Allogeneic Stem Cell Transplant Patients Research Articles

Neurological complications in adult allogeneic hematopoietic stem cell transplant patients: Incidence, characteristics and long-term follow-up in a multicenter series.

Neurological complications (NCs) represent a diagnostic and clinical challenge in allogeneic hematopoietic stem cell transplant (alloHSCT) patients. We retrospectively analyzed NC incidence, etiology, timing, characteristics, outcome, and long-term effects in 2384 adult patients transplanted in seven Italian institutions between January 2007 and December 2019. Ninety-three (3.9%) patients were affected by 96 NCs that were infectious (29.2%), immune/inflammatory (26%), drug-related (12.5%), cerebrovascular (5.2%), metabolic (3.1%), related to central nervous system disease relapse (11.5%) and malignancy (3.1%), or undefined (9.4%). Six patients (6.4%) had neurological manifestations of chronic graft-versus-host disease (GVHD). NCs occurred on average at day +128 (from -5 to +4063). Early (< day +120) and late NCs had similar frequencies (46.9% vs 53.1%, p = 0.39). Thirty-one patients (33.3%) were affected by acute or chronic GVHD at the NC onset. With a median follow-up of 25.4 (0.4-163) months, the overall mortality due to NCs was 22.6%. The median time between NC onset and death was 36 (1-269) days. Infectious NCs were the main cause (61.9%) of NC-related mortality. A persistent neurological impairment occurred in 20.4% patients, 57.9% of whom being affected by immune/inflammatory NCs. This study highlights the rare, yet severe impact of alloHSCT-associated NCs on patient survival and long-term functional ability.

Circulating endothelial cells and endothelial progenitor cells as potential predictors of acute GVHD after allogeneic hematopoietic stem cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation. Endothelial cell damage may trigger the initiation of aGVHD. Endothelial damage and repair were evaluated by counting circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in 17 allogeneic hematopoietic stem cell transplantation patients at pre-conditioning, day 0, day 7, day 14, day 30, and day 60 by multicolor flow cytometry. Von Willebrand factor activity was simultaneously measured. Eight patients developed aGVHD and were compared to non-aGVHD patients. Patients' characteristics were not different, except for previous treatment courses. There was no difference in von Willebrand factor activity between the two groups. Both CEC and EPC counts were decreased on day 7 and day 14 and then increased thereafter. The CEC count on day 7 was significantly lower in the aGVHD group than in the non-aGVHD group (p=.0401). Restoration of the EPC count on day 60 was significantly suppressed in the aGVHD group (p=.0464). The CEC count on day 7 could predict aGVHD development (AUC 0.8214, p=.0372). The present results showed that CEC count on day 7 could be a predictor of aGVHD.

Evaluation of a group-based exercise and relaxation rehabilitation program during hospitalization for allogeneic hematopoietic stem cell transplant.

Exercise and relaxation interventions have demonstrated benefits in allogeneic hematopoietic stem cell transplant (allo-HSCT) patients; however, little is known about the implementation enablers and barriers for inpatient rehabilitation or its impact on health outcomes. To conduct a program evaluation of group-based rehabilitation consisting of exercise and relaxation classes for allo-HSCT inpatients. Prospective program evaluation using the RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) framework. Inpatient hospital unit at a tertiary care center. Forty-five adult patients admitted for allo-HSCT. Standard of care rehabilitation. Program attendance, safety, satisfaction, and fidelity were assessed. Exploratory effectiveness analyses were conducted via the measurement of physical, psychosocial, clinical, and health resource use outcomes at hospital admission and discharge. Forty-seven of the 63 patients receiving allo-HSCT between November 2019 and March 2020 were consented. Data presented in this publication are from the 33 participants who completed study assessments (high attrition due to cancellation of research during the COVID-19 pandemic). Eighty-two percent of participants attended at least one class; however, 55% of the participants invited to the classes on a daily basis were not able to attend. Barriers to participation included transplant complications, isolation for infection prevention, and fatigue. There were no adverse events associated with the intervention and 82% of participants adhered to the prescribed activities. Participants reported satisfaction with the program and enjoyed the motivational support and social interaction. Between hospital admission and discharge, anxiety scores improved; however, fatigue, depression, grip strength, functional mobility, and quality of life scores declined. Physical activity volume and lower body strength were maintained. Group-based exercise and relaxation classes seem to be feasible and safe during hospitalization for allo-HSCT; however, there are pragmatic barriers to be considered for optimal program implementation. Further research examining program effectiveness and adoption is warranted.

