Risk Assessment After Relapse of CML

Michael J. Mauro, MD:As we follow this case further, unfortunately, the end, or the second half of the story, isn’t as good as the first. But we might have expected a patient who had an early molecular response and an early cytogenetic response to dasatinib not to have resistance or have relapsed, and that is in fact, what happened. Past the 3-year mark, despite an early and deep molecular remission, the patient started experiencing symptoms that might make us concerned that there’s a change in her status or her disease is returning, fatigue, weight loss, etc. And a prompt investigation, which is the first thing to do when there’s any suspicion, showed us that she had a fairly robust relapse. She had a molecular relapse of significance and had return of CML detected by cytogenetics and from the bone marrow. Fortunately, her blood counts hadn’t risen and that wouldn’t be the way to check for relapse.

Obviously, a deeper dive and more careful investigation would have been warranted. And the most important thing, I think, is that the mutation testing was done and that aT315Imutation was identified. Now, in a patient with chronic CML with resistance after dasatinib, I think that’s an important line of questioning, could that mutation be present? And that really is an important fact because it definitely drives decision making and treatment choice. There really are limited options for these patients but there are very good options, particularly ponatinib.

There are other things one could treat a patient like this with, such as omacetaxine or historical therapies that we use prior to the tyrosine kinase inhibitors. But I think the response and the safety, even with some of the concerns we have over cardiovascular risk and other issues, is clearly pointing us towards ponatinib in this case, and that’s what was chosen. I think that was appropriate. Currently, the starting dose of ponatinib is 45 mg per day, and I think that’s the right answer right now, although many of us are interested in settling the question about could a lower dose be a more proper starting dose for all patients. I think we have important trials that are running that should answer those questions. But according to the label and according to general recommendations right now, 45 mg would be a good initial choice for this patient with this robust relapse.

The side effects of ponatinib are well known at this point, and in a patient with active CML, I think thrombocytopenia, which is what happened in her case, isn’t surprising. As is appropriate, a dose reduction can be considered and taken. A dose of 30 mg may be quite effective still in many patients, and may be ultimately a dose that we feel like that is better to use for most cases on many patients. As we can see over time, this patient did quite well. She had improvement in her molecular parameters after 3 months, showing more than a log reduction. By 6 months, she started to have deeper response and by the 6-to-12-month window, she has already reestablished a deeper molecular remission. We actually can’t detect aT315Imutation the longer her disease burden is very low, and that mutation may not be evident at this point. This is now a success again and I think this is a difficult situation, resistance after initial success. But as we can see, there are solutions to these problems. There can be data-driven patient mutation testing and knowing the details of the case. We can still salvage such patients quite well.

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