B3a2 Transcript Is an Independent Factor for the Achievement of a Deep Molecular Response in Chronic Phase - Chronic Myeloid Leukemia Patients Treated with Imatinib in First-Line
Authors: Da Silva Matheus Sebastian , Miranda Eliana C , Delamain Marcia Torresan , Duarte Gislaine Oliveira , Vergilio Bruna R , Lopes Ana Beatriz Pascoal , Vianna Jessica CN , De Souza Carmino Antonio , De Paula Erich Vinicius , Pagnano Katia B 
Published: October 2019

Abstract
Introduction: The achievement of a deep and sustained molecular response after treatment with tyrosine kinase inhibitors (TKI) is one of the requirements for therapy discontinuation in chronic myeloid leukemia (CML) patients.
Objectives: This study aimed to evaluate the proportion of CML patients treated with imatinib in first-line that achieve MR4.5 (BCR-ABL transcripts ≤ 0.0032% in the international scale) after imatinib treatment and the predictive factors for this response. The secondary objectives were to evaluate the rate of MMR (PCR ≤0.1%), MR4.0 (PCR ≤ 0.01%), time to molecular responses, event-free survival, progression-free and overall survival.
Patients and methods: This is a retrospective analysis of CP-CML patients treated in first-line with imatinib in a single center. Patients diagnosed after 2006 were managed according to the European Leukemia Net recommendations. All patients started CML imatinib within six months from diagnosis. The type of BCR-ABL1 transcript was determined by multiplex RT-PCR from cDNA synthesized from total leukocytes RNA at diagnosis. BCR-ABL transcripts by quantitative real-time polymerase chain reaction were assessed at baseline, and then every three months for the first year until reaching a stable major molecular response, then every 3-6 months. The SPSS software was used for the Cox Regression model for univariate and multivariate analysis, using backward Wald. The cumulative incidence was calculated with the R Program, with Gray test for curve comparisons. Event-free, progression-free and overall survivals were calculated with the Kaplan-Meier method, and the curves were compared with the log-rank test.
Results: From January 2005 to December 2015 172 patients were treated with imatinib, median age 48 years (18-93), 55.8% male. Sokal score: 31% low-risk, 40% intermediate-risk and 29% high-risk. The median follow-up was 56 months (0-157). The Cumulative Incidence (CI) of MMR was 48% in 24 months and 84% in 5 years, while the CI of MR4.0 and MR4.5 was 63% and 51%, respectively, in 5 years. The median time to MMR, MR4.0 and MR4.5 was 16.7 (2-102), 31 (5-150) and 36 months (7-153), respectively. The univariate regression factors related to MR4.5 achievement were: age >48 years (HR 1.79; 95%CI: 1.08-2.98; P=0.023); days between diagnosis and imatinib start (HR=0.99; 95%CI: 0.98-0.99, P=0.020); e14a2 (b3a2) transcript (HR= 3.37; 95%CI: 1.67-6.81; P=0.001), which was the only factor in the multivariate analysis. Imatinib was discontinued in 96/172 (55.8%) patients due to resistance (36.5%), intolerance (20.8%), clinical trials (25%), death (15.6%) and adherence (2.1%). Eighteen out of 67 (26.8%) patients that achieved MR4.5 are currently participating in a discontinuation trial. Overall survival, PFS and EFS were 92%, 87% and 61% in 5 years.
Conclusion: Approximately half of the patients that start imatinib in first-line obtain deep molecular responses within five years and could be candidates for treatment discontinuation. B3a2 transcript was an independent factor for MR4.5 achievement in the multivariate analysis, confirming the results of other studies that have reported earlier and deeper molecular responses in patients with b3a2 transcripts.

Disclosures
De Paula: Hematology and Transfusion Medicine Center, University of Campinas: Employment. Pagnano:Abbvie: Consultancy; EMS: Other: Financial support for participation in congress; Shire: Other: Lecture; Novartis: Consultancy.