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CBS Journal Club

CBS Journal Club. Christopher Sharpe MD, FRCPC R7 Transfusion Medicine October 4, 2011. 1. Objectives. to highlight the clinical implications of neutropenia

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CBS Journal Club

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  1. CBS Journal Club Christopher Sharpe MD, FRCPC R7 Transfusion Medicine October 4, 2011 1

  2. Objectives • to highlight the clinical implications of neutropenia • to systematically review the literature to assess the potential benefit of granulocyte transfusions given as prophylaxis against infection in the setting of neutropenia • critical appraisal of a systematic review

  3. Focus of Journal Club “Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction (Review)” Massey E, Paulus U, Doree C, Stanworth S The Cochrane Collaboration 2009

  4. Introduction • infections in the setting of neutropenia are often severe and life-threatening despite appropriate antimicrobial therapy • neutropenia is usually encountered post-chemotherapy or post-hematopoietic stem cell transplantation • G-CSF does not lead to appreciable granulocyte production in the setting of neutropenia

  5. Introduction • granulocyte transfusions may be potentially beneficial to neutropenic patients (prophylactic vs. therapeutic) • however...granulocytes for transfusion purposes are difficult to procure/process/store: - apheresis procedure is required (takes several hours) - separation of the granulocyte component is difficult - donor exposure to G-CSF (? safety concerns) - difficulty in securing donors (random vs. directed) - granulocytes have a finite storage period at room temperature (several hours) - product irradiation required (risk of TA-GVHD) - cross-match compatible product required

  6. Introduction • dose of transfused granulocytes is important • studies performed prior to the availability of G-CSF involved granulocyte dosages that were lower than the minimally acceptable dose of 1 x 1010 cells per transfusion and showed no benefit (Cochrane Reviews: Vamvakas 1997 Stanworth 2005) • the use of granulocyte transfusion disappeared from clinical use from ~1985-1995 due to improvements in antimicrobials and supportive care

  7. Introduction • However... • a single donor stimulated with G-CSF and steroids can procure a granulocyte dose of 5-10 x 1010 (renewed clinical interest in this area) • Adkins (1997) reported a mean ANC increment of 1000/microL that was maintained for 1 to 1.5 days with a mean granulocyte dose of 5.1 x 1010 • limited evidence exists to demonstrate that transfused granulocytes maintain their function

  8. Determinants of the efficacy of prophylactic granulocyte transfusions: a meta-analysis Vamvakas EC, Pineda AA. Journal of Clinical Apheresis 1997; 12:74-81 • Objective: meta-analysis of studies of prophylactic granulocyte transfusions to identify the determinants of efficacy of this intervention • Selection Criteria: RCTs from 1970-1995 involving the efficacy of prophylactic granulocyte transfusions • Results: 8 RCTs eligible. Transfusion of adequate doses of granulocytes reduced the RR of infection, death, and death from infection in transfused patients vs. controls (RR=0.075, 0.224, 0.168, respectively; P<0.05)

  9. Granulocye transfusions for treating infectons in patients with neutropenia or neutrophil dysfunction Stanworth S, Massey E, Hyde C, et al. Cochrane Database Syst Rev 2005 • Objective: To determine the effectiveness of granulocyte transfusions compared to no transfusion for treating patients with neutropenia • Selection Criteria: RCTs involving THERAPEUTIC granulocyte transfusions to patients with neutropenia • Results: 8 RCTs involving 310 patients

  10. Granulocye transfusions for treating infectons in patients with neutropenia or neutrophil dysfunction Stanworth S, Massey E, Hyde C, et al. Cochrane Database Syst Rev 2005 • Results: RR for mortality for 6 trials was 0.64 in favour of transfusion (95% CI 0.33-1.26); chi-square 11.3; I2=56% (significant clinical heterogeneity between studies) - RR for mortality for 4 studies that transfused granulocyte doses greater than 1.0 x 1010 was 0.37 (95% CI 0.17-0.82); chi-square 3.9; I2=23% • Conclusion: Inconclusive evidence exists from RCTs to support or refute the use of granulocyte transfusions in neutropenic patients

  11. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia Mohan P, Broklehurst P, Cochrane Database Syst Rev 2003 Mar 16; 3 • Objective: To determine the efficacy and safety of granulocyte transfusions as adjuncts to antibiotics for the TREATMENT of confirmed or suspected sepsis in neonates with neutropenia in reducing all-cause mortality (and several secondary outcomes) • Selection Criteria: RCTs and quasi-randomized studies involving neonates with suspected or confirmed sepsis and neutropenia who received granulocyte transfusions at any dose or duration compared with placebo or no granulocyte transfusion

