I have a 13 year old male patient with no past medical history who has at least 6 months of lethargy but no other specific symptomatology. A routine GP visit at which the lethargy was mentioned prompted a blood count which was abnormal so he was referred to me.

To examine he is clinically well, has no significant lymphadenopathy but has a spleen well across the umbilicus but not quite down in the pelvis. He also has mild hepatomegaly. Blood count below:

Haemoglobin 103 g/L L 125-160
Haematocrit 0.31 Ratio L 0.37-0.47
MCV 90 fL 78-93
MCH 30 pg 25-31131313
Platelets 382 x10(9)/L 150-400
WBC 253 x10(9)/L H 4.2-10.0
Neutrophils 157 x10(9)/L H 1.8-7.0
Lymphocytes 2.5 x10(9)/L 1.4-4.0
Monocytes 2.5 x10(9)/L H 0.3-0.9
Eosinophils 2.5 x10(9)/L H 0.0-0.8
Basophils 7.6 x10(9)/L H 0.0-0.2
Meta/Myelocytes 68.3 x10(9)/L H
Promyelocytes 10.1 x10(9)/L H
Blasts 2.5 x10(9)/L H
Nucleated RBC's 2.5 x10(9)/L H

Bone marrow aspirate is consistent with this blood picture with well less than 5% blasts present. BCR-ABL1 fusion has been confirmed on peripheral blood by FISH. Karyotype not yet back so CCA not yet known.

I have not treated an adolescent with CML in chronic phase and it poses a number of unique challenges. Firstly the selection of TKI. The literature in paediatrics is sparse but from what I can see imatinib is established as efficacious and safe. I believe BMS still have the phase 2 dasatinib trial for CML open and the phase 2 data for dasatinib with the EsPhALL chemotherapy backbone for Ph+ ALL is maturing currently. I can't find much data on nilotinib safety or efficacy in children. I would be very interested in your opinion on whether the TKI data for adults with CML is able to be translated to the paediatric group and what you would recommend as first line therapy.

Secondly, of course, is the issue of 70+ years TKI therapy vs allogeneic transplantation. I will be tissue typing and testing the 2 siblings but even if he has a matched sibling the choice is not easy.

Any help or advice would be greatly appreciated.

This is an interesting case and I suspect there would be no consensus amongst experts on what would be the best approach. I haven't calculated his Sokal risk but his large spleen does concern me. My first inclination would be to recommend dasatinib given the better tolerance profile, lower risk of transformation, and better chance of achieving a deep molecular response compared to imatinib. Others may have differing opinions.

The questions are all good ones. Here is a pediatric oncologist’s thoughts.
- Children tend to present with more aggressive symptoms (larger spleen and higher WBC) if it does not necessarily translate into worse outcome. We cannot rely on existing prognostic scores. There is data showing discordance in children. (Gurrea Sallas et al Ann Hematol 2015, 94, 1363)

- Phase 2 dasatinib study and phase 2 nilotinib study have been completed but the data has not been presented. In our practice, we have used imatinib or dasatinib based on availability and physician’s preference. Non-compliance in teenagers can be especially challenging. I would carefully monitor compliance.

- Another great question is transplant and there is no right or wrong answer here. I totally agree to do typing of the siblings now. If siblings are perfect match and the response to TKI is optimal, then pros and cons should be discussed with the family extensively. In the literature, 5 year OS is up to 87±11% with matched sibling donor (Suttorp et al. Klin Padiatr 2009, 221, 351). Transplant is better tolerated in children in general, but still morbidity is not negligible. If the response is not optimal, then it may be a little easier decision. In pediatric oncology, we are trying to gather more data to address this.

Not sure how the Sokal risk core applies to the paediatric population, but based on the normal platelet count and the low blast count, the formal Sokal score is calculated to be low. However, the large spleen is concerning.

The bulk of the data in paediatric ALL still concerns the use of imatinib, most commonly used at 340mg/m2. The efficacy in children has certainly been well established. I'm not sure whether this boy has started his pubertal growth spurt, or whether he is quite tall already, as height growth retardation is a concern with imatinib treatment. We expect the same to apply to dasatinib, but data for the latter is still not yet mature. (the same definitely would apply to SCT)

The most commonly used dasatinib dose is 60mg/m2. I don't think any of the trials are formally reported, apart from the phase I study. (I cannot find any currently recruiting study for dasatinib in the paediatric population - all finished enrolling, perhaps?) Pleural effusion may be an issue in children, as it is in adults.

There is at least one study looking at nilotinib in children - again no published data EudraCT Number: 2013-000200-41

Michael has more experience than me, so I will defer to his better judgement (including switching a boy to dasatinib from imatinib for treatment failure). However, I think the TIDEL-II approach may be applicable, especially in a patient in whom long term safety is as much of a priority as speed of response. I would be incline to start on imatinib and monitor BCR-ABL, switching the dasatinib for failure to achieve <10% at 3 months, or <1% at 6 months.

