Peri-transplant Period Research Articles

GRAIN Study - Granulocytes Against Infections - Use of granulocyte transfusion in haematopoietic stem cell transplant

Granulocyte transfusions (GTx) combat infections in neutropenic patients. However, immune-mediated off-target effects in transplant settings are unknown. Between January 2020 and December 2021, all transplants that used GTx during the peri-transplant period were analysed. Engraftment, infections, and days to clearance were retrieved from clinical records. Overall survival is compared with the mean total PMN count and the different products. Pooled buffy coat was used in 110 patients (98 %), of which 38 (34 %) additionally received an apheresed product. The median days of GTx was 4. The median bags pooled to prepare a single buffy coat product was 4. The mean total PMN count was 0.98 × 1010/ L granulocytes per pooled buffy coat and 1.93 × 1010/L granulocytes per apheresis product. A higher PMN count (>1 × 1010/L) was achieved in 48 % with pooled buffy coat versus 85 % with apheresis. Respiratory worsening occurred in 39 % receiving GTx. All patients who received granulocytes had engrafted with a median time of 14 days for neutrophil and 20 days for platelet engraftment. Blood cultures cleared in 81 %, whereas only 28 % cleared other cultures. Fungal pneumonia cleared in 25 %, and invasive fungal sinusitis or otitis cleared in 50 %. Overall survival was 47 %, non-significantly higher (57 % vs 39 %, P = 0.1) with a higher PMN dose. The pooled buffy coat is an affordable alternative to apheresis for an effective PMN dose. Ease of availability and low cost of pooled buffy coat, with comparable overall survival points toward a safe and efficacious product, in the peri-transplant period.

Invasive Fungal Disease in Pediatric Heart Transplant Recipients

Abstract Background The epidemiology of IFD following pediatric heart transplantation (pHT) is poorly characterized. We sought to evaluate use of antifungal prophylaxis and describe the epidemiology of IFD in pHT at two large children’s hospitals. Methods We performed a retrospective cohort study of pediatric and young adult (≤21 years) patients undergoing heart transplantation at Cincinnati Children’s Hospital Medical Center (CCHMC) and Children’s Hospital of Philadelphia (CHOP) between 2012 and 2021. We recorded demographic, clinical, medication, and laboratory data for pHT patients through 12 months post-transplant. We identified use of topical (oral nystatin) and systemic antifungal prophylaxes in the peri-transplant period (7 days prior through 14 days following transplant) and analyzed if certain transplant variables were associated with the administration of systemic antifungals during this period using rank sum and chi squared tests. Applying published definitions, we quantified the incidence of proven and probable IFD and explored the characteristics of these cases. Results A total of 201 patients underwent heart transplant at CCHMC and CHOP. The majority were male (60.2%), White (66.7%), and not Hispanic or Latino (88.1%). Median age at time of transplant was 7.4 years (IQR 0.9-14.2). During the peri-transplant period, 143 (71.1%) patients received oral nystatin and 37 (18.4%) received systemic antifungal prophylaxis, not including PJP prophylaxis. 41 individuals (20.4%) were not on any antifungal prophylaxis throughout this period. Delayed chest closure was significantly associated with the administration of systemic antifungals (p<0.001) while several other variables (age, hospital, immunosuppression medication, ECMO/LVAD pre-transplant) were not. In total, 8 patients (4%) developed proven (n=5) or probable (n=3) IFD. In our cohort, the incidence rate of proven/probable IFD in the first year post-transplant was 44.8 per 1000 patient-years. The characteristics of these cases are shown in Table 1. Time from pHT to IFD ranged from 11 days to 196 days (median time = 25.5 days). All cases of proven IFD occurred within 28 days of transplant. In three cases of proven/probable IFD, patients were receiving a systemic antifungal or PJP prophylaxis in the seven days prior to IFD onset. Two cases met the definition of probable IFD but the infections resolved without directed therapies. Four patients with proven IFD died within 1 year following transplant, although in only 3 cases was IFD a contributing factor. The one-year all-cause mortality rate among pHT patients with proven/probable IFD (50%) was higher than that in pHT patients without IFD (10.3%; Fisher’s exact p=0.008). Conclusion Over a 10-year period at CCHMC and CHOP, 4% of pHT patients developed proven or probable IFD within one-year post-transplant. All proven IFD cases occurred within a month of transplant while probable cases occurred more than 100 days post-transplant. Delayed chest closure was significantly associated with the administration of systemic antifungal prophylaxis. Patients with proven IFD had poor outcomes despite receipt of appropriate antifungal treatment. Given the low incidence of IFD at these two centers, we were unable to evaluate risk factors for IFD in this population and so larger studies would be needed.

Recent solid-phase microextraction-based analytical approaches for the profiling of biliary bile acids in pre-transplant assessments of liver grafts subjected to normothermic ex vivo liver perfusion

BackgroundLiver transplantation is the definitive treatment for end-stage liver failure, but the scarcity of donor organs remains a significant challenge. Leveraging organs from extended criteria donors (ECD) offers a potential avenue to address worldwide shortages, though these organs are more susceptible to post-reperfusion injury. This study explores the use of normothermic ex vivo liver perfusion (NEVLP) as a method for organ preservation – an approach that sustains liver metabolism and facilitates pre-transplant assessments of organ viability via bile analysis. The focal point of this study revolves on the development of analytical methods for determining the bile acid profile throughout the peritransplantation period as a potential indicator of liver function and viability. ResultsThe study optimized and validated a high-throughput analytical method to quantify selected bile acids in bile samples using a thin-film microextraction-liquid chromatography-mass spectrometry (TFME-LC-MS) platform. Furthermore, it introduced a solid-phase microextraction-microfluidic open interface-mass spectrometry (SPME-MOI-MS) method for rapid direct analysis of bile acid isobar groups. In the animal study, discernible variations in the concentrations of specific bile acids were observed between donors after circulatory death (DCD) and heart-beating donors (HBD), particularly following normothermic perfusion and reperfusion. Noteworthy fluctuations in individual bile acid concentrations were observed throughout the entire organ transplantation process, with taurocholic acid (TCA), glycocholic acid (GCA), and glycochenodeoxycholic acid (GCDCA) emerging as promising indicators of organ quality. The efficacy of the SPME-MOI-MS platform in corroborating these trends highlights its potential for real-time bile acid analysis during liver transplantation procedures. SignificanceOur findings underscore the efficacy of NEVLP in tandem with advanced bile acid analysis methods as a reliable strategy for pre-transplant assessments of organ viability, potentially increasing the use of ECD organs and reducing organ shortages. The ability to monitor bile acid profiles in real-time provides crucial insights into liver function and ischemic injury, making significant strides in improving transplant outcomes and patient survival rates.

Biomarkers in a phase 1b study of investigational microbiome therapeutic SER-155 in adults undergoing allogeneic hematopoietic cell transplantation (allo-HCT).

6554 Background: Acute graft- versus-host disease (aGvHD) is a life-threatening complication following allo-HCT. Microbiome dysfunction and associated GI barrier disruption may contribute to aGvHD via activation of inflammatory immune responses. Circulating biomarkers in the peri-transplant period are correlated with risk of severe aGvHD, including suppression of tumorigenicity 2 (ST2), regenerating islet-derived 3-alpha (Reg3a) and inflammatory cytokines (IL6, IFNϒγ & TNFα). SER-155 is an investigational cultivated oral microbiome therapeutic designed to restructure the GI microbiome, improve GI barrier integrity and reduce GI inflammation and is being assessed in a 2-part Phase 1b study in adults undergoing allo-HCT. We present preliminary safety, GvHD, PK, and exploratory biomarker data from the completed open-label Cohort 1 through Day 100 post-HCT. Methods: Adult recipients of allo-HCT were eligible. HCT conditioning and aGvHD prophylaxis were per investigator discretion. Patients received 2 courses of SER-155 (pre-HCT and post-neutrophil engraftment, each comprised of 4 days of microbiome conditioning with oral vancomycin followed by 10 days oral SER-155. The primary endpoint was safety. Strain engraftment (PK) and biomarkers were assessed in stool and plasma samples. Results: Fifteen adults enrolled; 13 received at least 1 course of study drug (median age 67; 54% male), and 11 underwent allo-HCT. Following each course, the majority of the 16 SER-155 strains were detected in stool. Treatment-emergent adverse events (AEs) were reported in all patients with GI AEs the most common. No serious AEs (SAEs) were deemed related to SER-155. Most SAEs and AEs of special interest (ie, BSIs, invasive or GI infections) occurred between HCT and the 2nd SER-155 course. There were no deaths before Day 100. No BSIs were attributable to SER-155 strains. The rate of grade 2-4 aGvHD based on MAGIC criteria through Day 100 was 45.5%; no severe grade 3-4 aGvHD was observed. Median levels of plasma biomarkers REG3α, ST2 and inflammatory cytokines were not elevated relative to a reference range (Table). Conclusions: In this small open-label cohort, SER-155 was generally well-tolerated through Day 100 without drug-related SAEs and no severe aGvHD. Plasma biomarkers were not elevated at HCT Day 0 or neutrophil recovery. These preliminary observations align with the design and preclinical evaluation of SER-155. Clinical trial information: NCT04995653 . [Table: see text]

#2578 Safety profile of dapagliflozin therapy in the kidney peritransplant period

