Evaluation of the impact of thyroiditis development in patients receiving immunotherapy with programmed cell death-1 inhibitors.

PURPOSE: We evaluated if the development of thyroiditis in patients who received treatment with immune checkpoint inhibitors across various tumor types was associated with tumor response. METHODS: In this retrospective, single-center, cross-sectional study, patients with various tumor types who received treatment with nivolumab or pembrolizumab as standard of care were evaluated. The primary endpoint was to evaluate the objective response rate in patients who developed thyroiditis compared with patients who did not develop thyroiditis. Secondary endpoints included disease control rate, progression-free survival, and overall survival. RESULTS: One hundred and three patients were included for analysis with a median follow-up duration of 12.8 months (range, 4.0-21.6). The data cutoff was 31 December 2016. The objective response rate was 38.2% among the 34 patients in the thyroiditis group and 17.4% in the 69 patients in the non-thyroiditis group (p = 0.028). Progression-free survival was longer in the thyroiditis group than in the non-thyroiditis group. The median progression-free survival was 10.1 months (95% CI, 1.6-18.5) in the thyroiditis group and 3.7 months (95% CI, 2.5-4.9) in the non-thyroiditis group (hazard ratio, 0.45; 95% CI, 0.27-0.76; p = 0.002). CONCLUSION: Patients with various tumor types who received treatment with immune checkpoint inhibitors and developed thyroiditis had a higher objective response rate than those who did not develop thyroiditis. The development of thyroiditis should be investigated further in the context of prospective randomized trials as a surrogate marker for tumor response to treatment with immune checkpoint inhibitor therapies.

Identifying opportunities to advance practice at a large academic medical center using the ASHP Ambulatory Care Self-Assessment Tool.

PURPOSE: The use of the ASHP Ambulatory Care Self-Assessment Tool to advance pharmacy practice at 8 ambulatory care clinics of a large academic medical center is described. SUMMARY: The ASHP Ambulatory Care Self-Assessment Tool was developed to help ambulatory care pharmacists assess how their current practices align with the ASHP Practice Advancement Initiative. The Henry Ford Hospital Ambulatory Care Advisory Group (ACAG) opted to use the "Practitioner Track" sections of the tool to assess pharmacy practices within each of 8 ambulatory care clinics individually. The responses to self-assessment items were then compiled and discussed by ACAG members. The group identified best practices and ways to implement action items to advance ambulatory care practice throughout the institution. Three recommended action items were common to most clinics: (1) identify and evaluate solutions to deliver financially viable services, (2) develop technology to improve patient care, and (3) optimize the role of pharmacy technicians and support personnel. The ACAG leadership met with pharmacy administrators to discuss how action items that were both feasible and deemed likely to have a medium-to-high impact aligned with departmental goals and used this information to develop an ambulatory care strategic plan. This process informed and enabled initiatives to advance ambulatory care pharmacy practice within the system. CONCLUSION: The ASHP Ambulatory Care Self-Assessment Tool was useful in identifying opportunities for practice advancement in a large academic medical center.

Similar incidence of typhlitis in patients receiving various doses of daunorubicin or idarubicin as induction for acute myeloid leukemia.