Firstly with regards to the question of TKI vs transplant as frontline treatment of paediatric CML, the current consensus is that TKIs are the treatment of choice and that the only indications for BMT are failure of TKI therapy, progression while on TKI, or blast phase. The main argument in favour of TKIs is that, even though transplant is potentially curative, it is associated with a small but definite risk of transplant-related mortality (overall survival at 5 years was 71% in a recent retrospective CIBMTR study by Chaudhury et al, 2014). It can also be argued that chronic GvHD may be as bad or worse than TKI toxicity. However, some argue that the role of transplant should be re-evaluated given that the risks of early complications of transplant are much lower today. Both sides of the argument are addressed in a recent paper co-authored by the main members of the I-BFM CML subgroup (Hijiya et al, Blood 2016). Susanne Matthes-Martin from Vienna is a fairly vocal advocate for transplanting and she argues for reduced intensity conditioning (flu / mel / thiotepa). At the I-BFM meeting in 2014, she reported that 18 chronic phase patients had received this regimen with TRM of 0%, grade III-IV GvHD in 2 of 18 patients, and extensive chronic GvHD in 1 of 18 patients (and this ultimately resolved). While these results looked promising, it's worth noting that 4/17 patients had mixed chimerism, and it's well established in adult patients that CML can recur many years after transplant. Also, this study has been open for a long time and accrual has been really slow, which suggests to me that most paediatric haematologists view TKIs as standard frontline treatment. In support of this view, only 6 of the 18 patients that were reported by Matthes-Martin in 2014 went to transplant because of physician/patient choice, with the others all being referred for insufficeint response, secondary loss of response, imatinib intolerance, etc. In summary, the question of TKI vs transplant is difficult because a head-to-head study would be unfeasible, and comparing current outcomes with TKIs to pre-2000 transplant outcomes is not really valid because of improvements in transplant care since that time. The bottom line is that TKIs are currently the treatment of choice.

With regards to which TKI to choose, imatinib has the longest safety and efficacy record in children. Its toxicity in children is similar to adults apart from the well-described slowing of longitudinal growth (which I have to admit has not been observed in my patients). The phase I data (Zwan 2013, Aplenc 2011) suggested that dasatinib is well tolerated, but the phase 2 study (BMS CA180-226) is not yet reported. I'm fairly certain that this study is no longer accruing - it closed in Adelaide last year. It was expected that the primary outcome measures would be ready for reporting in 2016, so perhaps we will hear something later this year. I have switched one of my paediatric patients from imatinib to dasatinib for suboptimal response, and he has tolerated the drug better than imatinib. On the other hand, Peter Shaw has had a patient who had really troublesome treatment-resistant pleural effusions on dasatinib. My main concern about dasatinib is the unknown risk of pulmonary artery hypertension over many decades of use. There is a small phase I and II nilotinib study, but they remain unpublished years after they started, and the paediatric CML community were fairly spooked by the data from adults suggesting an increased risk of vascular events from nilotinib. On a practical level, nilotinib is difficult to schedule given the need for avoiding food for a couple of hours around dosing and also the twice daily dosing is more inconvenient than the once daily dosing of imatinib and dasatinib. These features risk worse adherence in an AYA patient. Nobuku Hijiya from Chicago has told me that she thinks bosutinib might not be associated with as much growth retardation as the others, but I'm not sure what has informed that viewpoint. Personally, I would start with imatinib 400 mg daily, but may consider switching if he has an inadequate early molecular response or appears to be failing to meet the European LeukaemiaNet (adult) response guidelines.

Finally, Tim raised the question of the spleen size and Sokal score in children. Neither the Sokal score, Eutos score, Euro score nor Hasford score have been validated in children. Frederic Millot from France has done an (as yet unpublished) exploratory analysis on patients from the I-BFM CML Registry using CCR at 1 year as the endpoint. On univariate analysis, the Sokal score and Euro score were not predictive of outcome but spleen size, Eutos score, hematocrit, marrow monocytes, lymphocytes and myelemia (whatever that is) were. However on multivariate analysis none of these held up and he was not able to identify any independent prognostic factors. A current goal of the group is to develop and validate a paediatric predictive score. For now, I think molecular response at various timepoints is the only validated prognostic marker in kids.

So in summary, I would feel confident recommending that your patient should start a TKI - probably imatinib as it has the longest track record of efficacy and safety, and is an economically sound choice. Equally, starting with dasatinib, based on the speedier time to MMR in adults, would be a very reasonable choice. I would emphasise the importance of adherence from day 1, and if there are any adverse social factors or family difficulties I would work very hard to fix these as supportive family relationships appear to predict for better adherence in other chronic illnesses in AYAs. I would tissue type him just in case he turns out to be a bad player, but would not go to the length of initiating an unrelated donor search yet. I would do 3-monthly marrows until he achieves a CCR, and would do 3-monthly BCR-ABL PCRs indefinitely. If he has a suboptimal early molecular response or fails other timepoints I would consider switching him (although we are somewhat constrained by the PBS as to when this can be done). I would also track his growth carefully. (I have tended to monitor growth hormone, beta crosslaps, Vit D, osteocalcin, P1NP, calcium and PTH out of interest, but that's probably unnecessary and on reflection I doubt that any of these would be management altering.)

I believe we agree that this is a classical pediatric case of CML in chronic phase. The median WBC in pediatric cohorts is 240 000/µl which is higher than in adults. Also the moderate decrease in Hb is quite common, and with 2.5% blasts in the pB and 5% in the BM it is definitely a chronic phase.
Assumed that the 13 year-old boy is of normal weight and body length I would recommend to start with imatinib 400 mg once daily. The drug is the only TKI licensed for pediatric use and since 2004 we have accumulated most experience with imatinib compared to 2nd gen TKI.
Ratio
BCR-ABL1/ABL1 should be monitored in monthly intervals until months 3 and thereafter in 3-monthly intervals. A change to dasatinib may be considered if the ratio is still <10% at months 3 and <1% at month 6. Side effects occurring highly probably will comprise transient neutropenia in the first weeks after initiation of TKI. The pediatric guidelines published in 2014 give details on how to handle this and other side effects (do not interrupt imatinib for more than 1 week, use G-CSF to treat neutropenia and transfusion of red cells or Erythropoetin for symptomatic anemia). Bone and muscle pain during the first 9 months are quite common (all grades, 30 - 50% of all pediatric patients) and should be treated with ibuprofen.
I would not recommend SCT up-front -also not in cases with a fully matched sibling donor available.