Posted: Tuesday, March 20, 2018
A New Entrant for Patients With Newly Diagnosed Chronic-Phase Philadelphia Chromosome–Positive Chronic Myeloid Leukemia
Chronic myeloid leukemia (CML) is characterized by a balanced chromosomal translocation [t(9;22), known as the Philadelphia (Ph) chromosome], resulting in a fusion of the Abelson gene (ABL1 on chromosome 9) with the breakpoint cluster region gene (BCR on chromosome 22). This fusion oncogene (BCR-ABL1) encodes a fusion BCR-ABL1 oncoprotein with constitutive tyrosine kinase activity.1
The advent of small-molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment and outcomes of patients with chronic-phase CML, who now, on average, may enjoy a normal life expectancy.2 Until recently, the available TKIs in the front-line setting included a first-generation TKI, imatinib,3 and two second-generation TKIs, dasatinib4 and nilotinib.5 As of December 2017, a third second-generation TKI, bosutinib, has joined the U.S. Food and Drug Administration (FDA)-approved armamentarium for patients with newly diagnosed chronic phase CML.6 This most recent FDA approval of bosutinib in this setting offers clinicians another option to personalize therapy in the front-line setting.7
BFORE Trial: Road to FDA Approval of Bosutinib in Front-Line Setting
Bosutinib is a potent dual SRC/ABL inhibitor with considerable activity against most imatinib-resistant BCR-ABL1 mutants, except T315I and V299L, and minimal activity against PDGFRa/b or c-KIT.8,9 Until recently, it had been approved only for patients with chronic-, accelerated-, or blast-phase CML with resistance or intolerance to other TKIs.10 Its new indication for use in patients with newly diagnosed chronic-phase CML was based on the efficacy and safety findings from the randomized, ongoing, phase III BFORE trial, which compared 400 mg once daily of bosutinib (n = 246) with 400 mg once daily of imatinib (n = 241).11
The major molecular response (MMR) rate at 12 months was significantly higher with bosutinib (47.2%) versus imatinib (36.9%; P = .02), with higher MMR rates also at 3, 6, and 9 months and deeper molecular responses at 3, 6, 9, and 12 months. The complete cytogenetic response rate at 12 months was also higher with bosutinib (77.2%) than with imatinib (66.4%; P = .0075).
Overall, bosutinib was associated with a favorable toxicity profile. Most adverse events (AEs) were low-grade, manageable, and improved over time. The most common (incidence ≥ 20%) bosutinib-associated AEs of any grade were diarrhea (70.1%), nausea (35.1%), thrombocytopenia (35.1%), increased alanine aminotransferase (ALT) levels (30.6%), and increased aspartate aminotransferase (AST) levels (22.8%), whereas imatinib-associated AEs were nausea (38.5%), diarrhea (33.6%), muscle spasms (26.4%), and neutropenia (20.8%). Grade ≥ 3 nonhematologic AEs with bosutinib versus imatinib were increased ALT levels (19.0% vs 1.5%), increased AST levels (9.7% vs 1.9%), increased lipase levels (9.7% vs 5.3%), and diarrhea (7.8% vs 0.8%).
Treatment Considerations: Selection of First-Line TKI Therapy
According to Michael W. Deininger, MD, PhD, Professor and Chief of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, when initiating therapy, the decision-making process should take into account a patient’s disease characteristics (eg, low-, intermediate-, or high-risk disease as defined by Sokal or Hasford score), past and current medical conditions (eg, cardiovascular disease, diabetes), toxicity profile of the TKI under consideration, anticipated ability to tolerate therapy, patient’s age, treatment convenience, and therapeutic objective.
Patient’s Disease Characteristics, Age, and Therapeutic Objective
“Most patients with low-risk disease are as likely to benefit from imatinib as they are from the second-generation TKIs, in terms of progression-free and overall survival. Conversely, for patients with intermediate-, and especially high-risk, disease, second-generation TKIs should be considered,” explained Dr. Deininger. This is because dasatinib, nilotinib, and bosutinib are associated with higher rates of molecular response and a lower risk of disease progression than imatinib in intermediate- and high-risk patients.11-13 In line with these data, the most recent National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Chronic Myeloid Leukemia include imatinib as a category 2A recommendation and second-generation TKIs as a category 1 recommendation for patients with an intermediate- or high-risk score.7 Of note, the reduced risk of life-threatening disease progression with second-generation TKIs may be especially relevant to younger patients with a longer life expectancy. Additionally, for this patient population, it may be worthwhile to take into account potential toxicity associated with long-term TKI therapy and consider adjusting the therapeutic objective, aiming for treatment-free remission that is more likely with second-generation TKIs.14,15 Dr. Deininger added that “young women who want to start a family should definitely be considered for the second-generation TKIs for this reason.”
