Case 1: Molecular Testing & Treatment in CP-CML

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

James K. McCloskey II, MD:Michael, how do you approach these patients for molecular testing and monitoring?

Michael J. Mauro, MD:I think the more information you have the better. Certainly, PCR [polymerase chain reaction] is our workhorse, having baseline transcript levels, so we can measure early response, which really gave us direction in this case. That was vital. Baseline BCR/ABL testing before treatment exposure is very important, and we have that in this patient. In addition, historical and classical testing in CML [chronic myeloid leukemia] is also important: not just molecular testing but cytogenetic testing, classic cytogenetics. And of course, the bone marrow testing is still indicated in guidelines for a newly diagnosed CML patient to rule out accelerated phase and to look for any other features. I’ll bet my colleagues agree and we try to get as much information as we can before we start treatment so we know where we’re going.

Elias Jabbour, MD:Often, we get patients referred without bone marrow testing anymore. They get PCR or FISH [fluorescence in situ hybridization] testing or karyotyping, and they said it was chronic phase CML, as you clearly highlighted. A bone marrow test is a must for this patient to be done up front. I’m not saying biopsies, but at least you have a bone marrow aspirate and evaluation of the bone marrow findings before going into therapy and then knowing what kind of transcript we have. Because sometimes they can have the atypical ones that we missed to diagnose up front and then we get somebody on therapy coming to see us. They are in CMR [complete molecular response], and we missed the right transcript earlier. We have no way to follow them.

Michael J. Mauro, MD:Great points. I think it’s tough because with risk stratification for CML, you can stratify a patient without a bone marrow test. But on the other hand, if someone is being careful and looks at guidelines and understands all the breadths of things you want to understand at diagnosis, the bone marrow test is essential.

B. Douglas Smith, MD:I think there’s another interesting clue here, that the blood count is a little atypical for a traditional chronic phase patient. They’re a little bit anemic, there’s a little bit of thrombocytopenia that you may not typically see in patients, so you want to understand what’s happening in the bone marrow. Eight percent blasts in the peripheral blood raises a flag and suggests that maybe this is more advanced phase disease. So again, I agree with everybody, a bone marrow test is clearly indicated when you’re newly diagnosing and staging somebody with chronic phase CML.

James K. McCloskey II, MD:Adam, do you feel like the bone marrow test is usually useful at the start of treatment?

Adam Bagg, MD:Yes, I do. From a hematopathologic point of view, the primary reason for getting a bone marrow test is to get good quality metaphases, in which the yield is likely better than in the peripheral blood, not that you cannot get metaphases from the peripheral blood. And of course, on occasion the phase of the disease that may seem chronic in the peripheral blood may be more advanced in the bone marrow. But I think it’s also important just to overview the initial discussion points of what molecular testing should be done. We should be cautious about, as has been highlighted, not restricting ourselves to molecular testing. It’s genetic testing, broadly spoken. And so there are cytogenetics, there are molecular genetics, and with molecular genetics, typically RT-PCR [reverse transcriptase-polymerase chain reaction] based analyses and FISH. We haven’t really spoken about FISH. I’m not going to talk about FISH immediately, but I just want to highlight the fact that classical cytogenetics are still key for the initial diagnosis of CML and to determine whether there are additional chromosomal abnormalities. Their relevance we can discuss later.

With regard to RT-PCR, it is important to realize there are two types of RT-PCR that can be performed, qualitative and quantitative, giving us different information. Qualitative PCR is still required to determine where the breakpoint is. Yes, you totally expect the E13 [exon 13] or E14 breakpoint, but on occasion, 2% of cases perhaps, you will find them in other regions, and that may not be picked up on subsequent quantitative RT-PCR, which is used for monitoring. Should we be using quantitative PCR at diagnosis? I think that’s still an open question of whether that’s useful. I think emerging data suggest it may be, although historically we have not done so or mandated comparing patients’ kinetics to the International Standard. But maybe it’s better to compare kinetics to the patients’ quantitative level at diagnosis.

With regard to FISH, I think FISH can certainly help in the initial diagnosis of CML. It’s as good as RT-PCR, although perhaps even better than RT-PCR since FISH spans a wider region than PCR primers. And you will with FISH pick up positivity when RT-PCR may miss the breakpoint.

Elias Jabbour, MD:Let me ask you a question. At my institution, we do FISH and PCR and cytogenetics. Do we need FISH if you have a good karyotyping and you have a molecular test? Because that’s an added test.

Adam Bagg, MD:I don’t believe we do. I’m not sure what the added value of doing FISH is if you’ve got positivity by RT-PCR.

Elias Jabbour, MD:If you have RT-PCR positive and you have the breakpoints you want and you have a good 20 metaphases analyzed and you have 922 plus something else you want, you do not need FISH.

Adam Bagg, MD:I agree with that.

Elias Jabbour, MD:But then you can use FISH for the follow-up, eventually.

Adam Bagg, MD:Perhaps, yes.

Michael J. Mauro, MD:I think you made a great point on identifying the fusion type. I think there’s definitely emerging data, but there may be differences between patients within the typical fusion, E13 or E14 response, perhaps treatment-free remission. And at the clinical levels for providers, that’s an important question because the tests they order may not tell them that. Because if it’s a broad molecular assay, it’s not going to tell you which breakpoint it is, it’s just going to quantify it. I’m finding myself ordering both. A separate study. A qualitative, which is going to tell me which fusion type, and a quantitative, which is going to give me the patient’s individual baseline. So I can probably use both in the International Standard expectations and then put that in context. If the patient was well above 100% and they have a good 1-log reduction in early molecular spot, that’s probably sufficient, but they may not reach 10%. You have these judgment calls to make.

Elias Jabbour, MD:But Mike, this should not be part of standard of work-up when you see somebody. Because when they come to see us, we will do all this automatically, up front. It’s in the Epic system where we get all the atypical and full findings, qualitative and quantitative. It’s not done at your institution the same way?

Michael J. Mauro, MD:No. I think a lot of providers probably face that they’re looking at molecular assays and making choices, so I think it’s important that everyone knows what are they looking for. I think knowing the level, knowing it’s a typical fusion, and perhaps knowing which type may not change your approach to the patient. But at least having those data so you can start and as you navigate with the patient, you’re going to be able to make good decisions.

Elias Jabbour, MD:Pay attention as well to cytogenetics, especially certain abnormalities, and we’ll discuss them hopefully later during our tumor board. For example, with chromosome 17, we know these patients don’t do well and they may have to go to second- or third-line therapy immediately and go for transplant. So it still requires to do karyotyping.

Transcript edited for clarity.