Impact of the Type of BCR-ABL Fusion Transcripts on Response and Survival in Patients with Chronic Phase CML Treated with Four Frontline TKI Modalities
Authors: Jain Preetesh , Kantarjian Hagop M. , Luthra Raja , Nogueras Gonzalez Graciela , Jabbour Elias , Sasaki Koji , Guillermo Romo Carlos , Patel Keyur P. , Kadia Tapan , Borthakur Gautam , Estrov Zeev , Ravandi Farhad , O'Brien Susan , Cortes Jorge E. 
Published: October 2019

Abstract
Introduction: Most commonly observed BCR-ABL transcripts in CML are b3a2 (e14a2) and b2a2 (e13a2). The significance of transcript type regarding r outcome after frontline therapy with different TKI is not well known.
Methods: 481 pts with newly diagnosed CML-CP treated in single institution clinical trials with imatinib 400, imatinib 800, dasatinib or nilotinib were analyzed. Cytogenetic and molecular response, and survival endpoints were analyzed by transcript type.
Results: 200 (42%) expressed b2a2, 196 (41%) b3a2 and 85 (18%) coexpressed both transcripts. Pts with b2a2 had significantly lower platelets (Median 288 K/µL; range 15-1906 K/µL) compared to b3a2 (405 K/µL; 77-1476 K/µL) or both transcripts (358 K/µL; 100-2928 K/µL) (p<0.001). Other baseline characteristics (Sokal score, hemoglobin, WBC, blast%, spleen size and serum LDH) were not significantly different. The proportion of b2a2, b3a2 and both transcripts pts achieving complete cytogenetic response (CCyR) at 3 months was 59%, 67% and 63%, and at 6 months 73%, 81% and 82%, respectively. MMR 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, and MR4.5 at 6 and 12 months were 10%, 29%, and 30%, and 19%, 42% and 41%, respectively. At 3-months, BCR-ABL levels ≤10% were achieved in 75% with b2a2, 79% with b3a2 and 83% with coexpression. The median levels of transcripts (b2a2, b3a2 and both) at 3 months were 0.2004, 0.056 and 0.0612 respectively. Similarly the median levels of transcripts at 6 months were 0.091, 0.0109 and 0.0130 respectively. Pts with b2a2 transcripts demonstrated a slower rate of decline over time (3, 6, 12, 18, 24, 36 and 60 months) after treatment with TKI's as compared with b3a2 and coexpressed b2a2 and b3a2 transcripts (Figure-1A). Furthermore, median time to CCyR was similar in pts expressing b2a2, b3a2 and coexpressed b2a2 with b3a2 - 3 months in each transcript while time to MMR and MR4.5 was much longer in pts with b2a2 transcripts compared to b3a2 and coexpressed b2a2 with b3a2 (6, 3.5 and 3.5 months for MMR and 20, 10 and 11 months for MR4.5 respectively) (Figure-1B). Decline in b3a2 and coexpressed transcript levels over time was faster compared to b2a2 transcripts. For b2a2 transcripts, only the pts treated with nilotinib achieved reduction in levels similar to b3a2 and coexpressed transcripts. Overall, 5 year survival outcomes for b2a2, b3a2 and both transcripts cohorts were 78%, 89%, 87% for event-free survival (EFS; p=0.09); 91%, 97% and 99% for transformation-free survival (TFS; p=0.01) (Figure-1C-D); and 89%, 95% and 98% for overall survival (OS; p=0.34), respectively. In multivariate analysis (MVA), b3a2 and coexpressed transcripts predicted for significantly superior CCyR and MMR at 6 and 12 months. Similarly, type of transcripts significantly predicted for longer EFS (p=0.043; b3a2) and TFS (p=0.04 for coexpressed and 0.07 for b3a2) compared to b2a2.
Conclusions: Patients with b3a2 and coexpressed b2a2 and b3a2 achieve earlier and deeper and more durable responses compared to those with b2a2. This translates into improved TFS but not OS. The mechanism of differential responsiveness of pts with b2a2 and b3a2 warrants further investigation.
Figure 1. Kinetics of the type of transcript over time and time to achieve CCyR, MMR and MR4.5 according to the type of transcript. Event free and transformation free survival is shown after treatment with different TKI modalities. Figure 1. Kinetics of the type of transcript over time and time to achieve CCyR, MMR and MR4.5 according to the type of transcript. Event free and transformation free survival is shown after treatment with different TKI modalities.

Disclosures
Estrov: incyte: Consultancy, Research Funding. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.