Oral eltrombopag versus subcutaneous recombinant human thrombopoietin for promoting platelet engraftment after allogeneic stem cell transplantation: A PROSPECTIVE, NON-INFERIORITY, RANDOMIZED CONTROLLED TRIAL
Hematological oncology. 2022
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.
Systemic therapy of necrobiotic xanthogranuloma: a systematic review
Orphanet journal of rare diseases. 2022;17(1):132
BACKGROUND Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. OBJECTIVE To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. METHODS All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. RESULTS The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. CONCLUSIONS Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG.
A Multicenter Cross-Sectional Study and Systematic Review of Necrobiotic Xanthogranuloma With Proposed Diagnostic Criteria
JAMA dermatology. 2020
Importance: Necrobiotic xanthogranuloma (NXG) is a non-Langerhans cell histiocytosis classically associated with paraproteinemia attributable to plasma-cell dyscrasias or lymphoproliferative disorders. Despite the morbidity of NXG, the literature is limited to case reports and small studies, and diagnostic criteria are lacking. Objective: To evaluate the characteristics of NXG and propose diagnostic criteria. Design, Setting, and Participants: This multicenter cross-sectional study was conducted at tertiary academic referral centers and followed by a systematic review and a consensus exercise. The multicenter cohort included patients with NXG diagnosed at the Brigham and Women's and Massachusetts General Hospitals (2000-2018), the University of Iowa Hospitals and Clinics (2000-2018), and the University of Pennsylvania Health System (2008-2018). The systematic review was conducted in 2018 and included patients with NXG identified in the Cochrane, Ovid EMBASE, PubMed, and Web of Science databases. The consensus exercise was conducted by 8 board-certified dermatologists to identify diagnostic criteria. Main Outcomes and Measures: Demographic factors, comorbidities, clinical features, and treatment response. Results: Of 235 included patients with NXG (34 from the multicenter cohort and 201 from the systematic review results), the mean (SD) age at presentation was 61.6 (14.2) years; 147 (62.6%) were female. Paraproteinemia was detected in 193 patients (82.1%), most often IgG-kappa (117 patients [50.0%]). A malignant condition was detected in 59 patients (25.1%), most often multiple myeloma (33 patients [14.0%]). The overall rate of paraproteinemia and/or a malignant condition was 83.8% (197 patients). In the multicenter cohort, evolution of paraproteinemia into multiple myeloma was observed up to 5.7 years (median [range], 2.4 [0.1-5.7] years) after NXG presentation. Cutaneous lesions consisted of papules, plaques, and/or nodules, typically yellow or orange in color (113 of 187 [60.4%]) with a periorbital distribution (130 of 219 [59.3%]). The eye was the leading site of extracutaneous involvement (34 of 235 [14.5%]). In the multicenter cohort, intravenous immunoglobulin had the best treatment response rate (9 of 9 patients [100%]), followed by antimalarial drugs (4 of 5 patients [80%]), intralesional triamcinolone (6 of 8 patients [75%]), surgery (3 of 4 patients [75%]), chemotherapy (8 of 12 patients [67%]), and lenalidomide or thalidomide (5 of 8 patients [63%]). The consensus exercise yielded 2 major criteria, which were (1) clinical and (2) histopathological features consistent with NXG, and 2 minor criteria, consisting of (1) paraproteinemia, plasma-cell dyscrasia, and/or other associated lymphoproliferative disorder and (2) periorbital distribution of cutaneous lesions. In the absence of foreign body, infection, or another identifiable cause, fulfillment of both major and at least 1 minor criterion were proposed to establish the diagnosis of NXG. Conclusions and Relevance: Necrobiotic xanthogranuloma is a multisystem disorder associated with paraproteinemia and malignant conditions. The proposed diagnostic criteria may advance clinical research and should be validated.
rhTPO combined with chemotherapy and G-CSF for autologous peripheral blood stem cells in patients with refractory/relapsed non-Hodgkin's lymphoma
Cancer management and research. 2019;11:8371-8377
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.
Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial
The Lancet. Haematology. 2017;5((1):):e34-e43. e34
BACKGROUND Thrombocytopenia is a life-threatening complication in patients with advanced myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study (ASPIRE), we aimed to assess eltrombopag, an oral thrombopoietin receptor agonist, for thrombocytopenia (grade 4) treatment in adult patients with advanced MDS or AML. METHODS ASPIRE consisted of an open-label, double-blind phase for 8 weeks and a randomised, double-blind phase (parts 1 and 2, reported here) for 12 weeks, and an open-label extension (part 3). Eligible patients were men and women aged 18 years or older, with intermediate-2 or high-risk MDS or AML, with bone marrow blasts of 50% or less, and had either grade 4 thrombocytopenia due to bone marrow insufficiency (platelet counts <25 x 10(9) per L) or grade 4 thrombocytopenia before platelet transfusion, with 25 x 10(9) platelets per L or greater after transfusion. Additionally, eligible patients had at least one of the following within the screening period of 4 weeks: platelet transfusion, symptomatic bleeding, or platelet count of less than 10 x 10(9) per L. During part 1, patients received eltrombopag, and dose-escalation criteria for part 2 were determined. In part 2, we randomly allocated patients 2:1 using an interactive voice-response system to eltrombopag or placebo, stratified by baseline platelet count (<10 x 10(9) platelets per L vs ≥10 x 10(9) platelets per L) and disease (MDS vs AML). In parts 1 and 2, patients received supportive standard of care and initiated eltrombopag or placebo at 100 mg per day (50 mg per day for patients of east-Asian heritage) to a maximum of 300 mg per day (150 mg per day for patients of east-Asian heritage). The part 2 primary objective was assessed by a composite primary endpoint of clinically relevant thrombocytopenic events (CRTE) during weeks 5-12, defined as one of the following events, either alone or in combination: grade 3 or worse haemorrhagic adverse events; platelet counts of less than 10 x 10(9) per L; or platelet transfusions. Efficacy analyses were based on intention to treat; clinically meaningful efficacy was defined as 30% absolute difference between groups. This trial is registered with ClinicalTrials.gov, number NCT01440374. FINDINGS In part 1, 17 patients received eltrombopag and 11 patients completed treatment; four experienced significantly increased platelet counts, and ten had reduced platelet transfusion requirements. In part 2 we randomly allocated 145 patients to receive supportive care plus eltrombopag (n=98) or placebo (n=47); similar proportions had MDS (50 [51%] patients to eltrombopag, 22 (47%) patients to placebo) or AML (48 [49%] patients to eltrombopag, 25 [53%] patients to placebo). Average weekly CRTE proportions from weeks 5-12 were significantly lower with eltrombopag (54% [95% CI 43-64]) than with placebo (69% [57-80], odds ratio [OR] 0.20, 95% CI 0.05-0.87; p=0.032) although the difference between treatment groups was less than 30%. The most common grade 3 and grade 4 adverse events were fatigue (six [6%] in the eltrombopag group and one [2%] in the placebo group), hypokalaemia (six [6%] and two [4%]), pneumonia (five [5%] and five [11%]), and febrile neutropenia (five [5%] and six [13%]). Serious adverse events were reported in 56 (58%) eltrombopag-treated patients and 32 (68%) placebo-treated patients. Seven eltrombopag recipients and two placebo recipients had serious adverse events that were suspected to be study drug-related (eltrombopag: acute kidney injury, arterial thrombosis, bone pain, diarrhoea, myocardial infarction, pyrexia, retinal vein occlusion, n=1 each; placebo: vomiting, white blood cell count increased, n=1 each). Two eltrombopag recipients (arterial thrombosis n=1; myocardial infarction n=1) and no placebo recipients experienced fatal serious adverse events suspected to be study drug-related. INTERPRETATION No new safety concerns were noted with eltrombopag and the trial met the primary objective of a reduction in CRTEs; eltrombopag might be a treatment option for thrombocy
Comparison of prophylactic use of intravenous immunoglobulin versus Pentaglobin in pediatric patients after hematopoietic stem cell transplantation
Pediatric Transplantation. 2016;20((2)):276-83.
There are few studies evaluating the use of IgM-enriched IVIG (Pentaglobin() ) in HSCT recipients. This study aimed to compare the efficacy of prophylactic use of IVIG versus prophylactic use of Pentaglobin() within the first 100 days after allogeneic HSCT. We performed a prospective, randomized study of the use of prophylactic IVIG versus prophylactic use of Pentaglobin() in patients after allogeneic HSCT. The first dose of IVIG or Pentaglobin() was given before conditioning regimen and after transplant was given on day +1, +8, +15, and +22. And then, it was given if IgG level was below 400 mg/dL. Twenty-seven patients in IVIG group and 32 patients in Pentaglobin() group were included in the study. There were no significant differences in the duration of neutropenia, hospitalization, fever, and in the number of pyrexial episode, septicemia, bacteremia, local infection, CMV infection, acute GVHD, VOD, and adverse events between the IVIG group and Pentaglobin() group. Randomized placebo-controlled trials are needed to conclude that utilization of IVIG or Pentaglobin() has no beneficial effect in HSCT.Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Thrombopoietin receptor agonist eltrombopag for advanced MDS or AML and severe thrombocytopenia: 12-week, randomized, placebo-controlled, phase 2 ASPIRE study
Haematologica. 2016;101((s1)):15-16.. s130.
