Case 3: TKI Therapy and Treatment Monitoring in CML



Elias Jabbour, MD:Recently I had a similar case, but the young woman was 45 years old, who I started on dasatinib frontline. She had a complex karyotype, not isochromosome 17. And then her doctor at home said, “You go for transplant, you have very bad features.” So I started her on dasatinib. I did a bone marrow test at 3 months, and she was in CCyR [complete cytogenetic response], all things gone. I monitored her so I was more reassured that there’s nothing missing.

Adam Bagg, MD:You answered my second question because I was curious. James, what would you do if this resolved? So the chromosome abnormality goes away and you get a good response by 6 months that you’re satisfied with saying they’re responding, does that change your transplant direction?

James K. McCloskey II, MD:I think for this patient obviously the high-risk features observed at the time of diagnosis will indicate that is a patient we’re going to follow very closely. And we’re definitely shooting for a 60-year-old patient like this to get them into an MMR [major molecular response] by 18 months. I think for us if they achieved those milestones transplant isn’t something we would pursue at that time, but we would definitely be doing more frequent bone marrow biopsies in a patient like this and be looking for some of those other cytogenetic abnormalities to resolve entirely.

Elias Jabbour, MD:So, James, if this patient did not achieve an MMR, you will take her for transplant?

James K. McCloskey II, MD:No, not necessarily, but I think that that person who’s not achieving an MMR by 18 months is a person who we’re going to follow more closely, observe more closely, and consider a bone marrow test and repeat genetic testing for at that time. But I would not take a patient to transplant with a PCR [polymerase chain reaction] less than 1%.

Michael J. Mauro, MD:Maybe to shine a little light on that subject for a minute, regarding the importance of cytogenetic complete remission—and maybe in this case clearing the clonal changes—how long do we wait for MMR? Because I think we all would recognize that MMR has not become more prominent but perhaps less prominent in the guidelines with regard to timing and expectation. And I know there were some data looking at when a patient faces increased risk having not achieved their major molecular remission. Maybe it’s closer to 24 months. Because I get asked that routinely by colleagues and patients; I swear I’m on the green but I’m not in the hole. And I’m in a deep remission already. Do we have to change therapy or raise the dose simply because they haven’t had an MMR say between 12 and 18 months? Maybe they’re just shy. How do you guys feel about that?

Elias Jabbour, MD:Practice has been as long as your PCR gets to 1%, it doesn’t matter. And you stay on treatment, you don’t skip medication because you’re not progressing, but I keep monitoring, I will not go for transplant. And for these specific patients with slow responses, I would have switched therapy to second-generation TKI [tyrosine kinase inhibitor], not kept him on imatinib therapy. But in this case if he comes to see me tomorrow with 1% PCR, I will not do anything. I want to make sure he is monitored and compliant.

James K. McCloskey II, MD:I think one of the important things to remember, too, is that when we reference these studies, these trials took place in what is not really the real-world scenario. And I think that all the data we refer to are captured from how their patients were monitored very closely. And I think that this really highlights the importance of close monitoring in these patients, which is not always accomplished in the community. So I think that every 3 month PCRs for this patient is something that is really critical to their management.

B. Douglas Smith, MD:Yes, I tend to think it’s somewhere right in that space where we believe that cytogenetics are really important. And achieving a complete cytogenetic remission remains almost the gold standard, even in the molecular world. And the MMR may be becoming less and less important. When you hit it, it’s nice, it predicts some stability. It’s not likely that people leave an early MMR to go into blast or accelerated or even die with their CML [chronic myeloid leukemia]. So for my perspective, I do follow them. I’m not typically switching TKIs at 18 or 24 months if people are around an MMR but just haven’t hit it. If they’re tolerating it well, if they’re being compliant, those are people, James, I follow closely. I’m pretty religious about every 3 months for most of those people who are still borderline and have never hit an MMR. Because we’re all afraid of Case No. 2, right? We’re all afraid of this great early deep response that blows up and becomes accelerated and/or blast phase and presents out of the blue feeling poorly. So I do follow pretty carefully patients who haven’t achieved every milestone, and rely on it less as being a true goal.

Elias Jabbour, MD:Outside of this case about monitoring, I want to get your opinion on a case I had. So a woman who’s 50 years old had CML, had dasatinib frontline, had a CMR [complete molecular response], undetectable levels for 6 years. I stopped her TKI and I monitored her. Regular analysis every 3 months showed PCR undetectable, OK? And then in March this year she had a one-time PCR showing positive at 0.1%.

Michael J. Mauro, MD:How long after stopping?

Elias Jabbour, MD:Two years.

Michael J. Mauro, MD:Two years after stopping?

Elias Jabbour, MD:Two years after stopping, 0.1% in March. I told her to come back and see me. She comes back with a count of 50,000. Within a month I repeated PCR. She’s coming to see us and it’s just to repeat her PCR testing because it turned to be positive at one time point, 50,000; repeated PCR, 100%. She is lymphoblast phase.

Michael J. Mauro, MD:This is a case you need to report to the NCCN [National Comprehensive Cancer Network] for the guidelines because it’s an unusual outcome.

Elias Jabbour, MD:Correct. And they keep saying if you pass 6 months and you don’t have a relapse, you’re done, no progression, no transformations whatsoever. And yet this is a case out 3 years having transformation. So we should be very careful with monitoring for this patient. It does still happen, it’s rare, but it’s not impossible.

Michael J. Mauro, MD:The good news is the NCCN guidelines, although I know the data say there’s optimism around if you pass 6 months and things are good, say monitoring still needs to happen and it needs to happen meticulously: monthly for a year, 6-weekly for the second year, quarterly in the third year. Because we still haven’t uncovered all the potential nuances of treatment-free remission or treatment cessation.

Elias Jabbour, MD:I’m working with my fellow on a review, and in fact in all the papers published, there’s no transformation. It will say you can stop therapy, if relapsed, you can resume TKIs, and there’s no transformation; but here is a case of transformation, because these are outside the follow-up or outside trials.

B. Douglas Smith, MD:Your case is an important one too because in addition to telling people they may have aches and pains if they stop their drug, and in addition to saying it’s going to be a hassle, you’re going to come back frequently because we are going to monitor you monthly and then every 2 months and then quarterly for many years. We need to tell people that it is possible that your disease will change, and it will go from undetected, or nearly undetected, and a more advanced phase can exist because we know that it can exist while you’re on a TKI, so certainly it has to be able to exist when you’re off it. I think those types of risks need to be fully discussed with your patients prior to discontinuation.

Michael J. Mauro, MD:I think we’ve learned a lot about monitoring. We need to look for clonal evolution, and unfortunately clinical trial data would tell us that even when watched, the SIMPLICITY study, which has been published in a few different iterations, shows that many patients don’t get cytogenetic testing or molecular testing within a 12-to-18-month timeframe. So monitoring is key, especially in treatment-free remission. And guidelines give us the roadmap and we’ll hope for good news on that case.

Elias Jabbour, MD:Well I started her on blinatumomab and ponatinib, and she’s already in CR [complete response].

Michael J. Mauro, MD:Very good.

James K. McCloskey II, MD:Very good.

Transcript edited for clarity.

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