Past and Current Medical Conditions, Toxicity Profile, and Treatment Convenience
“With regard to the distinct toxicity profiles, there are several relatively clear-cut scenarios that would disfavor certain TKIs over others,” explained Dr. Deininger. “For example, nilotinib is associated with significant cardiovascular toxicity, specifically arterial occlusive events such as stroke, heart attack, and peripheral arterial occlusive events. So, in a patient with a high risk for cardiovascular events, nilotinib should be used with a great deal of caution. Dasatinib is sometimes associated with pulmonary hypertension and frequently with pleural effusion, implying that patients with a history of significant pulmonary disease may not be the best candidates for dasatinib. Bosutinib is generally well tolerated, but it has been associated with hepatic toxicity such as transaminitis and hyperbilirubinemia. Therefore, it should be used with caution in patients with a history of chronic liver disease or other liver issues. Finally, treatment convenience should also be considered. For example, once-daily TKIs are likely to increase compliance.”
On the issue of adherence, Dr. Deininger said, “I think adherence is a big deal. We stress its importance first by trying to explain there is a clear correlation between adherence and outcomes. In other words, suboptimal adherence translates into suboptimal outcomes. Second, we try to emphasize the importance of adherence by stressing the only way for a patient to have a chance at treatment-free remission is by optimal adherence. One important way to encourage that is by urging patients to report promptly any side effects so they can be managed accordingly.”
I think adherence is a big deal. We stress its importance first by trying to explain there is a clear correlation between adherence and outcomes. In other words, suboptimal adherence translates into suboptimal outcomes.
Bosutinib: Management of Newly Diagnosed Chronic-Phase Ph-Positive CML
“When starting a patient with newly diagnosed chronic-phase CML on bosutinib, or any other TKI for that matter, it is very important to manage patient expectations appropriately from the very outset,” explained Dr. Deininger. “We work in teams that typically include a nurse, pharmacist, physician assistant, and an attending physician, as we believe in the importance of having a team perspective on various disease management issues.” In line with that, Marisa Hine, NP, a nurse practitioner at Memorial Sloan Kettering Cancer Center in New York, added, “We focus a lot on education of our patients in terms of what to expect once bosutinib has been initiated.”
When it comes to bosutinib dosing, Dr. Deininger explained, “What we frequently do in our practice is we start patients on a low dose, say 100 mg or 200 mg daily, and then we titrate up, sticking with a very firm plan, to 400 mg daily or the maximum tolerated dose. With that approach, we have been quite successful in avoiding gastrointestinal [GI] toxicities such as diarrhea and liver function abnormalities, which have been well described with bosutinib therapy. In our experience, the responses are not compromised with this approach, perhaps because you avoid the ‘stop-and-go’ mode, which is sometimes necessary due to the toxicity that may be associated with higher doses.”
Similarly, Ms. Hine added, “We often start bosutinib at the lower dose (100 mg daily) and have weekly dose escalations, in 100 mg/d weekly increments, which helps mitigate some of the GI toxicities and allows patients to ‘trial and error’ some of the management strategies. If there is an increase in AEs with a certain dose, we may try to stay at that dose before escalating. If the symptoms become more pronounced, we may attempt to go back to the lower dose with which a patient was more comfortable before re-challenging them with a higher dose. Also, we recommend that bosutinib be taken in the evening, because its peak onset of activity is approximately 4 to 6 hours; that way we can mitigate fatigue.” Finally, according to Dr. Deininger, “monitoring responses with quantitative reverse transcriptase polymerase chain reaction, per the NCCN Guidelines,7 is critical. “This also helps patients to feel connected and stay on the ball with their therapy.”
