Strategies for Transfusion of Platelets to Patients with Thrombocytopenia (SToP)

1. Strategies for Transfusion of Platelets to Patients with Thrombocytopenia (SToP) CBS Resident Journal Club February 2009 Elianna Saidenberg

2. Background-1 • Platelet transfusions are used to prevent or manage bleeding in patients with decreased platelet counts or defects of platelet function • 1950’s: Platelet transfusions first shown to reduce mortality due to bleeding in patients with acute leukemia • Multiple advances in preparation, storage and transfusion methods since then

3. When to transfuse platelets? • Typical thresholds in non-bleeding patient: • Platelets <10 in stable patient • Platelets <20 in patient with additional bleeding risks such as fever or sepsis (Gmur et al 1991) • Surgery: • Most procedures platelet count of >50 is sufficient • CNS procedures require platelet count >100 • Prophylactic transfusions represent the greatest proportion of platelet transfusions carried out

4. How to assess effectiveness of platelet transfusion? • Clinical outcomes (ie bleeding, bruising, petechiae) • Objective measure so can be difficult to assess, grade and adjudicate • Absolute platelet increment (API)= (post-transfusion plt count) – (pre-transfusion platelet count) • Corrected count increment (CCI)=(post-transfusion plt count – pre-transfusion plt count) x (BSA)/ number of platelets transfused • Response considered adequate if >4500 plt/m2 @ 10-60 min post-transfusion and/or >2500 plt/m2 @ 18-24 hours post-transfusion • Percent platelet increment (PPI)= observed platelet count increment / expected platelet count increment • Expected increment is based on number of plt transfused and patient’s blood volume • Response considered adequate id >20% @ 10-60 min and/or >10% at 18-24 hours • If responses are not adequate, patient is considered refractory to platelet transfusion

5. What dose to transfuse? • Optimal platelet dose remains controversial. • Practices based on need to raise patient’s platelet count to a hemostatic level as well as the number of platelets that can be recovered from a standard donation • In practice, platelet doses vary from 1.7x109 plt/ 10 kg body weight to 294.2 x109 plt/ 10 kg body weight (Heddle et al 2006)

6. Platelet Dosing Trials • Norol et al Blood 2003 • Compared medium (4-6x1011), high(6-8x1011), and very high (>8x1011), doses of fresh (<24 hours), ABO compatible apheresis platelet concentrates • Endpoints: Platelet recovery, platelet increment and transfusion interval • Recovery similar in all 3 groups • Increment (33 vs 52 vs 61) and intervals (2.6 d vs 3.3 d vs 4.1 d) better in high and very high groups

7. Platelet Dosing Trials-2 • Klumpp et al Transfusion 1999 • Administered paired transfusions which consisted of a low (2.3-3.5 x 1011) and a high (4.5-6.1 x 1011) dose platelet component transfused in a random order to the same patient. • Outcomes: Platelet increment and probability of requiring additional transfusions per unit time • Mean increment for LDP 17,010/ mL, for HDP 31, 057/ mL • Mean transfusion free interval for LDP 2.16 days, for HDP 3.03 days • Use of LDP was associated with an increased risk of requiring another transfusion

8. Platelet Dosing Trials-3 • Goodnough et al Blood 2001 • Compared transfusions of platelets from TPO-treated donors (median 18.4x109 plt/dose) and placebo treated donors (median 12x109 plt/dose) • Outcomes: Platelet increment (early 1-4 h and late 18-24 h), transfusion-free intervals • Increment: Placebo early 19x109/L, late 8x109/L; TPO early 61x109/L, late 41x109/L • Transfusion-free intervals: Placebo 1.72 days, TPO 2.64-3.8 days

9. Platelet Dosing Trials-4 • Tinmouth et al Transfusion 2004 • Compared low dose (3U) vs standard (5U) platelet doses • Outcomes: Major bleeding • 10.7% in low dose group vs 7.3% in standard dose group

10. Platelet Dosing Trials-5 • Sensebe et al Blood 2005 • Compared transfusions of 0.5x1011/10 kg vs 1.0x1011/10 kg • Outcomes: Time between 1st and 2nd transfusions • 63 hours in lower dose group and 95 hours in higher dose group

11. Platelet Dosing Trials-6 • Optimal Platelet Dose Strategy for Management of Thrombocytopenia (PLADO) • Compared lower (1.1 x 1011/m2), medium (2.2 x 1011/m2), and higher dose (4.4 x 1011/m2) platelet therapy in patients with hypoproliferative TCP due to cancer or chemotherapy • Outcome: Grade 2 or higher bleeding as determined by the Platelet Dose Trial Bleeding Scale (Grade 2 bleeding corresponds to bleeding that is moderate, but not severe enough to warrant red blood cell transfusion). • Grade 2 bleeding occurred in 64% (LD), 59% (MD), and 64%(HD) (p=NS) • Authors’ Conclusions: Prophylactic low dose plt transfusions have no effect on the frequency of any bleeding grade. The total amount of plts transfused is significantly less in the LD arm compared to both the MD and HD arms, with the trade-off being that patients in the LD arm had more plt tx episodes. In summary, Hematology/Oncology patients with hypoproliferative thrombocytopenia can be safely transfused with low dose plts at a 10,000/µl plt tx trigger. Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 285

