Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and ...safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45-88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.
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The significant morbidity and mortality associated with iron overload can be reduced by effective iron chelation. Magnetic resonance imaging ...(MRI) provides accurate and reproducible iron load assessment. The aim of this epidemiological study was to assess the prevalence and severity of cardiac and hepatic siderosis by MRI and to evaluate the impact of MRI on clinical management in patients with transfusion‐dependent anemia and non‐transfusion‐dependent thalassemia (NTDT). We enrolled 243 patients with myelodysplastic syndromes (MDS), thalassemia major (TM), NTDT or other chronic anemia. Overall, 10% and 48% had cardiac and hepatic siderosis, respectively. Mean liver iron concentration (LIC) was above target range in all groups; mean myocardial T2∗ was normal. Hepatic siderosis was more prevalent than myocardial siderosis in patients with MDS, occurring in 54.4% and 4.4% of patients, respectively. As also observed in patients with NTDT or other anemia, hepatic siderosis was present in a large proportion of MDS patients who were chelation naïve (57.7%), as well as in patients receiving iron chelation therapy (ICT) (52.4%), despite a lower transfusion load compared with TM. Correlation between LIC and serum ferritin was observed across diseases; however, not all patients requiring ICT could be identified with serum ferritin alone, as serum ferritin underestimated LIC in 4.4% and overestimated LIC in 7.5% of patients. Exploratory analyses showed serum ferritin thresholds for liver siderosis detected by MRI at approximately 300 ng/mL higher in MDS than in TM. Most patients reported low–medium adherence to ICT; MRI assessment led to change in ICT in 46% of evaluable patients, including 52% of MDS patients. Accurate organ iron monitoring by MRI facilitated appropriate initiation of chelation, dose optimization and clinical decision making.
Trial registration: ClinicalTrials.gov: NCT01736540.
Abstract
Patients with glioblastoma have a poor prognosis despite extensive efforts to develop new treatments. Standard of care for newly diagnosed patients is surgery followed by radiotherapy plus ...temozolomide. However, temozolomide only provides a clinical benefit to patients who have glioblastomas with a methylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promotor. Disease recurrence is inevitable and subsequent treatments have poor outcomes due to limited efficacy and a lack of established therapeutic regimens. 68GaGa-DOTA-TATE is a radioligand imaging agent that selectively binds to somatostatin receptors (SSTRs) and is used with positron emission tomography (PET) for the molecular imaging of SSTR-positive neuroendocrine tumors. Glioblastoma tumoral PET scans have shown moderate uptake of 68GaGa-DOTA-TATE. The radioligand therapy 177LuLu-DOTA-TATE has the same SSTR-targeted ligand and demonstrated promising clinical activity in a pilot study in patients with Grade III/IV gliomas. This Phase 1b open-label dose-finding study (NCT05109728) will determine the recommended 177LuLu-DOTA-TATE dose in three different groups of glioblastoma (newly diagnosed with methylated MGMT promoter group 1, newly diagnosed with unmethylated MGMT promoter group 2, and recurrent disease group 3). All participants will be scanned with 68GaGa-DOTA-TATE imaging during screening and, for each group, approximately 15 participants will be enrolled in consecutive cohorts of 3–6 participants. All participants will receive up to 6 administrations of 177LuLu-DOTA-TATE (initial dose 150 mCi with 3 provisional dose levels up to 250 mCi) using the Bayesian Optimal Interval design. Group 1 will receive 177LuLu-DOTA-TATE every 4 weeks with concomitant radiotherapy and temozolomide, followed by temozolomide maintenance. Group 2 will receive 177LuLu-DOTA-TATE every 4 weeks for 3 doses with radiotherapy then every 3 weeks as a single agent. Group 3 will receive 177LuLu-DOTA-TATE only, every 3 weeks. The primary endpoint is incidence of dose limiting toxicity. Secondary endpoints include overall objective status (modified RANO criteria), progression free survival, overall survival and safety.
