Development and Validation of a Concise Objectifiable Risk Evaluation Score for Non-Relapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation

Reviewer 1:

Comments 1: Of risk factors, categories of albumin, creatinine, LVEF, vital capacity, and FEV1 are too busy. I suggest making categories more simplify may proper to analyze.

Response 1: -  We have modified Table 2 accordingly to improve readability

Serum albumin

    Serum albumin ≥LLN

reference

0

    Serum albumin <LLN-30g/L

1.29 (0.77-2.15)

1

    Serum albumin <30-20g/L

1.60 (0.91-2.81)

1

    Serum albumin <20g/L

3.47 (0.42-28.53)

3

Serum creatinine

    Serum creatinine ≤ULN

reference

0

    Serum creatinine >ULN-1,5xULN

1.86 (1.09-3.17)

1

    Serum creatinine >1,5xULN

2.21 (0.66-7.35)

2

Left ventricular ejection fraction (LVEF)

    LVEF >50%

reference

0

    LVEF 50-40%

1.62 (0.77-3.4)

1

    LVEF <40%

1.63 (0.52-5.13)

1

Patient age

    Patient age <60 years

reference

0

    Patient age 60-69 years

1.56 (0.95-2.55)

1

    Patient age ≥70 years

2.14 (1.23-3.75)

2

Forced expiratory volume (FEV1)

    FEV1 ≥60%

reference

0

    FEV1<60%

1.45 (0.72-2.91)

1

Vital capacity (VC)

    VC ≥75%

reference

0

    VC <75%

1.43 (0.79-2.59)

1

C-reactive protein (CRP)

    CRP <6mg/L

reference

0

    CRP ≥ 6mg/L

1.25 (0.8-1.96)

1

ULN - upper limit of normal, LLN - lower limit of normal

Adjusted for disease risk

For the training cohort with n=553

Dear Editors,

Dear Reviewers,

Thank you very much for taking time to review or manuscript and for giving us the opportunity to resubmit after minor revisions. Below is a point-by-point address of the Reviews’ comments.

We hope you now find our manuscript acceptable for publication in Cancers.

Kind regards,

Gunnar Weise

Reviewer 2:

Comments 1: Is it possible that myeloma patients are more likely to have hypoalbuminemia overall, causing their CORE scores to appear high?

Response 1: Reasons for hypoalbuminemia could for example be kidney injury (as in myeloma patients), inflammation (negative acute phase protein), malnutrition or diarrhea. We did not analyze the cause of hypoalbuminemia in individual patients.

Comments 2: Was the CRP measurement method used this time a low-sensitivity method rather than a high-sensitivity method?

Response 2: Measurement method of serum C-reactive protein (CRP) was a low and not a high-sensitive method. The Cut-off for the used measurement method is 5.0 mg/dl. CRP levels above 5.0mg/dl indicate infection or other inflammation.

Comments 3: Creatinine may be underestimated if the patient are large. Please tell me the authors' views on this point.

Response 3: We agree with the reviewer that serum creatinine is influenced by multiple factors such as gender, muscle mass, age and physical activity. Additionally, it lacks sensitivity in minor changes of renal function and low muscle mass of cachectic patients. Still, serum creatinine is the most widely used parameter of renal function and can thus be accessed by any laboratory in a simple and fast manner. Alternatively, other estimates of renal function such as estimated Glomerular Filtration Rate (eGFR) or serum Cystatin-C are either dependent on serum creatinine (eGFR) or not commonly used in monitoring practices (Cystatin-C). In case of the CORE HCT Score, our main goal is to provide an easy and objectifiable risk evaluation tool that is widely accessible. We believe renal dysfunction, as a key driver of morbidity and mortality after allogeneic stem cell transplantation, should be assessed and depicted by such a tool to provide risk information to the transplanting practitioner.

Dear Editors,

Dear Reviewers,

Thank you very much for taking time to review or manuscript and for giving us the opportunity to resubmit after minor revisions. Below is a point-by-point address of the Reviews’ comments.

We hope you now find our manuscript acceptable for publication in Cancers.

Kind regards,

Gunnar Weise

Reviewer 3:

Comments 1: This prognostic factor predicted clearly NRM just after allo-SCT was done. I considered that this prognostic model predicted especially NRM within day180 considering the survival curve. During this period, the main causes of death were infection and acute GVHD. Therefore, this prognostic model might predict NRM due to infection and acute GVHD. The author should describe the cause of death in detail.

Response 1: We agree with the reviewer, that NRM occurs mostly during the first 180 days. This is the case in our cohort as is in allogeneic transplant in general. As in other studies, acute GVHD and infection are the main causes of NRM in our cohort. We did not train or validate the models in our analysis for individual causes of death. This would be a thought for future analysis.

Comments 2: The author should describe the prophylaxis for acute GVHD.

Response 2: We have included the following statement in the methods section: “GVHD prophylaxis included cyclosporine A and mycophenolic acid in 97% and ATG in 81% of the patients” (Lines 71-72)

Comments 3: When were the Cr, Alb, and CRP levels evaluated? At diagnosis or just before conditioning treatment started?

Response 3: For more clarity, the statement in the methods section has been modified to read as follows: “The timepoint for data collection was the date of hospital admission for allo-HCT. In case of prior hospitalization of the patient, results from the last check-up prior to start of conditioning were used” (lines 76-78)

Dear Editors,

Dear Reviewers,

Thank you very much for taking time to review or manuscript and for giving us the opportunity to resubmit after minor revisions. Below is a point-by-point address of the Reviews’ comments.

We hope you now find our manuscript acceptable for publication in Cancers.

Kind regards,

Gunnar Weise

Reviewer 4:

Comments 1: Line 69: One should mention both lower (18 years old) and upper age limits for allo-HCT patients in training and validation groups (median of 58 y.o. in Table 1).

Response 1: Age range for the training and validation cohorts has been included in table 1 as suggested by the reviewer

Comments 2: Line 77. A common list of exclusion criteria should be also presented (or referred) under Methods.  

Response 2: The statement in the methods section has been modified to read: Consecutive adult patients (≥ 18 years old) with malignant hematological diseases (AML, ALL, CML, MDS, MPN, Multiple Myeloma or lymphomas, (Table 1)) who underwent an allo-HCT between 2013 and 2020 were included, all other patients were excluded.

Comments 3: Line 70 (Patient cohort): The criteria of non-relapse mortality in multiple myeloma and non-Hodgkin’s lymphoma could be provided in more details (defining the relapse criteria). 

Response 3: We have included the following statement in the statistics section to clarify that NRM also includes death without progression, e.g. for patients not in complete remission (line 108): “NRM was defined as death without relapse or progression of underlying disease”.

Comments 4: Lines 153, 159. What was the impact of early transplant-related mortality (TRM) upon the 2-year survival (Fig.1, Table 3). 

Response 4: NRM occurred mostly within the first 6 months. The purpose of our current study was to develop and validate a score that predicts overall NRM to improve patient selection and counselling. We did not examine specific causes of mortality or study the impact of the CORE score on early vs. late mortality. We will address these in future studies.

Comments 5: Line 119:  … with the category above them… may be, …in higher (or broader) category…?

Table 2: Abbreviation for Vital capacity (VC) should be deciphered here for better understanding.

Response 5: Thank you, we modified the mentioned section and the table accordingly.