Leukemia supplements最新文献

Autophagy inhibition has been shown to sensitize tumor cells to cell death induced by tyrosine kinase inhibitors (TKIs). The remarkable responses obtained in seven patients with the combination of clarithromycin and TKIs support the hypothesis that the inhibition of autophagy may make chronic myeloid leukemia cells sensitive to killing by TKIs.

The aim of minimal residual disease (MRD) studies in patients with acute leukemia is to measure initial treatment response accurately, provide an assessment of the residual leukemic burden throughout therapy and detect relapse early. Therefore, information resulting from MRD monitoring can substantially improve many facets of clinical management. Methods for MRD detection, namely flow cytometry and PCR, have been applied to study the remission status of thousands of patients with acute lymphoblastic leukemia and acute myeloid leukemia. Collectively, the data indicate that MRD is a powerful prognostic indicator and an indispensable parameter for risk-adapted therapy. The current status of MRD in acute leukemia is briefly reviewed in this paper.

Impressive response rates and good tolerability have led imatinib 400 mg once a day to become the standard frontline therapy for chronic myeloid leukemia (CML) patients. However, approximately one-third of the treated patients do not respond in an optimal manner to this drug, and the appropriate type and rhythm of CML monitoring, as well as the correct action to be undertaken in case of failure or suboptimal responses to imatinib therapy have been published in specific recommendations by European Leukemia Net and National Comprehensive Cancer Network. Failure and also cytogenetic suboptimal responses strongly demand for a change in treatment and for a switch from imatinib to one of the two second-generation tyrosine kinase inhibitors (TKIs) so far registered, dasatinib and nilotinib, for which efficacy as second-line therapy in imatinib-resistant or intolerant cases has been clearly demonstrated in phase II studies, and for which 4-year updates are now available. Other TKIs, at the moment, still under clinical investigation for imatinib-resistant patients include bosutinib and the next-generation TKI ponatinib. Different efficacy and safety criteria characterize each of the mentioned compounds and may help to decide on the one to be preferably used in individual patients.

Tyrosine kinase inhibitors (TKIs) directed against the ABL kinase are now used routinely during frontline therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) and result in hematologic remission rates exceeding 90%. Minimal residual disease levels are generally lower when TKIs are used in combination with chemotherapy rather than as monotherapy. Although outcome has improved substantially with TKI-based regimens compared with historic controls, allogeneic stem cell transplantation (SCT) in first remission provides the best chance of cure for the majority of patients eligible for SCT. Administration of imatinib after SCT further reduces molecular recurrence and is associated with greatly improved relapse-free and overall survival. The high relapse rate in non-transplanted patients is largely attributable to the emergence of leukemic clones with mutations in the tyrosine kinase domain of BCR-ABL. Ongoing studies with newer TKIs will determine whether these more potent agents are able to sustain remissions without SCT. Assessment of minimal residual disease has become an integral part of the management of Ph+ALL, as it has prognostic importance and is used to guide therapeutic intervention. Novel immunotherapeutic interventions and combinations of TKIs are currently being investigated in clinical trials and may further improve the prognosis of patients with Ph+ALL.

Although chronic myeloid leukemia (CML) is now defined on the basis of the presence of the BCR-ABL1 fusion gene, which may or may not be the initial genetic event that triggers the inappropriate expansion of the myeloid cell mass, CML, similar to other leukemias, is in fact clinically heterogeneous. The biological basis for this heterogeneity is unknown. Here, we summarize some of the data illustrating this heterogeneity and speculate about possible mechanisms that may cause it. It could, for example, be intrinsic in the leukemia stem cell or could be related to some aspect of the patient's response to the leukemia.

Bacterial infection is a very common complication in hematological neutropenic patients whose treatment is extremely challenging for several reasons. First, they are frequently caused by resistant pathogens (multidrug resistant (MDR)), and this may limit the availability of effective therapeutic weapons. Second, these patients often present peculiar pathophysiological conditions that may alter the pharmacokinetic behavior of antimicrobials, and this may explain the need for a new administration schedule and new dosing regimens of antibiotics in this setting. In an era in which there are only few new therapeutic weapons for the treatment of MDR bacterial infections, while advocating for new drugs, what could be effectively done nowadays is to increase the knowledge on appropriateness of the use of currently available drugs to improve clinical outcome and to preserve their activity.

The myeloproliferative neoplasm, myelofibrosis (MF), has only one therapeutic intervention that is potentially curative in these individuals, specifically that of allogeneic stem cell transplantation (ASCT). ASCT has been utilized up to this juncture, primarily in younger individuals with higher risk disease. There is more limited data on outcomes in individuals over the age of 60 years. The choice of an individualized therapeutic intervention for a patient with MF is a very complex issue and is dependent on several factors. The first factor being their overall prognosis with their illness (which can vary from a median of 2 years in high-risk patients to over 10 years in low-risk patients) and the potential impact of a therapeutic intervention not only on survival but also on quality of life. Current available therapies have been strictly palliative for disease-associated anemia and/or splenomegaly. At present, we have a new generation of inhibitors of JAK2 (Ruxolitinib, CYT387, SB1518, TG101348, with others in development), which have been shown to improve splenomegaly, improve symptomatic burden of illness and improve quality of life. In addition, these inhibitors of JAK2 may have an impact on the natural history of MF, but confirmation of the presence and degree of this impact is still pending. Clinical availability of JAK2 inhibitors may alter the timing of transplant in marginal transplant candidates (that is, those over the age of 60), may have a role preceding ASCT to improve spleen size and performance status before transplant and might be frontline therapy in intermediate and high-risk patients who are not candidates for ASCT.