BACKGROUND: The current standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) is an anthracycline plus cytarabine. Both anthracyclines and cytarabine have been associated with the development of typhlitis, a serious adverse event characterized by inflammation of the bowel wall in patients with profound neutropenia, diagnosed by abdominal CT imaging and clinical symptoms. Given the paucity of available data, the aim of our study was to determine the incidence of typhlitis among AML patients receiving induction chemotherapy with idarubicin 12 mg/m2 (IDA), daunorubicin 60 mg/m2 (DNA60), or daunorubicin 90 mg/m2 (DNA90). METHODS: Adult patients with AML or MDS receiving either daunorubicin or idarubicin along with cytarabine as part of their induction regimen between January 1, 2009 and June 30, 2013 were included. A definition of typhlitis required CT confirmation of inflammation of the cecum only, defined as non-tumoral bowel wall thickening with or without pericolonic fat infiltration and fluid, according to CTCAE version 4.03 along with clinical symptoms. The primary endpoint was to determine the incidence of typhlitis among IDA, DNA60, and DNA90. Secondary endpoints included characterizing the variability of doses used in induction therapy and identifying any potential risk factors for the development of typhlitis. RESULTS: The overall incidence of typhlitis was 2.5%. When the definition was broadened to include the colitis, enteritis, or enterocolitis, the incidence increased. The inter-reliability ratings of the 2 radiologists' evaluations for each definition indicated substantial agreement (0.803 cecum, 0.834 ileocecal region only, and 0.752 enterocolitis). Neither the anthracycline chosen, nor the dose had a statistically significant impact on the incidence of typhlitis. In patients that developed typhlitis, all patients had clinical symptoms in addition to documented cecum inflammation on CT scan. All patients were managed conservatively with intravenous broad-spectrum antibiotics. CONCLUSION: To our knowledge, this is the first study to compare the incidence of typhlitis in adult patients receiving idarubicin or daunorubicin for the treatment of AML. The cumulative incidence of typhlitis was similar to the currently published literature, with the incidence being similar irrespective of the anthracycline chosen or dose. All patients were managed conservatively with broad-spectrum antibiotics. A more definitive definition of typhlitis may help clinicians identify affected patients sooner and choose appropriate targeted therapy.

Immunotherapy: A New Approach to Treating Multiple Myeloma with Daratumumab and Elotuzumab.

OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of daratumumab and elotuzumab for the treatment of relapsed refractory multiple myeloma (RRMM). DATA SOURCES: A literature search of MEDLINE, PubMed, the US National Institutes of Health Clinicaltrials.gov, the Food and Drug administration, and relevant meeting abstracts was conducted using the terms daratumumab, elotuzumab, multiple myeloma, anti-CD38, HuMax-CD38, HuLuc63, SLAMF7, and anti-CS1 STUDY SELECTION/DATA EXTRACTION: Human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daratumumab and elotuzumab for MM were identified. DATA SYNTHESIS: Daratumumab (anti-CD38) and elotuzumab (anti-CS1) have been recently FDA approved for the treatment of RRMM after showing efficacy in clinical trials. Elotuzumab approval was based on phase III data, and daratumumab gained accelerated approval based on phase I/II trials. Daratumumab has demonstrated significant single-agent activity, with an overall response rate (ORR) of 36% in patients with a median of 4 prior lines of therapy. Elotuzumab has not been shown to have single-agent activity. But the efficacy of both these antibodies in combination with lenalidomide and dexamethasone in RRMM showed an ORR exceeding 80%. Tolerability of elotuzumab and daratumumab seems to be acceptable, with the most common adverse event being infusion reactions. CONCLUSION: Daratumumab and elotuzumab have shown encouraging results in RRMM that led to their FDA approval. Both are well tolerated with minimal toxicities. Phase III clinical trials will define optimal combination and place in therapy of daratumumab and elotuzumab.

Role of Histone Deacetylase Inhibitors in Relapsed Refractory Multiple Myeloma: A Focus on Vorinostat and Panobinostat.

Multiple myeloma is a neoplastic plasma cell disorder that is characterized by clonal proliferation of plasma cells in the bone marrow, monoclonal protein in the blood and/or urine, and associated organ dysfunction and biomarkers. There have been multiple recent advances in the relapsed and refractory setting. Major steps forward include the introduction of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide) in various combinations. These drugs have changed the management of multiple myeloma and have extended overall survival in the past decade. Established curative therapy is not yet available for patients diagnosed with multiple myeloma, supporting the development of new treatment targets. Histone deacetylase inhibitors have multiple proposed mechanisms of action in the treatment of multiple myeloma. Both vorinostat and panobinostat have demonstrated some activity against multiple myeloma, and due to the benefits reported with panobinostat, the U.S. Food and Drug Administration has recently approved the drug for the treatment of relapsed and refractory multiple myeloma. In this article, we describe the pharmacology, efficacy, and toxicity profile of vorinostat and panobinostat and their possible place in therapy.

The promising impact of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the management of lymphoid malignancies.

Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Bruton's tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B-cell signaling. Dysregulated Btk results in uncontrolled B-lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment-naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms.