18 yrs/male was diagnosed as CML in accelerated phase at an outside centre in March,2016 (Bone marrow-Hypercellular with 15% blasts.BCR/ABL gene translocation–detected. Patient was put on Hydroxyurea.

Patient had repeated fever,discomfort with low WBC counts, repeat BMA was done- blast:2%,basophils:3%. BCR/ABL transcript(p210):56.58%). Imatinib 600 mg od was started(April 2016) continued for 1 month,then Nilotinib 300 mg bd in May 2016.

In July 2016,complaints of not able to eat, pain in the teeth since 1 month.WBC 21010(60% blasts),FCM: lymphoid blast crisis, hence Dasatinib 100 mg was started.

Now in Aug, 2016 patient has come to our centre for second opinion.
Case of CML- Progressed to lymphoid blast transformation, treated with Imatinib then changed to nilotinib and dasatinib.

We performed a Tyrosine Kianse Domain mutation analysis by Sanger Sequencing which showed three mutations(2 substitution mutations T315I and F359I along with a 459 base pair deletion mutation [c.931_1401del;p.(Phe311_Lys467del)] invoving Exon 6,7,8.
Since we have performed Sanger Sequencing it is difficult to say whether these mutations are polyclonal or compound mutations.

I would like to know how we should go about further in management of these mutations which are known to be resistant to almost all TKIs.

Thanks,
Dr. Sushant Vinarkar

My preferred option for this young patient would be to use ponatinib 45mg OD in association with prednisone 100mg per day, trying in this way to reach as soon as possible the a cytogenetic and molecular remission and then to move the patient to allotransplant (compatible sibling or MUD preferable). Ponatinib is indeed the only TKI able to overcome the mutations detected and I would continue its administration even after transplant at a reduced dose (15 mg are generally well tolerated). If the amount of ponatinib is limited I would use it however for the induction phase rather than for the maintenance after transplant.

Some groups (MdAnderson) think that it is better to add chemo according to the scheme used for the Ph-positive ALLs. In Italy we use the chemo only for cases who are not responding immediately well to ponatinib+prednisone, as we prefer not to add toxicity and problems of infections during the induction phase and we prefer to reserve the chemo for the conditioning treatment before transplant.

If ponatinib is not available, the only option is chemo (Hyper-CVAD or BFM scheme) and then the allo transplant, but of course the use of ponatinib would be important in this case because of the mutations detected (that I do not think that in this case are compound mutations as the compound mutations have been established to be rare even in ponatinib treated patients and this patient has never been treated with ponatinib).

Let me know if I can be of more practical help.

This is an 18 year old and I think you have one chance to do this right. I would take the MD Anderson approach of chemo plus ponatinib. Chemo ccould be something like hyperCVAD as per MDA or a modified Dana Farber regimen, something with upfront intensity and good CNS prophylaxis/therapy. Since this is progression from chronic phase, and despite the phenomenal MDA Ph-positive ALL results report earlier this year, I would proceed to an allograft whether it is a related or unrelated donor. Although I understand the concerns about toxicity, if a ponatinib response is lost, then there is not much that could be done successfully. I do not think that it really matters whether the compound mutation or multiple mutation status impacts on my decision.

Thank you very much for the response Dr. Jeff Lipton and Dr. Giuseppe Saglio.
The patient was started on Hyper-CVAD protocol following which the Bone marrow examination done showed <3% blasts and was called as marrow in remission. The clinical condition of the patient has improved and the clinicians are going to take the patient for allo-transplant.

Thank you very much for the prompt response...