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

Abstract

Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.

Fig. 1. Overall treatment outcome in 106 CML patients after starting a 1L-2GTKI.

The figure shows the long-term outcome in the whole cohort of CML patients in 1st chronic phase (N = 106) treated with an upfront second-generation TKI (2GTKI) at a single center. RIP deceased patients, alloSCT allogeneic hematopoietic stem cell transplant, TFR treatment-free remission.

Fig. 2. Cumulative probabilities of response after starting a 1L-2GTKI.

The figure shows the cumulative probabilities of achievement of each response level after commencing an upfront second-generation TKI (1L-2GTKI) in CML patients in first chronic phase. The x axis indicates the time from the 1L-2GTKI start to the date of response, regardless to which TKI line this was achieved on. CCyR Complete cytogenetic response.

Fig. 3. Long-term outcomes (EFS, OS and TFR) in 106 patients treated with 1L-2GTKI.

Panel a shows the probability of event-free survival for the entire patient cohort. The x axis indicates the time from diagnosis until the occurrence of any event (failure of 1L-2GTKI due to any cause, disease progression to accelerated (AP)/blast phase (BP), death) or censoring, done at last follow-up on 1L-2GTKI. Panel b shows the probability of overall survival for each patient group: those who remained on 1L-2GTKI (no switch, n = 61, blue line), those who failed their 1L-2GTKI due to intolerance (intolerant, n = 28, green line) and the resistant patients (resistant, n = 17, yellow line). The x axis indicates the time from diagnosis until the occurrence of death from any cause or censoring, done at last follow-up on TKI. The p-value reported on the right bottom of the Kaplan-Meier plot refers to the log-rank test. Panel c shows the probability treatment-free remission for 28 patients at their first TFR attempt (after discontinuation of 1L-2GTKI and ≥2L-TKI in 22 and 6 patients, respectively). The x axis indicates the time from TKI discontinuation until the occurrence of MR3 loss or censoring, done at last follow-up in MR3 while off TKI.