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

In a multicenter, phase 2, investigator-initiated trial of sequential pembrolizumab and AVD (doxorubicin, vinblastine, and dacarbazine), nearly two-thirds of patients with untreated, unfavorable, or advanced-stage classic Hodgkin lymphoma (cHL) achieved positron emission tomography (PET)-defined, complete or near-complete metabolic responses (CMRs), following pembrolizumab monotherapy. Furthermore, all patients achieved CMR after 2 cycles of AVD, with 100% of patients alive and without relapse at initial publication. We now report long-term follow-up, including the 3-year overall survival (OS) and planned correlative analyses. Thirty patients received 3 cycles of single-agent pembrolizumab, followed by AVD chemotherapy for 4 to 6 cycles depending on the stage and bulk. PET/computed tomography 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 programmed cell death protein 1 (PD-1) pathway markers. At a median follow-up of 33.1 months (range, 26.0-43.0), progression-free survival and OS remained 100%. All patients had genomic alterations in 9p24.1 and were positive for programmed death ligand 1 (PD-L1) by immunohistochemistry. There was no relationship between depth of response to single-agent pembrolizumab and 9p24.1 alterations or PD-1 pathway H-scores. After additional follow-up, sequential pembrolizumab and AVD remained highly effective. The high response rates observed at all PD-L1 levels suggest that even low levels of PD-L1 expression are sufficient for response to PD-1 blockade in untreated cHL. An international phase 2 trial (registered at www.clinicaltrials.gov as #NCT03226249) is ongoing to confirm our findings.

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

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 2 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 (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were 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 reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

Phase I adjuvant radiation with docetaxel in high-risk head and neck cancer.

BACKGROUND: This phase I study was designed to determine the maximum tolerated dose (MTD) and preliminary efficacy of docetaxel with concurrent radiotherapy (RT), in high-risk squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: Eligible patients had resected squamous cell carcinoma of the head and neck, histologically involved lymph nodes, and/or extranodal disease, and/or involved surgical margins and performance status 0 to 1. Treatment included weekly docetaxel with concurrent RT in a dose-finding study; a subsequent small cohort of patients was treated using the MTD of docetaxel. RESULTS: Twenty patients were enrolled. Planned accrual was 25, but the study was closed prematurely because of slow accrual. The MTD was 15 mg/m2. Dose-limiting toxicity was oral stomatitis. Therapy was well tolerated. Five patients experienced locoregional relapse at a median follow-up of 32 months. CONCLUSION: Docetaxel with concurrent RT has acceptable toxicity. This approach warrants further investigation in a phase II trial.

Case report and brief review: IL-2-induced myocarditis.

High dose bolus interleukin 2 (IL-2) used in the treatment of metastatic melanoma and renal cell carcinoma is known to have the potential for serious cardiac toxicity. At our institution 2 of 57 (3.5%) patients developed IL-2 induced myocarditis. The constellation of electrocardiographic changes and elevated troponin I is the hallmark of myocarditis. In this setting of high dose IL-2 therapy it is important to keep myocarditis in the differential in addition to the more frequently sought diagnosis of acute myocardial infarction. Although the gold standard for diagnosis is endomyocardial biopsy, there is considerable false negative rate. It may be reasonable to make the diagnosis on clinical grounds, while providing supportive care. Future investigation is required to better understand the pathophysiology and what factors may influence expression of this toxicity.