Prognostic Significance of Prior Best Response to Imatinib in Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Second Generation Tyrosine Kinase Inhibitors (TKIs).
Authors: Jabbour Elias , Kantarjian Hagop , Shan Jenny , O’Brien Susan , Wierda William , Ravandi Farhad , Borthakur Gautam , Kornblau Steven , Walker Brenda K. , Rios Mary Beth , Cortes Jorge 
Published: April 2020

Backgound. Imatinib mesylate therapy has significantly improved the prognosis of CML. A minority of pts in CP-CML are primary resistant to imatinib or develop resistance during treatment. Second generation TKIs such as dasatinib and nilotinib demonstrated efficacy in overcoming imatinib resistance, with high rates of hematologic and cytogenetic responses in CML post imatinib failure.

Study Aims and Study Group. We assessed the impact of prior best response to imatinib on outcome of 120 pts in CP treated with new TKIs at our institution after imatinib failure: 75 (62%) received dasatinib and 45 (38%) recived nilotinib. Median age was 57 years (range, 21–83). The median duration of the disease was 67 months (range, 4–241). Pts have been followed for a median of 22 months (range, 1–44) from the start of 2nd generation TKIs.

Results. Best response to imatinib was hematologic in 47 pts (40%) and cytogenetic in 60 (50%) (complete in 28, partial in 16, minor in 16). Five pts (4%) were primary refractory and 8 (6%) were intolerant. At the start of 2nd generation TKIs, 87 pts (73%) were in active CP with no complete hematologic response (CHR). Eighty-five (71%) harbored more than 90% Philadelphia-positive metaphases, and clonal evolution was noted in 28 pts (23%). Patients that had achieved a cytogenetic response at any time during their imatinib therapy had a better outcome than those who had only a hematologic response: CHR rates 98% vs 68%, p &lt;0.001; major cytogenetic response (MCyR) rates 75% vs 26%, p&lt;0.001; and complete cytogenetic response (CCyR) rates 68% vs 23%, p&lt;0.001. This translated into an improved 12-month event-free survival (EFS) of 92% vs 68% (p&lt;0.001) and a trend for better 12-month survival of 92% vs 89% (p=0.06) (Table1). Pts with CHR at the start of therapy with 2nd generation TKIs had higher rates of cytogenetic response than those not already in CHR (88% vs 64%; p=0.01). Low disease burden defined by Philadelphia-positive metaphases &lt;90% was associated with higher rates of hematologic response (p=0.006), MCyR (p&lt;0.001) and CCyR (p=0.003), with no impact on EFS. There was no difference in activity between the two 2nd generation TKIs with CHR rates of 89% and 80% (p=0.18), MCyR rates of 57% and 51% (p=0.57) and CCyR rates of 52% and 47% (p=0.71) for dasatinib and nilotinib, respectively.

Conclusion. The probability of response to 2nd generation TKIs is highly dependent on prior response to imatinib and disease burden at the start of therapy.

Table 1. % CG response % 12-Month Best response to imatinib N % CHR Major Complete EFS Survival EFS=Event-free survival; CG=Cytogenetic; CHR=complete hematologic response No CHR 4 80 40 40 80 80 CHR 32 68 26 23 68 89 Any CG response 59 98 75 68 92 92 P-value &lt;0.001 &lt;0.001 &lt;0.001 &lt;0.001 0.06