Better Molecular Response to Imatinib for Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Carrying the b3a2 Transcript Compared to b2a2.
Authors: Vega-Ruiz Arturo , Kantarjian Hagop , Shan Jenny , Wierda William , Burger Jan , Verstovsek Srdan , Garcia-Manero Guillermo , Cortes Jorge 
Published: April 2020

Background. Different types of BCR-ABL fusion mRNAs can be found in pts with CML due to different genomic breakpoints and alternative splicing. The two major forms join ABL exon 2 with exons 13 or 14 of BCR, resulting in two main transcripts, b2a2 and b3a2, respectively, that codify for a p210 protein present in the majority of CML patients. b3a2 is more frequent in newly diagnosed patients than the b2a2 transcript, and occasionally both transcripts may be present. The clinical significance of the specific transcript among CML pts treated with imatinib has not been clearly established, and some have suggested that b2a2 may be associated with better outcome. (Blood2006108: Abstract 4780) Genet.Mol. Res.4(4): 803–811 (2005)Journal of Clinical Oncology, 2007 Vol 25, No 18S (June 20 Supplement), 2007: 7043.

Purpose: To determine if there is a difference in outcome after imatinib therapy in CML pts according to their BCR-ABL transcript.

Methods: We analyzed 480 pts with CP CML treated with imatinib, 251 receiving imatinib as frontline therapy and 229 after interferon (IFN) failure. Molecular response was evaluated using RT PCR every 3 months (mo).

Results: The median follow-up was 62 mo (range 1–92 mo) Median age was 51 years (range 15–84). Overall, 187 of 480 (39%) pts expressed b2a2, 234 (49%) b3a2, 55 (11%) expressed both, and 4 (1%) expressed e1a2. The rates of major and complete cytogenetic response were similar for pts with b3a2 and b2a2, both in the newly diagnosed and the post-IFN failure: CCyR 91% for b3a2 and 89% for b2a2 in frontline, and 72% and 78%, respectively in the post-IFN failure group. However, among 433 pts evaluable for molecular response, transcript levels were significantly lower at 3, 6 and 12 months from start of therapy for pts with b3a2 compared to those with b2a2 (Table 1).

Table 1. Median BCR-ABL transcript levels over time by transcript type 3 months 6 months 9 months overall b2a2 1.8284 0.318 0.186 0.0464 b3a2 0.5175 0.0553 0.0352 0.0033 p-value 0.001 &lt;0.001 &lt;0.001 &lt;0.001

This resulted in a significantly higher probability of achieving a major molecular remission (MMR) and complete molecular remission (CMR; ie, undetectable transcript levels) for pts with the b3a2 transcript (Table 2).

Table 2 Molecular Response in patients Post IFN failure and patients newly treated Transcript No.* MMR** (%) P value CMR*** (%) P value *Number of evaluable patients. Dx=Diagnosis New Dx b2a2 106 63 59 26 25 New Dx b3a2 115 88 77 0.008 54 47 0.002 Post IFN b2a2 62 21 34 10 16 Post IFN b3a2 97 61 63 0.001 41 42 0.001

There was a trend for an improved transformation-free survival for pts with b3a2 compared to those with b2a2 (4-yr rates 98% vs 93%, respectively, p=0.08) and event-free survival (94% vs 87%, p=0.37). Although fewer pts co-expressed both transcript types, they behaved like the pts with b3a2.

Conclusion: Pts with the b3a2 transcript have a better molecular response to imatinib that those with b2a2. This prognostic factor should be considered when evaluating response to therapy.