Molecular Response to First Line Imatinib Therapy Is Predictive for Long Term Event Free Survival in Patients with Chronic Phase Chronic Myelogenous Leukemia – An Interim Analysis of the Randomized German CML Study IV
Authors: Müller Martin C. , Hanfstein Benjamin , Erben Philipp , Schnittger Susanne , Saussele Susanne , Leitner Armin , Proetel Ulrike , Lauseker Michael , Pfirrmann Markus , Ehninger Gerhard , Fischer Thomas , Hasford Joerg , Hossfeld Dieter K. , Kolb Hans Jochem , Krause Stefan W , Nerl Christoph , Pralle Hans , Gratwohl Alois , Tobler Andreas , Hehlmann Ruediger , Hochhaus Andreas ,   The German CML Study Group
Published: October 2019

Abstract
The introduction of imatinib has significantly changed prognosis of CML patients. Despite favourable hematologic and cytogenetic response (CyR) data, patients (pts) on first line imatinib therapy may relapse. Thus, studies have been conducted to improve initial therapy by dose escalation or combination with other drugs. CML Study IV was designed to compare imatinib in standard dose (400 mg/d) vs high dose (800 mg/d) vs combinations with low dose cytarabine or interferon alpha. We sought to evaluate the predictive impact of early molecular response for long term event free survival (EFS). 539 pts (59% m, median age 54 years, range 16–84) randomized to imatinib based therapies by December 2005 were investigated, the median follow up was 39 mo (range, 0–69). At baseline, multiplex PCR was applied to determine the dominating BCR-ABL transcript: b2a2 (n=204), b3a2 (n=247), b2a2 and b3a2 (n=80), e1a2 (n=2), e19a2 (n=4), b3a3 (n=1) and e8a2 (n=1). Quantitative PCR from 5,419 peripheral blood samples was performed using the LightCycler technology in two central labs. PCR data were aligned to the international scale (IS) by introduction of conversion factors (Hughes et al., BLOOD 2006). Cumulative molecular response of 539 pts at 3, 6, 12, 18, and 24 mo after randomization is summarized in the Table:
Month 3 6 12 18 24 BCR-ABLIS Achieved by % of pts ≤10% 41 66 81 85 86 ≤1% 16 41 65 76 78 ≤ 0.1% (MMR) 3 16 37 51 59 ≤0.01% 1 3 10 21 28
For analysis of prognostic impact, events were defined as (i) loss of complete hematologic response, (ii) loss of major CyR following loss of complete CyR, (iii) accelerated phase, (iv) blast crisis, and (v) death for any reason. Pts were censored at the time of allogeneic stem cell transplantation or switch to 2nd generation tyrosine kinase inhibitors because of imatinib intolerance or resistance. The minimum molecular response levels predictive for EFS were BCR-ABLIS of 10% after 6 mo (p=0.0029), 1% after 12 mo (p<0.0001), and 0.1% (major molecular response, MMR; p=0.0016) after 18 mo of imatinib based therapies. In order to investigate the reasons for unsatisfying responses BCR-ABL kinase domain mutations were assessed in 175 pts. 30 pts (17%) harbored 35 mutations affecting 18 different aminoacids. In conclusion, prospective molecular surveillance of CML shows that early response predicts stable remissions on first line imatinib therapy. After 6 mo of treatment, PCR data start to be predictive for EFS. In pts with unsatisfactory response or molecular, cytogenetic and hematologic relapse, BCR-ABL mutations have been detected in only 17% of pts. Calculation of molecular response rates dependent on the various imatinib based therapies will be performed after stop of randomization which is expected by the end of 2009.