ONC: Glutamine (2006)


Dickson TMC, Wong RM, Negrin RS, Shizuru JA, Johnston LJ, Hu WW, Blume KG, Stockerl-Goldstein KE. Effect of oral glutamine supplementation during bone marrow transplantation. J Parenteral Enteral Nutr. 2000;24(2):61-66.

PubMed ID: 10772184
Study Design:
Randomized Controlled Trial
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Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To evaluate the role of oral glutamine supplementation in bone marrow transplant patients.

Inclusion Criteria:
  • Bone marrow transplant (BMT) patient
  • Peripheral blood progenitor cell transplant (PBPCT) patient
  • Met criteria to receive the transplant
  • Signed consent forms.
Exclusion Criteria:
Patients excluded from transplantation protocol.
Description of Study Protocol:


  • Enrolled from June 1995 to August 1997 from the Stanford University Medical Center.


  • 58 BMT or PBPCT patients were enrolled into a prospective, double-blinded RCT with 29 receiving gln and 29 getting placebo.

Blinding used

  1. BMT or PBPCT patients were registered with data managers
  2. Randomized to receive glutamine or placebo. Matched according to:
    1. Graft
      1. Allogeneic
      2. Autologous.
    2. Preparative regimen
      1. Fractionated total body irradiation (FTBI)
      2. No FTBI.
  3. Data collection from medical record review also blinded from study drug.


Intervention/placebo was initiated the first day of the preparative regimen and continued until discharge or no later than 28 days after transplant.

  • Intervention
    • 30 g of pharmaceutical grade glutamine powder administered daily in 10 g doses
    • Powder (supplied by Ajinomoto USA, Inc, Teaneck, NJ) was mixed in a liquid or soft solid food chosen by the patient.
  • Placebo
    • Received powdered sugar mixed in a manner similar to that of the intervention.
    • Glutamine or placebo was stopped if a patient was not able to take oral intake until they were able to continue (it was usually not restarted).
  • Planned dose modification and withdrawal was not needed for this study.
  • TPN
    • Initiated when intake reached half their estimated needs.
    • Supplied 1.5 times basal energy requirements (calories)
    • Supplied 1.5 g protein/kg body weight per day
    • TPN was discontinued when patient consistently tolerated oral intake at least 50% of estimated calorie needs.
  • Mucositis Grading
    • Stanford University BMT toxicity scale
    • 0-1: Not considered significant
    • 2-4: Mucositis
    • Only grades 2-4 were used for # days of mucositis.
  • Other information collected
    • Daily stool output measurements >500 mL in 24 hours = diarrhea
    • Amount of glutamine taken daily recorded by patients and staff
    • Length of time to WBC engraftment (WBC>1000/mL3)
    • Whether or not resolution of mucositis occurred at the time of WBC engraftment
    • Lowest serum albumin
    • Cost of therapy
    • Tolerance and consumption of glutamine.

Statistical Analysis

  • Patient’s characteristics and outcomes of the two groups
    • All tests used:
      • Two-sided alternative hypothesis
      • Alpha level of 0.05
    • Wilcoxon’s rank sum test
    • Pearson’s ?2 test
    • Fisher’s exact test.
  • Probabilities of survival and relapse estimated with:
    • Product-limit method of Kaplan and Meier
    • Log-rank statistic.
  • Pearson’s correlation coefficient for correlation between glutamine dose and length of stay and days of TPN.
  • IRB approval.
Data Collection Summary:

Timing of Measurements

  • After consent: Complete medical history, physical exam and labs taken.
  • Various measures/outcomes evaluated daily for duration.
  • Drug consumption recorded daily during hospitalization.
  • All other information was obtained from medical record after discharge.

Dependent Variables

  • Glutamine supplementation.

Independent Variables

  • Number of days and highest level of mucositis
  • Duration of TPN
  • Length of hospital stay (LOS)
  • White blood cell count
  • Stool output (volume and number of days)
  • Serum albumin.

