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Effect of single-unit transfusion in patients treated for haematological disease including acute leukemia: A multicenter randomized controlled clinical trial
Chantepie SP, Mear JB, Briant AR, Vilque JP, Gac AC, Cheze S, Girault S, Turlure P, Marolleau JP, Lebon D, et al
Leukemia research. 2023;129:107058
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Editor's Choice
Abstract
BACKGROUND Retrospective studies in hematological unit have suggested that single red blood cell (1-RBC) unit transfusion policy may reduce the number of RBC used without negative clinical impact. METHOD Acute leukemia patients requiring intensive chemotherapy or patients receiving autologous or allogeneic transplantation were randomly assigned to receive either single RBC (1-RBC arm) or double RBC (2-RBC arm) per transfusion with a hemoglobin trigger of 8 g/dL. The primary composite endpoint was the percentage of patients experiencing serious complications, such as a non-hematological adverse event grade ≥ 3 or intensive care admission or death. FINDINGS A total of 981 and 592 RBC transfusions were required in the 1-RBC arm (n = 125) and the 2-RBC arm (n = 120), respectively. The mean pre-transfusion hemoglobin levels were 7.49 ± 0.83 g/dL in the 1-RBC arm and 7.46 ± 0.67 g/dL in the 2-RBC arm (p = 0.275). The predefined non-inferiority criteria was achieved with 28/125 patients reaching the primary endpoint in the 1-RBC arm (22.4 %) and 28/120 patients in the 2-RBC arm (23.3 %) (Risk difference 0.009; 95 %, Confidence interval [-0.0791 to 0.0978], p = 0.021). The median (IQR) of RBC units transfused per patient was 7 (4-12) in the 1-RBC arm and 8 (4-12) in 2-RBC arm. Hemoglobin levels at discharge were also comparable in both arms. INTERPRETATION The results of this trial indicate that a single RBC transfusion policy is not inferior to a double RBC transfusion policy for patients receiving a bone marrow transplant or intensive chemotherapy in a hematological intensive care unit. However, the single RBC transfusion policy did not reduce the number of RBC units transfused per stay. FUNDING This trial was funded by a grant from the French Ministry of Health.
PICO Summary
Population
Adult acute leukemia patients requiring intensive chemotherapy or patients receiving autologous or allogeneic transplantation (n= 245).
Intervention
One unit of red blood cell (RBC) transfusion (1-RBC arm, n= 125).
Comparison
Two units of RBC transfusion (2-RBC arm, n= 120).
Outcome
The mean pre-transfusion haemoglobin levels were 7.49 ± 0.83 g/dL in the 1-RBC arm and 7.46 ± 0.67 g/dL in the 2-RBC arm. The predefined non-inferiority criteria was achieved with 28/125 patients reaching the primary endpoint in the 1-RBC arm (22.4 %) and 28/120 patients in the 2-RBC arm (23.3 %), (Risk difference 0.009; 95% CI [-0.0791, 0.0978]). The median (IQR) of RBC units transfused per patient was 7 (4-12) in the 1-RBC arm and 8 (4-12) in 2-RBC arm. Haemoglobin levels at discharge were also comparable in both arms.
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Risk of HLA antibody generation after receipt of Mirasol versus standard platelets in the MIPLATE randomized trial
Kaidarova Z, Di Germanio C, Custer B, Norris PJ
Transfusion. 2023
Abstract
BACKGROUND Human leukocyte antigen (HLA) alloimmunization can occur after platelet transfusion. These antibodies can complicate future platelet transfusions or organ transplantation. Animal data suggest that Mirasol pathogen reduction treatment (PRT) can prevent alloimmunization after transfusion. STUDY DESIGN AND METHODS The MIPLATE trial enrolled 330 of a planned 660 participants with hematological malignancies at risk for grade 2 or greater bleeding. The study was halted early for futility after a planned interim analysis. Participants were randomized to receive PRT versus standard control platelets. Serum samples were collected from participants at baseline (pretransfusion), weekly for the first 4 weeks, then at days 42 and 56. HLA antibody levels were determined using a commercial multianalyte bead-based assay. HLA antibody levels were analyzed using low, medium, and high cutoffs based on prior studies. RESULTS The rate of alloimmunization was low in both arms of the study, particularly at the high HLA antibody cutoff (total of 6 of 277 subjects at risk, or 2.2%). The risk of alloimmunization did not differ between study arms, nor did the risk of immune refractoriness to platelet transfusion. CONCLUSIONS The data do not support the conclusion that Mirasol exerted a protective effect against alloimmunization after platelet transfusion in the MIPLATE trial.
