The prevention and treatment of thrombosis and bleeding disorders are constantly evolving. This was clearly reflected by a large number of oral and poster presentations at the 2017 EHA Congress, such as the presentation of Dr Donna DiMichele at the Plenary Session II. Another example is the promising treatment of immune thrombocytopenia with all-trans retinoic acid and danazol. Furthermore, the results of Dr Lazo-Lagner and colleagues provided a better insight in the risks associated with the use of anticoagulants in cancer patients. A Joint Symposium of the EHA and the International Society on Thrombosis and Hemostasis (ISTH) addressed anticoagulation in difficult to treat patients.
Hemophilia A and B result from hereditary deficiencies in factor VIII and IX, respectively. To improve the treatment of these clotting diseases a substantial number of clinical trials evaluates the outcome of innovative therapies, including gene therapy with viral vectors. “Gene therapy often modifies the disease from one with a severe phenotype to a mild phenotype, such that these individuals require less factor replacement therapy. Some therapies even result in 20-40% of the normal level of the clotting factor in a number of patients that do not require steroids, for over a year. However, most patients do require steroids due to immune responses against the adeno-associated virus used as vector for the transgene, illustrating that gene therapy is still a challenge”, said Dr Donna DiMichele (NIH, Bethesda, USA) at the Plenary Session II of EHA 2017.
In addition to gene therapy clinical studies have focused on extending the half-life of recombinant factor VIII and IX in order to reduce the prophylactic administration of these clotting factors. DiMichele: “Currently, five factor VIII products with an extended half-life are marketed or under investigation: Elocta, Adynovate, NN7088, Bay 94-9027 and Afstyla. The improvement in all of these models has been moderate, with a general increase in half-life of around 30%. Furthermore, three factor IX products with an extended half-life are registered or being tested in clinical trials: Alprolix, Idelvion and N9-GP. However, in contrast to the factor VIII products, the half-life of these products has been augmented to a much greater extent with a four to five fold extended half-life.”
Currently, there exists an increasing demand to change the current prophylactic treatment strategies to a precision medicine approach. “Critical to this are predictive models of individual disease severity and bleeding, especially those derived from deep phenotype data informing and informed by transcriptomics. However, as yet there has not been a major move towards genomics and transcriptomics in hemophilia, although the NIH recently initiated a project on the transcriptomics of 5,000 hemophilia patients”, said DiMichele.
Immune thrombocytopenia (ITP) is a common autoimmune disorder characterized by increased platelet destruction and/or impaired platelet production. Although patients can be effectively treated with corticosteroids in the first line, a substantial number of patients is refractory, relapses or does not tolerate this treatment. “We previously reported that all-trans retinoic acid (ATRA) increases the response rate following treatment with corticosteroids.1 Here, we report on the results of a multicenter, randomized trial investigating the efficacy and safety of ATRA plus danazol, a common agent in ITP management, versus danazol alone in patients with corticosteroid-resistant and/or relapsed ITP”, said Dr Fei-Er Feng (Peking University People’s Hospital, Beijing, China) at the Annual EHA Congress.
At twelve months of follow-up a sustained platelet response, the primary endpoint, was observed in 62% of the 45 patients in the combination arm versus 25% of the 48 patients in the control arm.2 The overall and complete response rates were 82% and 38%, respectively, following ATRA plus danazol and 44% and 8% after danazol monotherapy. In addition, ATRA also significantly improved the time to relapse, the peak platelet count and the duration of response. The most common adverse events in the combination arm were desquamation of the skin (64% versus 6% in the control arm), gastrointestinal events (20% versus 19%) and headache and dizziness (20% versus 17%). Feng: “In conclusion, treatment with ATRA plus danazol resulted in favorable and stable platelet counts, and is associated with minimal side effects. Therefore we believe that this combination treatment is a promising therapy in ITP.”
Cancer patients have an increased risk of deep vein thrombosis and pulmonary embolism (VTE) but also of bleeding. While anticoagulant therapy lowers the risk of thrombosis recurrence in these patients it also further increases the risk of bleeding. “Our objective was to determine the risk of dying from a thrombosis recurrence or bleeding in elderly patients with cancer and thrombosis. Hereto, we conducted a population-based retrospective cohort study in Ontario, Canada, that included patients of at least 65 years old with a VTE diagnosed within six months of cancer diagnosis. We estimated the VTE recurrence, gastrointestinal or CNS major bleeding (MB) events, and mortality rate at day seven following VTE recurrence or MB events”, said Dr Alejandro Lazo-Lagner (Western University, Ontario, Canada) at a press briefing of EHA 2017.
Between 2004 and 2014 6,967 VTE events in cancer patients (mean age 75 years, 52% male) were included in the study.3 Lazo-Lagner: “At six months of index VTE we observed 235 (3%) MB and 1,184 (17%) VTE recurrences. Interestingly, the 7-day mortality rate was 0.5% for VTE and 11% for MB, and the estimated 7-day mortality rate ratio was 22 (95% CI 9-53). These results indicate that that the use of anticoagulants in older cancer patients with thrombosis results in a higher mortality rate if they develop an MB event, compared to a VTE recurrence. This information should be confirmed in further studies and taken into account when designing studies and clinical practice interventions in this population.”
A Joint Symposium of the EHA and the International Society on Thrombosis and Hemostasis (ISTH) discussed anticoagulation in difficult to treat patients, such as frail patients. According to Chair Dr Francesco Rodeghiero (San Bortolo Hospital, Vicenza, Italy) this Joint Symposium recognized “the common role of the two international societies to foster education and understanding of thrombosis and hemostasis with particular attention to the practicing hematologists”. Updated results were presented on how to reliably estimate a favorable risk/benefit ratio of anticoagulation in old/frail patients, including the promising perspectives offered by non-vitamin K oral anticoagulants (NOACs). These patients have an increased risk of both thrombotic and hemorrhagic events and hence require expert attention. Furthermore, Dr Walter Ageno (University of Insubria, Varese, Italy) addressed the challenging aspects of risk factors, diagnosis and management of thrombosis in unusual sites like splanchnic and cerebral veins. These rare complications may occur also in the young and pose difficult choices in the hematology consultative setting. The use of NOACs in these patients remains unexplored.