495 - Outcomes of COVID-19 Infection in Allogeneic Hematopoietic Stem Cell Transplant Patients Treated with Hyperbaric Oxygen: A Case Series

495 - Outcomes of COVID-19 Infection in Allogeneic Hematopoietic Stem Cell Transplant Patients Treated with Hyperbaric Oxygen: A Case Series

382 - Association of Tacrolimus Levels and Time from Transplant with Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant Patients

382 - Association of Tacrolimus Levels and Time from Transplant with Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant Patients

Ruxolitinib for the Treatment of Chronic GVHD and Overlap Syndrome in Children and Young Adults.

Ruxolitinib, a JAK1/2 inhibitor, is used to treat chronic graft versus host disease (cGVHD) in adult allogeneic hematopoietic stem cell transplant patients, but experience in children is limited, perhaps because of lack of pediatric dosing information. In this report, we describe our pediatric and young adult dosing strategy experience in cGVHD. Ruxolitinib was administered orally at 5 mg twice daily for children ≥25 kg or 2.5 mg twice daily if <25 kg. The dose was halved with concurrent azole administration and increased to a maximum of 10 mg twice daily if tolerated. Responses were evaluated using the 2014 NIH consensus criteria. Phosphorylation of lymphocyte STAT5 following dosing, a surrogate of JAK inhibition, was evaluated by flow cytometry. Twenty patients with a median age 14.6 y (range 5-26 y) received ruxolitinib for severe (n = 9) and moderate (n = 11) cGVHD. Median steroid dose was 0.5 mg/kg/d (range 0.08-1.5 mg/kg/d) at ruxolitinib initiation. Two patients with moderate cGVHD achieved a complete response (CR), while 12 patients achieved a partial response (PR) at a median of 48 d (range 17-98 d) from the first ruxolitinib dose, for an overall response rate of 70%. Eleven patients are maintaining their PRs. pSTAT5 on lymphocytes was absent or decreased (0%-6% events) in 5 evaluated patients, suggesting adequate inhibition. Three patients discontinued ruxolitinib because of neutropenia, thrombocytopenia, or elevated alanine aminotransferase. Four patients developed bacterial infections, and 3 experienced symptomatic viral infections. Two patients died from complications related to progressive severe cGVHD. Ruxolitinib using our dosing strategy demonstrates promise for treating cGVHD in children.

Salvage High-dose Melphalan With Autologous Stem cell Transplantation as Bridge to Consolidation Therapy for Chemoresistant Aggressive B-cell Lymphoma

BackgroundPatients suffering from refractory aggressive B-cell lymphoma not responding to salvage chemotherapy have a dismal prognosis. CAR T-cells or allogeneic stem cell transplantation (SCT) are potentially curative approaches. However, obtaining a remission, and lowering tumor burden before consolidation seems crucial for long-term efficacy of both treatment modalities. Materials and MethodsIn this retrospective analysis, we reviewed patients with chemoresistant aggressive B-cell lymphoma, defined as being refractory or progressive to at least second line salvage chemotherapy including the regimen immediately preceding autologous stem cell transplantation (ASCT), treated at 2 tertiary centers, who were eligible for intensive treatment using single agent high-dose (HD) melphalan to obtain a remission before consolidating therapy. ResultsWe identified 36 patients that received single agent HD melphalan and ASCT as remission induction followed by CAR T-cells or allogeneic stem cell transplantation (SCT). Thirteen of the evaluable patients (39.4%) achieved a partial remission and 9 patients (27.73%) a complete remission, resulting in an overall response rate (ORR) of 66.7%. High remission rates were seen across all subgroups including patients with primary refractory lymphoma (ORR 58.3%), uncontrolled disease and high tumor burden as indicated by increased LDH levels (ORR 66.7% for patients with elevated LDH above 2 times upper limit of norm). 22 patients proceeded to allogeneic SCT and 5 to CAR T-cell therapy. Treatment related mortality of ASCT was 5.5% (2 patients, both due to infections). Two-year overall survival of all patients was 15.8%, primarily due to a high non–relapse mortality (45.5%) of allogeneic SCT patients treated with myeloablative conditioning chemotherapy. ConclusionSingle agent HD melphalan produces high remission rates in patients with chemoresistant, uncontrolled aggressive B-cell lymphoma and provides a window of opportunity for consolidation therapy. MicroabstractPatient with refractory/relapsed aggressive B-cell lymphoma after salvage therapy are an unmet medical need because of their very poor prognosis. In our retrospective analysis of 36 patients we showed that single agent high-dose melphalan can achieve high response rates (ORR 66.7%) even in uncontrolled disease enabling consolidation therapy e.g. with allogeneic stem cell transplantation or CAR T-cell therapy.

Evaluating the Efficacy, Toxicity and Pharmacokinetic Profile of Oral Busulfan in Allogeneic Stem Cell Transplant Patients.

