This is an unusual situation – out of about 500 patients we manage in Adelaide there are 2 or 3 with a similar story to this - severe joint/muscle pains with any TKI. I am assuming this patient has never had resistance – just intolerance that has been the cause of his multiple switches. I don’t think ponatinib is a great choice for a patient with intolerance problems – it hits so many targets that can cause intolerance as well as toxicity. My preference would be to use the most highly targeted drug available – asciminib or another allosteric TKI. Surprisingly he had the worst side effects on asciminib – I have never seen this. It would be interesting to see how he tolerated one of the other TKIs in clinical development which is highly targeted – I would certainly try that if it was available on trial (Tern -701, TGRX-678, or Enliven). If that is not possible I would abandon the ponatinib – it is not working at a tolerable dose. I would probably try low dose dasatinib – 50 mg/day initially planning to go lower if mol response (MMR) is restored and side effects are still significant. No easy answers here I am afraid.

51 year old CP CML diagnosed 2017. On 6th line Ponatinib. Had all TKIs and Asciminib (Asciminib worst for side effects) but all stopped due to severe joint, and muscle pain causing disability. Started Ponatinib Sept 2023 15mg 3x weekly with good response and MMR. Initially had no pain and tolerated well. Now has severe joint and muscle pain and hypertension even on 15mg weekly Ponatinib. Due to treatment breaks and low dosage, BCR ABL has now risen to 5%. Will respond to increasing Ponatinib but at cost of patient disability. No KD mutations and has no issues with treatment failure, only tolerance. Declined allograft. Patient is a self employed builder. No other medical history and no other cause for pain. Pain stops with cessation of TKI after several weeks then recurs immediately on restarting. How can we manage this patient?