Impact of the BCR-ABL1 fusion transcripts on different responses to Imatinib and disease recurrence in Iranian patients with Chronic Myeloid Leukemia.

One genomic breakpoint can result in variable BCR-ABL1 transcript types due to alternative splicing. The influence of different BCR-ABL1 transcript types on clinical outcome is still controversial. The objective of this analysis was to determine the impact of transcript type on response, clinical outcome, recurrence risk after treatment with Imatinib mesylate in Chronic Myeloid Leukemia (CML) patients. Sixty CML patients in chronic phase were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and banding standard protocols. There was a significant difference in collective incidence of complete cytogenetic response (CCR) between the e14a2 and e13a2 groups (P=0.04). The median time to achieve CCR was shorter in e14a2 patients than to e13a2 (P=0.01). This finding is paralleled by the molecular response where the median of the BCR-ABL1/ABL1 expression levels were significantly lower in e14a2 transcript compared to e13a2 type at 3, 6, 9 and 12months from the start of therapy (P<0.01). The probability of recurrence after treatment discontinuation was 9.33 fold higher in e13a2 transcript, that is reported here for the first time (χ2=5.49; P=0.01; OR: 9.33; 95% CI: 1.59, 54.67). No significant difference was observed regarding overall survival (OS), although Patients with e14a2 transcript displayed a significant tendency toward a higher event free survival (EFS) ratio (P=0.03). We found that patients with the e14a2 transcript achieved better and faster responses to Imatinib mesylate. In this study, parallel data regarding molecular and cytogenetic responses, impact of transcript type on the probability of recurrence might suggest a general outcome that the type of transcript can be used as a prognostic marker at diagnosis.

Rostami G ，Hamid M ，Jalaeikhoo H 《-》

The BCR-ABL1 transcript type influences response and outcome in Philadelphia chromosome-positive chronic myeloid leukemia patients treated frontline with imatinib.

The 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 MR3.0 (6 and 12 months) and MR4.0 (41 and 61 months) was significantly shorter for e14a2 patients compared to e13a2 patients, with a higher cumulative probability of MR3.0 (88% and 83%, P < .001) and MR4.0 (67% and 52%, P = .001). The 7-year overall survival (90% and 83%, P = .017), progression-free survival (89% and 81%, P = .005) and failure-free survival (71% and 54%, P < .001) were significantly better in patients with e14a2 transcript. In conclusion, patients with e13a2 transcript had a slower molecular response with inferior response rates to imatinib and a poorer long-term outcome.

Castagnetti F ，Gugliotta G ，Breccia M ，Iurlo A ，Levato L ，Albano F ，Vigneri P ，Abruzzese E ，Rossi G ，Rupoli S ，Cavazzini F ，Martino B ，Orlandi E ，Pregno P ，Annunziata M ，Usala E ，Tiribelli M ，Sica S ，Bonifacio M ，Fava C ，Gherlinzoni F ，Bocchia M ，Soverini S ，Bochicchio MT ，Cavo M ，Giovanni M ，Saglio G ，Pane F ，Baccarani M ，Rosti G ，GIMEMA CML Working Party ... -  《-》

No influence of BCR-ABL1 transcript types e13a2 and e14a2 on long-term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib.

Pfirrmann M ，Evtimova D ，Saussele S ，Castagnetti F ，Cervantes F ，Janssen J ，Hoffmann VS ，Gugliotta G ，Hehlmann R ，Hochhaus A ，Hasford J ，Baccarani M ... -  《-》

Influence of BCR-ABL Transcript Type on Outcome in Patients With Chronic-Phase Chronic Myeloid Leukemia Treated With Imatinib.

The prognostic significance of breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) transcripts in chronic myeloid leukemia (CML) is still controversial. All consecutive CML patients in chronic phase treated with imatinib in a single center were analyzed (n = 170). BCR-ABL1 transcript was evaluated using multiplex reverse transcription polymerase chain reaction. Exclusively patients with BCR-ABL transcripts e13a2 and/or e14a2 were included in this analysis. Patients with e14a2 transcripts presented higher rates of optimal molecular responses at 3 months and higher rates of complete cytogenetic response (CCR) at 6 months. E13a2, e14a2, and e14a2 with e13a2 (e14a2+e13a2) groups presented similar rates of 5-year event-free, progression-free, and overall survival. There was a superior 10-year overall survival in patients with transcripts e13a2 compared with e14a2 (alone or coexpressed with e13a2; 93% vs. 73%; P = .03), although the 5-year overall survival was 96% vs. 88%, respectively (P = not significant). In a multivariate analysis, high/intermediate Sokal score and e14a3/e14a3+e14a2 were independent factors for poor overall survival (hazard risk [HR], 4.63; P = .023 for Sokal score and HR, 10.6; P = .041 for BCR-ABL transcript). Patients with BCR-ABL transcripts e14a2 transcripts have higher rates of CCR at 6 months and higher rates of optimal molecular response at 3 months compared with e13a2 or with both transcripts, but no difference in 5-year overall, progression-free, and event-free survival. There was a superior 10-year overall survival among patients with transcripts e13a2 compared with e14a2 (alone or coexpressed with e13a2).

Pagnano KBB ，Miranda EC ，Delamain MT ，Duarte GO ，de Paula EV ，Lorand-Metze I ，de Souza CA ... -  《-》

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

Vasconcelos AP ，Azevedo IF ，Melo FCBC ，Neves WB ，Azevedo ACAC ，Melo RAM ... -  《Genetics and Molecular Research》