Treatment for CML: Dose Adjustment or Discontinuations


Daniel DeAngelo, MD, PhD, provides his perspective on improving CML care through dose adjustment or treatment discontinuation.


Daniel J. DeAngelo, MD, PhD: There are some subtle challenges to treating patients who are receiving third-line therapy. There are 2 groups of patients. There are patients who are intolerant to 2 prior lines of therapy and who’ve had some toxicity requiring a dose adjustment and obviously discontinuation, and there are patients who are refractory or have a suboptimal response. It’s mitigating the toxicities that I find very difficult in terms of enhancing the compliance adherence and, therefore, the efficacy of the agent. In those groups of patients, you manage the toxicities as much as you can, depending on what the patient is experiencing. Oftentimes that will result in dose reduction for the particular agent, which on occasion will interfere with the efficacy and lead you to another line of therapy. In general, that’s 1 of the struggles we all have when patients evolve into third-line therapy.

The other issue we have for patients entering third-line therapy is refractory or suboptimal response. There it’s important to look for mutations. A third to 40% of patients who have failed 2 prior lines of therapy, may have a mutation within the ABL kinase domain that may mitigate resistance to other TKIs [tyrosine kinase inhibitors], so it’s important to at least look at that aspect. That will help guide you in terms of alternative therapy. There are 2 groups of patients in the third line. The ones I find the most challenging are those who are intolerant. The ones who are suboptimal looking for mutations, and then just trying your best to try and find an agent who’s going to be more efficacious than what the patients received previously.

We have a very good surrogate marker for survival and therefore treatment efficacy and chronic-phase CML [chronic myeloid leukemia], and that’s the quantitative PCR [polymerase chain reaction] for the BCR-ABL1 transcript. This is an international standardized unit, so it’s a little easier. There may be some sensitivity between some of the labs, but with the international or IS units being reported from all the reference labs, it makes it a lot easier to compare 1 lab with another and to get a very good assessment of the patient’s response.

It’s very important to think about the goal of therapy. If I have an older person with significant comorbidities, I know that a patient who achieves a cytogenetic remission—based on the molecular quantitative PCR, that’s 1% or lower—should have a normal life expectancy. For some patients, that’s the goal. If I have a patient who’s less than 1%, they may not have achieved an MMR [major molecular response]. I may not need to push the dose because the goal is long-term survival, and they’ve already achieved that. However, if the goal is to minimize the chance of progression and potentiate ability to get off the drug—that is, enroll in a TKI discontinuation trial or start that—then the lower the transcript level, the better. The goal is getting into a 3-log or a major molecular response, or even a 4-log. A 4-log response or better for 2 or more years will open the option for a patient to enter a TKI discontinuation.

A lot of it depends on the discussion with the patient. What are the goals of therapy? What are the realistic goals? Everybody wants to be off drugs, but survival is the most important thing. As long as the patient is tolerating the drug, survival is the most important thing. There’s a difference between older patients, patients who are middle-aged, and patients who are younger but have a very good surrogate marker for all of that: the quantitative PCR. In my practice, I follow that religiously every 3 months during the first few years. Once patients get into an MMR or better, I start extending the values or measurements for patients who enter a TKI discontinuation. If I’m lowering the dose, then I’ll increase the frequency based on the guidelines.

Transcript edited for clarity.

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