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Chronic Myeloid Leukemia Treatment

CME

Chronic Myeloid Leukemia: Optimizing Use of TKIs to Individualize Treatment Across the Disease Spectrum

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: August 15, 2024

Expiration: February 14, 2025

Fadi Haddad
Fadi Haddad, MD
CME/CE Information

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Overview

Today, most patients with CML are diagnosed in the chronic phase. Many are asymptomatic and the presence of CML is identified incidentally, for example, during a routine blood check for an annual physical. Of importance, as good as outcomes are with current targeted therapies, if patients do not receive treatment or are not properly treated, eventually they will progress from an indolent chronic phase, to the accelerated phase with aggressive features, and eventually to the blast phase which can be life-threatening.1

CML is characterized by the Philadelphia (Ph) chromosome, which occurs when the ABL1 gene from chromosome 9 joins to the BCR gene on chromosome 22; the resulting BCR::ABL1 fusion gene is oncogenic. The BCR::ABL1 protein has increased autonomous kinase activity, which led to the development of BCR::ABL1 TKI targeted therapy.

The introduction of TKI for Ph-positive CML over 2 decades ago changed the treatment paradigm for CML. Imatinib became the first approved TKI for the treatment of CML. Imatinib and subsequently approved TKIs (bosutinib, dasatinib, nilotinib, ponatinib) and the STAMP inhibitor asciminib have profoundly changed the patient experience and clinical outcomes in CML. These targeted drugs have substantially improved the management of patients with CML and made optimistic goals more realistic. For individuals in chronic phase CML, either imatinib or one of the second-generation TKIs (dasatinib, nilotinib, bosutinib) are the standard initial management strategy.

The natural history of the disease has been substantially changed by these targeted therapies. It has been shown that the life expectancy of a patient diagnosed with chronic-phase CML is very similar to that of the general population. A patient with good access to individualized treatment, who is appropriately monitored and managed, and who is adherent to therapy, will likely have a normal life.2  

However, many challenges remain. A multidisciplinary team approach with an engaged patient and/or family is critical, given that CML is a chronic disease and the need for treatment changes may occur quickly. Treatment decisions must factor in the many therapy choices with an individual patient’s characteristics and comorbidities. There are other challenges that may develop during the course of therapy, including resistance mutations, drug-related adverse events (AEs), and the potential need for dose adjustments. It is important for HCPs to understand the key differences among the various therapeutic agents available and to know how to use them for maximum clinical benefit in different circumstances.

Approved BCR::ABL1–Targeted Therapy for CML in Adults

As of 2024, 5 BCR::ABL1 TKIs and 1 BCR::ABL1 STAMP inhibitor have been approved as treatment for CML.3-8 Imatinib and all second-generation TKIs are approved for both frontline and second-line therapy (for imatinib, the second-line indication is after failure of interferon). The third-generation TKIs, ponatinib and asciminib, are characterized by their ability to inhibit the T315I mutation and are approved as second-line or later therapy for adult patients with CML in chronic phase with intolerance or resistance to 2 or more prior TKIs, or in adults with CML in chronic phase and the T315I mutation. All these targeted drugs are approved for accelerated-phase CML except for asciminib, and all are approved for blast-phase CML except for asciminib and nilotinib.

It is important to recognize that the dose varies for each of these drugs between the different disease phases and between different indications. For example, for asciminib, the recommended starting dose for patients who are resistant or intolerant to previous TKIs and who do not have the T315I mutation is either 40 mg twice daily or 80 mg once daily. But for patients with T315I, the recommended starting dose is 200 mg twice daily. Of note, this drug must be taken at least 2 hours after or 1 hour before a meal on an empty stomach.

With bosutinib, the frontline dose is 400 mg once daily, but the dose for second or subsequent lines of therapy is 500 mg once daily. This drug is given with food.

Dasatinib is given at the recommended starting dose of 100 mg once daily in the chronic phase, but 140 mg once daily for the accelerated or blast phase. It can be given with or without food.

Imatinib is given at the recommended starting dose of 400 mg once daily in the chronic phase, but 600 mg once daily in advanced stages. Imatinib is typically taken with food.

Nilotinib is given at the recommended starting dose of 300 mg twice daily in the frontline setting, vs 400 mg twice daily in the resistant or intolerant second-line setting. Like asciminib, nilotinib is given on an empty stomach.

Ponatinib is given at the recommended starting dose of 45 mg once daily for chronic, accelerated, or blast phase. However, once the patient achieves a response (≤1% BCR::ABL1) in the chronic phase, the dose is dropped to 15 mg once daily to minimize AEs.

Three of the TKIs—imatinib, dasatinib, and nilotinib—are FDA-approved for pediatric patients. The presentation and management of CML or drug-related AEs in children and adolescents differs from adults and is beyond the scope of this module.9

To optimize the management of patients with CML, it is important to keep in mind these differences in dosing and schedule, and whether these targeted agents are administered with or without food.

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Factors to Consider in CML Treatment Selection

Now that multiple BCR::ABL1–targeted therapies are available, physicians may be challenged to select the optimal frontline treatment for an individual patient with CML; age, comorbidities, and CML risk category all play a role.2 The decision is further impacted by the patient’s goals. One important aspect of the second-generation TKI is a better probability of deep molecular response (DMR) than imatinib; by contrast, imatinib has fewer high-risk AEs but a lower probability of DMR. For example, in a younger patient, the desire for treatment-free remission (TFR) may prompt initiation of a TKI which will induce a deeper response. Cost and affordability of TKIs can be quite significant and varies depending on the specific medication and whether a generic version is available. Generic imatinib has been available since 2016 and dasatinib is expected to become available generically in the near future in the US. Below we will consider multiple case scenarios that illustrate current management recommendations for patients with chronic-phase CML.

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