Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV

Hehlmann, Rüdiger; Müller, Martin C.; Lauseker, Michael; Hanfstein, Benjamin; Fabarius, Alice; Schreiber, Arnd; Proetel, Ulrike; Pletsch, Nadine; Pfirrmann, Markus; Haferlach, Claudia; Schnittger, Susanne; Einsele, Hermann; Dengler, Jolanta; Falge, Christiane; Kanz, Lothar; Neubauer, Andreas; Kneba, Michael; Stegelmann, Frank; Pfreundschuh, Michael; Waller, Christiane; Spiekermann, Karsten; Baerlocher, Gabriela M.; Ehninger, Gerhard; Heim, Dominik; Heimpel, Hermann; Nerl, Christoph; Krause, Stefan W.; Hossfeld, Dieter K.; Kolb, Hans‐Jochem; Hasford, Joerg; Saußele, Susanne; Hochhaus, Andreas

doi:10.1200/jco.2013.49.9020

Cited by 281 publications

(271 citation statements)

References 35 publications

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“…Imatinib is recognized as one of the best and safest first line treatments for chronic phase CML [5][6][7] and is associated with a normal or near-normal life expectancy among treated patients [8,9], even at diagnosis [10]. Imatinib induces complete cytogenetic response (CCyR) in up to 86% of CML patients, while major molecular responses (MMR) develop in 33-90% of the patients according to treatment duration [10,11].…”

Section: Introductionmentioning

confidence: 99%

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

et al. 2015

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Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10 7 , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class 45 to <65 years and 33% of patients 65 years [P(v 2 ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR1) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

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Section: Introductionmentioning

confidence: 99%

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

et al. 2015

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“…With 5 years of follow-up in ENESTnd, 54% of patients in the nilotinib 300-mg twice-daily arm achieved MR 4.5 and 96% of patients had freedom from progression to AP/BC (vs. the imatinib arm: 31% [P < 0.0001] and 92% [P 5 0.0403], respectively) [16]. Retrospective landmark analyses of other independent clinical trials have demonstrated similar associations between deeper molecular responses and improved OS, event-free survival, and failure-free survival [20,29,35]. For example, patients who achieved a confirmed MR 4.5 at 4 years on frontline imatinib in the German CML IV trial had significantly higher OS at 8 years than patients who did not achieve this level of stable molecular response [20].…”

Section: Importance Of Achieving Deep Molecular Responses To Tki Therapymentioning

confidence: 97%

“…The latest NCCN guidelines recommend additional monitoring to detect any disease progression and the consideration of a change in the treatment regimen when BCR-ABL1 IS is > 10% at the 3-month time point [7]. This recommendation is based on several retrospective landmark analyses that show the prognostic significance of early molecular response with TKIs [9,[20][21][22][23]. As a result of these changes in response criteria, recommendations for monitoring responses, including molecular responses, are also evolving.…”

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confidence: 99%

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

Erba

2015

American J Hematol

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Imatinib was the first BCR-ABL1 tyrosine kinase inhibitor (TKI) developed for the treatment of patients with chronic myeloid leukemia (CML); subsequently, the introduction of more potent BCR-ABL1 TKIs has raised expectations regarding the speed and depth of response. This review discusses how molecular monitoring is being used as an integral part of the treatment regimen to achieve improved outcomes in patients with CML. The long-term prognostic implications of achieving early molecular response to TKI therapy and the feasibility of maintaining treatment-free remission will also be discussed in light of current clinical data.

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“…Similarly, molecular response is assessed at 3,6,12 and 18 months and thereafter periodically for follow-up. It is evident from the literature that the patients who have suboptimal cytogenetic or molecular response at a given point of time fare poorly in the long run [32][33][34]. Interpretation of these tests and alteration in treatment for management of suboptimal response is out of purview of this article.…”

Section: Chronic Myelogenous Leukemia (Cml)mentioning

confidence: 99%

Current Role of Genetics in Hematologic Malignancies

Prakash

Kaur

Malhotra

et al. 2015

Indian J Hematol Blood Transfus

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Rapidly changing field of genetic technology and its application in the management of hematological malignancies has brought significant improvement in treatment and outcome of these disorders. Today, genetics plays pivotal role in diagnosis and prognostication of most hematologic neoplasms. The utilization of genetic tests in deciding specific treatment of various hematologic malignancies as well as for evaluation of depth of treatment response is rapidly advancing. Therefore, it is imperative for practitioners working in the field of hemato-oncology to have sufficient understanding of the basic concepts of genetics in order to comprehend upcoming molecular research in this area and to translate the same for patient care.

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Deep Molecular Response Is Reached by the Majority of Patients Treated With Imatinib, Predicts Survival, and Is Achieved More Quickly by Optimized High-Dose Imatinib: Results From the Randomized CML-Study IV

Abstract: MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.

Cited by 281 publications

References 35 publications

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Molecular monitoring to improve outcomes in patients with chronic myeloid leukemia in chronic phase: Importance of achieving treatment‐free remission

Current Role of Genetics in Hematologic Malignancies

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