Molecularly Targeted Small Molecule Inhibitor Therapy for Pediatric Acute Lymphoblastic Leukemia: A Comprehensive Review of Clinical Trials

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Methodological and Factual Inconsistencies

 

Contradictory Data on the Number of Clinical Trials: One of the most serious inaccuracies is the internal contradiction in the methodology concerning the number of included studies. This is a fundamental error that undermines the reliability of the entire review. The manuscript states that the initial search of the clinicaltrials.gov database yielded 274 records. After removing 96 duplicates, 178 studies were sent for eligibility assessment. The authors then state that 76 studies met the inclusion criteria, and after adding two additional studies from references, the total number of included studies was 78. However, an analysis of the attached tables reveals that the number of listed studies, both included and excluded, is significantly larger. The actual number of 76 included studies cannot be verified based on the attached materials. Such an inconsistency, while it may seem like a minor error, is a critical problem in a scientific report, where numerical data must be consistent throughout the document.

Incorrect Dates for Clinical Trials: In the methodology section, the authors state that the database search was conducted on "May 15, 2025." This is an error that seriously undermines the manuscript's credibility, as it indicates a date in the future. Such an error in a text submitted for review suggests that the manuscript is an unfinished draft or that the authors are trying to present an incomplete work as a finished methodology. This error must be explicitly pointed out in the expert review, as it demonstrates a lack of due diligence in preparing the scientific document.

Misleading Reporting of Study Status: There are clear discrepancies between the study statuses given in the text and those in the attached tables, which indicates a lack of thorough verification. For example, the manuscript describes the EsPhALL 2017/COG AALL1631 (NCT03007147) study, stating that it has "recently completed recruitment." However, in the attached table (Table 1), the status of this study is listed as "Recruiting." This is a direct contradiction that must be corrected. Such errors can mislead readers about the current status of the studies and the potential for patient enrollment.

Conceptual Flaws and Scope Limitations

 

Exclusion of Immunotherapies: The most significant conceptual flaw is the arbitrary exclusion of immunotherapies from a review that is marketed as "comprehensive." This approach distorts the current therapeutic landscape by omitting the most important and innovative advancements in the treatment of pediatric ALL. The authors themselves admit that immunotherapies have "undoubtedly reshaped the ALL treatment landscape," yet their methodology states that "immunotherapeutic agents and cellular therapies, including CAR-T cells, were considered to be beyond the scope of this review." This contradiction in the description results in a review that is inherently incomplete and fails to allow for a full comparison of small molecules with the most effective new agents. The final report should explicitly recommend that the authors either change the title to be more precise (e.g., "A Review of Small Molecules...") or include a full chapter on immunotherapies, which would significantly increase the scientific value of the work.

Critical Analysis of Drug-Specific Sections

 

Tyrosine Kinase Inhibitors (BCR::ABL1-TKI): The narrative regarding the superiority of second-generation TKIs (dasatinib) over first-generation TKIs (imatinib) is not fully supported by the data cited from large studies. The authors note that dasatinib has higher inhibitory potency in vitro (>300-fold). However, they cite results from studies like COG AALL0622 (NCT00720109) and COG AALL1122 (NCT01460160), which showed that 5-year EFS (event-free survival) was 60%, a result that was "virtually identical" or "no better" than outcomes from imatinib-containing protocols. Although they then mention the Chinese CCCG study (ChiCTR-IPR-14005706), which showed better results for dasatinib, they immediately add that the imatinib group in that study had outcomes "significantly worse compared to prior results from the COG and EsPhALL trials." This key point invalidates the apparent superiority of dasatinib in that specific study and highlights that the final conclusions on the superiority of one drug over another when combined with intensive chemotherapy are not clear-cut.

Proteasome Inhibitors: The review excellently illustrates how promising early signals from trials don't always translate into benefits in large, randomized trials. The narrative on bortezomib should clearly emphasize this relationship. The initial Phase I/II TACL consortium study (NCT00440726) showed a high overall response rate (73%), which provided the basis for further research. This led to the COG AALL1231 study (NCT02112916), a large Phase 3 trial that was intended to definitively confirm bortezomib's efficacy in first-line treatment. The final results of this study "did not show an overall, statistically significant improvement in outcomes in the bortezomib arm." This fact is an important lesson in oncological drug development and should be presented more clearly in the narrative. The authors correctly note that a post-hoc analysis showed a benefit in the T-ALL subgroup, which should be viewed as a hypothesis for future studies rather than a definitive conclusion.

BH3 Mimetics and Other Novel Agents: The discussion of newer agents, such as venetoclax and menin inhibitors, accurately points out their potential. However, the narrative could benefit from a more balanced perspective. The review should temper the initial enthusiasm that led to the FDA's approval of revumenib with the reality of the challenges associated with combining these drugs with existing chemotherapy. The AUGMENT-102 study (NCT05326516) showed that adding menin inhibitors to chemotherapy yielded "preliminary efficacy results similar to those observed with revumenib monotherapy." This finding is crucial because it signals that a promising response rate in monotherapy doesn't guarantee improved outcomes in complex regimens. This point aligns with the authors' overall conclusion that pediatric drug development faces "significant hurdles, including limited commercial incentives and smaller patient populations," which necessitates a more strategic approach.

Author Response

Please see attachment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This is really cutting-edge, very comprehensive review, very extensive very broad and detailed and updated that covered all targeted therapies and immunotherapies for childhood ALL. The authors made a thorough search of the available information as for the completed list of ongoing clinical trials for children with ALL The review focuses upon 51
molecularly targeted therapy approaches for childhood ALL and highlights the current landscape of ongoing and upcoming trials, and to provide insights into future directions for precision-driven optimization of pediatric B-ALL and T-ALL treatments.

