Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib

Hanfstein, Benjamin; Lauseker, Michael; Hehlmann, Rüdiger; Saußele, Susanne; Erben, Philipp; Dietz, Christian; Fabarius, Alice; Proetel, Ulrike; Schnittger, Susanne; Haferlach, Claudia; Krause, Stefan W.; Schubert, Jöerg; Einsele, Hermann; Hänel, Matthias; Dengler, Jolanta; Falge, Christiane; Kanz, Lothar; Neubauer, Andreas; Kneba, Michael; Stegelmann, Frank; Pfreundschuh, Michael; Waller, Christiane; Spiekermann, Karsten; Baerlocher, Gabriela M.; Pfirrmann, Markus; Hasford, Joerg; Hofmann, Wolf‐Karsten; Hochhaus, Andreas; Müller, Martin C.

doi:10.3324/haematol.2013.096537

Cited by 107 publications

(179 citation statements)

References 28 publications

(21 reference statements)

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“…Consistent with previous reports, our analysis shows a higher platelet count in patients with e14a2 transcripts 21,35 ; however, we did not detect any difference in white blood cell counts as had been reported by Hanfstein et al, 21 nor did we identify any other significant difference in the baseline characteristics of patients with different transcripts. In our analysis, the rates of MCyR and CCyR, as well as MMR and MR4.5, were lower in patients with e13a2 transcripts at various time points.…”

Section: Bcr-abl Transcripts and Tki In CML 1273supporting

confidence: 78%

“…This is consistent with what was reported by Hanfstein et al in 1105 imatinib-treated patients. 21 Superior molecular responses in patients with e14a2 transcripts were reported previously in patients treated with standard-dose imatinib. 21,23 The median time to achieve MMR or MR4.5 was longer in patients with imatinib 400 compared with the other 3 TKI modalities, irrespective of the type of transcript.…”

Section: Bcr-abl Transcripts and Tki In CML 1273mentioning

confidence: 93%

“…The prognostic significance of the BCR-ABL1 transcripts 16,17 has been reported from patients treated with interferon alone 18 or imatinib 400 mg. 19 Improved response has been reported in patients carrying the e14a2 (b3a2) transcript compared with those with the e13a2 (b2a2) transcripts after treatment with standard-dose imatinib. 14,[19][20][21][22][23][24] This observation correlates with higher activity of phospho CrKL (CT10 regulator of kinase-like) a surrogate marker of BCR-ABL1 tyrosine kinase activity in patients with e13a2 transcripts. 25 Secondary structure elements are different in e14a2 due to the presence of extra 25 amino acids not seen in e13a2 transcripts, possibly indicating that e14a2 and e13a2 transcripts may have different roles in mediating signal transduction pathways in CML.…”

Section: Introductionmentioning

confidence: 98%

“…Previous reports have suggested that patients with e14a2 achieve deeper molecular response to standard dose imatinib 23 and have higher platelet counts compared with patients with e13a2 transcripts. 19,21 To our knowledge, no prior analyses have suggested any influence of transcript type on survival outcomes or tested whether the type of transcript can predict for an optimal ELN response. Of further note, we showed that patients expressing the e13a2 transcript have a significantly lower incidence of sustained MR4.5 response compared with e14a2 and coexpressed transcripts (supplemental Figure 4).…”

Section: Bcr-abl Transcripts and Tki In CML 1273mentioning

confidence: 99%

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

Jain

Kantarjian

Patel³

et al. 2016

Blood

129

216

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• Patients with e13a2 transcripts have inferior outcomes with imatinib 400; e14a2 has favorable outcomes regardless of treatment modality.• Multivariate analysis showed that the expression of e14a2 or both e14a2 and e13a2 predicts optimal ELN responses and longer EFS and TFS.The most common breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts in chronic myeloid leukemia (CML) are e13a2 (b2a2) and e14a2 (b3a2). The impact of the type of transcript on response and survival after initial treatment with different tyrosine kinase inhibitors is unknown. This study involved 481 patients with chronic phase CML expressing various BCR-ABL transcripts. Two hundred patients expressed e13a2 (42%), 196 (41%) expressed e14a2, and 85 (18%) expressed both transcripts. The proportion of patients with e13a2, e14a2, and both achieving complete cytogenetic response at 3 and 6 months was 59%, 67%, and 63% and 73%, 81%, and 82%, respectively, whereas major molecular response rates were 27%, 49%, and 50% at 3 months, 42%, 67%, and 70% at 6 months, and 55%, 83%, and 76% at 12 months, respectively. Median (international scale) levels of transcripts e13a2, e14a2, and both at 3 months were 0.2004, 0.056, and 0.0612 and at 6 months were 0.091, 0.0109, and 0.0130, respectively. In multivariate analysis, e14a2 and both predicted for optimal responses at 3, 6, and 12 months. The type of transcript also predicted for improved probability of event-free (P 5 .043; e14a2) and transformation-free survival (P 5 .04 for both). Compared to e13a2 transcripts, patients with e14a2 (alone or with coexpressed e13a2) achieved earlier and deeper responses, predicted for optimal European Leukemia Net (ELN) responses (at 3, 6, and 12 months) and predicted for longer event-free and transformation-free survival. (Blood. 2016;127(10):1269-1275

