Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV
Christian MichelAndreas BurchertAndreas HochhausSusanne SaußeleAndreas NeubauerMichael LausekerStefan W. KrauseHans‐Jochem KolbDieter K. HossfeldChristoph NerlGabriela M. BaerlocherDominik HeimTim H. BrümmendorfAlice FabariusClaudia HaferlachBrigitte SchlegelbergerLeopold BalleisenMaria-Elisabeth GoebelerMathias HänelAnthony D. HoJolanta DenglerChristiane FalgeRobert MöhleStephan KremersMichael KnebaFrank StegelmannClaus-Henning KöhneHans‐Walter LindemannCornelius F. WallerKarsten SpiekermannWolfgang E. BerdelLothar MüllerMatthias EdingerJiřı́ MayerDietrich W. BeelenMartin BentzHartmut LinkBernd HertensteinRoland J. FuchsMartin WernliFrank SchlegelRudolf SchlagMaike de WitLorenz TrümperHolger HebartMarkus HahnJörg ThomallaChristof ScheidPhilippe SchafhausenWalter VerbeekMichael J. EckartW. GaßmannMichael SchenkPeter BrossartThomas WündischThomas GeerStephan BildatErhardt SchäferJoerg HasfordRüdiger HehlmannMarkus Pfirrmann
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Abstract:
Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.Keywords:
Chronic myelogenous leukemia
Imatinib Mesylate
Imatinib Mesylate
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The discovery of molecularly targeted agents that selectively inhibit bcr-abl tyrosine kinase activity, such as imatinib, has revolutionized the treatment and natural history of chronic myelogenous leukemia (CML). Treatment of chronic-phase CML with imatinib showed complete cytogenetic response rates of more than 40% in patients after failure of interferon-α, and more than 80% in patients with newly diagnosed CML. Patients with CML can now expect excellent long-term survival, often without major side effects. In most patients, however, residual leukemic burden remains detectable using a sensitive reverse transcription-polymerase chain reaction method. In addition, many patients undergoing imatinib therapy will either not respond or lose their response over time because of resistance or intolerance. The introduction of second-generation tyrosine kinase inhibitors (TKIs) re-establishes response in approximately half of these patients. Several agents are being developed for treating patients who experience suboptimal response to second-generation TKIs and for those who develop resistance caused by the emergence of highly resistant BCR-ABL1 mutations. This article provides an overview of novel targeted agents available for CML.
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Chronic myelogenous leukemia
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Plasma imatinib levels vary widely in patients with the chronic myeloid leukemia-chronic phase, and studies have shown improved hematological, cytogenetic, and molecular responses in patients with the higher trough imatinib levels.We analyzed 50 consecutive patients with the chronic myeloid leukemia-chronic phase and performed plasma imatinib levels at 1 month and 12 months and correlated them with complete hematological response at 3 months and molecular response at 12 months, respectively.Trough plasma imatinib levels at 1 month correlated well with complete hematological response at 3 months (P = 0.007) and levels at 12 months correlated with molecular response at 12 months (P = 0.04). Compliance to imatinib also significantly correlated with imatinib levels at 1 month (P = 0.0008) and imatinib levels at 12 months (P = 0.0002).Plasma imatinib levels may be of benefit in patients not achieving desired response at defined time intervals. The plasma level monitoring also helps in the assessment of drug compliance.
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Objective To investigate the relationship between Axl and imatinib resistance.Methods Fifty-nine cases of chronic myeloid leukemia in the first affiliated hospital of Zhengzhou university between March 2009 and May 2012 were selected.The level of Axl mRNA was detected,and the expression levels of patients with different prognosis were compared.Results With the different efficacy of imatinib,Axl mRNA expression level of chronic myeloid leukemia patients were different.Axl mRNA expression levels had significant difference among patients with different treatment effect (P ＜ 0.05).Conclusions Axl is related to imatinib resistance in chronic myeloid leukemia patients.And the overexpression of Axl predicted the high incidence rate of matinib resistance.
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Imatinib-resistant; Chronic myeloid leukemia; Axl
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Treatment with imatinib has demonstrated high response rates and improved prognosis in chronic myelogenous leukemia. However, while the short-term response to imatinib is high, there are some concerns that the long-term response is substantially lower. Durable response with imatinib is difficult to achieve in patients with resistant disease. The use of higher doses has also been associated with increased toxicity and intolerance. Dasatinib is a new SRC–ABL-kinase inhibitor that has been developed for treating chronic myelogenous leukemia patients, across all phases of disease, who are resistant or intolerant to imatinib. This article details the existing evidence on the clinical efficacy, safety and value for money of dasatinib in the treatment of imatinib-resistant and -intolerant patients with chronic myelogenous leukemia. Dasatinib is associated with higher levels of response compared with high-dose imatinib. In addition, higher levels of response are associated with improved health outcomes in terms of both quality- and quantity-of-life years.
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OBJECTIVE To observe the efficacy and safety of low dosage imatinib in the treatment of chronic myelogenous leukemia in the blast crisis (CML-BC). METHODS 8 patients with CML-BC who had received interferon and hydroxyurea were treated with 200-300 mg·d -1 of oral imatinib for 18 to 94 weeks. RESULS 4 patients achieved complete hematological response and 2 patients achieved major hematological response.Imatinib induced major cytogenetic response in 2 patients and improved cytogenetic response in 2 patients. The adverse effects were little and tolerable. CONCLUSION Low dosage imatinib has also improved hematologic and cytogenetic responses in patients with CML-BC who had failed in previous therapy of interferon and hydroxyurea. Further investigation is required for long_term effects of low dosage imatinib on CML-BC.
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Multiple new agents are currently being developed in chronic myelogenous leukemia (CML). Most of these agents are now being investigated in patients who have developed resistance to imatinib. Their mechanisms of action are diverse and many may be synergistic with imatinib. These agents will be used soon in different combinations, most likely including imatinib, with the hope of obtaining a complete blockade of the intracellular pathways that are triggered by Bcr-Abl. If this is successful, complete eradication of disease may become a reality for the majority of patients with CML.
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Targeted Therapy
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