Oral busulfan and intravenous cyclophosphamide (Bu/Cy) are common myeloablative preparations used in allogeneic hematopoietic stem cell transplantation (HSCT). Herein, we investigated the safety of (Bu/Cy) administration during HSCT. Patients administered Bu/Cy for allogeneic HSCT at Royal Perth Hospital and Fiona Stanley Hospital between 2007 and 2017 were reviewed for inclusion in the study. We performed busulfan pharmacokinetic (PK) testing for a subset of patients and allometric scaling modeling to assess the best method of busulfan dosing in patients at extremes of weight. Sixty-nine patients were included in the clinical outcome analysis. The median follow-up period was 32 months (range, 9-114 months). The three-year overall survival rate was 62% (95% confidence interval (CI), 51%-75%), and transplant-related mortality was 4% at 6 months (95% CI, 1-7%), with a low rate of sinusoidal obstruction syndrome of the liver being observed. In addition, relapse was 38% (95% CI, 30%-44%) at 3 years. The PK information of 15 patients receiving busulfan was available after oral dosing. The average per-dose busulfan exposure was 1,350 μmol.min/L (range, 878-1,717 μmol.min/L), and the within target range was 1,000-1,500 μmol.min/L in 73% of patients. Of the size measures investigated, ideal and adjusted body weight (ABW40) provided the best fit. No association was observed between busulfan exposure, toxicity, and relapse. Overall, Bu/Cy administration appeared safe when dosed in relation to weight, showing a low early transplant-related mortality rate following adequate busulfan exposure in majority of the cases. Body size measures, such as ideal body weight or ABW40, are likely more suitable for use during busulfan dosing, particularly at high extremes of the body mass index classification.

Antibiotic Therapy and Gastrointestinal Graft-Versus-Host Disease in the Allogeneic Stem Cell Transplantation Population.

Purpose:Hematopoietic stem cell transplantation patients undergo rigorous courses of myeloablative chemotherapy that increase vulnerability for infections. Complications can arise in the form of graft-vs.-host disease (GvHD) manifesting in various organs, including the skin, lung, liver, and gastrointestinal (GI) tract. Antibiotic therapy is generally begun in order to prevent further complications from infection but may increase the risk for acute GI GvHD. Studies that investigated antibiotic therapy and the subsequent occurrence of GI GvHD in allogeneic stem cell transplantation (aSCT) patients were reviewed.Methods:PubMed, Scopus, and CINAHL databases were utilized. Articles published between January 1, 2009, and December 15, 2019, were included in this review. A total of 1,142 articles were retrieved. Duplicates, reviews, letters to the editors, irrelevant interventions/outcomes, and non-English articles were excluded. Inclusion criteria included individuals who were undergoing an aSCT and received antibiotic therapy. A total of seven articles were included for this review after applying the inclusion and exclusion criteria.Results:The use of broad-spectrum antibiotics increased the risk of developing GI GvHD. Stool analysis when available showed a decrease in the diversity of the gut microbiome, which in turn led to the increase in acute GvHD.Implications:The increased risk of GvHD may have implications for the standard of care therapy, which includes treatment, for infections during SCTs. Providers will need to weigh the risk vs. benefit of antibiotic therapy and exercise judicious selection of antibiotics prior to engraftment.

Exploring Stem Cell Transplanted Patients' Perspectives on Medication Self-Management and Electronic Monitoring Devices Measuring Medication Adherence: A Qualitative Sub-Study of the Swiss SMILe Implementation Science Project.

PurposeLittle is known about allogeneic stem cell transplant (alloSCT) patients’ medication adherence strategies. Acceptability and preferences regarding electronic monitoring (EM) systems to assess all three phases of medication adherence (ie, initiation, implementation, persistence) are crucial to allow their successful implementation in clinical or research settings but have not yet been evaluated. We therefore aimed to explore: 1) alloSCT patients’ medication adherence and self-management strategies; and 2) their acceptability and preferences of three different EM systems (MEMS Cap, Helping Hand, Button) as part of the Swiss SMILe study.Patients and MethodsRespecting anti-pandemic measures, we used a purposive sample of six adult alloSCT patients from the University Hospital Basel, Switzerland (USB)—6 weeks to 2 years post-alloSCT—to conduct three focus group sessions with two patients each. Using a semi-structured outline, we explored 1) patients’ medication adherence strategies and medication self-management; and 2) their acceptance and preferences regarding EM use. The three tested EM systems were available for testing during each session. Discussions were audio-recorded, visualized using mind-mapping and analyzed using Mayring’s qualitative content analysis.ResultsPatients (33% females; mean age 54.6±16.3 years; 10.4±8.4 months post-alloSCT) used medication adherence enhancing strategies (eg, preparing pillbox, linking intake to a habit). Still, they indicated that post-alloSCT medication management was challenging (eg, frequent schedule changes). All participants preferred the MEMS Button. Participants said its small size and the possibility to combine it with existing pillboxes (eg, putting it into/next to them) made them more confident about implementing it in their daily lives.ConclusionRegarding EM systems for medication adherence, end-user preferences and acceptability influence adoption and fidelity. Of the three systems tested, our sample found the MEMS Button most acceptable and most preferable. Therefore, we will use it for our USB SMILe study.

