Treating CML in 2025: TKIs and Transplant
Key Points
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Asciminib is the most recently approved tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML).
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Treatment response is evaluated via BCR::ABL1 concentrations, but clinicians must be aware of atypical BCR::ABL1 transcript types that may not appear on standard testing.
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The OPTIC study showed that dose reducing ponatinib can effectively control associated toxicities, improving its viability for patients resistant to other TKIs.
Performing the Initial Workup for CML
Cohosts of the Oncology Brothers podcast, Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, spoke with Jorge Cortes, MD, of Georgia Cancer Center to discuss the treatment algorithm for patients with CML.
Clinicians should perform fluorescence in situ hybridization (FISH) testing as a basis for a CML diagnosis in patients with leukocytosis or neutrophilia after ruling out secondary causes. Both the European LeukemiaNet and National Comprehensive Cancer Network guidelines recommend a bone marrow biopsy as part of the initial workup for CML, as fibrosis can alter responses, side effects, and myelosuppression.
Cytogenetic testing is also necessary as chromosomal abnormalities can impact prognosis, and a baseline profile can be a valuable reference for identifying emergent abnormalities as treatment continues, said Dr. Cortes. Based on these initial tests, the disease can be staged as accelerated phase CML (AP-CML) or chronic phase CML (CP-CML), and patients with CP-CML can be stratified as low, intermediate, or high risk.
CML Treatment Selection in 2025
Studies show that newer-generation TKIs have a therapeutic benefit across risk groups, said Dr. Rahul Gosain. As such, a patient’s risk score may not be the primary factor driving treatment selection. Instead, treatments should be selected based on the patient’s treatment goals, and clinicians should focus on educating patients about the characteristics of available agents, including their side effects. “Put it into perspective and see what works best for the patient,” said Dr. Cortes.
For example, if a patient wants to have the best chance to eventually stop therapy, asciminib may be the preferred agent as it can yield rapid, deep responses. Comparatively, if a patient is focused on having the lowest risk for a heart attack, imatinib may be the best agent as it is associated with less cardiovascular toxicity.
Considering Transplant in CML
There is some overlap between the definitions of high-risk CP-CML and AP-CML, but, regardless of terminology, “it’s a group of patients that need special attention,” Dr. Cortes said. While a patient diagnosed in this stage may do well without transplant, a patient who progresses to this stage should likely receive a transplant. Another subgroup that may benefit from earlier transplant is patients with ASXL1 mutations. “If they have ASXL1 mutations, we know that with all the TKIs, the prognosis is poor—I think it is time to consider transplant in that patient,” said Dr. Cortes.
Monitoring Treatment Response
The standard when measuring response in patients with CML is BCR::ABL1 concentration, with a major molecular response defined as a concentration of 0.1% of total blood cells on the International Scale. Notably, some polymerase chain reaction (PCR) tests do not capture atypical BCR::ABL1 transcripts, and it’s important to identify patients with them to avoid misinterpreting a response due to a transcript type that isn’t captured by PCR, said Dr. Cortes. For these patients, FISH testing is the most sensitive tool to quantify a response.
Recent Updates on Dose Adjusting Ponatinib
Ponatinib is a notable treatment option for CML because it is active in all single gene mutations, including mutations that engender resistance against other TKIs. However, ponatinib is associated with arterial occlusive events. The OPTIC study, on which Dr. Cortes was the lead author, randomized patients to receive ponatinib at starting doses of 45 mg (the standard dose), 30 mg, or 15 mg once daily. In this study, the ponatinib dose was reduced to 15 mg in patients who responded.
The OPTIC study verified that the 45 mg starting dose was the most effective dose, but the data also showed that reducing the dose after response significantly lowered the risk of arterial occlusive events. This dose optimization strategy can make the drug much more tolerable for patients who may benefit from it, particularly those with T359 mutations, Dr. Cortes said.