Precision Oncology in Hodgkin’s Lymphoma: Immunotherapy and Emerging Therapeutic Frontiers

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The present manuscript represents a brief review dealing with recent developments in Hodgkin’s lymphoma. It deals specifically with its epidemiology and the emerging immunotherapy. The review is concise (maybe too much so, it would benefit from more scope), containing interesting information concerning this disease and its therapy. The analysis of the epidemiological data is sound. It is generally well written; the language quality of the manuscript is good. I have only the following ‘technical’ remarks:

1. The abstract is over-sized. I would recommend reducing its size, especially since a considerable part of it is repeated exactly, word-for-word, in the Epidemiology section.
2. There is a similar problem with the Conclusion section – too much redundancy.
3. All tables and figures should be referenced within the text (they are not).

 

 

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

Overall, the review is impressively up-to-date and well-referenced, reflecting a strong grasp of contemporary trends in HL management. Below are key observations and recommendations, organized by section:

1. Genetic Risk Statistics (Line 58–60)

"a 13 fold increase in lifetime risk for first-degree relatives of HL patients, and a 57 fold increase for same-sex twins"

• Issue: It cites both a 3-fold and a 13-fold increased risk for first-degree relatives, which seems contradictory.
• Recommendation: Clarify whether the 13-fold increase refers to siblings only, or another subgroup. The original Kharazmi et al. (Blood 2015) paper can resolve this.

2. ICIs in Frontline Therapy (Lines 160–181)

• Issue: While SWOG S1826 is well-described, the paper claims:

“Nivolumab-AVD as the standard frontline regimen for advanced-stage HL”

This is slightly premature. While the data are compelling, official guidelines (e.g., NCCN, ESMO) may still list BV+AVD as an acceptable alternative.

• Recommendation: Consider rephrasing as:

“...is emerging as a new standard of care…”

3. Use of ctDNA as a Prognostic Biomarker

"...no relapses among patients who cleared ctDNA..."

• Issue: While promising, this statement might overstate certainty based on relatively small cohorts.
• Recommendation: Qualify with language such as:

“...suggesting ctDNA clearance may correlate with reduced relapse risk, pending validation in larger cohorts.”

4. AI in ICI Response Prediction (Lines 217–219)

“AI-driven models... show promise for predicting ICI response... though further validation is needed.”

• Issue: This is accurate, but consider noting the lack of prospective clinical trial integration for AI in HL thus far.
• Recommendation: Add:

“...though no AI-guided clinical trials in HL are yet underway.”

5. Late Immune-Related Adverse Events (Lines 221–230)

“...required intensive care... required indefinite therapy...”

• Issue: These outcomes, while illustrative, are anecdotal.
• Recommendation: Add a sentence:

“While these reports highlight potential severity, irAEs remain uncommon and largely manageable with steroids.”

6. CD30 CAR-T Therapy (Line 266 and Ref. 38)

• Issue: The statement implies broader efficacy than supported.
• Recommendation: Specify:

“CD30-directed CAR-T therapy has shown early efficacy in relapsed/refractory settings, though durability of response remains under study.”

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript reviews emerging immunotherapy in treating Hodgkin’s lymphoma (HL), thus potentially benefiting future studies. Yet, some amendments and additions are highly recommended for the interests of our future readers.

It is suggested to introduce some basic information about HL in section 1, such as the subtypes.

Reference (1) seems to be a key citation that appears multiple times in this review. Additional information beyond “NCI” is highly recommended, such as the database webpage etc.

It seems the age group recited in lines 24 and 100, is different from that in line 55 or 240, while all refer to the bimodal age distribution peaks. Would the authors mind sharing the reasons why?

Kindly clarify the 13-fold increase mentioned in line 59.

Supports/citations are needed for lines 131-135 and 148-152.

In addition to the ctDNA studies, would the authors mind expanding the precision medicine portion of the current review?

Is there any progress in early diagnosis in the field so far?

Also, the current abstract seems to simply repeat certain parts of the manuscript, such as the second paragraph of section 2 and section 3.2. A concise summary would be really appreciated.

Further, it is suggested that the full names of the abbreviations be provided upon and only upon their first appearance and that the same abbreviations, such as HL, ASCT, ICI, HLPHL, ctDNA, N+AVD, and AI, be used thereafter for consistency.

Author Response

Please see attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Many thanks for the authors’ amendments. Much appreciated. I do have some quick follow-up questions as detailed below.

Concerning Ref 1, my understanding is that in a review paper, the references are provided so that our future readers can dig more into the details if they are of any interest. Yet, I am not sure the currently provided “NCI. (National Cancer Institute, Bethesda, MD, 2025).” as Ref 1 will serve this function.

Concerning the bimodal age distribution, I am not sure if Figure 1 shows that the second peak falls between 50 and 60, as indicated in the text. It actually looks like 80-84.

Concerning the added sentence spanning lines 126-127, it is suggested to provide more details about how IPS is being used currently, for example, in Section 6.3 or 6.5.

Additionally, I am not sure if I missed something. It seems CAR-T therapies were never discussed except in the conclusion section. Is it possible to include some discussion in the earlier sections before drawing a conclusion in line 243?

Concerning acronyms, the full names of NLPHL, ASIR, and ICE are needed in lines 27, 67, and 191 (or Table 1), respectively. Also, since they have been provided in an earlier section, there is no need to provide the full names of ICIs, MRD, IPS, ctDNA, IPS, and MRD in lines 131, 137, 160, 204, 252, and 260, respectively. Further, the acronym of N+AVD used in lines 246, 248, and 258 is different from the version used in the earlier sections.

The () in line 132 seems unnecessary.

Author Response

Please see attachment.

Author Response File: Author Response.pdf