Outcomes of patients with chronic myeloid leukemia receiving second-line therapy after failure of frontline second-generation tyrosine kinase inhibitor

Abstract Introduction Some patients (pts) with chronic myeloid leukemia (CML) eventually develop disease resistance or treatment intolerance after first-line therapy (1L) with a second-generation tyrosine kinase inhibitor (2G-TKI). Second-line therapy (2L) with a 2G-TKI is standard of care. However, outcomes with 2L after 1L 2G-TKI failure are not well described. Methods We retrospectively reviewed pts diagnosed with CML in chronic phase (CP) or accelerated phase (clonal evolution only) between May 2000-November 2023, treated with 1L 2G-TKI, and identified the reasons for switching to 2L. We then analyzed the type of 2L received, the best response achieved, and survival outcomes. Results 276 pts were included, 258 (94%) were in CP and 149 (54%) were males. The median age was 51 years (range, 15-83). 1L therapy consisted of dasatinib in 181 pts (66%), nilotinib in 84 (30%), and bosutinib in 11 (4%). Pts switched to 2L mostly due to intolerance (n=133; 48%), resistance (n=51; 18%), or both (n=65; 24%); 22 pts (8%) switched due to other reasons. Of 116 pts with resistance (including those with concomitant intolerance), 55 (47%) had lost their cytogenetic response while 61 (53%) had never achieved a cytogenetic response. Fifty pts with disease resistance had mutational analysis performed, of them, 9 (18%) had ABL1 mutations detected: T315I in 5 (one of them in combination with C464G), and V299L, Q252H, F317L, and E281fs in one pt each. The 10-year EFS, TFS, and OS rates with 1L were 57%, 100%, and 79%, respectively. 2L consisted of imatinib in 74 pts (27%), bosutinib in 64 (23%), nilotinib in 57 (21%), dasatinib in 43 (15%), ponatinib in 31 (11%), asciminib in 6 (2%), and investigational drug in 1 (1%). After a median follow-up of 6 years, the best cumulative response to 2L among 234 evaluable pts was MCyR in 203 (87%), CCyR in 178 (76%), MMR in 151 (65%), MR4 in 113 (48%), and MR4.5 in 106 (45%). Of 269 pts with available BCR::ABL1 transcript levels at the time of 2L initiation, 112 had transcripts >10% IS, of them 66 (60%) responded to <10% or deeper. 46 pts had transcripts between 1-10% at the start of 2L, of them 32 (70%) maintained (n=9; 20%) or deepened their responses (n=23; 50%). Of 39 pts with transcripts between 0.1-1%, 35 (90%) maintained (n=6; 16%) or deepened their responses (n=29; 74%). 51 pts had disease resistance (without intolerance) to 1L. Of 28 pts with transcripts >10%, 19 (68%) deepened their response with levels 1-10% in 5 (18%), 0.1-1% in 3 (11%), and <0.1% in 11 (39%). Of 23 with transcripts between 1-10%, 16 (70%) deepened their response with levels 0.1-1% in 3 (13%) and <0.1% in 13 (57%). Among the 51 pts with resistance only (BCR::ABL1 transcript >1%), 23 received a 2G-TKI, 22 a third-generation (3G)-TKI, 5 imatinib, and 1 an investigational drug as 2L. Of 22 pts who received 2G-TKI, 1 (4%) responded with a transcript level between 0.1-1% and 7 (30%) with transcripts <0.1%. These rates were significantly lower than those of pts who received 3G-TKI as 2L, with 4 (18%) and 17 (77%) achieving transcripts of 0.1-1% and <0.1%, respectively (P=0.001). A best cumulative response of CCyR, MMR, MR4, and MR4.5 was achieved in 35% and 95%, 30% and 77%, 13% and 64%, 13% and 55%, of pts treated with 2G-TKI versus 3G-TKI, respectively (P=0.001). 103 pts had treatment intolerance and BCR::ABL1 transcripts available at the time of initiation of 2L. Of them, 4 had a transcripts >10% (discontinued initially due to toxicity then subsequently lost response while off therapy), 8 between 1-10%, 26 between 0.1-1%, and 65 <0.1%. All 4 pts (100%) responded, 2 (50%) with transcripts of 0.1-1% and 2 (50%) <0.1%. Four of the 8 pts (50%) deepened their response with transcripts <0.1%. Of 26 pts, 20 (77%) deepened their response with transcripts <0.1%. Of 65 pts with transcripts <0.1%, 59 (91%) maintained their response. The estimated 10-year EFS, TFS, and OS rates on 2L therapy were 67%, 87%, and 71%, respectively. Conclusion Overall, 2L after 1L 2G-TKI resulted in cytogenetic remissions in approximately 80% of the pts and molecular remissions in more than 60% of the pts. Response rates were significantly higher in pts treated with a 3G-TKI compared to a 2G-TKI in the second line.