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CML intolerant/resistant to all TKIs

9 years 3 months ago #241 by
I have a 57 yo male patient diagnosed with CML, CP, intermediate risk in 1/2012. He has been treated with dasatinib, then nilotinib, then bosutinib, and now ponatinib. With each drug he has moderate to severe pancytopenia despite dose reduction. His best cytogenetic response was 55% Ph + by FISH, but now he is back to 77% Ph+.
He has no siblings but he has 12 potential donors in the NMDP registry.
I think that an allogeneic transplant is the best option for him. I would appreciate any suggestions.

David Snyder
City of Hope
  • Michele Baccarani
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9 years 3 months ago #244 by Michele Baccarani
Replied by Michele Baccarani on topic Re: CML intolerant/resistant to all TKIs
This is a rather unusual case of a patient with CML who does not tolerate, hematologically, four TKI. Severe leukopenia and thrombocytopenia prevent from giving “full dose” of any drug, and are probably due to a significant reduction of the normal hemopoietic stem cell pool, that can be considered as a marker of advanced disease. Therefore, on one hand I agree with the indication for allogeneic SCT. The problem is not so much the donor – a good, matched, unrelated donor, possibly also sex-matched, male in this case – can be as good as a matched sib. The problem is GVHD, particularly the chronic one. For a patient who is 57 years old, the probability of developing an extensive GVHD is likely close to 50%, and it is not much different if one does a myeloablative or a RIC transplant. The choice between a myeloablative and a RIC transplant should be based on the clinical conditions of the patient (comorbidities, smoking habit, and so on). The results are not different in terms of overall survival, but are probably slightly better for leukemia-free survival, in case of a myeloablative procedure.
Curiously, this patient was never given imatinib. I would strongly recommend to try imatinib  before SCT, beginning 200 mg daily for 10 days, then moving to 300 mg daily for another 10 days, then, if blood counts are fine, to 400 mg daily, and assessing at 3 months the molecular response on peripheral blood, and the cytogenetic response on marrow, with conventional chromosome banding analysis. A patient like this is worthy of a bone marrow aspirate, of a bone marrow biopsy, and also of a mutational analysis.
Good luck, and best regards, Michele Baccarani
  • Pankaj Malhotra
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9 years 3 months ago #245 by Pankaj Malhotra
Replied by Pankaj Malhotra on topic Re: CML intolerant/resistant to all TKIs
In this very brief summary, it may be important to know whether the inadequate response is because of interruption/decreased dose of medication or because of resistance to medication.
  • John Goldman
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9 years 3 months ago #247 by John Goldman
Replied by John Goldman on topic Re: CML intolerant/resistant to all TKIs
I think that a trial of imatinib along the lines suggested by Michele Baccarani is reasonable though I agree with the suggestion that he probably has an unusually small residual population of Ph- cells and may do equally badly with imatinib as with other TKIs. I would certainly move slowly in the direction of SCT with the best available donor and probably use RIC – with the intention of supplementing this with DLI when necessary.

Not sure that this helps very much

John Goldman
  • Jerald Radich
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9 years 3 months ago #248 by Jerald Radich
Replied by Jerald Radich on topic Re: CML intolerant/resistant to all TKIs

I would probably go with an allo. If you have a research protocol for NMA, or if the gent has tons of toxicities, NMA would be be fine. We would probably opt for a full with targeted bu-cy, since we (my paper, Blood) didn't show any survival difference with ages up to 65 yrs.

Jerald Radich, MD
  • Giuseppe Saglio
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9 years 3 months ago #249 by Giuseppe Saglio
Replied by Giuseppe Saglio on topic Re: CML intolerant/resistant to all TKIs
It is reasonable to try also with imatinib as suggested by Michele (just in case) and with the help of growth factors, but it is unlikely that a patient resistant/intollerant to 3 different TKIs (including ponatinib) will respond. So I think that the only available option will remain allo.

Beppe Saglio
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