Disease overview Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma originating from the germinal center, and it represents a heterogeneous group of diseases with variable outcomes that are differentially characterized by clinical features, cell of origin (COO), molecular features, and most recently, frequently recurring mutations. Diagnosis DLBCL is ideally diagnosed from an excisional biopsy of a suspicious lymph node, which shows sheets of large cells that disrupt the underlying structural integrity of the follicle center and stain positive for pan-B-cell antigens, such as CD20 and CD79a. COO is determined by immunohistochemical stains, while molecular features such as double-hit or triple-hit disease are determined by fluorescent in situ hybridization analysis. Commercial tests for frequently recurring mutations are currently not routinely used to inform treatment. Risk stratification Clinical prognostic systems for DLBCL, including the rituximab International Prognostic Index, age-adjusted IPI, and NCCN-IPI, use clinical factors for the risk stratification of patients, although this does not affect the treatment approach. Furthermore, DLBCL patients with non-germinal center B-cell (GCB)-like DLBCL (activated B-cell like and unclassifiable) have a poorer response to up-front chemoimmunotherapy (CI) compared to patients with GCB-like DLBCL. Those with c-MYC-altered disease alone and in combination with translocations in BCL2 and/or BCL6 (particularly when the MYC translocation partner is immunoglobulin) respond poorly to up-front CI and salvage autologous stem cell transplant at relapse. Risk-adapted therapy This review will focus on differential treatment of DLBCL up-front and at the time of relapse by COO and molecular features.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.25460

Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment

PD-1 expression and clinical PD-1 blockade in B-cell lymphomas.

Summary Heat shock protein 90 (HSP90) is a molecular chaperone that is crucial for the stability and function of many proteins essential for cell survival. Many oncogenes, including tyrosine kinases, transcription factors, and cell-cycle regulatory proteins, are client proteins of HSP90. Inhibition of HSP90 causes client protein degradation via the ubiquitin–proteasome pathway, and is a mechanism that might simultaneously downregulate several redundant pathways crucial for cell viability and tumour development. HSP90 inhibitors are currently being developed as anticancer agents, and have shown early promising results in molecularly defined subgroups of solid tumours (eg, ALK-rearranged non-small-cell lung cancer and HER2-amplified breast cancer) and some haematological malignancies (eg, multiple myeloma). Here, we review the current status of HSP90 inhibitors in clinical development, including geldanamycin derivatives, resorcinol derivatives, purine analogues, and other synthetic inhibitors. We also discuss novel strategies and future perspectives on how to optimise the therapeutic potential of this exciting new class of drugs.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(13)70169-4.pdf

Inhibition of HSP90 molecular chaperones: moving into the clinic.

PURPOSEAnti–programmed death-1 (PD-1) monotherapy induces a high response rate in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but complete remission (CR) is infrequently obser...

https://ascopubs.org/doi/pdf/10.1200/JCO.18.02151

Addition of Low-Dose Decitabine to Anti-PD-1 Antibody Camrelizumab in Relapsed/Refractory Classical Hodgkin Lymphoma

Introduction: Heat shock protein 90 (HSP90) serves as a critical facilitator for oncogene addiction. There has been augmenting enthusiasm in pursuing HSP90 as an anticancer strategy. In fact, since the initial serendipitous discovery that geldanamycin (GM) inhibits HSP90, the field has rapidly moved from proof-of-concept clinical studies with GM derivatives to novel second-generation inhibitors. Areas covered: The authors highlight the current status of the second-generation HSP90 inhibitors in clinical development. Herein, the authors note the lessons learned from the completed clinical trials of first- and second-generation inhibitors and describe various assays attempting to serve for a more rational implementation of these agents to cancer treatment. Finally, the authors discuss the future perspectives for this promising class of agents. Expert opinion: The knowledge gained thus far provides perhaps only a glimpse at the potential of HSP90 for which there is still much work to be done. Lessons from th...

Heat shock protein 90 inhibitors in the treatment of cancer: current status and future directions.

A phase 1 study of IPI-504 (retaspimycin hydrochloride) administered intravenously twice weekly for 2 weeks at 22.5, 45, 90, 150, 225, 300 or 400 mg/m2 followed by 10 days off-treatment was conducted to determine the safety and maximum tolerated dose (MTD) of IPI-504 in patients with relapsed or relapsed/refractory multiple myeloma (MM). Anti-tumor activity and pharmacokinetics were also evaluated. Eighteen patients (mean age 60.5 years; median 9 prior therapies) were enrolled. No dose-limiting toxicities (DLTs) were reported for IPI-504 doses up to 400 mg/m2. The most common treatment-related adverse event was grade 1 infusion site pain (four patients). All other treatment-related events were assessed as grade 1 or 2 in severity. The area under the curve (AUC) increased with increasing dose, and the mean half-life was approximately 2–4 h for IPI-504 and its metabolites. Four patients had stable disease, demonstrating modest single-agent activity in relapsed or relapsed/refractory MM.

A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma.

A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)

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A phase 1 study of IPI-504 (retaspimycin hydrochloride) in patients with relapsed or relapsed and refractory multiple myeloma.

A Phase 1 Study of Nivolumab in Combination with Ipilimumab for Relapsed or Refractory Hematologic Malignancies (CheckMate 039)