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Recombinant human thrombopoietin promotes platelet recovery in DCAG-treated patients with intermediate-high-risk MDS/hypoproliferative AML
Chen X, Wang Y, Zang Y, Wei Z, Zhang W, Wei X, Luo G, Chen L, Zhang Y, Xu Z
Medicine. 2023;102(13):e33373
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Abstract
BACKGROUND This study aimed to explore the effects of recombinant human thrombopoietin (rhTPO) on platelet recovery in decitabine, cytarabine, aclarubicin, and G-CSF (DCAG)-treated patients with intermediate-high-risk myelodysplastic syndrome/hypo proliferative acute myeloid leukemia. METHODS Recruited patients were at a ratio of 1:1 into 2 groups: the rhTPO group (DCAG + rhTPO) and control group (DCAG). The primary endpoint was the time for platelets to recover to ≥ 20 × 109/L. The secondary endpoints were the time for platelets to recover to ≥ 30 × 109/L and ≥ 50 × 109/L, overall survival (OS), and progression-free survival (PFS). RESULTS The time required for platelet recovery to ≥ 20 × 109/L, ≥30 × 109/L, and ≥ 50 × 109/L in the rhTPO group was significantly shorter (6.5 ± 2.2 vs 8.4 ± 3.1 days, 9.0 ± 2.7 vs 12.2 ± 3.9 days, 12.4 ± 4.7 vs 15.5 ± 9.3 days, respectively; all P < .05 vs controls). The amount of platelet transfusion in the rhTPO group was smaller (4.4 ± 3.1 vs 6.1 ± 4.0 U, P = .047 vs controls). The bleeding score was lower (P = .045 vs controls). The OS and PFS were significantly different (P = .009 and P = .004). The multivariable analysis showed that age, karyotype, and time for PLT recovery to ≥ 20 × 109/L were independently associated with OS. Adverse events were similar. CONCLUSIONS This study suggests that rhTPO leads to a faster platelet recovery after DCAG treatment, reduces the risk of bleeding, reduces the number of platelet transfusions, and prolongs the OS and PFS.
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Long-term Safety and Efficacy of Eltrombopag for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia: Results of the ASPIRE Extension Study
Mittelman M, Platzbecker U, Grosicki S, Lawniczek T, Zhu Z, Selleslag D
Acta haematologica. 2023
Abstract
ASPIRE, a three-part, international, phase II trial (ClinicalTrials.gov identifier: NCT01440374), investigated eltrombopag efficacy and safety in patients with advanced myelodysplastic syndrome or acute myeloid leukemia, and grade 4 thrombocytopenia (<25 × 109 platelets/L). Approximately 30-65% of patients in this open-label extension phase experienced clinically relevant thrombocytopenic events; no conclusions could be made regarding long-term efficacy (non-randomized design, no placebo control), and survival rates may simply reflect advanced disease. Long-term safety was consistent with the double-blind phase and contrasted with earlier SUPPORT study findings in higher-risk patients, suggesting that eltrombopag may have a role in treating thrombocytopenia in patients with low-/intermediate-risk myelodysplastic syndrome.
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Symptom burden and quality of life in patients with high-risk essential thrombocythaemia and polycythaemia vera receiving hydroxyurea or pegylated interferon alfa-2a: a post-hoc analysis of the MPN-RC 111 and 112 trials
Mazza, G. L., Mead-Harvey, C., Mascarenhas, J., Yacoub, A., Kosiorek, H. E., Hoffman, R., Dueck, A. C., Mesa, R. A.
