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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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Palliative Radiotherapy for Haemostasis in Malignancy: a Systematic Review
Song, J., Brown, C., Dennis, K., Gaudet, M., Haddad, A.
Clinical oncology (Royal College of Radiologists (Great Britain)). 2023
Abstract
AIMS: Palliative radiotherapy is commonly used to achieve haemostasis for malignancy-induced haemorrhages. Our study aimed to examine the efficacy of palliative radiotherapy in the control of haemorrhages caused by various types of malignancy. MATERIALS AND METHODS A systematic review of the literature was conducted to determine the level of evidence for the use of palliative radiotherapy in achieving haemostasis. Searches of the Medline, Embase and Cochrane databases were completed for studies published between January 1947 and May 2017. Studies that reported either a qualitative or a quantitative effect of radiotherapy were selected for inclusion during the review process. RESULTS In total, 836 abstracts were screened; 13 prospective and 45 retrospective studies met the criteria for inclusion in the review. Selected studies were sorted based on the underlying tumour type to provide readers the opportunity to compare dose and fractionation schedules. Significant variations in reporting of outcomes and low total patient numbers did not allow for a quantitative analysis to be carried out. A higher median dose and a hypofractionated schedule seem to provide numerically higher rates of control based on the available data. CONCLUSIONS Palliative radiotherapy is useful in the management of bleeding related to advanced and incurable malignancies. Brachytherapy seems to be effective in haemostasis of certain malignancies, especially that of gynaecological origin. Treatment should be tailored to individual patient situations given the palliative goals of any such therapy. Further prospective studies could help to delineate optimal dose and fractionation schedules.
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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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Efficacy of topical hemostatic agents in malignancy-related gastrointestinal bleeding: a systematic review and meta-analysis
Karna R, Deliwala S, Ramgopal B, Mohan BP, Kassab L, Becq A, Dhawan M, Adler DG
Gastrointestinal endoscopy. 2022
Abstract
BACKGROUND AND AIMS Despite advances in endoscopic therapies, malignancy-related gastrointestinal (GI) bleeding remains difficult to manage with high rates of treatment failure and rebleeding. Topical hemostatic agents (THA) are easier to apply to the wide bleeding surface of tumors. We conducted this systematic review and meta-analysis to evaluate the efficacy of THAs in malignancy-related GI bleed. METHODS We conducted a comprehensive search of multiple electronic databases to identify studies reporting on the use of THAs in malignancy-related GI bleeding. The primary outcome was the achievement of hemostasis; secondary outcomes were early rebleeding (≤ 3 days), delayed rebleeding (>3 days), aggregate rebleeding, all-cause mortality, and GI bleed related mortality. A meta-analysis of proportions was done for all outcomes. RESULTS Out of 355 citations, total 16 studies with 530 patients were included. Primary hemostasis was achieved in 94.1% (95% CI: 91.5 - 96.0%). Early rebleeding was seen in 13.9% (95% CI: 9.7 - 19.4%) while delayed rebleeding was seen in 11.4% (95% CI: 5.8 - 21.1%). Aggregate rebleeding was seen in 24.2% (95% CI:18.5 - 31.0%). All-cause mortality was 33.1% (95% CI: 23.7 - 44.0%) while GI bleed related mortality occurred in 5.9% (95% CI: 2.2% - 14.8%). CONCLUSIONS THAs are highly effective for achieving primary hemostasis in malignancy-related GI bleeding. It should be considered as an alternative to traditional endotherapy methods in malignancy-related GI bleeds. Future studies should be designed to evaluate its efficacy and safety as a primary method of hemostasis as compared to traditional endotherapy measures.
