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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 naive (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.Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.

Deep molecular response in chronic phase chronic myeloid leukaemia (CP-CML) is associated with superior event free survival, provides a platform for treatment free remission and is increasingly being adopted as a goal of therapy. Interferon was a commonly used CML therapy in the pre-imatinib era, exerting direct anti-leukemic activity and immune-stimulatory properties. Combining interferon and tyrosine kinase inhibitors (TKI) may lead to synergistic anti-leukemic effects. We report the interim analysis of the Pinnacle phase II study, combining nilotinib with pegylated interferon alfa-2B (Peg-IFN) in CP-CML, evaluating tolerability of the combination and efficacy as measured by molecular responses. All patients received nilotinib 300mg BID for the first 3 months (mths). Peg-IFN (PegIntron, MSD) was added at 30mcg/week in the 4 mth in patients without persistent haematological toxicities, increasing to 50mcg/week as tolerated over the following mth. Combination therapy continued until 24 mths, when patients reverted to TKI monotherapy. Switching to imatinib 400-600mg QD was allowed for patients with persistent grade II or any grade III/IV toxicity from nilotinib. The co-primary end points are MR4.5 (BCR-ABL1 <=0.0032% IS) at 24 mths and MMR (BCR-ABL1 <=0.1% IS) at 12 mths. Patients were screened for cardiac / vascular disease and associated risk factors at baseline (EKG, ejection fraction via ultrasound or nuclear med, arterial duplex of carotids and lower limbs, blood HbA1c and lipid profiles). Patients with uncontrolled vascular risk factors (diabetes, hypertension, dyslipidemia) or a history of vascular events were excluded. Sixty patients were recruited from 12 Australian centres. Median age was 48.5 years (range 19-72), and 45% were female. Sokal risk was low in 43% and high in 18%. Median follow up was 14 mths (2.4-37). Figure 1 shows BCR-ABL1 transcript levels over time. Of the 59 patients followed up for >=3 mths, 5 had BCR-ABL1 >10% at 3 mths (8.5%). Two pati

Background: Iron overload can lead to impaired organ function and is associated with significant morbidity and mortality, the risks of which can be reduced by effective long-term iron chelation therapy (ICT) and control of iron loading. Magnetic resonance imaging (MRI) allows accurate, reproducible assessment of iron load and its use may affect clinical management decisions, leading to improved patient care. The epidemiological 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 non-transfusion- dependent thalassemia (NTDT). In this analysis of the TIMES study, we report the impact of MRI results on investigator treatment decisions. Aim(s): To determine the prevalence of iron overload by MRI and its impact on the clinical management of iron overload in a population of patients with transfusion- dependent anemia or NTDT. Method(s): Patients with thalassemia major (TM), NTDT (beta thalassemia intermedia, beta thalassemia/Hb E, Hb H disease), myelodysplastic syndromes (MDS) or other chronic anemias were enrolled. Patients with NTDT had serum ferritin (SF) >300 ng/mL; others had a lifetime history of >=20 units red blood cell (RBC) transfusions and SF >500 ng/mL. Past medical history was collected (including red blood cell (RBC) transfusion, ICT and hematologic data). Prospective MRI (FerriScan) was used to determine R2 liver iron concentration (LIC) and myocardial T2* (mT2*). Treatment decisions were assessed and recorded using an investigator questionnaire after evaluation of patient MRI results. Result(s): Of the 243 enrolled patients, 10 and 48% had cardiac and hepatic siderosis, respectively. In all disease groups, mean LIC was above the target range (3-7mg Fe/g dw), while mean mT2* was normal (>=20ms). 65.8% of patients received ICT for >=1 month before or during the study. During the 12- month period prior to the study, 55.9% received deferasirox

Embedded Image 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. Method(s): TIMES was an epidemiological study to assess cardiac and hepatic iron load in Australian, adult patients with thalassemia major (TM), NTDT (beta thalassemia intermedia, beta 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. Result(s): 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 ethnici

Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML). Pleural effusions, an adverse event related dasatinib treatment, may lead to intolerance and drug discontinuations. Strategies aimed at minimising this may improve outcomes. In the Phase III Dasision study, pleural effusion affected ~22% of patients after 4 years of dasatinib treatment at 100mg/d (Cortes et al, 2016 JCO 34(20) 2333-40). The elderly are at particular risk (Latagliata et al 2013 Hem Onc 31(2) 103-9), and there is suggestion that higher dasatinib trough (Cmin) levels may increase the risk of pleural effusions. The randomised OPTIM study (EHA 2014 abstract 5678) has previously reported that patients with Cmin >3nM benefited from dose reductions with preservation of molecular responses. The CML12 (DIRECT) study, run by the Australasian Leukaemia & Lymphoma Group (ALLG) with financial support from BMS, is a single arm phase II study with the aim of minimizing dasatinib related toxicity whilst preserving efficacy using a similar treatment schema to the OPTIM study. Here, we report results of a per-protocol interim analysis based on early molecular response (EMR; BCR-ABL1 <=10% at 3 months) and MMR (BCR-ABL1 <=0.1%) at 12 months, both key secondary endpoints of the study. The primary endpoint of the study- the cumulative incidence of pleural effusion at 24 months - is not yet evaluable. DIRECT initially only enrolled patients >60 years old, predicted to derive the greatest potential benefit from a reduction in toxicity. The protocol was amended after 34 pts were accrued to include patients >18 years old at the recommendation of the trial management committee. All patients started treatment with dasatinib 100mg/day. Dasatinib Cmin was taken at 7, 28 and 56 days after treatment commencement. All Cmin directed dose adjustments were made prior to assessment of BCR-ABL1 at 3 months. Patients sequentially dose reduced to 70mg/day, then to 50mg/day, for C

Dasatinib treatment leads to excellent molecular responses in chronic phase chronic myeloid leukemia (CP-CML). Pleural effusions, an adverse event related dasatinib treatment, may lead to intolerance and drug discontinuations. Strategies aimed at minimising this may improve outcomes. In the Phase III Dasision study, pleural effusion affected ~22% of patients after 4 years of dasatinib treatment at 100mg/d (Cortes et al, 2016 JCO 34(20) 2333-40). The elderly are at particular risk (Latagliata et al 2013 Hem Onc 31(2) 103-9), and there is suggestion that higher dasatinib trough (Cmin) levels may increase the risk of pleural effusions. The randomised OPTIM study (EHA 2014 abstract 5678) has previously reported that patients with Cmin >3nM benefited from dose reductions with preservation of molecular responses. The CML12 (DIRECT) study, run by the Australasian Leukaemia & Lymphoma Group (ALLG) with financial support from BMS, is a single arm phase II study with the aim of minimizing dasatinib related toxicity whilst preserving efficacy using a similar treatment schema to the OPTIM study. Here, we report results of a per-protocol interim analysis based on early molecular response (EMR; BCR-ABL1 <=10% at 3 months) and MMR (BCR-ABL1 <=0.1%) at 12 months, both key secondary endpoints of the study. The primary endpoint of the study- the cumulative incidence of pleural effusion at 24 months - is not yet evaluable. DIRECT initially only enrolled patients >60 years old, predicted to derive the greatest potential benefit from a reduction in toxicity. The protocol was amended after 34 pts were accrued to include patients >18 years old at the recommendation of the trial management committee. All patients started treatment with dasatinib 100mg/day. Dasatinib Cmin was taken at 7, 28 and 56 days after treatment commencement. All Cmin directed dose adjustments were made prior to assessment of BCR-ABL1 at 3 months. Patients sequentially dose reduced to 70mg/day, then to 50mg/day, for C