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A Therapeutic Platelet Strategy

Journal Club – Feb 21, 2007

Kristine Roland MD FRCPCTM Resident, UBC

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Context

Prophylactic plt transfusion strategies for thrombocytopenic pts are standard practice

The appropriate plt count ‘trigger’ has evolved:

- Gaydos et al, NEJM 1962: observed that serious bleeding in pts with acute leukemia rare when plts > 20 x 109/L

- Numerous studies indicate threshold of 10 x 109/L is safe:Heckman KD et al, J Clin Oncol 1997

Rebulla P et al, NEJM 1997Zumberg MS et al, Biol Blood Marrow Transplant 2002Callow CR et al, Br J Haematol 2002

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Context

Does reducing the trigger from 20 to 10 improve plt utilization?

- Hersh et al 1998: mathematical modeling predicts a 14.5% decrease in plt utilization

- Rebulla 21.5% reduction in plt usageHeckman 35% fewer transfusions (not significant)Callow 36% reduction (compared to retrospective)Zumberg no difference

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Context

Other factors impact utilization: frequency of checking plt counts, development of additional risk factors for bleeding, compliance with guidelines

Two studies in the recent issue of Transfusion (Feb 2007) report poorer than expected compliance with prophylactic thresholds:

- Greeno et al – overall 28% compliance (up to 43% on Heme/Onc service)

- Cameron et al – overall 22% compliance (and reasons for non-compliance were poorly documented)

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Context

Mark Brecher editorial (Transfusion Feb 2007):

If goal is to reduce plt utilization, other approaches may need to be investigated

- Lower plt doses (PLADO study underway)

- Employing a therapeutic strategy vs the prophylactic strategy …

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The Study:

A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantation

Wandt H et alBone Marrow Transplantation (2006) 37:387-392

Objective: “ assess the safety and feasibility of a therapeutic platelet transfusion strategy”

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Population

Single-centre study from Germany 106 pts prospectively enrolled after 2001 Adults undergoing autologous PBSCT- range 18-70 years, median 54 years- male: female 2:1 - MM (43%), lymphoma (32%), acute leukemia (16%), solid

tumour (8%)- total of 140 transplant procedures (76 pts received 1

transplant; 30 received 2 or 3)- 87 pts received chemo; 19 pts received chemo +TBI

Exclusion criteria: AL-amyloid, aspergillus infxn, cerebral lesion, prior life-threatening bleeding during chemo

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Intervention

daily morning plt counts twice daily clinical exam for hemorrhage therapeutic platelet transfusion if bleeding

WHO ≥ grade II* prophylactic platelet transfusion if plt < 10 x

109/L and unstable†

all plts were ABO-compatible apheresis LR

PRBC transfusion to maintain Hb > 80g/L

Grade 0 None

Grade I Petechial

Grade II Mild blood loss

Grade III Gross blood loss

Grade IV Debilitating blood loss

†Definition of clinically unstable:Fever > 38.5 CSuspicious for aspergillus infectionSepsisCoagulation disorderPlanned surgery (goal plt count > 20)

*WHO Bleeding

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Matched pair analysis

Retrospectively reviewed 60 transplant procedures matched for the first 60 procedures in the prospective cohort

Matched for: gender, Dx, conditioning

These historical patients would have received prophylactic platelet transfusions routinely for morning plt < 10 x 109/L

Prospective 60 transplants(50 pts)

Retrospective 60 transplants(54 pts)

Median ageAge range

5518-67

4917-61

Female to male 21:29 25:29

MM or lymphomaAcute leukemiaSolid tumour

41109

41109

TBI conditioning 5 5

Table 4: Retrospective Analysis

Not comparedstatistically

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Results – Bleeding

Of the 140 prospective transplant procedures:

- 114 (81%) no bleeding- 28 (20%) WHO grade I

- 26 (19%) WHO grade II (mainly epistaxis, mucositis)

Of the 60 retrospective matched transplants:

- 20% WHO grade II- 1% WHO grade III

No. of thrombocytopenic days:plts < 20 plts < 106 (0-92) 3 (0-62)

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Results – Transfusions

48 (34%) of 140 transplants could be performed without a plt transfusion.

Of the total 235 plt units that were transfused:

81 therapeutic vs 154 prophylactic- main indications for prophylactic were fever and

septicemia- but 27% of transfusions given for no clear reason

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Analysis by Dx and conditioning

MMother

47%22%

P < 0.05

Non-TBITBI

37%0%

P < 0.05

Percentage of transplants (n = 140) NOT requiring platelet transfusion

TBI associated with increased mucositis-related bleeding

Mann-Whitney U-test

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Results – Transfusions

Prospective cohort (60 transplants)

Retrospective matched cohort (60 transplants)

Total plt transfusions

111 237

RangeMeanMedian

0-181.91

0-2743

Therefore the therapeutic strategy reduced total transfusions by ~50%

Comparison with 60 historical transplants:

Nostatisticalanalysis

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Authors’ conclusions

A therapeutic plt transfusion strategy is safe in autologous PBSCT patients

- No major bleeding (WHO grade III or IV)- Only 19% minor bleeding (WHO grade II)

A therapeutic strategy reduces the total number of plt transfusions compared to a prophylactic strategy

Pts treated with TBI conditioning regimens more likely to require plt transfusion

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Critical Appraisal Was there randomization?- No; prospective observational cohort (n=140) and a

smaller cohort (n=60) of matched historical transplants

Was follow-up complete?- In the prospective cohort, pts followed until plt count

> 20 for 2-3 consecutive days- No pts lost after enrolment

Was there blinding?- No; treating physicians needed to be aware of plt

transfusion protocol- Bleeding recorded by responsible physician and reviewed

by one of the authors (HW or KS)

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Critical Appraisal

Were the two groups matched?- First 60 transplants matched for gender, Dx, and TBI

conditioning but prospective cohort slightly older (mean 55 vs 49) – no p value given

- presumably the two groups were treated similarly except for plt transfusion strategy

Outcomes- Not clear whether all the outcomes reported were

predefined at start of study- e.g. # of transfusions related to Dx and conditioning – was

this posthoc analysis? Was study powered to detect differences?

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Critical Appraisal Can results be applied to patient care?- Applies to adults undergoing autologous PBSCT- This study used only LR apheresis plts- Pts with prior life-threatening bleeding were excluded,

and 34% of all transplants were performed without transfusions – was this a lower risk pt population?

Were all important outcomes considered?- Safety: bleeding complications and number of

thrombocytopenic days- no mention of days in hospital or overall mortality

- Plt utilization: reduced number of plt transfusions compared to historical controls- significant rate of off-protocol transfusions

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ASH 2006: Abstract #577 Oral Session

Interim analysis of a prospective randomised study comparing a therapeutic platelet transfusion strategy with the prophylactic platelet transfusion standard in patients after autologous peripheral stem cell transplantation (ASCT).

Schaefer-Eckart K, Wendelin K, Wilhelm M, Mahlknecht MU, Conradi R, Schaich M, Leimer L, Wandt H.

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Interim Analysis Prospective randomised study started 2005 Multicentre Plan to enrol 200 pts Prophylactic arm: receive plts if morning plt < 10 Therapeutic arm: stable pts receive plts only for clinically

relevant bleeding Apheresis or pooled platelet units

Prophylactic (n=45)

Therapeutic (n=47)

Days plts < 10 63 110

Days in hospital 15 14

Minor bleeding 4 (8.9%) 9 (19.2%)

Transfused units 68 37NSp<0.005

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THE END

Thank you!

Comments and questions …