Effect of Early Nutritional Support on Quality of Life by EORTC QLQ-C30 in Allogeneic Hematopoietic Stem Cell Transplantation.

Increasing attention is being paid to the importance of nutritional management of allogeneic hematopoietic stem cell transplant (allo-HSCT) patients. However, few studies have conducted detailed evaluations of both nutritional intake and quality of life (QOL) in allo-HSCT patients. Therefore, we investigated the nutritional status and quality of life of our allo-HSCT patients. The subjects were 26 adults who underwent allo-HSCT at Hamamatsu University Hospital between August 2018 and October 2021. Early nutritional intervention was provided from the time of the decision to perform allo-HSCT to the time of discharge, and it incorporated regular QOL assessments. The analyzed indices were nutritional intake, anthropometric measurements, body mass index (BMI), grip strength, body composition analyzer (InBody S10) measurements, and blood laboratory values including transthyretin levels. QOL was assessed using the QLQ-C30 questionnaire of the European Organization for Research and Treatment of Cancer (EORTC) (version 3.0) and calculated according to the EORTC scoring manual. The indices were compared at pre-transplantation, 30 days post-transplantation, 60 days post-transplantation, and at discharge. The association between pre-transplantation nutritional status and QOL was examined. The median hospital stay after transplantation was 97 days (range, 78-123 days). Energy intake was maintained at 31 kcal/day/kg through 30 days post-transplantation, 60 days post-transplantation, and discharge, and protein intake was maintained at 1.0 g/day/kg throughout all time periods. There was a significant positive correlation between the pre-transplantation transthyretin level and the 60-day post-transplantation QOL scores for "global health", "physical functioning", "cognitive functioning", and "emotional functioning", and there were significant negative correlations with "fatigue" and "pain" that indicated improvement. Early nutritional management of allo-HSCT patients prior to transplantation allowed maintenance of nutritional intake, and higher pre-transplant transthyretin levels were associated with higher QOL scores at 60 days post-transplantation.

Association of early donor chimerism status with survival outcomes in post allogeneic haematopoietic stem cell transplant patients of nonmalignant diseases.

To highlight the association of early donor chimerism status at 2nd month with various survival outcomes. The retrospective study was conducted at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan, and comprised patient data from January 2011 to July 2016. Data related to participants who underwent human leukocyte antigen-matched transplants for bone marrow failure syndrome and beta thalassemia major. Short tandem repeat-based polymerase chain reaction was used to assess donor chimerism status. Overall survival, disease-free survival, relapse-free survival, and graft versus host disease-free survival rates were noted. Data was analysed using SPSS 23. Of the 106, 64(60.4%) had bone marrow failure syndrome and 42(39.6%) had beta thalassemia major. The overall median follow-up was 13.53 months (range: 1.81-62.73 months). Early donor chimerism status was associated with overall survival (p=0.02) and disease-free survival (p=0.01). Mixed donor chimerism was less hazardous in terms of overall survival (p=0.04) and disease-free survival (p=0.02). Early mixed donor chimerism contributed to optimal survival in nonmalignant disease.

