Optimizing use of TKIs in CML


Hagop Kantarjian, MD

DUBROVNIK, CROATIA—Long-term efficacy and toxicity should inform decisions about tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), according to the keynote presenter at Leukemia and Lymphoma: Europe and the USA, Linking Knowledge and Practice.

Studies have indicated that long-term survival rates are similar whether CML patients receive frontline treatment with imatinib or second-generation TKIs.

However, the newer TKIs pose a higher risk of uncommon toxicities, said Hagop Kantarjian, MD, a professor at MD Anderson Cancer Center in Houston, Texas, who gave the meeting’s keynote speech.

Dr. Kantarjian said most CML patients should receive daily treatment with TKIs—even if they are in complete cytogenetic response or 100% Ph-positive—because they will live longer.

Frontline treatment options for CML that are approved by the U.S. Food and Drug Administration include imatinib, dasatinib, nilotinib, and bosutinib.

Dr. Kantarjian noted that dasatinib and nilotinib bested imatinib in early analyses from clinical trials, but all three TKIs produced similar rates of overall survival (OS) and progression-free survival (PFS) at extended follow-up.

Dasatinib and imatinib produced similar rates of 5-year OS and PFS in the DASISION trial.1 In ENESTnd, 5-year OS and PFS rates were similar with nilotinib and imatinib.2

However, Dr. Kantarjian said the higher incidence of uncommon toxicities with the newer TKIs must be taken into account.

Choosing a TKI

Dr. Kantarjian recommends frontline imatinib for older patients (≥ 65 to 70) and those who are low-risk according to Sokal score.

Second-generation TKIs should be given upfront to patients who are higher-risk by Sokal and for “very young patients in whom early treatment discontinuation is important,” according to Dr. Kantarjian.

“In accelerated or blast phase, I always use the second-generation TKIs,” he said. “If there’s no binding mutation, I prefer dasatinib. I think it’s the most potent of them. If there are toxicities with dasatinib, bosutinib is equivalent in efficacy, so they are interchangeable.”

Dr. Kantarjian also said a TKI should not be discarded unless there is loss of complete cytogenetic response (not major molecular response) at the maximum tolerated adjusted dose that does not cause grade 3-4 toxicities or chronic grade 2 toxicities.

“[W]e have to remember that we can go down on the dosages of, for example, imatinib down to 200 mg a day, dasatinib as low as 20 mg a day, nilotinib as low as 150 mg twice a day or even 200 mg daily, and bosutinib down to 200 mg daily,” Dr. Kantarjian said.

“So if we have a patient who’s responding with side effects, we should not abandon the particular TKI, we should try to manipulate the dose schedule if they are having a good response.”

Dr. Kantarjian noted that pleural effusion is a toxicity of particular concern with dasatinib, but lowering the dose to 50 mg daily results in similar efficacy and significantly less toxicity than 100 mg daily. For patients over the age of 70, a 20 mg dose can be used.

Dr. Kantarjian said vaso-occlusive and vasospastic reactions are increasingly observed in patients treated with nilotinib. Therefore, he prefers to forgo upfront nilotinib, particularly in patients who have cardiovascular or neurotoxic problems.

“The incidence of vaso-occlusive and vasospastic reactions is now close to 10% to 15% at about 10 years with nilotinib,” Dr. Kantarjian said. “So it is not a trivial toxicity.”

For patients with vaso-occlusive/vasospastic reactions, “bosutinib is probably the safest drug,” Dr. Kantarjian said.

For second- or third-line therapy, patients can receive ponatinib or a second-generation TKI (dasatinib, nilotinib, or bosutinib) as well as omacetaxine or allogeneic stem cell transplant.

“If you disregard toxicities, I think ponatinib is the most powerful TKI, and I think that’s because we are using it at a higher dose that produces so many toxicities,” Dr. Kantarjian said.

He added that the reason ponatinib is not used upfront is because of these toxicities, particularly pancreatitis, skin rashes, vaso-occlusive disorders, and hypertension.

Dr. Kantarjian suggests giving ponatinib at 30 mg daily in patients with T315I mutation and those without guiding mutations who are resistant to second-generation TKIs.

When to discontinue TKIs

Dr. Kantarjian said patients can discontinue TKI therapy if they:

  • Are low- or intermediate-risk by Sokal
  • Have quantifiable BCR-ABL transcripts—B2A2, B3A2 (e13a2 or e14a2)
  • Are in chronic phase
  • Achieved an optimal response to their first TKI
  • Have been on TKI therapy for more than 8 years
  • Achieved a complete molecular response (MR4.5)
  • Have had a molecular response for more than 2 to 3 years
  • Are available for monitoring every other month for the first 2 years.

Dr. Kantarjian did not report any conflicts of interest at the meeting. However, he has previously reported relationships with Novartis (makers of imatinib and nilotinib), Bristol-Myers Squibb (makers of dasatinib), Pfizer (makers of bosutinib), and Ariad Pharmaceuticals (makers of ponatinib, now owned by Takeda Pharmaceutical Company Limited).

1. Cortes JE et al. J Clin Oncol. 2016 Jul 10; 34(20): 2333–2340. doi: 10.1200/JCO.2015.64.8899

2. Hochhaus A et al. Leukemia. 2016 May; 30(5): 1044–1054. doi: 10.1038/leu.2016.5

Next Article: