Bone Marrow Transplant Recipients Research Articles

Human parainfluenza virus type 3 infections in a haemato-oncology unit: social distancing measures needed in outpatient clinics

Human parainfluenza virus type 3 (HPIV3) infections are associated with high mortality in immunocompromised settings, especially in bone marrow transplant recipients. Asymptomatic infection and lack of effective antiviral treatment makes HPIV3 prevention and treatment a real challenge. To retrospectively investigate the epidemiological characteristics, clinical characteristics and outcomes of 51 haematology patients with confirmed HPIV3 infections, detected between February and May 2019 in the haematology unit at King's College Hospital, London. Between February and May 2019, HPIV3 RNA was detected in combined nose and throat swab samples collected from 51 symptomatic haematology patients, 41 of whom attended the haematology outpatient unit. Clinical data were reviewed retrospectively and a timeline of patients' appointments drawn up to investigate transmission. Sequencing analysis was performed on 14 stored samples. Fifty-one patients were identified with HPIV3 infection. Mean age was 54 years (SD: 12; range: 19-72) and 60% (31/51) were male. There were 41 (80%) bone marrow transplant recipients, 24 had an allograft, and 17 an autograft. Thirty-day and 3-month mortality post HPIV3 was 6% and 14%, respectively. Lower respiratory tract infection and inpatient acquisition were associated with higher mortality (6/7 vs 1/7, P= 0.010; and 5/7 vs 2/7, P= 0.031). Onset of HPIV3 infection in patients within 6 days of attending the clinic was associated with the clusters identified in phylogenetic analysis (64% (9/14) vs 21% (8/37); odds ratio: 6.5 (confidence interval: 95% 1.7-25); P= 0.006). Timelines suggested community transmission, but also possible transmission patterns within the outpatients and subsequent nosocomial transmission within the same ward. Early recognition of HPIV3 infection and the use of polymerase chain reaction and sequence analysis is fundamental in identifying respiratory virus outbreaks and person-to-person transmission. Careful planning of outpatient clinic attendance is required to minimize contact and prevent respiratory virus transmission in immunosuppressed patients.

Hyperpolarized 129Xenon MRI Ventilation Defect Quantification via Thresholding and Linear Binning in Multiple Pulmonary Diseases

There is no agreed upon method for quantifying ventilation defect percentage (VDP) with high sensitivity and specificity from hyperpolarized (HP) gas ventilation MR images in multiple pulmonary diseases for both pediatrics and adults, yet identifying such methods will be necessary for future multi-site trials. Most HP gas MRI ventilation research focuses on a specific pulmonary disease and utilizes one quantification scheme for determining VDP. Here we sought to determine the potential of different methods for quantifying VDP from HP 129Xe images in multiple pulmonary diseases through comparison of the most utilized quantification schemes: linear binning and thresholding. HP 129Xe MRI was performed in a total of 176 subjects (125 pediatrics and 51 adults, age 20.98±16.48 years) who were either healthy controls (n=23) or clinically diagnosed with cystic fibrosis (CF) (n=37), lymphangioleiomyomatosis (LAM) (n=29), asthma (n=22), systemic juvenile idiopathic arthritis (sJIA) (n=11), interstitial lung disease (ILD) (n=7), or were bone marrow transplant (BMT) recipients (n=47). HP 129Xe ventilation images were acquired during a ≤16 second breath-hold using a 2D multi-slice gradient echo sequence on a 3T Philips scanner (TR/TE 8.0/4.0ms, FA 10-12°, FOV 300×300mm, voxel size≈3×3×15mm). Images were analyzed using 5 different methods to quantify VDPs: linear binning (histogram normalization with binning into 6 clusters) following either linear or a variant of a nonparametric nonuniform intensity normalization algorithm(N4ITK) bias-field correction, thresholding ≤60% of the mean signal intensity with linear bias-field correction, and thresholding ≤60% and ≤75% of the mean signal intensity following N4ITK bias-field correction. Spirometry was successfully obtained in 84% of subjects. All quantification schemes were able to label visually identifiable ventilation defects in similar regions within all subjects. The VDPs of control subjects were significantly lower (p<0.05) compared to BMT, CF, LAM, and ILD subjects for most of the quantification methods. No one quantification scheme was better able to differentiate individual disease groups from the control group. Advanced statistical modeling of the VDP quantification schemes revealed that in comparing controls to the combined disease group, N4ITK bias-field corrected 60% thresholding had the highest predictive efficacy, sensitivity, and specificity at the VDP cut-point of 2.3%. However, compared to the thresholding quantification schemes, linear binning was able to capture and label subtle low-ventilation regions in subjects with milder obstruction, such as subjects with asthma. The difference in VDP between healthy controls and patients varied between the different disease states for all quantification methods. Although N4ITK bias-field corrected 60% thresholding was superior in separating the combined diseased group from controls, linear binning is able to better label low-ventilation regions unlike the current, 60% thresholding scheme. For future clinical trials, a consensus will need to be reached on which VDP scheme to utilize, as there are subtle advantages for each for specific disease.