25. Immunogenicity and Reactogenicity of COVID-19 mRNA Vaccines in Allogeneic Stem Cell Transplant Recipients

BackgroundAllogeneic stem cell transplant (SCT) recipients are at an increased risk of poor outcomes from COVID-19. While the mRNA-1273 (Moderna) and BNT162b2 (Pfizer) COVID-19 mRNA vaccines are highly immunogenic in the general population, the immune response in SCT recipients is poorly understood. We characterized the immunogenicity and reactogenicity of COVID-19 mRNA vaccines in a cohort of SCT patients.MethodsWe performed a prospective cohort study of 16 allogeneic SCT patients and 23 healthy controls. Blood samples for both cohorts were collected prior to first vaccination (baseline), at the time of second vaccination, and approximately 28 days post-second vaccination. Anti-Spike (S), anti-S1, anti-receptor binding domain (RBD), and anti-Nucleocapsid (N) IgG levels were measured quantitatively from plasma using a multiplexed single molecule array (Simoa) immunoassay. Reactogenicity was captured for the SCT cohort via a self-reported post-vaccination diary for 7 days after each dose.ResultsDemographics and SCT recipients’ characteristics are shown in Table 1. In the SCT cohort, we observed a significantly lower anti-S (p< 0.0001), S1 (p< 0.0001), and RBD (p< 0.0001) IgG responses as compared to healthy controls, both at the time of dose 2 and 28 days post-vaccine series (Fig 1). Overall, 62.5% of SCT recipients were responders after vaccine series completion, as compared to 100% of healthy controls (Fig 2). While no patients had a reported history of COVID-19 diagnosis, 2 patients in the SCT cohort had elevated anti-S IgG levels and 1 showed elevated anti-N at baseline. 10/16 participants in the SCT cohort completed at least one post-vaccination diary. Local and systemic reactions were reported by 67% and 22% of participants, respectively, after dose 1, and 63% and 50% after dose 2 (Figure 3). All reported events were mild. Table 1: Demographics Figure 1: Plasma IgG Titers Anti-Spike (A), anti-S1 (B), anti-RBD (C), and anti-nucleocapsid (D) IgG titers were measured at baseline, time of second dose, and approximately 28 days after second vaccination. IgG levels were measured quantitatively using multiplexed single molecule array (Simoa) immunoassays, and are reported as Normalized Average Enzymes per Bead (AEB). Allogeneic stem cell transplant recipients (mauve) showed significantly lower anti-S, S1, and RBD IgG responses as compared to healthy controls (mint). Low titers of anti-N IgG demonstrates no history of COVID-19 natural infection during the course of the study.Figure 3. Solicited Local and Systemic Adverse Events 10 allogeneic stem cell transplant recipients completed at least one diary for 7 days after vaccination. Reactions after dose 1 are shown in light blue, and reactions after dose 2 are shown in dark blue. Local reactions (A) were reported by 67% (6/9) of participants after dose 1, and 63% (5/8) after dose 2. Systemic reactions (B) were reported by 22% (2/9) of participants after dose 1, and 50% (4/8) after dose 2. All reported events were mild (Grade 1).ConclusionAmong SCT recipients, mRNA COVID-19 vaccines were well-tolerated but less immunogenic than in healthy controls. Further study is warranted to better understand heterogeneous characteristics that may affect the immune response in order to optimize COVID-19 vaccination strategies for SCT recipients.Figure 2: Response Rate to COVID-19 Vaccination An internally validated threshold for responders was established using pre-pandemic sera from healthy adults. A positive antibody response was was defined as individuals with anti-Spike IgG levels above the 1.07 Normalized AEB threshold.Disclosures Amy Joyce, NP, Kadmon (Advisor or Review Panel member) Lewis A. Novack, MS, Lumicell Inc. (Scientific Research Study Investigator, Research Grant or Support)Precision Healing, Inc. (Scientific Research Study Investigator, Research Grant or Support) David Walt, PhD, Quanterix Corporation (Board Member, Shareholder) Robert Soiffer, MD, alexion (Consultant)gilead (Advisor or Review Panel member)jazz (Advisor or Review Panel member)juno/bms (Advisor or Review Panel member)kiadis (Board Member)precision bioscience (Consultant)Rheos (Consultant)takeda (Consultant) Nicolas C. Issa, MD, AiCuris (Scientific Research Study Investigator)Astellas (Scientific Research Study Investigator)GSK (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)

COVID-19 Vaccination after Allogeneic Stem Cell Transplantation: Real Word Data on Safety and Efficacy. a Single Center Experience.

