Choosing First-Line CML Treatment

Allison Strider

Chronic myeloid leukemia, also known as CML, can present in different ways. It’s important to distinguish which phase of CML your patient is presenting with before considering treatment options. There are three phases of CML: chronic, accelerated, and blast phase. We’ll mostly be discussing chronic phase, or CP-CML, but it’s important to also mention the more advanced phases of CML: accelerated phase (AP-CML) and blast phase (BP-CML).

Sarah Worth

Currently, there are five tyrosine kinase inhibitors (TKIs) approved in the United States for the treatment of CML: first-generation imatinib; second-generation dasatinib, nilotinib, and bosutinib; and third-generation ponatinib. Patients with AP-CML at diagnosis will be treated with a second- or third-generation TKI; dasatinib, bosutinib, nilotinib, and ponatinib are all approved by the FDA for the treatment of AP-CML. Ponatinib is only indicated in this setting in certain circumstances, such as when there is resistance or intolerance to at least two prior TKIs or with a T315I mutation.¹ We also consider evaluating the patient for allogenic hematopoietic cell transplant (HCT). There are no restrictions for TKI therapy use prior to HCT.²

BP-CML is currently defined as 30% or more blasts and presence of extramedullary disease,² and it can present suddenly or develop over time through AP-CML. Treatment is determined based on myeloid or lymphoid phenotype and includes either an acute myeloid leukemia– or acute lymphocytic leukemia–type induction chemotherapy accordingly, as well as a TKI. Only dasatinib, bosutinib, and ponatinib are FDA approved in blast phase, but nilotinib is also an option in this setting.² Recommended starting doses of TKIs are higher in the advanced setting to overcome resistance.^2,3 For example, for newly diagnosed CP-CML, the initial starting dose of bosutinib is 400 mg once daily, but for CP, AP, or BP-CML with resistance or intolerance to prior therapy, the recommended starting dose is 500 mg once daily.^2,3

Allison Strider

Central nervous system (CNS) involvement is an important consideration for these patients, in which lumbar puncture and CNS prophylaxis is recommended for lymphoid BP-CML.² Transplant-eligible patients with BP-CML should proceed to allogeneic HCT if possible.^2,4 So it’s definitely important to understand the different phases of CML, even though most patients will present in the chronic phase.

Sarah Worth

Yes, and out of the five previously mentioned TKIs, all except ponatinib are approved for use in newly diagnosed CP-CML patients.

There are also several factors to consider when selecting one of these TKIs for CP-CML treatment. One is the risk score to determine disease progression and survival with CML. To determine this, it is recommended that we use a scoring system prior to starting TKI therapy in these patients. The Sokal score is a formula based on age, blast count in the blood, platelet count, and spleen size. There are also other risk scores including Hasford and most recently ELTS, which is based on the same variables as Sokal but is superior to other scores in predicting CML-related death in CP-CML patients treated with imatinib.⁴ The Hasford score considers all factors included in Sokal score with the addition of basophils and eosinophils.²

Based on the risk score, patients are classified as having low-, intermediate-, or high-risk disease. Disease progression is more frequent in patients with intermediate- or high-risk scores. Second-generation TKIs are associated with lower risk of disease progression than imatinib. Therefore, second-generation TKIs are preferred for intermediate- or high-risk disease. Imatinib and second-generation TKIs are both considered preferred options for low-risk scores. However, risk stratification alone doesn’t determine the treatment choice. Allison, what are the other factors we need to consider?

Allison Strider

So once we’ve made the diagnosis and assessed risk stratification, we also want to consider comorbidities, the toxicity profile of each TKI, possible drug interactions, patient preference, and cost burden. Comorbidities are common in patients with CML, and having multiple comorbidities may increase the risk of developing adverse effects from TKI therapy.⁵ In fact, comorbidities are now known to be the main cause of death for patients with CML treated with TKIs.⁶

Consideration of the patient’s comorbidities along with the best TKI option is important. For example, the 10-year analysis from the ENESTnd trial further confirmed the cardiovascular risks associated with nilotinib with higher cumulative rates of cardiovascular events with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) versus imatinib (3.6%).⁷ Therefore, imatinib or bosutinib is preferred in patients with cardiovascular disease.⁵ Nilotinib or bosutinib may be preferred for patients with history of lung disease or pulmonary arterial hypertension, or those who are at risk for developing pleural effusions.⁵ These are only a few examples, but it’s important to consider and discuss with each patient the specific TKI’s toxicity profile in relation their personal goals, comorbidities, and other medications.

Cost is also a factor for some patients. The only TKI that is currently available in the United States in a generic formulation is imatinib. Unfortunately, even generic imatinib can still be costly for some patients, so this really is a discussion we need to have with our patients. It is also important to collaborate with your pharmacy and social work team to help lessen the financial toxicity for our patients. For patients who have private insurance plans, pharmaceutical companies have copay assistance programs to help with these often high copays. Organizations like the Leukemia & Lymphoma Society occasionally have grants open that also offer additional financial assistance for patients.

Sarah Worth

These are definitely important points to consider. We also need to factor in the potential side effects patients could experience. To date, there are no differences in overall survival observed between imatinib and each second-generation TKI.⁴ However, they differ in pharmacokinetic and adverse effect profiles. Although TKIs as a class are relatively well tolerated, for all of them, we need to assess patients for cytopenias and hepatic and renal function—more frequently at initiation and periodically after.