The Lancet. Haematology. 2022;9(1):e38-e48
Abstract
BACKGROUND Patients with essential thrombocythaemia or polycythaemia vera have several symptoms that can worsen their quality of life. We aimed to assess how symptom burden changes over time with cytoreductive therapy. METHODS We performed a post-hoc analysis of data from MPN-RC 111-a single-arm, open-label, phase 2, multicentre trial at 17 hospitals and cancer centres in Italy and the USA, evaluating the clinical-haematological response to pegylated interferon alfa-2a in patients who were resistant or intolerant to hydroxyurea (NCT01259817)-and MPN-RC 112-a randomised, open-label, phase 3, multicentre trial at 25 hospitals and cancer centres in France, Germany, Israel, Italy, the UK, and the USA, comparing the clinical-haematological response to pegylated interferon alfa-2a versus hydroxyurea in therapy-naive patients with either high-risk essential thrombocythaemia or polycythaemia vera (NCT01258856). Patients completed the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the European Organisation for the Research and Treatment of Cancer Core Quality of Life Questionnaire through 12 months after initiation of treatment as secondary endpoints. In this post-hoc analysis, we examined the association of symptom burden with the clinical-haematological response at 12 months and the effect of baseline symptom burden (ie, high burden [total symptom score ≥20] vs low burden [total symptom score <20]) on subsequent changes in symptoms, estimated via mixed models. A clinically significant improvement in symptom burden was defined as 50% or greater improvement in the MPN-SAF total symptom score from baseline to 12 months in patients with a total symptom score greater than zero at baseline. FINDINGS 135 patients were enrolled in MPN-RC 111 between Feb 15, 2012, and Dec 23, 2015, and 168 were enrolled in MPN-RC 112 between Sept 24, 2011, and June 30, 2016. For this analysis, we included data from 114 patients from MPN-RC 111 (64 [56%] with essential thrombocythaemia and 50 [44%] with polycythaemia vera; 56 [49%] were female, and 100 [91%] of 110 were white) and 166 patients from MPN-RC 112 (79 [48%] with essential thrombocythaemia and 87 [52%] with polycythaemia vera; 68 [41%] were female, and 145 [93%] of 156 were white). At 12 months, a clinically significant improvement in symptom burden was reported by 12 (32%) of 38 complete responders and seven (20%) of 35 partial responders treated with pegylated interferon alfa-2a in MPN-RC 111; five (19%) of 27 complete responders and six (18%) of 34 partial responders treated with pegylated interferon alfa-2a in MPN-112; and eight (27%) of 30 complete responders and six (22%) of 27 partial responders treated with hydroxyurea in MPN-112. More complete and partial responders reported a clinically significant improvement than did non-responders (44 [22%] of 191 complete and partial responders vs four [5%] of 76 non-responders; Fisher's exact p=0·0003). Symptom burden improved between 3 and 12 months in patients with high baseline symptom burden, both those treated with pegylated interferon alfa-2a (mean total symptom score change -10·2, 95% CI -13·2 to -7·2) and those treated with hydroxyurea (-6·8, -11·2 to -2·4). However, symptom burden worsened between 3 and 12 months in patients with low baseline symptom burden (patients treated with pegylated interferon alfa-2a: mean total symptom score change 3·2, 95% CI 0·9 to 5·4; patients treated with hydroxyurea: 3·4, 0·6 to 6·2). INTERPRETATION Results can inform treatment decisions, including treatment timing and goals in managing essential thrombocythaemia and polycythaemia vera, because measuring symptom burden from the patient perspective is crucial to understanding treatment efficacy and tolerability. FUNDING US National Cancer Institute of the National Institutes of Health, and Roche Genentech.
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Prophylactic tranexamic acid in patients with hematologic malignancy: a placebo controlled, randomized clinical trial
Gernsheimer TB, Brown SP, Triulzi DJ, Key NS, El Kassar N, Herren H, Poston JN, Boyiadzis M, Reeves BN, Selukar S, et al
Blood. 2022
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Editor's Choice
Abstract
Evidence of effectiveness of prophylactic use of tranexamic acid (TXA) in thrombocytopenia is lacking. To determine whether TXA safely reduces bleeding incidence in patients undergoing treatment for hematologic malignancies, a randomized double blind clinical trial was conducted June 2016 through June 2020. Of 3120 screened adults 356 patients were eligible and enrolled, and 337 patients (mean age, 53.9; 141 (41.8%) women), randomized to 1,300mg TXA orally or 1,000mg TXA intravenously (n=168) versus placebo (n=169) thrice daily for maximum 30 days. 330 patients were activated when their platelet counts fell below 30,000/µl; 279 (83%) had complete outcome ascertainment. WHO grade 2 or higher bleeding was observed in the 30 days following activation in 50.3% (73/145) and 54.2% (78/144) of patients in the TXA and placebo groups, adjusted odds ratio: 0.83 (95%CI:0.50,1.34; p=0.44). There was no statistically significant difference in mean number of platelet transfusions (0.1;95%CI:-1.9,2.0), mean days alive without grade 2 or higher bleeding (0.8;95%CI:-0.4,2.0), thrombotic events (6/163 (3.7%) TXA, 9/163 (5.5%) placebo), or deaths due to serious bleeding. Most common adverse events were: diarrhea [(116/164 (70.7%) TXA and 114/163 (69.9%) placebo)]; febrile neutropenia [111/164 (67.7%) TXA, 105/163 (64.4%) placebo]; fatigue [106/164 (64.6%) TXA, 109/163 (66.9%) placebo]; and nausea [104/164 (63.4%) TXA, 97/163 (59.5%) placebo]. Among patients with hematologic malignancy undergoing chemotherapy or hematopoietic stem cell transplantation, prophylactic treatment with tranexamic acid compared with placebo did not significantly reduce the risk of WHO grade 2 or higher bleeding. Trial Registration: Clinicaltrials.gov Identifier: NCT02578901.
