Treatment of BRAF V600E mutant gastrointestinal stromal tumor with dabrafenib: a case report.

Background: Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor arising in the gut, most commonly stomach or small bowel. The most common driver mutations are KIT and PDGFRA which can be treated with imatinib or avapritinib (for PDGFRA D842V-mutant GIST), respectively. BRAF V600E mutant GISTs are rare and these do not respond to imatinib. Multiple clinical trials have shown antitumor effects with dabrafenib in BRAF-mutant melanoma and a few case reports have demonstrated treatment of BRAF V600E mutant GIST with a BRAF kinase inhibitor. Case Description: We present a case of a 67-year-old woman diagnosed with high-risk GIST following initial resection. She was initially treated with adjuvant imatinib which was discontinued after 7 months because molecular analysis of her tumor showed the absence of KIT and PDGFRA mutations and a BRAF V600E mutation. When her disease progressed, she was started on sunitinib and subsequently regorafenib. Both agents were discontinued due to severe palmar-plantar erythrodysesthesia and clinical progression. She was subsequently started on dabrafenib based on the presence of a BRAF V600E mutation; this therapy led to a partial response. Her disease remained stable on this medication for 19 months before progression and addition of trametinib to her treatment. Her disease continued to progress and she was switched to everolimus with mixed response before re-challenging with dabrafenib and trametinib. Her imaging showed a mixed response to the re-challenge before progressing after 5 months and transitioning to hospice. Conclusions: We describe an uncommon molecular subtype of GIST with a BRAF V600E mutation. As expected, her disease was resistant to standard GIST therapy, however there was notable tumor regression following treatment with dabrafenib. This case shows the importance of molecular testing in GIST and adds to the current body of literature on the treatment of BRAF-mutant GIST.

Humoral immune reconstitution following therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd), autologous hematopoietic cell transplantation, and measurable residual disease-response-adapted treatment cessation.

Quadruplet induction, autologous hematopoietic cell transplant (AHCT), and measurable residual disease (MRD) response-adapted consolidation yield an unprecedented depth of response in newly diagnosed multiple myeloma. Patients treated on MASTER (NCT03224507) ceased therapy and entered active surveillance (MRD-SURE) after achieving MRD negativity. This study characterizes quantitative changes in the immunoglobulin (Ig) gene repertoire by next-generation sequencing and serum gamma globulin levels. Quadruplet therapy leads to profound hypogammaglobulinemia and reduction in the Ig gene repertoire. Immune reconstitution (IR) is delayed in patients who received post-AHCT consolidation compared to those who do not. Eighteen months after treatment cessation, there was no statistically significant difference between the groups.

Assessing the risk of thromboembolism in cancer patients receiving immunotherapy.

Malignancy has long been implicated with hypercoagulability, leading to an increased rate of both venous and arterial thromboembolic events (VTE and ATE). Immunotherapy has established itself as a cornerstone of modern cancer therapy by promoting antitumor immune responses, though there have been some suggestions that immune-related adverse events could include increased rates of VTE and ATE. In this review, we examine the available evidence regarding the use of immune checkpoint inhibitors (ICIs) and thrombosis. First, we describe the potential mechanisms by which ICIs might lead to thrombophilia given the overlap between the immune system, coagulation cascade, and platelet adhesion and activation. In addition, while there are some preclinical data evaluating immunotherapy-associated ATEs in animal models, there is a paucity of evidence exploring potential mechanism of VTEs in ICIs. Second, we review the incidence of ATE and VTE in patients receiving ICIs in the published literature. Finally, we discuss current limitations in understanding, areas of conflicting evidence, and approaches to further investigation.

A purified, fermented, extract of Triticum aestivum has lymphomacidal activity mediated via natural killer cell activation.

Non-Hodgkin lymphoma (NHL) affects over 400,000 people in the United States; its incidence increases with age. Treatment options are numerous and expanding, yet efficacy is often limited by toxicity, particularly in the elderly. Nearly 70% patients eventually die of the disease. Many patients explore less toxic alternative therapeutics proposed to boost anti-tumor immunity, despite a paucity of rigorous scientific data. Here we evaluate the lymphomacidal and immunomodulatory activities of a protein fraction isolated from fermented wheat germ. Fermented wheat germ extract was produced by fermenting wheat germ with Saccharomyces cerevisiae. A protein fraction was tested for lymphomacidal activity in vitro using NHL cell lines and in vivo using mouse xenografts. Mechanisms of action were explored in vitro by evaluating apoptosis and cell cycle and in vivo by immunophenotyping and measurement of NK cell activity. Potent lymphomacidal activity was observed in a panel of NHL cell lines and mice bearing NHL xenografts. This activity was not dependent on wheat germ agglutinin or benzoquinones. Fermented wheat germ proteins induced apoptosis in NHL cells, and augmented immune effector mechanisms, as measured by NK cell killing activity, degranulation and production of IFNγ. Fermented wheat germ extract can be easily produced and is efficacious in a human lymphoma xenograft model. The protein fraction is quantifiable and more potent, shows direct pro-apoptotic properties, and enhances immune-mediated tumor eradication. The results presented herein support the novel concept that proteins in fermented wheat germ have direct pro-apoptotic activity on lymphoma cells and augment host immune effector mechanisms.

A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma.

Lenalidomide, an immunomodulatory drug that the US Food and Drug Administration (FDA) approved for the treatment of multiple myeloma, 5q- myelodysplasia and mantle-cell lymphoma (MCL), has encouraging efficacy in other B-cell malignancies. Its unique mechanism of action is in part due to altering the tumor microenvironment and potentiating the activity of T and natural-killer (NK) cells. Impressive clinical activity and excellent tolerability allows broad applicability. Lenalidomide has been used in a wide range of B-cell malignancies for years, but in 2013, the FDA marked its approval as a single agent only in relapsed/refractory mantle-cell lymphoma. Perhaps most impressive is the efficacy of lenalidomide when combined with monoclonal antibodies. Impressive efficacy and toxicity profiles with the combination of lenalidomide and rituximab in B-cell lymphomas in both the upfront and relapsed/refractory setting may allow a shift in our current treatment paradigm in both indolent and aggressive non-Hodgkin lymphoma (NHL). This review will summarize the current data in the relapsed/refractory and front-line setting of NHL with single-agent lenalidomide as well as its use in combination with other agents.