Data from the large, prospective, multinational, phase 3b JUMP study were analyzed to identify factors predictive of spleen and symptom responses in myelofibrosis patients receiving ruxolitinib. ...Factors associated with higher spleen response rates included International Prognostic Scoring System (IPSS) low/intermediate-1 risk vs intermediate-2/high risk (43.1% vs 30.6%; adjusted OR aOR 0.65 95% CI 0.44-0.95), ruxolitinib as first- vs second- or later-line therapy (40.2% vs 31.5%; aOR 0.53 95% CI 0.38-0.75), and a ruxolitinib total daily dose at Week 12 of >20 mg/day vs ≤20 mg/day (41.3% vs 30.4%; aOR 0.47 95% CI 0.33-0.68). No association was seen between baseline characteristics or total daily dose at Week 12 and symptom response. Ruxolitinib led to higher spleen response rates in patients with lower IPSS risk, and when used earlier in treatment. Higher doses of ruxolitinib were associated with higher spleen response rates, but not with symptom improvement.
Trial registration
INC424 for patients with primary myelofibrosis, post polycythemia myelofibrosis or post-essential thrombocythemia myelofibrosis (JUMP).
2010-024473-39; NCT01493414
Date of registration: 16 December 2011
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2010-024473-39
https://clinicaltrials.gov/ct2/show/NCT01493414
Uterine leiomyomas, benign tumours of the human uterus, are the most common uterine neoplasm and are composed of smooth muscle with varying amounts of fibrous connective tissue. As a functional ...imaging modality, 2-Ffluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography can be used to obtain information about glucose metabolism in tissues. In this study, the findings of the F-FDG scans of four patients who were suspected of having malignant gynaecological tumours because of clinical and radiological findings and finally diagnosed as uterine leiomyoma based on histopathological examination were evaluated. Moderately intense F-FDG accumulation was detected in uterine mass localization in lower pelvis. The reason for the accumulation of F-FDG in uterine leiomyomas is not known. It may be explained by the existence of higher levels of growth factors, including basic fibroblast growth factor, transforming growth factor beta, granulocyte-macrophage colony-stimulating factor and receptors, and proliferation of smooth muscle cells in leiomatous uterus.
Background: The Janus kinase (JAK) inhibitor ruxolitinib (RUX) is approved for the treatment of disease-related splenomegaly and symptoms in patients with myelofibrosis (MF). Treatment with RUX has ...been shown to significantly reduce splenomegaly and provide marked improvements in MF-related symptoms and quality-of-life. A number of mutations have been identified with known or likely functional significance in patients with MF (Vannucchi AM, et al. Leukemia. 2013), which may therefore have the potential to affect treatment response. This exploratory analysis aimed to investigate the mutational status of patients in the REALISE trial and to assess the relationship between baseline mutational status and outcome.
Methods: REALISE was a multicenter, open label, single arm phase 2 study (NCT02966353). Eligible patients (N=51) had primary MF, post-essential thrombocythemia (ET) MF or post-polycythemia vera (PV) MF, with palpable (≥5 cm) spleen and hemoglobin level <10 g/dL. Patients started RUX at 10 mg bid with up titrations to 15 or 20 mg bid allowed after 12 weeks based on efficacy and platelet counts. The primary endpoint was achievement of ≥50% reduction in spleen length at Week 24. Secondary endpoints included transfusion requirements/dependence over time, adverse events, and patient-reported outcomes (PRO) (7-point MF score MF-7, MF Symptom Assessment Form MFSAF version 2.0). Next generation sequencing (NGS) analysis using a 236 gene panel (Navigate BioPharma, Carlsbad, CA, USA) was performed on whole blood samples to identify genetic alterations.
