Effects of Prophylactic Platelet (Plt) Dose on Transfusion (Tx) Outcomes (PLADO Trial)

Abstract

Background: The dose of plts transfused may have major effects on both hemostasis and plt usage. No large-scale clinical trial has previously been performed to evaluate the effects of plt dose on tx outcomes.Methods: Patients with hypoproliferative thrombocytopenia who were expected to be hospitalized with plt counts of ≤10,000 plts/μl for ≥5 days were enrolled. Patients were randomly assigned to receive plts at a medium target dose (MD) of 2.2 × 1011 plts/m2 (equivalent to 4–6 pooled plt concentrates or one apheresis tx), a lower target dose (LD) of 1.1 × 1011 plts/m2 (1/2 the MD), or a higher target dose (HD) of 4.4 × 1011 plts/m2 (2x the MD). An acceptable dose was within ±25% of the target dose. Randomization was balanced by trial site and stratified by four treatment groups: chemotherapy for hematologic malignancy or solid tumor and autologous or allogeneic stem cell transplant (SCT). Daily detailed hemostatic assessments were based on physical exam, patient interview, and chart review by an observer blinded to the patient's randomization arm. The highest grade of bleeding for each patient per day was calculated by a computer algorithm using WHO Bleeding Grades 0 to 4. The primary endpoint was the percentage of patients with Grade 2 or higher bleeding. Grade 2 bleeding was gross bleeding such as hematuria, hematemesis, etc.; Grade 3 bleeding required RBC transfusion; and Grade 4 bleeding was life-threatening. Plts were transfused prophylactically for morning plt counts of ≤10,000 plts/μl or at a different tx trigger or dose if therapeutically indicated. Pre- and post-tx plt counts, plt counts of the transfused plts, and daily plt and Hct were measured.Results: Data were analyzed on 1,272 hospitalized patients at 26 trial sites who received at least one plt tx. Overall, 91% of the 5,465 plt txs were given at their protocol-assigned dose, and, on 92% of the 24,690 hospital days, the tx trigger was followed. Among the 398 patients (31% of the patients) who had at least one change in their plt tx dose or trigger, 33%, 27%, and 29% were in the LD, MD, and HD arms, respectively (p=NS). The primary endpoint of Grade 2 or greater bleeding occurred in 71%, 69%, and 70%; Grade 3 or higher in 12%, 9%, and 10%; and Grade 4 in 3%, 2%, and 2% of the 417, 423, and 432 patients in the LD, MD, and HD arms, respectively (p=NS for all bleeding comparisons among the arms). There was one bleeding-related death in the HD arm. Median total number of RBC units transfused was 4 in each arm. As Grade 2 bleeding can include skin, soft tissue, and musculoskeletal bleeding which some physicians might not consider clinically-relevant, a secondary analysis was done that excluded this type of Grade 2 bleeding from consideration. For this modified outcome, ≥ Grade 2 bleeding occurred in 64%, 59%, and 64% of the patients in the LD, MD, and HD arms, respectively (p=NS). In the 1,008 transfused patients with no Grade 2 or greater bleeding before their first plt tx, median time from their first plt tx to onset of ≥ Grade 2 bleeding was 2, 2, and 3 days in the LD, MD, and HD arms, respectively (p=NS). The median number of days of ≥ Grade 2 bleeding was one in all of the arms. Grade 2 or greater bleeding occurred in 79% of the 523 patients with an allogeneic STC, 73% of the 313 patients with chemotherapy for hematologic malignancy, and 57% of the 429 patients with an autologous SCT (p=0.04 for allogeneic SCT vs chemotherapy, and p<0.0001 for autologous SCT vs the other two strata). Only 7 patients had a solid tumor. Tx dose did not effect bleeding in any patient stratum. Median plt tx events were 5, 3, and 3 for LD, MD, HD, respectively (p<0.0001 for LD compared to MD and HD). Median total number of plts transfused were 11 × 1011, 12 × 1011 (9% > LD), and 22 × 1011 (100% > LD) for LD, MD, and HD arms, respectively (LD vs MD, p=0.02; LD and MD vs HD, p≤0.0001).Conclusions: Prophylactic plt doses ≥1.1 × 1011/m2 given at a plt tx trigger of ≤10,000/μl have no effect on the frequency of any bleeding grade in patients with hypoproliferative thrombocytopenia due to chemotherapy or stem cell transplant. 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.