Predictive Factors For An Achievement Of 6-Month Early Molecular Response In New CP CML Patients Treated With Imatinib

Recent studies have demonstrated that early molecular response (EMR) is predictive for long-term outcomes. However, the value of EMR has not been fully defined. Recently, European Leukemia Net (ELN) recommended that BCR-ABL1 ≤ 10%, and/or Ph+ <35% at 6 months of treatment was an optimal response. The aim of this study was to identify predictive factors for an achievement of 6-month EMR (BCR-ABL1 ≤ 1%) and to evaluate prognostic implications of 6-month EMR.

CP CML patients who were newly diagnosed and receiving 400mg IM once daily with no prior treatment were eligible for this study. Molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). All qRT-PCR tests were performed in a single laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea). Pharmacokinetics data of IM, drug adherence, and dose intensity as well as baseline biological characteristics were included as variables affecting the achievement of 6-month EMR.

A total of 102 patients (including 61 men and 41 women) were enrolled. One patient changed IM treatment to second-generation TKI due to less than complete hematologic response before 3 months. At the time between 3 and 6 months, 9 patient were discontinued permanently from IM treatment due to progression (n = 1), ELN failure (n = 3), and intolerance (n = 5). Ninety-two patients’ molecular responses were analyzed at 6 months. Day 29 trough IM level data were available from 99 patients and trough IM level data on the end of cycle 6 were available from 84 patients. Univariate analyses revealed that age of ≥ 40 years (P = 0.061), male sex (P = 0.042), b3a2 transcript type (P = 0.008), intermediate (P = 0.007) and high Sokal risk (P = 0.013), increased leukocyte count (P = 0.018), increased blast percentage (0.028), large splenic size (P = 0.020), and mean daily dose by 6 months of <350 mg/day (P = 0.004) were potential predictive factors for no achievement of 6-month EMR. Increased log reduction of BCR-ABL1 from baseline to 3 months (P <0.001) was associated with achievement of 6-month EMR. After adjusting for factors affecting relapse on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 9.35, P = 0.013), increased log reduction of BCR-ABL1 from baseline to 3 months (RR of 9.58, P = 0.001), and mean daily dose by 6 months of ≥350 mg/day (RR of 13.10, P = 0.019) were independent factors for a achieving of 6-month EMR. In addition, patients with high Sokal risk had a lower 6-month EMR, compared with those with low Sokal risk (RR of 0.02, P= 0.035).

In the current study, patients with BCR-ABL1 ≤1% at 6 months had a better MMR rates at 12 months (63% vs 10%, P<0.001), 3-year CI of CCyR (100% vs 76.1%, P<0.001) and MMR (100% vs 66.4%, P<0.001), EFS (78.9% vs 30.6%, P<0.001), and FFS (97.2% vs 68.7%, P<0.001). Patients with BCR-ABL1 >1% at 6 months showed a trend for lower 3-year PFS, compared with those who achieved ≤1% (100% vs 94.1%, P = 0.063).

In this study, we re-confirmed the prognostic significance of 6-month EMR and found that b2a2 transcript type, early decline of BCR-ABL1 transcript, mean daily dose by 6 months (≥350 mg/day), and Sokal risk were associated of the achievement of 6-month EMR. These predictive factors for 6-month EMR should be considered in the clinical decision of changing therapy at this time point. Further clinical investigations in a larger patient population with longer follow-up are needed.

No relevant conflicts of interest to declare.