PF405 DASCERN 2‐YEAR EXTENDED FOLLOW‐UP OF DASATINIB EFFICACY AND SAFETY IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML‐CP) WHO HAVE SUBOPTIMAL RESPONSES TO 3 MONTHS OF IMATINIB
Authors: G. Saglio, Q. Jiang, J. Wang, J. Weng, H. Zhu, X. Liu, A. Hochhaus, D.‐W. Kim, J. Radich, M. Savona, P. Martin‐Regueira, O. Sy, R. Gurnani, J.E. Cortes
Journal: HemaSphere (2019)

Background: Second‐generation tyrosine kinase inhibitors (2G‐TKIs) demonstrate higher response rates than imatinib for first‐line (1L) CML‐CP treatment. Achievement of BCR‐ABL1 ≤10% on the International Scale (IS) at 3 mo with a TKI improves probability of achieving deep molecular response and superior progression‐free and overall survival (PFS; OS). Although BCR‐ABL1 ≤10% IS at 3 mo is considered an optimal response by European LeukemiaNet (ELN) 2013 guidelines, 1/3 of pts on 1L imatinib do not achieve this, and the appropriate management of these pts is not yet established. We previously reported that pts who switched to dasatinib early had significantly higher major molecular response (MMR; BCR‐ABL1 ≤0.1% IS) at 12 mo than pts who remained on imatinib (29% vs 13%; P = 0.005) (Cortes Blood 2018). Aims: To assess longer‐term efficacy of an early switch (at 3 mo) to dasatinib in pts with suboptimal responses to imatinib. Methods: DASCERN (CA180–399/NCT01593254) is a randomized, open‐label, multinational phase 2b trial in adult pts with CML‐CP who achieved a complete hematologic response but had BCR‐ABL1 &gt;10% IS at 3 mo after initial treatment with 400 mg imatinib once daily (QD). Pts were randomized 2:1 to receive 100 mg dasatinib QD or continue on imatinib at any dose selected by the investigator. After randomization, pts in the imatinib arm who met ELN 2013 failure criteria and without dasatinib‐resistant mutations could cross over to dasatinib. The primary endpoint was the rate of MMR at 12 mo after day 1 of 1L imatinib (9 mo after randomization). Secondary endpoints include time to MMR and MR 4.5 ( BCR‐ABL1 ≤0.0032% IS), PFS (transformation to accelerated/blast phase or death), and OS. Tertiary endpoints include safety and molecular and cytogenetic responses over time. Results: All 260 pts (dasatinib 174, imatinib 86) had ≥2 y of follow‐up at the time of this analysis; 203 (79%) were continuing in the study (135 [79%] on dasatinib; 68 [79%] on imatinib). Median age was 37 y (range 18–82; 95% were &lt;65); 73% of pts were Asian. Baseline pt characteristics were balanced between treatment arms (Cortes Blood 2018). To date, 45 imatinib‐randomized pts (52%) have crossed over to dasatinib (all but 1 due to imatinib failure). Cumulatively, 141 of 219 pts (64%) on dasatinib (including 115 initially randomized pts and 26 pts who crossed over) and 35 of 86 pts (40%) on imatinib achieved MMR by 2 y. In the intent‐to‐treat population, 2 y PFS and OS were 96% (95% confidence interval [CI] 92, 98) and 98% (95% CI 94, 99) for pts randomized to dasatinib and 95% (95% CI 88, 98) and 97% (95% CI 90, 99) for pts randomized to imatinib. In pts initially randomized to imatinib who crossed over to dasatinib, PFS and OS were 93% (95% CI 80, 98) and 96% (95% CI 83, 99), respectively. The safety profile was consistent between 1 and 2 y (5 additional pts on dasatinib developed pleural effusion [16 pts (9%) in total]). Twelve (7%) and 4 (5%) pts randomized to dasatinib and imatinib, respectively, discontinued due to toxicity. Summary/Conclusion: In this extended follow‐up of DASCERN, pts who switched to dasatinib early after suboptimal responses to imatinib had significantly higher MMR at 2 y, with responses improving over time. Additionally, &gt;50% of pts who crossed over to dasatinib due to imatinib failure had an improved MMR. These data further emphasize the need for early monitoring and intervention for pts who do not receive a 1L 2G‐TKI, and suggest that switching to dasatinib in such instances will increase total MMR numbers. Longer follow‐up is warranted.