Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial.

This analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325-0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395-1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151-0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days' therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

Veno-occlusive disease risk in pediatric patients with acute myeloid leukemia treated with gemtuzumab ozogamicin before allogeneic hematopoietic cell transplantation.

BACKGROUND: Gemtuzumab ozogamicin (GO) administered before allogeneic hematopoietic cell transplantation (alloHCT) has been linked to an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS). PROCEDURE: This retrospective analysis examined VOD/SOS risk and clinical outcomes in pediatric patients with acute myeloid leukemia who received myeloablative alloHCT in 2008-2011 with (n = 148) and without (n = 348; controls) prior GO exposure and were reported to the Center for International Blood and Marrow Transplant Research. RESULTS: Cumulative incidences (95% confidence interval [CI]) of VOD/SOS and severe VOD/SOS, respectively, at 100 days were 16% (11-23%) and 8% (4-13%) for GO-exposed patients and 10% (7-13%) and 3% (2-5%) for controls. With a median follow-up of approximately 7 years, the 5-year adjusted overall survival probability (95% CI) after alloHCT was 51% (43-58%) and 55% (50-60%) for GO-exposed patients and controls, respectively; three (4%) and one (<1%) deaths were attributed to VOD/SOS. In multivariate analyses, GO exposure was observed to be associated with an increased risk of VOD/SOS at 100 days, but was not associated with overall survival, disease-free survival, relapse, or nonrelapse mortality. CONCLUSIONS: Results suggest that GO treatment prior to alloHCT in pediatric patients may increase the risk of VOD/SOS but not death.

Glasdegib plus low-dose cytarabine for acute myeloid leukemia: Practical considerations from advanced practitioners and pharmacists.

OBJECTIVE: Acute myeloid leukemia (AML) is primarily a disease of older adults. These patients may not be candidates for intensive treatment, and there has been an ongoing need for treatment options for this group. We review the use of glasdegib, a hedgehog-pathway inhibitor available for use in combination with low-dose cytarabine (LDAC).Data Sources: PubMed and relevant congress abstracts were searched using the term "glasdegib". In addition, based on our experience with glasdegib, we considered treatment aspects of particular relevance to pharmacists and advanced practitioners.Data Summary: In a randomized phase II study, the combination of glasdegib plus LDAC demonstrated superior overall survival versus LDAC alone (hazard ratio 0.51, 80% confidence interval 0.39-0.67, p = 0.0004). The trial reported adverse events (AEs) of special relevance for older patients, such as hematologic events, gastrointestinal toxicity, and fatigue, as well as AEs associated with Hh-pathway inhibitors (alopecia, muscle spasms, dysgeusia). Educating patients about typical AEs can facilitate adherence as well as early AE identification and proactive management. For LDAC, which is a long-established therapy in AML, various stages of delivery need consideration, with attention to individual circumstances. Practical measures such as dispensing a longer supply can reduce the number of return clinic visits, providing a meaningful difference for many patients. CONCLUSIONS: Pharmacists and advanced practitioners play important roles in treatment with glasdegib plus LDAC. Ultimately, framing plans for treatment delivery within the individual circumstances of each patient may enable them to stay on therapy longer, giving them the greatest potential to achieve benefit.

Prior Gemtuzumab Ozogamicin Exposure in Adults with Acute Myeloid Leukemia Does Not Increase Hepatic Veno-Occlusive Disease Risk after Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

Gemtuzumab ozogamicin (GO) therapy before allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years were reported to the Center for International Blood and Marrow Transplant Research. Adults with AML who had GO exposure before myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (control subjects). One hundred thirty-seven patients with GO exposure and 548 matched control subjects who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median ∼8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control groups (P = .97). Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI], 1% to 7%) and 3% (95% CI, 1% to 6%) in GO-exposed patients and 3% (95% CI, 2% to 5%) and 1% (95% CI, 0% to 2%) in control subjects. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI, 5% to 72%) and 27% (95% CI, 11% to 47%; P = .78). In multivariate analyses, GO exposure before alloHCT was not associated with an increased risk of VOD/SOS (odds ratio, 1.10; P = .85) or death (hazard ratio, 1.08; P = .57). Three deaths (3%) in the GO group and 3 deaths (<1%) in the control group were attributed to VOD/SOS. Our results suggest that GO treatment before myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.

A quality-adjusted survival time without symptoms or toxicities analysis of glasdegib plus low-dose cytarabine versus low-dose cytarabine as initial therapy for acute myeloid leukemia in patients who are not considered candidates for intensive chemotherapy.

