Dynamics of BCR-ABL1 Transcripts during Dasatinib Therapy in Patients with Chronic Myeloid Leukemia (CML).

Background: Mutations in the BCR-ABL kinase domain are a common mechanism (40%) of imatinib-resistance. Dasatinib has 2-log higher inhibitory potency than imatinib against ABL kinase and has activity against all BCR-ABL kinase mutants, except T315I. We investigated the molecular response to dasatinib in patients (pts) receiving this compound both as frontline therapy and after imatinib failure.

Methods: 179 pts in chronic (CP) (n=107), accelerated (AP) (n=34) and blast (BP) (n=38) phase CML received dasatinib therapy at various doses in phase I or II studies. Thirty-six patients in CP received dasatinib as frontline therapy. Quantitative reverse transcription PCR in peripheral blood samples was performed prior to dasatinib and every 3 mo thereafter.

Results: The median BCR-ABL1/ABL1 ratio (%) at dasatinib start for the whole cohort was 76.21 (range, 0–100), including 75.04 (range, 0–100) for pts in CP, 88.96 (range, 0.19–100) for AP, and 79.25 (range, 3.76–100) for BP. Fifty-two (50%) of 105 assessed pts (24/57 in CP, 18/25 in AP, and 10/23 in BP; all after imatinib failure) harbored 26 different BCR-ABL1 mutants. The most common mutations were G250E (n=9), M351T (n=7), and T315I (n=6). The lowest PCR values for pts in CP, AP, and BP were achieved after 9 (0.24), 24 (1.36), and 9 (21.84) months, respectively (0.22 at 12 months for pts receiving frontline dasatinib therapy). After 24 mo of therapy, the median BCR-ABL1/ABL1 ratios for pts in CP, AP, and BP were 0.94, 1.36, and 48.22, respectively. BCR-ABL1/ABL1 ratio reductions occurred in 98 (87%) of 112 pts who had at least 2 PCR analyses during dasatinib therapy: <1-log in 35 (31%) pts (26 CP, 6 AP, 3 BP) after a median of 24 wks (range, 12 to 48); >1-log in 26 (23%) pts (18 CP, 7 AP, 1 BP) after a median of 48 wks (range, 12 to 96); >2-logs in 22 (20%) pts (19 CP, 2 AP, 1 BP) after a median of 38.5 wks (range, 12 to 96) and >3-logs in 15 (13%) pts (12 CP, 2 AP, 1 BP) after a median of 51 wks (range, 12 to 96). A major molecular response (MMR) was seen in 24 (13%) pts (20 CP, 3 AP, 1 BP). Eight (4%) pts achieved a complete molecular response (CMR; undetectable BCR-ABL1 transcripts), including 5 CP, 2 AP, and 1 BP. Among pts treated in CP followed for at least 6 months, MMR occurred in 13 (36%) of 36 treated after imatinib failure (median follow-up 21 mo) and 9 (25%) of 36 treated as frontline therapy (median follow-up 11 mo). CMR occurred in 4 (11%) and 1 (3%) pts, respectively. Forty-nine (44%) pts (40 CP, 7 AP, 2 BP) had at least 1 follow-up PCR analysis after their lowest transcript level, and in 7 pts the BCR-ABL1/ABL1 ratio increased >1 log (baseline mutations: K247R, M315T/F317L, G250E, F359V, 2 wild-type, 1 unknown), and in 1 CP pt >2 logs (baseline mutation G250E).

Conclusion: Dasatinib therapy induces molecular responses in a significant number of pts both as frontline therapy and after imatinib failure. These responses can be observed across a wide variety of BCR-ABL kinase mutations. Longer follow-up is needed to define the stability and durability of MMR and CMR in these pts.