Overcoming <scp>TKI</scp> resistance in a patient with chronic myeloid leukemia using combination <scp>BCR‐ABL</scp> inhibition with asciminib and bosutinib
Authors: Kevin H. Hall, Angelique Brooks, Edmund K. Waller
Journal: American Journal of Hematology (2021)

A 43-year-old female was diagnosed with chronic myeloid leukemia in chronic phase (CML-CP) in 2001 when she presented with leukocytosis and a subsequent bone marrow biopsy confirmed the presence of BCR-ABL1 t(9;22) fusion oncogene. She was initially treated with interferon alpha and cytarabine before being placed on imatinib once commercially available. She achieved hematologic remission without cytogenetic remission of her CML with an imatinib dose of 800 mg per day. She experienced progressive disease in 2008, and a BCR-ABL1 kinase mutation analysis demonstrated the presence of a F317L mutation. Subsequently, she was switched from imatinib to nilotinib dosed at 400 mg twice daily and achieved a hematological remission with a partial cytogenetic response. She continued on nilotinib until mid-2015 but unfortunately lost hematologic remission and was switched to dasatinib. However, dasatinib was relatively ineffective in controlling her leukocytosis, likely due to the presence of the F317L mutation. Thus, she switched to bosutinib 500 mg per day in August 2015. While taking bosutinib she developed angioedema in her lower lip and hives on her forehead. Fortunately she did not have any further angioedema events and was able to continue therapy with use of daily oral antihistamines. The patient reached and maintained a complete hematologic response on bosutinib, although her BCR-ABL1 transcript detected via polymerase chain reaction (PCR) remained in the 2%–6% range despite increasing the dose up to 600 mg daily. A tyrosine kinase inhibitor (TKI) domain mutation analysis remained negative for T315I mutation but positive for F317L. Her quantitative BCR-ABL1 transcript rose from 4% to 18% in January 2020 in conjunction with bone marrow biopsy results that demonstrated t(9;22) in 12% of cells. Ponatinib was not recommended due to a history of pulmonary embolism and carotid bruit, and the patient did not wish to proceed with allogeneic stem cell transplant at that time. As the patient had previously failed all other available TKIs, approval was obtained for use of asciminib through compassionate use. The patient stopped bosutinib and started asciminib 40 mg twice daily based on phase I single agent data in April 2020.1 Unfortunately, her quantitative BCR-ABL1 transcript continued to rise, and bosutinib 500 mg daily was resumed in addition to asciminib in August 2020 when her BCR-ABL1 transcript was 54.6%. Her transcript peaked 2 weeks later at 95% but dramatically declined down to 0.1% within 3 months of starting the combination (Figure 1). Her most recent BCR-ABL1 transcript in January 2021 was detectable but below the lower limit of accurate quantitation (<0.0063%), thus indicating a major molecular response (MMR). She has now continued combination therapy with bosutinib and asciminib for more than 8 months to date with no discernable side effects. This case is the first to report on the clinical activity of asciminib combined with another TKI, and the patient has achieved her deepest molecular response to date after only a few months of combination treatment. While sequencing for mutations in the myristoyl-pocket site were not available, it appears that our patient's CML is resistant to both bosutinib and asciminib as individual drugs but responds to the combination. Her level of response suggests the activity of CML-targeted TKIs may be modified with allosteric interaction through ligand binding. The mainstay of treatment for CML-CP is the use of oral TKIs. These TKIs bind competitively to the ATP-binding site of BCR-ABL1, which is constitutively activated in patients with CML, thus preventing the formation of the BCR-ABL1 fusion protein.1, 2 Unfortunately, many patients fail therapy due to drug resistance or intolerable side effects.1 Resistance to available TKI therapy can occur through both BCR-ABL1 dependent or independent mechanisms.2 Although ponatinib is active against the T315I mutation, which confers resistance to imatinib, dasatinib, nilotinib, and bosutinib, its use is often limited due to severe vascular adverse events.1, 3 In contrast, the newly developed TKI asciminib (ABL001), a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, provides allosteric inhibition of BCR-ABL1 kinase activity.1, 2 In contrast to currently available therapies, mutations occurring within the kinase domain of ABL1 do not cause resistance to asciminib. Additionally, mutations within the myristoyl pocket where asciminib binds are not associated with resistance to available TKIs.1, 2 As asciminib binds ABL1 at site distinct from ATP-competitive TKIs, preclinical studies have proposed synergistic combinations with available TKI therapy.2 Recent data demonstrates the efficacy of asciminib monotherapy in CML-CP in heavily pretreated patients with and without the T315I mutation.1, 3 While this patient does not possess the T315I mutation, ponatinib was decided against due to a history of pulmonary embolism after the birth of her first child and presence of a carotid bruit. Many patients have similar relative contraindications to therapy with ponatinib, thus opening the door for new therapeutic approaches with fewer side effects. Single-agent asciminib was initially trialed in this patient based on published phase I results. However, due to the rapid rise in PCR bosutinib was resumed in combination with asciminib based on preclinical data. Clinical trials are in progress evaluating the efficacy of asciminib in combination with TKIs in both the frontline and relapsed setting, but results have not as yet been published.4-6 Despite the lack of current evidence, it was decided to proceed with combination therapy for our patient due to the proposed benefits and relative safety of asciminib when compared to the lack of efficacy or risks associated with the alternatives available to her. As this is the first case described in the literature of asciminib used in combination with another TKI for the treatment of CML-CP, ongoing and future trials are needed to validate this approach. Success of this approach in larger patient populations will provide many patients with CML additional therapeutic options and combinations. E.K.W. has received consulting fees and research support from Novartis related to CART products. The other authors declare no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data sharing is not applicable to this article as no new data were created or analyzed in this study.