Managing TKI Therapy in CML

Michael J. Mauro, MD:So, details weren’t available in this case, but I think an important point has been raised that comorbidities matter in CML. It matters in initial treatment choice to predict, perhaps minimize, the risk of complications but still maximize chances of response and benefit from therapy. When we get to the point of resistance or a more difficult setting, comorbidities may seem less important because the disease may be driving us or pointing us towards only one choice or specific treatment choices. But we just have to learn how to manage that risk and balance that risk, the benefit of treatment and the benefit of the proper treatment versus what the potential risks may be. In the case of ponatinib, we have questions about vascular occlusive disease and cardiovascular risk. With other agents, we have concern about metabolic changes, also vascular disease risk, and other problems.

For the case of ponatinib, I think knowing the patient’s cardiovascular risk status, their cardiovascular risk can be calculated quite easily, much like their risk assessment of CML. A Framingham score or a European scoring system is also available that tell you what the patient’s likely vascular event is and that can be managed. Clearly, we need to know what comorbidities exist. Does the patient have hypertension, do they have coronary disease, do they have other vascular disease, and manage that risk? Hyperlipidemia as well.

So, I think we probably have been undermanaging the comorbidities of CML patients and focusing on their disease. But in the case of both initial treatment and the treatment of resistant disease, particularly with a medication like ponatinib, it’s important to know the whole spectrum, identify what should be treated anyway, irrespective of what medication they’re on. And then perhaps focus a bit on what can maximally manage the risk of a TKI while patients can still derive benefit and get good response, like in this case.

In this case, we see the patient had a dose reduction from 45 mg to 30 mg due to toxicity early on. We clearly learned from studies of ponatinib—in looking backwards, and we have current trials looking forward—that initial and subsequent dosing may not need to be the same. At the current time, 45 mg still is a recommended starting dose in the United States. But there is instruction that if the patient achieved response, that that dose should be lowered once a patient achieves a categorical improvement, cytogenetic response. If a patient has a lesser degree of relapse, perhaps they still have cytogenetic response. We may want to wait until they achieve a molecular response, and that’s just my opinion. But overall, the party line would be to consider and really to execute a dose reduction once the patient has begun to respond nicely to ponatinib, to lower their risk of complications, from 45 mg to 15 mg. Or, if in this case the patient had been on 30 mg, we could consider reducing the dose to 15 as well, especially given her very nice molecular response.

Again, studies are continuing to help us understand the long-term outcome for patients who have those strategies deployed, either starting at a lower dose and, clearly, the question about dose reduction after response. So, we should stay tuned for those, but those are the current recommendations.

The take-home message for this case would be that although patients can do very well in the beginning, we have to pay attention to their risk. This was a higher-risk patient by risk stratification from the get-go. And while they did well initially, resistance and relapse may be possible. And while it’s an uncomfortable and a difficult situation, the proper testing can really inform us, give us the path, and, in this case, identify aT315Imutation that led us to the right drug, which was ponatinib. And if we are careful and knowledgeable about risks versus benefits, we can salvage patients effectively, use the right therapy, and manage any risks or any complications that emerge and still have good outcomes in CML, even in the case of resistance.

Transcript edited for clarity.

Case: A Younger Patient With Relapsed CML

May 2013

• A 48-year-old female was diagnosed with CP-CML with a splenomegaly, 3.2 cm below the costal margin
• Laboratory values:
  • WBCs, 157,000/μL
  • HCT, 30% hematocrit
  • Platelets, 359,000/μL
  • Myeloblasts, 6%
• Bone marrow biopsy: Ph+ in 20/20 metaphases
• Q-PCR, showed a BCR-ABL1/ABL1 ratio of 176%
• The patient was started on dasatinib 100 mg; she achieved MMR after 6 months, and a deeper molecular remission (>MR4) after 12 months on therapy and remained in remission for 3 years

December 2016

• The patient complained of increasing fatigue and weight loss.
• Q-PCR showed a significant increase in BCR-ABL1 transcript ratio (to 50% IS)
• Bone marrow biopsy; 80% cellularity, 18/20 Ph+ metaphases
• Mutation testing showed the presence of T315I
• CBC WNL
• The patient was started on ponatinib 45 mg daily
• She developed grade 3 thrombocytopenia; the ponatinib dose was reduced to 30 mg daily

March 2017

• Cytogenetics, 3/20 Ph+ metaphases
• BCR-ABL1 transcript ratio, 5%

June 2017

• BCR-ABL1 transcript ratio, 0.75%.

October 2017

• BCR-ABL1 transcript ratio, 0.01% and no T315I mutation was detected