Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma.

PD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457.

Ibrutinib for central nervous system lymphoma: the Australasian Lymphoma Alliance/MD Anderson Cancer Center experience.

Primary and secondary central nervous system lymphomas (PCNSL/SCNSL) are aggressive rare malignancies with dismal outcomes. Encouraging data have emerged from Phase I/II clinical trials treating relapsed/refractory PCNSL/SCNSL with ibrutinib. We analysed 33 patients who received ibrutinib, alone or with other therapies, for PCNSL (n = 9) or SCNSL (n = 24). The objective response rate was 58% (complete response 55%). The median progression-free survival and overall survival for patients with PCNSL were both 3·1 months; for SCNSL, 10·2 and 11·5 months respectively. Only one invasive fungal infection was observed, despite concurrent or recent use of dexamethasone 8-16 mg daily in 14 patients (42%). Ibrutinib has encouraging activity in these aggressive malignancies.

Novel Agents Beyond Immunomodulatory Agents and Phosphoinositide-3-Kinase for Follicular Lymphoma.

Follicular lymphoma is the most common indolent non-Hodgkin lymphoma. Although median overall survival rates exceed 12 years with rituximab, follicular lymphoma remains largely incurable. The growing understanding of the molecular drivers of lymphomagenesis and the tumor microenvironment have led to novel therapies. Prognostic markers have identified a subset of patients with chemoresistant and/or refractory disease-associated poor outcomes. We identify the patients with follicular lymphoma in need of novel therapies, describe the drivers of lymphomagenesis and importance of the tumor microenvironment, and summarize the novel agents under investigation in relapsed/refractory and upfront follicular lymphoma.

The Diagnostic, Prognostic, and Therapeutic Utility of Molecular Testing in a Patient with Waldenstrom's Macroglobulinemia.

The application of molecular genomics and our understanding of its clinical implications in the diagnosis, prognostication and treatment of lymphoproliferative disorders has rapidly evolved over the past few years. Of particular importance are indolent B-cell malignancies where tumour cell survival and proliferation are commonly driven by mutations involving the B-cell receptor and downstream signalling pathways. In addition, the increasing number of novel therapies and targeted agents have provided clinicians with new therapeutic options with the aim of exploiting such mutations. In this case report, we highlight one such success story involving the diagnostic impact of the MYD88L265P mutation in Waldenstrom's macroglobulinemia (WM), its prognostic implications and effect on choice of therapy in the era of novel therapies.

How I treat patients with aggressive lymphoma at high risk of CNS relapse.

Central nervous system (CNS) relapses are an uncommon yet devastating complication of non-Hodgkin lymphomas. The identification of patients at high risk of secondary CNS relapse is therefore paramount. Retrospective data indicate prophylactic CNS-directed therapies may reduce the risk of CNS involvement; however, no consensus exists about dose, timing, or route of therapy. In addition, prophylaxis is not without risk of treatment-related complications and morbidity. Here, we present a series of case vignettes highlighting our approach to common dilemmas encountered in routine clinical practice. We review the method of assessing CNS relapse risk, factors that increase the likelihood of relapse including histologic subtype, MYC rearrangement, protein expression, and extranodal involvement, and review our clinical practice based on available evidence in administering CNS-directed prophylaxis.