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? 

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.

That's an interesting scenario. I am from NIMS, Hyderabad, India, and we commonly across muscle and joint pains with TKI, though not as severe as you cited. I believe other causes of joint pains like rheumatological conditions are ruled out and supplements like calcium, vitamin D etc are being given and proper hydration is maintained. Check what other medications he is on and closely monitor for drug interactions. If all this is already done, try low dose steroid for a short duration with TKI and look for side effect response!

As Tim has mentioned, very unusual and rare presentation. Let's try to summarize about what we know and do not know.
1. multiple joint/muscle issues that are TKI/ASC related as remit when drugs are stopped.
2. No other etiology has been identified
3. we have no information given on co-meds - drug interactions? drugs such as steroids or NSAIDs and impact on pain?
4. no info on response to other TKIs - I assume that patient responded to all
5. no info on how long on each of the medications before they were stopped
6. allograft refused
7. all TKIs? Which ones specifically?

Before picking a therapy
1. have all inflammatory markers, CK etc been tested
2. are there any other meds on board, specifically statins and if so which ones
3. have any co-meds such as NSAIDs, pregabalin, steroid been tried to control pain
4. were CML drugs continued for a minimum of 3 months before discontinuation as MSK issues present early, can resolve with time
5. I know that using DAS has some advantages in terms of dosing options, but the target spectrum for DAS is one of the broadest, like PON or BOS
6. experimental drugs might work, but are they available and because of number of drugs tried on this man, would he be eligible?

My preference would be an allograft, but with refusal
1. consider low dose of TKI with the narrowest targeting, ie nilotinib, assuming no medical contraindications and aggressive management of any risks. I would start low at 200mg once daily and work up every week or two if no return of MSK symptoms. I am assuming that this was tried with ASC and/or other drugs
2. again I am assuming that all other marginally needed drugs are held as this is done
3. start patient on co-med such as COX2 NSAID at the start and taper off if it worked once optimal TKI dose attained
4. if NIL fails, try with BOS although target spectrum is not narrow, but dose options such as ramping up available

If all fail and no availability of experimental drugs, patient has following options
1. tolerate and continue
2. reconsider allograft knowing the other options - hard sell this one
3. palliative hydroxyurea to control counts, knowing where this is heading
4. something comes to mind - consider pegIFN. Yes, MSK side effects can occur, but are they from the same cause as what is being seen with TKI? Available?

Good luck and please let us know where this has gone