Challenging Cases: Frontline TKI for CML and Options Upon Progression

Fadi Haddad, MD MD Anderson Cancer Center | Gabriela Hobbs, MD Massachusetts General Hospital | Rahul Gosain, MD, MBA Wilmot Cancer Institute | Rohit Gosain, MD Roswell Park Comprehensive Cancer Center

Key Points

• A patient’s age, comorbidities, and goals of therapy should be considered when selecting a frontline tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML).

• The first-generation TKI, imatinib, may be preferred for patients with cardiovascular toxicities over new-generation TKIs.

• If patients progress on frontline therapy, mutational testing is necessary to identify known resistance-driving mutations, particularly T315I.

• Ponatinib, a third-generation TKI, overcomes T315I and other resistance mechanisms, but requires response-based dose optimization to manage cardiovascular toxicity.

Treatment Options for Challenging CML Cases

Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, met with CML experts, Fadi Haddad, MD, of The University of Texas MD Anderson Cancer Center, and Gabriela Hobbs, MD, of Massachusetts General Hospital, to discuss CML treatment options for two cases as part of the Challenging Cases series on the Oncology Brothers podcast.

In the US, the FDA has approved six TKIs for CML: imatinib, dasatinib, nilotinib, bosutinib, ponatinib, and asciminib. Imatinib is a first-generation TKI, while dasatinib, nilotinib, and bosutinib are second-generation TKIs. Ponatinib is a third-generation TKI designed to overcome treatment resistance. Asciminib is a first-in-class STAMP (specifically targeting the ABL myristoyl pocket) inhibitor that is sometimes referred to as a third-generation TKI.

Optimal Frontline Treatment Selection in CML

The first case described a 49-year-old man presenting with worsening fatigue, night sweats, and left upper quadrant fullness, with a known history of well-controlled diabetes, hypertension, and peripheral artery disease. Initial workup was consistent with CML, and fluorescence in situ hybridization and BCR-ABL polymerase chain reaction (PCR) testing confirmed a diagnosis of chronic phase CML.

In the frontline setting, a patient’s age, comorbidities, and treatment goals are primary criteria that drive TKI selection. For instance, new-generation TKIs may be preferred for younger patients to potentially achieve more rapid deep molecular remission and allow for a treatment-free interval. Conversely, imatinib has a more favorable cardiovascular risk profile compared with new TKIs, and may be preferred for patients with notable comorbidities. 

For this case, given the patient’s young age but significant cardiovascular comorbidities, Drs. Hobbs and Haddad agreed imatinib would be the more safety-driven selection, but asciminib could be attempted with close cardiovascular monitoring if the patient’s goal is a treatment-free remission. Reduced-dose bosutinib or dasatinib could strike a middle ground between safety and potency, but nilotinib is absolutely contraindicated based on the patient’s comorbidities. In addition, this patient could start on imatinib and switch to a new TKI if they don’t show signs of an early molecular response within 3 months, Dr. Hobbs suggested. 

Follow-Up Treatment After Frontline TKI

Next, the doctors considered a 54-year-old woman who received a chronic phase CML diagnosis 2 years ago and started on imatinib. After her BCR-ABL1 International Scale score increased from 2.1% at 12 months to 4.8% at 18 months, kinase domain mutation testing was performed and identified T315I mutation. The patient’s history included hypertension, type 2 diabetes mellitus, BMI 30, and a 10 pack-year smoking history. 

When any patient with CML progresses on a frontline TKI, oncologists should perform ABL1 kinase mutational testing. There are a variety of kinase domain alterations that can emerge and drive resistance to certain TKIs while remaining sensitive to others, guiding treatment selection. The T315I mutation, however, drives resistance to all first-generation and second-generation TKIs, leaving only ponatinib and asciminib as effective second-line options. In this case, the patient was switched to ponatinib and her BCR-ABL1 score reduced to 0.4% after 9 months. Beyond ponatinib, Drs. Haddad and Hobbs agreed that a transplant should be considered in the absence of available clinical trials. 

While ponatinib overcomes many resistance mechanisms in CML, it is associated with notable cardiovascular toxicities. When using ponatinib, oncologists should follow the dose optimization strategy defined in the OPTIC study, starting at a higher dose and reducing to lower dose once a patient achieves a BCR-ABL response on PCR.