Genetic mutations in chronic myelogenous leukemia: when to check and what to do?
Curr Opin Hematol. 2012 Jan 13;
Authors: Berman E
Abstract
PURPOSE OF REVIEW: The review will appraise the literature concerning ABL kinase domain mutations that has appeared over the last year and identify new questions, answers to old questions, and discuss new trends in clinical and laboratory based research. RECENT FINDINGS: A concise summary of European LeukemiaNet guidelines for kinase domain mutation studies was published this year. A new controversial topic emerged: the relevance of IC50 data to guide second-line tyrosine kinase inhibitor (TKI) therapy. Although flaws in the methodology have been acknowledged, one group summarily rejected IC50 data and recommended that clinicians use individual patient comorbidities and drug safety profiles. The influence of kinase domain mutations on response to second-line and third-line TKI therapy was also published this year; unexpectedly, kinase domain mutations were found to have no effect on response or survival. However, the presence of a kinase domain mutation did influence survival following hematopoietic stem cell transplantation. Lastly, new findings from laboratories identified transcription factors BCL6 and STAT5 as potential new treatment targets. SUMMARY: The last 12 months has brought much attention to clinical management of patients with kinase domain mutations and identified a new controversy concerning IC50 data use in the clinic. Kinase domain mutations do not appear to influence response to second-line and third-line response to TKI therapy. New targets that do not directly involve BCR-ABL added potential new therapeutic approaches.
PMID: 22248877 [PubMed - as supplied by publisher]
Optimizing hypomethylating agents in myelodysplastic syndromes.
Curr Opin Hematol. 2012 Jan 13;
Authors: Itzykson R, Fenaux P
Abstract
PURPOSE OF REVIEW: Hypomethylating agents (HMAs) improve the outcome of higher-risk myelodysplastic syndromes (MDS) and provide multilineage response in lower-risk patients but their results must be optimized, especially as the poor outcome of patients after HMA failure is now established. RECENT FINDINGS: Current efforts include evaluation of novel outpatient administration schedules and routes, improving compliance and drug exposure to reach continuous hypomethylation. Novel combination strategies are emerging, with histone deacetylase inhibitors or immunomodulatory compounds, but none has proven superior to HMA single-agent therapy so far. Improved understanding of the epigenetic deregulation of MDS and of HMA’s mode of action has allowed putative biomarkers to emerge, including multiple gene methylation patterns, and gene mutations, notably TET2 mutations. As HMAs may elicit antileukemic immune responses, they are also being evaluated in patients eligible for allogeneic stem cell transplantation. SUMMARY: The indication and practical use of HMAs in MDS so far remain those of phase III registration studies, but will hopefully be modified with future results of ongoing clinical and translational research.
PMID: 22248878 [PubMed - as supplied by publisher]
New induction and postinduction strategies in acute myeloid leukemia.
Curr Opin Hematol. 2012 Jan 13;
Authors: Burnett AK
Abstract
PURPOSE OF REVIEW: Improving or replacing the traditional induction (3 + 7) and consolidation (high-dose cytarabine; Ara-C) as the standard of care for acute myeloid leukemia (AML) has proved disappointing. RECENT FINDINGS: Recent studies have raised the possibility that daunorubicin dose escalation might have the potential to improve survival. Antibody-directed therapy by means of gemtuzumab ozogamicin as an adjunct to induction chemotherapy may yet be a viable option in older patients, and alternative nucleoside analogues in induction could help higher risk subgroups. In consolidation, the number of courses and dose level of Ara-C required are being clarified. New treatments for older patients who will not be subjected to conventional chemotherapy are an active area, but randomized trials have not yet usurped low-dose Ara-C (LDAC). SUMMARY: Recent information in these areas is reviewed.
PMID: 22248879 [PubMed - as supplied by publisher]
Treatment for relapsed acute myeloid leukemia: what is new?
Curr Opin Hematol. 2012 Jan 6;
Authors: Ofran Y, Rowe JM
Abstract
PURPOSE OF REVIEW: Despite enormous progress in the understanding of leukemia pathophysiology and novel transplantation protocols, the prognosis following acute myeloid leukemia (AML) relapse is still uniformly poor. In the current review, advances in risk stratification, protocols involving novel agents and allogeneic stem cell transplantation (ASCT) will be discussed in light of the vision of personalized therapy. RECENT FINDINGS: The role of ASCT in relapsed/refractory AML is well established and has been recently confirmed as mandatory for cure. Retrospective observations of different large cohorts categorized patients with early relapse, poor cytogenetics or fms-like tyrosine kinase receptor-3 internal tandem duplication mutation as the most challenging population. Multiple novel agents have been studied with various promising results; however, these agents can only serve as a bridge to transplantation. If ASCT is not an option, therapy should focus on prolongation of patient’s life at its best possible quality. Accumulated molecular data open new horizons for personalizing therapy and assigning each patient to the drug or protocol from which the patient will benefit most. SUMMARY: Relapsed/refractory AML is a heterogeneous disease and no uniform protocol will provide cure to all patients. Molecular tests may contribute to future personalizing therapy resulting in improved outcome. Meanwhile, novel and more effective induction and postremission protocols are warranted to lower the relapse rate.
PMID: 22227525 [PubMed - as supplied by publisher]
Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission: have the indications changed?