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a class of glucose-lowering drugs that have demonstrated important cardio- and nephroprotective effects. These effects, according to preclinical data, may include attenuation of ischemia/reperfusion injury due to downregulation of pro-inflammatory cytokines and necroptosis mediators. This effect could be critical in the peritransplant period, protecting the allograft and potentially reducing delayed graft function (DGF). However, administration of SGLT2i immediately after deceased-donor kidney transplantation (KTx) could potentially be associated with adverse outcomes, such as urinary tract infections (UTI). We report the results of the first 10 patients of an ongoing study aimed at describing the safety profile of dapagliflozin in the peri-KTx period. Method Prospective, uncontrolled pilot study of consecutive, incident KTx patients that received a daily dose of dapagliflozin 10 mg, starting immediately before surgery and continuing until completing the first week post-transplant. All subjects provided informed consent for the study. Those with liver dysfunction, known allergy to SGLT2i, programmed for live-donor or multiorgan kidney transplantation or unable to provide informed consent were excluded. The primary outcome was the development of UTI during index hospitalization, defined either as a positive urine culture and/or symptoms suggestive of UTI. For comparison purposes, a retrospective sample of age- and sex-matched patients that received a KTx prior to the start of this study was included in this analysis. Two controls were selected for each case. Results Demographics and clinical characteristics of both patients in the study and retrospective controls are summarized in Fig. 1. Recipients that received dapagliflozin had similar rates of UTI when compared to controls, and were prescribed less frequently antibiotic therapy for UTI, although none of these differences reached statistical significance. Most cases of both groups consisted in asymptomatic bacteriuria. Of all four cases of documented UTI among treated patients, only one subject developed UTI during the days of dapagliflozin administration (the first 7 days after surgery). This patient did not require antibiotic therapy. The other three cases developed UTI after dapagliflozin discontinuation. Conclusion Results of this preliminary and limited experience lead us to believe that dapagliflozin in the peritransplant period may be a safe and feasible therapy that could help protect the renal allograft from ischemia/reperfusion injury.

Prevention and management of acute toxicities from conditioning regimens during hematopoietic stem cell transplantation.

Hematopoietic stem cell transplantation (HSCT) remains the only curative option for several hematological malignancies. Its use has continued to grow, with an estimated 23,500 transplants performed annually in the United States alone. The acute toxicities that occur from conditioning chemotherapy can impact the peri-transplant period and have substantial implications on patients' tolerability and outcomes, irrespective of the treatment of their disease. Chemotherapy-induced nausea vomiting (CINV), mucositis, transplant-associated thrombotic microangiopathy (TA-TMA), and sinusoidal obstruction syndrome, also known as a veno-occlusive disease (SOS/VOD) can all have significant implications for patients. These acute complications begin with the start of conditioning chemotherapy and add to potential toxicity for patients throughout the early post-transplant period, from Day +30 for CINV, mucositis, and SOS, and which can continue through at least Day +100 with the onset of TA-TMA. These toxicities must be prevented and managed appropriately. This review will summarize the literature surrounding them and guide their management.

Inhibition of Toll-like Receptor 4 Using Small Molecule, TAK-242, Protects Islets from Innate Immune Responses.

Islet transplantation is a therapeutic option to replace β-cell mass lost during type 1 or type 3c diabetes. Innate immune responses, particularly the instant blood-mediated inflammatory reaction and activation of monocytes, play a major role in the loss of transplanted islet tissue. In this study, we aimed to investigate the inhibition of toll-like receptor 4 (TLR4) on innate inflammatory responses. We first demonstrate a significant loss of graft function shortly after transplant through the assessment of miR-375 and miR-200c in plasma as biomarkers. Using in vitro models, we investigate how targeting TLR4 mitigates islet damage and immune cell activation during the peritransplant period. The results of this study support the application of TAK-242 as a therapeutic agent to reduce inflammatory and innate immune responses to islets immediately following transplantation into the hepatic portal vein. Therefore, TLR4 may serve as a target to improve islet transplant outcomes in the future.

Modification of Preservative Fluids with Antioxidants in Terms of Their Efficacy in Liver Protection before Transplantation.

Transplantation is currently the only effective treatment for patients with end-stage liver failure. In recent years, many advanced studies have been conducted to improve the efficiency of organ preservation techniques. Modifying the composition of the preservation fluids currently used may improve graft function and increase the likelihood of transplantation success. The modified fluid is expected to extend the period of safe liver storage in the peri-transplantation period and to increase the pool of organs for transplantation with livers from marginal donors. This paper provides a literature review of the effects of antioxidants on the efficacy of liver preservation fluids. Medline (PubMed), Scopus, and Cochrane Library databases were searched using a combination of MeSH terms: "liver preservation", "transplantation", "preservation solution", "antioxidant", "cold storage", "mechanical perfusion", "oxidative stress", "ischemia-reperfusion injury". Studies published up to December 2023 were included in the analysis, with a focus on publications from the last 30 years. A total of 45 studies met the inclusion criteria. The chemical compounds analyzed showed mostly bioprotective effects on hepatocytes, including but not limited to multifactorial antioxidant and free radical protective effects. It should be noted that most of the information cited is from reports of studies conducted in animal models, most of them in rodents.

Limitations of antifungal prophylaxis in preventing invasive Candida surgical site infections after liver transplant surgery.

Invasive primary Candida surgical site infections (IP-SSIs) are a common complication of liver transplantation, and targeted antifungal prophylaxis is an efficient strategy to limit their occurrence. We performed a retrospective single-center cohort study among adult single liver transplant recipients at Duke University Hospital in the period between 1 January 2015 and 31 December 2020. The study aimed to determine the rate of Candida IP-SSI according to the peri-transplant antifungal prophylaxis received. Of 470 adult single liver transplant recipients, 53 (11.3%) received micafungin prophylaxis, 100 (21.3%) received fluconazole prophylaxis, and 317 (67.4%) did not receive systemic antifungal prophylaxis in the peri-transplant period. Ten Candida IP-SSIs occurred among 5 of 53 (9.4%) micafungin recipients, 1 of 100 (1.0%) fluconazole recipients, and 4 of 317 (1.3%) recipients who did not receive antifungal prophylaxis. Our study highlights the limitations of antifungal prophylaxis in preventing invasive Candida IP-SSI after liver transplant surgery. We hypothesize that pathogen, host, and pharmacokinetic-related factors contributed to the occurrence of Candida IP-SSI despite antifungal prophylaxis. Our study reinforces the need for a risk-based, multi-pronged approach to fungal prevention, including targeted antifungal administration in patients with risks for invasive candidiasis and close monitoring, especially among patients with surgically complex procedures, with timely control of surgical leaks.

Prevention of Delayed Graft Function in Kidney Transplant Recipients through a Continuous Infusion of the Prostaglandin Analogue Iloprost: A Single-Center Prospective Study.

Delayed graft function (DGF) is common after kidney transplantation from deceased donors and may significantly affect post-transplant outcomes. This study aimed to evaluate whether an innovative approach, based on the administration of the intravenous prostaglandin analogue iloprost, could be beneficial in reducing the incidence of DGF occurring after kidney transplantation from deceased donors. This prospective, randomized (1:1), placebo-controlled study enrolled all consecutive patients who received a kidney transplant from a deceased donor from January 2000 to December 2012 and who were treated in the peri-transplant period with the prostaglandin analogue iloprost at 0.27 μg/min through an elastomeric pump (treatment group) or with a placebo (control group). A total of 476 patients were included: DGF was reported in 172 (36.1%) patients in the entire cohort. The multivariate analysis showed that the donor's age > 70 years (OR 2.50, 95% confidence interval (CI): 1.40-3.05, p < 0.001), cold ischemia time > 24 h (OR 2.60, 95% CI: 1.50-4.51, p < 0.001), the donor's acute kidney injury (OR 2.71, 95% CI: 1.61-4.52, p = 0.021) and, above all, the recipient's arterial hypotension (OR 5.06, 95% CI: 2.52-10.1, p < 0.0001) were the strongest risk factors for developing post-transplant DGF. The incidence of DGF was 21.4% in the treatment group and 50.9% in the control group (p < 0.001). Interestingly, among patients who developed DGF, those who received iloprost had a shorter duration of post-transplant DGF (10.5 ± 8.3 vs. 13.4 ± 6.7, days, p = 0.016). This study showed that the use of a continuous infusion of iloprost could safely and effectively reduce the incidence of DGF in recipients of deceased-donor kidneys, allowing a better graft functionality as well as a better graft survival.

The Role of Neuromonitoring During Anaesthesia of Liver Transplantation: A Case Report

Background: Acute hepatic failure (ALF) is a disease characterized by rapid deterioration of hepatic function with encephalopathy in a patient without pre-existing liver disease. Bispectral Index (BIS) during the peri-transplant period in patients with fulminant hepatic failure had an important role and its values had a significant correlation with cerebral perfusion. Transcranial Doppler (TCD) can assess changes in cerebrovascular function and has the advantages of being noteworthy, safe, and widely available. Case report: This is a case report of a serious hepatic encephalopathy occurring during a deceased donor liver transplant (LT) in a patient presenting fulminant hepatitis. Discussion: We briefly discuss some diagnostic methods highlighting the role and the challenges of the anaesthesiologist in managing this kind of patient in the context of a major surgery. Keywords: Anaesthesia, Bispectral index monitor, Doppler transcranial ultrasonography, Fulminant liver failure, Hepatic encephalopathy, Intracranial hypertension, Liver transplantation

Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study.

Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.

Planning GvHD preemptive therapy: risk factors, biomarkers, and prognostic scores.

Prevention of acute and chronic graft-versus-host disease (aGvHD and cGvHD) is an important objective of allogeneic hematopoietic cell transplantation (HCT). While there is has been significant progress in preventative approaches in the peritransplant period to minimize development of GvHD, no preventative approach has completely eliminated development of either aGvHD or cGvHD. Recently, posttransplant immune biomarker profiling early post-HCT by the Mount Sinai Acute GvHD International Consortium group has resulted in a validated risk assignment algorithm and development of preemptive approaches to decrease aGvHD and mortality in high-risk patients. cGvHD risk assignment algorithms have been developed based on measurements at day 100 and may be used for future preemptive intervention trials to minimize cGvHD. This article discusses the current state of the art in aGvHD and cGvHD preemptive algorithms and therapeutic interventions and what is needed to move these into validated approaches.

Endo-Hepatology: The Buzz Goes Much beyond Liver Biopsy—A Narrative Review

AbstractThe word endo-hepatology evokes many perceptions. Some believe it to be the emerging new interventional branch and some believe it to be an extension of endoscopy. Nonetheless, it has continued to evolve into an exciting area of active work. With the advent of endoscopic ultrasound (EUS) based procedures, new vistas have opened up. EUS-guided liver biopsies, portal hypertension management, and multiple new procedures are being described. EUS also plays a large role in the management of patients in the peritransplant period. With this review, we present an overview of the role of EUS in the field of hepatology as well as during the peritransplant period and its applications.

