Case 1: TKI Therapy in CP-CML

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

James K. McCloskey II, MD:Mike, can you comment on the risk status of this patient and how that might impact your choice of treatment for them?

Michael J. Mauro, MD:So we cheated, we gave it away. We did the math. But I think it’s interesting that we still use a model that’s quite old. I think the Sokal risk model still is valid in a typical chronic phase CML [chronic myeloid leukemia] patient, but we clearly have evolved models, particularly outside of the United States with the European risk models that actually look at things beyond just the presenting features of the CML. They’re able to predict survival. But what we’re looking for is some gauge regarding response to therapy. In this case, Sokal risk was calculated and the patient is higher risk. The main features Dr Smith pointed out. This is maybe not as simple and as benign looking as chronic phase CML cases you might expect. The white cell count is high, the blast count is a bit higher. We heard that there was splenomegaly.

How does that impact your treatment? I think if you look at guidelines and look at available data, there may not be a mandate to treat a patient with higher-risk disease by whatever model you use with a different therapy. But there’s definitely a suggestion that you may want to consider that, although all therapies are good in typical chronic phase CML. I’ll open it to others to comment on that point. But I think in a high-risk patient, you want to definitely think about more aggressive therapy but not dismiss the fact that imatinib still could be effective.

Elias Jabbour, MD:The scores, it’s hard to get them. You have to Google them. It’s not just IPSS [International Prognostic Scoring System]. So you need to go online, do the formula, and get it calculated. Usually at our institution we have a database, and somebody will do it for you. But mainly these patients come presenting with high disease burden, a low count, and high tumor burden. He’s symptomatic, so essentially these are patients who have high-risk disease and a big spleen. Europe came up with the EUTOS [European Treatment and Outcome Study] score, which is essentially separately filing things into the basophil percentage, as well as into size, and these patients fit well into high-risk categories regardless of which score you’re using. It would be nice to have molecular signature as well like we do with AML [acute myeloid leukemia] and other diseases where we’ll define the risk scoring system more by biology than what we’ve done before. Knowing that the scoring systems we have, they precede the era of tyrosine kinase inhibitors [TKIs]. And there’s conflicting data about which one is still valid or not.

James K. McCloskey II, MD:I agree with you. I think there’s a lot of difficulty. The Sokal score, as you mentioned, was developed in patients receiving interferon. And I think the other challenge we run into is it’s not as dynamic, so you can’t use it later to reassess where a patient is. It doesn’t incorporate some of the important things we mentioned like clonal evolution and other cytogenetic abnormalities. But it’s still where we’re stuck. That being said, would you have usually started imatinib in this patient with high-risk disease at age 62?

Michael J. Mauro, MD:I think it’s a loaded question. I offer these options to the patients and talk about the relative risks and benefits. I don’t say it’s a bad choice. I think I might encourage a patient like this to be treated with as good a therapy as possible to obtain remission. But I think what this case is highlighting for us is, how do you choose therapy in the whole context of the patient and their comorbidities and what trouble might befall them? Not just inadequate CML response, but what about other health issues that could arise from therapy or as complications of therapy?

B. Douglas Smith, MD:What’s interesting, at our institution we probably would actually have started a second-generation drug, or we would have leaned in that direction. There’s not a lot of prospective data to really guide us there. A lot of it’s retrospective. And if you look at this case, it’s a real challenging one. The patient has a history of effusion, something some of your second-generation drugs are associated with. The person has a history of some cardiovascular risk factors, dysrhythmia. Some of your second-generation drugs have black box warnings about QTc prolongation. So you’re really narrowing down your choices in a disease where we think we have lots of choices: 5 different oral drugs available, 4 of which are approved as upfront therapy. And suddenly you begin to narrow them down to only a couple left. So I do think this is a really great case for discussing, but it’s a real challenge because with the patient’s comorbidities you have to think really hard about what’s the best drug to start them with.

Elias Jabbour, MD:Like you mentioned, Doug, you have 3 features. You have pleural effusion, you have heart issues, hypertension, and you have renal insufficiency with a clearance of 47. Potentially, with all second-generation TKIs, each one of them has an issue here. And then you add to that the payers. I mean he’s 62. He’s not yet into Medicare, so he may have to have a co-pay, although lots of assistance programs are available. But sometimes the choice is dictated by the payers. How much I’m willing to ask my patient to co-pay for new drugs is compared to something we call today’s generics. Are they available? That is something to consider as well.

James K. McCloskey II, MD:I agree. I think that often the challenge, especially with first-line therapy, is choosing the right drug for each patient. We’re very fortunate in CML that we have a variety of options to choose from. But I would agree, at our center, with a high-risk patient at the age 62, we probably have the tendency to start a second-generation drug. Based on the 3-month time point though, Mike, would you have done something different at that time?

Elias Jabbour, MD:Let me ask you a question, and I’ll ask everybody here. If we have to go for a second-generation TKI, which one would have you chosen in the light of these comorbidities?

Michael J. Mauro, MD:I was going to ask that question. I think we have to be careful not to directly assume that these problems are going to happen on therapy. Does having a pneumonia and effusion mean you’re going to have an effusion with dasatinib? Does having some minimal SVT [supraventricular tachycardia] and a QT of 450, which is actually quite acceptable….

Elias Jabbour, MD:Acceptable, but you have hypertension, too.

Michael J. Mauro, MD:We have hypertension, so that could be another issue. And what does renal insufficiency mean? I think that’s probably the foggiest of the comorbidities with regard to the implications for the TKIs. But you’re right, we have to choose, so we have to choose with our patient.

Elias Jabbour, MD:And that being said, when you use TKIs in the front line and the dose is lower than the relapsed setting, that is the case for bosutinib or nilotinib as well. And we have data on dasatinib at the lower dose showing equal efficacy. So I think we have room to adjust the dose with the TKI.

Michael J. Mauro, MD:I’ll put my quarter down first because I’m supposed to be looking after this case, and I think dasatinib wouldn’t be an unreasonable choice here because I’m going to have to assume that the pneumonia with the pleural effusion mean that this patient is going to have a pleural effusion on dasatinib. And it may be among the less morbid adverse effects, which you could manage if it recurred. A 62-year-old man might have more cardiovascular disease than you actually know, so that would be worth looking into, not that nilotinib is a bad choice. It could be more complicated. And I think bosutinib is now a frontline option, and it’s unclear how much effect it would have on renal insufficiency. I think it certainly could, but it also has some other subjective and objective toxicities that can happen early, liver enzyme elevations and GI [gastrointestinal] toxicity. So I don’t know how others feel about it.

Elias Jabbour, MD:With nilotinib, hypertension, the cumulative risk of cardiovascular events is at least 12% over 6 years, 2% per year. I feel more comfortable with either dasatinib or bosutinib. I would use a 50% dose reduction of dasatinib. We have a trial with 50 mg per day. We did not see mainly pleural effusions. And this man, as Mike mentioned, had only 1 episode of pneumonia. We all could have had in our life 1 episode of pneumonia. It doesn’t seem to really be controversial. And then finally for bosutinib, yes, it does lower the clearance by 20%, but that is reversible. I will use 400 mg or lower, so these 2 options I will feel comfortable with.

Michael J. Mauro, MD:Yes.

B. Douglas Smith, MD:I think it’s well outlined that we have some options there and the past medical history is certainly really important here.

Transcript edited for clarity.