Pediatric-Inspired Regimens in the Treatment of Acute Lymphoblastic Leukemia in Adolescents and Young Adults: A Systematic Review

Round 1

Reviewer 1 Report

 

This is an exciting research paper.

However, a few suggestions are placed to further improve the manuscript.

 

 

Introduction:

 

Comment 1: Nicely written. However, one can elaborate more on the recent development in the field of Immunotherapy for ALL and what changes it has made in the management of ALL.

 

Method:

 

Comment 2: one of the MeSH could have been immunotherapy.

 

Results:

 

Comment 3: looks good but too extensive, needs to be curtailed.

 

Discussion:

 

Comment 4: It is always better to include the immunotherapy part as the future of the treatment (eg BiTE, CART etc).

 

Reference:

 

Comment 5: Looks Ok

 

Table and Figure:

 

Comment 6: looks good

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The study drew little measurable or actionable takeaway to the clinicans to delineate what constitutes pediatric-like regimens and how they should be treated differently in the AYA population, to name a few problems, see below:

1.       Page 1: To generate a clear background introduction, the authors will need to define clearly and precisely and clearly what is pediatric vs. pediatric-inspired regimen vs. conventional adult protocols in terms of patient populations, drugs commonly used and therapeutic end-point differences. This

 

2.       Explain why “the data on treatment strategies in AYA with ALL is limited due to the lack of randomized comparative studies and thus prone to bias”, so why there is a need to draw comparisons between pediatric-inspired regimen vs. conventional regimens if the data are limited? If there is no meta-analysis, how would your work improve the limitations? C an it still be called a systemic review?

 

3.       Page 3: “Discrepancies were solved by a third reviewer (KS).” How? PIR vs conventional regimens? Define what standard regimens were used.

 

4.       Page 10: “the reported OS for PIR tended to be higher 139 [18,24,29-31]. Higher compared to what? How is survival defined in each study?

 

5.       Page 10: “HRs were given for different time points (2 years, 3 years, 144 5 years.” How would different time points affect survival and HR?

 

6.       Page 10: “Most commonly an increased incidence of pancreatitis, hypofi- 159 brinogenemia, neuropathy, hepatic toxicity, and infections was reported by the studies 160 [10,22,24,29] (Table 2)” Are these  the class effects of vincristine, asparaginase, and general systemic chemotherapy? If so, why are they different than adult regimens? Is pegaspargase used?

 

7.       Page 14: “However, the follow-up duration was significantly shorter in 177 patients who were treated with PIR”. Would this affect overall survival and EFS?

 

8.       Table 3 did not stratify pediatric vs. pediatric inspired regimens, which seemed to b discussed under separate entities, bias of this analysis must be addressed or clarified.

 

9.       Page 24: “delays during re- 233 inductions as well as vincristine or asparaginase dose modifications were significantly 234 more frequent in young adults than in adolescents (p=0.04 and p=0.03 respectively.” Does that reflect the differences in tolerability or different threshold in stopping/withholding certain treatments? Why is this clinically meaningful?

 

10.   Page 24:’ it is also well-documented that treatment completion in the AYA age 244 group is often low” why? Explain or propose an explanation.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

The authors present a thorough and thoughtful analysis of the literature regarding the use of the PIR in this patient population. The manuscript is well written.

Abstract:

The authors state “However, the gathered data shows a significant improvement in outcomes and an acceptable toxicity profile in patients treated with PIRs, compared to conventional adult-type regimens”.

This statement is not true. Although there are several non-randomized studies that suggest a benefit, there are others that do not. The authors should not ignore the latter reports in their conclusion.  

Line 48:

The authors state “However, the data on treatment strategies in AYA with ALL is limited due to the lack of randomized comparative studies and thus prone to bias, making interpretation and comparisons difficult”. This is a very strong statement and should be the conclusion of their manuscript.

Figure 1: What was the reason the first 4946 records were excluded?

Table 1. There are tabular errors with the columns.

Discussion:

The authors state “This systematic review of 26 published comparative studies, reporting outcomes of AYA patients with ALL, confirmed a significant improvement in outcomes and an acceptable toxicity profile in patients treated with PIRs, compared to conventional adult type regimens. While direct comparison and analysis were difficult due to heterogeneous study populations, treatment settings, treatment eras, and treatment protocols, most of the included studies nevertheless report an increase in survival with the use of PIR”. Again the authors analysis does not support this statement. There were several trials that did not show a benefit. It would be a stronger paper if the authors took a more objective and balanced interpretation of the data rather than being biased toward the PIR results.

The authors have stated that [1] none of the studies are a randomized clinical trial, [2] while some suggest improved outcomes with PIR, others do not and [3] many studies show an increase in toxicity with the use of PIR. I would therefore conclude that it is not clear if the use of PIR represents an improvement over more traditional regimens and that a well-designed, large, randomized clinical trial is needed to finally settle this issue.

Conclusions

The authors state “While the gathered data doesn’t allow for clear conclusions about the best treatment protocols to be used in the AYA population, it is nonetheless safe to conclude that AYAs with ALL should be treated in specialized centers with experience with pediatric-like treatment approaches and if possible enrolled in randomized controlled trials”. The authors have not provided any data supporting this statement. Even if it is true, it is not appropriate here in the absence of supportive evidence in the main body of the manuscript.  

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Revision is fine. Evidence presented seems reasonable.