I would be very grateful for any further thoughts you may have about this young patient of mine.

Ph+ CML was diagnosed at age 2.5y
Additional abnormalities seen in the Ph+ population –Y and +8.
Commenced on imatinib 340mg /m2 and had suboptimal response, remaining at PCYR and QPCR 10% with 9 months into therapy despite and increase in dose at 6mo.
Lab did sensitivity testing and mutational analysis (neg) for us at that stage.
We commenced dasatinib at that time 60mg/m2.
Family were reluctant to consider SCT.

After 12 months dasatinib therapy QPCR 0.115%
Dose was increased 40mg daily (53mg/m2) to 50mg daily (67mg/m2) due to growth
After 24 months dasatinib therapy QPCR 0.035% MMR
After 36mo dasatinib therapy QPCR equivocal
March 2013 QPCR 0.007%
June 2013 QPCR 0.365%

Patient has tolerated therapy reasonably well.
There are no compliance concerns.
Growth is somewhat slowed.
Currently on 50mg at 0.86m2 =58mg/m2

Has not had a BMA for morph and cytogenetics/FISH for some time so I will arrange this.

Wondering if the child needs sensitivity testing and mutational analysis at this point.
Wondering if a dose increase is advisable and whether one again SCT should be considered.
Thank you so much for your thoughts,
Lisa

Lisa Orme
Paediatric and Adolescent Oncologist Australia

The most common cause for a rise in BCR-ABL of this type is a loss of drug compliance but I gather that you are quite confident that this is not the case. The next possibility to consider would be that this is just assay fluctuation – very unlikely with this rise but I would want to see more than one result before I was convinced of the rise. The doubling time here is short (10-20 days). In our recent publication on doubling times (Branford et al, Vol 119, 2012 Blood) this very rapid rise was associated with transformation to blast crisis OR drug cessation. By contrast most cases of resistance with mutations had doubling times of 40+ days. So I agree a marrow examination with cytogenetics and RQ-PCR as well as a repeat mutation screen would be important at this stage.

Assuming that this rise in confirmed and that no mutation or evidence of blast crisis emerges the options would be –

1. Increase dasatinib dose to >80 mg daily. Possible if his tolerance to 50 mg is very good with minimal cytopenia.

2. Switch to ponatinib. Limited experience in children and I am not sure that the compassionate program extends to children but if this is acquired resistance to dasatinib then it is more likely that he will achieve a deep and durable molecular response to ponatinib than he would achieve with higher dose dasatinib. It does have worrying toxicities though (pancreatitis and thrombotic events) so the risks are higher.

3. Proceed to an allograft – I would favour this if you can’t achieve molecular control with (1) or (2).
Sensitivity studies aren’t possible unless the BCR-ABL level is >10%.

Whatever you do you should monitor response with monthly RQ-PCR to give you the earliest indication of if and when to proceed with the allograft option.

Tim,
We had a patient with Ph+ALL and T315I mutation and received ponatinib through the compassionate program. However, I am curious to know why ponatinib if it is not T315I mutation. We have a little more experience with nilotinib in children although less in younger population.

Lisa,
I would definitely look at mutation. If there is mutation and there is a good matched donor, HSCT would be a good option.

Nobuko Hijiya

Northwestern University Feinberg School of Medicine
Ann & Robert H Lurie Children’s Hospital of Chicago

The presenting cytogenetics were of a major concern to begin with and the response to various drugs worrisome as well. As Tim suggested, there may be some mileage with dose or drug switches, but this kid is a ticking bomb for going acute. If there is a reasonable donor available, I would strongly favor an allograft. This is probably going to be necessary at some point in the future and the results of doing this in CP1 far exceed those of doing it in advanced disease whether or not CP2 can be achieved.

I agree with Tim that strict molecular monitoring is essential and it is important also to check again for the presence of mutations. If and as soon as the BCR-ABL level will be above 1%, it is important also to perform BM aspiration in order to evaluate morphology as well as cytogenetics. In case of an emergence of a dasatinib resistant clone (even at the present dose) I would take in great consideration the SCT option, as I do not believe that ponatinib at this moment is available for pediatric cases and furthermore we do not have any information on its long-term effects on growth.

This is certainly a challenging problem. If adherence seems not to be a problem, then I would do nothing until you have repeated the RQ-PCR (very soon) and confirmed the substntial rise you have observed between March and June. If not confirmed then probably make no changes.

If confirmed it would indeed be worth doing a marrow aspirate and KD mutation analysis. Treatment options then include ponatinib and SCT, probably in that sequence.