Similar Efficacy and Distinct Safety Profile of Nilotinib, Dasatinib and Flumatinib in Chronic Myeloid Leukemia Patients Resistant or Intolerant to 1st Line Imatinib

Objective: To evaluated the efficacy and safety of nilotinib, dasatinib and flumatinib as the 2^nd line treatment in chronic myeloid leukemia (CML) patients with prior imatinib therapy.

Experimental Design: In this retrospective study, 554 adult CML patients using nilotinib, dasatinib and flumatinib as 2nd line therapy were recruited.

Results: The clinical data of 349 male and 205 female CML patients between 2007.11 to 2023.7.31 were collected .The median age was 45 (18-79) years. 181(32.7%), 256(46.2%) and 117(21.1%) patients received nilotinib, dasatinib and flumatinib respectively.402 patients had ELTS information with 238(59.2%), 132(32.4%) and 28(9.3%) patients in low, intermediate and high ELTS risk group.478 subjects detected ABL mutation before switching to 2L treatment, 48 (10%) patients had ABL mutation. According to the response to prior imatinib therapy, 108(19.5%), 120(21.7%) and 326(58.8%) patients were stratified into intolerance, warning and failure group respectively. In the failure group, 51/554(9.2%) patients were in advanced phase. 54.2%, 64.1% and 41.9% patients had >10% BCR::ABL transcripts in nilotinib, dasatinib and flumatinib group respectively. The median time from 1L imatinib to 2L were 12.5(1-131.5), 12.7(1-152.8) and 10.5(1-120.9) months in nilotinib, dasatinib and flumatinib cohort. The median dosage of nilotinib, dasatinib or flumatinib was 800mg/day, 100 mg/day and 600 mg/day respectively. The median follow up for nilotinib, dasatinib and flumatinib cohort were 74.2, 73.9 and 41.4months. The median duration of 2L treatment with nilotinib, dasatinib and flumatinib were 42.7(1-135.4), 24.8(1-198.1) and 18.4(1.2-49.1) months. The estimated 5 year EFS, PFS and OS after 2L therapy were 42%, 84% and 88%. The patients with 2L flumatinib had superior EFS than the patients with nilotinib or dasatinib therapy. Compared with 2L dasatinib, flumatinib had better PFS and OS. CHR, CCyR/MR2, MMR and MR4 responses were improved from 81.23%, 29.6%, 9.93% and 3.07% to 90.61%, 77.26%, 61.37% and 37.91% after 2L treatment（figure 1). Most patients who achieved hematological or molecular responses at baseline could maintain the corresponding response during 2G TKI therapy. The patients without clinical responses at baseline achieved CCyR/MR2, MMR and MR4 in 67.9%, 57.3% and 36% patients and with the median time to corresponding response of 9.2, 26.4 and 74.9 months respectively. The patients without response at baseline treated with nilotinib, dasatinib and flumatinib, achieved CCyR/MR2 in 68.8%, 64.5% and 76.6% patients, with the median time of 9.1, 13.4 and 5.4 months to CCyR; achieved MMR in 43.4%, 44% and 45.3% patients, with the median time of 23.8, 33 and 15 months to MMR; achieved MR4 in 42%, 33.3% and 32.7%patients, with the median time of 67.1, 74.9 months and not reached to MR4. In overall patients without response at baseline, 2L flumatinib had superiority on inducing molecular response than 2L nilotinib and dasatinib treatment. In each group of intolerant, warning, failure and advanced phase, 2L treatment with nilotinib, dasatinib and flumatinib had similar EFS, PFS and OS, and induced similar CCyR/MR2, MMR and MR4 response. The safety profile were different between patients treated with nilotinib, dasatinib or flumatinib. Side effects of concern were rash, bilirubin increasing, cholesterol elevation, thrombotic event and thyroid disease in nilotinib group; pleural effusion, increased pulmonary artery pressure, pericardial effusion, thrombocytopenia, and edema in dasatinib group; increased creatinine and thyroid disease in flumatinib group.

Conclusion: The patients intolerant/resistant to imatinib receiving nilotinib, dasatinib or flumatinib as 2L therapy had similar molecular response and survival and suffered different side effects.