  12. Granulocyte transfusions for neonates with confirmed or suspected sepsis and neutropenia Mohan P, Broklehurst P, Cochrane Database Syst Rev 2003 Mar 16; 3 • Results:- 4 RCTs involving 79 neonates - RR for all-cause mortality was 0.89 (95% CI 0.43-1.86) with no statistical heterogeneity in the results • Conclusion: Inconclusive evidence exists from RCTs to support or refute the use of granulocyte transfusions in neonates with sepsis and neutropenia to reduce mortality (and morbidity)

  13. Introduction • no systematic reviews examining the efficacy of PROPHYLACTIC granulocyte transfusions in the setting of neutropenia have been performed in over ten years (Vamvakas 1997) • no prior Cochrane review exists which examines the use of PROPHYLACTIC granulocyte transfusion in neutropenic patients using a significant number of trials that would have used G-CSF

  14. Focus of Journal Club “Granulocyte transfusions for preventing infections in patients with neutropenia or neutrophil dysfunction (Review)” Massey E, Paulus U, Doree C, Stanworth S The Cochrane Collaboration 2009

  15. Study Objectives • systematic review to assess the effectiveness and safety of prophylactic granulocyte transfusions in patients with neutropenia or disorders of neutrophil function compared with a control population not receiving this intervention for preventing: - mortality - mortality due to infection - evidence of infection - adverse events

  16. Cochrane Review: Outcomes • Primary Outcome: - overall mortality • Secondary Outcomes: - mortality due to infection - number of infections - number of days with fever - number of days on treatment with antimicrobials - neutrophil count increment post-transfusion (x109/L) - duration of neutropenia reversal after transfusion

  17. Cochrane Review: Outcomes • adverse events for patients or granulocyte donors - death - hospitalization - significant disability - requiring discontinuation of intervention

  18. Cochrane Review • Search strategy (up to October 2008): - the Cochrane Central Register of Controlled Trials (CENTRAL) 2008 - MEDLINE - EMBASE - other specialized databases (including ongoing trial databases) - contact with experts in the field - article reference list searches

  19. Cochrane Review • Study Selection Criteria: - studies involving patients with neutropenia or inherited disorders of neutrophil function (excluding neonates) in which granulocyte transfusions were given as prophylaxis prior to the development of documented infection compared to a control group not receiving granulocyte transfusions • RCTs and quasi-randomised, controlled studies (allocation to receive granulocyte transfusion was dependent upon the availability of suitably-matched donors)

  20. Cochrane Review • Control group: - prophylactic granulocyte transfusions were not administered • subgroup analysis: - performed on the study outcomes based on the dose of granulocytes transfused

  21. Cochrane Review • two review authors independently assessed studies for eligibility and extracted data onto study specific data extraction forms • criteria for evaluation of study methodological quality: - generation of allocation sequence - concealment of treatment allocation schedule - blinding of outcome assessment (for clinician, participant, and outcome assessor) - the proportion of randomized participants included in the main analysis

  22. Cochrane Review • studies were assigned a label of adequate, unclear, or inadequate for each of the criteria

  23. Cochrane Review • Study details collected: - place and date of publication - population characteristics - study setting - detailed nature of study intervention - detailed nature of study comparator - detailed nature of study outcome - use of therapeutic granulocyte transfusions during the study - use of colony-stimulating factors in recipients - use of prophylactic and therapeutic antimicrobials - method of preparation and source of transfused granulocytes

  24. Study Specific Data Extraction Form

  25. Cochrane Review • Review Manager 5 was used for data analysis - main method of analysis was qualitative (conclusions were based on the patterns of results across studies) • statistical heterogeneity between studies was tested using the chi-squared and I2 test (a statistical significance level of < 0.10 was interpreted as evidence of heterogeneity) • the main summary outcome was a summary risk ratio (dichotomous data) and a weighted mean difference (continuous data) - fixed and random effect models were used

  26. Cochrane Review: Included Trials

  27. Cochrane Review: Results • ten prospective clinical trials met inclusion criteria (8 from US, one from Spain, one from UK) • control arm received no prophylactic therapy except in one trial in which the control group received specific prophylactic antibiotics • all trials were conducted prior to 1987 with the exception of one trial from 2006

  28. Cochrane Review: Results • Granulocyte donor priming: - four trials did not administer any form of medication to the donors to increase the granulocyte yield • five trials administered steroids to donors- dexamethasone, hydrocortisone, prednisone • one trial administered G-CSF to donors (Oza 2006)

