Prognostic Impact of Serum β₂-Microglobulin Levels in Hodgkin Lymphoma Treated with ABVD or Equivalent Regimens: A Comprehensive Analysis of 915 Patients

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a well performed and presented study addressing the utility of beta2 microglobulin testing for prognostication of cHL. Although the idea is not new, this is the largest study covering all significant clinical, laboratory and histology data. The authors make a clear conclusion with mentioning some of the critical points of their studies. A long term correlation with earlier data published is also a valuable part of the paper.

My only suggestion concerns the editing of the results: data are presented for both FFP and OS in a continous fashion which is difficult to follow. Subchapters should be created under these separate categories by consistent renumbering: 

3.3 Freedom From Progression, followed by subchapters 3.3.1 All Patients, 3.3.2 Early stages, etc. and similarly

3.7 Overall Survival, 3.7.1 All Patients, 3.7.2 Early Stages... etc.

 

Comments on the Quality of English Language

No specific concerns

Author Response

Comment #1: The structure of the manuscript was modified according to reviewer’s suggestion.

Reviewer 2 Report

Comments and Suggestions for Authors

1. This was a retrospective study, the authors should clearly state this.

2. The Etical Committe approval, and consent form of the patients should be added.

3. No data are given, regarding a possible correlation between serum β2-Microglobulin and total metabolic tumor volume at FDG PET at baseline.

4. No data are given, regarding a possible cerrelation between serum  β2-Microglobulin level and ct-DNA.

Comments on the Quality of English Language

Minor revision

Author Response

Comment #1: The retrospective nature of the study was reported clearly (see Patients and Methods, first paragraph).

Comment #2: We added the sentence: “The study was approved by the appropriate Institutional Review Board. As a non-interventional retrospective study, informed consent was waived”.

Comments #3 and 4: Unfortunately there are no data regarding a possible correlation of serum beta-2 microglobulin levels and total metabolic tumor volume (TMTV) and circulating tumor DNA. As serum beta-2 microglobulin levels were correlated with almost all factors reflecting disease extent and aggressiveness, a strong correlation with TMTV and total lesion glycolysis (TLG) is rather predictable, but this does not exclude its independent prognostic contribution. These associations should be evaluated in future studies. These considerations have been added in the Discussion as follows: “. In addition, as novel prognostic factors appear, their correlation with sβ₂m should be accurately determined. Unfortunately, there is no data regarding the correlation of sβ₂m neither with the circulating tumor DNA[70,71] and its changes during treatment nor with PET metrics including baseline total metabolic tumor volume (TMTV)[72-76], total lesion glucolysis (TLG)[77,78] or tumor distance[79-81]. As sβ₂m levels correlated strongly with almost all baseline features reflecting disease extent and aggressiveness in this study, it is reasonable to hypothesize s strong correlation with PET metrics, which however does not exclude the persistence of the independent prognostic significance of sβ₂m. As sβ₂m levels correlated strongly with almost all baseline features reflecting disease extent and aggressiveness in this study, it is reasonable to hypothesize s strong correlation with PET metrics, which however does not exclude the persistence of the independent prognostic significance of sβ₂m.”.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

- The period of the study, i.e., the time of the collection of the date from .... to ..., should clearly state in the Material and Methods section and in the Results section;

- Was the sample size based on the number of patients collected or on the specific period of time pre-established?

- The Discussion and Conclusion section should be improved, adding in the text the reference of Pepe F, et al. (Cytopathology. 2023 Jun 21. doi: 10.1111/cyt.13255) on liquid biopsy in Hodgkin lymphoma, and the reference of Picardi M et al (Eur J Cancer. 2020 Jun;132:85-97. doi: 10.1016/j.ejca.2020.03.008. Epub 2020 Apr 23) on the prognostic role of FDG PET at the end of treatment with ABVD.

Comments on the Quality of English Language

Minor editing

Author Response

Comment #1: We modified the text as follows: "We analyzed 915 patients who received a diagnosis and first-line treatment for HL between 1990 and 2019, and had available sβ₂m levels at diagnosis. The study period was extended from the beginning of sβ₂m levels determination in clinical practice until the change of the method of sβ₂m measurement implying a different cutoff in 2019.".

Comment #2: No sample size calculation was applied. The study period was extended from the beginning of sβ₂m levels determination in clinical practice (1990) until the change of the method of sβ₂m measurement implying a different cutoff in 2019. All consecutive patients with available sβ₂m levels during that period were included. 

Comments #3: The suggested references were incorporated in the conclusion. The second one was supported by the sentence: "Similar considerations apply regarding the potential association of sβ₂m levels with the results of end-of-treatment PET.".

 

70. Picardi M, Fonti R, Della Pepa R, et al. 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography Deauville scale and core-needle biopsy to determine successful management after six doxorubicin, bleomycin, vinblastine and dacarbazine cycles in advanced-stage Hodgkin lymphoma. Eur J Cancer. Jun 2020;132:85-97. doi:10.1016/j.ejca.2020.03.008
71. Pepe F, Giordano C, Russo G, et al. Liquid biopsy: A promising tool for driving strategies and predicting failures in patients with classic Hodgkin lymphoma. Cytopathology. Jun 21 2023;doi:10.1111/cyt.13255