Axitinib in Ponatinib-Resistant B-Cell Acute Lymphoblastic Leukemia Harboring a T315L Mutation

Abstract

Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs.

Keywords: TKI inhibitor; acute lymphoblastic leukemia; axitinib; ponatinib.

Figure 1

Clinical course of our ponatinib-resistant acute lymphoblastic leukemia (ALL) patient. Lymphocyte (black) and monocyte (green line) counts are reported from diagnosis to death (w, week). Type and duration of each treatment are reported: ponatinib 45 mg/daily from day 0 to +14 w; hydroxyurea (HU) 500 mg/twice daily and vincristine (V) 2 mg/weekly (light blue dashed square) from +14 w to +16 w; axitinib 5 mg/daily from +18 w to +28 w; HU 500 mg/twice daily and mercaptopurine (6-MP) 50 mg/daily based on CBC from +25 w until death. Lumbar puncture (black arrows) was performed at +6 w and +12 w with methotrexate (MTX) 10 mg, cytarabine (Ara-C) 40 mg, and steroids 4 mg. Vincristine infusion (red arrows) at 2 mg was given on weeks +19, +22, +25, and +32.

Figure 2

Ex vivo sensitivity of primary leukemic cells to axitinib. Patient’s peripheral blood mononuclear cells were treated with serial dilutions of axitinib (0–25 µM, n = 5 doses), dasatinib (0–5 µM, n = 5 doses), bosutinib (0–2 µM, 5 doses) and bosutinib isomer (0–2 µM, n = 5 doses) for 24 h at 37 °C and 5% CO₂. Cell viability was determined by colorimetric assay and normalized on vehicle-control (DMSO-treated cells) for each drug. Axitinib showed a significant growth inhibitory effect. Data are shown as mean + SD of 3 replicates, and the inhibitory concentration 50 (IC50) for axitinib is reported.