Challenging Cases in CML: Treatment Failure in First-line Therapy

Elias Jabbour, MD
Associate Professor
Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas




I am going to review with you a case I had in my practice about CML with resistance to TKI. So, the case is a 58-year-old gentleman who is African American. He was diagnosed with chronic phase chronic myeloid leukemia following a regular checkup in 2010. His past medical history was significant for diabetes mellitus on metformin and chronic obstructive pulmonary disease, or COPD, on bronchodilators p.r.n. This patient was initiated on imatinib 400 mg daily.
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By 3 months, he did achieve complete hematologic response. At 12 months, his transcript levels were 17%. His karyotype revealed 14 Philadelphia-positive metaphases among 20 assessed. He had no kinase domain mutation identified.


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CHALLENGE QUESTIONS
The question at this stage was what to do with this patient. He clearly did not reach his milestone. At 12 months, he still did not achieve a major cytogenic response as reflected by his PCR and his karyotype. So, his options are do we need to continue him on imatinib 400 mg daily, shall we escalate imatinib dose to 400 mg twice daily, or switch him to nilotinib 300 mg twice daily, dasatinib 100 mg daily, or bosutinib 500 mg per day?

How would you treat this patient?







 

This patient has history of diabetes mellitus and history of lung injuries and therefore based on his comorbidities we elected to switch him to bosutinib 500 mg daily.  

So, this patient was started on bosutinib. The treatment was well tolerated. He had just minor episodes of diarrhea early on grade 1 and 2 that were resolved with abortive care only. He was followed at 3 months. He had molecular assessment revealing a level of 7% on international scale. He was monitored. No further intervention. Diarrhea is well controlled.
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At 6 months, his PCR was checked, and it was found to be 1%, which is equivalent to what we called complete cytogenic response.
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He was further monitored, and at 18 months, he does come to see us and he was assessed, and we discovered that he was losing his response. His PCR was found to be 20% international scale, and by karyotype, he lost his CCyR. In fact, 16 metaphases among 20 were found to be Philadelphia positive. Of note, the treatment was still well tolerated.
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CHALLENGE QUESTIONS
So, at this stage, this patient had failed the imatinib, and now he is failing bosutinib. What shall we do? Well, shall we check for mutation, shall we switch him to ponatinib, or keep the same therapy, consider transplantation, or switch him to another second generation tyrosine kinase inhibitor?

What would you do next?







 

So, we did check for mutations in this patient. There was no mutation identified. And this patient has failed already second-generation tyrosine kinase inhibitors. The question is shall we rotate them or move to ponatinib? We decided to move to ponatinib, and this patient was started at 45 mg per day, and we were careful. We did give him prophylactic therapy with low-dose aspirin and a low-dose statin as well. He had no risk of bleedings obviously.
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So this patient was started on ponatinib 45 mg per day. At 3 months, he achieved 2% by PCR. He had a very good tolerance. The treatment was reduced to 30 mg per day.
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At 6 months, he achieved a major molecular response of 0.1% international scale, and the treatment continued to be well tolerated.
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At 18 months, he reached a deeper response with 0.01% BCR-ABL level by international scale, and therefore, the dose was further reduced to 15 mg per day in order to optimize his safety.
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So, this patient continues to do well on ponatinib.
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This case illustrates an effective story of how to manage resistant CML in the patient who failed imatinib and failed second-generation tyrosine kinase inhibitor and then received ponatinib and did extremely well.