I have a 27 year old male who presented to an outside center with some vague symptoms, found to have an high WBC and was diagnosed with CML chronic phase, standard Ph-positive cytogenetics, low Sokal. Started on dasatinib 100mg daily, easily achieved EMR at 3 months and MMR by 6 months. Severe headaches and visual disturbances at the 7 month mark. High CSF WBC on LP with flow confirming lymphoid blast crisis. Repeat bone marrow appeared normal and MMR sustained by pcr on peripheral blood. Cytogenetics now normal. Thus, isolated CNS lymphoid blast crisis of CML, despite excellent response to therapy with the one TKI that can actually penetrate the CSF.
Treated with intrathecal triple therapy - cytarabine, MTX, hydrocortisone - with a good initial response. Continued on dasatinib given the lack of evidence of systemic relapse. After two months, CNS symptoms again appeared and CSF positive with no obvious fixed lesions by MRI. Now treated with craniospinal radiation to full dose. Has an HLA-matched sibling with plans to proceed to stem cell allograft in a couple of weeks.
Questions for discussion are:
1. management of an isolated CNS blast crisis in the face of no obvious systemic recurrence. Would people have changed the dasatinib?
2. post-transplant TKI therapy. I plan to restart dasatinib and give an additional 6 IT treatments starting about 2 months post transplant. Thoughts on this management?

CNS transformation whilst on effective TKI therapy is a rare complication; as it could happen with conventional systemic chemotherapy of past eras, it can happen at present in the TKI era. Unfortunately this patient needed a significant amount of therapy to salvage response.

Once this situation developed, I think would have been difficult to definitively choose an alternate TKI therapy with intention to better treat the CNS; clarity of data on CNS penetration, concentration and efficacy is limited. Imatinib and nilotinib are reported to be less penetrant but efficacy with nilotinib has been noted as well as proof that it may prove efficacious for parkinsons' disease (also related to ABL targeting); dasatinib has data and literature supporting CNS penetration and efficacy; ponatinib experience is more limited.

Given the instability and capacity of the clone to trigger CNS relapse, one may consider an alternative TKI as potentially 'better' for systemic control and/or for any reduction in risk of recurrent CNS relapse. The risk/benefit always needs to be considered but for dasatinib resistant or evasive disease ponatinib should be considered, especially in this case where its use may be limited to the bridging period prior to and the post-transplant period. Dosing of ponatinib is under re-investigation and one could consider lower doses of ponatinib subsequent to initial exposure to 45 mg dosing.