Expert review of hematology
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Pixantrone is a first-in-class aza-anthracenedione approved as monotherapy for treatment of relapsed or refractory aggressive diffuse B-cell non-Hodgkin's lymphoma (NHL), a patient group which is notoriously difficult to treat. It has a unique chemical structure and pharmacologic properties distinguishing it from anthracyclines and anthracenediones. Areas covered: The chemical structure and mode of action of pixantrone versus doxorubicin and mitoxantrone; preclinical evidence for pixantrone's therapeutic effect and cardiac tolerability; efficacy and safety of pixantrone in clinical trials; ongoing and completed trials of pixantrone alone or as combination therapy; and the risk of cardiotoxicity of pixantrone versus doxorubicin and mitoxantrone. ⋯ Pixantrone is currently being investigated as combination therapy with other drugs including several targeted therapies, with the ultimate goal of improved survival in heavily pretreated patients. In order for pixantrone to be acknowledged in the treatment of aggressive NHL, the perception of pixantrone as an anthracycline-like agent that has anthracycline-like activity and cardiotoxicity needs to be changed. Further data from ongoing clinical trials will help in confirming pixantrone as an effective and safe option.
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After the CLOT study, LMWHs (low-molecular weight heparins) have gradually replaced warfarin as the treatment of choice for VTE (venous thromboembolism) in cancer patients. Randomized controlled studies comparing DOACs (direct oral anticoagulants) to LMWHs in cancer patients are still limited. However, new emerging data are supporting the use of DOACs in cancer-associated thrombosis. ⋯ Expert commentary: Up until the Hokusai VTE Cancer study, data on the use of DOACs in cancer patients have been limited but supportive of their use in such patients. The Hokusai VTE Cancer study shows that edoxaban is non-inferior to dalteparin in prevention of recurrent VTE but at expense of higher major bleeding namely in patients with gastrointestinal cancer. Although further studies involving other DOACs may reinforce the efficacy of DOACs in this population of patients, studies looking at subpopulation of cancer patients may be of more clinical value to clinicians who are trying to balance between treatment of thrombosis and risks of bleeding.
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The majority of patients with acute myeloid leukemia (AML) are older and exhibit a poor prognosis even after intensive therapy. Inducing differentiation and apoptosis of leukemic blasts by DNA-hypomethylating agents, like e.g. azacytidine (AZA) and decitabine (DAC), represent well-tolerated alternative treatment approaches. Both agents show convincing response as single agents in AML. ⋯ Expert commentary: Numerous studies have demonstrated that HMA therapy with AZA or DAC may lead to significant response rates, even in pre-treated patients. Nevertheless, there is still an unmet need to further improve outcome in elderly AML patients. Therefore, novel treatment combinations are needed and some of them, such as AZA plus venetoclax, already show promising results.
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Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease. Deregulation of apoptosis is a major pathogenetic feature, and represents a therapeutic target. TP53 disrupted patients are categorized as high risk patients and are treated with novel target therapies. ⋯ Expert commentary: The availability of venetoclax represents a major advance in CLL treatment and offers new opportunities to further improve the results obtained until now by combining venetoclax with other agents. Venetoclax has achieved responses also in patients with TP53 disruption. These results strongly suggest that the mechanism by which venetoclax kills CLL cells might overcome a dysfunctional TP53 that is a major hallmark of chemorefractoriness to conventional antineoplastic agents.
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Immunotherapy is a promising modality of treatment of neoplastic diseases, including acute lymphoblastic leukemia (ALL). The CD19/CD3-bispecific T cell-engaging (BiTE®) monoclonal antibody blinatumomab can transiently bind cytotoxic T cells to CD19+ target B cells of ALL inducing their serial lysis. ⋯ Blinatumomab has a favorable safety profile, although reversible CNS events and cytokine release syndrome can occur. Ongoing trials in ALL incorporate blinatumomab in the first line therapy of BCP ALL in combination with chemotherapy, targeted therapies or other immunotherapies with the aim of increasing the depth of the remission and decreasing the probability of relapse.