Outcome of Patients (pts) with Chronic Myeloid Leukemia (CML) After Failure to 2nd and 3rd Tyrosine Kinase Inhibitors (TKIs)
Authors: Li Liunan , Kantarjian Hagop , Zhao Meng , O'Brien, MD Susan , Jabbour Elias , Quintás-Cardama Alfonso , Burton Elizabeth , Faderl Stefan , Ferrajoli Alessandra , Cortes Jorge E. 
Published: October 2019

Abstract
Abstract 1238

Background:
First and second generation tyrosine kinase inhibitors are effective for most pts with CML in chronic phase. Approximately 80% of pts achieve complete cytogenetic response (CCyR) with imatinib, but nearly 15% of them eventually lose response. With dasatinib, nilotinib or bosutinib, approximately 50% of those who failed imatinib achieve CCyR, and about 15% of them eventually lose response. Using one of these agents after failure to 2 prior TKIs results in CCyR in only about 20%, usually of short duration. Thus, some pts receive and fail therapy with 3rd TKI. No standard therapy is available for these pts. Although their outcome is presumed to be poor, this has not been systematically analyzed. Understanding their outcome is important since new investigational options are being developed to treat this patient population, and understanding their expected outcome is needed to better comprehend the results obtained.

Aim:
To analyze the outcome of patients who have received and failed 2nd and 3rd TKI.

Methods:
We reviewed the records of 64 CML pts treated at MD Anderson Cancer Center from 2005–2009 who received treatment with 3 sequential TKIs. The second TKI was bafetinib (INNO-406, 1pt), bosutinib (12 pts), dasatinib (13 pts), and nilotinib (38 pts). Upon failure to 2nd TKI, 27 pts were in chronic (CP), 20 pts in accelerated (AP), 14 pts in blast phase (BP), and 3 pts in 2nd chronic phase, and were started on a 3rd TKI: bafetinib (6 pts), bosutinib (12 pts), dasatinib (35 pts), and nilotinib (11 pts).

Results:
After a median follow-up of 36 months (mo) (range, 3 – 71), 14 (22%) pts were still on 3rd TKI, including nilotinib (4 pts), dasatinib (7 pts), bafetinib (1 pt), and bosutinib (2 pts). Fifty (78%) pts failed therapy, including 16 pts (1 in 2nd CP, 2 in CP, 4 in AP, and 9 in BP) died during therapy with 3rd TKI. Among the 34 pts alive after 3rd TKI failure, their median age was 59 years (range, 19 to 92), and 17 were female. Their median time from diagnosis of CML was 76 mo (22 to 241). They failed the 3rd TKI after a median of 5.8 mo (range, 0.3 to 45) on therapy, with 27 pts being resistant (1 had minor cytogenetic response, all others 100% Ph+) and 7 pts were intolerant to 3rd TKI. The best response to a 3rd TKI was 1 partial cytogenetic (PCyR), 1 minor and 1 minimal cytogenetic response, 7 complete hematologic responses (CHR), and 24 with no response (NR). Upon failure to 3rd TKI, 16 pts were in CP (4 with BCR-ABL kinase domain mutations including two F359V, and one Y253H and one F317L), 11 in AP (6 with BCR-ABL kinase domain mutations including two G250E, and one each for F317L, F359C, T315I, and F317L), and 7 in BP (3 pts with BCR-ABL kinase domain mutations, two T315I and one V299L). These stages at the end of 3rd TKI represented no stage change in 26 patients, a progression in 5 pts (3 from CP to AP, 1 from CP to BP, 1 from AP to BP), and an improvement in 3 (from AP to CP in 2, from BP to AP in 1). Of those in CP, 16 pts were in complete hematologic responses (CHR). The median Ph+ metaphase after failure to 3rd TKI was 94% (8 to 100). After failure to 3rd TKI, 4 pts received dasatinib, 5 nilotinib, 4 bafetinib, 2 AP24534, 3 omacetaxine + imatinib, 6 single-agent omacetaxine, 4 stem cell transplantation, and 1 each for MK-0457, hydroxyurea, vincristine + deaxmethasone, idarubicin + imatinib + Ara-C, and DCC-2036. One pt was lost to follow-up. Response to subsequent therapy is described in the table 1 . After a median follow-up of 4 mo since failure to 3rd TKI, 15 of 34 pts have died, including 4 of 16 in CP, 5 of 11 in AP, and 6 of 7 in BP. The median survival from failure to 3rd TKI was 25 mo (12 mo for pts in CP, 6 in AP, and 1 in BP). Among patients who are still alive, 12 pts are still receiving the 4th therapy which were 3 pts received nilotinib, 2 dasatinib, 2 homoharringtonine, 2 AP245341, 1 bafetinib, 1 DCC-2036, and 1 hydroxyurea since failure to 3rd TKI, and 6 pts have changed to subsequent therapies after 4th therapy, including 5 pts on AP24534, 1 pt on XL228, and one lost to follow-up.

Conclusions:
Patients who have failed therapy with 2nd and 3rd TKI have a very poor prognosis with rare responses and a very short expected survival. New therapies that may improve their outcome and prolong their survival are urgently needed for this patient population.

Disclosures:
No relevant conflicts of interest to declare.