IntroductionDifferent vaccines have been recently approved by FDA and EMA for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating a protection rate ranging from 60% to almost 95% in phase II/III trials. Immunocompromised patients, including those undergoing allogeneic stem cell transplantation (allo-SCT), were excluded from vaccine trials. While EBMT recommended the vaccination for transplanted patients, data concerning efficacy and safety in this particular setting are scarce. Since infections represent a relevant cause of transplant-related mortality and the treatment and management of SARS-CoV-2 infection in allo-SCT patients proved to be challenging and complex, we prospectively evaluated the safety and the development of protective response against SARS-CoV-2 vaccines in our allogeneic transplanted patients.Materials and MethodsStarting in March 2021, allogeneic stem cell transplanted patients with different hematological diseases underwent COVID-19 vaccination. Taking into account the EBMT recommendations, we considered patients suitable for vaccination when (1) they were at least 3-6 months after allo-SCT, (2) didn't have any graft versus host (GvHD) activity, and (3) received less than 0,5 mg/kg steroids as part of the immunosuppressive treatment. There was no recommendation for a specific type of vaccine, with the only exception for life-attenuated vaccines, which are mostly contraindicated in the post allo-SCT setting. Vaccinated patients were regularly monitored for the potential development of adverse events. The anti-SARS-CoV-2 Spike protein antibodies were measured in blood samples to assess the humoral response. In case of no response with undetectable anti-Spike antibodies 2 week after the second dose of vaccine, we repeated the measurements at regular intervals until week + 6-8 after the completion of vaccination. Patients with no measurable antibodies 8 weeks after completion of the vaccination were considered as no responders.ResultsBetween 03/2021 and 06/2021 a total of 83 patients underwent COVID-19 vaccination (including first and second dose) during the post allo-SCT follow-up. Patients' characteristics are listed in Table 1. Most patients (77%) received BNT162b2, while only a small subgroup (8%) underwent a mixed vaccination after a first dose of ChAdOx1-S. We considered the mixed vaccination mostly to maximize the response. Overall, the two vaccine doses were well tolerated, with only 5% of patients developing a reactivation of GvHD. No relevant grade 3 or 4 organ toxicities were observed. Overall, 66% of patients in our cohort showed a humoral response. The incidence of positive serology was lower in patients who underwent the vaccination within the first 18 months after allo-SCT (29% vs 83% for patients >18 months after allo-SCT, p< 0.001). In multivariate analysis other risk factors that were associated with poor or no response were lack of immune reconstitution (p< 0.001) and ongoing immunosuppressive therapy (p= 0.009). The age of patients at the time of vaccination, sex, intensity of conditioning regimen and the use of ATG did not prove to have an influence for a humoral response during the post-transplant follow up.DiscussionThe achievement of a protective immunity against SARS-CoV-2 represents a crucial event for a frail population, like allogeneic stem cell transplanted patients. So far and to our knowledge little is known about the safety and efficacy of the COVID-19 vaccination in this particular setting. Here, we report one of the first series of patients undergoing COVID-19 vaccination after allo-SCT. We demonstrated that a humoral response can be achieved, especially for those patients who are in the long-term follow-up, underwent immune reconstitution and are free from immunosuppressive drugs. For the other patients, who represent the frailer subgroup, in the absence of a documented immune response after 2 doses of vaccine, the option of a third dose in order to increase the probability of response should be evaluated in prospective clinical trials. [Display omitted] DisclosuresViardot: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University Hospital of Ulm: Current Employment; Amgen: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Döhner: Roche: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Ulm University Hospital: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Helsinn: Consultancy, Honoraria; Pfizer: Research Funding; Berlin-Chemie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; GEMoaB: Consultancy, Honoraria. Sala: Novartis: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jazz: Consultancy, Honoraria.

Association between CYP3A4, CYP3A5, and ABCB1 Genotype, Tacrolimus Concentrations, and Outcomes Among Allogeneic Hematopoietic Stem Cell Transplantation Patients

Association between CYP3A4, CYP3A5, and ABCB1 Genotype, Tacrolimus Concentrations, and Outcomes Among Allogeneic Hematopoietic Stem Cell Transplantation Patients

Longitudinal Analysis of Gut Bacteriome, Mycobiome, Virome and Metabolome in Allogeneic Stem Cell Transplantation Reveals Susceptibility for Acute Graft-Versus-Host Disease

