I would like to have your expert opinion on this patient:

31 yo male, non-smoker with no comorbidities.

CML chronic phase with a high risk SOKAL score diagnosed early May 2023. 

a. Presented with white cell count of >500 and massive splenomegaly -up to RIF. 
b. Transcript type e14a2 (b3a), FISH for BCR-ABL positive, cytogenetics no additional abnormality.
c. Had 1 session of leukodepletion followed by hydroxyurea
d. Started on Dasatinib 100mg from 21st May 2023. 

Bcr-abl was 3.67 at 3 months and dropped to 0.24 at 6 months (24/11/23), increased to 3.24 on 11/2 24 and 7 on 14/3/2425/3/24:

Mutational study done at IMVS – 100% T315I

This is a pretty uncommon scenario but hopefully the resistance is all driven by T315I so that a T315I-active TKI may be quite effective – even over the long term. The choices you have are:

1. Ponatinib 45 mg/day possibly reducing to 15 mg/day once you get BCR::ABL1 levels below 1% (as per the OPTIC trial). You would have a good chance of achieving disease control at this initial dose and toxicity with this dose step down looks to be a lot better than keeping the dose at 45 mg/day. However up to a third of patients will lose response when you reduce to 15 mg/day and need to go back to 45 mg/day. In terms of toxicity, the main concern is arterial vascular events which are still at the level of around 5 per 100 patient years in the OPTIC study – I guess you might expect a lower risk than this in a young fit man.

2. Asciminib at the higher dose of 200 mg twice daily (5 times the normal dose). The dose can also be reduced once you achieve good response, although we don’t have a clinical trial to know how safe and effective dose modification is in this setting. The chances of achieving disease control are probably similar to ponatinib, but I think the tolerance and toxicity is better. We don’t have a randomised study to know for sure though.

Either is a good choice in this setting. My marginal preference would be asciminib because of its better toxicity profile. You can always switch to the other agent if choice 1 fails so you get two chances to achieve good disease control.

The two are indeed good options. I will start with the SCT question: I would not do SCT at this time. In CP, ponatinib has shown better results (survival) than SCT. The comparison is from separate databases but I think it is credible. Regarding what drug to use, both are good and you cannot go wrong. In T315I I tend to go more with ponatinib more often. The rate of AOEs with the 45 mg dropping to 15 mg after response is associated with a much lower rate of AOEs and I have actually not seen one in a long time. The main issue with asciminib is the schedule and the number of pills, which if the patient does not mind, has not shown any major weaknesses. I hope this helps.

Both are possible good options.
If we consider the last data it seems that after ponatinib less patients achieved molecular responses with asciminib. We have no data for patients who failed asciminib and then received ponatinib, but all myristoilic mutations can have the option to answer to 2 or 3gen TKIs. Ponatinib dose should be 45 mg with a possible option to reduce the dose after the response. Even with the optimization of the dose the risk of possible CV events is higher and the characteristics of your patient can guide your choice.