ONC: Glutamine (2006)

Study Design:
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Quality Rating:
Research Purpose:

The purpose of the research was to determine whether supplementation of TPN with glutamine enhances the process of immune reconstitution and improves the mucositis score of patients undergoing high-dose chemotherapy and autologous peripheral blood stem-cell transplantation (aPBSCT) or immunoselected CD34+aPBSCT for hematologic malignancies.

Inclusion Criteria:
  • Patients admitted for selected or unselected aPBSCT at the Hematology Department, Catholic University A. Gemelli Hospital, Rome, Italy
  • Informed consent obtained from all patients/guardians.
Exclusion Criteria:

Not mentioned.

Description of Study Protocol:


  • Study 1: 27 consecutive patients of the Catholic University "A Gemelli" hospital, Rome, Italy, admitted to selected or unselected aPBSCT between October 1998 and August 1999
  • Study 2: 21 consecutive patients of the Catholic University "A Gemelli" hospital, Rome, Italy, admitted to selected or unselected aPBSCT beginning in September 1999.


  • Study protocol approved by institutional review board
  • The trial consisted of two consecutive randomized controlled studies.

Blinding used

  • Some study personnel were blinded
  • No specific statement on blinding.


Study One (October 1998 to August 1999)

  • 27 consecutive patients admitted for selected or unselected aPBSCT were randomized to one of two groups:
    • Study One Glutamine group, 12 patients
      • Received Glamin (Fresenius Kabi), a parenteral amino acid solution containing 20 g free glutamine, 1,000 mL/day, from Day +1 after aPBSCT
    • Study One placebo group, 15 patients
      • Received a placebo.
  • Daily parenteral nutrition regimen
    • Glutamine group
      • Intralipid: 10% (Fresenius Kabi), 500 ml
      • Glamin: (Fresenius Kabi), 1,000 ml
        • 18 essential and non-essential amino acids
        • 30.27 g stable glycil-L-glutamine
        • 10.27 g glycine
        • 20 g glutamine.
      • 33% glucose solution, 1,000 ml
      • Hydrosoluble and liposoluble vitamins.
    • Placebo group
      • Intralipid: 10% (Fresenius Kabi), 500 ml
      • Freamine: 8.5% (Fresenius Kabi), 1,000 ml
      • 33% glucose solution, 1,000 ml
      • Hydrosoluble and liposoluble vitamins.

Study Two (Beginning September 1999)

  • 21 consecutive patients admitted for selected or unselected aPBSCT were randomized to one of two groups:
    • 10 patients (Study Two Glutamine group)
      • Received Dipeptiven (Fresenius Kabi), a parenteral solution containing 13.46 g glutamine, 100 mL/day, from Day +1 after aPBSCT.
    • 11 patients (Study Two placebo group)
      • Received a placebo.
  • Daily parenteral nutrition regimen
    • Glutamine group:
      • Kabimix 1830 (Fresenius Kabi)
      • Dipeptiven (Fresenius Kabi), 100 mL
      • Hydrosoluble and liposoluble vitamins.
    • Placebo group:
      • Kabimix 1830 (Fresenius Kabi)
      • Hydrosoluble and liposoluble vitamins.

Interventions for all patients, both studies:

  • Prophylactic antibiotics
  • Broad-spectrum antibiotics for sustained fever >38° C
  • RBC infusions if RBC<8g/dL
  • Platelet infusions if platelets <15x109/L
    • All blood products were irradiated.

Statistical Analysis

Statistical significance defined as P<0.05

  • Analysis of continuous factors: Mann-Whitney U-test
  • Multiple comparisons: Kruskal-Wallace
  • Post-hoc evaluation: Dunn's test
  • Analysis of categorical factors: x2 test.

Data from Study One and Study Two were analyzed separately; then data from both studies was pooled and analyzed to check for consistency.

Data Collection Summary:

Timing of Measurements

  • Clinical outcomes were evaluated daily
  • Immune recovery was measured by lymphocyte subset analysis at baseline, 15, 30, 60, and 90 days
  • Mucositis was assessed daily.

Dependent Variables related to cancer symptoms (for both Study One and Study Two)

  • Variable One: Clinical outcomes
    • Days of hospitalization (in days)
    • Days of non-prophylactic antibiotics (in days)
    • Number of days with body temperature >38° (in days).
  • Variable Two: Immune recovery
    • Lymphocyte subset analysis
      • Measured by flow cytometry at baseline, 15, 30, 60, and 90 day.
  • Variable Three: Severity of mucositis
    • Measured daily from day 0 to discharge by Daily Mucositis Score (DMS).

Independent Variables

  • Study One: Glamin (Fresenius Kabi), a parenteral amino acid solution containing 20 g free glutamine, 1000 mL/day, from Day +1 after aPBSCT.
  • Study Two: Dipeptiven (Fresenius Kabi), a parenteral solution containing 13.46 g glutamine, 100 mL/day, from Day +1 after aPBSCT.

Control Variables

  • Study One: Placebo solution.
  • Study Two: Placebo solution.
Description of Actual Data Sample:

Initial and Final N (no attrition)

  • Study One: N=27
    • 12 treatment (five females, seven males)
    • 15 placebo (five females, 10 males).
  • Study Two: N=21
    • 10 treatment (five females, five males)
    • 11 placebo (three females, eight males).

