Expert review of hematology
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Although assessment of prior personal and familial bleeding history is an important aspect of the diagnosis of bleeding disorders, patients with mild inherited bleeding disorders are sometimes clinically asymptomatic until presented with a hemostatic challenge. However, bleeding may occur after incursion of trauma or surgery, so detection of these conditions reflects an important facet of clinical and laboratory practice. ⋯ Following determination of abnormal screening tests, subsequent investigation should follow a systematic approach that targets specific diagnostic tests, and including factor assays, full platelet function assays and more extensive specialized hemostasis testing. The current report provides a personal overview on inherited disorders of blood coagulation and their detection.
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Inhibitor development is the most serious adverse event linked to the treatment of hemophilia, as it renders standard hemostatic therapy ineffective. Consequently, inhibitor patients are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. ⋯ In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or IX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined.
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The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. ⋯ Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ≥65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL.
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B-cell receptor (BCR) signaling plays a vital role in B-cell malignancies; Bruton tyrosine kinase is a critical mediator of this signaling. BCR signaling, either constitutively or following antigen binding, leads to activation of several downstream pathways involved in cell survival, proliferation and migration. The efficacy observed in studies of the Bruton tyrosine kinase inhibitor, ibrutinib, confirms that BCR signaling is critical for the growth of B-cell malignancies. ⋯ Ibrutinib has been shown to have an excellent safety profile and does not cause myelosuppression. Early data from combination studies of ibrutinib with anti-CD20 monoclonal antibodies have shown more rapid responses compared to those seen with ibrutinib monotherapy. Current data strongly support continued clinical evaluation of ibrutinib in B-cell malignancies.
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Once characterized by a very poor outcome, multiple myeloma (MM) now has a significantly prolonged survival, with major improvements allowed by the use of 'novel agents': proteasome inhibitors (first-in-class bortezomib) and immunomodulatory compounds (IMiDs; first-in-class thalidomide and lenalidomide). However, the vast majority - if not all - of patients with MM ultimately end up being refractory to all existing drugs, including these efficient novel agents. There is a clear unmet medical need in this situation, which warrants the development of the next generation of proteasome inhibitors and IMiDs, as well as new drug classes. This drug profile focuses on pomalidomide, the next generation IMiD, recently approved by the US FDA and the EMA for patients with relapsed or refractory MM who have received at least two prior therapies, including lenalidomide and bortezomib, and have demonstrated disease progression on their last therapy.