The intestinal microbiome directly effects outcomes in patients undergoing allogeneic stem cell transplantation (ASCT) (Peled et al., N Engl J Med, 2020). Recent developments in microbiome research allow us to look beyond bacterial communities at the composition of the intestinal mycobiome and virome. However, only few studies have addressed these fungal (Zhang et al., Nat Commun, 2021; Legoff et al., Nat Med, 2017) and viral communities (Van Der Velden et al., Biol Blood Marrow Transplant, 2013) in the ASCT setting.Loss of bacterial diversity and domination of single taxa was linked to increased incidence of graft-versus-host-disease (aGvHD) and mortality. However, the functional consequences of intestinal dysbiosis remain poorly understood. Recently, microbial-derived metabolites such as short-chain fatty acids (SCFAs), indoles and secondary bile acids (BA) have been proposed to explain how microbiota exert effects on epithelial and immune responses and shown to protect from GVHD in animal models.To assemble a complete picture of the phylogenetic and metabolic changes which occur as patients undergo ASCT we designed a multiomics approach and identified patterns in bacteriome, mycobiome, virome and metabolome dynamics in relation to clinical factors and GvHD.353 stool samples from 80 patients undergoing ASCT were obtained at two different transplantation centers (Munich and Regensburg) at defined timepoints before and after transplantation. Changes in metabolite composition were evaluated via mass spectrometry using a targeted metabolomic profiling approach, accompanied by bacterial 16S rDNA-, fungal 18S-ITS- and deep virome sequencing. Results were linked among each other and with clinical metadata such as GvHD, response to steroids, antimicrobial therapy and mortality.Longitudinal profiling of ASCT patients revealed a significant loss of bacterial, fungal and viral diversity following ASCT. At both centers, the effect was most pronounced in the early post-transplant period. Patients that developed GI-GVHD had the lowest diversity scores (Panel 1). GVHD patient samples were dominated by Enteroccocus and Candida, and loss of Caudovirales species, indicative of deep dysbiosis effecting all intestinal communities.ASCT had a strong impact on microbiome function and their ability to produce metabolites. We assayed each sample for production of metabolites with reported protective effects: SCFAs (acetate, butyrate and propionate), indoles (indole-3-carboxylaldehyde, ICA) and BAs (deoxycholic and lithocholic acid). When admitted to the transplantation unit (timepoint “conditioning”) most patients had rich metabolite expression profiles. In the early post-transplant period, metabolite levels became progressively more depleted. GVHD patients displayed a nearly complete loss of metabolites (Panel 2a). Importantly, levels of the metabolite ICA at early timepoints could predict the occurrence of GVHD, leading us to consider prophylactic administration in future studies.We performed beta diversity analysis to identify clinical factors that had the highest impact on microbial communities. As expected, we noted that administration of broad-spectrum antibiotics had a profound impact of bacteria, fungi and viruses; but also had a significant negative effect on metabolites levels.Lastly, we report on a case of successful treatment of severe GI-GVHD with fecal microbiota transplant. Response to treatment was characterized by the recipient adopting the FMT donor's rich metabolite expression profile (Panel 2b) .To our knowledge, this is the first multicenter study that combines bacteriome, mycobiome, virome and metabolome analyses a longitudinal fashion in matched patient cohorts. Our results are consistent with previous findings that there are major alterations in gut microbiome and metabolite composition after ASCT. We expand upon those findings by characterizing the time course of phylogenetic alterations and their functional consequences. Those alterations play an important role in GvHD pathogenesis and might serve as potential biomarkers to identify patients at high risk for developing lethal GvHD early on. Our results highlight two strategies for targeted microbiome-based interventions: (1) preventing loss of microbial communities by restrictive use of antibiotics and (2) prophylactic administration of metabolite cocktails. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Harnessing the Immune System to Fight Multiple Myeloma.

Simple SummaryMultiple myeloma treatment has developed enormously within the last two decades. Most recently immunotherapies have been introduced. Monoclonal antibodies targeting the plasma cell surface marker CD38, daratumumab and isatuximab, have revolutionized the standard of care treatment, and CAR T-cell therapy has been FDA-approved for the treatment of relapsed, refractory multiple myeloma. However, many other immunotherapeutic principles are under current clinical testing. It is well described that immune dysfunction is present in multiple myeloma and worsens by disease progression and may even be involved in the transformation to malignancy from benign precursor states, smoldering myeloma, and MGUS. Thus, attempts to revive and engage the innate and adaptive immune system are appealing. The ultimate goal is the cure or prevention of cancer development. In this review, the reader receives basic information on the immune dysfunction in multiple myeloma, a thorough summary of the ways to harness the immune system in treatment, the current status of clinical development, and future aspects.Multiple myeloma (MM) is a heterogeneous plasma cell malignancy differing substantially in clinical behavior, prognosis, and response to treatment. With the advent of novel therapies, many patients achieve long-lasting remissions, but some experience aggressive and treatment refractory relapses. So far, MM is considered incurable. Myeloma pathogenesis can broadly be explained by two interacting mechanisms, intraclonal evolution of cancer cells and development of an immunosuppressive tumor microenvironment. Failures in isotype class switching and somatic hypermutations result in the neoplastic transformation typical of MM and other B cell malignancies. Interestingly, although genetic alterations occur and evolve over time, they are also present in premalignant stages, which never progress to MM, suggesting that genetic mutations are necessary but not sufficient for myeloma transformation. Changes in composition and function of the immune cells are associated with loss of effective immune surveillance, which might represent another mechanism driving malignant transformation. During the last decade, the traditional view on myeloma treatment has changed dramatically. It is increasingly evident that treatment strategies solely based on targeting intrinsic properties of myeloma cells are insufficient. Lately, approaches that redirect the cells of the otherwise suppressed immune system to take control over myeloma have emerged. Evidence of utility of this principle was initially established by the observation of the graft-versus-myeloma effect in allogeneic stem cell-transplanted patients. A variety of new strategies to harness both innate and antigen-specific immunity against MM have recently been developed and intensively tested in clinical trials. This review aims to give readers a basic understanding of how the immune system can be engaged to treat MM, to summarize the main immunotherapeutic modalities, their current role in clinical care, and future prospects.