Allison Strider

We also need to educate patients on the potential adverse effects—both serious and common—the administration of the TKIs, and how we will monitor them while on therapy. Imatinib commonly is associated with fluid retention, gastrointestinal (GI) upset, muscle cramps, and rash. It must be taken with food and is typically administered only once daily.⁸

Nilotinib has a black box warning for prolonged QT interval, so we should obtain an electrocardiogram at baseline, seven days after initiation, and then after any dose adjustments and periodically thereafter. Patients must take nilotinib on an empty stomach, so it’s important to discuss with patients that they should avoid food for 2 hours before and 1 hour after taking each dose. Other adverse effects associated with nilotinib include rash, peripheral arterial occlusive disease, hyperglycemia, hyperlipidemia, and elevated amylase and lipase.⁹

For patients taking dasatinib, they may experience rash, GI upset, fluid retention, pulmonary hypertension, and pleural/pericardial effusions.¹⁰ Bosutinib, which must be taken with food, has a similar AE profile as the other TKIs—rash, GI upset, fluid retention—but more common with bosutinib is diarrhea.³

Ponatinib is approved for patients with CP-CML with resistance or intolerance to at least two prior TKIs or with a T315I mutation. This third-generation TKI has several black box warnings including arterial occlusive events, venous thromboembolic events, heart failure, and hepatoxicity. It also has numerous additional warnings including pancreatitis, neuropathy, ocular toxicity, and hemorrhage.¹

Sarah Worth

In addition, drug-drug interactions are common for all TKIs, and we should be assessing patients for these at every encounter we have with them. We should also work with patients to perform a medication reconciliation, creating an accurate list of all medications, dose, frequency, and route of administration. Common interactions include acid-suppressing medications, medications that prolong QT interval, and CYP3A4 inhibitors. One drug-drug interaction example I see often is with statins. Coadministration of nilotinib and imatinib with atorvastatin and simvastatin can result in increased exposure to the statin.^8,9 Pravastatin and rosuvastatin are often preferred to avoid potential drug-drug interactions.¹¹ The CML NCCN Guidelines have a helpful chart that summarizes these interactions.²

Allison Strider

Once we choose the right therapy and initiate a patient on it, we need to monitor their response. We do this by assessing clinical, hematological, cytogenetic, and molecular levels. A patient’s response to therapy is related to long-term outcomes, and NCCN and ELN¹² have defined specific milestones when evaluating response. Complete hematologic response is the resolution of all CML-related symptoms and normalization of white blood cell count, differential, and platelets. Complete cytogenetic response correlates to overall survival and is defined as the absence of Ph+ metaphases. Molecular response is evaluated by PCR; quantitative PCR (qPCR) should be performed at baseline and every 3 months initially.² Once BCR-ABL1 (International Scale [IS]) 1% has been reached, qPCR should be done every 3 months for the next 2 years and then every 3 to 6 months afterward.²  

Milestones are crucial when starting therapy and monitoring for response. The first milestone is an IS level of less than 10% at 3 months of therapy and is referred to as an early molecular response (EMR).² This correlates with progression-free and overall survival. Major molecular response (MMR) is defined as BCR-ABL1 (IS) 0.1% or less, or a 3-log or greater reduction in BCR-ABL1 mRNA from the standardized baseline if qPCR (IS) is not available.² MMR at 12 months is associated with low likelihood of loss of response and high likelihood of achieving a deep molecular response (DMR).²

A DMR response, defined as reduction of BCR-ABL1 mRNA by 4 or 4.5 logs (MR⁴ or MR^4.5), is the minimum depth of response that must be reached and maintained to be considered for a trial of treatment-free remission. These milestones should be interpreted in the clinical context, but if they aren’t reached, we should consider patient noncompliance and/or drug interactions and conduct a mutational analysis. Depending on the results, you should consider switching TKIs or referring the patient for allogeneic HCT, to a clinical trial, and to a specialized CML center.² Speaking of treatment-free remission, which patients are eligible to discontinue their TKI therapy, and how do we monitor them?

Sarah Worth

The discontinuation of TKIs is safe in select patients with CML.² Numerous trials have evaluated patients on various TKIs with treatment-free remission and all have shown similar results.⁴ NCCN Guidelines recommend that patients have a consultation with a CML specialist prior to discontinuation.² Treatment-free remission is often a goal of patients and would allow them to potentially avoid the long-term complications that develop as a result of being on a TKI. We consider discontinuation only for patients who are 18 years or older, have CP-CML, have been on a TKI for at least 3 years, have prior evidence of quantifiable BCR-ABL1 transcript, and have maintained DMR for 2 or more years.²

Compliance is also important to consider, and patients will need access to reliable qPCR monitoring as it will be required monthly for the first 6 months after discontinuation, bimonthly during months 7 to 12, and then quarterly thereafter.² If a patient has a loss of MMR, the TKI should be restarted within 4 weeks, and the patient would need monthly molecular monitoring until MMR is achieved.²

Allison Strider

When discussing TKI discontinuation with patients, it’s important to explain that about one-fourth of patients who stop TKIs will develop withdrawal syndrome.¹³ This is associated with musculoskeletal pain and flushing and may be more likely to occur in patients with preexisting arthritis.⁴ Patients often are prescribed NSAIDs or a short course of steroids, but in more severe cases, opioids or restarting the TKI is required.