The Plateau of BCR-ABL Transcript Level ≥0.1% May Select CML Patients in Complete Cytogenetic Remission for Mutation Analysis.
Authors: Polakova Katerina Machova , Polivkova Vaclava , Rulcova Jana , Klamova Hana , Jurcek Tomas , Dvorakova Dana , Zackova Daniela , Pospisil Zdenek , Mayer Jirí , Moravcova Jana 
Published: October 2019

Abstract 2216

Poster Board II-193

Introduction.

The major cause of the imatinib resistance is the presence of point mutations within the ABL kinase domain of BCR-ABL that are occurred in approximately 35-70% of patients displaying resistance to imatinib. Identification of mutation also in imatinib responders is associated with disease progression (Khorashad et al. 2008, J Clin Oncol 29:4806). According to ELN (European LeukemiaNet) patients should be screened for mutations in the case of: 1) hematological resistance / relapse, 2) cytogenetic resistance / relapse, 3) 5 – 10-fold increase of BCR-ABL transcript, 4) prior to therapy with 2nd generation TKIs, and 5) at 3-month intervals under therapy with 2nd generation TKIs. The BCR-ABL rise fold threshold for mutation analysis is highly discussed nowadays. Recently Press et al. (Blood 2009, prepublished online) identified a 2.6-fold increase in BCR-ABL RNA as the optimal cutoff for predicting a concomitant KD mutation, with a sensitivity of 77% (94% if including subsequent samples).

Aims.

In this study, we aimed to detect BCR-ABL mutation in patients responding to imatinib with CCgR expressing the plateau of BCR-ABL transcript level ≥0.1% (IS; International Scale) in a minimum of 3 subsequent samples (minimal duration 6-9 months) and to evaluate the risk of disease progression in this group of patients.

Materials and methods.

From 140 CML patients in CCgR after imatinib therapy, 32 showed constant BCR-ABL transcript levels ≥0.1% after the initial reduction. Altogether 134 samples of peripheral blood of these 32 patients were tested for mutation in BCR-ABL kinase domain by direct sequencing. Patients with constant BCR-ABL values <0.1% were not included because of the limitation of mutation detection by sequencing as shown our tests of reproducibility and repeatability.

Results.

Median follow-up of BCR-ABL transcript level plateau within the range of evaluated variability of RQ-PCR analysis was in 32 patients 12 months (range 6-64); 22/32 patients were treated with imatinib in the first line. Mutation was detected by direct sequencing with the measured sensitivity of 20-100% of mutant BCR-ABL present in the sample with the minimum copy number of total BCR-ABL 100 (corresponding to 0.1% of BCR-ABL measured by our RQ-PCR) in 9/32 patients (28%); 5/9 were in the first line imatinib treatment. Loss of CCgR or 1 log rise of BCR-ABL was observed in 5/9 patients median 5 months (range 4-17) since first detection of mutation. One patient with no mutation relapsed 12 months after the start of the BCR-ABL plateau. In 5/32 patients without mutation the BCR-ABL level significantly decreased after the 1st plateau to the levels that stayed unchanged for a median of 11 months (range 7-28); three of them achieved major molecular response (MMR; <0.1% BCR-ABL).

Conclusion.

In our study, patients expressing plateau of BCR-ABL transcript level ≥0.1% did not achieve MMR and were at more risk to lose their responses. We suppose that the fluctuation of BCR-ABL values ∼0.1% within the consecutive samples should not be classified as MMR achievement. Only levels constantly below 0.1% should be defined as MMR. The BCR-ABL constant levels ≥0.1% clearly select patients in CCgR for mutation analysis. This approach highly reduces the number of examinations for mutation in CML responders presenting a cost-effective alternative applicable in clinical practice.

Supported by MZOUHKT2005 and research grant from Bristol-Myers Squibb.

Disclosures:

Machova Polakova: Bristol-Myers Squibb: Research Funding.