Hodgkin lymphoma: A review and update on recent progress.

Hodgkin lymphoma (HL) is a unique hematopoietic neoplasm characterized by cancerous Reed-Sternberg cells in an inflammatory background. Patients are commonly diagnosed with HL in their 20s and 30s, and they present with supradiaphragmatic lymphadenopathy, often with systemic B symptoms. Even in advanced-stage disease, HL is highly curable with combination chemotherapy, radiation, or combined-modality treatment. Although the same doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapeutic regimen has been the mainstay of therapy over the last 30 years, risk-adapted approaches have helped de-escalate therapy in low-risk patients while intensifying treatment for higher risk patients. Even patients who are not cured with initial therapy can often be salvaged with alternate chemotherapy combinations, the novel antibody-drug conjugate brentuximab, or high-dose autologous or allogeneic hematopoietic stem cell transplantation. The programmed death-1 inhibitors nivolumab and pembrolizumab have both demonstrated high response rates and durable remissions in patients with relapsed/refractory HL. Alternate donor sources and reduced-intensity conditioning have made allogeneic hematopoietic stem cell transplantation a viable option for more patients. Future research will look to integrate novel strategies into earlier lines of therapy to improve the HL cure rate and minimize long-term treatment toxicities. CA Cancer J Clin 2018;68:116-132. © 2017 American Cancer Society.

Efficacy and safety of nivolumab in Japanese patients with previously untreated advanced melanoma: A phase II study.

Treating advanced or recurrent melanoma remains a challenge. Cancer cells can evade the immune system by blocking T-cell activation through overexpression of the inhibitory receptor programmed death 1 (PD-1) ligands. The PD-1 inhibitor nivolumab blocks the inhibitory signal in T cells, thus overcoming the immune resistance of cancer cells. Nivolumab has shown promising anticancer activity in various cancers. We carried out a single-arm, open-label, multicenter, phase II study to investigate the efficacy and safety of nivolumab in previously untreated Japanese patients with advanced melanoma. Twenty-four patients with stage III/IV or recurrent melanoma were enrolled and received i.v. nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was overall response rate evaluated by an independent radiology review committee. The independent radiology review committee-assessed overall response rate was 34.8% (90% confidence interval, 20.8-51.9), and the overall survival rate at 18 months was 56.5% (90% confidence interval, 38.0-71.4). Treatment-related adverse events (AEs) of grade 3 or 4 only occurred in three patients (12.5%). Two patients discontinued nivolumab because of AEs, but all AEs were considered manageable by early diagnosis and appropriate treatment. Subgroup analyses showed that nivolumab was clinically beneficial and tolerable regardless of BRAF genotype, and that patients with treatment-related select AEs and with vitiligo showed tendency for better survival. In conclusion, nivolumab showed favorable efficacy and safety profiles in Japanese patients with advanced or recurrent melanoma, with or without BRAF mutations. (Trial registration no. JapicCTI-142533.).

Role of DNA Methylation Profiles as Potential Biomarkers and Novel Therapeutic Targets in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and is associated with high mortality. The main reasons for treatment failure are a low rate of early diagnosis, high relapse rates, and distant metastasis with poor outcomes. These are largely due to a lack of diagnostic, prognostic, and predictive biomarkers in HNSCC. DNA methylation has been demonstrated to play an important role in the pathogenesis of HNSCC, and recent studies have also valued DNA methylation as a potential biomarker in HNSCC. This review summarizes the current knowledge on DNA methylation profiles in HPV-positive and HPV-negative HNSCC and how these may contribute to the pathogenesis of HNSCC. It also summarizes the potential value of DNA methylation as a biomarker in the diagnosis, prognosis, and prediction of the response to therapy. With the recent immunotherapy era in head and neck treatment, new strategies to improve immune responses by modulating TIMEs have been intensely investigated in early-phase trials. Therefore, this study additionally summarizes the role of DNA methylation in the regulation of TIMEs and potential predictive immunotherapy response biomarkers. Finally, this study reviews ongoing clinical trials using DNA methylation inhibitors in HNSCC.

Geographic heterogeneity in the outcomes of patients receiving immune checkpoint inhibitors for advanced solid tumors: a meta-analysis.

BACKGROUND: Little is known about the effect of geographic location on efficacy of immune checkpoint inhibitors (ICI). We performed a systematic review and meta-analysis to assess the heterogeneity of ICI efficacy between different geographic locations. METHODS: We searched PubMed, EMBASE, and the Cochrane Library through October 2019 for phase III randomized controlled trials (RCT) that provided sufficient data for hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) or progression-free survival (PFS) according to designated geographic region. We calculated pooled HRs and 95% CIs for North American, European and Asian cancer patients, and assessed data heterogeneity using subgroup and sensitivity analysis. The INPLASY registration number was INPLASY202050062. RESULTS: Of 10151 publications identified in our research, 17 RCTs including 7462 patients met our selection criteria. The pooled HRs for OS of North American, European and Asian patients were 0.67 (95% CI: 0.57 to 0.78), 0.72 (95% CI: 0.64 to 0.81), and 0.74 (95% CI: 0.66 to 0.84) respectively; the pooled HRs for PFS of North American, European and Asian patients were 0.58 (95% CI: 0.49 to 0.69), 0.61 (95% CI: 0.41 to 0.90), and 0.87 (95% CI: 0.38 to 1.99) respectively. Both anti-PD-1 inhibitors and anti-PD-L1 inhibitors showed clinical benefit in North American and European arms while anti-PD-L1 inhibitors failed to show benefit in Asian arms. CONCLUSIONS: Our meta-analysis indicates that the magnitude of benefit from ICI varies in North America, Europe, and Asia. Asian patients experience inferior outcomes compared to Western patients. Notably, anti-PD-L1 therapies do not result in survival improvements in Asian patients.

Programmed Death 1 Inhibitor-Induced Hypothyroidism on the Palliative Care Unit: Case Report.

Novel immune-based cancer therapies such as programmed death 1 (PD-1) inhibitors continue to emerge for both curative and palliative intent. Post-market data of PD-1 inhibitors indicate that there are a wide range of side effects associated with these drugs, including ones that have relevance to symptom control and represent a diagnostic challenge at the end of life. We present a case of pembrolizumab-induced hypothyroidism causing extreme fatigue and persistent hypoglycemia.

Immunotherapy combination strategies (non-chemotherapy) in non-small cell lung cancer.

Immune checkpoint inhibitors enhance the activation and antitumor activity of the immune system, resulting in durable response rates in a select group of patients. Cytotoxic T lymphocyte antigen 4 (CTLA4) inhibitors target the inhibitory interaction between CTLA4 and CD80 or CD86. Programmed death 1 (PD1) inhibitors target the interaction between PD1 receptors on T-cells and PD-ligand 1 (PD-L1) and PD-ligand 2, blocking the inhibitory signaling and resulting in activation of T-cell effector function. These therapeutic drugs were originally evaluated in patients with metastatic melanoma before expansion to all tumor types, including non-small cell lung cancer (NSCLC) with promising results. The PD1 inhibitors such as pembrolizumab have now received FDA approval in the first-line setting for patients with positive PD-L1 expression tumor types; however, only a portion of patients have shown objective and sustainable responses. To expand the number of patients with observed response to immunotherapeutic agents including patients with negative PD-L1 expression tumors, clinical trials are ongoing to assess the safety and efficacy of combination immune checkpoint inhibitors and combination immune checkpoint inhibitors with targeted therapy. Immune checkpoint inhibitors have been found to be a promising therapeutic drug class with sustainable response rates and a tolerable safety profile, and efforts continue to improve these drugs in patients with NSCLC.