Dynamics of BCR-ABL1 Transcripts during Nilotinib Therapy in Patients with Chronic Myeloid Leukemia (CML).
Authors: Quintás-Cardama Alfonso , Kantarjian Hagop , Jones Dan , O’Brien Susan , Rios Mary Beth , Cortes Jorge 
Published: October 2019

Abstract
Background: Mutations in the BCR-ABL kinase domain are a common mechanism (40%) of imatinib-resistance. Nilotinib is approximately 30-fold more potent than imatinib against ABL kinase and has activity against most BCR-ABL kinase mutants, except T315I. We investigated the molecular response to nilotinib in patients (pts) receiving this agent both as frontline therapy as well as after intolerance or resistance to imatinib.
Methods: 144 pts in chronic (CP) (n=63), accelerated (AP) (n=44) and blast (BP) (n=37) phase CML received nilotinib therapy. Twenty-seven pts in CP received nilotinib as frontline therapy. Quantitative reverse transcription PCR in peripheral blood samples was performed prior to nilotinib and every 3 mo thereafter.
Results: The median BCR-ABL1/ABL1 ratio (%) at nilotinib start was 64.50 (range, 0.67-100), including 67.09 (range, 0.01–100) for pts in CP (100 [range, 6.87–100] for pts receiving frontline nilotinib therapy), 46.44 (range, 0.01–100) for AP, and 73.31 (range, 0.16–100) for BP. Fifty-two (45%) of 116 assessed pts (19/43 in CP, 23/40 in AP, and 10/33 in BP) harbored 26 different BCR-ABL1 mutants. The most common mutations were G250E (n=8), E355G (n=5), M351T (n=4), and T315I (n=4). The lowest PCR values for pts in CP, AP, and BP were achieved after 18 (0.20), 18 (0.88), and 18 (0.18) mos, respectively (0.1 at 12 mos for pts receiving frontline nilotinib therapy). After 24 mos of therapy, the median BCR-ABL1/ABL1 ratios for pts in CP, AP, and BP were 0.21, 6.99, and 0.05, respectively. BCR-ABL1/ABL1 ratio reductions occurred in 80 (72%) of 112 pts who had at least 2 PCR analyses during nilotinib therapy: <1-log in 22 (20%) pts (6 CP, 8 AP, 8 BP) after a median of 18 wks (range, 12 to 96); >1-log in 19 (17%) pts (10 CP, 6 AP, 3 BP) after a median of 36 wks (range, 11 to 96); >2-logs in 20 (18%) pts (12 CP, 6 AP, 2 BP) after a median of 48 wks (range, 12 to 96) and >3-logs in 19 (17%) pts (13 CP, 4 AP, 2 BP) after a median of 36 wks (range, 12 to 116). A major molecular response (MMR) was seen in 21 (19%) pts (12 CP, 7 AP, 2 BP). Nine (8%) pts achieved a complete molecular response (CMR; undetectable BCR-ABL1 transcripts), including 5 CP, 2 AP, and 2 BP. Among pts treated in CP followed for at least 6 months, MMR occurred in 7 (22%) of 32 pts treated after imatinib failure (median follow-up 23 mos) and 6 (55%) of 11 pts treated as frontline therapy (median follow-up 9 mos). CMR occurred in 2 (6%) and 3 (27%) pts, respectively. Fifty-three (47%) pts (21 CP, 22 AP, 10 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: M244V, G250E, wild-type, wild-type, A433T, E355G, Q252H), in 6 pts >2 logs (baseline mutation: F359V, E453K, wild-type, E355G, G250E, wild-type), and in 1 AP >3 logs (wild-type).
Conclusion: Nilotinib 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.