Curr Opin Hematol. 2012 Jan 6;
Authors: Paun O, Lazarus HM
Abstract
PURPOSE OF REVIEW: Many improvements in chemotherapy and supportive care, as well as greater understanding of immunology and procuring graft sources, have led to more acute myeloid leukemia patients proceeding to hematopoietic cell transplantation, now the most common indication for this procedure. RECENT FINDINGS: As treatment-related mortality rates have been reduced, more practitioners and patients are amenable to use of this modality if the risk : benefit ratio appears justified. Clinical factors initially were used to identify patients at highest risk for relapse using conventional approaches, a strategy supplanted by one based on the genetic alterations of the leukemia cells. More recently, molecular factors are used to identify such candidates; the issue of which first remission acute myeloid leukemia patients receive hematopoietic cell transplantation is referred to as risk stratification. SUMMARY: With significant improvements in donor : recipient matching and a more varied graft source, greater numbers of patients can proceed to alternative donor hematopoietic cell transplantation. Advancing age appears to be less of a barrier and outcomes are reasonable in patients with good performance status and few comorbidities. The most interesting aspect of the moving target of which patients to take to hematopoietic cell transplantation is to define those with favorable-risk disease and avoid the procedure, while using the armamentarium at hand to identify those at higher and highest risk for relapse as the group most likely to benefit. The field, however, still awaits the data that demonstrate improved outcome in these poor-risk patients using the hematopoietic cell transplantation approach.
PMID: 22227526 [PubMed - as supplied by publisher]
Transplantation for myelodysplastic syndrome in the era of hypomethylating agents.
Curr Opin Hematol. 2012 Jan 6;
Authors: Gerds AT, Deeg HJ
Abstract
PURPOSE OF REVIEW: This review summarizes the available data on the role of hypomethylating agents in the setting of hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). RECENT FINDINGS: Although hypomethylating agents have been established as standard of therapy for MDS in the nontransplant setting, the role of these agents in patients who are candidates for HCT or are undergoing HCT is less well defined. Hypomethylation therapy has been investigated in both the pre-HCT and post-HCT setting. Patients who are transplant candidates and are given pre-HCT hypomethylating therapy should proceed with HCT when ‘best response’ is achieved; HCT when hypomethylation has failed is associated with inferior outcome. Only limited data have been presented on the use of hypomethylating agents after HCT. Although this approach may prove to be useful in reducing post-HCT relapse, such therapy should only be given in the setting of clinical trials. SUMMARY: Treatment planning for patients with MDS who are HCT candidates should comprise the entire treatment arc including pre-HCT debulking, possibly with hypomethylating agents, conditioning regimen, and potential post-HCT treatment, be it prophylactic, pre-emptive or therapeutic.
PMID: 22227527 [PubMed - as supplied by publisher]
New generation small-molecule inhibitors in myeloproliferative neoplasms.
Curr Opin Hematol. 2012 Jan 6;
Authors: Passamonti F, Maffioli M, Caramazza D
Abstract
PURPOSE OF REVIEW: Myeloproliferative neoplasms (MPNs) are diseases that carry the JAK2 (V617F) mutation in about 70% of the patients. The purpose of this review is to describe the recent advances in the therapy of MPNs with JAK2 inhibitors. RECENT FINDINGS: Many drugs are now under investigations targeting different pathways critical for MPN development, such as the JAK-STAT (JAK2 inhibitors: INCB018424 or ruxolitinib, TG101348 or SAR302503, CYT387, SB1518, CEP701 and LY2784544) and the PI3K/AKT/mTOR (everolimus) pathways, or act through remodeling of chromatin with a key role in epigenetics (givinostat, panobinostat and vorinostat). The most relevant effects were spleen size reduction and relief of constitutional symptoms. SUMMARY: Patients who might benefit from JAK2 inhibitors in clinical practice are mostly those with splenomegaly or with constitutional symptoms. We should alert patients with lower hemoglobin levels that these therapies might, although temporarily, favor the need for red blood cell transfusions.
PMID: 22227528 [PubMed - as supplied by publisher]
Current treatment strategies in chronic myeloid leukemia.
Curr Opin Hematol. 2012 Jan 6;
Authors: Guilhot F, Roy L, Tomowiak C
Abstract
PURPOSE OF REVIEW: Imatinib was registered several years ago for the treatment of chronic-phase chronic myeloid leukemia. Because of the occurrence of resistance with imatinib, new drugs have been developed recently, two of which, nilotinib and dasatinib, are being registered for frontline therapy. However physicians may be confused as to how to treat and manage their newly diagnosed patients. The value of new scoring systems and well known surrogate markers such as cytogenetic and molecular responses as well as recent data from phase II or III trials are presented and discussed. RECENT FINDINGS: The analysis of trials comparing 400 mg of imatinib to higher doses suggests that 400 mg still seems to be the appropriate initial dose. However, doses of 800 mg could be proposed for high-risk patients or for those with slower response. Sokal and Euro scoring systems are useful and should be calculated before initiating the treatment. The achievement of early complete cytogenetic response is still a valid surrogate marker, although close molecular monitoring is also mandatory. Second-generation tyrosine kinase inhibitors have proved their efficacy by reducing the rate of progression to advanced phases. SUMMARY: Long-term follow-up of ongoing trials investigating tyrosine kinase inhibitors, alone or in combination with interferon, will assess their efficacy on overall survival.
PMID: 22227529 [PubMed - as supplied by publisher]