Author Response

Comment 1: Summary: This is really cutting-edge, very comprehensive review, very extensive very broad and detailed and updated that covered all targeted therapies and immunotherapies for childhood ALL. The authors made a thorough search of the available information as for the completed list of ongoing clinical trials for children with ALL The review focuses upon 51 molecularly targeted therapy approaches for childhood ALL and highlights the current landscape of ongoing and upcoming trials, and to provide insights into future directions for precision-driven optimization of pediatric B-ALL and T-ALL treatments.

Authors' response: We appreciate the careful review of our manuscript by the reviewer and her or his very positive comments regarding our manuscript.

 

Reviewer 3 Report

Comments and Suggestions for Authors

1. This is a well-written and organized review of molecularly targeted therapies in pediatric ALL This review is comprehensive and informative, but several revisions would enhance its clarity, completeness, and clinical relevance.
2. Please clarify the literature search strategy, including databases searched, search terms, inclusion/exclusion criteria, and cut-off dates. This will improve reproducibility and transparency of the review process.
3. I recommend standardizing the presentation format across all clinical trial summaries. Each entry should include trial ID, phase, patient number and age range, treatment backbone, primary endpoints, outcomes (e.g., CR, MRD, survival), and key toxicities. This will allow readers to compare results more easily.
4. While tables organized by individual agents are helpful, consider adding summary tables by pathway or drug class (e.g., ABL-class, JAK/STAT, BCL-2, proteasome inhibitors). Such comparative tables could highlight mechanisms of action, advantages and limitations, clinical outcomes, and toxicities across agents, making the synthesis clearer.
5. The introductory figure mapping therapies to pathways and protein targets is very effective. To strengthen it further, add annotations or an additional figure highlighting agents approved in adults but not yet widely available in children, thereby clarifying translational gaps and future opportunities.
6. Toxicities are currently discussed within each drug section. A dedicated summary table grouping adverse effects by drug class or molecular target (e.g., cardiovascular, hepatic, hematologic, infectious) would allow readers to quickly compare safety profiles across therapies.
7. The manuscript currently lacks a discussion of combination approaches involving targeted therapies and immunotherapies (e.g., BsAbs, CART). Adding this perspective would enhance completeness and highlight an important direction for future pediatric ALL treatment.
8. Ensure consistent use of terminology (e.g., “Ph+” vs. “Philadelphia-positive,” “Ph-like,” “R/R”) and provide absolute patient numbers alongside percentages for clarity. Minor editorial polishing of section length and flow would also improve readability.
9. Consider adding a brief Future Directions or Clinical Implications section summarizing how targeted therapies may be integrated with current treatment standards, the main challenges (e.g., toxicity management, access to adult-approved agents), and research priorities for pediatric cohorts.

Author Response

Please see attachment.

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Editor,

The manuscript entitled "Molecularly targeted therapy for pediatric acute lymphoblastic leukemia: a comprehensive review of clinical trials" by Peccatori et al is a comprenhensive and up to date review or targeted therapies of children with relapsed/refractory ALL. 

To my opinion the manuscript is accepted for your journal and could be of help for pediatrician hematologists and those who treat AYAs.

Minor comments:

1. Please add a short paragraph in the introduction section about the use of immunotherapy not also as treatment for r/r disease but also as 1st line treatment.
2. LIne 223: what do you mean in terms of time as "protracted use of imatinib"?
3. Line 227: please mention main toxicities and toxicity rate related mortality of imatinib
4. Are any results regarding the efficacy of imatinib in CNS +patients in comparison to those CNS negative?
5. Are any data that compare results of Ph+ patientsw in comparison to those ABL fusion + in terms of survival and DFS?
6. Please add 1-2 sentences of the main toxicities of each agent reported in the manuscript.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 5 Report

Comments and Suggestions for Authors

Q1.                         Long-term disease-free survival of children withB-acute lymphoblastic leukemia (B-ALL) now exceeds 90%. Why this review is necessary?

Q2.                         Patients with high-risk genetic features and those who experience a relapse or are refractory to front-line therapy still have a poorer prognosis. The chance of relaptation needs to be specified.

Q3.                         Immunotherapeutic agents and cellular therapies, including CAR T-cells, authors reconsidered outside the scope of this review. The reason is not specified.

Q4.                         After removing the duplicate records, 178 studies were assessed for eligibility. On what basis duplicate records are eliminated.

Q5.                         78 are included clinical trials. Why small numbers are selected?

Q6.                         Flow diagram reporting the results of the search is at https://clinicaltrials.gov. It can be converted to algorithm. Specify it and time complexity of the algorithm is to be given.

Q7.                         What are the initial symtoms of the disease? It was not mentioned in the paper.

Q8.                         Higher imatinib dosing in Cohort 5 significantly improved the patient outcomes of disease. It is a good sign but reason is not specified.

Q9.                         Authors mentioned that firstly, the follow-up of the study was short, considering the slightly high rate of late relapse in the TKI era for Ph+ ALL. Why it is short in study the disease?

Q10.                       In children, conversely, its approval is limited to patients with CML-CP either in first line or R/I to previous TKI treatment. If it is used then what type of effects in children?

Q11.                       Drug development in pediatric oncology continues to face significant hurdles. It is true not only for children but also for adult since the origin of cancer is still not known. Can authors have any idea about this?

Author Response

Please see the attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

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