12. The SToP Study • International multi-centre randomized controlled trial investigating 2 different dosing strategies for prophylactic transfusion of platelets in patients with thrombocytopenia caused by chemotherapy • Low dose= 3.0-6.0 x1011 platelets/product • Standard dose= 1.5-3.0x1011 platelets/product • Designed to demonstrate non-inferiority of low dose platelet transfusions compared to standard dose

13. The SToP Study-2 • Primary outcomes: WHO grade ≥2 bleeding • Daily bleeding assessment; included physical exam, patient questions, chart review • Grading done by 2 independent adjudicators • Secondary outcomes: • Frequency of individual grades of bleeds • Time to 1st bleed • Mean number of bleeding days over time per 100 patients • Duration of TCP • Platelet transfusion requirements • RBC transfusion requirements • Interval between platelet transfusions • Association between the platelet dose transfused and risk of bleeding over next 24 hours

14. Were the patients randomized? Was randomization concealed? • Yes • Treatment allocation scheme generated by computer and stratified by centre and diagnostic group • Patients were allocated through a secure central web-based randomization scheme • Block randomization was used with variable block sizes within strata to help conceal treatment allocation

15. A note on block randomization • Basic idea: To divide potential patients into m blocks of size 2n, randomize each block such that npatients are allocated to A and n to B. The blocks are then chosen randomly • This method ensures equal treatment allocation within each block if the complete block is used. • Example: Two treatments of A, B and Block size of 2 x 2= 4 • Possible treatment allocations within each block are: (1) AABB, (2) BBAA, (3) ABAB, (4) BABA, (5) ABBA, (6) BAAB • Block size depends on the number of treatments, it should be short enough to prevent imbalance, and long enough to prevent guessing allocation in trials. • The block size should be at least 2x number of treatments. • The block size is not stated in the protocol so the clinical and investigators are blind to the block size. • If blocking is not masked in open-label trials, the sequence becomes somewhat predictable (e.g. 2n= 4): B A B ? Must be A. A A ? ? Must be B B. • This could lead to selection bias; solution is (1)Do not reveal blocking mechanism, (2) Use random block sizes

16. Were patients analyzed in the groups to which they were assigned? Yes

17. Were patients in each group similar? • Mostly • Mean platelet count at baseline was lower in the low dose arm (31x109/L) vs standard dose arm (46x109/L) • Author’s comment: “This finding may be due to chance and the clinical relevance of this finding is unknown.”

18. Were patients, clinicians or outcome assessors aware of treatment allocation? • No

19. Was follow up complete? • “Most patients remained in the study until at least one of the pre-specified criteria for the end of the period thrombocytopenia” • 10 patients withdrew early for the following reasons: • Patient choice to withdraw (2 in standard dose arm, 1 in low dose arm) • MD choice to withdraw (1 in standard dose arm, 6 in low dose arm) • Data from withdrawn patients were included in analysis until time of withdrawal

20. What are the results? • Key finding: Frequency of Grade 4 bleeding was 5.2% in low dose arm and 0% in standard dose arm • Hence, SToP study was stopped • Primary outcome finding (WHO grade ≥2 bleeding) • Low dose arm 51.7% • Standard dose arm 49.2%

21. What are the results?-2 • Other outcomes: • Time to 1st bleed- no difference • Expected number of bleeds per 100 patients- no difference • Transfusion triggers- tended to be higher in low dose arm • Mean age of platelets transfused- no difference • Total number of platelet transfusion episodes- 553 in low dose arm, 325 in standard dose arm • Mean # platelet transfusion episodes- Significantly higher in low dose arm • Total # donor exposures- Standard dose arm 1354; low dose arm 1524 • Mostly due to increased number of therapeutic transfusions in low dose • Total # RBC transfusions- no difference • Duration of thrombocytopenia- no difference • No significant relationship between platelet dose and bleeding on the following day

22. What do the authors have to say? • The increased number of grade 4 bleeds in the low dose arm could be due to chance. “However, supporting the suggestion that this difference may be real are the observations that the frequency of other types of bleeding were also higher with low-dose platelets” • It had been hypothesized that the benefits of low dose transfusions would include fewer platelets transfused, fewer donor exposures and fewer days of thrombocytopenia • This was not the case

23. What do the authors have to say?-2 • Limitations of the study • Generalizability is limited by lack of demographic information on some patients screened for eligibility. Hence, no way to assess possibility of a selection bias related to recruitment • 6/7 patients withdrawn by treating MD were in low dose arm. This raises questions about blinding of health care workers • Because study stopped early, power is an issue which limits conclusions about non-inferiority

24. What do the authors have to say?-3 • Conclusions: • “…even if a low dose platelet transfusion strategy is safe, the proposed benefits were not found using the dosing strategy that was applied in this study”

25. Does this study matter? • In clinical practice at the present time- probably not • MDs will have to continue to order standard dose platelet transfusions. • CBS will continue to make standard dose platelet components • Does practice need to change? • Platelet transfusion is not a perfect science and current practice is not based on abundant or robust research • We should always aim to minimize patient exposure to blood products and strive to improve outcomes for transfused patients • This requires additional research and innovations • So, what about future research in the area of platelet dosing? • When a well-designed trial is stopped early because of serious events and the analysable data shows possible harm and unlikely benefit….Well, what would you do? • Do the results of PLADO make a difference?