BCR-ABL1 TKIs in Relapsed/Refractory CML - Episode 1

CML as an Ideal Cancer for Targeted Therapy With TKI

June 24, 2019

Harry Erba, MD, PhD:Welcome to thisTargeted Oncology™ presentation in precision medicine called “BCR-ABL1Tyrosine Kinase Inhibitors in Relapsed-Refractory Chronic Myeloid Leukemia.”

Targeted therapies have really come to the forefront of treatment of cancer. Today we are going to talk about an important therapeutic class that has revolutionized the treatment of chronic myeloid leukemia, or CML. Beginning with the approval of imatinib in 2001, these agents represent a paradigm-changing advance in precision oncology, as newerBCR-ABL-targeted TKIs [tyrosine kinase inhibitors] have been developed to address relapse and resistance mutations.

I am Dr Harry Erba, a professor of medicine and the director of the leukemia program at Duke University, in Durham, North Carolina. Joining me today is my colleague, Dr Jorge Cortes, the deputy chair and a professor of medicine in the department of leukemia at The University of Texas MD Anderson Cancer Center in Houston, Texas.

Welcome, Dr Cortes.

What makes CML a perfect candidate for targeted therapy?

Jorge Cortes, MD:Well, the 1 thing that’s unique in CML is that by definition, every patient with the disease has the same molecular abnormalities—a rearrangement betweenBCRandABLgenes—which is manifested usually with the Philadelphia chromosome. That’s a cytogenetic manifestation of that molecular rearrangement. We know that a few patients don’t have the chromosome visible, at least that you cannot detect it by cytogenetics, but they will have the molecular rearrangement. Everybody has that, and in the chronic phase, that seems to be the main driver of the disease. That makes it ideal because it’s in all patients; it has meaning. It’s not just as a marker. It starts a disease. That was why there was a quest for an inhibitor of this. Well, the other thing that I would add is that it translates into a kinase that’s considered to be activated, and kinases are good targets for therapy as well. All these were a good combination of factors that created a quest to try to find a drug that could inhibit that activation.

Harry Erba, MD, PhD:When I see a patient with a high white blood cell count, shift immaturity, some basophilia, maybe a spleen tip on exam, I know I can make this diagnosis by just checking peripheral blood for theBCR-ABLfusion, either by PCR [polymerase chain reaction] or by FISH [fluorescence in situ hybridization]. Why do I need to do a bone marrow biopsy? Or, do I need to do a bone marrow biopsy?

Jorge Cortes, MD:You definitely can make the diagnosis of CML, I agree with you. What you cannot do is get all the features of the disease and all the proper classification. We need to know the percentage of blasts and basophils, not only in the blood but also in the bone marrow to know that the patient is in chronic phase, otherwise it may be an accelerated phase. Although they correlate, they don’t always go hand in hand. You also want to have a cytogenetic profile, a complete karyotype because some patients present with chromosomal abnormalities in addition to the Philadelphia chromosome, and those you cannot detect by FISH. Of course, you could do a FISH for each 1 of the chromosomes, but then it becomes totally impractical. As uncomfortable as the bone marrows are, it definitely could lead to a diagnosis. I would say that whenever you have a patient who experiences resistance, that you need to change therapy. You need to have that full assessment. We know that during follow-up, our need for bone marrow is much less, but at diagnosis you need a bone marrow.

Harry Erba, MD, PhD:Do you need the PCR test if you know the patient has the Philadelphia chromosome or if the FISH is positive? Do you need all 3 tests, basically?

Jorge Cortes, MD:Yeah, I think you do. I think that’s an important issue that you bring up because it is not just a matter of finding the disease. But there are instances in which 1 test may be positive and the other 1 may be negative. For example, there are patients who may be Philadelphia chromosome—negative—the karyotype does not show the Philadelphia chromosome. Yet, the PCR will show the rearrangements. These cryptic abnormalities were perhaps too little to be able to be identified by a karyotype, regular banding.

There are other instances, on the other hand, where you have a patient who may have an atypical rearrangement. You have a patient who, when you get your results, you see that they have the Philadelphia chromosome, but they’reBCR-ABLnegative. That is because our standard test, the standard PCR, does not typically identify those atypical transcripts. It’s important to have that information, so that you know at baseline what tests are positive, which ones are not picking up what that patient characteristics may be. When you follow up, you’re not misguided by, for example, after 3 months or 6 months, you get a PCR that’s negative. You didn’t have 1 at baseline. You think that’s a wonderful response, and in fact, that may be an atypical transcript that you’re never going to detect, no matter whether the patient is responding well or not.

In that case, you know that your best way to monitor the patient will be FISH or cytogenetics. That’s why at baseline, the value doesn’t tell you too much in the PCR at baseline. But whether it is present or not, it will tell you if that’s what it is. Of course, for most patients, that’s what you need. But you will find that occasional patient for whom you know you have to do something else.

Harry Erba, MD, PhD:I’m glad you brought up the issue of the value. I really want to delve into some of these nuances that can throw us off in the diagnosis and management of these patients. There are situations, for example, in which the Philadelphia chromosome is not seen, so you do a PCR and it’s positive. But how about if it’s positive like 0.1%? Is that real at the time of diagnosis? Could it be real, or how do you interpret that?

Jorge Cortes, MD:Well, it is very important that we know that the PCR forBCR-ABLhas evolved a lot. But it’s a test that’s gone through different stages. And PCRs are prone for contamination, and there’s this issue of standardization and all that. The first thing you need to do if you have something like that is confirm. Just do it again to make sure that it’s not a contamination. Things happen even in the best laboratories. We see this once in a while, and there’s technical error or something like that. But if it is confirmed that that’s the level, there are occasional patients who you pick up very early, and they indeed have a very small clone. That patient really does need treatment. In some instances, for 1 reason or another, that patient has not been treated, you see that clone eventually will grow. I think that once you have confirmation that indeed the results are real—low but real—you do need to consider that that patient has CML and treat accordingly.

Harry Erba, MD, PhD:Now that we’re considering treatment-free remissions, 1 of the criteria is that the PCR is informative at baseline.

Jorge Cortes, MD:Correct. Well, yeah, certainly, when you’re going to stop the therapy that is important.

Transcript edited for clarity.