Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications

Morishita, Takanobu; Okabe, Motohito; Kawaguchi, Yuuka; Lee, Yoonha; Ohbiki, Marie; Osaki, Masahide; Goto, Miyo; Araie, Hiroaki; Sato, Takahiko; Goto, Tatsunori; Ozawa, Yukiyasu; Miyamura, Koichi

doi:10.1016/j.bbmt.2018.07.029

Cited by 13 publications

(9 citation statements)

References 30 publications

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“…Additionally, bacterial endotoxins [lipopolysaccharide (LPS)] move through damaged intestinal mucosa and can increase EC activation. Other agents used during HCT, such as sirolimus and calcineurin inhibitors (CNIs; ciclosporin, tacrolimus), potentiate endothelial injury and accelerate senescence 17,44,45 . Higher peak tacrolimus concentrations after transplantation increase the risk of HCT complications related to endothelial damage 45 …”

Section: Factors Leading To Endothelial Damagementioning

confidence: 99%

Endothelial cell function and endothelial‐related disorders following haematopoietic cell transplantation

Hildebrandt

Chao

2020

Br J Haematol

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Summary Use of haematopoietic cell transplantation (HCT) in the treatment of haematologic and neoplastic diseases may lead to life‐threatening complications that cause substantial morbidity and mortality if untreated. In addition to patient‐ and disease‐related factors, toxicity associated with HCT puts patients at risk for complications that share a similar pathophysiology involving endothelial cells (ECs). Normally, the endothelium plays a role in maintaining homeostasis, including regulation of coagulation, vascular tone, permeability and inflammatory processes. When activated, ECs acquire cellular features that may lead to phenotypic changes that induce procoagulant, pro‐inflammatory and pro‐apoptotic mediators leading to EC dysfunction and damage. Elevated levels of coagulation factors, cytokines and adhesion molecules are indicative of endothelial dysfunction, and endothelial damage may lead to clinical signs and symptoms of pathological post‐HCT conditions, including veno‐occlusive disease/sinusoidal obstruction syndrome, graft‐versus‐host disease, transplant‐associated thrombotic microangiopathy and idiopathic pneumonia syndrome/diffuse alveolar haemorrhage. The endothelium represents a rational target for preventing and treating HCT complications arising from EC dysfunction and damage. Additionally, markers of endothelial damage may be useful in improving diagnosis of HCT‐related complications and monitoring treatment effect. Continued research to effectively manage EC activation, injury and dysfunction may be important in improving patient outcomes after HCT.

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Section: Factors Leading To Endothelial Damagementioning

confidence: 99%

Endothelial cell function and endothelial‐related disorders following haematopoietic cell transplantation

Hildebrandt

Chao

2020

Br J Haematol

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“…It has a reported overall mean incidence of 8% to 14%, with an incidence of up to 60% in some high-risk populations [1][2][3]. VOD/SOS occurs as a result of activation and damage of the sinusoidal endothelium [4,5]. VOD/SOS with multiorgan dysfunction (MOD; renal and/or pulmonary) is reported to be associated with >80% mortality when treated with supportive care alone [1,6].…”

Section: Introductionmentioning

confidence: 99%

Incidence of Anicteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Outcomes with Defibrotide following Hematopoietic Cell Transplantation in Adult and Pediatric Patients