BACKGROUND: In a randomized study, glasdegib (a hedgehog inhibitor) plus low-dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) approach was used to evaluate comparative quality-adjusted survival. METHODS: Overall survival was partitioned into the following: time with any treatment-emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q-TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility-adjusted time. RESULTS: At 20 months of follow-up, the survival probabilities for the glasdegib-LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib-LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8-5.2 months) and TOX (+0.8 months; 95% CI, 0.1-1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, -1.9 to 2.3 months). Q-TWiST was 4.0 months (95% CI, 2.1-5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality-adjusted survival with respect to LDAC. Results were robust to the length of follow-up (6-24 months) and remained significant when all adverse events, regardless of grade, were included. CONCLUSIONS: These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively "good" health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option.

A real-world, cross-sectional, community survey of symptoms and health-related quality of life of adults with acute myeloid leukemia.

Aim: We used Adelphi Real World Disease-Specific Programme data to characterize adults with newly diagnosed or relapsed/refractory de novo acute myeloid leukemia (AML). Materials & methods: Community-practice hematologists/oncologists completed patient record forms for their regular AML patients. Patients were invited to complete patient self-completion forms including 3-Level EuroQol 5-Dimensions (EQ-5D-3L) and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaires. Results: Physicians provided patient record forms for 389 patients (339 newly diagnosed, 50 relapsed/refractory); 68 patients completed patient self-completion forms. Mean EQ-5D visual-analog scale and index and FACT-General scores were significantly lower than US population norms (p < 0.0001); health-related quality of life (HRQoL) scores were generally lower than 11 other cancers. Conclusion: HRQoL impairment is grave in AML. Efforts are needed to improve HRQoL in affected patients.

Real-World Treatment Patterns and Costs for Patients with Renal Cell Carcinoma Initiating Treatment with Sunitinib and Pazopanib.

BACKGROUND: Sunitinib and pazopanib are among the most prescribed targeted therapies for the systemic management of advanced renal cell carcinoma (RCC), but published cost comparisons between the 2 agents are few and limited by methodological and population differences. Also, sunitinib is administered on a 4-week on/2-week off cycle, and pazopanib is taken continuously. Thus, appropriate use and cost comparisons between the 2 drugs require methodological approaches to account for these differences. One way to accomplish this is to substitute expected for observed days supply. Recognizing the effects of nonrepresentative days supply values is important for assessing real-world treatment patterns and costs. OBJECTIVES: To (a) characterize demographic and clinical characteristics among patients with RCC newly initiating sunitinib or pazopanib, using a large administrative claims dataset; (b) characterize treatment patterns, persistence, and costs for each treatment group; and (c) assess the effect on treatment patterns and costs for sunitinib by substituting 42 days for prescriptions with 28- or 30-day supplies to account for sunitinib's 4-week on/2-week off dosing schedule. METHODS: This was a retrospective cohort study using health care claims data from the Truven MarketScan Research Databases, which include enrollment information and medical and pharmacy claims. Baseline patient demographic and clinical characteristics and treatment patterns (continuation, discontinuation, switching, or interruption; days supply; and persistence) were compared. Health care costs were calculated as mean daily index medication costs and as total, medical, and medication (all-cause and RCC-related) costs over the 12 months post-index period. Inclusion criteria were continuous health plan enrollment between 6 months pre-index and 12 months post-index; no RCC medications 6 months pre-index; ≥ 2 RCC diagnoses within ±180 days of index; and age ≥ 20 years. For demographic and clinical characteristics, treatment patterns, and costs, means (± standard deviations) for continuous data and relative frequencies for categorical data were reported. Chi-square tests or Student t-tests were used to evaluate differences other than costs. A generalized linear model with gamma distribution and log link was used for evaluating costs, controlling for patient demographic and pre-index clinical characteristics, persistence days, and index medication. All statistical tests were 2-tailed with significance set at P < 0.05 for all comparisons except for interactions with significance set at P < 0.10. The effects of substituting 42 days supply for sunitinib prescription records with 28 or 30 days supply were determined. RESULTS: In total, 609 (15.1% of the sunitinib overall sample) sunitinib patients and 183 (8.3% of the pazopanib overall sample) pazopanib patients were included. Demographic and clinical characteristics were similar for each treatment cohort. The persistence periods and number of prescriptions filled were also similar. Without substitution, significant differences were observed between treatment groups in patterns of index medication use (overall P = 0.0409), with fewer patients taking sunitinib continuing treatment than patients taking pazopanib. However, with substitution, treatment patterns differed significantly (overall P = 0.0026), but with more sunitinib patients than pazopanib patients continuing treatment. Without substitution, unadjusted daily mean index medication costs were significantly different for sunitinib ($216) versus pazopanib ($177, P < 0.0001). Substitution of sunitinib days supply eliminated the significant differences in daily index medication costs between treatment groups. The 1-year RCC-related and all-cause medication, medical, and total unadjusted costs were not significantly different between treatment groups, and substitution had no effect on these costs. After adjustment for possible confounding factors, these cost results were similar to those found with unadjusted analyses. CONCLUSIONS: In this study, patients with RCC who were initiating sunitinib and pazopanib had similar demographic and clinical characteristics and drug persistence patterns. The effect of substituting days supply values was demonstrated as an approach to considering differences in dosing cycles. Substitution significantly reduced sunitinib mean daily index medication costs and eliminated or reversed the direction of significant differences in costs between drugs during the persistence period. No significant differences were observed in unadjusted or adjusted 1-year costs. DISCLOSURES: This study was funded and conducted fully by Pfizer. All authors are employees of Pfizer. This work was presented in part as posters at the 2015 Genitourinary Cancers Symposium, of the American Society of Clinical Oncology; Rosen Shingle Creek, Orlando, FL; February 26-28, 2015, and the 20th Annual International Meeting of the International Society for Pharmacoeconomics and Outcomes Research; Philadelphia, PA; May 16-20, 2015. All authors contributed to study concept and design and to data interpretation. Mardekian was primarily responsible for data collection, along with Harnett. MacLean and Harnett worked on the manuscript, which was revised by MacLean and Mardekian.

