Drug interactions with Bruton's tyrosine kinase inhibitors: clinical implications and management.

Bruton's tyrosine kinase (BTK) plays an essential role in B-cell development, differentiation and B-cell receptor (BCR) signaling. The use of Bruton's tyrosine kinase inhibitors (BTKi) in the treatment of lymphoid malignancies has dramatically increased, owing to both impressive efficacy and ease of administration. However, BTKi have a range of drug-drug and drug-food interactions, which may alter drug efficacy and/or increase toxicity. Healthcare professionals should be aware of the probability of drug interactions with BTKi and make recommendations accordingly. In this article, we discuss the relevant drug-drug and drug-food interactions associated with ibrutinib, acalabrutinib, and zanubrutinib, and provide clinical practice recommendations for managing these interactions based on the available literature.

Moxetumomab pasudotox: A first-in-class treatment for hairy cell leukemia.

Hairy cell leukemia is a rare indolent B-cell lymphoid malignancy. Durable remission can be obtained with purine analogues, but relapse is inevitable, and effective treatment options may be limited. Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin that has recently been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory hairy cell leukemia. Approval was based on a pivotal phase III study in this unique patient population. Rationale for use, clinical trial data, and current treatment recommendations are detailed. Common adverse effects are reviewed, and management strategies for select adverse effects are suggested. Implications for contemporary practitioners are also provided, as use of this novel agent is likely to increase as follow-up studies are reported.

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor.

Cabozantinib is an oral small-molecule multitargeted tyrosine kinase inhibitor (TKI) that may confer an advantage over other TKIs that target a single receptor. It was approved by the U.S. Food and Drug Administration for the treatment of both advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, and it is being investigated for a wide array of other malignancies. Rationale for use, clinical trial data, and current recommendations for cabozantinib in renal cell cancer, thyroid cancer, prostate cancer, hepatocellular cancer, and lung cancer are detailed in this article. Common adverse events are reviewed, and management strategies for select adverse events are discussed. Implications for contemporary practitioners are also provided because use of this novel agent is likely to increase as more studies are completed.

Comparison of two different formulas for body surface area in adults at extremes of height and weight.

BACKGROUND: Different equations for predicting body surface area have been derived. The DuBois and Mosteller body surface area equations are considered equivalent, but the accuracy in adult patients at extremes of height and weight is unknown. PURPOSE: To compare body surface area in patients at extremes of height and weight using both formulas to determine whether a difference affected chemotherapy dose. METHODS: Anthropometric data were extracted from the 2012 Centers for Disease Control and Prevention Vital and Health Statistics. Data for both males and females were examined. The 50th percentiles of weight and height were used to calculate the body surface area with both formulas. Calculations were repeated using the 5th through 95th percentiles for weight, then the 5th through 95th percentiles for height, and so forth until all extremes of height and weight were examined. Each body surface area was used to calculate a chemotherapy dose. A difference of ≥4.5% in dose was considered clinically significant. RESULTS: Differences were apparent in both males and females. Dosing differences were most apparent in patients in the 50th, 75th or 95th percentile for both height and weight. Differences are also noted in other percentiles, suggesting that patients of smaller stature may also be affected. CONCLUSION: Guidelines recommend full doses of chemotherapy for patients with curative intent but do not specify which body surface area formula is preferred. Our results imply that the Mosteller equation provides a greater chemotherapy dose, and this difference may be clinically significant in patients who are in the 50th to 95th percentiles for height, weight or both. Further study is necessary to validate these results and determine the impact on patient outcomes.

Off-Target Effects of BCR-ABL and JAK2 Inhibitors.

The advent of targeted oncolytic agents has created a revolution in the treatment of malignancies. Perhaps best exemplified in myeloproliferative neoplasms (MPN), the tyrosine kinase inhibitors, including inhibitors of BCR-ABL tyrosine kinase and JAK2, have dramatically changed outcomes in persons with MPN. However, clinically relevant dosing of these adenosine triphosphate-mimetic agents in humans leads to inhibition of numerous tyrosine kinases beyond those touted by drug manufacturers and studied in landmark clinical trials. These so-called off-target effects have been linked to both clinical efficacy and toxicity. Rational drug development and serendipitous discovery of drug molecules allows the clinician to select targeted oncolytic agents to treat a specific clinical diagnosis and/or avoid exacerbation of concomitant disease states due to effects upon signaling pathways. Understanding the off-target binding and effects upon signaling pathway of the agents approved for the treatment of MPN will empower the clinician to adroitly select pharmacotherapy, predict toxicities, and utilize these agents in clinical practice for indications beyond MPN.