How much has allogeneic stem cell transplant–related mortality improved since the 1980s? A retrospective analysis from the EBMT

Penack, Olaf; Peczynski, Christophe; Mohty, Mohamad; Yakoub-Agha, Ibrahim; Styczyński, Jan; Montoto, Silvia; Duarte, Rafael F.; Kröger, Nicolaus; Schoemans, Hélène; Koenecke, Christian; Perić, Zinaida; Basak, Grzegorz W.

doi:10.1182/bloodadvances.2020003418

Cited by 121 publications

(89 citation statements)

References 27 publications

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“…32,67 We analyzed the transplantation efficiency at 2 weeks after transplantation, which is within the critical period for recipient survival that requires rapid proliferation and expansion of transplanted HSPCs. 13,22,68 Irradiated WT recipients that had received Drd-DKO LSK cells (Drd-DKO DHC ) show significantly delayed hematopoietic reconstitution, with lower numbers of BMNCs, LSK cells, and CD45 1 leukocytes relative to controls receiving WT LSK cells (Figure 4A-C). Drd-DKO LSK transplant-derived cells show a reduced Ki67 signal in BM, indicating reduced proliferation (Figure 4D).…”

Section: -Type Dopamine Receptors Regulate Bm Transplantation Efficiencymentioning

confidence: 99%

Dopamine signaling regulates hematopoietic stem and progenitor cell function

Liu

Chen

Jeong

et al. 2021

Blood

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Hematopoietic stem and progenitor cell (HSPC) function in bone marrow (BM) is controlled by stroma-derived signals, but the identity and interplay of these signals remain incompletely understood. Here, we show that sympathetic nerve-derived dopamine directly controls HSPC behavior through D2-subfamily dopamine receptors. Blockade of dopamine synthesis as well as pharmacological or genetic inactivation of D2-subfamily dopamine receptors lead to reduced HSPC frequency, inhibition of proliferation and low BM transplantation efficiency. Conversely, treatment with a D2-type receptor agonist increases BM regeneration and transplantation efficiency. Mechanistically, dopamine controls expression of the kinase Lck, which, in turn, regulates mitogen-activated protein kinase-mediated signaling triggered by stem cell factor in HSPCs. Our work reveals critical functional roles of dopamine in HSPCs, which may open up new therapeutic options for improved BM transplantation and other conditions requiring the rapid expansion of HSPCs.

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Section: -Type Dopamine Receptors Regulate Bm Transplantation Efficiencymentioning

confidence: 99%

Dopamine signaling regulates hematopoietic stem and progenitor cell function

Liu

Chen

Jeong

et al. 2021

Blood

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“…As HCT practices evolve and older, high-risk patients are considered more frequently for an allogeneic HCT, it is likely that the potential benefits of improved clinical care and currently available antifungal treatments are outweighed by patient comorbidities. However, data from the European Bone Marrow Transplant (EBMT) cohort show improved survival in patients transplanted after 2010 [ 32 ]. With azoles representing the major tool for the treatment of IA, one has to wonder if a certain plateau in the potential effect of this class might have been reached—particularly when considering the multiple associated toxicities, drug interactions, and therapeutic drug monitoring inconsistencies frequently leading to discontinuation of those agents [ 33 , 34 ].…”

Section: Discussionmentioning

confidence: 99%

Invasive Mold Infections in Allogeneic Hematopoietic Cell Transplant Recipients in 2020: Have We Made Enough Progress?

Roth

Masouridi‐Levrat

Chalandon

et al. 2021

Open Forum Infectious Diseases

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Background Despite progress in diagnostic, prevention and treatment strategies, invasive mold infections (IMI) remain leading cause of mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT-recipients). Methods We describe the incidence, risk factors, and mortality of allo-HCT-recipients with proven/probable IMI in a retrospective single-center 10-year (01.01.2010-01.01.2020) cohort study. Results Among 515 allo-HCT-recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%) and other molds (8/51, 15%). Overall 35/51 (68.6%) breakthrough-IMI (bIMI) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31-180, and >180 days post-HCT, respectively. Risk factors for IMI included: prior allo-HCT (SHR:4.06, p=0.004) and ≥grade-2 acute graft-versus-host disease (aGvHD; SHR: 3.52, p<0.001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (p=0.02). Mortality predictors included: disease relapse (HR:7.47, p<0.001), aGvHD (HR:1.51, p=0.001), CMV-serology-positive recipients (HR:1.47, p=0.03), and IMI (HR:3.94, p<0.001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (logrank 0.47). At 1-year post-IMI diagnosis, 70.8% (34/48) of patients were dead. Conclusions IA mortality has remained relatively unchanged during the last two decades. More than two thirds of allo-HCT-recipients with IMI die by 1-year post-IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.