PICO Summary
Population
Patients who were thrombocytopenic due to primary bone marrow disorders or chemotherapy, immunotherapy, and/or radiation therapy (n= 337).
Intervention
Tranexamic acid (TXA) orally or intravenously (n= 168).
Comparison
Placebo (n= 169).
Outcome
The primary outcome of WHO grade 2 or higher bleeding during the first 30 days after activation was observed for 73 out of 145 (50.3%) and 78 out of 144 (54.2%) patients in the TXA and placebo groups, respectively. There was no statistically significant difference in mean number of platelet transfusions (0.1), mean days alive without grade 2 or higher bleeding (0.8), thrombotic events (6/163 (3.7%) TXA, 9/163 (5.5%) placebo), or deaths due to serious bleeding.
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Do liberal thresholds for red cell transfusion result in improved quality of life for patients undergoing intensive chemotherapy for acute myeloid leukemia? A randomized cross over feasibility study
Morton S, Sekhar M, Smethurst H, Mora A, Hodge RL, Hudson CL, Parsons J, Hopkins V, Stanworth SJ
Haematologica. 2022
Abstract
Not available.
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Oral eltrombopag versus subcutaneous recombinant human thrombopoietin for promoting platelet engraftment after allogeneic stem cell transplantation: A PROSPECTIVE, NON-INFERIORITY, RANDOMIZED CONTROLLED TRIAL
Wen B, Zhang X, Chen S, Fan J, Yang S, Cai Y, Wang P, Zhang Q, Gu Q, Du X
Hematological oncology. 2022
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Abstract
Delayed platelet engraftment (DPE) is associated with poor survival and increased transplantation-related mortality after allogeneic haematopoietic stem cell transplantation (allo-HSCT). Therefore, treatments are needed to improve platelet engraftment and prevent DPE. We performed a phase 3, non-inferior, randomized controlled study of eltrombopag or recombinant human thrombopoietin (rhTPO) to promot platelet engraftment after allo-HSCT. Candidates for allo-HSCT were randomly assigned to receive oral eltrombopag (50mg daily) or subcutaneous rhTPO (15000U daily ) from the first-day post-transplantation. The primary endpoint was the cumulative numbers of platelet engraftment (platelet recovery ≥ 20 × 10(9) /L, without transfusion, for seven consecutive days) on day 60 after transplantation. We performed intention-to-treat analyses with a non-inferior margin of -15%. A total of 92 participants underwent randomization. 44 and 48 patients were randomized to the eltrombopag and rhTPO groups, respectively. The median duration of follow-up was 360 days (range: 12-960 days). The cumulative incidence of platelet engraftment on day 60 after transplantation in eltrombopag group was 86.4% (38/44) compared with 85.4% (41/48) in the rhTPO group (absolute risk difference [ARD] 1%, one-sided lower limit of 95% confidence interval [CI] -13.28%, P(non-inferirioty) =0.014). The rate of DPE in the eltrombopag group was 6.8% (3/44) compared with 12.5% (6/ 48) in the rhTPO group (ARD -5.7%, one-sided higher limit of 95% CI 6.28%, P(non-inferirioty) =0.063). Approximately, 3/4 of non-haematologic adverse events were not observed in the eltrombopag group but three patients (3/48, 6%) experienecd them in the rhTPO group. In addtion, platelet transfusions unite from day 0 to day 21, or from day 22 to day 60, progression-free survival, overall survival were not significantly different between both groups. Eltrombopag was non-inferior to rhTPO in promoting platelet engraftment post allo-HSCT for patients with haematological malignancy. Oral eltrombopag was more convenient for patients than subcutaneous rhTPO (NCT03515096). This article is protected by copyright. All rights reserved.
