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.

Utilization patterns for oral oncology medications in a specialty pharmacy cycle management program.

BACKGROUND: The cycle management program (CMP) was implemented in 2008 at a national specialty pharmacy with a focus on providing specialized counseling and monitoring for patients on select oral oncology medications. The program now includes nine medications: bexarotene, dasatinib, erlotinib, everolimus, nilotinib, pazopanib, sorafenib, sunitinib, and vorinostat. Patients receive frequent assessments to encourage adherence, identify adverse events, and track discontinuations through a pharmacist outreach at the initiation of therapy, day 10 and 20 of the first month, then monthly thereafter. The use of oral agents is increasing in cancer patients, shifting away from regimens exclusively involving intravenous chemotherapy. This offers advantages for patients in terms of convenience, but introduces risk as patients become more responsible for the administration and monitoring of the medications. PURPOSE: To evaluate utilization patterns of the oral oncology medications in the CMP including adverse event occurrence, medication discontinuations, and adherence markers. METHODS: This study is a retrospective review of patient-reported data from the CMP assessments completed in 2013. Data collected include adverse events and grades, adherence markers, and discontinuation rates. A total of 1163 assessments were reviewed from 557 patients. The assessments included in the analysis were the initial assessment, 10-day assessment, 20-day assessment, and the first monthly follow-up assessment, which encompasses the first two months of therapy. RESULTS: A total of 1453 adverse events were reported. Adverse events were cited as the reason for 39% of discontinuations and 28% of missed/held doses. A total of 101 discontinuations were reported across the nine CMP medications based on the first two months of data. Missed or held doses were reported in 130 assessments. CONCLUSIONS: Patient engagement and pharmacist interventions, through programs such as the CMP, are important to help patients manage these complex, high-risk medications.

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.

Analysis of gene expression in a developmental context emphasizes distinct biological leitmotifs in human cancers.

BACKGROUND: In recent years, the molecular underpinnings of the long-observed resemblance between neoplastic and immature tissue have begun to emerge. Genome-wide transcriptional profiling has revealed similar gene expression signatures in several tumor types and early developmental stages of their tissue of origin. However, it remains unclear whether such a relationship is a universal feature of malignancy, whether heterogeneities exist in the developmental component of different tumor types and to which degree the resemblance between cancer and development is a tissue-specific phenomenon. RESULTS: We defined a developmental landscape by summarizing the main features of ten developmental time courses and projected gene expression from a variety of human tumor types onto this landscape. This comparison demonstrates a clear imprint of developmental gene expression in a wide range of tumors and with respect to different, even non-cognate developmental backgrounds. Our analysis reveals three classes of cancers with developmentally distinct transcriptional patterns. We characterize the biological processes dominating these classes and validate the class distinction with respect to a new time series of murine embryonic lung development. Finally, we identify a set of genes that are upregulated in most cancers and we show that this signature is active in early development. CONCLUSION: This systematic and quantitative overview of the relationship between the neoplastic and developmental transcriptome spanning dozens of tissues provides a reliable outline of global trends in cancer gene expression, reveals potentially clinically relevant differences in the gene expression of different cancer types and represents a reference framework for interpretation of smaller-scale functional studies.

High incidence, early onset of histiocytic sarcomas in mice with Hertwig's anemia.

OBJECTIVE: Histiocytic sarcoma (HS) is a rare, rapidly disseminated, usually lethal tumor in humans. Treatment specific for HS has not been developed primarily due to deficiencies of appropriate animal models with high incidence/early onset. Mice with Hertwig's anemia (an/an) provide a potential model. METHODS: Here, we compare HS susceptibility in an/an and unaffected control mice maintained on three genetic backgrounds. As a potential therapeutic measure, genetically marked bone marrow is transplanted between high and low susceptibility animals. RESULTS: HS is detected earlier and the overall incidence is 15-fold higher in WBB6F1(F1)-an/an than in F1-+/?, B6-an/an and -+/? mice. Neither WB-an/an nor their normal WB-+/? littermates present with HS. Liver myelopoiesis and aneuploidy coexist with HS but the former is also rampant (33.7% incidence) in HS-free +/? and an/an mice. Marrow transplantation experiments provide evidence that (1) myelopoiesis is associated with HS and (2) early-onset/high-incidence HS is blocked by using late-onset F1-+/+ mice, as either donor or recipient. CONCLUSIONS: Homozygosity for an on an F1 genetic background is essential for high-incidence/early-onset HS; myelopoiesis and HS coexist; and therapeutic transplantation may be feasible.

