Dear Professor Lipton, dear Jeff,

Again, thank you very much for your answer.

Anton Schattenberg

Dear Professor Porkka, dear Kimmo,

Patient had only 4 leukocytes/3mm3 in his cerebrospinal fluid. Not a MRI but a CT scan of the brain was performed and was without abnormalities.
Thank you again for your answer,

Anton Schattenberg

Dear Professor Raghunadharao Digumarti, dear colleague,

Thank you very much for your answer,

Anton Schattenberg

This is a very unfortunate scenario and the long term outlook for this individual is very grave even with the most aggressive management such as a second allograft. As stated, there is no mention of pre-transplant IT therapy. Agreed that dasatinib is the only TKI to get into the CNS, but this in itself is probably insufficient therapy. Blast crisis CML patients should be checked for CNS disease and treated if positive with the same type of drugs that one would use for an ALL patient. Consideration of post SCT IT therapy should also be made. Unfortunately as well, this patient had what sounds like a double dose of T-cell depletion, both with the use of a T-depleted graft and the addition of ATG to the conditioning. With a disease such as CML in a young individual, where the GVL effect is so important, this becomes an issue and needs to be considered if regrafting is a thought in this individual.
Unless you can clear the CNS, then nothing will work. Personally, I would favor very aggressive management despite the toxicity potential. I would go with craniospinal irradiation at full dose and a CyTBI based regimen, where the TBI is built into the last part of the craniospinal irradiation. Regrafting should be with unmanipulated PBSCs and avoidance of any t-depleting whether ex vivo or in vivo. Early discontination of immunosuppression, say by 60-90 days, in the absence of any acute GVHD should be considered and although the evidence is weak, restarting dasatinib post allograft. Again, consideration of post allograft IT therapy is a possibility.
Despite this, the likelihood of controlling the CML is poor, but I believe anything short of this is palliative. And as mentioned by Kimmo, be prepared for major toxicity.
One last issue. Given that there was little GVH, my assumption has been that this was because of the preparative regimen and not the donor/recipient incompatibility. If a second related donor is available, again with not a lot of evidence, they could be considered.

Jeff Lipton
Toronto

This obviously is a very challenging patient.

Dasatinib is the only TKI with some penetration through the BBB and has shown significant clinical activity in CNS leukemia (even as monotherapy). However, relapses are common and, as in BM disease, mostly due to expansion of a mutant clone in the CSF. Dasatinib is quite insoluble in aqueous media, so i.t. administration is not feasible (and can be toxic).

No mention on the CSF blast/leukocyte counts were given, is the current disease burden in CSF significant (e.g. >100)? Have you performed MRI scan of the brain to rule out parenchymal lesions/tumors?

If the current CSF leukemia burden is high, I suggest performing a mutation analysis. If not and if the leukocyte/blast count is decreasing or low, I would still continue with dasatinib 140 mg x1 (no less than 100 mg), higher doses are poorly tolerated (we have used 200 mg for 2 weeks in one patient), perhaps supplemented with liposomal cytarabine i.t. once a month or with a GMALL-type triple therapy every 2 weeks.

Total CNS irradiation is quite toxic and we would consider it with an increasing and high tumor CSF burden, as a palliative measure.

If the patient did not develop GVHD after the DLI post allografting and now relapses (lymphocytes should cross the BBB), I doubt that using i.t. DLI would be very useful. Instead, we might consider a 2nd allograft.

The longest responses we have seen with CNS relapses and dasatinib monotherapy is 1+years.

Best of luck with the patient,


Kimmo Porkka
Helsinki

The reason why we see CNS disease in CML with no evidence of systemic disease is due to the poor penetration of TKIs into the CSF. There are a few studies documenting this. We ourselves have described this phenomenon in 2 patients. Appropriate approach to prevent a relapse in the CNS would be to give cranial irradiation, in addition to the intrathecal depot cytosine arabinocide already given.
With best wishes,
Yours sincerely,
Raghunadharao Digumarti
Professor of Medical Oncology,
Director, Tata Cancer Hospital, Visakhapatnam