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Exploring the components of bleeding outcomes in transfusion trials for patients with hematologic malignancy
Balitsky AK, Liu Y, Van der Meer PF, Heddle NM, Arnold DM
Transfusion. 2020
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Editor's Choice
Abstract
Clinically significant bleeding in patients with hematologic malignancies is a heterogeneous composite outcome currently defined as World Health Organization (WHO) bleeding Grades 2, 3, and 4. However, the clinical significance of some minor bleeds categorized as WHO Grades 1 and 2 remains controversial. We analyzed the number and frequency of individual signs and symptoms of WHO Grades 1 and 2 bleeds and explored their association with more severe incident bleeds graded as WHO Grades 3 and 4. STUDY DESIGN AND METHODS We aggregated daily bleeding assessment data from three randomized controlled trials conducted in patients with hematologic malignancies that used bleeding as an outcome. Cox proportional hazard regression analysis was used to identify signs and symptoms categorized as WHO Grades 1 and 2 bleeds that were associated with more severe bleeds (Grades 3 and 4). RESULTS We collected data from 315 patients (n = 5476 daily bleeding assessments; 3383 [61.8%] with a bleed documented). A total of 98.3% (3326/3383) were Grade 1 and 2 bleeds and 1.7% (57/3383) were Grades 3 and 4. Grade 1 and 2 bleeds were composed of 20 different bleeding signs and symptoms. Hematuria (hazard ratio, 16.1; 95% confidence interval, 4.4-59.2; P < .0001) was associated with incident Grade 3 or 4 bleeds. CONCLUSION In patients with hematologic malignancy, only hematuria (microscopic and/or macroscopic) was associated with more severe incident bleeds. This findings require validation in independent data sets.
PICO Summary
Population
Patients with haematologic malignancies and chemotherapy-induced thrombocytopenia (3 randomised controlled trials (RCTs), n= 315).
Intervention
Less severe bleeds (WHO Grades 1 and 2).
Comparison
More severe bleeds (WHO Grades 3 and 4).
Outcome
The total data aggregated from the 3 RCTs was 5,476 daily bleeding assessments, 61.8% with a bleed documented. A total of 98.3% were Grade 1 and 2 bleeds and 1.7% were Grades 3 and 4. Grade 1 and 2 bleeds were composed of 20 different bleeding signs and symptoms. Haematuria was associated with incident Grade 3 or 4 bleeds. In patients with haematologic malignancy, only haematuria was associated with more severe bleeds.
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rhTPO combined with chemotherapy and G-CSF for autologous peripheral blood stem cells in patients with refractory/relapsed non-Hodgkin's lymphoma
Zhu J, Hao SG, Hu J, Zhuang JL, Wang C, Bai HT
Cancer management and research. 2019;11:8371-8377
Abstract
Objective: The mobilization and collection of sufficient autologous peripheral blood stem cells (APBSCs) are important for the fast and sustained reconstruction of hematopoietic function after autologous transplantation. This study aims to evaluate the mobilization effect and safety of thrombopoietin (TPO) combined with chemotherapy + G-CSF for APBSCs in patients with refractory/relapsed non-Hodgkin's lymphoma. Methods: A total of 78 patients were included in the present study. After receiving mobilization chemotherapy, all patients were randomly divided into two groups: TPO group (n=40), patients were given subcutaneous injection of rhTPO + G-CSF, and control group (n=38), patients were given subcutaneous injection of G-CSF. The primary endpoint was the total number of obtained CD34+ cells. The secondary endpoints were the mononuclear cell count, the proportion of target and minimum mobilization, the engraftment time of neutrophils and platelets after APBSCT, the number of platelet and red blood cell infusions, the incidence of infectious fever and fever duration, and TPO-related side effects in patients. Results: TPO participation significantly increased the total CD34+ cell count. A higher proportion of patients in the TPO group achieved the minimum and target CD34+ cells, when compared to the control group. TPO-related adverse events were not observed in either of these groups. In addition, there were no significant differences in engraftment time, the number of platelet and red blood cell transfusions, the incidence of infectious fever, and fever duration between these two groups. Conclusion: TPO combined with chemotherapy + G-CSF can safely and effectively enhance the mobilization effect for APBSCs in patients with refractory/relapsed non-Hodgkin's lymphoma.