Corbacioglu

Kernan

Pagliuca

et al. 2020

Biology of Blood and Marrow Transplantation

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A B S T R A C T Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin 2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level <2 mg/dL before and after Day 21 post-HCT in T-IND patients enrolled following the amendment allowing for diagnosis by the modified Seattle criteria. Survival of adult and pediatric patients with or without hyperbilirubinemia and with or without multiorgan dysfunction (MOD) was also evaluated. Of 803 post-HCT patients with VOD/SOS enrolled following the protocol amendment, 181 (23%) had a bilirubin level <2 mg/dL and would not have been diagnosed if hyperbilirubinemia was required. The bilirubin level at diagnosis was <2 mg/dL in 165 of 331 patients (50%) diagnosed by the modified Seattle criteria and in 16 of 23 patients (70%) diagnosed by biopsy. VOD/SOS with a bilirubin level <2 mg/dL was more common in pediatric patients (29%), although it also occurred in adult patients (15%). Patients with hyperbilirubinemia had lower Day 100 survival (54% versus 87% in patients with bilirubin <2 mg/dL) and a higher incidence of MOD (41% versus 26% in patients with bilirubin <2 mg/dL). The incidence of treatment-emergent adverse events and serious adverse events was lower in patients with a bilirubin level <2 mg/dL. These results indicate that anicteric VOD/SOS occurs in both adult and pediatric patients post-HCT and can be diagnosed before and after Day 21 in both groups. The worse survival in patients with bilirubin 2 mg/dL suggests that requiring hyperbilirubinemia may result in a progressed disease stage associated with worse outcomes. Taken together, these results highlight the importance of awareness and the possibility of VOD/SOS in the absence of elevated bilirubin level.

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“…Ganetsky et al reported that TAC concentration 1 week after HSCT, performed with either HLA‐matched or unmatched donors, is associated with the occurrence of aGVHD, but this association is lost in the second to fourth weeks 4 . Recently, we reported that higher peak TAC concentration (>13.5 ng/mL) at week 3 may accelerate the risk of transplantation‐related complications with endothelial cell damage (TRC‐EC), but that this was not associated aGVHD incidence 3 . Although several studies reported the utility and importance of assessing mean TAC concentration, the optimal range of mean TAC concentration and intervention time period still remain to be elucidated.…”

Section: Discussionmentioning

confidence: 81%

“…Although TAC is valuable for GVHD prophylaxis, it has a narrow range of therapeutic concentrations, and its clinical use is complicated by its pharmacokinetic variability 2 . Moreover, previous studies have shown that inappropriate concentrations of CNIs immediately after allo‐HSCT may result in aGVHD and other non‐infectious transplantation–related complications (TRCs) 3‐6 . Therefore, therapeutic drug monitoring (TDM) is essential.…”

Section: Introductionmentioning

confidence: 99%

The stability of initial tacrolimus concentration following allogeneic hematopoietic stem cell transplantation reduces the risk of acute GVHD

Okabe¹,

Morishita²,

Ichiki³

et al. 2020

Clinical Transplantation

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Background Early tacrolimus (TAC) concentrations correlate with the risk of acute graft‐versus‐host disease (aGVHD); however, whether the variability of early TAC concentrations after allo‐HSCT governs the occurrence of aGVHD remains unknown. Here, we evaluate the correlation between the intrapatient variability (IPV) of initial TAC concentrations and the development of aGVHD. Methods We retrospectively assessed 202 patients who underwent allo‐HSCT and received standard GVHD prophylaxis by continuous intravenous (iv) infusion of TAC and iv methotrexate. IPV was calculated by using the % coefficient of variation in the initial 4 weeks. Results With median follow‐up duration of 20.7 months, 24 patients were diagnosed with grades II‐IV aGVHD. Overall survival (OS) and relapse at 12 months after allo‐HSCT were 70.6% (95% confidence interval [CI], 63.7%‐76.4%) and 18.9% (95% CI, 13.0%‐24.4%), respectively. When IPV was categorized into two groups (high: ≥9.5%; low: <9.5%), the cumulative incidence of grades II‐IV aGVHD was greater in the IPV‐high group at week 3 (odds ratio: 4.15; 95% CI, 1.37%‐12.6%, P = .01). No significant differences were observed in OS and relapse between the two groups. Conclusion We concluded that adjusting early TAC concentration stable may reduce aGVHD after allo‐HSCT without affecting the relapse rate.

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Higher Peak Tacrolimus Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation Increase the Risk of Endothelial Cell Damage Complications

Cited by 13 publications

References 30 publications

Endothelial cell function and endothelial‐related disorders following haematopoietic cell transplantation

Endothelial cell function and endothelial‐related disorders following haematopoietic cell transplantation

Incidence of Anicteric Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome and Outcomes with Defibrotide following Hematopoietic Cell Transplantation in Adult and Pediatric Patients

The stability of initial tacrolimus concentration following allogeneic hematopoietic stem cell transplantation reduces the risk of acute GVHD

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