A Phase 2, Single-Arm, Multicohort, Open Label, Multicenter Trial of Off-the-Shelf Natural Killer Cells (SAR445419) in Patients with High-Risk Myeloid Malignancies Undergoing Allogeneic HSCT

Background and Significance: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although the risk depends on parameters such as age and conditioning intensity, relapse is experienced in 30-50% of patients after conventional HSCT in high-risk AML/MDS. Initial safety and post-HSCT relapse risk reduction results were reported in a phase I study of haploidentical (haplo) donor-derived natural killer (NK) cells expanded ex vivo on feeder cells expressing IL-21 and 4-1BBL in conjunction with haplo-HSCT (Ciurea et al, Leukemia, 2022). This study supported exploring SAR445419 (SAR'419), an off-the-shelf (OTS) product, derived from universal donor NK cells and expanded ex vivo in a feeder cell-free system using plasma membrane particles bearing membrane-bound IL-21 and 4-1BBL. Here, we aim to test whether SAR'419 can mediate an effective anti-leukemia response and reduce post-transplant relapse rate when administered in the peri-transplant period. Study Design and Methods: In this multicenter, multicohort, phase 2, single-arm trial (NCT05726682), patients with high-risk AML/MDS planned for allo-HSCT from matched sibling, matched unrelated or haplo donors will be enrolled in 2 cohorts. Cohort A will comprise patients aged 18‒65 years undergoing myeloablative conditioning with hematopoietic cell transplantation comorbidity index ≤3 and cohort B will comprise patients aged 18‒75 years undergoing reduced intensity conditioning. Patients with prior allogeneic transplantation or AML beyond first complete remission will be excluded from the study. Patients will undergo HSCT conditioning starting on Day ‒7 and will receive a peripheral blood stem cell graft on Day 0. Prophylaxis for Graft-versus-host disease (GVHD) using cyclophosphamide, mycophenolate mofetil, and tacrolimus will start on Day +3. SAR'419 will be administered as adjunctive therapy to the HSCT on Day ‒2, Day +7, and Day +28. To confirm the anticipated safety profile of SAR'419, a safety run-in will be conducted in 6‒12 patients in each cohort prior to open enrollment. Patients will be enrolled until 51 and 44 patients in cohorts A and B, respectively, receive at least the first 2 doses of SAR'419 at the target dose confirmed during safety run-in. In total, approximately 107 patients will be enrolled. The primary endpoint, relapse free survival (RFS), will be assessed at 12 months post-HSCT. Additional primary endpoints include frequency of graft failure, life-threatening infusion-related reactions or cytokine release syndrome, tumor lysis syndrome, immune cell-associated neurotoxicity syndrome, acute GVHD, overall mortality at 100 days post-HSCT, non-relapse mortality, and cytomegalovirus reactivation/infection. Secondary endpoints are safety, tolerability, and the impact of SAR'419 on HSCT outcomes, stem cell engraftment, GVHD, infection, and quality of life. Exploratory assessments include evaluation of the impact of SAR'419 on immune reconstitution, cytomegalovirus seroconversion, minimal residual disease, resource utilization, SAR'419 immunogenicity and persistence and their impact on outcomes in whole blood (including serum and plasma) and bone marrow aspirates. RFS will be reported as the percentage of patients who are relapse free and alive at 12 months from the date of HSCT and who received at least the first 2 planned doses of SAR'419. Adverse events will be graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 and will be summarized using descriptive statistics.

Efficacy of Venetoclax Combined with Decitabine Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in High-Risk and Elderly Patients with Myeloid Neoplasms

