Déan, Eric; Lukas, Jason; Martin, Patrick; Marzbani, Edmond; Voutsinas, Jenna; Gopal, Ajay K.

doi:10.1182/blood-2021-144610

Cited by 6 publications

(5 citation statements)

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“…Preliminary results of a trial of concurrent pembrolizumab and AVD therapy in early-stage unfavorable and advanced-stage cHL were recently reported by Lynch et al 16 with a short follow-up; the 1-year PFS and OS were 96% and 100%, respectively, similar to our study. The reasons for differences in outcomes across trials are not clear and may be related to patient selection, differences in central imaging review, small numbers of patients, and possible differences between pembrolizumab and nivolumab in untreated cHL.…”

Section: Discussionsupporting

confidence: 91%

“…Biomarkers such as circulating tumor DNA may more precisely predict response in the setting of immunotherapy or may complement PET-assessed response. 16 , 17 Additionally, the high efficacy of our approach may impede the analysis of PD-1 biomarkers by eliminating comparative groups, as all patients in this study achieved and retained CMR following chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Sequential pembrolizumab and AVD are highly effective at any PD-L1 expression level in untreated Hodgkin lymphoma

Allen

Chen

et al. 2023

Blood Advances

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In a multicenter, phase II investigator-initiated trial of sequential pembrolizumab and AVD, nearly two-thirds of patients with untreated unfavorable or advanced stage classic Hodgkin Lymphoma (cHL) achieved PET-defined complete or near complete metabolic responses (CMR) following 3 doses of pembrolizumab monotherapy. Furthermore, all achieved CMR following 2 cycles of AVD chemotherapy and 100% of patients were alive without relapse at the time of initial publication. We now report long-term follow-up, including 3-year OS and planned correlative analyses. Thirty patients received single agent pembrolizumab every 3 weeks x 3, followed by AVD chemotherapy for 4-6 cycles depending on stage and bulk. PET/CT scan was performed after pembrolizumab monotherapy, 2 cycles of AVD, and at the end of therapy. Baseline biopsy samples were analyzed for genomic alterations of chromosome 9p24.1 and PD-1 pathway markers by immunohistochemistry. At a median follow up of 33.1 months (range, 26.0-43.0), PFS and OS remain 100%. All patients had genomic alterations in 9p24.1 and were positive for PD-L1 by immunohistochemistry. There was no relationship between response to single agent pembrolizumumab measured by decline in metabolic tumor volume and 9p24.1 alterations or PD-1 pathway H-scores. With additional follow-up, sequential pembrolizumab and AVD remains highly effective. The high response rates observed at all PD-ligand levels suggest that even low levels of PD ligand expression are sufficient for response to PD-1 blockade in untreated cHL. An international phase II trial (NCT05008224) to confirm these findings is ongoing.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Sequential pembrolizumab and AVD are highly effective at any PD-L1 expression level in untreated Hodgkin lymphoma

Allen

Chen

et al. 2023

Blood Advances

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“…This study highlighted the potential of obtaining a CMR after a short course of pembrolizumab even in patients with bulky disease, which consisted of the 40% of study population. Lynch et al assessed the effectiveness of pembrolizumab administered concurrently with AVD (AVD + P) in another single-arm study of 30 untreated, all-stage HL patients (60% with advanced disease and 20% early unfavorable per NCCN criteria) [74,80]. According to the Lugano criteria, after two cycles of AVD + P, 68% of the patients were iPET2-negative, while 78% had a negative EoT-PET after two to six AVD + P cycles (two, four and six cycles in 17%, 10% and 73% of the patients).…”

Section: Checkpoint Inhibitors In the First-line Therapy Of Classical...mentioning

confidence: 99%

“…According to the Lugano criteria, after two cycles of AVD + P, 68% of the patients were iPET2-negative, while 78% had a negative EoT-PET after two to six AVD + P cycles (two, four and six cycles in 17%, 10% and 73% of the patients). Although these "metabolic" results in interim and EoT-PET appear inferior to those achieved with ABVD alone Lynch et al assessed the effectiveness of pembrolizumab administered concurrently with AVD (AVD + P) in another single-arm study of 30 untreated, all-stage HL patients (60% with advanced disease and 20% early unfavorable per NCCN criteria) [74,80]. According to the Lugano criteria, after two cycles of AVD + P, 68% of the patients were iPET2negative, while 78% had a negative EoT-PET after two to six AVD + P cycles (two, four and six cycles in 17%, 10% and 73% of the patients).…”

Section: Checkpoint Inhibitors In the First-line Therapy Of Classical...mentioning

confidence: 99%

“…Of note, at least one dose was missed or pembrolizumab treatment was interrupted in 20% of patients due to toxicity, while 10% of the patients developed temporary and well-manageable grade ≥ 3 transaminitis, leading to pembrolizumab discontinuation. None of the patients who stopped treatment with pembrolizumab due to toxicity has relapsed yet [80]. With a median follow-up time of 2.1 years, the 2-year PFS and OS were 97% and 100%, respectively [74].…”

Section: Checkpoint Inhibitors In the First-line Therapy Of Classical...mentioning

confidence: 99%

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Incorporating Monoclonal Antibodies into the First-Line Treatment of Classical Hodgkin Lymphoma

Vassilakopoulos,

Liaskas,

Pereyra

et al. 2023

IJMS

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The long-term survival of Hodgkin lymphoma (HL) patients treated according to the current standard of care is excellent. Combined-modality schedules (ABVD plus radiotherapy) in early-stage disease, along with treatment intensity adaptation to early metabolic response assessed by PET/CT in advanced stage HL, have been the cornerstones of risk stratification and treatment decision-making, minimizing treatment-related complications while keeping efficacy. Nevertheless, a non-negligible number of patients are primary refractory or relapse after front-line treatment. Novel immunotherapeutic agents, namely Brentuximab Vedotin (BV) and immune checkpoint inhibitors (CPI), have already shown outstanding efficacy in a relapsed/refractory setting in recent landmark studies. Several phase 2 single-arm studies suggest that the addition of these agents in the frontline setting could further improve long-term disease control permitting one to reduce the exposure to cytotoxic drugs. However, a longer follow-up is needed. At the time of this writing, the only randomized phase 3 trial so far published is the ECHELON-1, which compares 1 to 1 BV-AVD (Bleomycin is replaced by BV) with standard ABVD in untreated advanced-stage III and IV HL. The ECHELON-1 trial has proven that BV-AVD is safe and more effective both in terms of long-term disease control and overall survival. Just recently, the results of the S1826 SWOG trial demonstrated that the combination nivolumab-AVD (N-AVD) is better than BV-AVD, while preliminary results of other randomized ongoing phase 3 trials incorporating anti-PD-1 in this setting will be soon available. The aim of this review is to present the recent data regarding these novel agents in first-line treatment of HL and to highlight current and future trends which will hopefully reshape the overall management of this disease.

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