Mean Age

  • Study One 
    • Treatment group: 37.5 years
    • Placebo group: 47 years.
  • Study Two
    • Treatment group: 31.5 years 
    • Placebo group: 49 years.


  • Not mentioned.

Other relevant differences between groups

  • There were no significant differences between the Study One and Study Two groups in age, sex, conditioning regimen, and diagnosis.


  • Hematology Institute, Catholic University "A Gemelli" Hospital, Rome, Italy.
Summary of Results:

Study 1 Results

Variable Glutamine Group Control Group Statistical Significance of Group Difference
Clinical Outcomes
Neutrophils* >0.5x109 (in days) 12 (10-21) 12 (9-21) P=0.69

Lymphocytes >0.5x109/L  (in days)

16.5 (10-27) 29 (12-50) P=0.005
Platelets >20x109/L  (in days) 12 (7-30) 12  (7-21) P=0.9
Days in hospital 27.5 (23-70) 25 (16-37) P=0.22
Days of non-prophylactic antibiotics 11 (5-15) 9.5 (4-22) P=0.66
Body temperature >38° (in days) 2 (0-17) 2 (0-10) P=0.6

Lymphocyte Subset Recovery

CD4+/µg  (at Day 30) 300 (86-882) 115 (47-360) P=0.014
CD16+CD56+/µg  (at Day 30) 156 (10-980) 319 (81-681) P=0.02
CD4+/CD8+ratio  (at Day 60) 0.35 (0.2-1.6) 0.25 (0.1-0.5) P=0.025
Daily Mucositis Score (peak scores) 3.5 (2-9) 5 (3-12) P=0.044

Mucositis Duration

10.5 (6-15)

13 (11-15)



















Study 2 Results

Variable Glutamine Group Control Group Statistical Significance of Group Difference
Clinical Outcomes
Neutrophils* > 0.5x109 (in days)     10 (8-19) 13 (11-22) P=0.001
Lymphocytes > 0.5x109/L  (in days) 18 (12-22) 29 (12-60) P=0.009
Platelets > 20x109/L  (in days) 13 (8-33) 13 (10-22) P=0.57
Days in hospital 29 (23-40) 27 (23-39) P=0.45
Days of non-prophylactic antibiotics 8.5 (0-6) 10 (5-15) P=0.64
Body temperature >38° (in days) 0.5 (0-6) 2 (0-5) P=0.38
Lymphocyte Subset Recovery
CD8+/µg  (at Day 15) 258.5 (48-1006) 50.5 (13-112) P=0.041
CD8+/µg  (at Day 30) 460 (306-1314) 266 (156-469) P=0.038
CD16+CD56+/µg  (at Day 60) 205 (10-300) 297.5 (221-800) P=0.029
Daily Mucositis Score (peak scores) 7 (4-8) 8 (5-11) P=0.12

Mucositis Duration

13 (10-21)

13 (10-22)



















*Measured as PMNs (polymorphonuclear granulocytes)

Summary of pooled data

  • Researchers pooled data from Study One and Study Two. Findings included:
    • Glutamine-supplemented patients had a significantly lower DMS on Day 10 (2 vs. 5; P=0.046), Day 11 (2 vs. 5; 0.016), and Day 12 (1.5 vs. 3.5; P=0.041)
    • Glutamine-supplemented patient days at peak mucositis score was significantly lower (6 vs. 7; P=0.047)
    • Glutamine-supplemented patients had better immune reconstitution:
      • Higher number CD4+ cells at Day +15 (106 vs. 59 cells/µg; P=0.016), Day +30 (191 vs. 116 cells/µg; P=0.026).
  • There were no other significant differences between the treatment and control groups when pooled data was analyzed.    


Author Conclusion:
  • Both studies showed that parenteral glutamine supplementation strongly improved immune reconstitution in autologous transplant patients, probably through rapid CD4+ subset reconstitution and the limiting of NK overshoot after transplant.
  • Both studies showed that parenteral glutamine supplementation significantly reduced peak mucositis and reduced the duration of mucositis and that the effect was dose-related.
    • Study One patients who received 20 g glutamine showed a significantly lower mucositis peak than placebo
    • Study Two patients who received 13.46 g glutamine showed a trend toward reduced mucositis peak.
  • Reduction of mucositis may result in better compliance with high-dose chemotherapy by reducing infections
  • Positive effects of parenteral glutamine supplementation were balanced by much higher costs of parenteral nutrition.
Funding Source:
University/Hospital: Hematology Institute
Reviewer Comments:
  • Discussion of blinding was not thorough
  • Implementation of the second study was not planned in the original study design
  • Both Study One and Study Two showed a large difference in mean age of treatment and control groups, suggesting that positive effects could have been related to difference in age
  • Generalizability of study may be limited by small sample of patients who received generally heterogenous conditioning regimens.
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? ???
  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) Yes
  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? N/A
  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%.) N/A
  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? ???
  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? Yes
  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? 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? 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? ???
  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)? ???
  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? N/A
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