Dear colleagues,

Please, can you help me with the patient described beneath?
A male, now aged 46 years, presented in January 2013 with CML in myeloblastic phase. He was treated with dasatinib en entered complete hematological remission within 14 days. In April 2013 he was transplanted with a 10/10 matched VUD after conditioning with cyclophosphamide, ATG and Busulfex. The graft was T cell depleted with CD34 selection. Transplantation was without any problem, ciclosporin was stopped two months after SCT. Patiënt had not any sign of GVHD. PCR-BCR/Abl was negative and he was given pre-emptive DLI on August 27, 2013 (following a local protocol for patients who remain without GVHD after SCT). He did very well but on December 20, 2013 he had headache and a lumbar punction showed CD34+, CD117+, CD33+ and CD15 negative blasts. He had no systemic relapse of his CML. Patiënt started with dasatinib 140 mg daily and was given Depocyte (liposomal ara-C) 50 mg intrathecally on december 21, 2013, January 3, 2014, January 17, 2014 and January 31 2014. Morphology and immunophenotyping of his cerebrospinal fluid was negative from January 17 onwards. He was sheduled for a next dosis (the fifth dosis) of Depocyte but called on January 24 2014 with headache. At that time he still used 140 mg dasatinib daily. Lumbar punction was done and 50 mg Depocyte was given intrathecally and cerebrospinal fluid (morphology and immunophenotyping) was positive again for myeloblasts (CD34+, CD117+, CD33+ and CD15 negative). On January 24, 2014 PCR-Bcr/Abl in the blood was negative. Patient is young and in a very good condition.
Also on behalf of my colleagues my question is what to do? A higher dose of dasatinib and every two weeks Depocyte intrathecally? Dasatinib intrathecally and/or donor lymphocytes intrathecally? Cranio-spinal irradiation?
I strongly hope that you can help my patient.
Many thanks and greetings,
Anton Schattenberg, Radboud University Medical Center, Nijmegen, The Netherlands

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

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

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

Dear Professor Raghunadharao Digumarti, dear colleague,

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