Early BCR-ABL1 Reduction Is Predictive of Better Event-free Survival in Patients With Newly Diagnosed Chronic Myeloid Leukemia Treated With Any Tyrosine Kinase Inhibitor

Fava, Carmen; Rege‐Cambrin, Giovanna; Dogliotti, Irene; Gottardi, Enrico; Berchialla, Paola; Gioacchino, Bruno Di; Crasto, Francesca; Lorenzatti, Roberta; Volpengo, Alessandro; Daraio, Filomena; Fantino, Cristina; Saglio, Giuseppe

doi:10.1016/j.clml.2016.03.008

Cited by 12 publications

(15 citation statements)

References 20 publications

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“…Like Fava et al, we were able to show that landmark analysis is valuable using the ABL1 gene as a control gene. Because most laboratories use either ABL1 or BCR as a control gene, this method can be applied in many medical institutions.…”

Section: Discussionsupporting

confidence: 69%

Rapid reduction in BCR‐ABL1 transcript predicts deep molecular response in dasatinib‐treated chronic‐phase chronic myeloid leukaemia patients

Murai

Yamaguchi

Ito

et al. 2017

European J of Haematology

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Objectives We conducted a phase‐II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic‐phase chronic myeloid leukaemia (CML‐CP) in Japan (IMIDAS PART 2 study). Methods Seventy‐nine patients were administered 100 mg dasatinib once daily. We examined pretreatment and post‐treatment influences of various factors. The BCR‐ABL1 international scale (IS), halving time (HT) and reduction rate of BCR‐ABL1 transcript within the initial 1 or 3 months of therapy (RR‐BCR‐ABL11m,3m) were the post‐treatment factors investigated to predict the molecular response. Results The estimated major molecular response (MMR), molecular response 4.0 (MR4.0) and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4% and 35.4%, respectively, at 12 months. Grade 3/4 non‐haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post‐treatment factors at 3 months predicted DMR by univariate analysis. However, RR‐BCR‐ABL13m was the only significant landmark for predicting DMR by multivariate analysis. Conclusions Primary treatment of CML‐CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR‐BCR‐ABL13m was found to be a more useful predictor of DMR than HT‐BCR‐ABL1 and BCR‐ABL1 IS.

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Section: Discussionsupporting

confidence: 69%

Rapid reduction in BCR‐ABL1 transcript predicts deep molecular response in dasatinib‐treated chronic‐phase chronic myeloid leukaemia patients

Murai

Yamaguchi

Ito

et al. 2017

European J of Haematology

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“…We thereafter investigated whether another cutoff point could predict long-term achievement of molecular response and outcome in our cohort. Based on the fact that the initial tumor burden might reflect different extents of an ongoing disease 18 , 19 , our study focused on the kinetics of the BCR-ABL1 decline from the individual patient baseline point to the 3-month values. We observed that some patients had very little or no decline, whereas others had more than a 50-fold reduction.…”

Section: Resultsmentioning

confidence: 99%

Early BCR-ABL1 decline in imatinib-treated patients with chronic myeloid leukemia: results from a multicenter study of the Chinese CML alliance

Zhang

Wang

et al. 2018

Blood Cancer Journal

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An early molecular response is spectacularly predictive of outcome in chronic myeloid leukemia (CML) and early response landmarks may identify the high-risk patients likely to be benefit from an early therapy switch. In this study, we evaluated the most relevant cutoffs for early molecular response markers (BCR-ABL1 values at 3 months, log reduction and halving time between diagnosis and 3 months) in 476 first-line imatinib-treated Chinese patients with chronic phase CML. All outcomes were significantly superior for the 324 patients with 3-month BCR-ABL1 ≤10%, so did for the 270 patients with BCR-ABL1 >0.61 log reduction. BCR-ABL1 halving time ≤22 days was identified for patients with the most favorable outcome. Moreover, the prognosis was significantly poorest for patients with both halving time >44 days and BCR-ABL1 >10%. Importantly, multivariate regression analysis demonstrated that a BCR-ABL1 log reduction calculated at 3 months of 0.61 was the only variable that significantly predicted for OS. Our results highlight the importance of rapid initial decline of BCR-ABL1 in predicting satisfactory outcome. Our data support the evidence that monitoring BCR-ABL1 values at an early time point could contribute to accurately assess response and ultimately guide clinical decisions regarding the timing of therapeutic intervention.

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“…These recommendations were based on strong evidence collected over many years [27][28][29][30][31][32][33][34][35] and subsequent studies consolidated the recommendations. [36][37][38][39][40][41] The importance of a one-log reduction of BCR-ABL1 by 3 months and two-log reduction by 6 months for progression-free survival was reported as early as 2003. 28,29 The equivalent BCR-ABL1 transcript values on the IS are 10% and 1%, respectively.…”

Section: Why Is It Critical To Achieve a Deep Molecular Response In Cmentioning

confidence: 99%

Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

Branford

2020

haematol

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The primary goal of tyrosine kinase inhibitor (TKI) therapy for patients with chronic myeloid leukemia is survival, which is achieved by the vast majority of patients. The initial response to therapy provides a sensitive measure of future clinical outcome. Measurement of BCR-ABL1 transcript levels using real-time quantitative polymerase chain reaction standardized to the international reporting scale is now the principal recommended monitoring strategy. The method is used to assess early milestone responses and provides a guide for therapeutic intervention. When patients successfully traverse the critical first 12 months of TKI therapy, most will head towards another milestone response, deep molecular response (DMR, BCR-ABL1 ≤0.01%). DMR is essential for patients aiming to achieve treatment-free remission and a prerequisite for a trial of TKI discontinuation. The success of discontinuation trials has led to new treatment strategies in order for more patients to reach this milestone response. DMR has been incorporated into endpoints of clinical trials and is considered by some expert groups as the optimal treatment response. But is DMR a stable response and does it provide the ultimate protection against TKI resistance and death? Do we need to increase the sensitivity of detection of BCR-ABL1 to better identify the patients who would likely remain in treatment-free remission after TKI discontinuation? Is it necessary to switch current TKI therapy to a more potent inhibitor if the goal is to achieve DMR? These are issues that I will explore in this review.

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Early BCR-ABL1 Reduction Is Predictive of Better Event-free Survival in Patients With Newly Diagnosed Chronic Myeloid Leukemia Treated With Any Tyrosine Kinase Inhibitor

Cited by 12 publications

References 20 publications

Rapid reduction in BCR‐ABL1 transcript predicts deep molecular response in dasatinib‐treated chronic‐phase chronic myeloid leukaemia patients

Rapid reduction in BCR‐ABL1 transcript predicts deep molecular response in dasatinib‐treated chronic‐phase chronic myeloid leukaemia patients

Early BCR-ABL1 decline in imatinib-treated patients with chronic myeloid leukemia: results from a multicenter study of the Chinese CML alliance

Why is it critical to achieve a deep molecular response in chronic myeloid leukemia?

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