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Intravenous Iron Supplementation for the Treatment of Chemotherapy-Induced Anemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Buchrits S, Itzhaki O, Avni T, Raanani P, Gafter-Gvili A
Journal of clinical medicine. 2022;11(14)
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Editor's Choice
Abstract
BACKGROUND The pathophysiology of cancer-related anemia is multifactorial, including that of chemotherapy-induced anemia (CIA). The guidelines are not consistent in their approach to the use of intravenous (IV) iron in patients with cancer as part of the clinical practice. MATERIALS AND METHODS All randomized controlled trials that compared IV iron with either no iron or iron taken orally for the treatment of CIA were included. We excluded trials if erythropoiesis-stimulating agents (ESAs) were used. The primary outcome was the percentage of patients requiring a red blood cell (RBC) transfusion during the study period. The secondary outcomes included the hematopoietic response (an increase in the Hb level by more than 1 g/dL or an increase above 11 g/dL), the iron parameters and adverse events. For the dichotomous data, risk ratios (RRs) with 95% confidence intervals (Cis) were estimated and pooled. For the continuous data, the mean differences were calculated. A fixed effect model was used, except in the event of significant heterogeneity between the trials (p < 0.10; I(2) > 40%), in which we used a random effects model. RESULTS A total of 8 trials published between January 1990 and July 2021 that randomized 1015 patients fulfilled the inclusion criteria. Of these, 553 patients were randomized to IV iron and were compared with 271 patients randomized to oral iron and 191 to no iron. IV iron decreased the percentage of patients requiring a blood transfusion compared with oral iron (RR 0.72; 95% CI 0.55-0.95) with a number needed to treat of 20 (95% CI 11-100). IV iron increased the hematopoietic response (RR 1.23; 95% CI 1.01-1.5). There was no difference with respect to the risk of adverse events (RR 0.97; 95% CI 0.88-1.07; 8 trials) or severe adverse events (RR 1.09; 95% CI 0.76-1.57; 8 trials). CONCLUSIONS IV iron resulted in a decrease in the need for RBC transfusions, with no difference in adverse events in patients with CIA. IV iron for the treatment of CIA should be considered in clinical practice.
PICO Summary
Population
People with chemotherapy induced anaemia enrolled in randomised controlled trials (RCTs), and identified by systematic review (n= 1,015, 8 RCTs).
Intervention
Intravenous [IV] iron (n= 553).
Comparison
Oral iron (n= 271), or no iron (n= 191).
Outcome
IV iron decreased the percentage of patients requiring a blood transfusion compared with oral iron (Risk ratio [RR] 0.72; 95% confidence interval [CI] 0.55-0.95) with a number needed to treat of 20 (95% CI 11-100). IV iron increased the hematopoietic response (RR 1.23; 95% CI 1.01-1.5). There was no difference with respect to the risk of adverse events (RR 0.97; 95% CI 0.88-1.07; 8 trials) or severe adverse events (RR 1.09; 95% CI 0.76-1.57; 8 trials).
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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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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.
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Recombinant human thrombopoietin (rh-TPO) for the prevention of severe thrombocytopenia induced by high-dose cytarabine: a prospective, randomized, self-controlled study
Wang, Z., Fang, X., Huang, H., Hong, H., Li, X., Guo, C., Fu, X., Zhang, M., Lam, S. T., Li, S., et al
Leukemia & Lymphoma. 2018;59(12):2821-2828
Abstract
The aim of this randomized phase II study was to investigate the optimal timing of the administration of thrombopoietin to prevent cytarabine-induced thrombocytopenia. Fifty-two patients who were scheduled for high-dose cytarabine treatment were randomly assigned to receive either the standard prophylactic mode (starting thrombopoietin, 15,000 units/day on days 2-11) or the pre-chemo mode (starting thrombopoietin, 15,000 units/day on days -4, -2, and 2-9) during the first cycle of chemotherapy with a switch to the other mode in the second cycle. The thrombocytopenia rate in the standard mode and the pre-chemo mode were PLT < 50 × 10(9)/L, 67.3% versus 46.2% (p = .001); and PLT < 25 × 10(9)/L, 48.1% versus 26.9% (p = .001). The platelet transfusion rate was reduced in pre-chemo mode, with 7 patients requiring 10 units of platelets, whereas 13 patients required 24 units in standard mode (p = .038). Grade III/IV thrombopoietin-related toxicity was not observed. The prophylactic use of thrombopoietin was effective and safe. Trial registration: ChiCTR-OPB-15007591.