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Member and Professor
Clinical Research Division
Fred Hutchinson Cancer Research Center
Jerald Radich, MD, has disclosed that he has received consulting fees from Amgen, Bristol Myers Squibb, Genentech, and Novartis.
In this commentary, I describe the approaches and considerations to tailor tyrosine kinase inhibitor (TKI) treatment for individual patients with chronic myeloid leukemia (CML). I will discuss factors that physicians must consider when selecting therapy, the efficacy of TKIs, toxicity management, and why and when it would be appropriate to switch agents.
Factors That Affect Treatment Decisions
Patient goals and expectations: An important factor in selecting therapy for patients with CML is the ultimate outcome goal, which depends in part on the patients’ age and treatment outcome expectation. For example, for a routine chronic‑phase case, where the patient is approximately 70 years of age, the main goal is to get his or her disease under control with a survival advantage compared to no therapy. Any of the TKIs can achieve this survival goal. By contrast, in younger patients, the goal may be a deeper, faster result, with the expectation of possible discontinuation either short term (for having children) or long term to prevent years of potential adverse events (discontinuation and treatment-free remission). In addition, patients might prefer taking their TKI once daily (eg, imatinib, dasatinib, bosutinib) rather than twice (eg, nilotinib).
Clinical risk score: Most CML cases are diagnosed in the chronic phase. The clinical dilemma is that although we know that all untreated patients in the chronic phase will progress to advanced-phase disease (accelerated and blast phases), we do not know, at the time of diagnosis, how long the patients have actually had CML (thus, how far they are on the road to progression). Clinical risk scores (eg, Sokal, Hasford, EUTOS, ELTS) are proxies for CML disease time, because they measure differences of white blood cell counts, spleen, and so forth, from normal. Patients with higher-risk scores are closer to the conversion to advanced phase disease, and several clinical guidelines (eg, National Comprehensive Cancer Network [NCCN] and European LeukemiaNet) thus recommend a more potent second-generation TKI (compared with imatinib) in this setting.
Evaluating Responses to TKIs
At the time of diagnosis, a patient’s bone marrow biopsy is evaluated for cytogenetic evidence of the Philadelphia chromosome, in addition to looking for other cytogenetic changes indicative of more advanced phase disease. However, after starting on TKI therapy, the patient’s bone marrow is rarely evaluated for response to TKIs. Instead, we use peripheral blood BCR‑ABL1 testing by reverse transcriptase–polymerase chain reaction (RT‑PCR) every 3 months. The response milestones can be found in the NCCN guidelines. Generally, a patient should achieve a response of BCR-ABL1 <10% by 3-6 months and <1% by 12 months (this is the level that roughly corresponds to a cytogenetic remission). Other treatment milestones include major molecular response (or MMR, defined as BCR-ABL1 ≤0.1%). MMR is clinically important because it is a “safe harbor” as relapse or resistance is rare in patients who achieve it. Finally, a deep molecular response (BCR-ABL1 ≤0.01% for several years) is important as these patients can be considered for an attempt of TKI discontinuation.
Managing TKI Toxicities
All TKIs have adverse events. One of the challenges in managing CML is that patients are often diagnosed very early (eg, on a physical routine examination) when they do not feel sick. Thus, when they start therapy, any adverse event may make them feel worse than before they started the TKI. All TKIs have some myelosuppression effects, and each has characteristic adverse events (eg, fluid retention in imatinib, pleural effusions in dasatinib, metabolic abnormalities in nilotinib, diarrhea with bosutinib, cardiovascular effects and ponatinib). If a patient does have significant toxicity to one TKI, it is likely that there will be another TKI available that will not cause the same problem. If a patient is experiencing adverse events that cause quality-of-life issues that clearly aren’t improving, it is probably preferable to find a different drug than to adjust the dosing or schedule of their current drug. For example, a patient having a low-grade chronic adverse event such as grade 2 diarrhea is not life‑threatening, but it will strongly affect a patient’s quality of life if it happens over a long period of time.
