Posted: Wednesday, August 15, 2018
Current Therapeutic Landscape in Newly Diagnosed Chronic Phase Philadelphia Chromosome–Positive Chronic Myeloid Leukemia
As of December 2017, the U.S. Food and Drug Administration (FDA) approved four tyrosine kinase inhibitors (TKIs) in the front-line setting for patients with chronic phase, Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML), including a first-generation TKI, imatinib,1 and three second-generation TKIs, dasatinib,2 nilotinib,3 and bosutinib.4 Current NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) endorse all four as options for the initial management of chronic phase Ph+ CML.5
The factors that should be considered when choosing among these four TKIs in the front-line setting include the patient’s disease characteristics as defined by Sokal, Hasford, or EUTOS (European Treatment Outcome Study) scores [Note: EUTOS is not recommended for risk stratification in the NCCN Guidelines]; past and current medical conditions (eg, diabetes mellitus, cardiovascular risk factors, history of prolonged QT, limited pulmonary reserve, history of pulmonary arterial hypertension [PAH], pleural effusion); the toxicity profiles of each drug and anticipated therapy tolerance; patient’s age; convenience and patient’s potential adherence issues; the therapeutic objective; and cost.6
Management Considerations: The Case for Second-Generation TKIs
When asked about his perspective on management approaches to front-line treatment options for chronic phase CML and what goes into his decision-making process, Neil Shah, MD, PhD, Professor in the Department of Medicine (Hematology/Oncology) at UCSF Helen Diller Family Comprehensive Cancer Center, told JNCCN 360, “I think the most compelling reason to use one of the second-generation TKIs such as dasatinib7 relative to imatinib in a patient with newly diagnosed chronic phase CML is the greater ability to achieve a deep molecular response, which enables eventual treatment discontinuation or, in other words, treatment-free remission.8,9 Some patients do not want to be on therapy indefinitely, for various reasons, including a desire to become pregnant and a lack of understanding of the potential toxicities associated with the long-term use of TKIs. Encouragingly, however, with TKIs, we are not seeing many late toxicities thus far, but follow-up is relatively short. If you are 20 or 30 years old, the potential long-term toxicities may be more relevant. So, with younger patients, I discuss these issues and assess their desire for aiming at eventual treatment discontinuation. For women who are considering having children, the ability to attain a deep molecular response and discontinue treatment—maybe not indefinitely but for long enough to safely conceive and deliver a healthy child—becomes an important goal.”
I think the most compelling reason to use one of the second-generation TKIs...in a patient with newly diagnosed chronic phase CML is the greater ability to achieve a deep molecular response, which enables eventual treatment discontinuation.
Age is therefore an important factor that comes into play, but Dr. Shah does not use any particular age cutoff. “Some people who are in their 50s or 60s have strong feelings about taking any long-term medication,” he said. “In general, for people older than age 70, the likelihood of having a substantial benefit from treatment discontinuation is lower than in younger patients. Patients with intermediate- or high-risk Sokal scores also may benefit from starting with a second-generation TKI.”
Dr. Shah noted that comorbidities can influence the initial choice of TKI. “Although imatinib has the longest track record in clinical practice and appears to be the safest of the FDA-approved TKIs in terms of potential to cause serious and irreversible adverse events, the safety profile of dasatinib is not substantially less favorable, particularly when it comes to the possibility of minimizing toxicities and improving quality of life through exploration of lower dosing strategies.”10
When it comes to the initial therapy decision-making process, Sara M. Tinsley, PhD, ARNP, AOCN, a malignant hematology nurse practitioner at the Moffitt Cancer Center, shared her thoughts. “Before our team decides on initial therapy in a patient with chronic phase CML, we look at the whole person, not just the disease. We look at their age, comorbidities, and other medications they may be taking, history (including social history and support system), occupation, and lifestyle.”
Dr. Tinsley also emphasized the importance of discussing the goal of treatment with patients. “When we look at the disease itself, we use the Sokal score to risk-stratify patients. Typically, patients with higher Sokal scores are started on a second-generation TKI to rapidly reduce their disease burden and the risk of progression to the accelerated or blast phase. We also tend to push for more aggressive therapy with second-generation TKIs in our younger patients, because we want to give them an option of achieving treatment-free remission. We use dasatinib preferentially in patients with a history of arrhythmia, heart disease, pancreatitis, or diabetes. With dasatinib, there is also a convenience factor, because it is taken once daily and has no food restrictions. Finally, when deciding which TKI to use for any particular patient, we also take cost and insurance coverage into consideration.”
