Diffuse large B-cell lymphoma involving the central nervous system: biologic rationale for targeted therapy.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell lymphoma curable even in advanced stages. DLBCL involving the central nervous system (CNS) is more difficult to cure and fewer treatment options exist. Primary CNS lymphoma (PCNSL) refers to aggressive lymphomas confined to the CNS, and are almost always DLBCL. Standard approaches for PCNSL use high-dose methotrexate-based combinations as induction therapy and younger patients often receive dose-intensive consolidation. However, dose-intensive therapies are not suitable for all patients, and older patients have fewer effective treatment options. Patients with relapsed or chemotherapy-refractory disease have a very poor prognosis. Secondary CNS lymphoma (SCNSL) describes aggressive lymphomas involving the CNS at initial presentation or relapses within the CNS after treatment for systemic DLBCL. Isolated CNS relapse is often managed as PCNSL, but patients with synchronous involvement of DLBCL in both the periphery and the CNS pose a unique clinical challenge. Insights into the molecular circuitry of DLBCL have identified distinct genetic subtypes including cases with a predilection for CNS invasion. PCNSL and subsets of SCNSL are characterized by chronically activated B-cell receptor and NFκB signaling along with genetic evidence of immune evasion which may be exploited therapeutically. Improved mechanistic understanding of targetable pathways underpinning CNS lymphomas has led to numerous clinical trials testing targeted agent combinations and immunotherapy approaches with promising early results. Biologically rational strategies may further improve the cure rate of CNS lymphomas, either by overcoming intrinsic or acquired treatment resistance and/or by being broadly applicable to patients of all ages

The Clinical Impact of Precisely Defining Mantle Cell Lymphoma: Contributions of Elaine Jaffe

Mantle cell lymphoma (MCL) is an aggressive yet incurable B-cell lymphoma that was only first recognized as a distinct subtype in 1992, with early reports suggesting a poor median survival. Elaine Jaffe is a renowned hematopathologist and scientist from the National Cancer Institute who was instrumental in many of the early descriptions of MCL that distinguished it from other B-cell lymphomas. Further, she has led multiple international collaborations that have harmonized the lymphoma classification systems that are currently in use today. The early morphologic descriptions of MCL along with the contributions of immunologic and genetic techniques have confirmed MCL as a distinct entity with unique biology and clinical behavior. Importantly, these scientific discoveries laid the foundation for unprecedented therapeutic breakthroughs that have led to significant improvements in overall survival

Evolving therapeutic paradigms for multiple myeloma: back to the future

Multiple myeloma (MM) is an ancient disease, but until the alkylating agent melphalan was found to have anti-myeloma properties in the 1950s there was virtually no effective therapy. By the late 1960s, extended dosing with melphalan and prednisone tripled survival from diagnosis and became the standard of care for newly diagnosed MM. "Maintenance therapy" to prolong survival through sustained disease control following induction chemotherapy was sought by 1970, but early strategies were ineffective and toxic. Subsequent applications of high-dose therapy (HDT)/autologous stem cell transplant (ASCT) changed the treatment paradigm for MM from extended dosing to an intensive strategy designed to eradicate the malignant cells in a single course of treatment. Although HDT-ASCT resulted in prolonged duration of remission and improved survival, the vast majority of patients still relapsed. Interferon (IFN) and glucocorticoid maintenance therapies demonstrated marginal improvements in outcomes but significant adverse effects. Novel agents introduced over the last decade have prolonged survival when given for maintenance following HDT-ASCT, but have also challenged the HDT-ASCT paradigm by achieving comparable remission rates when used alone as extended frontline therapy. This article reviews the evolution of therapeutic strategies for MM and discusses future questions facing MM investigators