Treatment Failure in CML: Distinguishing Between Disease Resistance and Treatment Intolerance

Patients with chronic myeloid leukemia (CML) can have a near-normal life expectation when treated with BCR::ABL1 tyrosine kinase inhibitors (TKIs). Approximately 50% to 70% of patients will also achieve a durable deep molecular response (molecular response 4 score defined as BCR::ABL1 transcript levels on the international scale [IS] ≤ 0.01%). Responses lasting for at least 5 years could be associated with a treatment-free remission rate of 80% or higher.¹ This is provided that patients can afford this frontline TKI therapy, are adherent, and are appropriately managed in case of treatment failure.²

Treatment failure was initially referred to as CML resistance in the European LeukemiaNet guidelines. However, because only imatinib (Gleevec) was available initially and because some patients experienced adverse events from imatinib, the protocols evaluating second- and third-generation TKIs included patients with resistance and/or intolerance to imatinib (and later to other TKI) therapy; both groups were labeled as treatment “failure.” Also, some patients who have TKI adverse events and discontinue TKIs early on (before achieving a good molecular response) can manifest BCR::ABL1 transcript level increases and would be labeled as “failure attributed to toxicity plus resistance.” Treatment failure is reported to occur in 30% to 40% of patients with CML after 5 years of frontline TKI therapy. However, findings from long-term follow-up studies show TKI intolerance occurs in 15% to 25% of patients at 10 years of treatment and is the most common cause for changing TKI therapy.^3-7

The incidence of CML resistance, defined as BCR::ABL1 transcript levels on the IS of 1% or more after 12 months or more of therapy or CML transformation, is only 10% after 10 years of treatment.^8,9 The choice of subsequent TKI therapy is based on the prior TKIs used, the cause of failure (resistance or prohibitive intolerance), the presence and type of ABL1 kinase mutations, the patient’s comorbidities, and the cost of therapy.¹⁰

TKI intolerance should not be called failure anymore; it encourages an immediate change of TKI therapy. Failure refers to situations where physicians or patients switched TKIs due to toxicities, believing that reducing the dose would compromise treatment effectiveness. Currently, we recommend reserving the term failure for true disease resistance.

For patients experiencing TKI toxicities, dose reductions should always be considered before switching therapies in the absence of a prohibitive toxicity. Our strategy for dose reduction is detailed in the TABLE. Certain severe toxicities may be too risky to consider continuing the same TKI, even at reduced doses. These include recurrent pleural effusions (more common with dasatinib [Sprycel]), pulmonary hypertension (uncommon at 1%-2%; associated with dasatinib; may be reversible with sildenafil and corticosteroid treatments),⁴ arterial occlusive events (AOEs) or vaso-occlusive events (mainly with nilotinib [Tasigna] and ponatinib [Iclusig]), pancreatitis (rare at 1%-2%; seen with nilotinib and ponatinib),⁴ severe hypertension refractory to antihypertensive medications, enterocolitis with bosutinib (Bosulif), neurotoxicity (dementia-like symptoms, parkinsonism, intracranial hypertension; rarely observed with imatinib and dasatinib; symptoms may resolve over weeks or months after TKI discontinuation), and immune-mediated adverse events (pneumonitis, hepatitis, myocarditis, pericarditis, or nephritis).⁴ Among patients with good molecular response who are switching TKIs for prohibitive toxicity, the new TKI can be used at a lower-dose schedule.

Recently, there has been increasing recognition of TKI cross-intolerance, a phenomenon where multiple toxicities occur more frequently in a patient with a TKI toxicity or similar toxicities occur in the same patient with different TKIs. For instance, a patient who previously experienced AOEs on nilotinib or ponatinib is at higher risk of AOEs when switched to dasatinib compared with imatinib or bosutinib. Similarly, a patient who develops a pleural effusion while on dasatinib is more likely to experience subsequent pleural effusions with bosutinib compared with imatinib or nilotinib. In results from their study, Busque and colleagues found that intolerance was the primary reason for switching TKIs.¹¹ They observed that 20 patients switched TKIs sequentially throughout their treatment, indicating an incidence of sequential intolerance 6.6 times higher compared with sequential resistance.¹¹

Failure Caused by TKI Resistance

Treatment strategies for patients with TKI resistance are determined by the frontline TKI used (first- or second-generation TKI) and the presence of ABL1 kinase mutations. In patients with disease resistant to frontline imatinib without ABL1 mutations, the recommendation is to switch to a second-generation TKI (such as dasatinib, nilotinib, or bosutinib) based on the patient’s comorbidities.

In cases of resistance to frontline second- generation TKIs, subsequent therapy is chosen based on the ABL1 mutational profile. For cases of non-T315I mutation, patients can switch to an alternative second-generation TKI to which the mutation is sensitive. In the absence of any detectable guiding mutation in patients with CML resistant to second-generation TKI, switching to a third-generation TKI is favored over rotating second-generation TKIs (low response rates of 10% to 30%) because of its proven efficacy in inducing higher cytogenetic responses.12 For patients without detectable ABL1 mutation or those harboring the T315I mutation, switching to ponatinib is recommended. Based on findings from the OPTIC trial (NCT02467270), we recommend a starting dose of ponatinib of 45 mg daily in patients with T315I mutation and 30 mg daily in those without the mutation, with reduction to 15 mg daily once the BCR::ABL1 transcript levels on the IS are 1% or less.¹³ Allogeneic stem cell transplantation should be considered in patients with disease resistant to ponatinib and even in those who are taking ponatinib (but facing challenges such as toxicities or high annual cost of therapy).

In summary, a careful evaluation of the reason to modify the TKI therapy in patients with CML is essential before determining the optimal course of action. For patients experiencing TKI intolerance, a dose reduction is recommended before switching TKI treatment. In patients with CML resistance, selecting the most appropriate subsequent TKI should be based on several factors such as the previous TKI used, the ABL1 kinase mutational status, and the patient’s comorbidities.

Fadi G. Haddad, MD, is assistant professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston. Hagop Kantarjian, MD, is professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, where he is also the Samsung Distinguished Leukemia Chair in Cancer Medicine.