What Is Next in Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia

Round 1

Reviewer 1 Report

This paper represents an excellent overview of the field. It summarizes the main pillars of leukemia therapy including chemotherapy, targeted agents, stem cell transplantation and cellular therapy. In particular, the references in this manuscript include many of the sentinel papers that have shaped the field. That makes this paper an excellent resource for understanding how prior studies influence current research.

General comments:

This paper provides strong historical context that forms the basis of current lymphoblastic therapy. It also highlights major practice changes that have been made based on recent clinical studies. It is well written and easy to comprehend. The authors also identify key areas of investigation that are or will be the subject of new research seeking to improve outcomes in pediatric lymphoblastic leukemia.

This paper predominately, but not exclusively, addresses B-cell lymphoblastic leukemia. In particular, molecular therapy and chimeric antigen receptor (CAR) T-cell therapy are largely only applicable to B- and not T-cell leukemia. Readers should take care that advances in B-cell lymphoblastic leukemia may differ from T-cell lymphoblastic leukemia.

 

As with any paper, there are limitations on the amount of discussion that can occur. For example, in the section on CAR T-cell therapy the authors do not emphasize the large diversity of CARs that are being used to treat patients. While in-depth discussion of cellular therapy is beyond the scope of this paper, it may be worth acknowledging that two very different approaches are being taken 1) augment and optimize existing CARs and 2) development of novel CARs or CAR combinations. There is a temptation to lump all CAR studies together to compare outcomes. However, differences in CAR constructs, manufacturing practices, and clinical study design can all impact outcomes and goals of CAR T-cell therapy. 

Specific comments:

Paragraph 1: Many of the references in this paper are exclusive to St. Jude data which do not always participate in larger collaborations. I would like to see additional citations of work published by other groups as reported outcomes are not quite as favorable as the authors report. Would encourage including: (Larsen citation is included elsewhere in this publication already).

Mattano LA DM, Friedmann AM, et al: Outstanding Outcome for Children with Standard RiskLow (SR-Low) Acute Lymphoblastic Leukemia (ALL) and No Benefit to Intensified PegAsparaginase (PEG-ASNase) Therapy: Results of Children’s Oncology Group (COG) Study AALL0331. Blood 111:5477-5485, 2014 3.

Larsen RA SW, Devidas M, et al: Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. J CLin Oncol 29:Abstract 3, 2011

Line 75-77: Paragraph: Looking forward, we anticipate….” Consider adding FISH, chromosomal analysis and specific, targeted molecular testing such as BCR-ABL as historic modalities for evaluating for residual leukemia.

Section: “Improvements to Risk Stratification and Biological Classification”: While not necessary for the scope of the paper. Consider acknowledging that the field is learning about interactions between genetic mutations. For example, certain mutations initially thought to be high risk, may only be so when paired with other mutations. This is already broadly implied by the authors in the last paragraph of this section but is an area of considerable research.

Section: “Incorporation of Novel Agents”: Consider adding a comment about alternative agents that are could be used to replace chemotherapy with high rates of adverse events such as the substitution and possible replacement of pegaspargase with erwinia chrysanthemi, which was recently approved by the FDA. NCT04145531.

Section: “Cellular therapy”: I would consider acknowledging that the depth of remission has also impacted transplant outcomes and may direct the intensity of relapsed therapy. Cite:

Pulsipher MA, Han X, Maude SL, Laetsch TW, Qayed M, Rives S, Boyer MW, Hiramatsu H, Yanik GA, Driscoll T, Myers GD, Bader P, Baruchel A, Buechner J, Stefanski HE, Kalfoglou C, Nguyen K, Waldron ER, Thudium Mueller K, Maier HJ, Kari G, Grupp SA. Next-Generation Sequencing of Minimal Residual Disease for Predicting Relapse after Tisagenlecleucel in Children and Young Adults with Acute Lymphoblastic Leukemia. Blood Cancer Discov. 2022 Jan;3(1):66-81. doi: 10.1158/2643-3230.BCD-21-0095. Epub 2021 Dec 1. PMID: 35019853; PMCID: PMC9924295.

Line 176: “Beyond HCT….”: Would be sure to include sentinel CAR T-cell trial leading to FDA approval.

Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. PMID: 25317870; PMCID: PMC4267531.

Line 197: A primary area of investigation….” Consider mentioning there are patient subgroups that may not benefit from CAR such as those who have not responded to blina.  

Myers RM, Taraseviciute A, Steinberg SM, Lamble AJ, Sheppard J, Yates B, Kovach AE, Wood B, Borowitz MJ, Stetler-Stevenson M, Yuan CM, Pillai V, Foley T, Chung P, Chen L, Lee DW, Annesley C, DiNofia A, Grupp SA, John S, Bhojwani D, Brown PA, Laetsch TW, Gore L, Gardner RA, Rheingold SR, Pulsipher MA, Shah NN. Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL. J Clin Oncol. 2022 Mar 20;40(9):932-944. doi: 10.1200/JCO.21.01405. Epub 2021 Nov 12. PMID: 34767461; PMCID: PMC8937010.

Also consider mentioning the potential to develop new CAR constructs that are not as susceptible to exhaustion and tumor microenvironment such as syn-notch CARs. This is largely pre-clinical but is an area of ongoing investigation.

Choe JH, Watchmaker PB, Simic MS, Gilbert RD, Li AW, Krasnow NA, Downey KM, Yu W, Carrera DA, Celli A, Cho J, Briones JD, Duecker JM, Goretsky YE, Dannenfelser R, Cardarelli L, Troyanskaya O, Sidhu SS, Roybal KT, Okada H, Lim WA. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci Transl Med. 2021 Apr 28;13(591):eabe7378. doi: 10.1126/scitranslmed.abe7378. PMID: 33910979; PMCID: PMC8362330.

Line 93-94: “Hyperdiploid patients”. Consider revising: "Patients with hyperdiploid disease" to avoid identifying a patient as a disease. 

Author Response

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Reviewer 2 Report

I consider that the manuscript presented by Talleur et al., is adequately presented, with clear and specific ideas for the topic and for the type of article presented ("commentary"). I have no observations to make to improve the manuscript.

Author Response

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Reviewer 3 Report

Minor Comments.

1-) I would add a Question Mark at the end of the title.

2-) Row 54. I would include the chemo-immunotherapy into the therapeutic strategies.

3-) Row 90. Please reformulate the sentence. Low-level MRD can not be associated to an "adverse prognostic significance". 

4-) Row 93. I would use "are not" (instead of aren't).

5-) Row 128. I think that "disease" before "states" is repetitive. 

6-) Row 131. Maybe the authors intend "low disease level"?

7-) Row 138. "We anticipate current and future studies evaluating" (not "will evaluate").

Author Response

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