Management of Toxicities
“Overall, some of the most considerable AEs such as GI toxicities and liver function test abnormalities are transient and manageable, which makes bosutinib one of the safer TKIs available,” according to Ms. Hine.16 “At the start of therapy, patients should be monitored weekly for 4 to 6 weeks, including assessment of complete blood cell count and comprehensive metabolic panel for potential hematologic and metabolic toxicities. Thereafter, if no concerning changes are observed, monthly monitoring is generally performed. With regard to the GI AEs, we focus a lot on education of our patients in terms of what to expect once bosutinib has been initiated, including the management of diarrhea, typically with loperamide, and prevention of dehydration.”
Some of the nonpharmacologic management strategies for GI AEs may include adding fiber to the diet and avoiding alcohol, lactose-containing products, raw fruits and vegetables, spicy or fatty foods, and caffeine.16 With regard to potential liver toxicities, patients should be assessed for signs of elevated ALT and AST levels (eg, jaundice and/or dark or tea-colored urine). Currently, there are no pharmacologic interventions for ALT/AST elevations, and the appropriate management commonly consists of dose modifications.
As for cardiac and vascular toxicities, overall, they can occur with bosutinib but may be less common than with other second-generation TKIs; these side effects are typically managed with dose interruption, dose reduction, or concomitant medication.16 Myelosuppression including thrombocytopenia, anemia, and neutropenia is frequently reported within the first month of initiating bosutinib. In addition to dose interruptions and reductions, other interventions for myelosuppression may include growth factor support and transfusions.16 Other toxicities may include nausea and vomiting (managed with antiemetics) and rash (managed with hypoallergenic moisturizing creams, topical/systemic steroids, and antihistamines).16
Additional Clinical Pearls
Of note, Dr. Deininger emphasized that “we are very diligent about engaging patients in the treatment decision-making process and other important issues, as a CML diagnosis is still a significant life-changing experience for a patient. Also, we try to be as comprehensive as possible and collect as much prognostic information as possible at diagnosis, before starting any treatment. This includes bone marrow aspiration, biopsy, and conventional cytogenetics that can pick up additional chromosomal abnormalities.” He continued: “At Huntsman Cancer Institute, we are blessed with outstanding clinical pharmacology support. Thus, we have a pharmacist look closely into all the medications a patient is taking and try to go with only those that are essential, to avoid any possible drug-drug interactions that may lead to AEs.”
Finally, Ms. Hine emphasized the importance of providing education and social support to patients with CML, who are potentially treated with lifelong TKI therapies. She “often connects patients with relevant advocacy groups and puts them in touch with a social worker for extra support, if necessary.”
Michael W. Deininger, MD, PhD, has received honoraria for participating in advisory boards for ARIAD Pharmaceuticals, Inc, Blueprint, Galena Biopharma, Incyte, Novartis Pharma, and Pfizer, Inc; has received honoraria as a consultant for Incyte, Novartis Pharma, and Pfizer, Inc; and has received research funding from Novartis Pharma and Pfizer, Inc.
Marisa Hine, NP, has disclosed no relevant relationships.
- Mughal TI, Radich JP, Deininger MW, et al. Chronic myeloid leukemia: reminiscences and dreams. Haematologica 2016;101:541–558.
- Soverini S, Mancini M, Bavaro L, et al. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer 2018;17:49.
- Imatinib (Gleevecprescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021588s047lbl.pdf Accessed March 14, 2018.
- Dasatinib (SprycelÒ) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021986s020lbl.pdf Accessed March 14, 2018
- Nilotinib (TasignaÒ) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022068s026lbl.pdf Accessed March 14, 2018
- Bosutinib (BosulifÒ) prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203341s009lbl.pdf Accessed March 14, 2018
- Radich JP, Deininger M, Abboud CN, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN GuidelinesÒ): Chronic Myeloid Leukemia. Version 4.2018. Accessed February 23, 2018. To view the most recent version of these guidelines, visit NCCN.org.
- Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 2009;27:469–471.
- Remsing Rix LL, Rix U, Colinge J, et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia 2009;23:477–485.
- Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood 2012;119:3403–3412.
- Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol 2018;36:231–237.
- 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.
- Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia 2016;30:1044–1054.
- Saußele S, Richter J, Hochhaus A, Mahon FX. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia 2016;30:1638–1647.
- Shah NP. Front-line treatment options for chronic-phase chronic myeloid leukemia. J Clin Oncol 2018;36:220–224.
- Khoury HJ, Gambacorti-Passerini C, Brümmendorf TH. Practical management of toxicities associated with bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia. Ann Oncol 2018;29:578-587.