Real-life comparison of dasatinib and nilotinib as second-line therapy after imatinib failure for chronic phase CML

Background: Use of 2nd generation tyrosine kinase inhibitors (2G-TKIs) dasa- tinib (DAS) and nilotinib (NIL) in chronic phase (CP) chronic myeloid leukemia (CML) patients failing imatinib (IM) result in around 50% of sustained cytoge- netic response. However, it’s unclear if there’s a significant difference in efficacy of the two 2G-TKIs, especially in the long-term. Aims: To compare efficacy of DAS and NIL in CP-CML patients after IM resist- ance or intolerance. Methods: We retrospectively analysed 163 CP-CML patients resistant or intol- erant to IM that received either DAS (n=95) or NIL (n=68) as second-line therapy. We compared the characteristics of the two groups at the time of CML diagnosis and at the time of IM failure, including the cause of switch to 2G-TKI, duration of IM therapy, IM dose escalation and Hammersmith score to predict the prob- ability of response to 2G-TKIs. Cytogenetic and molecular responses were eval- uated according to the ELN recommendations. Time to treatment failure (TTF) was calculated from the start of 2G-TKI to any of the followings: progression to accelerated or blastic phase (ABP), death for any cause at any time, treatment discontinuation for primary or secondary resistance or intolerance. Progression free survival (PFS) was calculated from the start of 2G-TKI to ABP or death. Overall survival (OS) was calculated from the start of 2G-TKI to death. Results: Considering CML characteristic at diagnosis, the DAS and NIL cohorts were comparable for age, sex and risk score (Sokal and EUTOS). Median duration of IM therapy was similar (DAS 19 months, NIL 14 months), but 27/95 patients (28%) had IM dose escalation before DAS compared to only 9/68 (13%) before NIL (p=0.03). There was a higher rate of switch to DAS than to NIL for secondary resistance (26/95, 27% vs 7/68, 10%; p=0.01) while more patients changed from IM to NIL due to intolerance (31/68, 46%, vs 21/95, 22% for DAS; p=0.002). Rates of primary resistance did not differ (47/95, 49% for DAS vs 28/68, 41% for NIL; p=0.37), as other causes of switch (1/95, 1% for DAS vs 2/68, 3% for NIL; p=0.77). Hammersmith score was almost identical in the two groups. Complete cytogenetic response (CCyR) was attained in 53/73 (73%) patients not in CCyR at the time of DAS start, compared to 31/48 (65%) patients not in CCyR at the time of NIL start (p=0.46). Mean time to attain CCyR was similar (7.1 months for DAS and 5.3 months for NIL; p=0.30). Major molecular response (MMR) was achieved in 55/89 (65%) patients not in MMR at the time of DAS start and in 39/61 (65%) patients not in MMR at the time of NIL start (p=0.82). Again, mean time to MMR was not different in the DAS e NIL cohorts (12.4 vs 8.5 months; p=0.14). With a median follow-up of 44 months (range 1–124), 5-year TTF was similar for DAS (65%, 95%CI 52-75%) and NIL (61%, 95%CI 43-74%; p=0.40) [Figure 1a]. Thirty-two of 95 patients (34%) stopped DAS due to toxicity (19/32, 59%), resistance (11/32, 31%) or other causes (3/32, 10%); 22/68 patients (32%) interrupted NIL for toxicity (11/22, 50%), resistance (8/22, 36%) or other caus- es (3/22, 14%), Probability of survival and progression were almost identical, with a 5-year PFS of 84% (95%CI 68-89%) for DAS and 92% (95%CI 79- 97%) for NIL (p=0.27) [Figure 1b] and a 5-year OS of 89% (95%CI 78-95%) and 96% (95%CI 85-99%) (p=0.31), respectively. suggest similar efficacy of DAS and NIL after IM failure in CP-CML, with high rates of cytogenetic and molecular responses and excellent long-term survival.