Pembrolizumab followed by AVD in untreated early unfavorable and advanced-stage classical Hodgkin lymphoma

Abstract

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase II investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients > 18 years of age with untreated early unfavorable or advanced stage disease were eligible for treatment. Thirty patients with either early unfavorable (n=12) or advanced (n=18) stage cHL were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4-6 cycles depending on stage and bulk. Twelve had either large mediastinal masses and/or bulky disease (>10 cm). Following pembrolizumab monotherapy, 11 patients (37%) demonstrated CMR's, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography/computed tomography scanning (PET-CT) had >90% reductions in metabolic tumor volume. All patients achieved CMR following 2 cycles of AVD and maintained their responses at end of treatment. With a median follow-up of 22.5 months (range: 14.2-30.6) there have been no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well-tolerated. The most common immune-related adverse events were grade 1 rash (n=6), and grade 2 infusion reactions (n=4). One patient had a reversible grade 4 transaminitis and a second had a reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD proved both highly effective and safe in newly diagnosed cHL patients including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Latest advances in the management of classical Hodgkin lymphoma: the era of novel therapies

“…PFS and OS rates were 100%. Overall, sequential PEM and AVD were safe and highly active in this population [22].…”

Addition of chemotherapy to nivolumab after PD-1 inhibitor failure as bridge to allogeneic stem cell transplantation in classical Hodgkin’s lymphoma: report on three cases and literature review

“…10,12 On the contrary, combinations or sequential schedules of CT and PD-1 inhibitor are being tested in early phases of the disease as nivolumab or pembrolizumab plus AVD in first line. [13][14][15] Our three patients were treated with a CT schedule not used previously, and one might speculate that the tumor response is due to CT and not related to the immunomodulatory effect of nivolumab. However, the aforementioned studies suggest that treatment with PD-1 inhibitors may reset the immune balance by resensitizing the tumor microenvironment to CT and thus allowing the immune system to overtake chemorefractoriness, which is in accordance with our observations.…”

“… 10 , 12 On the contrary, combinations or sequential schedules of CT and PD-1 inhibitor are being tested in early phases of the disease as nivolumab or pembrolizumab plus AVD in first line. 13 – 15 …”

Personalized medicine for Hodgkin lymphoma: Mitigating toxicity while preserving cure

“…Responses were durable, with no progression or death at 22 months of follow-up, with no consolidation radiotherapy given at the end of the treatment. 17 Phase III trial data comparing N + AVD versus BV + AVD in the first-line setting are awaited.…”