Unique Considerations With TKIs for Chronic Myelogenous Leukemia

Michael Millenson, MD

At the recent NCCN 8th Annual Congress on Hematologic Malignancies, Michael Millenson, MD, Fox Chase Cancer Center, discussed considerations in selecting second- and third-generation tyrosine-kinase inhibitors (TKIs) for the management of chronic myelogenous leukemia (CML).

Millenson first noted that even with the FDA’s approval of several next-generation TKIs for CML, imatinib remains a reasonable choice for first-line therapy. Further, he said when imatinib becomes available as a generic drug, cost factors might make the drug an even more enticing choice in therapy selection.

The FDA approval of imatinib for CML was followed over the next decade by nilotinib (Tasigna) and dasatinib (Sprycel), for both frontline and second-line treatment, and more recently, bosutinib (Bosulif) and ponatinib (Iclusig) for second-line therapy.

Response criteria for evaluating the efficacy of TKIs in CML are evolving. At present, the optimal response is to achieve both complete cytogenetic response (CCyR) and major molecular response (MMR).

Many studies suggest that second-generation drugs improve upon the CCyR and MMR rates achieved with imatinib. The effect on overall survival awaits longer follow-up. The NCCN guidelines recommend second-generation drugs for newly diagnosed CML patients, especially high-risk patients.

If a patient fails to achieve CCyR after 12 months of treatment with a particular TKI, physicians should first be sure the failure is not due to nonadherence, which is common, Millenson said. If the patient is adherent, then a switch in therapy should be considered, and mutational analysis is recommended to guide that choice.

Millenson recommended mutational analysis in the following circumstances:

• Patients with an inadequate response to treatment (BCR-ABL >10% or < partial CCyR at 3 months, less than CCyR at 12 and 18 months)
• Any sign of loss of response (hematologic relapse, cytogenetic relapse, and 1 log increase in BCR-ABL and loss of MMR
• Disease progression to accelerated or blast phase

Salvage therapy depends on the mutation identified that is associated with resistance or suboptimal response. Choices are: ponatinib (T315I); ponatinib or nilotinib (V299L); ponatinib, nilotinib, or bosutinib (T315A, F317L/V/I/C); ponatinib, dasatinib, or bosutinib (Y253H, E255KV, F359V/C/I ).

The side effects that are typical of all TKIs are self-limiting and improve over time. These include rash, nausea, myalgias, diarrhea, edema, and effusions. Topical or systemic steroids can be used to treat rash. To avoid nausea, TKIs should be taken with meals (except nilotinib) and antiemetics can be used. For management of myalgias, calcium and magnesium supplements and NSAIDs can be helpful. Antimotility agents and dose interruptions or reductions can be used to treat diarrhea. Edema is managed with sodium reduction, diuretics, and dose interruptions or reductions. Diuretics, dose interruptions and reductions, and steroids are used for effusions.

Each second- and third-generation TKI also has side effects that are specifically associated with its use (Figure).

TKIs are substrates for cytochrome P450 enzymes, raising the concern of drug-drug interactions. Physicians should avoid using proton pump inhibitors, since they reduce the bioavailability of TKIs, said Millenson.

He added that specific drugs that prolong the QT interval should be used with caution; these include antiarrhythmic agents (amiodarone, sotalol, procainamide), psychiatric drugs (tricyclic antidepressants, antipsychotics), antihistamines, antibiotics (macrolides, ketoconazole, voriconazole, chloroquine), and calcium channel blockers.

Figure. Side Effects Associated With Second- and Third-Generation TKIs in CML^a

Agent

Side Effects

nilotinib

food-drug interactions, QT interval prolongation, LFT abnormalities, and peripheral arterial disease (use with caution in patients with this disease); patients on nilotinib should refrain from eating 2 hours before and 1 hour after taking the drug; the drug has a black box warning for QT interval prolongation, and ECG should be obtained at baseline and 7 days after treatment is initiated; for QTc >480 msec, hold the drug and give potassium and magnesium

dasatinib

pleural and/or pericardial effusion in up to 30% of patients, reversible pulmonary arterial hypertension (rare but potentially serious), and reversible inhibition of platelet aggregation)

bosutinib

diarrhea, which is usually self-limiting, is seen in up to two-thirds of patients and is sometimes serious, leading to early discontinuation; LFT abnormalities can also occur

ponatinib^b

elevations of serum lipase, blood clots, LFT abnormalities, and pancreatitis

^aNote: There are side effects that are typical of all TKIs. The figure only lists the toxicities specifically associated with each drug.

^bThe FDA has placed a partial hold on the clinical development of ponatinib following the high occurrence of arterial thrombosis in patients treated with the drug. For more information, see “Safety Concerns Halt Ponatinib Development” on page 16. CML indicates chronic myelogenous leukemia; ECG, electrocardiogram; LFT, liver function test; TKIs, tyrosine kinase inhibitors.