Paradoxically, there are so many TKIs available that patients and physicians are often tempted to change TKIs even if the toxicity is minimal. This complicates issues because if a patient cycles through several TKIs, it may be difficult to determine if a high BCR-ABL1 level is due to true biological resistance vs adequate TKI therapy.
Addressing Multiple TKI Failure
A common scenario at a referral center is the patient who has a high BCR-ABL1 level in the context of cycling through several TKIs. As noted above, it is often difficult to assess whether TKI failure is a problem of biology, lack of adequate therapy, or poor adherence to therapy (although “TKI failure” is usually meant to indicate lack of effect of the TKI on CML, TKIs also fail if they cause serious adverse events). If it appears that the situation is truly disease resistance, the factors that influence choice of the next TKI include (1) the presence of a specific kinase domain mutation, (2) comorbidities of the patient, or (3) the previous TKI. Regarding the latter point, a patient with resistance to imatinib can be appropriately moved to a second-generation TKI (eg, dasatinib, nilotinib, bosutinib). By contrast, a patient resistant to a second-generation TKI might be well served by moving to a more potent TKI such as ponatinib.
Patients resistant to 2 or more previous TKIs have an increased risk of progression to the accelerated phase or blast crisis. The question arises: How long to try another TKI before declaring it ineffective? Several manuscripts suggest that resistance patients who go on to enjoy a good response show some sign of improvement by 3 months of exposure to the new drug. A reasonable approach is to start HLA typing on the patient and family as well as to arrange for a transplant consultation during this early period after starting the salvage TKI. If a patient fails to get a good response, a move to transplantation could be warranted, given that transplantation works far better in the chronic phase than in the advanced phase disease.
A promising new option for CML after 2 prior TKIs is asciminib, a first-in-class STAMP inhibitor. At the American Society of Hematology (ASH) 2021 annual meeting, results will be presented from the phase III ASCEMBL study of asciminib vs bosutinib in patients with chronic-phase CML and resistance or intolerance to 2 lines of TKI therapy. In the ASCEMBL study, MMR rates were significantly higher with asciminib (as seen in earlier analyses), and more patients who did not achieve MMR achieved BCR-ABL1 ≥1% with asciminib than with bosutinib. This drug isn’t perfect—patients can develop resistance to it—so for these patients as well, we prefer to have a transplant option ready in case they do not respond within a few months or their disease worsens.
The BCR-ABL1 T315I mutation is more common at each subsequent point of treatment resistance. In other words, the T315I mutation is relatively uncommon in patients with resistance to their initial therapy and more common with second-line and third-line treatment. There is currently no consensus on optimal third-line therapy for a patient with CML who has failed 2 lines of therapy and now has developed the T315I mutation. The current options are ponatinib, asciminib, or allogeneic transplantation.
Also worth noting, at ASH 2021, results from the phase IV BYOND study will be presented, highlighting 3-year results of bosutinib in previously treated chronic-phase CML and confirming it as a standard of care. The investigators of that study report that patients developed deeper molecular responses on bosutinib vs baseline, and that more than 80% of responders maintained MMR or major response at Year 3. Of importance, bosutinib appears safe, with the caveat that gastrointestinal toxicity remains a concern.
In conclusion, healthcare professionals treating patients with CML must take multiple factors into account, including patient preference, their age, their treatment goals, and clinical data such as blood counts. It is important that patients have their BCR-ABL1 levels regularly tested to assess for TKI efficacy. Managing treatment-related toxicities is key to helping patients maintain treatment over the long term. This can involve switching therapies, but caution is warranted here as some patients may be switched to another drug prematurely. However, patients may need to switch TKIs due to resistance.
What challenges have you encountered in treating CML patients with TKIs? I encourage you to answer the polling question and join the conversation in the discussion box below.