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Blast-phase myeloproliferative neoplasms: risk factors and treatment approaches.

ABSTRACT: Introduction: The past 10 years have seen dramatic advances in the understanding of the molecular pathogenesis of BCR-ABL negative myeloproliferative neoplasms (MPNs). With this knowledge has come novel, molecularly targeted therapies such as JAK inhibitors that may decrease symptoms and improve quality of life for patients with MPNs. Despite these advances, progression of the disease to an acute leukemic (blast) phase remains difficult to predict and even more difficult to treat, with high rates of disease relapse and mortality.Areas covered: We performed a literature review of known risk factors for progression of MPNs towards blast phase and treatment options for transformed disease, including approved and investigational agents. Herein, we review the current literature and suggest strategies for improving outcomes in the future.Expert commentary: Further understanding of the biologic basis for transformation of MPNs from the chronic to blast phase is needed in order to predict, prevent, and treat these cases. Patients with MPNs in blast phase should be encouraged to participate in clinical trials whenever possible.

SUBMITTER: Pettit K

PROVIDER: S-EPMC7521397 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Blast-phase myeloproliferative neoplasms: risk factors and treatment approaches.

Pettit Kristen K Odenike Olatoyosi O

Expert review of hematology 20160729 9

<b>Introduction:</b> The past 10 years have seen dramatic advances in the understanding of the molecular pathogenesis of <i>BCR-ABL</i> negative myeloproliferative neoplasms (MPNs). With this knowledge has come novel, molecularly targeted therapies such as JAK inhibitors that may decrease symptoms and improve quality of life for patients with MPNs. Despite these advances, progression of the disease to an acute leukemic (blast) phase remains difficult to predict and even more difficult to treat, ...[more]

PMID: 27385032

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Project description:JAK inhibitors have been developed following the discovery of the JAK2V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity. Thus, JAK inhibitors targeting preferentially JAK1 and JAK3 have been developed to treat inflammation, autoimmune diseases, and graft-versus-host disease. Ten years after the beginning of clinical trials, only two drugs have been approved by the US Food and Drug Administration: one JAK2/JAK1 inhibitor (ruxolitinib) in intermediate-2 and high-risk myelofibrosis and hydroxyurea-resistant or -intolerant polycythemia vera and one JAK1/JAK3 inhibitor (tofacitinib) in methotrexate-resistant rheumatoid arthritis. The non-approved compounds exhibited many off-target effects leading to neurological and gastrointestinal toxicities, as seen in clinical trials for MPNs. Ruxolitinib is a well-tolerated drug with mostly anti-inflammatory properties. Despite a weak effect on the cause of the disease itself in MPNs, it improves the clinical state of patients and increases survival in myelofibrosis. This limited effect is related to the fact that ruxolitinib, like the other type I JAK2 inhibitors, inhibits equally mutated and wild-type JAK2 (JAK2WT) and also the JAK2 oncogenic activation. Thus, other approaches need to be developed and could be based on either (1) the development of new inhibitors specifically targeting JAK2V617F or (2) the combination of the actual JAK2 inhibitors with other therapies, in particular with molecules targeting pathways downstream of JAK2 activation or the stability of JAK2 molecule. In contrast, the strong anti-inflammatory effects of the JAK inhibitors appear as a very promising therapeutic approach for many inflammatory and auto-immune diseases.

Dataset Information

Blast-phase myeloproliferative neoplasms: risk factors and treatment approaches.

Publications

Blast-phase myeloproliferative neoplasms: risk factors and treatment approaches.

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