TKI therapy in CP-CML: toxicity management & approaching a cure

Long-term safety of bosutinib in CP-CML: a 5-year update from BFORE

There are several tyrosine kinase inhibitors (TKIs) approved for the treatment of newly diagnosed chronic myeloid leukemia (CML). These include imatinib, dasatinib, nilotinib, bosutinib, and ponatinib.¹ With most trials and reports focusing on the efficacy of these agents, it is essential to better characterize the toxicity profile of TKIs in order to better manage complications and to make better treatment decisions.

Bosutinib is a second-generation TKI that has been approved for the management of both newly diagnosed and treatment-resistant patients with CML. The approval of bosutinib in first line was based on data from the Phase III BFORE trial (NCT02130557) comparing bosutinib with imatinib. The study reported a major molecular response (MMR) rate at 12 months of 47.2% for patients treated with bosutinib versus 36.9% for patients treated with imatinib.²

In this video, Jorge Cortes, MD, Georgia Cancer Center, Augusta, GA, reports on the long-term safety of bosutinib in patients from the BFORE trial.

After a follow-up of five years, the most common treatment-emergent adverse events (AEs) included increased lipase levels in 9.0% of patients treated with bosutinib. The study also reported GI, liver, effusion, and renal AEs in 79.9%, 44.0%, 6.0% and 10.4% of patients respectively. 25.4% of AEs led to permanent treatment discontinuation, with most patients discontinuing due to increased alanine aminotransferase levels during the first year of treatment.³

Overall, there were no new safety signals identified after this five-year follow-up. Indeed, the majority of AEs and treatment discontinuations occurred during the first year of treatment. These data support the use of bosutinib in the treatment of CP-CML.³ Other studies exploring the long-term toxicity of other TKIs such as imatinib reported similar results, with most adverse events typically observed within the first year of therapy.¹

Managing adverse events associated with TKIs in CML

Most patients treated with TKIs will experience AEs which are usually mild to moderate and are manageable. However, these AEs decrease the patient’s quality of life (QoL) and can lead to treatment discontinuation. Due to the length of TKI therapy and concerns about the long-term toxicity of TKIs, it is important to better prevent and manage treatment-related toxicities.⁴

TKI therapy is most commonly associated with cardiovascular, pulmonary, hepatobiliary, and gastrointestinal (GI) complications, as well as myelosuppression in patients who have been treated with cytoreductive therapies prior to TKI treatment. While most of these AEs are not associated with long-term toxicity, some AEs including hypophosphatemia or decreased glomerular filtration rate have been shown to alter bone mineralization and renal function respectively.¹

Each TKI has a distinct toxicity profile, with imatinib treatment linked to diarrhea, edema, muscle cramps and pain, and nilotinib treatment associated with rash, GI toxicity, pulmonary and vascular complications. In addition, the use of dasatinib is associated with a greater rate of myelosuppression, headache, and pleural and pericardial effusions, and treatment with bosutinib is linked to higher rates of diarrhea and increases in alanine and aspartate aminotransferase levels. Ponatinib, a third-generation TKI has been shown to induce higher rates of vascular and cutaneous AEs, as well as fatigue and pancreas inflammation, and asciminib, a novel STAMP (specifically targeting the ABL myristoyl pocket) inhibitor with a different mode of action, has been reported to have a more tolerable safety profile than other TKIs, with the most common AE being lipase elevation.¹

The European LeukemiaNet recommendations for the management and avoidance of AEs in CML indicate that grade 2 AEs should be managed with a dose hold or with an AE-specific treatment, and grade 3 AEs should be managed with a dose hold or TKI discontinuation if the AE is not resolved within four weeks. Finally, it is recommended to stop and switch to another TKI if the patient experiences a grade 4 AE. These guidelines also state that dose reduction or treatment interruption should only be done if it is not possible to manage the AE with an AE-specific treatment. Strict monitoring is also essential to prevent the occurrence of AEs associated with the use of specific TKIs, including cardiovascular complications linked to the use of ponatinib. Consideration of a patient’s comorbidities and potential drug interactions is also essential when choosing the first TKI.⁴

Working towards a cure in CML

In the past 20 years, the introduction of TKIs has revolutionized the treatment of CML, allowing patients to achieve a near-normal life expectancy. Whilst the initial aim of TKI therapy was to achieve disease control and prolong progression-free survival (PFS) and overall survival (OS), the impressive efficacy of these agents has completely changed the treatment paradigm of patients with CML, and achieving treatment-free remission (TFR) has now become the main goal of CML therapy. TFR, also called functional cure, is a term used to describe a sustained deep remission followed by TKI cessation.⁵

Attempting TFR is currently recommended for patients with CP-CML who do not carry an ABL kinase domain mutation, and who have been on TKI treatment for a minimum of three years and have achieved a sustained deep molecular response for at least two years. In addition, studies have shown that the duration of TKI treatment and the duration of remission are strong factors for TFR success. The impact of specific mutations, measurable residual disease (MRD) stability, and immune factors on TFR success are currently being investigated.¹

Patients who are in successful TFR should be carefully monitored in the long-term and should have a long-standing relationship with their treating physician.¹ In addition, it is also important to have good communication with patients as it has been shown that patients are afraid to discontinue therapy because of concerns related to disease recurrence, lack of information regarding TKI cessation, and withdrawal symptoms.⁵

Guidelines currently recommend restarting TKI therapy upon molecular recurrence. However, several studies have demonstrated that it is feasible to achieve a second TFR after an unsuccessful attempt for a first TFR. Importantly, patients treated with second-generation TKIs in first line have been shown to be more likely to achieve a second successful TFR.¹

Nevertheless, the proportion of patients who achieve long-term TFR is still relatively small, and it is essential to find strategies to increase that number. Jorge Cortes concluded: “Some patients have remained off-therapy without recurrence of the disease for many years. That is a reality now for probably about 20-25% of all patients treated with a TKI. So it’s still a small percentage and we’re trying to see how can we increase that – perhaps with combinations, meaning adding other drugs such as interferon, venetoclax, and other agents to try to increase the rate of patients who are eligible for discontinuation and decrease the rate of relapse after discontinuation”.