Dasatinib Dose Management
Dr. Shah shared his clinical approach to the use and dosage of dasatinib.11 “I typically start patients younger than age 60 on a recommended dose of 100 mg/d. If they are meeting treatment milestones, I am amenable to dose reduction. I typically go from 100 mg/d to 50 mg/d. Caution with dose reduction is indicated in patients taking long-acting antacids, in whom the absorption of dasatinib may be diminished. In my clinical experience, 50 mg/d appears to be as effective as 100 mg/d, although it is possible there may be some rare kinase domain mutations that are selectively resistant to lower doses of dasatinib. The vast majority of my patients who start with 100 mg/d end up on 50 mg/d or even 20 mg/d; lower doses appear to improve quality of life. Even prior to the recently published MD Anderson Cancer Center study suggesting that 50 mg/d of dasatinib is efficacious,12 I would initiate a dose of 50 mg in patients older than age 60.”
Dr. Shah’s approach is based on his extensive familiarity and experience with the drug, which dates back to the first-in-human trial initiated in 2003. “Back then, we saw patients achieving cytogenetic responses with 30 mg/d, 5 days per week. I have patients who have achieved a deep molecular response on 50 mg/d and who after discontinuing treatment and experiencing molecular relapse have resumed treatment with 20 mg/d and regained a sustained deep molecular response,” he related.
Dr. Tinsley described a similar approach, noting “we usually start at the recommended dose, but we also use lower doses in quite a few of our patients, even younger ones. You just need to make sure they are responding well to those lower doses. So, basically, we go with the lowest dose that gets the job done.”
Basically, we go with the lowest dose that gets the job done.
Dasatinib Toxicity Profile and Management of Adverse Events
With regard to the toxicity profile of dasatinib,13 Dr. Shah explained, “the main comorbidity that could steer me away from dasatinib would be poor pulmonary reserve, such as someone who is on oxygen. The concern is they might be symptomatic should they develop even a small pleural effusion. Although dasatinib is rarely associated with PAH, anyone with a history of PAH should not be treated with dasatinib. Otherwise, there are no comorbidities that would limit my use of dasatinib. I would rather prevent than treat pleural effusions and therefore routinely initiate 50 mg/d in patients who are 60 years of age or older, as they are at increased risk for pleural effusion. Data from a single-arm study recently published in Cancer are in line with my clinical experience.”12
As for hematologic adverse events, with any potent second-generation TKI, including dasatinib, Dr. Shah told JNCCN 360 that an increased incidence of cytopenia, compared with imatinib, is expected, and it typically is managed by dose-reducing strategies. “For those few patients who experience persistent cytopenia despite dose reduction, achievement of a cytogenetic or molecular response is unlikely with any TKI, and we recommend bone marrow transplantation if appropriate in these cases.”
Dr. Tinsley commented on her experience with managing hematologic adverse events such as anemia. “It is important to look at the patient and not just go by the numbers. For example, in a patient with a pre-existing cardiac condition who becomes symptomatic, the hemoglobin threshold for when to transfuse is higher, say 7.5 to 9 g/dL, than for an asymptomatic patient, who we would transfuse only if their hemoglobin drops below 7 g/dL.”
As for thrombocytopenia, in a symptomatic patient dasatinib can be withheld or the dose reduced when the platelet count drops below 50,000/mL. “If a patient didn’t have any bleeding episodes, we are sometimes more liberal and do not change the dasatinib dosing unless the platelet count drops below 30,000/mL. Also, it is important to keep in mind that patients with normal platelet counts that suddenly drop may be taking aspirin or other nonsteroidal anti-inflammatory drugs and should be educated about the associated risk of bleeding.”
As for neutropenia, dasatinib is withheld if the neutrophil count drops below 500 cells/mm3, and then laboratory results are regularly checked. “If neutropenia lasts for too long,” said Dr. Tinsley, “we give growth factors. Also, it is important to educate patients and their caregivers about febrile neutropenia and over-the-counter medications that can exacerbate it.”
With regard to many nonhematologic adverse events, such as fluid retention, gastrointestinal issues, and generalized rash, Dr. Shah explained that they seem to be generally less common with dasatinib than with other TKIs, particularly imatinib. “Biochemical and laboratory abnormalities are almost unheard of in my clinical experience with dasatinib and appear much less frequent when compared with other TKIs. It is important to periodically check thyroid function, regardless of the TKI used,” he said.
Pleural effusions seem to be far more common with dasatinib than pericardial effusions, which occur in approximately 1% of patients, explained Dr. Shah. “We educate patients about these toxicities and ask that they inform us if they experience gradual development of shortness of breath or dry cough, which may be a sign of pleural effusion. If they have breathlessness that cannot be ascribed to pleural effusions or anything radiographic, we consider a cardiac evaluation, pulmonary arterial pressure assessment (initially from the echocardiogram), and then, if necessary, right-sided heart catheterization. If there is evidence of PAH, which is rare (~0.5%), it is largely reversible upon cessation of the drug.”
