357 research outputs found
Monitoring Molecular Response to Tyrosine Kinase Therapy in Chronic Myelogenous Leukemia
No full textThe dramatic decline in mortality rates in chronic myelogenous leukemia (CML) is a direct result of the advent of tyrosine kinase inhibitors (TKIs) and the dawning of the targeted era. Although many patients experience long-term benefits from imatinib or related agents, problems with resistance and tolerance dampen the outcomes for many others. During his presentation at the NCCN 19th Annual Conference, Dr. Jerald Radich reviewed the ever-expanding menu of TKIs for CML and shared his thoughts on resolving the clinical questions regarding when to start which drugs, how to sequence the drugs, and how best to decide when to change the therapeutic tack.</jats:p
Long-term response to imatinib is not affected by the initial dose in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: final update from the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) study
No full textAbstract not availableMichele Baccarani; Brian J. Druker; Susan Branford; Dong-Wook Kim; Fabrizio Pane; Lidia Mongay; Manisha Mone; Christine-Elke Ortmann; Hagop M. Kantarjian; Jerald P. Radich; Timothy P. Hughes; Jorge E. Cortes; François Guilho
A Review of Mutation Analysis In the TOPS Trial of Standard Dose Versus High Dose IM In CML Suggests That Refinements to the ELN Recommendations for Mutation Screening May Be Appropriate
No full textPublished online October 12, 2015.Susan Branford, Hyun-Gyung Goh, Barbara Izzo, Lan Beppu, Christine-Elke Ortmann, Kamila Duniec, Yu Jin, Richard C. Woodman, Fabrizio Pane, Dong-Wook Kim, Jerald P. Radich, and Timothy P. Hugheshttp://ash.confex.com/ash/2010/webprogram/Paper31856.htm
Long-term outcomes of imatinib treatment for chronic myeloid leukemia
No full textBACKGROUND: Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy. METHODS: In this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events. RESULTS: The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment. CONCLUSIONS: Almost 11 years of follow-up showed that the efficacy of imatinib persisted over time and that long-term administration of imatinib was not associated with unacceptable cumulative or late toxic effects. (Funded by Novartis Pharmaceuticals; IRIS ClinicalTrials.gov numbers, NCT00006343 and NCT00333840.)Andreas Hochhaus, Richard A. Larson, François Guilhot, Jerald P. Radich, Susan Branford, Timothy P. Hughes, Michele Baccarani, Michael W. Deininger, Francisco Cervantes, Satoko Fujihara, Christine, Elke Ortmann, Hans D. Menssen, Hagop Kantarjian, Stephen G. O, Brien, and Brian J. Druker, for the IRIS Investigator
The Molecular Biology of Myeloproliferative Disorders
No full textThe myeloproliferative disorders (MPDs) are a spectrum of clonal disorders of the hematopoietic system. The discovery of activating mutations of the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and primary myelofibrosis has lead to in vitro and animal model studies that promise to lead to therapeutic advances
Initial molecular response at 3 months may predict both response and event-free survival at 24 months in Imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with Nilotinib
No full textPURPOSE: The association between initial molecular response and longer-term outcomes with nilotinib was examined. PATIENTS AND METHODS: Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). RESULTS: BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. CONCLUSION: Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response.Susan Branford, Dong-Wook Kim, Simona Soverini, Ariful Haque, Yaping Shou, Richard C. Woodman, Hagop M. Kantarjian, Giovanni Martinelli, Jerald P. Radich, Giuseppe Saglio, Andreas Hochhaus, Timothy P. Hughes and Martin C. Mülle
Optimizing outcomes for patients with advanced disease in chronic myelogenous leukemia
