Rationale for TKI Therapy in Relapsed CML

Javier A. Pinilla-Ibarz, MD, PhD:There is no doubt that all the drugs that we are going to prescribe for patients who fail from frontline imatinib can be used in this setting. Ponatinib is one of the choices. I think it’s something that we discuss with patients after frontline failure. It’s true that ponatinib may be indicated many, many times after failure of second-generation TKIs, so we know that in this setting, it has the higher effectivity. However, you may consider, in certain situations, to reuse ponatinib as a second-line therapy. Because of the cardiovascular toxicity associated with this drug, sometimes you have to really weigh the risk benefit to really introduce these early on rather to wait until patients fail a second-generation TKI. In this case, your choices will be nilotinib, bosutinib, or dasatinib. However, it’s important to emphasize that in this specific case, all of these 3 drugs may be associated with side effects that this patient has a history of. For example, prolonged QTC. Although prolonged QTC is a class effect, this patient had this problem previously. And not only for nilotinib, rather for all the TKIs, it is something that needs to be taken into consideration and really looked after.

The second one is the problems with the history of lung cancer and pleural effusion. Although it’s not really clear the problems of pulmonary function in this patient, dasatinib may, in patients like that, induce or predispose patients to really have farther pleural effusion. So, this is an important factor to be considered.

Finally, bosutinib is very well tolerated in this setting. In some cases—and in the long, long follow-ups—it may be associated with decrease of renal function, so it’s something that also needs to be taken into consideration. Finally, ponatinib after this consideration may be an option, but obviously, it’s important to produce or to recommend dose modification because 45 mg, the current dose approved by the label, may be extremely toxic in patient like him. So, lower doses of 30 mg, with even more decrease of the dose when the response is achieved, may be recommended to substantially decrease the potential toxicities, including the cardiovascular toxicity, that have been associated with this drug.

In my experience of treating a chronic phase CML with ponatinib, it’s important to consider the dosing. Once again, the current approved dose to start a therapy is 45 mg. However, we know that this dose sometimes exposed patients to certain toxicities. They may ask to reduce the dose immediately. This is the reason that many of my colleagues, including myself, start at the dose of 30 mg to really see a better tolerance. We know that ponatinib, today, is the more potent tyrosine kinase inhibitor that we have available. We know that it’s able to suppress any kinase or mutation present in the patient, and also produce a substantial response in patients who don’t have a kinase main mutation responsible for the resistance. This is the reason why ponatinib should be considered for the treatment of patients who have resistant CML, who are really failing frontline or second-line second-generation tyrosine kinase inhibitors, and always taking into consideration dose reduction from the very beginning. The patient can achieve responses that can be seen very, very fast with this drug in order to decrease, significantly, the toxicities that these drugs may be associated with in the long run.

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