Treatment for CML
Drugs that target the BCR-ABL have become the standard treatment for CML within the past 10 years. These drugs, known as tyrosine kinase inhibitors (TKIs), affect normal cells much less than conventional therapy does, so their side-effect profiles are not as severe as with standard chemotherapy or interferon therapy.
Imatinib (Gleevec®) was the first of the TKIs targeting BCR-ABL specifically. It is now known as a first-generation TKI, and after clinical trials demonstrated its efficacy over interferon/cytarabine, was approved as first-line treatment in 2002 (National Comprehensive Cancer Network [NCCN], 2011).
- Almost all patients with CML initially respond to imatinib.
- Responses can last for years, although patients must take the drug indefinitely.
- Newly diagnosed patients with very high circulating leukocytes may require immediate treatment to avoid cerebrovascular accident or death from leukostasis (National Cancer Institute, 2011a).
- Common side effects (typically low grade) include diarrhea, fatigue, muscle pain, nausea, pruritic rash, periorbital edema, and edema in feet and abdomen.
- Grade 3 or 4 toxicities include neutropenia and thrombocytopenia.
- Long-term treatment is rarely associated with congestive heart failure and cardiotoxicity; patients with previous cardiac history should be monitored closely.
- Has numerous drug-drug interactions. Drugs inducing the CYP3A4/5 enzyme levels may decrease therapeutic levels of imatinib, and CYP3A4 inhibitors may increase therapeutic blood levels. Use with caution with anticonvulsants and steroids. Use warfarin with caution.
- Patients can develop resistance over time.
- Primary (intrinsic): treatment was not effective since the start of therapy. Treatment is considered failed when any of the following is not achieved: complete hematologic response by three months of treatment; any sign of a cytogenetic response by six months of treatment; partial cytogenetic response by 12 months of treatment; or complete cytogenetic response after 18 months of treatment.*
- Secondary (acquired): initial therapy milestones are reached, followed by a loss of achieved response, either hematologic or cytogenetic, or progression of disease during treatment (Bauer & Romvari, 2009).
- Long-term clinical trials data show that only 7% of patients progress to accelerated or blast phases while on imatinib, showing that continuous treatment in the chronic phase maintains a durable response in many patients.
* Complete hematologic response = complete normalization of peripheral blood counts; cytogenetic response = decrease in number of Philadelphia chromosome-positive metaphases, determined by bone marrow aspirate analysis (the most commonly utilized method for monitoring response in patients)
High-dose imatinib has demonstrated higher response rates in patients evaluated. Several studies demonstrated superiority of high-dose protocols over traditional protocols, including for intermediate- and high-Sokal risk patients with chronic disease phase CML. Other studies have demonstrated superior initial responses, but with 12 month endpoints comparable to standard therapy. High-dose protocols have not demonstrated lower rates of disease progression and are associated with higher rates of dose interruption or reduction because of higher-grade toxicities. Given the current data, high-dose imatinib is currently not recommended as initial therapy for newly diagnosed CML (NCCN, 2011).
Bauer, S., & Romvari, E. (2009). Treatment of chronic myeloid leukemia following imatinib resistance.Clinical Journal of Oncology Nursing, 13, 523–534.
Dasatinib (Sprycel®) is a second-generation TKI that is active against nearly all imatinib-resistant BCR-ABL mutations. Studies demonstrate dasatinib as effective in inducing cytogenetic and hematologic responses in patients who demonstrate imatinib resistance (in all phases of CML). Dasatinib was approved by the U.S. Food and Drug Administration (FDA) in 2006 for patients with CML resistant to or intolerant of imatinib (American Cancer Society [ACS], 2011b; NCCN, 2011).
- Toxicities include pleural effusions, often leading to dose interruption or reduction. Patients with cardiac history or hypertension, or those receiving dasatinib in twice daily dosing, should be closely monitored because they are at increased risk of pleural effusions.
- Other side effects include lymphocytosis (which is associated with pleural effusion), thrombocytopenia, edema, nausea, diarrhea, and rashes.
- Multiple drug-drug interactions exist with dasatinib. Drugs inducing the CYP3A4/5 enzyme levels may decrease therapeutic levels of dasatinib, and CYP3A4 inhibitors may increase therapeutic blood levels. Avoid concurrent use. Do not use with H2 blockers or proton pump inhibitors.
- Studies have demonstrated that once per day and twice per day dosing is equally effective in patients with chronic phase CML previously resistant to imatinib; once per day dosing is now standard.
- Dasatinib was first approved as first-line therapy in previously untreated patients with chronic phase Philadelphia chromosome-positive CML in 2010, after studies demonstrated that dasatinib achieved response rates similar to high-dose imatinib and superior to standard dose imatinib, without significant differences in response rate or toxicities. Responses were achieved more quickly with dasatinib versus imatinib, and fewer patients advanced to the accelerated or blast phases while on dasatinib.
Galinsky, I., & Buchana, S. (2009). Practical management of dasatinib for maximum patient benefit.Clinical Journal of Oncology Nursing, 13, 329–335.
Bryant, G. (2009). A once-daily dasatinib dosing strategy for chronic myeloid leukemia.Clinical Journal of Oncology Nursing, 13, 316–323.
Nilotinib (Tasigna®) is a highly selective BCR-ABL TKI that is 20-50 times more potent when used against imatinib-resistant cells. In 2007, the FDA approved nilotinib for adult patients with chronic phase or accelerated phase Philadelphia chromosome-positive CML with demonstrated intolerance to or resistance of prior imatinib therapy. In 2010, the FDA approved it as first-line therapy for adult patients newly diagnosed with Philadelphia chromosome-positive CML (ACS, 2011b; NCCN, 2011).
- Patients taking nilotinib rarely exhibit fluid retention or muscle cramps.
- Grade 3 and 4 toxicities include thrombocytopenia and neutropenia, although in less than half of patients; lipase and bilirubin elevations; and hyperglycemia and hypophosphatemia (rare). Use with extreme caution in patients with hepatic dysfunction.
- Prolonged QTc is observed but managed well with dose reduction. This side effect is presented as a black box warning on nilotinib packaging.
- Sudden cardiac death has been reported in patients using nilotinib (Kantarjian et al., 2006). Patients with cardiac history or electrolyte imbalance should be carefully monitored; baseline electrocargiogram should be obtained and checked periodically.
- Multiple drug-drug interactions are possible with nilotinib. Drugs inducing the CYP3A4/5 enzyme levels may decrease therapeutic levels of nilotinib, and CYP3A4 inhibitors may increase therapeutic blood levels. If used concurrently with a CYP3A4 inducer, consider dose increase of nilotinib. If CYP3A4 inhibitor must be used, consider dose interruption or reduction of nilotinib.
- Nilotinib has demonstrated activity in clinical trials in patients with blast phase CML, but is not yet FDA-approved for this population.
- Nilotinib demonstrated superior control and fewer progressions than imatinib even among high-Sokal risk patients.
- Nilotinib at twice daily dosing is superior to imatinib in newly diagnosed, chronic phase, Philadelphia chromosome-positive CML (Saglio, et al, 2010)