TOPPS
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Clinical Question
In adult patients with hematologic malignancies, does a prophylactic platelet transfusion strategy as compared to no prophylaxis reduce bleeding episodes?
Bottom Line
Patients who underwent prophylactic platelet transfusion with a threshold of 10x109/mL had fewer bleeding episodes and a longer time to first bleeding episode when compared to a population not receiving prophylaxis.
Major Points
Patients with hematologic malignancies receiving chemotherapy or stem cell transplantation develop severe prolonged thrombocytopenia and often clinically significant bleeding. The role of prophylactic transfusions for severe thrombocytopenia was unclear, though this practice was commonplace in the 2010s. The 2012 Study Alliance Leukemia Platelet Transfusion Trial[1] found a benefit with prophylactic platelet transfusions among patients with hematological malignancies with a platelet count ≤10x109/L. This trial included only 197 patients. A larger trial was needed to confirm these findings.
Published in 2013, the Trial of Prophylactic Platelets was a noninferiority trial randomized 600 patients with hematological malignancy requiring treatment likely to cause thrombocytopenia to receive a prophylactic platelet transfusion when their daily platelet count was <10x109/L or receive no prophylactic platelet transfusion. Both arms received transfusions for bleeding events. Participants were followed for 30 days. The noninferiority margin was not met for the no prophylaxis group. There were fewer bleeding events among those receiving prophylactic transfusions, though most bleeding events were lower-risk WHO grade 2 bleeding events. TOPPS provided additional support to the practice of prophylactic transfusions to lower bleeding events among adults with severe thrombocytopenia related to treatment of hematological malignancies.
Guidelines
AABB platelet transfusions (2015, adapted)[2]
- Hospitalized adults with therapy-induced hypoproliferative thrombocytopenia should be transfused 1 unit of platelets at a platelet count of ≤10x109 cells/L to lower risk of spontaneous bleeding (grade: strong recommendation, quality of evidence: moderate)
Design
- Multicenter randomized open-label non-inferiority trial
- N=600
- No platelet transfusion prophylaxis (n=301)
- Platelet transfusion prophylaxis (n=299)
- Setting: 14 centers in the UK and Australia
- Enrollment: August 2006 - August 2011
- Follow-up: 30 days
- Analysis: Intention to treat
- Primary outcome: Bleeding events (WHO class 2-4) within 30 days of randomization
Population
Inclusion Criteria
- Undergoing or about to start chemotherapy or stem cell transplantation for a hematologic malignancy
- Expected to have a platelet count <50 x109/L for at ≥5 days
- Aged ≥16 years
Exclusion Criteria
- Prior serious bleeding episode (WHO grade 3-4)
- Bleeding episode on current admission (WHO grade 2)
- Inherited bleeding or clotting disorder
- Requirement for therapeutic anticoagulation
- Hematologic diagnosis of acute promyelocytic leukemia (APL) Note: Persons with APL commonly have higher platelet targets because of a low-lying consumptive coagulopathy with this condition -WJC eds
- Known platelet HLA antibodies
Baseline Characteristics
From the no prophylaxis group.
- Demographics: Age 55y, female sex 34%
- Diagnosis: AML 18%, ALL 2%, CML <1%, lymphoma 35%, myeloma 41%, other 4%
- Treatment plan: Chemotherapy 17% (induction 12%, consolidation 5%), stem cell transplant 83% (autologous 70%, allogeneic 13%)
- Relapse: 31%
- Prior stem cell transplant: 7%
- Prior fungal infection: 2%
- Coexisting disorder including organ failure: 8%
- Mean platelet count: 44 x109/L
Interventions
- Randomized to a group:
- No platelet transfusion prophylaxis
- Platelet transfusion prophylaxis - 1 unit of platelets if daily platelet count was <10x109/L
- Both arms received therapeutic platelet tranfusions for bleeding, invasive procedures or other reasons at clinician's discretion
- Data collection
- Patients were followed for up to 30 days and were taken off protocol if serious bleeding episode (WHO grade 3-4), with further transfusions at clinician's discretion
Outcomes
Comparisons are no prophylaxis vs. platelet transfusion prophylaxis groups
Primary Outcome
- WHO grade 2-4 bleeding events (% of patients)
- 50% vs. 43% (percent difference 8.4%; 90% CI 1.7 to 15.2; noninferiority P=0.06)
- Analysis by treatment and cancer type is included here for simplicity but is a secondary outcome.
