The outcomes of patients with chronic myeloid leukemia treated with third‐line BCR::ABL1 tyrosine kinase inhibitors

Abstract

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second-generation TKI (2G-TKI), the optimal third-line therapy in chronic phase CML (CML-CP) is not well established. We analyzed 354 patients with CML-CP treated with a third-line BCR:: ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G-TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy-three (49%) patients received 2G-TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 [94%] versus 75/135 [55%]; p < .001) compared with the 2G-TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + Àlog reduction of baseline transcripts (20% 2-log reduction and 32% 3 + Àlog reduction). Among the 128 evaluable patients treated with 2G-TKIs, 44 (34%) achieved 2 + Àlog reduction of baseline transcripts (13% 2-log reduction and 21% 3 + Àlog reduction). With a median follow-up of 46 months, the 3-year progression-free survival was 59% (60% before matching) with 2G-TKI and 83% (81% before matching) with ponatinib (p < .001). The 3-year survival was 83% (81% before matching) with 2G-TKI and 87% (89% before matching) with ponatinib (p = .03). By multivariate analysis, third-line therapy with ponatinib was the only independent factor associated with better survival (p = .003). In conclusion, ponatinib is an optimal treatment for patients with CML-CP failing two prior TKIs. | INTRODUCTIONMajor progress has occurred over the past two decades in the management of chronic myeloid leukemia (CML) since the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs). With TKI treatment, the Elias Jabbour and Koji Sasaki contributed equally to this study.

Dose modification dynamics of ponatinib in patients with chronic-phase chronic myeloid leukemia (CP-CML) from the PACE and OPTIC trials

“…A retrospective analysis comparing the outcomes of patients with CML-CP treated with 2G TKIs or ponatinib as third-line TKI therapy found the 3-year PFS rate with ponatinib was 81% versus 60% with 2G-TKIs and the 3-year OS rate was 89% with ponatinib versus 81% with 2G TKIs; these survival outcomes were maintained after propensity matching [ 34 ]. Furthermore, third- or fourth-line ponatinib yielded response rates (≤1% BCR::ABL1 IS : PACE, 46% by 12 months and 54% by ~5 years; OPTIC, 52% by 12 months and 56% by 24 months) [ 4 , 19 , 21 ] comparable or better than those reported for second-line bosutinib (≤1% BCR::ABL1 IS , 46–50%) [ 35 ], suggesting ponatinib could be beneficial in the second-line setting.…”

Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance

“…Of 11 studies analyzed, the authors found that in 3L-TKI treatment the sequential use of 2GTKI was of limited value: the probability of CCyR was 22–26% compared to 60% in the ponatinib-treated patients. Similarly, a retrospective multicenter study comparing the efficacy of ponatinib versus 2GTKI in 3 L therapy in 354 CML patients, including also PACE [ 15 ] and OPTIC [ 16 ] participants, found that 3GTKI allowed a higher rate of deeper responses, longer PFS and OS and was the only independent factor associated with better survival in a propensity score matching analysis [ 17 ]. The efficacy of ≥3L-ponatinib after failure of 2GTKI was also shown by another recent sub-analysis of the PACE and OPTIC studies [ 18 ].…”

Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors

“…9,54,56 This highlights the improved survival with ponatinib compared with second-generation TKIs in patients with resistant CML-CP. 52,[57][58][59] In contrast, with longer followup of the ASCEMBL trial in patients with CML-CP and $2 prior TKIs, no survival difference was noted between asciminib and bosutinib, with 2-year OS rates of 97% and 99%, respectively. 60 Treating patients with ponatinib or asciminib is expensive.…”