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ONC: Hematopoietic Cell Transplant (2006)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:
To assess the impact of oral protein intake on the risk of acute graft versus host disease (aGVHD) in patients with hematological malignancies undergoing allogeneic marrow transplantation.
Inclusion Criteria:
  • Hematological malignancy
  • Received an allogeneic marrow transplant at Fred Hutchinson Cancer Center between 1/1/85 and 7/30/05
    • IV cyclophosphamide 60 mg/kg on 2 successive days
    • Total body irradiation of 10 Gy in single exposure or 12.0-15.75 Gy given as 2.0 or 2.25 Gy/day for 6-7 days
    • Intrathecal methotrexate pre-transplant and every 2 weeks until day 102

                OR

    • Busulfan 4mg/kg/d for 4 days instead of irradiation followed by 50mg/kg of cyclophosphamide for 4 days
  • Successful engraftment (self sustaining granulocyte count exceeding 500x 106/L post infusion)
Exclusion Criteria:
  • Patients who expired within 14 days after marrow infusion
Description of Study Protocol:

Recruitment

The records of all patients with hematological malignancies that received an allogeneic marrow transplant at the Fred Hutchinson Cancer Center from 1/1/85 to 7/30/05 were reviewed for inclusion. Patients that acheived successful engraftment as identified by a self sustaining granulocyte count exceeding 500x 106/L post infusion were included.

Design

Information on disease, treatment, diet intake, and presence of aGVHD were collected retrospectively from patient medical records. Dietary intake was obtained from daily food records, assessment of aGVHD status was made based on standard criteria (published by Glucksberg et. al, 1974). Daily oral intake was combined over a 4 day period. aGVHD was also assessed on a 4 day interval. Relative risk was calculated for levels of protein intake within each time interval and in summary.

Blinding used (if applicable)

The determintaion of aGVHD status was made without knowledge of dietary protein intake.

Intervention (if applicable) Not applicable

Statistical Analysis

  • Relative Risk
  • Mantel-Hanzel analysis
  • Univariate Kaplan-Meyer survival analyses
  • Proportional hazards regression

 

 

Data Collection Summary:

Timing of Measurements

Data on dietary intake and and incidence of aGVHD were was collected daily for day of transplant to day 54.  There was no onset of aGVHD after day 52. Measurements wen subsequently combined into four day intervals.

Dependent Variables

  • Variable 1: Acute Graft versus host disease as measured by standard criteria (published by Glucksberg et. al, 1974)

Independent Variables

  •  Presence and amount of oral protein intake

 

Description of Actual Data Sample:

 

Initial N: 599 (sex not described)

Attrition (final N):

Total: 575 (334 males, 123 females) Sex breakdown unclear as it does not add up to the total final n.

aGVHD: 308 (185 Males, 123 Females)

Age:

Patient Age in Years

Age

Number studied
<20 206
20-29 158
30-39 134
>= 40 77

Total

 575

 

Ethnicity

Other relevant demographics:

Demographic n  
Disease:  
Acute Lymphoblastic Leukemia 146
Acute Nonlymphoblastic Leukemia 175
Chronic Myelogenous Leukema 161
Non- Leukemia 93
HLA Compatibility  
Identical Related 366
Non-identical Related 203
Non-identical Unrelated 6
Marrow Cell Dose  
<3.0 345
3.0-5.9 188
>= 6.0 38
GVHD Prophylaxis:  
None 2
Cyclosporin (CSP) 28
Methotrexate (MTX) 37
MTX + CSP 409
MTX + CSP + Prednisolone 83
T cell depletion 16
Laminar Airflow Isolation  
Yes 234
No 341
Year of Transplant  
1985 206
1986 245
1987 124
History of Food Allergy  
Yes 51
No 516

Grades of Graft versus Host Disease Experienced

Grade

n
 I 71 (23%)
II 112 (36%)
III 91 (30%)
IV 34 (11%)

 

Anthropometrics: 

Location: Fred Hutchinson Cancer Research Center, Seattle, Washington

 

 

Not Reported: Not reported
Summary of Results:

Oral Protein Intake Days 0-6 and Risk of Acute Graft Versus Host Disease

Variables

No Protein Intake

Any Protein Intake

Statistical Significance of Group Difference

Incidence of aGVHD

175 patients (50%) 

126 patients (58%)

p=0071

  • No relationship between protein intake and incidence of aGVHD (all stages)
  • In patients with grades II-IV aGVHD protein intake was associated with a decreased incidence of aGVHD
    • 43% patients consuming protein versus 53% patients not consuming protein (p=0.049)

Relative Risk of Acute Graft versus Host Disease in Four Day Intervals

Day

No Protein Intake n (%)

Some Protein Intake n (%)

Relative Risk (95% CI)

6-9

18 (7.9%)

16 (4.8%)

0.60 (0.31, 1.15)

10-13

69 (18.8%)

21 (12.8%)

0.68 (0.43, 1.07)

14-17

52 (15.7%)

4 (3.6%)

0.23 (0.09, 0.63)

18-21

30 (12.5%)

