Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors

Jain, Preetesh; Kantarjian, Hagop M.; Patel, Keyur P.; González, Graciela Nogueras; Luthra, Rajyalakshmi; Kanagal‐Shamanna, Rashmi; Sasaki, Koji; Jabbour, Elias; Romo, Carlos; Kadia, Tapan M.; Pemmaraju, Naveen; Daver, Naval; Borthakur, Gautam; Estrov, Zeev; Ravandi, Farhad; O’Brien, Susan; Cortes, Jorge

doi:10.1182/blood-2015-10-674242

Cited by 126 publications

(231 citation statements)

References 33 publications

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“…To our knowledge, this is the first report on the frequency of susMR4.5 in a prospective trial of frontline dasatinib in CML‐CP. We previously reported that the e14a2 transcript or e14a2 with the e13a2 transcript predicted improved EFS and TFS across patients taking different TKIs . Here, we show an association between the expression of non‐b2a2 (non‐e13a2) transcripts and the achievement of MR4.5 and susMR4.5.…”

Section: Discussionsupporting

confidence: 51%

Long‐term results of frontline dasatinib in chronic myeloid leukemia

Maiti

Cortes

Patel

et al. 2020

Cancer

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Background Dasatinib is a second‐generation tyrosine kinase inhibitor that, when used as frontline therapy, produces more and faster cytogenetic and molecular responses compared with imatinib. The authors report the long‐term follow‐up from the first study using dasatinib as initial therapy for chronic‐phase chronic myeloid leukemia. Methods Between November 2005 and August 2014, patients were randomly assigned to receive 100 mg daily or 50 mg twice daily. After June 2009, all patients started with 100 mg daily. Results With a median follow‐up of 6.5 years, 94 of 149 treated patients (63%) were still receiving dasatinib on study. The median patient age was 48 years (interquartile range, 37‐55 years), and 9% of patients had a high risk Sokal risk score. The cumulative complete cytogenetic response rate at 11 years was 92.6%, the major molecular response (MR) rate was 88.2%, and the MR4.5 rate (indicating a ≥4.5‐log reduction in BCR‐ABL1 transcripts) was 79.5%. The median time to a major MR and MR4.5 was 6 and 23 months, respectively. A sustained MR4.5 (≥2 years) was achieved in 82 patients (55%). The 10‐year overall survival, transformation‐free survival, event‐free survival, and failure‐free survival rates were 89%, 95%, 86%, and 65%, respectively. Univariate analysis showed that the achievement of a complete MR was associated with improved overall survival. The most common reasons for treatment discontinuation were toxicity and elective discontinuation. The most common treatment‐emergent grade 3 and 4 adverse events were fatigue, thrombocytopenia, and infections. Conclusions After this long‐term follow‐up, dasatinib continues to show an excellent safety profile and produces rapid cytogenetic responses and MRs, durable deep MRs, and excellent long‐term survival outcomes in patients with chronic‐phase chronic myeloid leukemia.

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Section: Discussionsupporting

confidence: 51%

Long‐term results of frontline dasatinib in chronic myeloid leukemia

Maiti

Cortes

Patel

et al. 2020

Cancer

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“…Some authors have found a better molecular response with the e14a2 transcript (Hanfstein et al, 2014;Lin et al, 2016;Jain et al, 2016) or e13a2 (de Lemos et al, 2005Sharma et al, 2010). Lin et al (2016) showed that males with e13a2 were a less favorable group in their response to imatinib treatment.…”

Section: Discussionmentioning

confidence: 99%

“…The identification of the type of transcript is important not only for minimal residual disease monitoring as different transcript types seem to represent distinct biological entities (Hanfstein et al, 2014), but also because the transcript type could be used to select treatment regimen for patients with CML (Jain et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

BCR-ABL1 transcript types showed distinct laboratory characteristics in patients with chronic myeloid leukemia

Vasconcelos¹,

Azevedo²,

Melo³

et al. 2017

Genet. Mol. Res.

