Relative response of patients with myelodysplastic syndromes and other transfusion-dependent anaemias to deferasirox (ICL670): a 1-yr prospective study

Objectives/methods: This 1-yr prospective phase II trial evaluated the efficacy of deferasirox in regularly transfused patients aged 3-81 yrs with myelodysplastic syndromes (MDS; n = 47), Diamond-Blackfan anaemia (DBA; n = 30), other rare anaemias (n = 22) or beta-thalassaemia (n = 85). Dosage was determined by baseline liver iron concentration (LIC). Results: In patients with baseline LIC >= 7 mg Fe/g dry weight, deferasirox initiated at 20 or 30 mg/kg/d produced statistically significant decreases in LIC (P < 0.001); these decreases were greatest in MDS and least in DBA. As chelation efficiency and iron excretion did not differ significantly between disease groups, the differences in LIC changes are consistent with mean transfusional iron intake (least in MDS: 0.28 +/- 0.14 mg/kg/d; greatest in DBA: 0.4 +/- 0.11 mg/kg/d). Overall, LIC changes were dependent on dose (P < 0.001) and transfusional iron intake (P < 0.01), but not statistically different between disease groups. Changes in serum ferritin and LIC were correlated irrespective of disease group (r = 0.59), supporting the potential use of serum ferritin for monitoring deferasirox therapy. Deferasirox had a safety profile compatible with long-term use. There were no disease-specific safety/tolerability effects: the most common adverse events were gastrointestinal disturbances, skin rash and non-progressive serum creatinine increases. Conclusions: Deferasirox is effective for reducing iron burden with a defined, clinically manageable safety profile in patients with various transfusion-dependent anaemias. There were no disease-specific adverse events. Once differences in transfusional iron intake are accounted for, dose-dependent changes in LIC or serum ferritin are similar in MDS and other disease groups

Molecular landscape and prognostic impact of FLT3 -ITD insertion site in acute myeloid leukemia : RATIFY study results

In acute myeloid leukemia (AML) internal tandem duplications of the FLT3 gene (FLT3- ITD) are associated with poor prognosis. Retrospectively, we investigated the prognostic and predictive impact of FLT3 -ITD insertion site (IS) in 452 patients randomized within the RATIFY trial, which evaluated midostaurin additionally to intensive chemotherapy. Next-generation sequencing identified 908 ITDs, with 643 IS in the juxtamembrane domain (JMD) and 265 IS in the tyrosine kinase domain-1 (TKD1). According to IS, patients were categorized as JMDsole (n = 251, 55%), JMD and TKD1 (JMD/TKD1; n = 117, 26%), and TKD1sole (n = 84, 19%). While clinical variables did not differ among the 3 groups, NPM1 mutation was correlated with JMDsole (P = 0.028). Overall survival (OS) differed significantly, with estimated 4-year OS probabilities of 0.44, 0.50, and 0.30 for JMDsole, JMD/TKD1, and TKD1sole, respectively (P = 0.032). Multivariate (cause-specific) Cox models for OS and cumulative incidence of relapse using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable identified TKD1sole as unfavorable and HCT as favorable factors. In addition, Midostaurin exerted a significant benefit only for JMDsole. Our results confirm the distinct molecular heterogeneity of FLT3 -ITD and the negative prognostic impact of TKD1 IS in AML that was not overcome by midostaurin

A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand.

The efficacy-safety and pharmacokinetics of the six-dose regimen of artemether-lumefantrine (Coartem/Riamet; Novartis Pharma AG, Basel, Switzerland) were assessed in a randomized trial in 219 patients (> or = 12 years old) with acute, uncomplicated Plasmodium falciparum malaria in Thailand. One hundred and sixty-four patients received artemether-lumefantrine and 55 received the standard treatment combination of mefloquine-artesunate. Both drugs induced rapid clearance of parasites and malaria symptoms. The 28-day cure rates were 95.5% (90% confidence interval [CI] = 91.7, 97.9%) for artemether-lumefantrine and 100% (90% CI = 94.5, 100%) for mefloquine-artesunate. This high-dose regimen of artemether-lumefantrine was very well tolerated, with very good compliance. The most frequent adverse events were headache, dizziness, nausea, abdominal pain, dyspepsia, vomiting, and skin rash. Overall, only 2% of patients in both groups showed QTc prolongations but without any cardiac complication, and no differences were seen between patients with and without measurable baseline plasma levels of quinine or mefloquine. Plasma levels of artemether, dihydroartemisinin, and lumefantrine were consistent with historical data for the same dose regimen, and were higher, particularly for lumefantrine, than those previously observed with the four-dose regimen, explaining the greater efficacy of the six-dose regimen in a drug-resistant setting. These results confirm the excellent safety and efficacy of the six-dose regimen of artemether-lumefantrine in the treatment of multidrug-resistant P. falciparum malaria