Results: NGS analysis data were available for 49/51 patients, median age was 67 years, 67.3% (33/49) had primary MF, 10.2% (5/49) had post-PV MF and 22.4% (11/49) had post-ET MF. DIPSS was available for 45 patients, 16.3% (8/49) were intermediate (Int)-1, 57.1% (28/49) were Int-2 and 18.4% (9/49) were high risk. The most frequent baseline mutations are shown in Figure 1. Classic driver mutations were found in JAK2 (n=33), CALR (n=11) and MPL (n=7), and did not affect response to RUX treatment. Two patients (4.1%) were triple negative for JAK2/CALR/MPL mutations, both responded to RUX treatment. The most commonly found non-driver mutations in patients with ≥50% reduction in spleen length at Week 24 (n=28) were TET2, ASXL1, U2AF1 and SRSF2; in non-responders, the most common non-driver mutations were TP53, FAT1 and ASXL1. The median number of mutations per patient was 2 (range 1-7); 35.7% (10/28) of patients with a response had ≥3 non-driver mutations vs 14.3% (3/21) of non-responders. Overall, no difference was seen in mutational distribution by change in spleen length at Week 24. In general, similar findings were seen for transfusion dependence status at baseline and improvements in symptom score with treatment (Table 1). However, there was a higher incidence of U2AF1 mutation in patients who were transfusion-dependent at baseline vs. non-transfusion dependent patients (4/8 50% vs 3/41 7.3%, respectively). U2AF1 mutation is known to be associated with anemia and/or thrombocytopenia in myelodysplastic syndromes (Li B, et al. Genes Chromosomes Cancer. 2018). Mutations in TP53 were present in 6 patients. One patient showed a response to treatment at Week 24, and 5 were classified as non-responders. None of these 5 patients completed 24 weeks of treatment and 3 died during the study or safety follow-up period. Two progressed to acute myeloid leukemia prior to death. All patients were ≥60 years old, 4 were male and 4 were DIPSS Int-2 risk. Four patients had primary MF, 1 had post-ET MF and 1 had post-PV MF.
Conclusions: Though these data should be interpreted with caution due to the small patient numbers, patients in the REALISE study showed variation in the type and number of genetic alterations with known/likely functional significance in MF. Compared with published mutational data on MF patients treated with RUX (Spiegel, et al. Blood Advances. 2017; Pacilli et al. Blood Cancer Journal. 2018) 12.2% of patients had a TP53 mutation compared to 4% and 4.2% respectively. This molecular difference may reflect the anemic study population. Despite the higher TP53 mutational burden, and alternative dosing strategy, 57.1% (28/49) patients had a response to RUX at Week 24. Although there was no strong association between mutation patterns and response, patients with TP53 mutations tended to have a poor outcome overall.
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Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria. Gisslinger:Novartis Pharma GmbH: Consultancy, Honoraria, Research Funding; Roche Austria GmbH: Consultancy; Myelopro GmbH: Consultancy; Celgene GmbH: Honoraria; Pharma Essentia: Other: Personal fees; Janssen-Cilag: Honoraria; AOP Orphan Pharmaceuticals: Consultancy, Honoraria, Research Funding. Passamonti:Janssen: Honoraria, Other: Advisory board , Speakers Bureau; Novartis: Honoraria, Other: Advisory board , Speakers Bureau; Celgene: Honoraria, Other: Advisory board , Speakers Bureau. Foltz:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Amgen: Other: Spouse Employment; Incyte: Research Funding; Constellation Pharma: Research Funding. Ross:Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Komatsu:Pharma Essentia: Research Funding, Speakers Bureau; Novartis K.K: Speakers Bureau; Wako Pure Chemical Industries, Ltd.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding, Speakers Bureau; Fuso Pharmaceutical Industries, Ltd.: Research Funding. Tiwari:Novartis: Employment. Zor:Novartis: Employment. Chaturvedi:Novartis Pharmaceuticals: Employment. Gilotti:Novartis Pharmaceuticals: Employment. Cervantes:Novartis: Honoraria, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.
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Background: Iron overload in patients receiving red blood cell (RBC) transfusions for treatment of anemia and in patients with non-transfusion-dependent thalassemia (NTDT) can lead to impaired ...organ function and is associated with significant morbidity and mortality. Regular iron load monitoring is essential and iron chelation therapy (ICT) should be promptly initiated when appropriate. Serum ferritin (SF) >1000 ng/mL is commonly used as an indicator of adverse clinical outcome resulting from iron overload. However, this is an indirect measure of tissue iron, whereas MRI allows accurate, reproducible assessment of cardiac and hepatic iron load, and its use may lead to improved patient care. The TIMES study used MRI to assess prevalence and severity of cardiac and hepatic siderosis in a large population of Australian patients with transfusion-dependent anemia or NTDT.