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Section: Bcr-abl Transcripts and Tki In CML 1273supporting

confidence: 78%

Section: Bcr-abl Transcripts and Tki In CML 1273mentioning

confidence: 93%

Section: Introductionmentioning

confidence: 98%

Section: Bcr-abl Transcripts and Tki In CML 1273mentioning

confidence: 99%

See 2 more Smart Citations

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

Jain

Kantarjian

Patel³

et al. 2016

Blood

129

216

View full text Add to dashboard Cite

show abstract

“…However, these assays fail to distinguish the type of BCR-ABL transcript present. Different BCR-ABL transcripts result in different clinical courses (18), and the impact of the type of transcript on response and survival rate subsequent to initial treatment with different tyrosine kinase inhibitors demonstrates different outcomes (19). True categorization of the BCR-ABL transcript by breakpoint is required in order to investigate and comprehend the different types of CML, and thus provides accurate guides for the treatment and prognosis of the disease.…”

Section: Discussionmentioning

confidence: 99%

How to detect the rare BCR‑ABL (e14a3) transcript: A case report and literature review

Yang

et al. 2017

Oncol Lett

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Abstract. The Philadelphia (Ph; BCR-ABL) chromosome originates from a translocation event between chromosomes 9 and 22, and results in the BCR-ABL fusion gene. In chronic myelogenous leukemia (CML), the BCR-ABL gene is mainly coded for by a major breakpoint cluster region (M-bcr, e13a2 and e14a2). However, in some patients, BCR-ABL genes are encoded by a minor (m)-bcr, e1a2, and a micro (µ)-bcr region, e19a2. These transcripts revealed a different clinical course. The present study described a CML patient whose cytogenetics and FISH analyses of bone marrow revealed a karyotype of 46, XY t(9,22) (q34;q11), while the commercial kits of quantitative PCR (qPCR) failed to detect the BCR-ABL fusion gene. Further multiplex Reverse transcription-PCR (RT-PCR) and sequencing analyses identified a rare e14a3 (b3a3) fusion transcript.

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The BCR‐ABL1 transcript type influences response and outcome inPhiladelphia chromosome‐positive chronic myeloid leukemia patients treated frontline with imatinib

et al. 2017

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Funding information BolognAIL, AIRCThe most frequent BCR-ABL1 fusion transcripts in chronic myeloid leukemia (CML) are the e13a2 (b2a2) and the e14a2 (b3a2) ones. In the imatinib era few studies addressing the prognostic significance of the BCR-ABL1 transcript type in early chronic phase CML have been published. Overall, these studies suggest that in e14a2 patients the response to imatinib is faster and deeper. To evaluate if the BCR-ABL1 transcript type (e13a2 compared to e14a2) affect the response to imatinib and the clinical outcome in newly diagnosed adult CML patients, 559 patients enrolled in 3 prospective studies (NCT00514488, NCT00510926, observational study CML/023) were analyzed. A qualitative PCR was performed at baseline: 52% patients had a e14a2 transcript, 37% a e13a2 transcript, 11% co-expressed both transcripts and 1% had other rare transcripts. The median follow-up was 76 months (95% of the patients had at least a 5-year observation). The complete cytogenetic response rates were comparable in e14a2 and e13a2 patients. The median time to MR 3.0 (6 and 12 months) and MR 4.0 (41 and 61 months) was significantly shorter for e14a2 patients compared to e13a2 patients, with a higher cumulative probability of MR 3.0 (88% and 83%, P < .001) and MR 4.0 (67% and 52%, P 5 .001). The 7-year overall survival (90% and 83%, P 5 .017), progression-free survival (89% and 81%, P 5 .005) and failure-free survival (71% and

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Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib

Cited by 107 publications

References 28 publications

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

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

How to detect the rare BCR‑ABL (e14a3) transcript: A case report and literature review

The BCR‐ABL1 transcript type influences response and outcome inPhiladelphia chromosome‐positive chronic myeloid leukemia patients treated frontline with imatinib

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