I am seeking advice on a 8 year old boy with CP CML diagnosed July 2013, so nearly a year into imatinib therapy. He has a sibling donor and also interestingly has low OCT-1 activity done in Adelaide at diagnosis. Since diagnosis he has been on 300mg of imatinib daily. Initially this dose equated to 352mg/m2 and his dose is still 349mg/m2. Initial imatinib trough levels were as high as 1800 ng/ml and he had early cytopenias of neutrophils and Hb but this has all settled to a mild macrocytic anaemia only. No other significant side effects. His BCR-ABL (IS) level was 0.5% at 3 months, 0.2% at 6 months. After 9 months of imatinib his BCR-ABL level went up (0.37%) at a time when his imatinib level was 1200 (we only measure it 6 monthly, just did by chance at that timepoint). We repeated the level 6 weeks later to find it 0.14 but because of the increase we had ordered mutation analysis which has just come back as Y253H mutation (cDNA 757T>C) in 10% of cells and BCR:ABL35ins in around 25% of cells. The former in Blood paper of Martinelli 2011, 119:1208-1215 indicates potential change to Dasatinib, the 35ins from Blood paper by Druker, 2011 indicates it is of no significance. We repeated the mutation screen on a more recent sample and found evidence of the Y253H mutation at the 20% level.

Also, he has only grown 2.4cm in the last 11 months, below 3rd centile (mean is 6cm in the 7th year). Our thinking was, if he is developing mutations on imatinib maybe we should switch to dasatinib, or should we consider increasing the dose of imatinib (already 349mg/m2 which I believe is the equivalent of 600mg for an adult). Given he has a matched sibling we are also entertaining the idea of RIC allo.

Hi Steven,

I always like getting queries from the paediatric haematologists because they monitor their patients so well! It is so rare to have OCT-1 activity, imatinib PK, serial RQ-PCR and mutation data all available when I get difficult cases from adult haematologists!

The low OCT-1 Activity (OA) is a concern and I would have only been partially reassured by the good molecular response at 3 months. You don’t give the BCR-ABL level pre-therapy – that is also relevant because the initial slope is highly predictive of long term response. Sue Branford has just published this finding in Blood.

The molecular response was optimal at 3 months and BCR-ABL continued to fall after that. A little bump at 9 months but that could be technical, not biological – not even a doubling. The 35INS is completely irrelevant as far as I know, the BCR-ABL level is still less than 1% but the low level Y253H mutation is a significant concern, particularly now that it has been confirmed on a second sample. I think it is very unlikely that imatinib will control this disease long term. We know these low level clones usually expand if the TKI is not active against them.

You should ideally switch to dasatinib ASAP (this mutation would not be sensitive to nilotinib) and get things moving for a possible allograft. You should know in 3-6 months if the dasatinib is likely to achieve a stable long term molecular response. If the BCR-ABL level cannot be kept below 1% on dasatinib, preferably below 0.1% and steadily falling, then I would start to consider the possibility of an allograft. Not sure if RIC or conventional allograft is a better choice in this age group – hopefully others could comment on this.

I totally agree with Tim and I am in favour of switching to Dasatinib, but if it does not work, before allo transplant I would also consider a short period of wash out with ponatinib. Although I do not know exactly the regulatory rules of this drug during pediatric age, I think that a short period of "induction therapy" with this drug could be of benefit in this case.

The failure to gain appropriate height is most discernible when imatinib is administered in the prepubertal period. The priority, of course is of maintaining molecular remission.
One could consider growth hormone (GH) stimulation test and serum IGF-1 levels. In a small cohort, it has been demonstrated that imatinib results in growth failure by disturbing the GH:IGF-1 axis. It is likely (not well proven) that growth failure would be observed with all the TKI's. On an 'individual case basis' one could consider GH therapy, if GH deficiency is proven.

Narayanan et al. Growth failure in children with chronic myeloid leukemia receiving imatinib is due to disruption of GH/IGF-1 axis. Pediatr Blood Cancer. 2013 Jul;60(7):1148-53.

Bansal et al. Imatinib has adverse effect on growth in children with chronic myeloid leukemia. Pediatr Blood Cancer. 2012 Sep;59(3):481-4.

I cannot comment on the growth issues but it sounds like from others that there is literature on imatinib and growth retardation.
I agree with Tim and Beppe about the switch and a decision on response be made by the 6 month mark.
If dasatinib fails, then allograft is an option and I do not favor RITC. We have unpublished (but ASH abstract 2014 submitted) suggestion that at least in adults, they do not do as well in TKI failures as myeloablative. Also long term issues such as chronic GVHD are generally no better and this is an issue with kids. At one point and I still think there is some truth in it, that a RITC which has not been looked at consistently with CML, should not be used if a myeloablative is an option.
The concern to think about now, is that endocrine dysfunction post allograft and growth retardation is a known issue in kids. You might want to get on with the GH recommendations ASAP with this as a possible future option.

Dear Steve, I totally agree with Tim and Beppe: the good molecular response (optimal at 3-6 months and BCR-ABL continuing to fall) means response to imatinib but now the rising level of the Y253H mutation means emerging less sensitive clone. Imatinib, is not active against this mutation.

I also suggest to switch to dasatinib ASAP controlling molecular response, as you are marvelous doing.
Immunophenotype of CD34 and CD19 bone marrow population will also fine to "control" lymphoid sub clones.

BW
Giovanni

(original case repeated here for reader reference)
I am seeking advice on a 8 year old boy with CP CML diagnosed July 2013, so nearly a year into imatinib therapy. He has a sibling donor and also interestingly has low OCT-1 activity done in Adelaide at diagnosis. Since diagnosis he has been on 300mg of imatinib daily. Initially this dose equated to 352mg/m2 and his dose is still 349mg/m2. Initial imatinib trough levels were as high as 1800 ng/ml and he had early cytopenias of neutrophils and Hb but this has all settled to a mild macrocytic anaemia only. No other significant side effects. His BCR-ABL (IS) level was 0.5% at 3 months, 0.2% at 6 months. After 9 months of imatinib his BCR-ABL level went up (0.37%) at a time when his imatinib level was 1200 (we only measure it 6 monthly, just did by chance at that timepoint). We repeated the level 6 weeks later to find it 0.14 but because of the increase we had ordered mutation analysis which has just come back as Y253H mutation (cDNA 757T>C) in 10% of cells and BCR:ABL35ins in around 25% of cells. The former in Blood paper of Martinelli 2011, 119:1208-1215 indicates potential change to Dasatinib, the 35ins from Blood paper by Druker, 2011 indicates it is of no significance. We repeated the mutation screen on a more recent sample and found evidence of the Y253H mutation at the 20% level.

Also, he has only grown 2.4cm in the last 11 months, below 3rd centile (mean is 6cm in the 7th year). Our thinking was, if he is developing mutations on imatinib maybe we should switch to dasatinib, or should we consider increasing the dose of imatinib (already 349mg/m2 which I believe is the equivalent of 600mg for an adult). Given he has a matched sibling we are also entertaining the idea of RIC allo.