- By treatment type: P-interaction=0.04
- Autologous stem cell transplant: 47% vs. 45% (percent difference 2.3%; 90% CI -5.7 to 10.3)
- Chemotherapy: 58% vs. 38% (percent difference 20.0%; 90% CI 7.9 to 32.2)
- By cancer type: P-interaction=0.10
- AML or ALL: 62% vs. 38% (percent difference 24.2%; 90% CI 9.6 to 28.9)
- Lymphoma or myeloma: 47% vs. 44% (percent difference 3.3%; 90% CI -4.4 to 11.0)
- CML or other: 50% vs. 47% (percent difference 3.3%; 90% CI -27.2 to 33.9)
Secondary Outcomes
- Highest bleeding grade
- No statistical comparison reported by authors
- WHO grade 0 or 1: 50% vs. 57%
- WHO grade 2: 48% vs. 43%
- WHO grade 3: 1% vs <1%
- WHO grade 4: 1% vs 0%
- Days until first WHO grade 2-4 bleeding episode
- 17.2 vs. 19.5 days (HR 1.3; 95% CI 1.04 to 1.64; superiority P=0.02)
- Serious bleeding (WHO grade 3-4)
- 2% vs. <1% (OR 6.05; 95% CI 0.73 to 279.72; superiority P=0.13)
- Number of days with WHO grade 2-4 bleeding episodes
- 1.7 vs. 1.2 days (RR 1.52, 95% CI 1.14 to 2.03; superiority P=0.004)
- Days in hospital
- 12 vs. 12 days; P=0.38
- Platelet transfusion
- Any: 59% vs. 89% (OR 0.14; 95% CI 0.09-0.23; superiority P<0.001)
- # transfusions per patient: 1.7 vs. 3.0 transfusions (RR 0.62; 95% CI 0.51 to 0.75; superiority P<0.001)
- # units per patient: 1.9 vs. 3.2 units (RR 0.67; 95% CI 0.55-0.82; superiority P<0.001)
- Time to thrombocytopenia resolution
- 14 vs. 14 days (P=0.76)
- Days with platelet count below certain thresholds (post-hoc)
- <20x109/L: 6.9 vs. 6.1 days (RR 1.18; 95% CI 1.08 to 1.30; superiority P<0.001)
- <10x109/L: 3.6 days vs. 1.8 days (RR 2.15; 95% CI 1.85 to 2.51; superiority P<0.001)
- RBC transfusions
- Any: 71% v.s 67% (OR 1.22; 95% CI 0.84 to 1.79; superiority P=0.29)
- # transfusions per patient: 1.5 vs. 1.5 transfusions (RR 1.14; 95% 0.96 to 1.34; superiority P<0.13)
- # units per patient: 3.0 vs. 2.8 units (RR 1.24; 95% CI 1.04 to 1.47; P=0.02)
Adverse Events
- 6% vs. 7% (OR 0.85; 95% CI 0.43 to 1.66; P=0.63)
Criticisms
- Large proportion of included patients (70%) were undergoing autologous stem cell transplant and had shorter periods of severe thrombocytopenia and less significant bleeding
- Most of documented bleeding episodes were WHO grade 2 and included skin bleeding, which can be of heterogeneous significance
Funding
- National Health Service Blood and Transplant Research and Development Committee
- Australian Red Cross Blood Service
Further Reading
- ↑ Wandt H et al. Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet 2012. 380:1309-16.
- ↑ Kaufman RM et al. Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015. 162:205-13.