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“…Allogeneic hematopoietic stem cell transplantation (HSCT) is a recognized curative treatment for several benign and malignant disorders. Although HSCT outcomes have improved significantly over time (1), long term survivors are at a defined relevant risk of developing complications; life expectancy remains lower compared to the age-and gender-matched population (2). Acute and chronic graft-versus-host disease (aGvHD and cGvHD, respectively) represent the most detrimental complications: with standard pharmacologic prophylaxis aGvHD occurring in 20-50% of patients and cGvHD in 30-50% (3).…”

Section: Introductionmentioning

confidence: 99%

Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients

et al. 2021

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IntroductionAllogeneic stem cell transplantation survivors are at a relevant risk of developing chronic GvHD (cGvHD), which importantly affects quality of life and increases morbidity and mortality. Early identification of patients at risk of cGvHD-related morbidity could represent a relevant tool to tailor preventive strategies. The aim of this study was to evaluate the prognostic power of immune reconstitution (IR) at cGvHD onset through an IR-based score.MethodsWe analyzed data from 411 adult patients consecutively transplanted between January 2011 and December 2016 at our Institution: 151 patients developed cGvHD (median follow-up 4 years). A first set of 111 consecutive patients with cGvHD entered the test cohort while an additional consecutive 40 patients represented the validation cohort. A Cox multivariate model for OS (overall survival) in patients with cGvHD of any severity allowed the identification of six variables independently predicting OS and TRM (transplant-related mortality). A formula for a prognostic risk index using the β coefficients derived from the model was designed. Each patient was assigned a score defining three groups of risk (low, intermediate, and high).ResultsOur multivariate model defined the variables independently predicting OS at cGvHD onset: CD4+ >233 cells/mm3, NK <115 cells/mm3, IgA <0.43g/L, IgM <0.45g/L, Karnofsky PS <80%, platelets <100x103/mm3. Low-risk patients were defined as having a score ≤3.09, intermediate-risk patients >3.09 and ≤6.9, and high-risk patients >6.9. By ROC analysis, we identified a cut-off of 6.310 for both TRM and overall mortality.In the training cohort, the 6-year OS and TRM from cGvHD occurrence were 85% (95% CI, 70-92) and 13% (95% CI, 5-25) for low-risk, 64% (95% CI, 44-89) and 30% (95% CI, 15-47) for intermediate-risk, 26% (95% CI, 10-47), and 42% (95% CI, 19-63) for high-risk patients (OS p<0.0001; TRM p = 0.015).The validation cohort confirmed the model with a 6-year OS and TRM of 83% (95% CI, 48-96) and 8% (95% CI, 1-32) for low-risk, 78% (95% CI, 37-94) and 11% (95% CI, 1-41) for intermediate-risk, 37% (95% CI, 17-58), and 63% (95% CI, 36-81) for high-risk patients (OS p = 0.0075; TRM p = 0.0009).ConclusionsIR score at diagnosis of cGvHD predicts GvHD severity and overall survival. IR score may contribute to the risk stratification of patients. If confirmed in a larger and multicenter-based study, IR score could be adopted to identify patients at high risk and modulate cGvHD treatments accordingly in the context of clinical trial.

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How much has allogeneic stem cell transplant–related mortality improved since the 1980s? A retrospective analysis from the EBMT

Cited by 121 publications

References 27 publications

Dopamine signaling regulates hematopoietic stem and progenitor cell function

Dopamine signaling regulates hematopoietic stem and progenitor cell function

Invasive Mold Infections in Allogeneic Hematopoietic Cell Transplant Recipients in 2020: Have We Made Enough Progress?

Immune Reconstitution-Based Score for Risk Stratification of Chronic Graft-Versus-Host Disease Patients

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