Control Variables

  • Graft type (autologous vs. allogeneic)
  • Preparative Regimen (FTBI vs. no FTBI).
Description of Actual Data Sample:

  • Initial N: 58
  • Attrition (final N): None withdrew; final N=58
  • Age: 17- 59
  • Location: Stanford University Medical Center inpatient and outpatients.

Subject Characteristics

Placebo (N=29)

Glutamine (N=29)





Acute lymphocytic leukemia




Acute nonlymphocytic leukemia




Chronic myelogenous leukemia




Myelo dysplastic syndrome




Multiple myeloma




Non-Hodgkins lymphoma




Admission weight (kg)

82.9 (54.5-12.5)

69 (42.5-114.1)


Median Age (y)

48 (21-59)

46 (17-58)














Regimen Type












Graft type












Disease Status




Early (1 chronic remission/1 chronic phase)




Advanced (>1 chronic remission/1 chronic phase)




Multiple myeloma








[Adapted from Table I presented in publication.]

Summary of Results:

Placebo (N=29)
Median (range)

Glutamine (N=29)
Median (range)


TPN (d)

13 (0-33)

12 (0-36)


Days oral intake >1 L

7.5 (0-29)

11 (0-30)


LOS (d)

19 (3-53)

21 (4-41)


Days of mucositis

13 (0-31)

13 (0-37)


Mucositis grades

2 (0-4)

3 (0-4)


Mucositis grades 2-4 (%)




Days of stool >500 mL

2 (0-14)

3 (0-9)


Stool volume in mL

3170 (2075-22535)

3900 (0-11215)


Total consumed (g)

210 (10-840)

180 (0-550)


Lowest albumin (mg/dL)

2.8 (1.5-3.4)

2.9 (2.1-3.7)


Highest creatinine (mg%)

1.1 (0.5-5.5)

1.1 (0.5-4.8)


Highest total bilirubin (mg/dL)

1.1 (0.4-37.9)

1.4 (0.5-19.3)


Days to WBC engraftment

10 (7-29)

9 (7-29)


Follow-up (mo) median    




2-year survival




Number relapsed












TPN (d)

7.5 (0-24)

10.5 (0-36)


LOS (d)

17 (3-30)

18 (4-41)










TPN (d)

22 (9-33)

22 (9-36)


LOS (d)

32 (17-53)

31 (16-39)


Other Findings

  • No significant differences between placebo and glutamine groups were demonstrated
  • Some nonsignificant trends in patients who consumed >0.285 g glutamine/kg daily toward (that are consistent with other results that show the response to gln is dose related):
    • Decreased length of stay by six days
    • Decreased median days of TPN by 3.5 days.
  • It “seemed” that FTBI limited the patient’s ability to take the glutamine throughout study.
Author Conclusion:
  • The appropriate timing, duration and route of administration of oral glutamine supplementation along with the clinical tools for evaluating effectiveness remain to be determined.
  • There was difficulty in maintaining oral intake and tolerance of gln.
  • A combination of gastrointestinal “tolerance” measures will need to be considered in future studies:
    • Volume and number of days of diarrhea
    • Antidiarrheal medicine type and amount used
    • Grades of and number of days of mucositis
    • Amount and type of pain medicine used for mucositis
    • Number of days of TPN
    • Number of days until oral intake returns to a standard level
    • LOS.
Funding Source:
University/Hospital: Small Grants Program, Stanford University Hospital's Nursing Management Department
Reviewer Comments:
  • Hypothesis was not clearly stated, although the roles of glutamine being investigated was inferred from statistical analysis/results discussion.
  • The purpose of recording the various outcomes described in the results was not clearly explained.
  • Funding source was a small grants program of Stanford University Hospital's Nursing Management Dept.

Positive points

  • Dosed gln by body weight
  • Had actual amount of gln consumed.


  • Did not use WHO or NCI grading for mucositis.
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? Yes
  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) No
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  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? N/A
  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? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  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%.) Yes
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  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? Yes
  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? N/A
  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? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  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? N/A
  6.6. Were extra or unplanned treatments described? N/A
  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? Yes
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? Yes
  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)? Yes
  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? Yes
  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