I was hoping to get some assistance about a complicated patient.

64Y AA with bilateral hearing loss, tinnitus. He was diagnosed with CML-CP 18 months ago and his baseline transcript level at was 43.1% and he was started on Dasatinib 50mg/day given tolerability concerns. His baseline BM showed grade 2 fibrosis and 7.5% blasts. At the 6.5 month, despite not reporting any missed doses, he lost his CHR and his ABL-PCR-b2a2 was 73%, (lowest was 16.25%). Repeat BM eval demonstrated showed ABL1 T315I, SUZ12 R121 and KMT2D R1219Q. No evidence of clonal evolution. He was started on ponatinib 45mg daily. Unfortunately, his transcript levels kept increasing to 74.35% without reaching hematologic remission, after being on therapy for 3 months. Due to concerning progression, he was started on Asciminib 200mg bid on 11/22/2021 and his transcript levels are unchanged at 3 months.

The patient has social barrier to getting an allo-transplant for several reason. Wanted to get advice on further management of this patient. Is there any evidence of adding any agent to Asciminib ? would you advice trying hydra and IFN?

This unfortunate patient has proven to be refractory to dasatinib, ponatinib and now (very likely) asciminib. He had evidence of the T315I mutation emerging on dasatinib plus other non BCR::ABL1 mutations. This would be one of the rare occasions where an allograft is appropriate in the chronic phase but this is apparently not an option for him. At this stage I would:

1. Repeat the bone marrow aspirate with cytogenetics to see whether he has clonal evolution and whether he has progressed to AP or BC.
2. Repeat the mutation study – he may well have kinase domain (KD) mutations in addition to the T315I mutation.
3. Assess his level of haematological control on asciminib

If he has a dominant clone with compound mutations (T315I plus another KD mutation on the same BCR::ABL1 protein) no single TKI will be effective but there is evidence (Eide et al, Cancer cell 2019) that combined ponatinib and asciminib may be effective in this specific setting. This is probably an unrealistic approach due the cost however.

If asciminib is achieving haematological control, that may be the best response you will be able to achieve and would likely prolong survival when compared to just switching him to palliative therapy. If you are not even achieving haematological control then your options are extremely limited and your suggestion of hydroxyurea plus or minus interferon may well be a reasonable option.

I am interested to hear from other CML clinicians whether they have any other thoughts on this challenging case.