Review Reports

Round 1

Reviewer 1 Report

The review article of Giona et al. gives an very interesting and insightful overview on management of CML in pediatric patients. The review is written by experts in the field and highlights in depth standard of care and future directions.

The article could be completed by 1 or 2 tables resuming differences between childhood CML concerning efficacy of TKI and disease characteristics.

Author Response

We thank you for reviewing the manuscript and for giving favourable feedback. As you can see in the text (line 174), a table (named Table 1) reporting the main studies with different TKIs was included in the original version of the paper. Unfortunately, this table has mysteriously disappeared.

Reviewer 2 Report

The review is comprehensive and emphasize the differences and specificity of diagnostic characteristics, therapy with TKI, resistance  and monitoring between children and adults. The disease is very rare in children. Particularly useful are reccomendations how to take drugs together with liquids and concerns about long-term effects on prepubertal children. It is a pity that there are not yet hard evidence for stopping the TKI in children as it is in adults. Furthermore, most of the experiences come from retrospective and registry based studies, though it looks that things are slowly changing. 

Author Response

We thank you for reviewing the manuscript and for giving favourable feedback. We rely on future studies to better understand and improve treatment approaches in paediatric CML patients.                                                       

Reviewer 3 Report

This is a comprehensive, up-to-date and well written review on childhood CML with much useful information for the pediatrician dealing with CML. It covers biologic and clinical features, prognosis, therapy with IFN, TKI and transplantation and molecular monitoring as well as TKI treament discontinuation. Some statements need to be aligned with the literature. Since this review is written in memoriam of Michele Baccarani, his work as far as discussed here should be cited and not covered in second line reviews.

Comments

1.       Line 47: the study of Kalmanti et al, Ann Hematol 2014 would add information due to sample size and adult comparator groups.

2.       Line 85: the reader expects mentioning the ELTS score here

3.       Line 96: the primary citation is Pfirrmann et al, Leukemia 2016 with Baccarani as second author. The outside validation by Geelen was much later.

4.       Lines 101-103. The response assessment was first published by Baccarani et al, Blood 2006. This paper should be cited since it has set the stage for molecular monitoring of TKI treament in CML globally and since this is a memorial edition for Michele Baccarani.

5.       Lines 105 and 110: Likewise I recommend to cite the ELN recommendations 2013 (Baccarani et al, Blood 2013) since they are the handwriting of Michele Baccarani and proved useful also for children.

6.       Line 113: Uniform language helps the reader: the terms „second-generation of TKIs“ and „second -generation TKIs“ are confusing. The general usage is „2nd generation TKI“ (2GTKI).

7.       Lines 114-126: Whereas the significance of early response is well described and cited, the introduction of high-dose imatinib remains unclear. Since it involves Michele Baccarani, a sentence to the first two randomized studies comparing imatinib 400 and 800 might be well placed: the TOPS-study of Novartis with Baccarani as second author (Cortes et al, JCO 2010) and the academic CML-study IV (Hehlmann et al, JCO 2011). The Deininger study was much later.

8.       Line 125: IM dose, not exposure.

9.       Line 134: two studies

10.   Lines 36, 354, 388: emotional terms, such as dramatic, weaken the statements. Profound is equally strong and not emotional.

11.   Lines 163-167: more effective in terms of outcome is not correct, only in terms of response, not survival. This should be corrected.

12.   Line 182: 33% after which time?

13.   Line 190: Eighty-four.

14.   Section 6: The reader will be interested to learn about pleural effusion after dasatinib in chidren. If it does not occur, it would be worth mentioning. I adults, dasatinib can be given at a dose of 50mg/day with satisfactory efficacy.

15.   References should be added in lines 264 (e.g.ELN 2020 recommendations), 266 (eg. Euro-ski study) and 267 (Legros etal).

16.   Lines 286-288: I don’t think this recommendation can be maintained, compare Flygt et al (2021) from the Swedish CML registry.

17.   Line 312: Mortality (not toxicity)

18.   Line 328: targeted therapy

19.   Line 345: is 2016 still recently?

20.   Lines 353 and 354: /day or daily

21.   Last sentence: Dangerous statement as it stands: a stable DMR is required of sufficiently long duration and after sufficiently long TKI treatment (> 6 years in adults).

Author Response

Please see the attachment

Author Response File: Author Response.pdf