Background High-risk and elderly patients with myeloid neoplasms are a special group because it's challenging to find the right balance between safety and efficacy during the peri-transplant period. Traditional transplant protocols have unsatisfactory treatment outcomes for patients with a high risk of recurrence, while the elderly couldn't tolerate the toxicity of high-dose chemotherapy drugs. Thus, new regimens are needed to improve treatment outcomes for high-risk and elderly patients. Through BCL-2 binding, venetoclax could induce leukemia cell apoptosis, increase chemosensitivity, and perform a synergistic role with HMAs. And its combination with HMAs or other cytotoxic drugs showed a promising effect on R/R AML. This prospective clinical study reported the efficacy and safety of adding venetoclax and decitabine to myeloablative conditioning regimens in high-risk and elderly patients receiving allogeneic hematopoietic stem cell transplantation. Methods We performed an investigator-initiated, prospective, one-arm, single-center, open-label trial. In total, 19 patients were enrolled in the trial between December 2021 and February 2023. Eligible patients met the following inclusion criteria: (1) undergoing allo-HSCT over the age of 50 years (i.e., ≥50 years), (2) having an Eastern Cooperative Oncology Group performance status of 0-2, and (3) having AML, MDS, and CMML with a high risk of recurrence: (a) For patients with MDS, (i) a diagnosis of MDS with excess blasts 2 (EB-2), (ii) a poor karyotype, (iii) a very high-risk disease according to the International Prognostic Scoring System-Revised, and (iv) a TP53 mutation; (b) For patients with AML, (i) relapsed/refractory AML, (ii) detected MRD test before transplantation, (iii) with adverse risk according to the European Leukemia Net (ELN) Guidelines 2017, and (iv) AML transformed from MDS or CMML. Venetoclax was administered at 400 mg per day orally from day -14 to day -1 in the initial regimen and from day -14 to day -5 in the modified regimen. Decitabine was administered at 20mg/m 2/d orally from day -7 to day -3. Detailed dosage of the Bu/Flu/Cy comprised of fludarabine 30 mg/m 2/d IV Qd, day -4 to -2, busulfan 3.2 mg/kg/d IV Q6h, day -7 to -5, and cyclophosphamide 40mg/kg/d IV Qd, day -3 to day -2. Either rabbit ATG or porcine ATG was administered at 2.5mg/kg/d IV Qd, day -4 to -1, or 20mg/kg/d IV Qd, day -3 to -1 for GVHD prophylaxis. Results 19 patients were enrolled in the trial with a median follow-up time of 258 (range, 35-544) days. Grade 3/4 adverse events included hematological events, hypertension, infections, allergy, and increased amylase. The 30-day cumulative incidence of neutrophil and platelet engraftment was 100% and 68% (Figure 1A). Acute GVHD occurred in 9 of 19 patients (grade I, n=2; grade II, n=1; grade III, n =4; grade IV, n =2). The cumulative incidence of grade II to IV acute GVHD events at 100 days was 31% (95% confidence interval (CI], 12-53) among all patients, and 45% (95% CI, 15-72), and 13% (95% CI, 0-45) for the initial regimen group and the modified regimen group, respectively (p=0.28, Figure 1B, C). While 1 patient in the modified regimen group occurred diarrhea and was clinically diagnosed with grade III acute GVHD (late-onset) at 132 days post-HSCT. The cumulative incidence of chronic GVHD at 1 year was 37% (95% CI, 16-58). For the entire cohort, OS and RFS at 6 months was 63% (95% CI, 45-89) and 63% (95% CI, 45-89), and the NRM and CIR at 6 months was 37% (95% CI, 16-58) and 0, respectively (Figure 1D, E). All 8 deaths were attributed to transplant-related complications, including 4 patients from aGVHD, 2 patients from infection, 1 from transplant-associated thrombotic microangiopathy (TA-TMA) and 1 from bloody pleural effusion. Here it should be pointed out that the patient with bloody pleural effusion couldn't exclude the probability of tumor invasion because he had previous esophageal carcinoma. Conclusion In conclusion, although the hematological and molecular recurrence rate of the venetoclax combined with the decitabine conditioning regimen is significantly decreased, the high incidence of severe aGVHD and NRM limits its clinical application. It still needs further exploration to optimize the conditioning regimen for high-risk and elderly patients with myeloid neoplasms.

Assessment of Inpatient Mortality in the Peri-Transplant Period in Elderly Allogeneic Stem Cell Transplant Recipients with Co-Existing Mental Health Illnesses

Background Allogeneic hematopoietic stem cell transplant (alloHCT) is a potentially curative treatment for patients with hematological malignancies and nonmalignant conditions. AlloHCT involves invasive procedures, conditioning chemotherapy regimens, and prolonged isolation during hospitalization, which is physically and emotionally challenging. Transplant related mortality is higher in older individuals. Careful assessment of mortality risk before transplant is essential for optimal patient selection and informed decision-making, especially in elderly patients. Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), an important prognostic scoring tool used in patients before alloHCT, includes psychiatric comorbidity as one of the scoring criteria. Patients with depression or anxiety disorders receive one point on the scoring scale, with the assumption that the two groups of patients are at an equivalent risk. However, there is literature showing decreased overall survival and worse inpatient outcomes in patients receiving alloHCT with co-morbid depression. Our primary objective was to evaluate the inpatient outcomes of elderly patients undergoing allogeneic stem cell transplant with a concurrent diagnosis of depression and patients with anxiety and adjustment disorders. Methods: Patients of ages ≥ 60 years, admitted with a principal procedure code of allogeneic stem cell transplant, were recruited from the 2016-2020 National Inpatient Sample. Three cohorts were created based on ICD-10 diagnostic codes for Depression and Anxiety and adjustment disorders: patients without depression and anxiety disorders, patients with depression only, and patients with anxiety and adjustment disorders only. Patients with diagnoses of other mental illnesses were excluded. The patient characteristics between the three cohorts were evaluated. Multiple Logistic Regression models were used to determine the impact of depression and anxiety disorders on inpatient mortality. Results: We evaluated 11655 hospital admissions with the primary procedure code for Allogeneic Stem Cell Transplant in patients aged 60 years and above. 8375 patients did not have any mental illness. 800 patients (9.5%) had a diagnosis of Depression, and 1640 patients (19.5%) had a diagnosis of Anxiety and adjustment disorders. Comparing the primary outcomes in patients with and without Depression, the length of stay was 31.3 days vs 28.2 days (p&amp;lt;0.01), the mean hospital charge was 558398.01 USD vs 498971.9 USD (p &amp;lt;0.01), and in-patient mortality was 8.1% vs 5.9% (aOR = 1.359, 95% CI 1.010-1.829, p=0.04). Utilization of mechanical ventilation was more prevalent in patients with depression (8.8 %vs 5.8 %, p &amp;lt;0.01). Out of different infectious complications, pneumonia was more common in patients with depression (14.4 % vs 9.8 %, p &amp;lt;0.01) (Table 1a). Baseline socio-demographic characteristics that were associated with having depression included: Female gender, White race, and Medicare insurance. Patients with depression had an increased prevalence of congestive heart failure, prior stroke, Obesity with BMI &amp;gt;= 35, chronic kidney disease, and COPD compared to patients without depression (p&amp;lt;0.01). For the primary outcomes in patients with and without anxiety and adjustment disorders, the length of stay was 29.15 days vs 28.2 days (p &amp;lt;0.01), the mean hospital charge was 474274.71 USD vs 498971.94 USD (p 0.612), and the in-patient mortality was 4% vs 5.9 % (aOR=0.61, 95% CI 0.45-0.83, p&amp;lt;0.01). Baseline socio-demographic characteristics that were prevalent in patients with anxiety and adjustment disorders were: female gender, white race, and Medicare as the most common insurance (P&amp;lt;0.01) (Table 1b). Conclusion We found that in elderly patients admitted for alloHCT, depression was independently associated with worse inpatient outcomes, while anxiety was not. Patients with depression were noted to have an increased incidence of infectious complications as compared to those without depression, possibly accounting for their increased mortality. Prognostic scoring systems like HCT-CI may need to be modified to assign more weight to depression as a psychiatric co-morbidity. Elderly transplant recipients with depressive disorders are a vulnerable group and multidisciplinary teams such as psychiatry and palliative care should be involved in their care.

