Cryptococcal infections in two patients receiving ibrutinib therapy for chronic lymphocytic leukemia.

Cryptococcal infections are responsible for significant morbidity and mortality in immunocompromised patients. Reports of these infections in patients on small molecular kinase inhibitors have not been widely reported in clinical trials. We describe one case of cryptococcal meningoencephalitis and one case of cryptococcal pneumonia in two patients who were receiving ibrutinib for chronic lymphocytic leukemia. Despite different sites of cryptococcal infection, both patients had similar presentations of acute illness. Patient 1 was worked up for health care-associated pneumonia, as well as acute sinusitis prior to the diagnosis of cryptococcal meningoencephalitis. He also had a more complex past medical history than patient 2. Patient 2 developed atrial fibrillation from ibrutinib prior to admission for presumed health care-associated pneumonia. Cryptococcal antigen testing was done sooner in this patient due to patient receiving high-dose steroids for the treatment of underlying hemolytic anemia. We conclude that patients who develop acute illness while receiving ibrutinib should be considered for cryptococcal antigen testing.

Homoleptic nickel(II) complexes of redox-tunable pincer-type ligands.

Different synthetic methods have been developed to prepare eight new redox-active pincer-type ligands, H(X,Y), that have pyrazol-1-yl flanking donors attached to an ortho-position of each ring of a diarylamine anchor and that have different groups, X and Y, at the para-aryl positions. Together with four previously known H(X,Y) ligands, a series of 12 Ni(X,Y)2 complexes were prepared in high yields by a simple one-pot reaction. Six of the 12 derivatives were characterized by single-crystal X-ray diffraction, which showed tetragonally distorted hexacoordinate nickel(II) centers. The nickel(II) complexes exhibit two quasi-reversible one-electron oxidation waves in their cyclic voltammograms, with half-wave potentials that varied over a remarkable 700 mV range with the average of the Hammett σ(p) parameters of the para-aryl X, Y groups. The one- and two-electron oxidized derivatives [Ni(Me,Me)2](BF4)n (n = 1, 2) were prepared synthetically, were characterized by X-band EPR, electronic spectroscopy, and single-crystal X-ray diffraction (for n = 2), and were studied computationally by DFT methods. The dioxidized complex, [Ni(Me,Me)2](BF4)2, is an S = 2 species, with nickel(II) bound to two ligand radicals. The mono-oxidized complex [Ni(Me,Me)2](BF4), prepared by comproportionation, is best described as nickel(II) with one ligand centered radical. Neither the mono- nor the dioxidized derivative shows any substantial electronic coupling between the metal and their bound ligand radicals because of the orthogonal nature of their magnetic orbitals. On the other hand, weak electronic communication occurs between ligands in the mono-oxidized complex as evident from the intervalence charge transfer (IVCT) transition found in the near-IR absorption spectrum. Band shape analysis of the IVCT transition allowed comparisons of the strength of the electronic interaction with that in the related, previously known, Robin-Day class II mixed valence complex, [Ga(Me,Me)2](2+).

Risk of Cancer-Associated Thrombosis and Bleeding in Veterans With Malignancy Who Are Receiving Direct Oral Anticoagulants.

The low incidence of venous thromboembolism formation in this study and similar rates of bleeding in other clinical trials indicate that direct oral anticoagulant agents are safe alternatives in patients with cancer.

Vemurafenib and ipilimumab: new agents for metastatic melanoma.

PURPOSE: The development and place in therapy of vemurafenib and ipilimumab for the treatment of metastatic melanoma are reviewed. SUMMARY: Vemurafenib is an adenosine triphosphate-competitive, reversible, and highly selective BRAF kinase inhibitor targeted at BRAF-V600E and is a first-line option for patients with BRAF-mutation-positive disease. Vemurafenib has clinically significant antitumor activity in metastatic melanoma, and response rates and overall and progression-free survival rates are improved when compared with dacarbazine. Responses also occur quickly, often within days to weeks of starting treatment. Disadvantages of vemurafenib include the short duration of response; significant skin toxicities, including skin cancers and severe photosensitivity; the need for long-term daily administration; and the potential for drug interactions. Ipilimumab is a fully human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 to enhance and prolong T-cell responses to elicit antitumor activity. Clinical trials have demonstrated the superiority of ipilimumab in terms of overall survival when compared with an immune stimulator and placebo. While the rate of response to ipilimumab is low, responses tended to be more durable than those achieved with vemurafenib. A disadvantage of ipilimumab is that a response may require months, making ipilimumab inappropriate as monotherapy for patients with symptomatic disease. Additional disadvantages are the adverse-effect profile and the requirement of enrollment in the risk evaluation and mitigation strategy program. CONCLUSION: Vemurafenib and ipilimumab are important advances in the treatment of metastatic melanoma. Benefit is typically short lived for vemurafenib and uncommon for ipilimumab. Neither agent is curative, and clinical trials remain an alternative first-line treatment option.

Vandetanib: a novel targeted therapy for the treatment of metastatic or locally advanced medullary thyroid cancer.

PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety and tolerability, drug and food interactions, cost, and place in therapy of vandetanib are reviewed. SUMMARY: Vandetanib is a small-molecule inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and receptor tyrosine kinase signaling pathways, which are involved in the pathogenesis of medullary thyroid cancer (MTC). Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Vandetanib was evaluated in a randomized, placebo-controlled, double-blind Phase III study comparing vandetanib with placebo in adult patients with unresectable locally advanced or metastatic hereditary or sporadic MTC. Vandetanib demonstrated a statistically significant longer progression-free survival (predicted median of 30.5 months) compared with placebo (median of 19.3 months) (hazard ratio, 0.46; 95% confidence interval, 0.31-0.69; p = 0.0001). The most commonly observed adverse effects of vandetanib include nausea, diarrhea, headache, rash, prolongation of the Q-T interval, and hypertension. Because it can prolong the Q-T interval, vandetanib is contraindicated for use in patients with serious cardiac complications, including congenital long QT syndrome, bradyarrhythmias, uncompensated heart failure, and a history of torsades de pointes. CONCLUSION: Vandetanib has been shown to be more effective than placebo in the treatment of advanced MTC; however, it has not been compared with radiation, resection, or embolization. Vandetanib also has significant and fairly common cardiac toxicities. The cost, benefits, and risks of vandetanib for patients with MTC should be weighed, as alternative treatments remain an option for most patients.