Methods: TIMES was an epidemiological study to assess cardiac and hepatic iron load in Australian, adult patients with thalassemia major (TM), NTDT (β thalassemia intermedia, β thalassemia/Hb E, Hb H disease), myelodysplastic syndromes (MDS) or other chronic anemias. Patients with NTDT had SF>300 ng/mL; others had a lifetime history of ≥20 units RBC transfusions and SF>500 ng/mL. Past medical history was collected (including anemia, RBC transfusion, ICT and hematologic data). Prospective MRI (FerriScan) was used to determine R2 liver iron concentration (LIC; siderosis >5 mg Fe/g dw for NTDT, >7 mg Fe/g dw for others) and myocardial T2* (siderosis <20 ms). The percentage of patients with hepatic and/or cardiac siderosis and mean LIC, SF and T2* were calculated for each disease group and according to ICT status. Linear regression was performed between screening SF and LIC within 60 days.
Results: 243 patients were enrolled and data for 239 were available for this analysis; 56% were male, 82% Caucasian, 10% Asian, 0.4% Aboriginal/Torres Strait Islander and 7% were of other ethnicity. Median age was 49.0 years (range 18-92). 77% of patients received ICT at any time before or during the study (59.8% deferasirox, 14.2% deferoxamine, 2.5% deferiprone), although not necessarily during the study. The degree of iron overload as determined by MRI is shown in Fig 1 and Table 1. Cardiac and hepatic siderosis was seen in 10 and 47% of patients, respectively. The prevalence of cardiac and hepatic siderosis in the different disease groups was: TM (22 and 32%), MDS (5 and 54%), NTDT (0 and 53%), and other anemia types (5 and 56%). All patients with cardiac siderosis had received ICT. Among patients with MDS, NTDT or other anemia types, some patients had iron overload (hepatic siderosis) but had not received ICT (MDS 19.4, NTDT 20.0, other anemias 25.8%). In all disease groups, mean LIC was above the target range (3-7 mg Fe/g dw, as established for TM by risk of morbidity), while mean cardiac T2* was above 20 ms. Although correlation between LIC and SF is observed in each disease group, some patients with high LIC had relatively low SF, indicating that SF is not an accurate indicator of iron load in these patients (Fig 2). Among patients analyzed (n=220), few (3.4%) patients with TM, MDS or other anemia types with SF<1000 ng/mL had LIC ≥7 mg Fe/g dw, confirming the utility of this SF chelation target in clinical practice; while in NTDT, 2 of 15 patients had LIC ≥5 mg Fe/g dw despite SF<800 ng/mL, supporting the importance of MRI evaluation in this subgroup.
Conclusion: In a large population of patients with heterogeneous causes of chronic anemia and elevated SF, there was a high prevalence of hepatic siderosis in all disease groups (32% in TM patients, who all received ICT; >50% in other disease groups), and a high prevalence of cardiac siderosis in TM patients (22%) despite ICT. Treatment guidelines recommend ICT initiation in patients with iron overload, followed by adequate dose adjustment and duration of ICT to maintain SF<1000 ng/mL, and to decrease risk of iron excess-related morbidities. Despite these recommendations, this study suggests iron overload still occurs in a large proportion of susceptible patients. Furthermore, not all patients in need of ICT can be identified using SF; MRI assessment of iron load is preferable. These data provide a real-life assessment of the magnitude of iron load, emphasizing the importance of adequate monitoring in patients with anemias receiving RBC transfusions and those with NTDT, to enable timely initiation of ICT and ongoing dose optimization.
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Ho:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aspen: Other: Conference Grant. Hiwase:Celgene Corporation: Research Funding. Viiala:Novartis: Honoraria. Zor:Novartis: Employment. Gervasio:Novartis: Employment. Bowden:Novartis: Research Funding.
The fluorine doped cadmium oxide samples have been deposited at 250
°C by ultrasonic spray pyrolysis method. X-ray diffraction patterns of the CdO:F samples have revealed that the samples are ...polycrystalline with cubic sodium chloride structure. The texture coefficients calculated for various planes at different fluorine concentrations indicate that the samples have exhibited (1
1
1) and (2
0
0) preferential orientations. The lattice parameters for cubic structure of each diffraction plane have been calculated. The crystallite size of the samples being nearly constant until 4% of fluorine doping showed reasonable decrease above this concentration value. The macro strain and dislocation density vary with fluorine concentrations.
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