Twenty-two molecular diagnostic laboratories from 14 countries participated in a consortium study to estimate the impact of Factor VIII gene inversions in severe hemophilia A. A total of 2,093 patients with severe hemophilia A were studied; of those, 740 (35%) had a type 1 (distal) factor VIII inversion, and 140 (7%) showed a type 2 (proximal) inversion. In 25 cases, the molecular analysis showed additional abnormal or polymorphic patterns. Ninety-eight percent of 532 mothers of patients with inversions were carriers of the abnormal factor VIII gene; when only mothers of nonfamilial cases were studied, 9 de novo inversions in maternal germ cells were observed among 225 cases (approximately 1 de novo maternal origin of the inversion in 25 mothers of sporadic cases). When the maternal grandparental origin was examined, the inversions occurred de novo in male germ cells in 69 cases and female germ cells in 1 case. The presence of factor VIII inversions is not a major predisposing factor for the development of factor VIII inhibitors; however, slightly more patients with severe hemophilia A and factor VIII inversions develop inhibitors (130 of 642 [20%]) than patients with severe hemophilia A without inversions (131 of 821 [16%]).

Turoctocog alfa pegol (N8-GP) is a novel glycoPEGylated extended half-life recombinant factor VIII (FVIII) product developed for prophylaxis and treatment of bleeds in patients with haemophilia A, to enable higher activity levels with less frequent injections compared with standard FVIII products. This phase III (NCT01480180), multinational, open-label, non-randomised trial evaluated the safety and clinical efficacy of N8-GP when administered for treatment of bleeds and for prophylaxis, in previously treated patients aged ≥12 years with severe haemophilia A. Patients were allocated to receive N8-GP for prophylaxis or on-demand treatment for up to 1.8 years. Patients on prophylaxis were administered one dose of 50 IU/kg of N8-GP every fourth day. Bleeds were treated with doses of 20-75 IU/kg. Total exposure to N8-GP in the trial was 14,114 exposure days (159 patient-years). For the prophylaxis arm (n=175), the median annualised bleeding rate (ABR) was 1.33 (interquartile range, 0.00-4.61), the mean ABR was 3.70 (95 % confidence interval 2.94-4.66) and 70 (40 %) patients had no bleeds during the trial. Across treatment arms, 83.6 % of bleeds resolved with one injection and 95.5 % with up to two injections. N8-GP had a favourable safety profile and was well tolerated. The frequency and types of adverse events reported were as expected in this population. One patient developed inhibitory antibodies against FVIII (≥0.6 Bethesda units [BU]) after 93 N8-GP exposure days. No clinically significant safety concerns were identified and N8-GP was effective for prophylaxis and treatment of bleeds in previously treated patients.

To investigate the time sequence of occurrence of p15INK4B gene methylation in myelodysplastic syndrome (MDS) and its correlation with leukaemic transformation and survival of patients, the methylation status of the p15INK4B promoter region was analysed in 50 patients and was serially studied in 22 of them. Of the 50 patients, 17 (34%) showed p15INK4B gene methylation, first demonstrated at diagnosis or during follow‐up. When FAB subtypes at the time of study were used in the analysis, the incidence of p15INK4B methylation in each risk group of MDS remained stable throughout the course: 0% for low‐risk MDS [refractory anaemia (RA) and RA with ring sideroblasts] and from 23% at diagnosis to 30% for high‐risk MDS [RA with excess of blasts (RAEB), RAEB in transformation and chronic myelomonocytic leukaemia] respectively. The incidence of p15INK4B methylation rose to 60% at initial study and, finally, to 75% in cases of acute myeloid leukaemia (AML) evolved from MDS. Most patients (69%) with p15INK4B methylation showed disease progression to AML; it could be detected before, at the time or after the diagnosis of leukaemic transformation. p15INK4B methylation in MDS patients implicated a shorter survival time in univariate analyses, but its prognostic significance disappeared in multivariate analyses. In conclusion, p15INK4B methylation can be detected early at the diagnosis of MDS or acquired during disease progression. It may play an important role in the pathogenesis of some high‐risk MDS and is related to leukaemic transformation of MDS.

The proliferation and differentiation of hematopoietic precursor cells depend on various cytokines. The suppressor of cytokine signaling-1 (SOCS1) down-regulates Janus kinases/signal transducers and activators of transcription (JAK/STAT) pathway activity and inhibits the biological effects of cytokines. SOCS1 has been shown to have tumor-suppressor activity, and methylation of this gene, resulting in transcriptional silencing, has been found in 65% of hepatocellular carcinoma and has been suggested to play an important role in the development of the cancer. The methylation status of the SOCS1 gene in acute myeloid leukemia (AML) has not been reported before. In this study, we analyzed SOCS1 methylation in 89 patients with newly diagnosed AML and correlated the result with immunophenotypes, cytogenetics, clinical features, and treatment outcome. SOCS1 methylation was found in the leukemic cells from 53 patients (60%). Thirteen (76%) of the 17 patients with t(15;17) had SOCS1 methylation, whereas this gene was methylated in only one (11%) of the nine patients with t(8;21). The frequencies of SOCS1 methylation among various cytogenetic subgroups differed significantly (P = 0.014). Other clinical and laboratory parameters and the disease-free survival and overall survival were similar between patients with and without SOCS1 methylation. In conclusion, SOCS1 methylation occurs in more than half of AML cases, correlates with cytogenetic abnormalities, and may play an important role in the development of subsets of AML.

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