Increased Incidence of Human Papillomavirus-Related Precancer or Second Malignancy Among Allogeneic Stem Cell Transplantation Patients: A SEER-Medicare Population Study

Each year, more than 8000 allogeneic stem cell transplantations (allo-SCT) are performed in the United States, with approximately 30% of these patients age ≥60 years. Allo-SCT recipients are at increased risk for developing human papillomavirus (HPV)-related precancer or second malignancy. It is important to evaluate HPV-related precancer or second malignancy among allo-SCT recipients to develop or enhance screening and preventive practice guidelines to improve patients' survival and quality of life. In this retrospective matched case-control study, we estimated the cumulative incidence of HPV-related precancer or second malignancy in both male and female Medicare beneficiaries who underwent allo-SCT and compared it with the cumulative incidence in non-SCT controls and noncancer controls. Hematologic cancer patients age ≥18 years who underwent allo-SCT between 2002 and 2011 were matched 1:5 to non-SCT controls and to noncancer controls by age, sex, race/ethnicity, and duration of follow-up. Proportions of HPV-related precancer or second malignancy were estimated and compared between cases and controls using the chi-square test and logistic regression. Kaplan-Meier cumulative incidences were estimated and compared using log-rank tests. We identified 700 allo-SCT cases (median age, 64 years; median follow-up post-transplantation, 4.3 years) matched with 3159 non-SCT controls and 3302 noncancer controls. Approximately 3.7% of allo-SCT cases developed HPV-related precancer or second malignancy post-transplantation, compared with 1.9% of the non-SCT controls and 1.1% of the noncancer controls. The odds ratio of developing HPV-related precancer or second malignancy of allo-SCT cases compared with non-SCT controls and noncancer controls was 2.0 (95% confidence interval [CI], 1.25 to 3.18) and 3.5 (95% CI, 2.1 to 5.8), respectively. Both allo-SCT cases and non-SCT controls had significantly higher proportions and odds of developing HPV-related precancer or second malignancy compared with noncancer controls. The 5-year cumulative incidence in allo-SCT cases was 5%, compared with 2.1% in non-SCT controls and 1.2% in noncancer controls. The cumulative incidence of HPV-related precancer or second malignancy was statistically significantly higher in the allo-SCT than in either of the 2 matched control groups, and the non-SCT controls had a higher cumulative incidence of HPV-related precancer or second malignancy than the noncancer controls. The allo-SCT cases were at increased risk of developing HPV-related precancer or second malignancy compared with the non-SCT controls and noncancer controls. Routine screening of HPV-related precancer or second malignancy in allo-SCT recipients is needed to help prevent HPV-related precancer or second malignancy. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Association of Host Factors With Antibody Response to Seasonal Influenza Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Patients.

BackgroundInfluenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood.MethodsWe investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison.ResultsBoth regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding.ConclusionsHSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups.Clinical Trials RegistrationNCT03467074.

Sequential Organ Failure Assessment Score and the Need for Organ Support Predict Mortality in Allogeneic Stem Cell Transplant Patients Admitted to the Intensive Care Unit

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy resulting in increased definitive cure rates or extended disease-free survival in various malignant and nonmalignant hematologic diseases. However, because of the high risk of severe complications of this therapy, up to 50% of patients may require being admitted to the intensive care unit (ICU) to manage life-threatening conditions. We aimed to evaluate the in-hospital mortality of allo-HSCT recipients admitted to the ICU and to identify those variables associated with in-hospital mortality. A 10-year (January 2010 to December 2019), single-center, retrospective study was conducted in Vall d´Hebron University Hospital, Barcelona. We included all consecutive allo-HSCT patients who required admission to the ICU. Baseline and disease-related characteristics were registered. Severity scores and the need for organ support were also assessed on days 1, 3, and 5 of ICU admission. In-hospital mortality-associated independent variables were identified using the Cox proportional hazards regression model. Three hundred twenty-three patients underwent allo-HSCT during the study period, of whom 82 (25%) were admitted to the ICU; 53 (65%) male, with a median age of 51 (38-59) years. Most patients received allo-HSCT for the treatment of lymphoma (20 patients [24%]) or acute leukemia (44 patients [54%]). The median Acute Physiology And Chronic Health Evaluation II score was 23 (17-28), and the median Sequential Organ Failure Assessment (SOFA) score on admission was 9 (7-11). Forty-nine (60%) patients died in the ICU, and 11 (13%) died in the hospital after being discharged from the ICU. Disease-related characteristics were not associated with mortality. Yet, SOFA score on day 1 (hazard ratio [HR]: 1.11 [95% confidence interval {CI}: 1.04-1.02]; P=.002), the need for vasopressors on day 3 (HR: 2.35 [95% CI: 1.27-4.36]; P=.007), and a nondecreasing SOFA score on day 5 (HR: 2.13 [95% CI: 1.03-4.39]; P=.04), were independently associated with in-hospital mortality. Mortality in allo-HSCT patients who require ICU admission remains high. In the present study, SOFA score, the need for vasopressors on day 3, and a nondecreasing SOFA score on day 5 predicted in-hospital mortality.