Easix before Conditioning Therapy Predicts Sepsis after Allogeneic Stem Cell Transplantation

Purpose: Endothelial complications are principal causes of non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). Sepsis is a dysfunctional endothelial response to harmful microorganisms with increased risk of microvascular damage and organ failure. We hypothesized that the endothelial activation and stress index (EASIX) predicts risk of sepsis after alloSCT. Methods: In this retrospective evaluation, 1290 patients (random 1:1 allocation into a training cohort and a validation cohort while balancing for sepsis events) were assessed for presence of neutropenic fever, sepsis and infectious pathogens within 50 days after alloSCT. Sepsis and septic shock were defined according to the modified Sepsis-3 guidelines by the Infectious Diseases Working Party (AGIHO) and Intensive Care Working Party (iCHOP) of the German Society of Hematology and Medical Oncology (DGHO) for neutropenic cancer patients. EASIX and additional serum markers were assessed longitudinally before and after transplantation and correlated with outcome. Established clinical risk scores (EBMT, HCT-CI and VOD-CIBMTR) were raised and compared to EASIX. Results: Within the full cohort of 1290 patients transplanted since 01/2004, neutropenic fever episodes until day+50 after alloSCT were reported in 989 (76.7%), sepsis in 93 (7.2%), catecholamine use in 35 (2.7%), and mechanical ventilation in 31 (2.4%) patients. Patients who developed sepsis until day+50 differed from patients without early sepsis in more frequently having a higher disease score (58% vs 33%, p<0.001), more often receiving ATG prophylaxis (77% vs 64%, p=0.007), myeloablative or aplasia conditioning (44% vs 20%, p<0.001), and less likely receiving MTX prophylaxis (33% vs 43%, p=0.06). Prior to conditioning therapy, EASIX(-pre) was the only marker to predict the hazard of early sepsis irrespective of pathogen detection in time-dependent ROC (AUC 0.85 at day 50) and multivariable cause-specific Cox regression analyses (HR per two-fold increase 2.3 (1.9-2.8, p<0.001). The prognostic value of uni- and multivariable models were evaluated in the second cohort. An optimized cutoff for EASIX defined in the training cohort (2.32) strongly predicted sepsis in multivariable cause-specific Cox regression in the second cohort (HR 16.3 (7.0-37.5), p<0.001). Although Ferritin significantly predicted time to death without sepsis (HR per two-fold increase 1.11 (1.03-1.19), p=0.008), EASIX performed superior to other scores in univariate analysis when predicting time to early sepsis with respect to predictive accuracy measured by the time-dependent Brier score (Figure 1). Accordingly, EASIX was the strongest pre-transplantation score to predict early non-relapse mortality (NRM) within 6 months after alloSCT. Pre-conditioning leukocyte counts, CRP or endothelial serum markers did not associate with early sepsis. After transplantation starting with day 0, sepsis associated with EASIX at any time point until day+28, and in addition with suppressor of tumorigenicity (ST)2 and interleukin-18. Conclusions: EASIX is a powerful predictor of early sepsis and 6-months NRM, irrespective of detected pathogens. Patients with EASIX-pre>2.32 represent a high-risk cohort requiring intensive prophylaxis and endothelial protective treatment strategies. Figure 1 Figure 1. Disclosures Schönland: Pfizer: Honoraria; Janssen: Honoraria, Other: Travel grants, Research Funding; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding; Takeda: Honoraria, Other: Travel grants. Hegenbart: Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Research Funding; Alnylam: Honoraria; Akcea: Honoraria; Prothena: Research Funding. Schmitt: Apogenix: Research Funding; Hexal: Other: Travel grants, Research Funding; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Bluebird Bio: Other: Travel grants; MSD: Membership on an entity's Board of Directors or advisory committees; TolerogenixX: Current holder of individual stocks in a privately-held company. Dreger: Novartis: Consultancy, Speakers Bureau; Bluebird Bio: Consultancy; Janssen: Consultancy; Gilead Sciences: Consultancy, Speakers Bureau; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau.

Bendamustine-induced nephrogenic diabetes insipidus – A case report

Introduction In patients with relapsed or refractory lymphoma, high-dose chemoimmunotherapy with subsequent autologous hematopoietic cell transplantation (HCT) is a standard of care. Bendamustine, an alkylating agent, is used in the BeEAM (bendamustine, etoposide, cytarabine, melphalan) protocol for conditioning therapy before autologous HCT in patients with relapsed or refractory lymphoma who are eligible for transplant. There is no consensus regarding an optimal salvage regimen and the approach varies according to toxicity. Case report We present a case of partial nephrogenic diabetes insipidus after receiving bendamustine, as part of the BeEAM protocol. Management and outcome: The patient was managed with parenteral fluid administration and intranasal desmopressin before the condition resolved on its own. Discussion We summarize published reports of bendamustine-induced diabetes insipidus.

Autonomic conditioning therapy reduces fatigue and improves global impression of change in individuals with post-acute COVID-19 syndrome

Post-acute COVID-19 syndrome (PACS) is a collection of persistent and debilitating symptoms lasting weeks to months after acute COVID-19 infection, with fatigue most commonly reported. There is controversy surrounding the role of exercise programs for this condition, due to concerns over the potential to worsen fatigue. We developed a novel physical therapy program known as Autonomic Conditioning Therapy (ACT) for PACS, and report on the preliminary patient-reported outcome (PRO) data from individuals who completed ACT for PACS, compared with those who did not. Seventy-eight (55 [71%] female, median [range] age 43 [12 to 78]) met the inclusion criteria and consented to have their data included in the analyses. A total of 31 (40%) individuals completed ACT for PACS. There was within-group improvement in fatigue in individuals who completed ACT for PACS (mean difference [95% CI] -14 [-27 to -1], p = 0.03), as well as greater between-group impression of change measured on the Patient Global Impression of Change scale (ACT for PACS median [range] 5 [1 to 7], no ACT for PACS 4 [1 to 7], p < 0.01). ACT for PACS is a novel physical therapy program that can reduce fatigue in individuals with PACS.

Variable CD34+ recovery of cryopreserved allogeneic HPC products: transplant implications during the COVID-19 pandemic

Donor registries and transplantation societies recommend cryopreservation of unrelated donor hemopoietic progenitor cell (HPC) products before the recipient commences conditioning therapy to mitigate the donor and travel risks associated with the COVID-19 pandemic. However, little is known regarding the postthaw quality of such allogeneic products or the effect of precryopreservation storage and processing on these characteristics. We investigated the postthaw CD34+ cell recovery and viability of 305 allogeneic HPC products cryopreserved at 9 laboratories across Australia. Median postthaw CD34+ cell recovery was 76% and ranged from 6% to 122%. Longer transit time before cryopreservation, white cell count (WCC) during storage, and complex product manipulation before cryopreservation were independently associated with inferior postthaw CD34+ cell recovery. Longer precryopreservation transit time and WCC were also associated with inferior postthaw CD34+ cell viability. We conclude that although postthaw CD34+ cell recovery and viability of cryopreserved allogeneic HPC is generally acceptable, there is a significant risk of poor postthaw product quality, associated with prolonged storage time, higher WCC, and complex product manipulation precryopreservation. Awareness of expected postthaw recovery and practices that influence it will assist collection, processing, and transplant centers in optimizing outcomes for transplant recipients.