No full textThe treatment of chronic myelogenous leukemia (CML) has been revolutionized by the development of the small-molecule tyrosine kinase inhibitor imatinib. The primary target for this drug is the oncogenic BCR-ABL kinase. Five-year survival rates for patients in chronic phase CML is now greater than 80%. Patients who have advanced beyond the chronic phase to the accelerated phase or blast crisis, however, have not faired as well. Progression occurs for a variety of reasons, including late diagnosis, slow response to imatinib, and the development of imatinib-resistant clones. Imatinib resistance has, in part, been addressed with the introduction of the new BCR-ABL inhibitors, namely dasatinib and nilotinib. These drugs have shown efficacy in CML patients with wild-type BCR-ABL and some BCR-ABL mutants that are imatinib-resistant. Unfortunately, some BCR-ABL mutations remain resistant to these therapies and will require the development of alternative treatments, and other mechanisms of imatinib resistance besides BCR-ABL mutation exist. In the future, genetic and pharmacologic tests may allow the clinician to predict response to imatinib. More aggressive therapies are being considered for high-risk patients, including increased dosage of the current tyrosine kinase inhibitors, along with combination therapies. Aggressive therapy holds promise, as the data suggest that responses are improved. Unfortunately, toxicities are also increased, and thus a balance must be found to ensure safety and compliance. This is especially important for young CML patients, who hopefully will remain in remission for decades. Polymerase chain reaction analysis has become of primary importance as a means of assessing disease burden, and given the idiosyncrasies of this technique, standards must be established to allow results to be compared across different institutions. Additionally, the nature of advanced disease is being explored. Intriguingly, genetic analysis of transformed blasts from patients in blast crisis has identified numerous members of the Wnt/B-catenin pathway and JunB as being activated. Increased activity of these pathways correlates with poor response and eventual disease progression. In addition to these data, evidence is emerging associating survival of the quiescent blast cell with Wnt activity, leading to the hope that Wnt inhibitors will increase the likelihood of eradicating these cells. Other areas such as microRNA profiling and DNA methylation patterns are likely to provide important information.Francis J. Giles, Daniel J. DeAngelo, Michele Baccarani, Michael Deininger, François Guilhot, Timothy Hughes, Michael Mauro, Jerald Radich, Oliver Ottmann and Jorge Corte
Implications of BCR-ABL1 kinase domain-mediated resistance in chronic myeloid leukemia
No full textPatients with chronic myeloid leukemia develop resistance to both first-generation and second-generation tyrosine kinase inhibitors (TKIs) as a result of mutations in the kinase domain (KD) of BCR-ABL1. A wide range of BCR-ABL1 KD mutations that confer resistance to TKIs have been identified, and the T315I mutant has proven particularly difficult to target. This review summarizes the prevalence, impact, and prognostic implications of BCR-ABL1 KD mutations in patients with chronic myeloid leukemia who are treated with current TKIs and provides an overview of recent treatment guidelines and future trends for the detection of mutations.Simona Soverini, Susan Branford, Franck E. Nicolini, Moshe Talpaz, Michael W.N. Deininger, Giovanni Martinelli, Martin C. Müller, Jerald P. Radich, Neil P. Sha
Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet
No full textPurpose: To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including monitoring, response definition, and first- and second-line therapy. Methods: These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008. Results: Cytogenetic monitoring was required at 3, 6, 12, and 18 months. Molecular monitoring was required every 3 months. On the basis of the degree and the timing of hematologic, cytogenetic, and molecular results, the response to first-line imatinib was defined as optimal, suboptimal, or failure, and the response to second-generation TKIs was defined as suboptimal or failure. Conclusion: Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.Michele Baccarani, Jorge Cortes, Fabrizio Pane, Dietger Niederwieser, Giuseppe Saglio, Jane Apperley, Francisco Cervantes, Michael Deininger, Alois Gratwohl, François Guilhot, Andreas Hochhaus, Mary Horowitz, Timothy Hughes, Hagop Kantarjian, Richard Larson, Jerald Radich, Bengt Simonsson, Richard T. Silver, John Goldman and Rudiger Hehlman
- …