Patient Recorded Outcomes from a Randomized, Controlled Phase 2 Trial of E-Selectin Inhibition with Uproleselan Vs Placebo to Reduce GI Toxicity during Melphalan-Conditioned Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Background: The use of high-dose melphalan conditioning followed by autologous hematopoietic cell transplant (AHCT) continues to be a key component in the treatment of patients with multiple myeloma (MM). However, high-dose melphalan is associated with a high rate of GI toxicity (&amp;gt;90%), which adversely impacts clinical outcomes and negatively influences patient quality of life (QoL). Indeed, it has been reported that AHCT leads to short-term deterioration of health-related QoL in patients with MM, and QoL typically improves by 2-3 months post-AHCT. Pre-clinical and clinical data suggest that E-selectin inhibition may play a role in reducing immune-mediated GI epithelial injury following cytotoxic chemotherapy. We hypothesized that uproleselan (upro), a synthetic, competitive E-selectin antagonist, may improve health-related QoL by reducing risk of chemotherapy-induced diarrhea in patients undergoing AHCT. Methods: We conducted a Phase 2, single-center, randomized, double-blind, placebo-controlled trial in patients with MM receiving high-dose melphalan (200 mg/m2) as conditioning for AHCT for MM. Patients were randomized 1:1 to receive prophylactic upro+standard of care (SoC) vs placebo+SoC. Uproleselan was given in 6 doses of 800 mg IV starting on day-3 through day 0. The primary endpoint was diarrhea severity as assessed by CTCAE v5.0 (secondary endpoint - Bristol Stool Scale). In addition, a key secondary endpoint was patient reported outcomes (PRO) of GI-related QoL using the National Cancer Institute (NCI) PRO-CTCAE Measurement System, a validated PRO tool developed to evaluate symptomatic toxicities in patients with cancer in clinical trials. Significance level of p&amp;lt;0.2 was pre-specified for all endpoints, per protocol. Patients were surveyed during the peri-transplant period at day-3 (baseline), day+8, and day+14 or day of discharge (DoD). Responses were graded on a scale of 1-5, with 1 indicating absence of symptoms or zero interference with daily activities and 5 indicating very severe symptoms or very significant interference with daily activities. GI-specific domains assessed included swallowing, mouth sores, appetite, nausea, vomiting, heartburn, bloating, abdominal pain, flatulence, and incontinence. Results: Fifty adult patients with MM were enrolled from 5/2021-10/2022. Baseline PRO symptoms were similar between the upro+SoC and placebo+SoC arms at baseline (day-3). By day+8 post-AHCT patients in the upro+SoC arm reported a significant improvement in severity of GI-related symptoms across 30% (6/20) of domains surveyed vs placebo+SoC (p=0.07-0.14). Furthermore, improvement in mouth sore-related symptoms continued to day+14 post-AHCT in the upro+SoC arm vs placebo+SoC (p=0.17). The remaining GI-related symptoms returned to baseline by D+14 or DoD (p&amp;gt;0.20). Also of note, a numerically lower mean diarrhea severity score and lower incidence of Grade 3 diarrhea (by CTCAE v5.0) was observed favoring upro+SOC which did not meet the pre-specified significance threshold (p=0.34, p=0.26, respectively). However, a significant reduction in severe diarrhea (by Bristol Stool Scale) was observed favoring upro+SoC (p=0.10) vs placebo+SoC, with improvement in the upro+SoC arm to mild diarrhea (p=0.02). Conclusions: Upro+SoC resulted in a clinically significant improvement in GI-toxicity related symptoms as assessed via PRO-CTCAE in patients with MM undergoing melphalan-conditioned AHCT, when compared to placebo+SoC. These improvements in patient reported outcomes are further supported by data from the primary and additional secondary endpoints of the study. Taken together, these results suggest prophylactic E-selectin inhibition may represent a promising strategy to mitigate chemotherapy-associated GI-toxicity. Further studies are needed to verify these findings and to further define the optimal dosing of upro in the peri-AHCT period.

