Best practice & research. Clinical haematology
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Best Pract Res Clin Haematol · Jun 2016
ReviewPreclinical models of Waldenström's macroglobulinemia and drug resistance.
Newer therapeutic strategies are emerging in Waldenström's Macroglobulinemia (WM), which has traditionally been an orphan disease diagnosis. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor was FDA-approved in 2015 as the first ever drug for the treatment of WM. This being a targeted therapy, has given rise to increased research into novel agents and pathways that can be exploited for clinical benefit in WM. ⋯ Historically there had been a lack of representative preclinical models in WM, but in recent years this has dramatically changed. This review highlights the currently available preclinical models and data regarding drug resistance pathways in WM. Knowledge from these will certainly help in paving the future course of treatment in this rare disorder which is indolent and yet, so far incurable.
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Best Pract Res Clin Haematol · Mar 2016
ReviewB cell receptor inhibition as a target for CLL therapy.
Inhibitors of the B cell receptor (BCR) represent an attractive therapeutic option for patients with chronic lymphocytic leukemia. Recently approved inhibitors of Bruton's tyrosine kinase (ibrutinib) and phosphatidylinositol 3-kinase (idelalisib), are promising agents because they are generally well tolerated and highly effective. These agents may be particularly important in the treatment of older patients who are less able to tolerate the myelosuppression (and infections) associated with chemoimmunotherapy. ⋯ Ibrutinib has specific toxicities including increased risk for bleeding and atrial fibrillation. Idelalisib also has some unique toxicities consisting of transaminitis, diarrhea and pneumonitis. Ongoing clinical trials are evaluating these agents in combination with antibodies, chemotherapy and other small molecules.
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Isocitrate dehydrogenase (IDH) catalyzes the conversion of isocitrate to alpha ketoglutarate. IDH occurs in three isoforms, IDH1, located in the cytoplasm, IDH2 located in the mitochondria, and IDH3, which functions as part of the TCA cycle. ⋯ Notably, many cases of acute myeloid leukemia (AML) have mutations in R172 and R140. The impact of these mutations and early results of inhibiting mutant IDH2 with the reversible inhibitor AG-221 are discussed in this review.
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Best Pract Res Clin Haematol · Mar 2015
ReviewGenetic predisposition syndromes: when should they be considered in the work-up of MDS?
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by cytopenias, ineffective hematopoiesis, myelodysplasia, and an increased risk of acute myeloid leukemia (AML). While sporadic MDS is primarily a disease of the elderly, MDS in children and young and middle-aged adults is frequently associated with underlying genetic predisposition syndromes. In addition to the classic hereditary bone marrow failure syndromes (BMFS) such as Fanconi Anemia and Dyskeratosis Congenita, in recent years there has been an increased awareness of non-syndromic familial MDS/AML predisposition syndromes such as those caused by mutations in GATA2, RUNX1, CEBPA, and SRP72 genes. Here, we will discuss the importance of recognizing an underlying genetic predisposition syndrome a patient with MDS, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common BMFS and familial MDS/AML syndromes which may be encountered in adult patients with MDS.
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The discovery of the activating mutation JAK2 V617F ushered a new era in MPN which included new diagnostic and prognostic criteria as well as a potential therapeutic target. JAK2 inhibition became a reality with first patients receiving drugs that targeted JAK2 in 2007 and was marked by the first approval in 2011 of Ruxolitinib a JAK 1 and 2-inhibitor to treat myelofibrosis (MF). ⋯ Reflecting upon what we have learnt from the chronic myeloid leukaemia field and for MF regarding disease complexity as well as individual patient factors including resistance we discuss why it is likely we will need several different agents with JAK inhibitory activity. The next chapter discusses combination therapies for myelofibrosis which is a logical step in both trying to cure this disease and improve patient outcome and toxicities with JAK inhibitors.