Imatinib Treatment Alone in Philadelphia-Positive Acute Lymphoblastic Leukemia: Is It Enough?

BCR-ABL fusion gene t(9;22)(q34;q11) occurs in only 3% of pediatric acute lymphoblastic leukemia (ALL) cases. Previously, less than 40% of Philadelphia-positive ALL patients were cured with intensive chemotherapy. The use of imatinib (340 mg/m2/day) added to an intensive chemotherapy regimen has improved the outcome in this population at 3 years to an event-free survival of 80%. Imatinib treatment alone was administered after remission induction chemotherapy to a patient with Philadelphia-positive ALL who presented with serious chemotherapy toxicity, so that intensive chemotherapy could not be maintained. This is the only patient in the literature who survived remission for more than 2.5 years with imatinib treatment only

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data

Introduction: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose‐dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. Aim: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. Methods: Free TFPI predictions were generated using an estimated concizumab‐free TFPI exposure‐response (Emax) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 μg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. Results: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re‐established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab‐free TFPI and concizumab‐TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once‐daily dosing would minimize within‐patient concizumab PK variability.Novo Nordis

Emicizumab prophylaxis in infants with hemophilia A (HAVEN 7): primary analysis of a phase 3b, open-label trial

Subcutaneous emicizumab enables prophylaxis for people with hemophilia A (HA) from birth, potentially reducing risk of bleeding and intracranial hemorrhage (ICH). HAVEN 7 (NCT04431726) is the first clinical trial of emicizumab dedicated to infants, designed to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab in those aged ≤12 months with severe HA without factor VIII (FVIII) inhibitors. Participants in this phase 3b trial received emicizumab 3 mg/kg maintenance dose every 2 weeks for 52 weeks and are continuing emicizumab during the 7-year long-term follow-up. Efficacy end points included annualized bleed rate (ABR): treated, all, treated spontaneous, and treated joint bleeds. Safety end points included adverse events (AEs), thromboembolic events (TEs), thrombotic microangiopathies (TMAs), and immunogenicity (anti-emicizumab antibodies [ADAs] and FVIII inhibitors). At primary analysis, 55 male participants had received emicizumab (median treatment duration: 100.3; range, 52-118 weeks). Median age at informed consent was 4.0 months (range, 9 days to 11 months 30 days). Model-based ABR for treated bleeds was 0.4 (95% confidence interval, 0.30–0.63), with 54.5% of participants (n = 30) having zero treated bleeds. No ICH occurred. All 42 treated bleeds in 25 participants (45.5%) were traumatic. Nine participants (16.4%) had ≥1 emicizumab-related AE (all grade 1 injection-site reactions). No AE led to treatment changes. No deaths, TEs, or TMAs occurred. No participant tested positive for ADAs. Two participants were confirmed positive for FVIII inhibitors. This primary analysis of HAVEN 7 indicates that emicizumab is efficacious and well tolerated in infants with severe HA without FVIII inhibitors

Laboratory Diagnosis and Management of von Willebrand Disease in Turkey: Izmir Experience

WOS: 000295698300022PubMed ID: 22102203von Willebrand disease (VWD) is caused by a deficiency or dysfunction of von Willebrand factor (VWF). The pathophysiology, classification, diagnosis, and management of VWD are relatively complex, but their understanding is important for proper diagnosis and management of patients with VWD. There are inherent difficulties in both the identification and classification of VWD because of clinical uncertainty and the limitations in the test processes and test panels typically used by laboratories. The most common test panel employed by laboratories, particularly in the geographic regions covered by the mutational studies, would comprise factor VIII coagulant (FVIII:C), VWF protein (antigen; VWF:Ag), and ristocetin cofactor (VWF:RCo). In our center, use of a desmopressin challenge with our core four-test panel (i.e., VWF:Ag, VWF:RCo, FVIII:C, and PFA-100) is expected to further assist laboratory diagnosis of VWD in Turkey. Molecular genetics is a rather new approach for Turkey, with gene analyses related to VWD being initiated in one center and the results used for confirmation of diagnosis in limited cases

The Prevalence of von Willebrand Disease and Significance of in Vitro Bleeding Time (PFA-100) in von Willebrand Disease Screening in the Izmir Region

WOS: 000316239000008PubMed ID: 24385752Objective: von Willebrand disease (vWD) is the most common hereditary bleeding disorder. The purpose of this investigation was to determine the prevalence of vWD among adolescents in Izmir and to assess the sensitivity and specificity of PFA-100 as a screening method in detecting this disease. Material and Methods: Our study was conducted on adolescents in the city of Izmir between October 2006 and March 2007. A total of approximately 1500 high school students between 14 and 19 years of age were planned to be included in the investigation. Survey forms prepared for assessing hemorrhagic diathesis were completed by 1339 individuals (512 males, 827 females). The necessary laboratory tests were performed after having obtained written informed consent from 40 individuals suspected to have hemorrhagic diathesis. Results: Based on the von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activity (vWF:RCo) levels and bleeding symptoms, vWD type-1 was diagnosed in 14 individuals (4 males, 10 females; prevalence: 1.04%). The most common bleeding symptom in these patients was found to be epistaxis (10/14). Screening with PFA-100 revealed prolongation in both cartridges (Col/ADP and Col/Epi) in 3 of the 14 patients. PFA-100 was determined to exhibit 21.4% sensitivity and 100% specificity in the diagnosis of vWD. Conclusion: The PFA-100 device was found to have high specificity but to have exhibited low sensitivity. Therefore, its utilization as a screening test may be problematic in patients with mild type-1 vWD. Specific tests (vWF:RCo, vWF:Ag) are required for the definite diagnosis of vWD. However, further studies with a large number of patients are needed

Investigation of Acquired Von Willebrand Syndrome in Children with Hypothyroidism: Reversal after Treatment with Thyroxine

WOS: 000282928800019PubMed ID: 21175099Background: Acquired von Willebrand Syndrome (AvWS) is a rare bleeding disorder associated with various underlying conditions. Many case reports have been published so far on bleeding tendency in hypothyroidism resembling AvWS. Objective: This study was designed to define the relationship between hypothyroidism and AvWS and to investigate the effects of L-thyroxine treatment. Subjects: Twenty four hypothyroid patients were included in the study. Nineteen patients were evaluated during treatment, 5 patients were evaluated before hormone replacement. Methods: Complete coagulation screening tests including levels of von Willebrand Factor antigen (vWF:Ag) and functional activity (vWF:RCo) were measured by thrombocyte aggregometer. Results: We demonstrated low vWF:Ag and vWF:RCo in 13 patients. Two of the 13 patients were diagnosed as AvWS, while another 2 patients were diagnosed as hereditary vWD Type 1. The remaining patients are still being followed-up. Conclusion: We would like to attract the attention of paediatricians to the possibility of bleeding due to decreased activity of vWF in hypothyroid children