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ABSTRACT. In chronic myeloid leukemia (CML) two main types of messenger RNA (e14a2 and e13a2) can be produced by BCR-ABL1 gene rearrangement. Due to conflicting results, the clinical value of these transcripts remains controversial. The aim of this study was to identify associations of e14a2 and e13a2 transcripts with laboratory variables and also the response to treatment. This study included 203 adult patients with CML treated with Imatinib as first-line drug in a reference hematology center in Northeast Brazil. Clinical and laboratory data were obtained after informed consent. Samples were collected for RNA extraction and analyzed by reverse transcription-polymerase chain reaction (PCR), according to the international protocol BIOMED-1. The LeukemiaNet 2013 criteria were used to establish the molecular response. The frequency distribution of the BCR-ABL1 transcripts was e14a2 (64%), e13a2 (34%), and double positives (2%). The results showed a statistically significant association of the e14a2 transcript type with thrombocytosis (P = 0.0005) and the e13a2 with higher leukocyte count (P = 0.0491). In a subgroup of 44 patients, the molecular response to treatment with Imatinib was assessed by quantitative PCR at 3 months (BCR-ABL1 ≤ 10%), 6 months (BCR-ABL1 ≤ 1%), or 12 months (BCR-ABL1 ≤ 0.1%). Although patients with the transcript e14a2 showed higher frequency of good responses than patients with the transcript e13a2, this difference was not statistically significant. In agreement with published data, our results showed association of the BCR-ABL1 transcript e14a2 with thrombocytosis and the BCR-ABL1 transcript e13a2 with higher leukocytosis in patients with chronic myeloid leukemia.

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“…Some exceptions could be patients with high-risk features such as high-risk Sokal scores, or the few with p190, or perhaps those with high-risk features determined by emerging biomarkers. 27,28 Proactive sequencing can then be planned by using strict criteria to optimize results. In this regard, it is important to set the goals for each patient from the start of therapy because goals may vary from patient to patient.…”

Section: A Proposalmentioning

confidence: 99%

Chronic myeloid leukemia: sequencing of TKI therapies

Cortes

Kantarjian

2016

Hematology

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Multiple tyrosine kinase inhibitors (TKIs) are available for managing patients with chronic myeloid leukemia. Although most patients have a favorable outcome with their initial therapy, whether imatinib or a second-generation TKI was used, some will require subsequent use of one or more different TKIs. Such sequencing might be indicated in a reactive way (ie, for patients who have experienced resistance or intolerance to their initial therapy) or in a proactive way (ie, for patients with a somewhat favorable outcome who have not reached an "optimal" outcome). Sequencing of TKIs has become standard practice, and the proper use of sequenced TKIs is likely to optimize outcomes and resource utilization. Learning Objectives• Assess the different scenarios in which TKI sequencing can be used in patients with chronic myeloid leukemia • Critically review the outcomes associated with sequencing of TKI in patients with chronic myeloid leukemia Tyrosine kinase inhibitors (TKIs) became standard therapy for patients with chronic myeloid leukemia (CML) not long after the first patient received STI571 (later known as imatinib mesylate) on a phase I clinical trial. 1 The initial approved indication was for patients with resistance to or intolerance of interferon alpha-based therapy, the standard at the time. By 2003, imatinib was approved as frontline therapy for CML, 2 and since then, nearly all patients with access to TKIs have received them as initial therapy. Shortly thereafter, secondgeneration agents, including dasatinib, nilotinib, and bosutinib, with increased potency, different structures that allowed them to overcome most mutations leading to resistance to TKIs, and different toxicity profiles, were introduced and eventually received regulatory approval. Later, ponatinib, a drug with activity against T315I and all mutations tested, proved effective in overcoming resistance in most patients, even those who had received 3 or more prior TKIs. All TKIs were eventually compared with imatinib in the first-line setting, and they generally demonstrated higher response rates, with deeper and faster responses which, in the case of dasatinib and nilotinib, were sufficient to lead to their approval as initial therapy for patients with chronic phase CML (CML-CP). This rapid development has resulted in the availability of multiple TKIs, and along with this, the sequential use of various TKIs in patients with CML-CP (Figure 1).The use of sequential TKI therapy, regardless of the choice of initial therapy, is perhaps more common than is usually appreciated. Despite the professed efficacy of initial therapy with TKIs, at least onethird of all patients initially treated in clinical trials with any TKI for newly diagnosed CML, whether imatinib or a second-generation TKI, have received at least one additional TKI. After 5 years of follow-up in the DASISION trial (in the final report), 39% of patients initially treated with dasatinib and 37% of those treated with imatinib are no longer receiving their initial therapy.3 Similarly, the 5-ye...

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Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors

Cited by 126 publications

References 33 publications

Long‐term results of frontline dasatinib in chronic myeloid leukemia

Long‐term results of frontline dasatinib in chronic myeloid leukemia

BCR-ABL1 transcript types showed distinct laboratory characteristics in patients with chronic myeloid leukemia

Chronic myeloid leukemia: sequencing of TKI therapies

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