RESUMO
An important pathogenetic distinction in the classification of myeloproliferative neoplasms (MPNs) is the presence or absence of the BCR-ABL fusion gene, which encodes a unique oncogenic tyrosine kinase. The BCR-ABL fusion, caused by the formation of the Philadelphia chromosome (Ph) through translocation, constitutes the disease-initiating event in chronic myeloid leukemia. The development of successive BCR-ABL-targeted tyrosine-kinase inhibitors has led to greatly improved outcomes in patients with chronic myeloid leukemia, including high rates of complete hematologic, cytogenetic, and molecular responses. Such levels of treatment success have long been elusive for patients with Ph-negative MPNs, because of the difficulties in identifying specific driver proteins suitable as drug targets. However, in recent years an improved understanding of the complex pathobiology of classic Ph-negative MPNs, characterized by variable, overlapping multimutation profiles, has prompted the development of better and more broadly targeted (to pathway rather than protein) treatment options, particularly JAK inhibitors. In classic Ph-negative MPNs, overactivation of JAK-dependent signaling pathways is a central pathogenic mechanism, and mutually exclusive mutations in JAK2, MPL, and CALR linked to aberrant JAK activation are now recognized as key drivers of disease progression in myelofibrosis (MF). In clinical trials, the JAK1/JAK2 inhibitor ruxolitinib - the first therapy approved for MF worldwide - improved disease-related splenomegaly and symptoms independent of JAK2 (V617F) mutational status, and prolonged survival compared with placebo or standard therapy in patients with advanced MF. In separate trials, ruxolitinib also provided comprehensive hematologic control in patients with another Ph-negative MPN - polycythemia vera. However, complete cytogenetic or molecular responses with JAK inhibitors alone are normally not observed, underscoring the need for novel combination therapies of JAK inhibitors and complementary agents that better address the complexity of the pathobiology of classic Ph-negative MPNs. Here, we discuss the role of tyrosine-kinase inhibitors in the current MPN-treatment landscape.
RESUMO
Patients with chronic lymphocytic leukemia (CLL) have a 2- to 5-fold risk of developing a second malignancy compared with the general population. The incidence of myeloid malignancies, such as acute myeloid leukemia and myelodysplastic syndrome, is increased in CLL and has been linked to previous therapy. In this study, we aim at describing characteristics and determining risk factors for developing second myeloid disorders (SMDs) in patients with CLL. From a total of 1269 patients diagnosed with CLL during the study time period, 30 (2.4%) were found to have an SMD. The majority of SMDs were myelodysplastic syndrome or acute myeloid leukemia (76.7%). The median time from diagnosis of CLL to diagnosis of SMD was 4.47 years. Most patients who developed an SMD had received treatment for their CLL (86%). The median time from treatment of CLL to diagnosis of SMD was 4.19 years. The overall survival of patients with CLL with no second malignancy was significantly longer than those with an SMD (11.9 vs. 7.1 years, P = .001). There was no association between developing SMD and age, gender, expression of CD38, expression of ZAP-70, and unmutated immunoglobulin heavy chain gene status. The risk of developing SMD in our cohort was higher in patients who received fludarabine- or alkylator-based therapy. Our analysis is one of the largest series showing that patients receiving fludarabine or alkylator-based therapies for CLL have a higher risk of developing SMD. Our study also confirms previous reports that prognostic factors in CLL do not increase the risk for development of SMD. Clinicians should understand the leukemogenicity of fludarabine or alkylator-based treatments when considering treatments for patients with CLL.