Oral thrombopoietin receptor agonist eltrombopag treatment during induction chemotherapy for acute myelogenous leukemia (AML): results of a randomized, double-blind, phase 2 study
Haematologica. 2016;101((s1)):40-41.. p185.
Safety and tolerability of eltrombopag versus placebo for treatment of thrombocytopenia in patients with advanced myelodysplastic syndromes or acute myeloid leukaemia: a multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial
The Lancet Haematology. 2015;2((10)):e417-26.
BACKGROUND Patients with myelodysplastic syndrome or acute myeloid leukaemia who are thrombocytopenic and unable to receive disease-modifying therapy have few treatment options. Platelet transfusions provide transient benefit and are limited by alloimmunisation. Eltrombopag, an oral thrombopoietin receptor agonist, increases platelet counts and has preclinical antileukaemic activity. We aimed to assess the safety and tolerability of eltrombopag for the treatment of thrombocytopenia in adult patients with advanced myelodysplastic syndrome, secondary acute myeloid leukaemia after myelodysplastic syndrome, or de-novo acute myeloid leukaemia. METHODS We did this multicentre, randomised, placebo-controlled, double-blind, phase 1/2 trial at 37 centres in ten countries in Europe, east Asia, and the Americas. Patients aged 18 years or older who had relapsed or refractory disease or were ineligible for standard treatments; had platelet counts of less than 30 x 10(9) platelets per L; had 10-50% bone-marrow blasts; or were platelet transfusion dependent were randomly assigned (2:1), via a telephone-based interactive voice-response system (GlaxoSmithKline Registration and Medication Ordering System) with a permuted-block randomisation schedule (block size of three), to receive once-daily eltrombopag or matching placebo dose adjusted from 50 mg to a maximum dose of 300 mg. Randomisation was stratified by presence of poor-prognosis (complex) karyotype (presence of at least three abnormalities, or chromosome 7 abnormalities, vs absence) and bone-marrow blast count (<20% vs >20%). Patients and study personnel were masked to treatment allocation. The primary endpoint was safety and tolerability, including adverse events, non-haematological laboratory grade 3-4 toxic effects, and changes in bone-marrow blast counts from baseline. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00903422. FINDINGS Between May 14, 2009, and May 9, 2013, we randomly assigned 98 patients to receive either eltrombopag (n=64) or placebo (n=34). 63 (98%) patients in the eltrombopag group and 32 (94%) patients in the placebo group had adverse events. The most common adverse events were pyrexia (27 [42%] vs 11 [32%]), nausea (20 [31%] vs 7 [21%]), diarrhoea (19 [30%] vs 6 [18%]), fatigue (16 [25%] vs 6 [18%]), decreased appetite (15 [23%] vs 5 [15%]), and pneumonia (14 [22%] vs 8 [24%]). Drug-related adverse events of grade 3 or higher were reported in six (9%) patients in the eltrombopag group and four (12%) patients in the placebo group. Increases in the proportion of peripheral blasts did not differ significantly between groups. Haemorrhage of grade 3 or higher was reported in ten (16%) patients given eltrombopag and nine (26%) patients given placebo. 21 (33%) patients receiving eltrombopag and 16 (47%) patients receiving placebo died while on treatment. No deaths in patients receiving eltrombopag and two deaths in patients receiving placebo were regarded as treatment related. Post-baseline bone-marrow examinations were done in 40 (63%) patients in the eltrombopag group and 17 (50%) patients in the placebo group. The most common reason for no examination was death before the scheduled 3 month assessment. There were no differences between median bone-marrow blast counts or proportions of peripheral blasts between groups. INTERPRETATION Eltrombopag doses up to 300 mg daily had an acceptable safety profile in patients with advanced myelodysplastic syndrome or acute myeloid leukaemia. The role of eltrombopag in these patients warrants further investigation. FUNDING GlaxoSmithKline.Copyright © 2015 Elsevier Ltd. All rights reserved.
Eltrombopag for post-transplant thrombocytopenia: results of phase II randomized double blind placebo controlled trial
Blood. 2015;126((23)): Abstract No. 738.