Clinical significance of slightly reduced von Willebrand factor activity.

Von Willebrand disease (VWD) is the most common congenital bleeding disorder, with a clinical presentation of mucocutaneous and surgical bleeding varying from mild to severe. It is inherited in an autosomal dominant or autosomal recessive manner. The disease is caused by quantitative or qualitative deficiency of the von Willebrand factor (VWF) and is classified as type 1, 2 (2A, 2B, 2M, 2N), and 3. Although type 1 VWD is the most common form of VWD, the f ormal cutoff for diagnosis remains a subject of debate. In our paper, we present results of studies regarding the clinical and laboratory importance of a new type of bleeding disorder called low VWF. The new guidelines for VWD diagnosis and management suggested that patients with historically type 1 VWD should be divided into 2 subsets: type 1 VWD with a VWF antigen level (VWF:Ag) of less than 30 IU/dl or less than 40 IU/dl, in which about 80% of patients exhibited VWF gene mutations, and low VWF with a VWF:Ag level of 30 to 50 IU/dl or 40 to 50 IU/dl, in which the causative mutation is detected in merely 40% of patients and in most families, inheritance is not dependent on the locus of VWF on chromosome 12. Previously, moderately reduced VWF levels (30-50 IU/dl) were considered a risk factor for bleeding, but not a true bleeding disorder, and this condition was named low VWF. Recently, it was documented in a large group of patients with type 1 VWD and low VWF that bleeding score does not correlate with VWF:Ag and bleeding symptoms in type 1 VWD (<30 IU/dl) and low VWF can change from infrequent and moderate to severe bleeds. Because the plasma concentration of VWF depends on many physiological and pathological factors that may mask the diagnosis of VWD, separation of the group of patients with low VWF (30-50 IU/dl) from those with type 1 VWD may delay or prevent them from receiving appropriate treatment. Diagnosis of VWD in each case, particularly those with a slight decrease in VWF (30-50 IU/dl), should be based primarily on the clinical manifestations and family history of hemorrhagic diathesis.

[A study to determine the safety and efficacy of imatinib mesylate in patients with chronic phase of chronic myeloid leukemia after interferon therapy failure. Four year follow-up]. / Ocena skutecznosci i bezpieczenistwa stosowania imatinibu mesylate u pacjentów z faza przewlekla przewleklej bialaczki szpikowej po niepowodzeniu leczenia interferonem 4 lata obserwacji.

UNLABELLED: Targeted therapy with the use of imatinib mesylate is a recognized option for patients with chronic myeloid leukemia (CML) not eligible for allogeneic hematopoietic cell transplantation. We present results of a multicenter phase II study on the use of imatinib in chronic phase after failure to interferon-alpha (IFN-alpha). Sixty patients (27 female, 33 male), median age 46 (range, 21-64), were included with hematologic relapse (n= 11), hematologic refractoriness (n=4), cytogenetic relapse/ /+65resistance (n=40) or intolerance to IFN-alpha (n=5). The median time from CML diagnosis was 39 months (range, 4-132), the median time of IFN-alpha therapy equaled 23 months (range, 1-78). Imatinib mesylate was administered at a dose of 400 mg/day for 1 year. In patients who achieved major cytogenetic response (MCR) the therapy was continued until progression. Thirty-three (55%) patients achieved MCR after one year of treatment. At 4 years the cumulative incidence of complete cytogenetic response equaled 40% (95% CI, 29-56). Among 27 patients who did not achieve MCR at 12 moths, in 12 cases the study course was discontinued prematurely because of blast crisis (n=9), prolonged neutropenia (n=l), severe transaminases elevation (n=l) or incidental death not related to the study drug or disease (n=l). The probability of OS at 4 years equaled 82% (95% CI, 72-91) and was lower for patients with the disease duration >36 months and those with Sokal index > or =0.8. Among patients who achieved MCR, the probability of progression-free survival was 78% (95% CI, 69-85). Time to progression (cytogenetic, n=6; blast crisis, n=l) varied from 3-36 months. CONCLUSIONS: Imatinib mesylate is characterized by good tolerance and allows achieving cytogenetic response in more than half of late chronic phase CML patients with failure of interferon therapy. However, the progression rate is substantial, which raises concern regarding the curative potential of monotherapy with imatinib in this group of patients.