“Transplant Changes Your Life”: Communication Strategies of Transplant Hematologists in High Risk Decision Making Conversations

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) offers a chance of cure for many patients with blood cancers including higher risk myelodysplastic syndromes (MDS) but carries many risks. In this high risk, high reward situation, shared decision making is essential to empower patients to make goal-concordant decisions. We detail communication strategies hematologists use to discuss treatment options including alloHCT and to facilitate shared decision making with patients. Methods: Our research team recruited hematologists who routinely perform alloHCT in the United States through email. Participants conducted a video-recorded virtual encounter lasting up to one hour with an actor portraying a 67-year-old man with recently diagnosed high risk MDS referred for specialty hematology consultation to discuss treatment options including alloHCT. We transcribed and qualitatively analyzed hematologists' communication approaches. Results: Participants (n=37) from 25 institutions were a median age of 44 years (range 33-73 years) and mostly male (65%) and white (65%). More than half spent &amp;gt;50% of their clinical time in managing alloHCT patients. Hematologists followed a similar conversation structure, though varied in the amount of detail they provided within each of the main sections (Figure 1). Their conversation routinely included an assessment of the patient's perception of his condition, information about MDS, and discussion of treatment options including transplant and chemotherapy and less commonly supportive care or a clinical trial. Many repeatedly highlighted that transplant was the only option with the potential for cure. Their discussion about transplant frequently followed a chronological approach from pretransplant considerations including donor issues, formal fitness testing, and disease control; to the peri-transplant period and hospital experience; and through the posttransplant course including need for dedicated caregiver support. Hematologists discussed risks, complications, and major outcomes at varying lengths. Decision making talk occurred at different points in the visit though was often concentrated in the latter part of the conversation. Hematologists referred to several elements that formed the basis of treatment decision making (Figure 2). While hematologists indicated that multiple factors should inform the patient's and hematologist's decision making, many honed in on transplant's position as the only chance for long-term survival. Although most hematologists acknowledged on a general level the importance of patients' goals and preferences in decision making, they elicited and incorporated the individual patient's specific goals into the discussion to varying degrees. Instead, in several conversations, hematologists' assessment of the patient's fitness and candidacy for transplant was prominent in their discussion about whether the patient could and should consider pursuing the curative option. Hematologists frequently recommended that the patient take time to think and talk with his family about the treatment decision in the immediate future. The strength of their longer-term recommendations ranged from strong recommendations for transplant or chemotherapy to conditional recommendations for transplant or deferral pending further information. These recommendations reflected a range of decision-making strategies, from a physician-led approach to a primarily patient-guided effort. In the middle, some hematologists described a collaborative effort with the patient, in which the patient and hematologist would work together to reach a shared decision. Within a single encounter, many hematologists expressed various statements suggesting that their approach to decision making did not fit tightly within a single domain but rather fell along a continuum which evolved as the encounter proceeded. Conclusions: The transplant decision making discussion is complex. The ways in which hematologists frame information and engage patients affect how they make decisions together. Hematologists consistently discuss similar major content areas as they navigate from beginning to end; identification of these key components can be used as the basis for creation of a communication tool to help hematologists discuss alloHCT with patients.

Pregnancy prediction via ultrasound-detected endometrial blood for hormone replacement therapy-frozen embryo transfer: a prospective observational study

BackgroundThis study aimed to assess the predictive value of endometrial blood flow branches on pregnancy outcomes after hormone replacement therapy-frozen embryo transfer (HRT-FET).MethodsThis prospective observational study involved 292 reproductive-aged women who underwent endometrial receptivity assessment in a tertiary care academic medical center in southwest China using power Doppler ultrasonography during HRT-FET. Three-dimensional power Doppler ultrasound was performed on the day of endometrial transformation and the day before embryo transfer. The endometrial blood flow branches of the endometrial and subendometrial regions were compared in the non-pregnant and pregnant groups at the two time points mentioned above.ResultsThe endometrial blood flow branches were higher in pregnant patients than in non-pregnant patients on the day of endometrial transformation (P = 0.009) and the day before embryo transfer (P = 0.001). Changes in endometrial blood flow pattern and endometrial blood flow branches at the two time points did not differ among the pregnancy outcome samples. After adjusting for age, antral follicles, and embryos transferred, the endometrial blood flow branches on the day before embryo transfer was the independent factor influencing the chance of clinical pregnancy, with an odds ratio of 3.001 (95% confidence interval: 1.448 − 6.219, P = 0.003).ConclusionsEndometrial blood flow perfusion during the peri-transplantation period of the HRT-FET cycle is a good indicator of pregnancy outcomes, suggesting that valuation of endometrial branches via power Doppler ultrasound is a simple and effective approach for achieving indicator measurements.