Chronic Myeloid Leukemia - Episode 9

Case 3: CML With Additional Cytogenetic Abnormalities

May 28, 2019

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Michael J. Mauro, MD:So case 3 is CML [chronic myeloid leukemia] with additional cytogenetic abnormalities, something definitely to talk about. So here we have a 60-year-old man who presents with weight loss, weakness, fatigue, feeling full all the time, and something is clearly not right. His past medical history includes type 2 diabetes, on metformin. Hypertension again on propranolol, and with a left ventricular ejection fraction of 45%.

He, on physical exam, is really unremarkable. So we’re saying there’s no splenomegaly, there’s no C-myelinated finding, and his presenting CBC [complete blood count], white count is 125,000, and mild anemia, hematocrit of 33% and platelets normal at 290. His cytogenetics I think are the focus of discussion here. There’s a Ph [Philadelphia] chromosome finding in 20/20 metaphases, but as well there is deletion of chromosome Y and isochromosome 17, and they found an addition.

Conventional molecular testing shows a transcript level 89% on the International Scale. So I’ll say diagnosis chronic phase CML, and that the patient started on imatinib 40 mg per day. But I think that’s where we should stop and pause and look at this patient’s presenting features and talk about it.

James K. McCloskey II, MD:Thank you. Adam, can you talk to us about the role of cytogenetic testing here for this patient, how it might impact our treatment decisions?

Adam Bagg, MD:I think it opens up the broad topic for discussion of ACAs, additional cytogenetic abnormalities. It’s important to segregate up front whether those ACAs are recurring in the setting of the Ph chromosome or in the absence of the Philadelphia chromosome. I think we won’t talk about the latter immediately but focus on a patient who presents with CML with the cytogenetic evidence of a 9;22 translocation, and an additional cytogenetic abnormality.

We can dispense with the loss of Y immediately. I think it’s important to know what percentage of cells have loss of Y. That may be a physiologic phenomenon or an aging phenomenon, although this patient is not that old. So that may not be necessarily indicative of cytogenetic progression. What I think obviously is indicative of cytogenetic progression here is the isochromosome 17q, and although we talk about 17q, it results as we know in loss of the P arm of chromosome 17, and takes up p53, which is a key step in the transformation of CML.

I think the relevance of additional chromosomal abnormalities at the time of diagnosis can be discussed differently from those that emerge during therapy. So if we focus now on those that appear at the time of diagnosis, there are a number of different groups who interpret things differently, to my knowledge. So WHO [the World Health Organization], for example, if you have 1 of the 4 major route cytogenetic abnormalities at diagnosis—if memory serves me correctly, isochromosome 17q; a duplication of the Philadelphia chromosome; trisomy 8; and trisomy 19—and 2 others, 3q267 abnormalities, or complex cytogenetics, the presence of 1 of those 6 abnormalities at the time of diagnosis indicates that the patient is in accelerated phase.

Not every group believes that. I think the ELN [European LeukemiaNet] pays less attention to the relevance of additional cytogenetic abnormalities at the time of diagnosis. And I think there are also data to indicate that therapy with TKIs [tyrosine kinase inhibitors] may be as effective in some settings with ACAs, depending which one is there, as compared with those patients who do not have additional cytogenetic abnormalities.

B. Douglas Smith, MD:A comment that I’ll make is that the addition of cytogenetic abnormalities in the era where interferon was the drug was pretty clear. We knew what to do with accelerated phase and we understood it much better. Accelerated phase were the high-risk presentation in the era of TKIs. A little more challenging to know exactly how to specifically manage the patients beyond when they get a response. And again, one of the questions raised here might be, are we going to treat this person differently in folks’ minds knowing that they’ve got this really important additional cytogenetic abnormality?

Elias Jabbour, MD:In practice we are, especially with somebody who’s having the isochromosome 17, or 3q267, we offer them frontline therapy with second-generation TKI. And then I would monitor carefully for all the responses because this is where at 3 months or 6 months I should have those done, not wait longer to assess for response, and make my treatment decision or treatment adjustment.

Michael J. Mauro, MD:I think this is all data driven. I think data from your institution, data from the German CML study group, have shown these major abnormalities or select bad actors—the chromosome 3 changes, isochromosome 17—those definitely need to be addressed differently because of the overall survival, and their response expectations are noticeably lower.

And what a great point, what does it mean in the era of TKIs? Very early on there was some sense that imatinib response for patients with isolated clonal evolution, not clinical accelerated phase, could approach chronic phase. But now we’ve clearly dissected it down much further, and we know that all patients are not created equal. Many of these patients for example had trisomy 8, which is probably much different than isochrome 17. So we have to know what the abnormalities are, and we have that information here.

Transcript edited for clarity.