Expression of metabotropic glutamate receptor 8 in autonomic cell groups of the medulla oblongata of the rat.

Metabotropic glutamate receptors (mGluRs) in the medulla oblongata have been suggested to have a functional role in the regulation of cardiovascular baroreflexes. The present study examines the localization of mGluR8 autonomic nuclei of the medulla of the rat. mGluR8 immunoreactivity was observed in the cell bodies and/or processes of the dorsolateral, interstitial, medial, intermediate, ventral, ventrolateral, subpostremal, commissural, parvicellular and gelatinosus subnuclei of the nucleus tractus solitarius (NTS). The intensity of mGluR8 staining was highest in the commissural and interstitial subnuclei at the level of the area postrema. Commissural NTS is involved in regulation of baro-, and chemo-reflexes whereas the interstitial nucleus mediates respiratory reflexes. In the area postrema, diffuse staining was observed in the cell bodies, dendrites and fibers of the dorsal and central regions. In vagal outflow nuclei, mGluR8 immunoreactivity was observed in: (1). the cell bodies and processes of the dorsal motor nucleus of the vagus (DMN) throughout the rostro-caudal extent; and (2). the cell bodies and fibers throughout the rostro-caudal extent of the dorsal and ventral division the nucleus ambiguus (NA). Staining in the ventrolateral medulla was restricted to regions ventral to the nucleus ambiguus and dorsal to the lateral reticulate nucleus. The present study is the first to provide a detailed mapping of mGluR8 within the autonomic nuclei of the medulla and suggests that this subtype may be involved in shaping synaptic transmission in these central nuclei.

Synthesis and two-photon photolysis of 6-(ortho-nitroveratryl)-caged IP3 in living cells.

The synthesis of a photolabile derivative of inositol-1,4,5-trisphosphate (IP3) is described. This new caged second messenger (6-ortho-nitroveratryl)-IP3 (6-NV-IP3) has an extinction coefficient of 5000 M(-1) cm(-1) at 350 nm, and a quantum yield of photolysis of 0.12. Therefore, 6-NV-IP3 is photolyzed with UV light about three times more efficiently than the widely used P(4(5))-1-(2-nitrophenyl)ethyl-caged IP3 (NPE-IP3). 6-NV-IP3 has a two-photon cross-section of about 0.035 GM at 730 nm. This absorbance is sufficiently large for effective two-photon excitation in living cells at modest power levels. Using near-IR light (5 mW, 710 nm, 80 MHz, pulse-width 70 fs), we produced focal bursts of IP3 in HeLa cells, as revealed by laser-scanning confocal imaging of intracellular Ca2+ concentrations. Therefore, 6-NV-IP3 can be used for efficient, subcellular photorelease of IP3, not only in cultured cells but also, potentially, in vivo. It is in the latter situation that two-photon photolysis should reveal its true forte.