Proteotypic classification of spontaneous and transgenic mammary neoplasms.

INTRODUCTION: Mammary tumors in mice are categorized by using morphologic and architectural criteria. Immunolabeling for terminal differentiation markers was compared among a variety of mouse mammary neoplasms because expression of terminal differentiation markers, and especially of keratins, provides important information on the origin of neoplastic cells and their degree of differentiation. METHODS: Expression patterns for terminal differentiation markers were used to characterize tumor types and to study tumor progression in transgenic mouse models of mammary neoplasia (mice overexpressing Neu (Erbb2), Hras, Myc, Notch4, SV40-TAg, Tgfa, and Wnt1), in spontaneous mammary carcinomas, and in mammary neoplasms associated with infection by the mouse mammary tumor virus (MMTV). RESULTS: On the basis of the expression of terminal differentiation markers, three types of neoplasm were identified: first, simple carcinomas composed exclusively of cells with a luminal phenotype are characteristic of neoplasms arising in mice transgenic for Neu, Hras, Myc, Notch4, and SV40-TAg; second, 'complex carcinomas' displaying luminal and myoepithelial differentiation are characteristic of type P tumors arising in mice transgenic for Wnt1, neoplasms arising in mice infected by the MMTV, and spontaneous adenosquamous carcinomas; and third, 'carcinomas with epithelial to mesenchymal transition (EMT)' are a characteristic feature of tumor progression in Hras-, Myc-, and SV40-TAg-induced mammary neoplasms and PL/J and SJL/J mouse strains, and display de novo expression of myoepithelial and mesenchymal cell markers. In sharp contrast, EMT was not detected in papillary adenocarcinomas arising in BALB/cJ mice, spontaneous adenoacanthomas, neoplasms associated with MMTV-infection, or in neoplasms arising in mice transgenic for Neu and Wnt1. CONCLUSIONS: Immunohistochemical profiles of complex neoplasms are consistent with a stem cell origin, whereas simple carcinomas might originate from a cell committed to the luminal lineage. In addition, these results suggest that the initiating oncogenic events determine the morphologic features associated with cancer progression because EMT is observed only in certain types of neoplasm.

Maternal beta-catenin and E-cadherin in mouse development.

The oocyte to embryo transition in metazoans depends on maternal proteins and transcripts to ensure the successful initiation of development, and the correct and timely activation of the embryonic genome. We conditionally eliminated the maternal gene encoding the cell adhesion molecule E-cadherin and partially eliminated the beta-catenin gene from the mouse oocyte. Oocytes lacking E-cadherin, or expressing a truncated allele of beta-catenin without the N-terminal part of the protein, give rise to embryos whose blastomeres do not adhere. Blastomere adhesion is restored after translation of protein from the wild-type paternal alleles: at the morula stage in embryos lacking maternal E-cadherin, and at the late four-cell stage in embryos expressing truncated beta-catenin. This suggests that adhesion per se is not essential in the early cleavage stage embryos, that embryos develop normally if compaction does not occur until the morula stage, and that the zona pellucida suffices to maintain blastomere proximity. Although maternal E-cadherin is not essential for the completion of the oocyte-to-embryo transition, absence of wild-type beta-catenin in oocytes does statistically compromise developmental success rates. This developmental deficit is alleviated by the simultaneous absence of maternal E-cadherin, suggesting that E-cadherin regulates nuclear beta-catenin availability during embryonic genome activation.