The Use of 2^nd generation Tyrosine Kinase Inhibitors (TKI) after Failure to 2 Prior TKI: Long-Term Follow-up.

The 2^nd generation tyrosine kinase inhibitors (TKI), nilotinib and dasatinib, are effective after imatinib failure. These agents are now also being used as 3^rd line therapy after failure to 2 prior TKI. Preliminary data suggests responses can be achieved with this strategy, but the long-term benefit is unknown.

To investigate the long-term benefit of using a 2^nd generation TKI after having failed imatinib and another TKI.

Patients with CML who were sequentially treated with 3 different TKI’s at M.D. Anderson Cancer Center were reviewed. Response to the 3^rd TKI were scored according to standard definitions. Event-free survival (EFS) was considered from the time the 3^rd TKI was started to loss of major hematologic response, loss of cytogenetic response, transformation to accelerated (AP) or blast (BP) phase, or death. Failure-free survival (FFS) was considered from start of 3^rd TKI to event as defined for EFS, or loss of complete cytogenetic response (CCyR) or discontinuation because of toxicity.

37 patients were treated: 29 with dasatinib after imatinib and nilotinib failure, and 8 with nilotinib after imatinib and dasatinib failure. The median age was 61 years (yrs) (range, 19 to 70). The median time on imatinib was 33 months (mo) and 15 (41%) had transformation before starting 2^nd TKI. Median time on 2^nd TKI was 7.7 mo. At the start of 3^rd TKI, 16 pts (43%) were in chronic phase (CP), 9 (24%) in AP, and 12 (32%) in BP. Best response to 3^rd TKI in CP was 1 major molecular response (MMR), 2 CCyR, 1 partial cytogenetic response (PCyR), 5 minor cytogenetic response (mCyR), 2 complete hematologic response (CHR), and 5 no responses (NR); in AP, there was 1 CCyR, 2 PCyR, 1 mCyR, 4 CHR, and 1 NR; in BP, 2 CCyR, 1 PCyR, 1 mCyR, 2 return to CP (RCP), and 6 NR. Four patients discontinued treatment because of toxicity despite an acceptable response. The median CCyR duration was 28 mo; only 2 pts in CP who achieved CCyR (1 had MMR) had a sustained response lasting 20 and 24 mo, respectively. Both received dasatinib after imatinib and nilotinib failure, and had G250E and H396R at start of dasatinib, respectively. The table shows median (in months) OS, EFS and FFS by disease stage.

7 pts continue on therapy (all CP): 2 sustained CCyR (1 MMR), 1 PCyR (lost CCyR), 2 mCyR, 2 no cytogenetic response (1 lost mCyR).

Use of 2^nd generation TKI after failure to 2 TKI may induce responses in some pts but these are usually not durable except in some pts in CP. New treatment options are needed for these pts.