High rates of durable response are achieved with imatinib after treatment with interferon α plus cytarabine: results from the International Randomized Study of Interferon and STI571 (IRIS) trial

Imatinib is the standard of care for patients with newly diagnosed chronic-phase chronic myeloid leukemia. This is the largest analysis to date describing the efficacy of imatinib in patients who have received prior therapies for chronic myeloid leukemia and it demonstrates excellent responses to imatinib in this context

Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial

BackgroundThis study evaluates the correlation between imatinib trough plasma concentrations (C(min)) and clinical response and safety in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in the Tyrosine Kinase Inhibitor OPtimization and Selectivity (TOPS) trial.Design and methodsPatients were randomized 1:2 to 400 mg/day or 800 mg/day imatinib. Imatinib C(min) levels were collected at pre-dose before treatment, and at the end of months 1 (day 29), 6, 9, and 12.ResultsImatinib C(min) were stable over time in the 400 mg/day dose arm, but showed a slight decrease in the 800 mg/day arm due to dose adjustments between months 1-6. The overall median imatinib C(min) levels were 1040, 1200, 1935, and 2690 ng/mL for the actual 300, 400, 600, and 800 mg/day doses, respectively. The rates of major molecular response (MMR) at 3, 6, 9, and 12 months, and complete cytogenetic response (CCyR) at 6 and 12 months were significantly lower among patients with the lowest imatinib C(min) levels at Day 29 (<1165 ng/mL, 25th percentile). There was an apparent association between high imatinib C(min) and the occurrence of grade 3/4 neutropenia and all-grade rash, diarrhea, arthralgia/myalgia, and all-cause edema. Conclusions Imatinib C(min) levels were relatively stable over time and proportional to the dose administered. Patients with an imatinib C(min) above 1165 ng/mL on Day 29 achieved MMR faster and had higher MMR and CCyR rates at 12 months. There appeared to be an association between imatinib C(min) and the frequency of some adverse events. This trial was registered at http://www.clinicaltrials.gov as NCT00124748.François Guilhot, Timothy P. Hughes, Jorge Cortes, Brian J. Druker, Michele Baccarani, Insa Gathmann, Michael Hayes, Camille Granvil and Yanfeng Wan

The comparative efficacy and tolerability of CGP 56697 (artemether+lumefantrine) versus halofantrine in the treatment of uncomplicated falciparum malaria in travellers returning from the Tropics to The Netherlands and France

CGP 56697 (Riamet(TM)) is a new oral anti-malarial drug composed of artemether and lumefantrine (benflumetol) which combines the fast, short-acting artemether for rapid parasite clearance with the prolonged action of lumefantrine for intended radical cure. In this double-blind, comparative trial, the efficacy and tolerability of CGP 56697, given as a course of 4x4 tablets over 48 h, was compared to halofantrine, given as 3x2 tablets over 12 h with a second course 1 week later. Patients (mostly non-immune) with acute, uncomplicated Plasmodium falciparum infection were randomly assigned to either CGP 56697 (n=51) or halofantrine (n=52). CGP 56697 proved superior with respect to parasite clearance time (median 32 vs. 48 h, P30 ms) were seen 6-12 h after halofantrine intake but not after CGP 56697 intake. CGP 56697 is an effective, well-tolerated treatment for uncomplicated falciparum malaria but for this dosing regimen the recrudescence rate is unacceptably high (18%). For travellers contracting malaria abroad, we propose a six-dose regimen of CGP 56697 over 3 days. Copyright (C) 1999 Elsevier Science B.V

Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study

Imatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (Cmins) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (\ub1 SD, CV%) steady-state Cmin for imatinib and CGP74588 were 979 ng/mL (\ub1 530 ng/mL, 54.1%) and 242 ng/mL (\ub1 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). Cmin of imatinib was significantly higher in patients who achieved CCyR (1009 \ub1 544 ng/mL vs 812 \ub1 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT0033384