Baseline Cytogenetic Response Is a Predictor of Outcome of Third Line 2^nd Generation TKI Treatment in Chronic Phase Chronic Myeloid Leukemia Patients

Introduction. 20-25% of patients (pts) with chronic myeloid leukemia (CML) in chronic phase (CP) failure second line therapy with 2^nd generation tyrosine kinase inhibitors (TKI). Many of them are non eligible for allogeneic stem cell transplantation(alloSCT) and are candidates for 3^rd line TKIs (TKI3). Thus,it is important to evaluate predictors of 3^rd line TKI efficacy.

Methods: Prognostic factors for TKI3 were evaluated in 43 pts (male -17; 39,5%) with CML in CP. Median age was 51 (range 23-88)years. All pts obtained Imatinib as first line treatment for a median 17 (range 1-85)months. Second line TKI were Nilotinib in 25 (58%), Dasatinib in 14 (33%) and Bosutinib in 4 (9%) of pts. Median duration of second TKI therapy was 13 (range 1-96) months. The main reason for treatment discontinuation was resistance for both first (35;81%) and second (38; 88%) TKIs.Mutations were revealed before second or third line TKI in 6/21(29%) and 12/28 (43%) pts, respectively, including 3pts with T315I mutation. Additional chromosomal abnormalities (ACAs) were observed in 9/36 pts. At baseline before TKI3 the best cytogenetic response was complete (CCyR), partial (PCyR), minimal or minor (mCyR), no CyR in 7(16%) 6(14%), 8(19%) pts and 22(51%), respectively. Complete hematologic response (CHR) without any CyR was observed in 13/22 (30%) pts.

Results: Nilotinib, Dasatinib or Bosutinib were used as TKI3 in 16(37%), 22(51%) and 5(12%) cases, respectively. Median time from diagnosis to TKI3 was 56 (range 13-314) months. Median observation time from TKI3 to data of analysis is 22 (range 8-119) months. Overall CCyR was obtained 8/36 pts (22%) pts without CCyR at baseline. CCyR was reached in 7/14(50%) and only 1/22 (4,5%) pts with any level CyR and no CyR, respectively (p=0,003). CHR obtained 7/9 (78%), but 3/7 (43%) subsequently lost the response within a median of 6 months follow-up. The cumulative rate of CCyR and major molecular response (MMR) on TKI3 according to baseline data are presented in table1. Nearly all patients (5/6; 83%) with PCyR before TKI3 responded. Progression to accelerated (AP) or blastic (BP) phase was observed in 10/22(45%) and 0/21 pts with no CyR or any level CyR at baseline(p=0,0003). Other unfavorable factorsfor disease progression were mutations. AP/BP were observed in 7/12 (58%) and 2/16 (12,5%)(p=0,015)with and without mutations, respectively. Any ACAs 4/9(44%) and 6/27(22%)(p=0,19) More than half of patients 25/43(58%) discontinued TKI3 - median treatment time was 16 (range 2-55)months. Reasons for treatment withdrawal were resistance (16; 64%), toxicity (4;16%), alloSCT (5;20%).

Conclusions: According to our study pts with any cytogenetic response, especially with PCyR, and without mutations at baseline benefit 2^nd generation TKIs as third line treatment. Thus, in case of alloSCT noneligibility, this cohort of pts are good candidates for 2^nd generation TKI as 3^rd line treatment.

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