Dose Reduction and Third-Line Therapy for CML

Javier A. Pinilla-Ibarz, MD, PhD:In the PACE trial, patients with chronic phase CML were started on 45 mg, but upon encountering toxicities and by recommendation of the FDA, many of the patients, if not all, were reduced to 30 mg and 50 mg doses. Currently, with more than 5 years of follow-up, patients who were dose reduced are still enjoying very durable responses. Not only complete cytogenetic response, but also major molecular responses and even deeper responses. So, it’s important to take this into consideration. In this case, the recommendation in my patient is 30 mg of ponatinib daily. As soon as the response is achieved, maybe at 3 months, maybe at 6 months, try to really go to a lower dose from 50 mg. That is a dose that can be easily tolerated, if it’s already tolerated at 30 mg, but also is associated with less long-term cardiovascular toxicities and is also able to produce durable responses.

We have been discussing in this case that there are many options for second-line introduction of tyrosine kinase inhibitors. We’ve discussed 4 drugs: nilotinib, dasatinib, bosutinib, and ponatinib. Of course, the third-line choice is going to depend on what is going to be the second-line choice. However, we know that in the case of ponatinib, the later we use a very powerful drug like this, the responses are going to be lower. So, I think it’s important to take this fact into consideration. And although it is very standard these days to use a second-line TKI before the introduction of ponatinib, in certain patients, they may lower the efficacy of ponatinib in the long run. However, something that needs to be discussed between patients and doctors, as well as evaluated, always, is the potential risk benefit of the introduction of these powerful drugs associated with some toxicities.

Transcript edited for clarity.

A Patient With Relapsed CML and Comorbidities

December 2015

• A 64-year-old male presented to his PCP with symptoms of fever, LUQ pain, and severe fatigue.
• PMHx:
  • 2012: fainting associated with Long QT syndrome managed on propranolol.
  • 2014: stage 3 kidney disease (GFR; 45 mL/min)
  • 2014: NSCLC, stage IIA squamous histology treated with resection and chemoradiotherapy, pleural effusion managed with thoracentesis
• PE: spleen palpable 1.5 inches below costal margin
• CBC:
  • WBCs, 172,000/μL (metamyelocytes, 3%; myelocytes, 6%; basophils, 6%; blasts, 2%;
  • HCT, 30%
  • Platelets, 536,000/μL
  • Hb, 9.9 g/dL
• Bone marrow biopsy: Ph+ in 20/20 metaphases
• Q-PCR; BCR-ABL1/ABL1 ratio, 90%
• The patient was started on therapy with imatinib 400 mg

• March 2015:BCR-ABL1, 10% Q-PCR
• June 2015:BCR-ABL1, 6% Q-PCR
• September 2015:BCR-ABL1, 9% Q-PCR

December 2016:

• BCR-ABL1, 15% Q-PCR
• Bone marrow biopsy: Ph+ in 10/20 metaphases
• Genetic testing was negative for known TKI resistance mutations
• CBC normal count