I would be grateful for your advice on this 22 year old male who was diagnosed with CML-CP at 18 years of age (ELTS score 1.27, cytogenetics notable only for t(9;22)). He was started on dasatinib 100 mg/day and achieved CCyR at 6 months. He is now 42 months post diagnosis, remains on dasatinib 100mg/day but still has not achieved MMR. BCR-ABL has been 0.3-0.4% IS for the past two years. He reports excellent medication compliance. Kinase domain mutation testing was negative. He has tolerated dasatinib very well until recently when he started complaining of palpitations and intermittent rash. (A thorough workup was negative. It is unclear that these symptoms are attributable to dasatinib since there have been no recent dose adjustments and temporarily holding dasatinib for 7 days made no difference to his symptoms.)

In light of his suboptimal response to dasatinib, I am wondering what my next steps in his management should be:
A) Continue dasatinib 100 mg/day?
B) Increase dasatinib to 140 mg/day?
C) Switch to nilotinib or ponatinib?

Additionally, at what point should I consider transplantation? He has no other medical comorbidities. He is one of identical twins and his twin is alive and healthy.

So, after 3 years of dasatinib 100mg/day he has achieved CCyR (or <1% IS which is equivalent) but not MMR. This is not an optimal response but is probably a sufficient response to make transformation to blast crisis very unlikely at this stage. On the other hand, if he continues dasatinib, his prospects for achieving a deep molecular response and having the opportunity for a treatment-free remission (TFR) attempt are quite low - probably less than 10% over the next 5 years. If he was currently taking imatinib I wold definitely recommend a switch to a more potent TKI, but since he is already on dasatinib at "full" dose the benefit of switching to nilotinib (which may be a bit more potent) is uncertain. This is especially so if he is tolerating his dasatinib well - I am always more reluctant to switch in this setting. Besides nilotinib the other options are bosutinib or ponatinib. I don't see any advantage in switching to bosutinib. Ponatinib is more potent than dasatinib and might well lead to an improved molecular response but the toxicity profile would probably make this unacceptable - unless he actually fails dasatinib therapy - i.e. loses CCYR or goes above 1% BCR_ABL.
Therefore, assuming that he doesn't have any additional bad risk features (e.g. additional chromosomal abnormalities or high risk ELTS score at diagnosis) and does tolerate dasatinib well and has good adherence, I would continue with dasatinib unless he loses CCyR. You could consider increasing his dasatinib dose to 140mg/day. It is a little more toxic, probably increasing the risk of a pleural effusion a bit, but he is young, so this is not a great concern. If TFR is a high priority for him a dasatinib dose increase or a switch to nilotinib are certainly worth discussing with the patient.

ORIGINAL CASE:
I would be grateful for your advice on this 22 year old male who was diagnosed with CML-CP at 18 years of age (ELTS score 1.27, cytogenetics notable only for t(9;22)). He was started on dasatinib 100 mg/day and achieved CCyR at 6 months. He is now 42 months post diagnosis, remains on dasatinib 100mg/day but still has not achieved MMR. BCR-ABL has been 0.3-0.4% IS for the past two years. He reports excellent medication compliance. Kinase domain mutation testing was negative. He has tolerated dasatinib very well until recently when he started complaining of palpitations and intermittent rash. (A thorough workup was negative. It is unclear that these symptoms are attributable to dasatinib since there have been no recent dose adjustments and temporarily holding dasatinib for 7 days made no difference to his symptoms.)

In light of his suboptimal response to dasatinib, I am wondering what my next steps in his management should be:
A) Continue dasatinib 100 mg/day?
B) Increase dasatinib to 140 mg/day?
C) Switch to nilotinib or ponatinib?

Additionally, at what point should I consider transplantation? He has no other medical comorbidities. He is one of identical twins and his twin is alive and healthy.