Transcript Platelet Refractoriness

Strategies for Transfusion of
Platelets to Patients with
Thrombocytopenia (SToP)
CBS Resident Journal Club
February 2009
Elianna Saidenberg
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
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
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 posttransfusion 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
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)
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
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
Platelet Dosing Trials-3
• Goodnough et al Blood 2001
– Compared transfusions of platelets from TPOtreated 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
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
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
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
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
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:
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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
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 webbased randomization scheme
– Block randomization was used with variable block
sizes within strata to help conceal treatment allocation
A note on block randomization
• Basic idea: To divide potential patients into m blocks of size
2n, randomize each block such that n patients 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
Were patients analyzed in the groups
to which they were assigned? Yes
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.”
Were patients, clinicians or
outcome assessors aware of
treatment allocation?
• No
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
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%
What are the results?-2
• Other outcomes:
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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
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
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
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”
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?