Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen

Tsirigotis, Panagiotis; Resnick, Igor B.; Avni, Batia; Grisariu, Sigal; Stepensky, Polina; Or, Reuven; Shapira, M Y

doi:10.1038/bmt.2014.168

Cited by 52 publications

(48 citation statements)

References 13 publications

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“…In our trial, a dosage of 3 mg/m 2 had only a modest impact on toxicity, especially with regard to the development of SOS directly after salvage therapy as well as after transplantation, with a rate of moderate/severe SOS after transplantation of 8.5%, which is expected in this patient population. 30,31,37,38 Thus, in contrast to previous data showing an enormously increased incidence of SOS (64%) by pre-treatment with GO (6 mg/m 2 or 9 mg/m 2 ) in a 3.5-month period prior to transplant, 39 we were able to show that salvage therapy including GO in a dosage of 3 mg/m 2 is safe and can be followed by allogeneic HCT without increasing the rate of SOS. Whether an increment of the GO dosage by using fractionated administration, 40,41 comparable to successful attempts in first-line therapy, 35 is safe in terms of SOS and even more effective compared to our GO-A-HAM regimens remains elusive.…”

Section: Discussioncontrasting

confidence: 52%

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

et al. 2016

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O utcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m² intravenously on day 1), all-trans retinoic acid (45 mg/m² orally on days 4-6 and 15 mg/m² orally on days 7-28), high-dose cytarabine (3 g/m²/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m² intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975) Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

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Section: Discussioncontrasting

confidence: 52%

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

et al. 2016

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“…88,89 Reduced intensity conditioning may decrease the risk of VOD/SOS post-HSCT, although VOD/SOS has still been reported in ;2% to 9% of allogeneic-transplant patients who received reduced intensity conditioning. 75,90 The pathophysiology of VOD/SOS begins with toxic injury to sinusoidal cells of the endothelium and hepatocytes of zone 3 of the liver acinus ( Figure 2); this may trigger a complex pathophysiologic cascade. 76,78,79,91 The damage to EC impairs their regulation of thrombo-fibrinolytic balance, results in reduced nitric oxide production and increased levels of matrix metalloproteinase, 92 and may be associated with multiple prothrombotic biomarkers, although these may vary by source of toxicity.…”

Section: Key Development Milestones and Approvals Grantedmentioning

confidence: 99%

The use of defibrotide in blood and marrow transplantation

et al. 2018

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propensity analysis-estimated between-group difference: 23%; P 5 .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graftversus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

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“…4 Although HSCT practice is changing rapidly, VOD/SOS with MOF is still a significant problem, even among patients undergoing reduced intensity conditioning and especially in the allogeneic setting. 5,6 Defibrotide, a sodium salt of complex single-stranded oligodeoxyribonucleotides derived from porcine mucosal DNA, is approved in the European Union for the treatment of patients .1 month of age with severe hepatic VOD/SOS following HSCT. [7][8][9][10][11] Preclinical data suggest that defibrotide stabilizes endothelial cells by reducing endothelial-cell activation and by protecting endothelial cells from further damage, resulting in the restoration of the thrombo-fibrinolytic balance.…”

Section: Introductionmentioning

confidence: 99%

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

Richardson

Riches

Kernan

et al. 2016

Blood

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Key Points• Defibrotide improves day 1100 survival and CR in patients with VOD and MOF compared with a historical control.• The historical control selection methodology offers a novel approach for investigation of a life-threatening orphan disease.Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n 5 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P 5 .0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P 5 .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as

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Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen

Cited by 52 publications

References 13 publications

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy

The use of defibrotide in blood and marrow transplantation

Phase 3 trial of defibrotide for the treatment of severe veno-occlusive disease and multi-organ failure

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