CML: Rationale for Mutation Testing and TKI Therapy

Michael J. Mauro, MD:So, as we can see in this case, mutation testing was quite important. Why do we do mutation testing? When and what are we looking for? It would be any clinical situation where we’re concerned that the disease may not be responsive to therapy any longer or any loss of a previously established response, particularly anything above major molecular response. In essence, if someone loses a major molecular response, a complete cytogenetic response, or even a major cytogenetic response, those become increasingly important scenarios where mutation testing is important.

Mutation testing may be more important in advanced-disease patients, because the frequency of mutations is higher, and other pH-positive leukemia settings like pH-positive ALL, for example. In chronic CML, again, a lost milestone, or clearly a missed milestone if someone never achieved a cytogenetic or molecular response, and by guideline was meeting criteria for treatment failure, those are situations where mutation testing offers a good yield. Maybe not as good as we think though. About half of cases, in general based on the research that has been over the years, of clinical resistance, are associated with a mutation. Amongst those, there’s a subset of patients who may have specific mutations that would drive treatment choice. And one of the most important, again, is theT315Imutation. That really drives treatment choice, currently, and points us towards one agent, ponatinib.

Other mutations may point towards or away from other medications. There are mutations that are particularly sensitive to erlotinib and are resistant to dasatinib and bosutinib, for example. Those are not common but they can be seen. And in turn, there are mutations that we may see more frequently after imatinib or nilotinib that are better served by treatment with dasatinib, bosutinib, or ponatinib, for that matter. And so, in summary, mutation testing is important for a missed milestone or a lost milestone. About half the time, it’s informative and in a fraction of those cases, it really does drive treatment choice. So is worth doing, particularly for the notion of not missing aT315Imutation.

This case also raises the question about the indications for ponatinib. How do we use ponatinib and what’s the right setting? A patient with aT315Imutation really doesn’t have any other easy treatment choices. There are historic agents we can use that we’ve used in CML before the TK era, and omacetaxine offers a treatment choice for patients with multidrug resistance or theT315Imutation. But currently, the FDA indications for ponatinib are for patients with aT315Imutation or for a patient in whom no other TKI is indicated. How do we define that? It can be a difficult journey for patients, and some have either a combination of resistance or intolerance to multiple agents or both. And there is clearly a fraction of patients in whom either drug resistance or intolerance or both have led us to, or closed the door on, all the other available TKIs and ponatinib makes sense for those patients. So, it’s beyond just patients with aT315Imutation, it’s patients with multidrug-resistant CML, as I like to call it, or patients with a mixture of resistance or intolerance.

In my view, I think patients who have a fair level of resistance to initial treatment with a second-generation inhibitor aren’t really well served by using another second-generation inhibitor as a second choice. You ought to think more carefully in those patients about using ponatinib earlier on, as their chances of response are clearly lower based on available data between switching to another second general TKI versus switching to ponatinib.

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