Chronic Myeloid Leukemia - Episode 4

Case 1: TKI Therapy and Sequencing Decisions in CP-CML

May 28, 2019


Michael J. Mauro, MD:James, you asked me about the response and to answer your question, with this patient, I think a reasonable choice was made with imatinib. It’s not a poor choice, maybe it’s a very conservative choice, but that is not a good response. I think there’s definitely improvement and the patient is moving along the response spectrum, but we expect more. And I think this is a warning and maybe he’s, as Doug mentioned, not perhaps the lowest-risk patient. Maybe there is an issue there. So that early response would be considered inadequate at 3 months, and there’s no early molecular remission. I think we’ve seen literature and guidelines will tell us you may not have to switch but you want to think about it. Look at adherence, concomitant medications, or whatever you’re considering that could be slowing this patient down. And then at 6 months we still don’t see the expectation of an early molecular response, nor the equivalent of what would be a major cytogenetic response. But I think it’s been looked at 2 ways, early response, either having a major cytogenetic response or a transcript level of 10% or lower both seem to be a good predictor in a 3- to 6-month window. So we’re missing both.

James K. McCloskey II, MD:So for this patient who’s now failed frontline therapy, what are your considerations for additional treatment for the next line of therapy?

Michael J. Mauro, MD:This is another open discussion. What do we do now? We have a patient with comorbidities. We might have started with a second-generation drug, but we didn’t. We started with imatinib and we had, pretty frankly, a miss. This patient has not had good early response. Do we think there’s going to be a lot of recovery with a second-generation drug? I think some might consider all options at this point. Some might even consider the most potent of drugs because the patient is not responding well enough. I think there are less data to support going right to very aggressive approach like ponatinib, but I think that some people might consider that.

There might be certain additional testing that should be done. What about resistance testing at this point? I think that would be an important question to answer. Could there be a mutation? Could there be a mutation that’s allowing this residual CML [chronic myeloid leukemia] volume to persist? A T315I would point to ponatinib. That’s really the only currently available choice that would have the highest expectation of response. So I think we need a little bit more data and probably a lot of thought in this case.

B. Douglas Smith, MD:One of the things we have at our disposal in taking care of patients with CML is that we do testing. We do get quick windows into the response every several months, every 3 months or so. Again, I agree with Michael completely. If you start with imatinib, what you have in your back pocket is a PCR [polymerase chain reaction] at 3 months, a PCR at 6 months, and the ability to move. Most certainly we would be thinking about resistance testing, and I’d really like your thoughts on the value of that testing early on when you see somebody who’s not really had a good primary response to help guide us, because we’re going to move to a different TKI [tyrosine kinase inhibitor] here to help us in that setting. Do you encourage early testing with mutation analysis for patients like this?

Adam Bagg, MD:Well, I think we follow the guidelines. Obviously, if a patient presents in accelerated or blast phase, you test for mutations. If a patient fails to meet certain milestones, we test for mutations. And that seems to be maybe the case here, the 3-month and 6-month drops were not as great as one would like. And then thirdly, there are patients who have response but then lose response, be it hematologic, be it cytogenetic, or molecular.

Elias Jabbour, MD:Another question I have to ask to Doug. If you do the Sanger sequencing technique and you have no mutation, is there any room today for deep sequencing or for next-generation sequencing to identify clones that we missed by Sanger?

Adam Bagg, MD:For sure. There’s literature on that to support it, and obviously, one of the virtues of Sanger sequencing is this insensitivity. If you have very sensitive sequencing technologies, you’ll pick up much smaller clones. And I think historically, the field has not been clear as to what the significance of those tiny clones are. But I think the emerging data now are that if you pick up a clone, even at diagnosis in chronic phase with no reasons to normally test for mutations, finding a small clone at 1% or less than 1% might be a rational thing to test for. It may make you think of what you might do management wise for that patient. But that’s probably an open point for discussion.

Elias Jabbour, MD:I want to ask a question again. In the light of this patient, of course, not responding, after which there is the discordance between PCR and karyotyping. For example, for this patient, the PCR is coming from almost 100% to 18%, but yet he still has 50% Philadelphia positivity. So my question to you is when you still have a lot of tumor identified by FISH [fluorescence in situ hybridization] or G-banding technique, do you need a PCR? Is PCR really relevant, especially when you make a decision at 10%? It could be 15%. It could be fluctuations. So in this case, there is true resistance, but sometimes you can have PCR that is not clear-cut.

Adam Bagg, MD:But I think if we understand what karyotyping is doing and what PCR is doing, it’s not a surprise that there would be discordance. PCR is a quantitative measurement, as you know, with the RNA bulk in the tumor. Usually 1 copy per cell, maybe 2 copies per cell. Whereas, karyotyping is not that. Karyotyping is gauging the cells that have a growth advantage. So it’s not really as quantitative as PCR. So I think that’s how you can sometimes see the discordance between the 2.

Michael J. Mauro, MD:I think it’s usually the other way around. We might see a PCR level that hangs up in a better cytogenetic response. Maybe the residual clones got a higher level of expression, but that’s a great question. I think that’s been even showing in some recent study of discrepancy.

Transcript edited for clarity.