Sustained Complete Molecular Response to Imatinib in Chronic Myeloid Leukemia (CML): a Target Worth Aiming and Achieving?.
Authors: Verma Dushyant , Kantarjian Hagop M , Shan Jenny , O'Brien Susan , Verma Amit , Jabbour Elias , Verstovsek Srdan , Kadia Tapan , Rios Mary Beth , Cortes Jorge 
Published: October 2019

Abstract 505

Background:

Therapy with imatinib and other tyrosine kinase inhibitors leads to complete cytogenetic response (CCyR) in 80-90% of patients in chronic phase (CP) of CML, but most patients have residual disease documented by real-time quantitative polymerase chain reaction (PCR). Only a minority of patients achieve complete molecular response (CMR), as defined by undetectable levels of BCR-ABL fusion transcripts by PCR with sensitivity of at least 4.5 logs. Achieving CMR may offer the possibility of treatment discontinuation.

Aims:

To identify patients with sustained CMR (CMR of at least 6 months consecutively on 2 different dates) so as to define i) incidence of sustained CMR, ii) significance in long-term outcome (event-free survival, survival, transformation), and iii) predictive factors for CMR.

Methods:

We analyzed records of all patients with CML in early chronic phase (ie, within 12 months from diagnosis) treated with imatinib as frontline therapy at MD Anderson Cancer Center from July 2000 to Aug 2009. Major molecular response was defined as a BCR-ABL/ABL ratio of ≤0.05%, and CMR as undetectable transcripts in an assay with a sensitivity of at least 4.5 logs. Molecular responses were considered sustained only if they met the criteria for response in at least 2 consecutive assays separated over a period of at least 6 months. All patients were followed by PCR every 3 months for the first 1-2 years, then every 3-6 months. Rates of molecular response are reported on an intention-to-treat analysis.

Results:

281 patients were included: 271 in CP and 10 in CP with clonal evolution at the time of diagnosis. The median age was 48 years (range 15-83), 119 (42%) were females, median CML duration 1 month (mo) (range 0-12). Seventy-three (26%) patients received an initial imatinib dose of 400 mg and 208 (74%) with 800 mg. The median follow-up is 65 mo (range 2-107) with 249 (89%) treated for over 12 mo, 225 (80%) for over 24 mo, 211 (75%) for over 36 mo, 154 (55%) for over 60 months, and 29 (10%) treated for over 96 mo. 55 (20%) have discontinued therapy (34 -12%-, because of resistance, and 21 -7%- because of intolerance). Overall, 248 (88%) achieved a CCyR, 80 (28%) a MMR without CMR, and 123 (44%) a CMR in at least one measurement. MMR was sustained in 95 (34%) and CMR in 84 (30%). The median time to CCyR was 3 mo (range 2-30), to sustained MMR 18 mo (range 6-78), and to sustained CMR 30 mo (range 6-84). The median event free survival was not reached for patients in CCyR with CMR/MMR without CMR/no MMR. Among patients who did achieve a CCyR, those that had a sustained CMR by 24 mo of therapy had an EFS of 100% at 5 yrs, compared to 96% for those with MMR but no CMR, and 86% for those with CCyR but no MMR (p=0.02). The rate of survival free from transformation to accelerated or blast phase at 5 yrs was 100% for those with CMR at 24 mo, compared to 96% for those with MMR but no CMR, and 91% for those with CCyR but no MMR (p=0.1). On univariate analysis, factors predicting sustained CMR were platelet count >450×109/L (p=0.001), CCyR at 3 mo (p=0.0005) and at 6 mo (p<0.0001).

Conclusion:

These results suggest that achieving a CMR is an important endpoint for patients with CML treated with imatinib as initial therapy. Treatment strategies that may increase the rate of sustained CMR should be investigated.

Disclosures:

Kantarjian: Novartis: Research Funding. Rios:Novartis: Consulting and speakers' bureau-honoraria . Cortes:Novartis: Research Funding.