As for the other relatively rare adverse events, colitis can be a concern, according to Dr. Shah. Dr. Tinsley agreed that “PAH is one of those adverse events that warrant permanent treatment discontinuation. For pleural or pericardial effusion, we look at the size of the effusion and how symptomatic the patient is. If it is relatively small and asymptomatic, we just monitor the patient. If there is gastrointestinal upset, which is pretty common, we first try over-the-counter medications and then, if necessary, properly timed H2 blockers or proton pump inhibitors (PPIs)—assuming the benefits of using them outweigh the risks. If there is no improvement, we refer [the patient] to a gastroenterologist for further evaluation. We also involve our dietitians to help educate patients about foods that may exacerbate symptoms and how to manage their diets.”
The concern with the simultaneous use of long-acting H2 blockers or PPIs is not toxicity but diminished dasatinib efficacy due to a suboptimal absorption, Dr. Shah explained.14 He added that “one way to handle this is to use a higher dose of dasatinib, say 100 mg/d or 140 mg/d. In patients taking drugs that inhibit CYP3A4 function, such as some antifungal and antiretroviral agents, TKI metabolism is impaired and toxicity can result; in this case, dose reduction of TKIs should be considered.” Dr. Tinsley also observed that, “at each patient visit, we go through all of their medications and educate them about what to be careful about. We also urge patients to call us before they start taking any new medication, so we make sure it doesn’t interact with dasatinib or another TKI.”
Dr. Shah itemized the reasons why he uses dasatinib more often than the other TKIs:
- “My extensive experience with it dates back to the phase I study, which has made me very familiar with its adverse-event profile and how to effectively manage toxicities with dose reductions.”
- Increased potency and diminished vulnerability to drug-resistant mutations;
- Low association with serious and irreversible toxicity (lack of black box warnings) and long track record of safety;
- Convenience of administration. “Unlike some other TKIs,” Dr. Shah added, “dasatinib can be taken once daily with or without food. These features generally make dasatinib the preferred TKI in patients with chronic phase CML in my clinical practice.”
Dr. Tinsley again stressed the importance of patient education. “First you need to develop a good relationship with patients and help them to be more comfortable and less anxious. Then they can understand and absorb what you are trying to teach them. Also, they need to feel confident that when they reach out, you will call back and will take care of any adverse events they are experiencing. At Moffitt, we also make a point of educating patients about their polymerase chain reaction results and make an appointment to discuss those results. We also educate spouses or partners to help in that journey, and sometimes we get our social workers involved to help with social support.”
The bottom line is we see patients as the center of our team, and we work with them as their coaches to help them stay on track with their treatment.
“There is lot of trust involved, and patients need to know you have their best interests at heart,” Dr. Tinsley concluded. “The bottom line,” she told JNCCN 360, “is we see patients as the center of our team, and we work with them as their coaches to help them stay on track with their treatment, so they can have long and fulfilling lives.”
Neil Shah, MD, PhD, has disclosed that he has received research funding from Bristol-Myers Squibb and Ariad for the conduct of clinical research.
Sara M. Tinsley, PhD, ARNP, AOCN, has disclosed that she has participated in speaker bureaus for Takeda, Jazz, Incyte, Novartis, and Celgene; she has also served as a consultant for Celgene, AbbVie, and Novartis.
- Imatinib (Gleevec) prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021588s052lbl.pdf. Accessed July 25, 2018.
- Dasatinib (Sprycel) prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf. Accessed July 25, 2018.
- Nilotinib (Tasigna) prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022068s027lbl.pdf. Accessed July 25, 2018.
- Bosutinib (Bosulif) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf. Accessed July 25, 2018.
- Radich JP, Deininger M, Abboud CN, et al. NCCN Clinical Practice Guidelines in Oncology: Chronic Myeloid Leukemia. Version 4.2018. Accessed July 25, 2018. To view the most recent version of these guidelines, visit NCCN.org.
- Shah NP. Front-line treatment options for chronic-phase chronic myeloid leukemia. J Clin Oncol 2018;36:220–224.
- Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol 2016;34:2333–2340.
- Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood 2017;129:846–854.
- Mahon FX. Treatment-free remission in CML: who, how, and why? Hematology Am Soc Hematol Educ Program 2017;2017:102–109.
- Talpaz M, Saglio G, Atallah E, et al. Dasatinib dose management for the treatment of chronic myeloid leukemia. Cancer 2018;124:1660–1672.
- Schiffer CA. The evolution of dasatinib dosage over the years and its relevance to other anticancer medications. Cancer 2018;124:2687–2689.
- Naqvi K, Jabbour E, Skinner J, et al. Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic-phase chronic myeloid leukemia. Cancer 2018;124:2740–2747.
- Medeiros BC, Possick J, Fradley M. Cardiovascular, pulmonary, and metabolic toxicities complicating tyrosine kinase inhibitor therapy in chronic myeloid leukemia: strategies for monitoring, detecting, and managing. Blood Rev 2018;32:289–299.
- Osorio S, Escudero-Vilaplana V, Gómez-Centurión I, et al. Drug-to-drug interactions of tyrosine kinase inhibitors in chronic myeloid leukemia patients: is it a real problem [published Jun 28, 2018]? Ann Hematol, doi: 10.1007/s00277-018-3413-7