Survival Impact of Patients (Pts) with Chronic Myeloid Leukemia (CML) Due to Failure from the Use of One or More Tyrosine Kinase Inhibitors (TKI)

 Background: Imatinib induces durable complete cytogenetic remissions (CCyR) in at least two thirds of pts with chronic phase (CP) CML, most of them also achieving a major molecular response (MMR).  However, some pts become intolerant or resistant to imatinib and require change of therapy to a 2^nd or 3^rd generation TKIs (dasatinib, nilotinib, bosutinib, and/or ponatinib). The projected 3-year survival for these pts was reported as 72% (Kantarjian et al. Cancer 2007) at a time when treatment options for such pts was limited. A smaller subset of pts may require additional changes to a third or fourth TKI. The impact of sequential TKI therapy, although standard practice, has not been well studied. We analyzed the long term outcome of pts receiving multiple TKIs.

Method: We analyzed the medical records of 1775 pts with CML-CP treated at a single institution between 02/2000 and 07/2015. Among them 582 (33%) received more than one TKI as follows: 2TKIs (n=370), 3TKIs (n=130), and 4+TKIs (n=82; 4 TKI n=59, 5 TKI n=20, 6 TKI n=1, 7 TKI n=2). For the purpose of this analysis, a TKI used more than once was counted as 2 TKI provided there was a different TKI used between the two periods when the TKI in question was used. We analyzed pt's characteristics, response to therapy, transformation to accelerated and blast phase, and long term outcomes.  Overall Survival (OS) and Transformation-Free Survival (TFS) probabilities were measured using Kaplan-Meier method starting from the date they began to use the their 2^nd TKI and grouped by the number of TKI used.

Results: The number of CML pts in early CP (diagnosis to start of therapy, ≤ 12 months) that used 2, 3, and 4+TKIs was 229, 54, and 34, respectively. The number of pts in late CP (diagnosis to start of therapy >12 months) that used 2, 3, and 4+TKIs was 141, 76 and 48 respectively. The median age (range) for pts that used 2, 3, and 4+ TKIs were 48 yrs (15-81), 52 yrs (18-87), and 53 yrs (18-80), respectively. The ratio of males to females in each cohort was 187:183, 58:72, and 37:45, respectively. The median time from diagnosis to 2^nd, 3^rd and 4^th TKI was 2, 4, and 6 years respectively. For the 3 cohorts (2, 3, 4+TKIs), TKIs used included imatinib (n=322, n=130, n=79), dasatinib (n=227, n=112, n=77), nilotinib (n=119, n=109, n=70), ponatinib (n=44, n=27, n=37) and bosutinib (n=26, n=13, n=29), respectively. The 3-year overall survival probability for pts treated with 2 TKI was 88% (median survival not reached); for those that used 3 TKI 72% (median survival not reached), and for those that used 4+ TKI 48% (median survival 34 months) (Fig. 1). Corresponding 5-year figures are 80%, 53% and 38%. The 3-year transformation-free survival probability for pts treated with 2 TKI was 93%; for those treated with 3 TKI 88%; and for pts treated with 4 TKI 80% (median not reached in any cohort ) (Fig. 2). Corresponding figures for 5-years are 90%, 84%, and 75%. 

Conclusion: With more and improved treatment options, pts with resistance or intolerance to multiple TKI have the potential for long-term survival. Nearly 80% of pts who receive 2 TKI are alive at 5 years and more than 90% remain in chronic phase. As pts experience subsequent failure, the outcome worsens. These results provide information that may help with treatment planning and set the expectations against which treatment options used in such pts should be measured.

 Figure 1 – Overall Survival Probability

Figure 2 – Transformation-Free Survival Probability