Managing patients with chronic myeloid leukemia who fail responding to second generation tyrosine kinase inhibitors

The report recommends how to manage patients with chronic-phase chronic myeloid leukemia (CP-CML) who failed to respond to 2^nd generation tyrosine kinase inhibitors (TKIs). The authors suggested to consider patient-specific factors and personalize treatment for such patients.

TKIs deactivate cancerous enzymes which cause CP-CML. Response to TKIs increases the chances of recovery. Imatinib (Gleevec) is the 1^st-generation TKI used for CML therapy. Patients failing this treatment are treated with 2^nd-generation TKIs such as nilotinib (Tasigna), dasatinib (Sprycel), and bosutinib (Bosulif). These are thought to be more effective than imatinib.

Treatments are modified for patients failing any TKI, to prevent leukemia’s progress. However, specific treatment modifications for patients failing 2^nd generation TKIs are lacking.

For patients who do not respond to 2^nd generation TKIs, mutations (cancerous genetic abnormalities) and co-existing medical problems should be assessed. Patients with multiple mutations can be treated with ponatinib (Iclusig), a 3^rd-generation TKI, or stem-cell transplantation. Suitable donors for transplants should be searched immediately. This can take 3-4 months. Patients may also become physically unfit for transplant. Half-matched donors can be considered in such cases.

Ponatinib should be considered for all eligible patients. However, its doses must be determined based on patients’ other medical conditions and mutations. More severe mutations may need higher doses. Severe cardiovascular (CV) defects are the most common side effects of this drug. Therefore, patients’ CV risks and medications should be assessed carefully. Lower doses can be given to patients with CV issues. Patients unfit for ponatinib can receive an alternative 2^nd-generation TKI which was never given before.

Transplants should not be delayed for patients who may not benefit from further TKIs. Transplants can be considered before ponatinib for very young patients with perfect donors. Attempts to achieve treatment-free remission (TFR) should be avoided. TFR signifies the disappearance of all genetic signs of CML where patients do not need to restart any therapy.

If none of the above guidelines are suitable for some patients, interferon-alpha and/or supportive hospital care are recommended.

The authors concluded that treatment must be personalized for patients with CP-CML who are resistant to 2^nd generation TKIs. Factors like age, genetic mutations, TKI side-effects, and other medical conditions should be considered.