Prolonged complete response to adjuvant tepotinib in a patient with newly diagnosed disseminated glioblastoma harboring mesenchymal-epithelial transition fusion.

The prognosis of patients with glioblastoma (GBM) remains poor despite current treatments. Targeted therapy in GBM has been the subject of intense investigation but has not been successful in clinical trials. The reasons for the failure of targeted therapy in GBM are multifold and include a lack of patient selection in trials, the failure to identify driver mutations, and poor blood-brain barrier penetration of investigational drugs. Here, we describe a case of a durable complete response in a newly diagnosed patient with GBM with leptomeningeal dissemination and PTPRZ1-MET fusion who was treated with tepotinib, a brain-penetrant MET inhibitor. This case of successful targeted therapy in a patient with GBM demonstrates that early molecular testing, identification of driver molecular alterations, and treatment with brain-penetrant small molecule inhibitors have the potential to change the outcome in select patients with GBM.

Pharmacologic management of myelofibrosis.

Myelofibrosis is a BCR-ABL-negative myeloproliferative neoplasm characterized by abnormal hematopoiesis. Alterations to the Janus kinase-signal transducer and activator of transcription pathway result in dysregulation of gene transcription and cell proliferation. Patients with symptomatic myelofibrosis present with a variety of signs and symptoms including, but not limited to myelosuppression, marked splenomegaly, abdominal discomfort, fatigue, and blood transfusion-dependence. Traditional myelosuppressive therapies including hydroxyurea, azacitidine, and cladribine aim to reduce constitutional symptoms and control the burden of disease. Immunomodulators can potentially reverse anemia associated with myelofibrosis, but are poorly tolerated by most patients. The novel Janus kinase 2 (JAK2) inhibitor, ruxolitinib, has demonstrated marked improvements to constitutional symptoms and splenomegaly. While survival benefit has not yet been demonstrated, continued research into pharmacologic management of myelofibrosis offers the promise of altering the course of disease progression.

Carfilzomib and pomalidomide: recent advances in the treatment of multiple myeloma.

Multiple myeloma is a hematologic malignancy characterized by plasma cell clonal expansion as well as end-organ damage due to increased levels of monoclonal proteins in both the plasma and urine. The clinical syndrome is characterized by hypercalcemia, renal insufficiency, anemia, and bone involvement that leads to pathologic fractures. This progressive disease can result in significant patient morbidity and mortality. Despite advances with treatment options and autologous stem cell transplantation, multiple myeloma remains incurable. Current front-line therapies include proteasome inhibitors, immunomodulators, anthracyclines, and steroids. Due to the advent of the immunomodulatory agents thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib, overall survival in patients with multiple myeloma has improved greatly. However, once patients progress through front-line therapy and have relapsed or refractory disease, treatment options have historically been very limited. Carfilzomib, a second-generation proteasome inhibitor, has shown impressive response rates as a single agent in the relapsed and refractory patient setting; this includes patients who are refractory to previous bortezomib therapy. In addition, a third-generation immunomodulator, pomalidomide, has also shown promising results in a similar patient population, including those patients who have been shown to be refractory to lenalidomide and bortezomib. Adverse effects of both of these medications have been considered tolerable in the relapsed or refractory population, especially considering the benefits that have been shown. Continuing clinical research will reveal the utility of these agents in combination regimens or in a front-line setting for patients with multiple myeloma.