  29. Cochrane Review: Results • Granulocyte procurement method: - 8 trials used either intermittent or continuous flow centrifugation - one study used only filtration leukapheresis (FL) (Winston 1980); FL is rarely used currently - one study used both FL and continuous flow centrifugation (Clift 1978)

  30. Cochrane Review: Results • Granulocyte transfusion triggers: - 0.2 x 109 in two studies - 0.5 x 109 in six studies • Donor selection: - three studies did not assess leukocyte (HLA) compatibility between the granulocyte recipient and donor - seven studies selected donors on the basis of some criteria of HLA compatibility

  31. Cochrane Review: Results • most of the participants in the studies had acute myeloid leukemia (AML) +/- allogeneic stem cell transplantation

  32. Cochrane Review: Results • Study Sample Size: - the median number of patients enrolled, randomized and analyzed in all the studies was 55 (range 18-151) - only one trial (Oza 2006) made an attempt to justify the statistical analysis or required sample size (limited evidence was available from the remainder of the trials on sample sizes required to power the trial around a main outcome)

  33. Cochrane Review: Results • eight studies randomly allocated patients to receive prophylactic granulocyte transfusions with no other intervention • one trial (Oza 2006) was quasi-randomized (allocation to prophylactic granulocyte transfusion was based on ABO-matching and availability of donors) • one trial (Petersen 1987) randomized between prophylactic granulocyte transfusions and prophylactic systemic antibiotics (Vancomycin, Ticarcillin)

  34. Cochrane Review: Results • data on neutrophil increment one-hour post-granulocyte transfusion was available from five studies CCI = count increment (mm3) x body surface area (m2) divided by the number of granulocytes transfused (x 1010) • total number of granulocyte transfusions given per patient was 2 to 23 (the ten included studies had a variable transfusion schedule) • granulocyte dose varied between studies: - for nine studies the mean range was 0.9 x 1010 (Sutton 1982) to 5.9 x 1010 (Oza 2006) - one trial did not state dose (Petersen 1987)

  35. Cochrane Review: Results • differences were found between studies with respect to the cointerventions given to patients (antibiotics) • specific regimens for anti-fungal therapy (Amphotericin B) were stated explicitly in only two trials (Oza 2006, Winston 1980)

  36. Cochrane Review: Results • definition of infection used to recruit uninfected patients into the study or to identify those who became infected during study: - temperature - clinical signs of infection - isolation of organisms • different criteria for the definition of infection were used by the studies (such as fever definition)

  37. Comparison 1: Overall Mortality

  38. Comparison 2: Mortality due to Infection

  39. Comparison 3: Patients with infection episodes

  40. Comparison 4: Patients with fever

  41. Comparison 5: Patients starting antibiotics

  42. Cochrane Review: Results • Subgroup analysis - excluding trials which transfused granulocyte doses of < 1.0 x 1010 (Strauss 1981, Sutton 1982)

  43. Comparison 1: Overall Mortality, excluding low dose studies

  44. Comparison 2: Mortality due to infection, excluding low dose studies

  45. Comparison 3: Patients with infection episodes, excluding low dose studies

  46. Cochrane Review: Results • blinding was not achieved in the trials since it is diificult to apply in this setting • no data was available on whether or not outcome assessors were blinded in any of the trials • adverse event data was reported for all trials except one (Oza 2006) 3 4 3

  47. Cochrane Review: Results • a high rate of adverse reactions were seen in recipients of granulocyte transfusions: - fever - TA-GVHD (one death) - HLA-alloimmunization - pulmonary reactions • the predominant reactions for granulocyte donors were febrile/shivering episodes (reported in two trials) 3 4 3

  48. Cochrane Review: Conclusions • prophylactic granulocyte transfusions given to neutropenic patients at a dose of at least 1 x 1010 do not decrease the risk of overall mortality but may possibly reduce the risk of mortality from infection and reduce the number of infective episodes • the majority of studies included in this systematic review are dated and involved the transfusion of lower numbers of granulocytes than what is currently recommended; standards of supportive care have also improved 3 4 3

  49. Cochrane Review: Conclusions • granulocyte transfusions cannot be recommended outside the setting of a clinical trial due to the resource and cost implications:- small sample sizes in studies - heterogeneous study definitions of infection • larger clinical trials that are adequately powered are required before the potential benefits of granulocyte transfusions can be validated • an NHLBI sponsored RCT studying THERAPEUTIC granulocyte transfusion using currently available doses in neutropenic patients is currently underway in the USA 3 4 3

  50. Critical Appraisal: Systematic Reviews • Systematic review: using methods designed to reduce the likelihood of bias • Meta-analysis: a systematic review that uses quantitative methods to summarize the results 3 4 3

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