14 (10.4%)

0.83 (0.46, 1.51)

22-25

15 (9.9%)

16 (9.6%)

0.97 (0.50, 1.89)

26-29

5 (6.3%)

15 (8.7%)

1.39 (0.52, 3.69)

30-33

1 (2.4%)

6 (4.3%)

1.80 (0.22, 14.53)

34-37

1 (4.5%)

10 (10.1%)

2.22 (0.30, 16.47)

38-41

0

2 (3.1%)

 -

42-45

0

1 (2.0%)

 -

46-49

0

2 (6.3%)

 -

50-53

1 (6.7%)

1 (4.8%)

0.71 (0.05, 10.54)

  • For the first 3 time periods oral protein intake decreased the risk of developing aGVHD, however this protection disappears at later timepoints
  • Relationship similar if only grades II - IV GVHD analyzed
  • When protein consuming group is further broken down into levels of protein consumption (1-5g protein vs. >5g protein) the risk dropped further with increased protein intake.
    • With each gram increase in protein intake the RR decreased exponentally (-0.003).
  • In multivariate analysis the addition of confounding factors (age <20, HLA non-identical, steroid use, year of transplant, infection, and laminar airflow room) indicated a non-significant decrease in risk of developing GVHD
  • Continuous oral protein intake not significantly (p 0.067) associated with decreased RR of aGVHD(RR 0.99, 95% CI 0.99, 1.00)
  • Discrete oral protein intake not significantly (p 0.09) associated with decreased RR of aGVHD(RR 0.86, 95% CI 0.73, 1.01)

Other Findings:

  • Median day of onset of aGVHD: day 28 post transplant (range 5-52 days)
  • Children more likely to develop aGVHD than adults
  • The factors found to be significantly associated (p< 0.0001) with a risk of aGVHD included:
    • HLA mismatch (RR 3.01, 95% CI 2.38, 3.8)
    • Year 1987 (RR 2.06, 95% CI 1.57, 2.71)
    • Cyclosporin (RR 2.61, 95% CI 1.74, 4.14)
    • Prophylactic steroids (RR 0.53, 95% CI 0.34, 0.75) 

  Number Studied     Number with aGVHD     Percentage p Value
Disease:        
Acute Lymphoblastic Leukemia 146 84 58% 0.1881
Acute Nonlymphoblastic Leukemia 175 88 50%  
Chronic Myelogenous Leukema 161 91 57%  
Non- Leukemia 93 45 48%  
HLA Compatibility        
Identical Related 366 149 41% 0.0001
Non-identical Related 203 153 75%  
Non-identical Unrelated 6 6 100%  
Marrow Cell Dose        
<3.0 345 176 51% 0.076
3.0-5.9 188 105 56%  
>= 6.0 38 24 63%  
GVHD Prophylaxis:        
None 2 1 50% 0.0072
Cyclosporin (CSP) 28 22 78%  
Methotrexate (MTX) 37 18 49%  
MTX + CSP 409 231 56%  
MTX + CSP + Prednisolone 83 30 36%  
T cell depletion 16 6 37%  
Laminar Airflow Isolation        
Yes 234 117 50% 0.162
No 341 191 56%  
Year of Transplant        
1985 206 110 53% 0.0006
1986 245 119 49%  
1987 124 79 64%  
History of Food Allergy        
Yes 51 29 57% 0.610
No 516 277 54%  

Age and Incidence of aGVHD

Age

Number studied

Number with aGVHD

Percentage

p Value
<20 206 126 61% 0.062
20-29 158 79 50%  
30-39 134 69 51%  
>= 40 77 34 44%  

Total

 575 308 54%  
Author Conclusion:

Early post transplant enteral feeding does not seem to increase the risk of acute graft versus host disease. Early oral feeding may confer a protective effect and decrease the risk of developing aGVHD. Enteral feeding may assist in the restoration of the mucosal barrier thereby decreasing the risk of bacterial translocation. This decrease in bacterial translocation may be responsible for the decrease in aGVHD.  Further research including direct measures of intestinal response to oral/enteral intake are needed.

Funding Source:
Government: NIH
Reviewer Comments:
  • Included adults (n=369) and children (n = 206) under 20 years old
  • No information provided on:
    • Supplemental non-oral sources of calories such as IVF or PN
    • Ethnicity
    • Total caloric intake
    • Anthropometric measurments
    • Weight loss
    • Indices/Presence of malnutrition
  • Limited information on:
    • Exclusion criteria
    • Sex of patients (n in each cateogory does not add up to total n)
    • Location of patients (inpatient versus outpatient)
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
 
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? No
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) Yes
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? No
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? Yes
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? N/A
  4.1. Were follow-up methods described and the same for all groups? N/A
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) N/A
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? N/A
  4.4. Were reasons for withdrawals similar across groups? N/A
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? N/A
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) Yes
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? Yes
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? N/A
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? Yes
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? No
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? Yes
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? No
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? N/A
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? No
  8.7. If negative findings, was a power calculation reported to address type 2 error? No
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? Yes
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? Yes