I would appreciate your advice with regards to a young CML patient on dasatinib who progressed to blast phase ALL last year.
I commenced him on ponatinib 45mg daily from July 2018 in conjunction with hyperCVAD therapy. He has been responding well and has now completed 7 of 8 cycles of HyperCVAD. His BCR-ABL transcript levels have fallen as follows

4/7 250% PB 330% BM
10/9 0.0055% PB
13/9 0.0037% BM
30/10 0.0015% PB
Latest result pending.

He has completed 7 cycles of Hyper CVAD and is due to commence his final cycle. He also had a positive LP mid way through treatment in September and has completed full CNS treatment with subsequent clear samples. He was quite unwell with neutropenic sepsis in cycle 6 and his cardiac function declined dramatically. I did not know if this was due to sepsis or if the ponatinib or doxorubicin could be implicated. He was commenced on cardiac remodeling drugs, sepsis resolved and a follow up ECHO demonstrated marked improved so I pushed ahead with cycle 7 and ponatinib at the same dose of 45mg. I have been going over the PACE trial data and it suggests that I should consider decreasing the dose of the ponatinib due to the increased risk of side effects if he has attained a good molecular response which he has. He has decided against transplant so my concern is that the ponatinib is the only thing at present keeping him from relapsing – should I decrease to 30mg. The other thing of note is that his disease was not resistant to dasatinib – he finally acknowledged that he had stopped taking the dasatinib which led to his progression to blast crisis.

Any advice would be greatly appreciated.

It's concerning that even with a combination approach, MRD is still detectable. On the PACE study, the median progression free survival with ponatinib monotherapy for CML-BC was ~4mos. I worry that the risk of relapse is high once a patient finishes chemo. I understand that non-adherence may have contributed to disease progression, though this does not imply a better prognosis - the horse has bolted...

There is no good evidence to guide us on the optimal dose of ponatinib for maintenance, especially for CML-BC. However, the general advice is that for medium to long term ponatinib use, dose de-escalation should be considered once a response is achieved. This is in keeping with your thoughts. Again, this was a conclusion extrapolated from post hoc analyses, and I'm not sure to what extent this is applicable for advance phase disease.

David Yeung

I agree with David. Given his high risk of relapse, his positive BCR-ABL result and his low risk of vascular events, I would be very reluctant to reduce the ponatinib dose at this stage. I doubt the ponatinib is the cause of his transient cardiac dysfunction. Hopefully he will heed your advice to proceed with an allograft – especially if he is still PCR positive in the marrow after cycle 6.

Tim Hughes

ORIGINAL CASE:
I would appreciate your advice with regards to a young CML patient on dasatinib who progressed to blast phase ALL last year.
I commenced him on ponatinib 45mg daily from July 2018 in conjunction with hyperCVAD therapy. He has been responding well and has now completed 7 of 8 cycles of HyperCVAD. His BCR-ABL transcript levels have fallen as follows

4/7 250% PB 330% BM
10/9 0.0055% PB
13/9 0.0037% BM
30/10 0.0015% PB
Latest result pending.

He has completed 7 cycles of Hyper CVAD and is due to commence his final cycle in early January. He also had a positive LP mid way through treatment in September and has completed full CNS treatment with subsequent clear samples. He was quite unwell with neutropenic sepsis in cycle 6 and his cardiac function declined dramatically. I did not know if this was due to sepsis or if the ponatinib or doxorubicin could be implicated. He was commenced on cardiac remodeling drugs, sepsis resolved and a follow up ECHO demonstrated marked improved so I pushed ahead with cycle 7 and ponatinib at the same dose of 45mg. I have been going over the PACE trial data and it suggests that I should consider decreasing the dose of the ponatinib due to the increased risk of side effects if he has attained a good molecular response which he has. He has decided against transplant so my concern is that the ponatinib is the only thing at present keeping him from relapsing – should I decrease to 30mg. The other thing of note is that his disease was not resistant to dasatinib – he finally acknowledged that he had stopped taking the dasatinib which led to his progression to blast crisis.