Four-Year (Yr) Follow-Up Of Patients (Pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Receiving Dasatinib Or Imatinib: Efficacy Based On Early Response
Authors: Cortes Jorge E. , Hochhaus Andreas , Kim Dong-Wook , Shah Neil P. , Mayer Jiri , Rowlings Philip , Nakamae Hirohisa , Bradley-Garelik M. Brigid , Mohamed Hesham , Kantarjian Hagop M. , Saglio Giuseppe 
Published: October 2019

Abstract

Background
The randomized phase 3 DASISION trial in pts with newly diagnosed CML-CP has demonstrated the improved efficacy of dasatinib 100 mg once daily (QD) compared with imatinib 400 mg QD based on the primary endpoint: rate of confirmed complete cytogenetic response (CCyR) within 12 mo (NEJM 2010 362 2260). Several studies have demonstrated the impact of early responses on long-term progression-free survival (PFS) and overall survival (OS), and the European LeukemiaNet (ELN) has recently updated its definitions of response to reflect the importance of achieving specific BCR-ABL transcript levels at 3, 6, and 12 mo. The aims of this analysis were to provide an update on efficacy and safety at 4 yrs and to examine the predictive value of early molecular responses in DASISION.

Methods
Pts with newly diagnosed CML-CP (n=519) were randomly assigned to receive dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260). Methods were reported previously. The protocol defined progression as increasing white blood cell count, loss of complete hematologic response or major cytogenetic response, transformation to accelerated phase (AP) or blast phase (BP), or death.

Results
After 4 yrs, 67% and 65% of pts in the dasatinib and imatinib arms, respectively, remain on study treatment. The proportions of pts achieving molecular responses by 4 yrs (dasatinib v imatinib) were: major molecular response (MMR; BCR-ABL ≤0.1%) 76% v 63%; MR4 (BCR-ABL ≤0.01%) 53% v 42%; and MR4.5 (BCR-ABL ≤0.0032%) 37% v 30%. The likelihood of achieving MMR at any time was 1.6-fold higher with dasatinib v imatinib (hazard ratio [95% CI], 1.6 [1.3–1.9]). In pts who achieved MMR, the median time to MMR was 9.2 v 15.0 mo (dasatinib v imatinib). Four-yr PFS rates were 90% in both arms, and OS rates were 93% (dasatinib) and 92% (imatinib). In an intent-to-treat analysis, fewer pts receiving dasatinib (n=12/259; 5%) v imatinib (n=18/260; 7%) transformed to AP/BP. More pts achieved 2013 ELN-defined optimal molecular responses at 3 mo (BCR-ABL ≤10%, 84% v 64%), 6 mo (BCR-ABL ≤1%, 69% v 49%), and 12 mo (BCR-ABL ≤0.1%, 46% v 30%) with dasatinib v imatinib. In a relative risk analysis, pts with BCR-ABL ≤10% at 3 mo (regardless of treatment) were more likely to achieve CCyR, MMR, and MR4.5 and were at a proportionally lower risk of transformation to AP/BP or death. In the dasatinib arm, BCR-ABL ≤10% v >10% at 3 mo was associated with better PFS (P=.0004, 92% v 67% at 4 yrs), better OS (P=.0092, 95% v 83% at 4 yrs), and reduced transformation to AP/BP (n=6/198 [3%] v n=5/37 [14%] at 4 yrs). In the imatinib arm, BCR-ABL ≤10% v >10% at 3 mo conferred similar advantages (PFS: P<.0001, 95% v 70%; OS: P=.0021, 96% v 84%; transformation: n=4/154 [3%] v n=13/85 [15%]). Regardless of treatment, relatively few pts with BCR-ABL >10% at 3 mo achieved an optimal response of ≤1% at 6 mo (Table). The subgroup of pts with ≤1% at 6 mo had no transformations or deaths, although the subgroup with >1–10% at 6 mo had 3 transformations and 4 deaths (imatinib arm only). Most drug-related adverse events occurred within the first yr of treatment, with no new safety signals observed through yr 4.

Conclusions
This 4-yr follow-up from the DASISION trial continues to support dasatinib 100 mg QD as first-line treatment for pts with newly diagnosed CML-CP, with more pts achieving ELN-defined optimal molecular responses and fewer transforming to AP/BP compared with imatinib. The achievement of BCR-ABL ≤10% at 3 mo, more common among pts treated with dasatinib v imatinib, was associated with better PFS and OS and reduced transformation to AP/BP in both arms.

Disclosures:
Cortes: Ariad: Consultancy, Grant to institution Other, Honoraria; BMS: Grant to institution, Grant to institution Other; Novartis: Grant to institution, Grant to institution Other; Pfizer: Consultancy, Grant to institution, Grant to institution Other, Honoraria; Teva: Consultancy, Grant to institution Other, Honoraria; Tragara: Membership on an entity’s Board of Directors or advisory committees; Ambit: Grants/grants pending for institution Other; Astellas: Grants/grants pending for institution, Grants/grants pending for institution Other; Incyte: Grants/grants pending for institution, Grants/grants pending for institution Other; Arog: Grants/grants pending for institution Other; Celgene: Grants/grants pending for institution, Grants/grants pending for institution Other; sanofi: Grants/grants pending for institution, Grants/grants pending for institution Other. Hochhaus:BMS: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Kim:BMS: Consultancy, Grant/grants pending for institution; travel support to meetings for study/other purposes Other, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Grants/grants pending for institution, Grants/grants pending for institution Other, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; ARIAD: Grants/grants pending for institution, Grants/grants pending for institution Other; ILYANG: Grants/grants pending for institution, Grants/grants pending for institution Other, Speakers Bureau. Shah:BMS: Consultancy, Grants/grants pending to institution for costs related to clinical research Other; Ariad: Consultancy, Grants/grants pending to institution for costs related to clinical research, Grants/grants pending to institution for costs related to clinical research Other. Rowlings:Newcastle Mater Hospital: Clinical trial support and travel to investigator's meeting paid to institution Other. Nakamae:Novartis: Consultancy, Grants/grants pending Other, Speakers Bureau; BMS: Consultancy, Grants/grants pending; travel/accomodations/meeting expenses unrelated to activities listed, Grants/grants pending; travel/accomodations/meeting expenses unrelated to activities listed Other, Speakers Bureau. Bradley-Garelik:BMS: Employment. Mohamed:BMS: Employment, Stock/stock options; travel/accommodations/meeting expenses unrelated to activities listed Other. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.