Delayed Neurologic Response to Dabrafenib and Trametinib in the Case of Mixed Histiocytosis (LCH/ECD): Case Report and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

I invite the authors to conduct a general review of the English language and to reformulate the introduction and discussion to make the reasoning more fluid, according to which the limited improvement may be attributable to the delayed initiation of targeted therapy. I suggest to also include 10.1016/j.bneo.2024.100023.

In addition, a general review of the language is welcome, focusing on the consistency of verb tenses.  I have highlighted the parts where rewording would be particularly welcome.

Comments for author File: Comments.pdf

Author Response

Comments 1: I invite the authors to conduct a general review of the English language and to reformulate the introduction and discussion to make the reasoning more fluid, according to which the limited improvement may be attributable to the delayed initiation of targeted therapy. I suggest to also include 10.1016/j.bneo.2024.100023.

Response 1: 

We have revised the highlighted parts from Reviewer 1 as follows:

Line 62: The patient was unable to walk even with the assistance of a walker and could not maintain a stable sitting position.

Line 77-79: At this point, the neurological symptoms remained unchanged. PET/CT demonstrated complete metabolic remission (CMR; Deauville score [DS] 1–2) in the bilateral long bone lesions, whereas partial remission (PR; DS 4–5) persisted in the maxillomandibular bone lesions.

Line 126-129: After 21 months of treatment with Dab/Tra, her ataxia, spastic gait, and dysarthria persisted. She lived alone, as both of her daughters were married and lived far away. At home, she ambulated by holding onto handrails and was able to manage toileting and bathing independently. When going out, she used a wheelchair for short distances and was usually driven by others for longer travel.

Line 143-144: In contrast, the combination of Dab/Tra was hypothesized to provide more rapid neurological improvement owing to dabrafenib’s superior CNS penetration compared with vemurafenib.

Line 171-172: In contrast to these earlier cases, our patient began Dab/Tra therapy six years after the onset of neurological symptoms (Table 3). Partial and transient improvement in neurological symptoms was observed after seven months of treatment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

1)The text states that at 18 months the scores had not improved and SARA 21/40 and ICARS 33/100 are reported (baseline), but Table 1 reports SARA 14/40 and ICARS 29/100 at 18 months and SARA 17/40 and ICARS 31/100 at 24 months. This appears to be a reporting error that must be correct. Consider to include a single table or figure with all timepoints, indicating also if there were intra or inter-rater variations or intercurrent clinical conditions.

2)It would be interesting to explain the clinical reasons for slow titration, if the patients had any comorbidities (from text"..Doses of Dab/Tra gradually increased...with concerns for drug toxicity...[line 92-93]) and patient adherence to therapy.

3)Line 187: correct vemrafenib to vemurafenib.

 

 

Author Response

Comments 1: 

1) The text states that at 18 months the scores had not improved and SARA 21/40 and ICARS 33/100 are reported (baseline), but Table 1 reports SARA 14/40 and ICARS 29/100 at 18 months and SARA 17/40 and ICARS 31/100 at 24 months. This appears to be a reporting error that must be correct. Consider to include a single table or figure with all timepoints, indicating also if there were intra or inter-rater variations or intercurrent clinical conditions.

Response1 :

We have stated that after 18 months, her SARA score was 14/40, but ICARS score 29/100, and at 24 months, her SARA score 17/40 while ICARS score 31/100, indicating that there were some contradictory results between SARA and ICARS scores. Clinically, her ataxia, spastic gait, and dysarthria persisted even after 21 months of Dab/Tra treatment as stated below.

Comments 2：

2) It would be interesting to explain the clinical reasons for slow titration, if the patients had any comorbidities (from text"..Doses of Dab/Tra gradually increased...with concerns for drug toxicity...[line 92-93]) and patient adherence to therapy.

Response 2:

We have explained the reason why we started slow increase of the Dab/Tra doses, as one major reason was that she lived far away and was only able to visit our hospital every one to two months. (Line 93-94). We also commented in Discussion that We did not consider gradual increase of Dab/Tra doses was responsible for this delay. (Line 181).

Comments 3:

3) Line 187: correct vemrafenib to vemurafenib.

Response 3: We have corrected as vemurafenib.

Author Response File: Author Response.docx