BCR-ABL Transcript Levels at Time of Complete Cytogenetic Remission Achieved after Salvage with Dasatinib or Nilotinib.
Authors: Mauro Michael J. , Press Richard D. , Deininger Michael W. , Druker Brian J. 
Published: April 2020

Abstract
Achievement of a CCyR is a favorable threshold response in CP CML, associated with an expected degree of BCR-ABL transcript reduction. Transcript level at the time of CCyR has been reported for ‘late CP’ (post-IFN) and IRIS trial cases as median reductions of 2–2.5 logs below a standard baseline. The level of BCR-ABL transcripts at the time of CCyR may be predictive of subsequent relapse risk, and expectations and relative levels of BCR-ABL transcript reduction may differ in patients with imatinib refractory CML. 28 CP CML patients were treated at our center with nilotinib (n=1) or dasatinib (n=26) or both (n=1), 27/28 on phase II clinical trials for imatinib refractory or intolerant CP CML. 15 of 28 patients received nilotinib or dasatinib for imatinib failure, achieved subsequent CCyR, and had a quantitative PCR (qPCR) result at the time of CCyR and were analyzed. 8/28 who did not achieve CCyR, 2/28 without a paired qPCR sample, and 3/28 switched for imatinib intolerance were excluded. 20-cell karyotype of BM metaphases was used to determine CCyR and qPCR was expressed as % BCR-ABL/G6PDH RNA ratio and log reduction below standard baseline. The median reduction of BCR-ABL transcripts at time of CCyR for this cohort was 1.6 logs (range 0 - 4.2, mean 1.7). Patient characteristics are shown in Table 1. One case had no reduction below standard baseline and only a 3-fold reduction (19 to 6.6%) in BCR-ABL transcripts at time of CCyR; cytogenetics prior to salvage therapy demonstrated duplication of the Ph chromosome in 100% of metaphases. Another case with a 4.2 log reduction (nested qPCR (+) only) in transcripts at time of CCyR had undergone prior allografting and received dasatinib for imatinib refractory cytogenetic relapse post transplant. BCR-ABL transcript reduction in the setting of salvage therapy after imatinib failure may have different kinetics than the setting of de novo CML and primary imatinib exposure, as the median reduction at time of CCyR in this cohort is noticeably lower that expected for late CP (∼2 log reduction) and newly diagnosed CP (∼2.5 log reduction) cases. Transcript level reduction may be variably affected by different mechanisms of resistance such as BCR-ABL amplification in the setting of duplication of the Ph chromosome. Further study in larger cohorts is warranted to better describe kinetics of transcript reduction in the salvage setting.
Table 1. Patient Characteristics Age/Sex Therapy (@CCyR) Time to CCR %BCR-ABL/G6PD Log Reduction Mutation Status *post Dasatinib; **non-trial patient 61/M Nilotinib 400 mg QD 5 mo 0.04 2.0 Not evaluated 60/M Dasatinib 80 mg QD 17 mo 0.10 1.6 M388L 69/M Dasatinib 70 mg BID 3 mo 0.039 2.0 None found 47/M Dasatinib 70 mg BID 11 mo 0.10 1.6 Deletion ABL exon 7 49/M Dasatinib 70 mg BID 3mo Undetectable 4.2 None found 54/F Dasatinib 40 mg BID 14 mo 0.20 1.3 Y253F 74/F Dasatinib 50 mg BID 6 mo 0.073 1.8 F486S 57/F Dasatinib 100 mg QD 6 mo 0.096 1.6 Not evaluated 62/M Nilotinib 400 mg BID 6 mo 0.17 1.4 M244V 56/F Dasatinib 50 mg BID 6 mo 0.12 1.5 None found 65/M Dasatinib 70 mg BID 3 mo 0.01 2.6 M351T, E279K 86/F Dasatinib 40 mg BID 3 mo 0.17 1.4 Not evaluated 55/F Dasatinib 140 mg QD 6 mo 0.32 1.1 None found 57/M Dasatinib 100 mg QD 3 mo 0.04 2.0 F359V 42/M Dasatinib 100 mg QD 3 mo 6.6 0 None found