Incidence and Outcomes of Chronic Myeloid Leukemia (CML) Patients (pts) with Other Chromosomal Abnormalities (OCA) Treated with Second Generation Tyrosine Kinase Inhibitors (TKI)

Development of OCA (i.e., chromosomal abnormalities in the Philadelphia chromosome negative metaphases) has been reported among patients receiving imatinib as initial therapy for CML. Little is known about incidence and outcomes of OCA in CML pts treated with frontline 2^nd generation TKI (dasatinib, nilotinib).

We describe incidence of OCAs in CML pts treated with frontline 2^nd generation TKI and determine the outcomes of pts who develop OCA events.

We reviewed pts treated with frontline 2^nd generation TKI, dasatinib (n=99) or nilotinib (n=117), treated on 2 parallel ongoing prospective single-arm Phase II protocols at our institution. An OCA was defined as a cytogenetic abnormality in one or more non-Philadelphia chromosome positive clones (different than clonal evolution). Pts were followed with cytogenetic analysis at 3 month (mo) intervals for the first year, then every 6–12 mo. 30 pts with OCA were identified. Pts in chronic (n=25) or accelerated phase (n=5) at diagnosis were included in the analysis.

With a median follow-up of 30 mo (range 0–71), 11 (11%) pts treated with dasatinib and 19 (16%) pts treated with nilotinib developed OCA. The difference in incidence of OCA with dasatinib and nilotinib was not statistically significant (p=0.280). At start of therapy, median age of pts developing OCA was 53 (41–71) with dasatinib and 52 (37–82) with nilotinib, compared to those pts without OCA: 48 (18–83 yrs) with dasatinib and 49 (17–87) with nilotinib. The most common OCA event overall was abnormality of chromosome 7 found in 5 pts (one pt with both inv(7) and +7) for total of 6 occurrences (including inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1) involving chromosome 7). The most common translocation event was t(6;13) in 2 pts. No pts developed trisomy 8 (historically most common OCA among imatinib treated pts). Median time to first appearance of OCA was 9 mo (range 3–58) for all 2^nd generation TKI pts (12 mo (range 3–58) for dasatinib group and 9 mo (3–48) for nilotinib group). 9 pts had OCA on more than one occasion. OCA disappeared in 25 pts during course of follow-up. Outcomes for OCA group versus non-OCA group are shown in Table 1, and outcomes with focus on chronic phase pts only in Table 2. For pts in accelerated phase, 3/6 pts (50%) in dasatinib group and 2/17 pts (12%) in nilotinib group developed an OCA. None of the pts who developed OCA has developed AML or MDS.

OCA are observed in 10–15% of pts receiving initial therapy with 2^nd generation TKI. At median follow up of 30 mo, occurrence of OCA confers no statistically significant adverse impact on outcomes when compared to non-OCA pts treated with 2^nd generation TKI and has not resulted in other hematologic disorders.

Off Label Use: Dasatinib and Nilotinib originally used in investigational setting when trials were begun. Kantarjian:Novartis Pharmaceuticals Corp: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cortes:Novartis, BMS, ARIAD, Pfizer: Consultancy, Research Funding.