Glasdegib is a Hedgehog pathway inhibitor. This phase II, randomized, open-label, multicenter study (ClinicalTrials.gov, NCT01546038) evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg (oral, QD) was administered continuously in 28-day cycles; LDAC 20 mg (subcutaneous, BID) was administered for 10 per 28 days. Patients (stratified by cytogenetic risk) were randomized (2:1) to receive glasdegib/LDAC or LDAC. Blank vidachi zadanij smezhnim otdelam. The primary endpoint was overall survival. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median (80% confidence interval [CI]) overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC (hazard ratio, 0.51; 80% CI, 0.39–0.67, P = 0.0004).

Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission ( P. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are clinically and genetically heterogeneous myeloid stem cell disorders with a median age at onset of about 67 years []. Older patients with AML or high-risk MDS have few treatment options and are often not eligible for intensive chemotherapy due to comorbidities and a higher incidence of high-risk biological features, which often lead to chemotherapy resistance. This population is thus treated with less-aggressive therapies, including low-dose cytarabine (LDAC) and hypomethylating agents. However, studies with LDAC have demonstrated low response rates (7–18%), with median overall survival (OS) of 5 months in older patients [,,,,,]. With the hypomethylating agent decitabine, the response rate (18%) and median OS (7.7 months) were only slightly improved []. Therefore, novel therapeutic strategies are needed to achieve higher response rates, more durable responses, and improved survival in this hard-to-treat population.

The Hedgehog signaling pathway plays a key role in embryonic development and is typically silenced in adults []. Aberrant Hedgehog signaling has been implicated in hematologic malignancies and is critical for leukemia stem-cell survival and expansion [,,]. Overexpression of Hedgehog pathway components was observed in chemotherapy-resistant myeloid leukemia cells, and pharmacologic inhibition of the Hedgehog pathway substantially enhanced the sensitivity to chemotherapy []. These findings provide the rationale for combining an inhibitor of Hedgehog pathway with chemotherapy.

Download Foxit PDF Editor 3.0.5.0. Edit content in any PDF file. Foxit PDF Editor is the application you need if you want to modify any PDF file. El corte de Oro - Download as PDF File (.pdf) or view presentation slides online. Test score sheet. Tomando como base la Regla de Oro, ingenieros alemanes inventaron y desarrollaron el Sistema Lutterloh, un sistema de corte a la medida conocido ahora como el Corte.

Glasdegib is a potent and selective oral inhibitor of Hedgehog signaling through binding to Smoothened. In preclinical studies, glasdegib produced rapid and complete tumor regression as a single agent or in combination with chemotherapy, reduced expression of key leukemia stem-cell regulators, and decreased leukemia stem-cell populations in patient-derived AML cells [, ]. Glasdegib monotherapy demonstrated preliminary clinical activity in phase I trials in patients with hematologic malignancies [, ]. Therefore, glasdegib plus chemotherapy represents a mechanistically attractive treatment approach for patients with AML or MDS.

A phase Ib/II, open-label, international, multicenter study evaluated safety and efficacy of glasdegib plus intensive chemotherapy (cytarabine and daunorubicin), LDAC, or decitabine in previously untreated patients with AML or high-risk MDS [, ]. Here we describe results from the ongoing phase II, randomized, open-label portion of the study that assessed the efficacy and safety of glasdegib plus LDAC (glasdegib/LDAC) versus LDAC in patients with AML or high-risk MDS who were not eligible for intensive chemotherapy. Patients Eligible patients were aged ≥55 years with newly diagnosed, previously untreated AML or high-risk MDS according to the World Health Organization (WHO) 2008 Classification []. For a diagnosis of high-risk MDS RAEB-2 (refractory anemia with excess blasts 2), the patient must have 10–19% bone marrow blasts. Patients had to have a known cytogenetic profile at study entry and considered not suitable for intensive chemotherapy, defined by ≥1 of the following criteria []: age ≥75 years; serum creatinine >1.3 mg/dL, severe cardiac disease (e.g., left ventricular ejection fraction  0.92. The futility boundary would be calculated accordingly using the chosen spending function and number of OS events actually observed at the IA.