Difference in the Cytomegalovirus-related Clinical Laboratory Findings Between Patients With Bone Marrow and Kidney Transplantations

Background: Despite close monitoring of transplant patients, Cytomegalovirus (CMV) infection has remained one of the most critical problems in transplantation. This study investigates the relationship between CMV viral load and clinical laboratory findings in transplant recipients. Materials And Methods: A total of 34 transplant recipients comprising 15 Kidney Transplant (KT) recipients and 19 Bone Marrow Transplant (BMT) recipients admitted to the Imam Reza Hospital in Kermanshah Province, Iran, were enrolled in this study. The CMV viral load was quantified by the real-time PCR technique. Results: The CMV viral load in KT recipients was significantly higher than in BMT recipients (P=0.03), and there was a positive association between the level of virus and the level of cyclosporine in the blood of patients (r=0.51, P=0.02). Besides, CMV viral load was positively correlated with WBC (r=0.32, P=0.04), urea (r=0.47, P=0.002), creatinine (r=0.39, P=0.01), aspartate aminotransferase (r=0.33, P=0.04), and lactate dehydrogenase (r=0.4, P=0.01). Also, it was negatively associated with albumin (r=-0.61, P&lt;0.001), sodium (r=-0.4, P=0.01), and calcium levels (r=-0.46, P=0.003). There were also significant differences between KT and BMT recipients regarding the CMV-related clinical laboratory findings of urea (P=0.02), creatinine (P=0.001), uric acid (P=0.005), direct bilirubin (P=0.04), albumin (P=0.04), platelet (P&lt;0.001), and sodium (P=0.04) levels. Conclusion: Based on present data, we conclude that despite careful monitoring of patients, infection with CMV is still one of the most important problems associated with organ transplantation, which is directly related to many laboratory findings.

Editorial introductions.

Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 11 sections that are reviewed once a year. Each section is assigned to a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Genovefa A. PapanicolaouGenovefa A. PapanicolaouGenovefa A. Papanicolaou is an Infectious Disease physician focusing in patients with hematologic malignancies and hematopoietic cell transplant recipients. She is the Director of Clinical Trials for the Department of Subspecialty Medicine at Memorial Sloan Kettering Cancer Center and Professor at Weill Cornell Medical College at Cornell University in New York, USA. Her research interests include viral infections, biomarkers and precision prevention. She serves in a volunteer capacity as Chair of the Infectious disease special interest group (ID-SIG) of the American Society of Transplantation and Cellular Therapy (ASTCT). Dionysios NeofytosDionysios NeofytosDionysios Neofytos is an Infectious Disease specialist with expertise in infectious disease complications in patients with hematologic malignancies and bone marrow and solid organ transplant recipients. Since the completion of his training in Infectious Diseases at Thomas Jefferson University Hospital in Philadelphia, PA, USA, in 2006 he has joined the Faculty and worked as an attending physician with the Transplant Infectious Disease Services at the Johns Hopkins University in Baltimore, MD, USA, and the Memorial Sloan Kettering Cancer Center in New York, NY, USA. Since 2016, he joined the Division of Infectious Diseases at the University Hospital of Geneva, in Geneva, Switzerland. His research and area of expertise are focusing on the epidemiology, diagnosis and management of viral and invasive fungal infections in immunocompromised hosts. Trish M. PerlTrish M. PerlTrish M. Perl, MD, MSc, is the Jay P Sanford Professor in the Departments of Medicine (Infectious Diseases) and the Chief of the Division of Infectious Diseases at UT Southwestern Medical Center in Dallas TX, USA. She formerly was at Johns Hopkins University School of Medicine, USA, in the Division of Infectious Diseases in the Department of Medicine, in Epidemiology at the Bloomberg School of Public Health and the Senior Epidemiologist for Johns Hopkins Health System. Dr Perl received her Bachelor of Arts and medical degree from the University of North Carolina at Chapel Hill, USA, and a Master of Science degree from McGill University in Montreal, Canada. She completed a residency in internal medicine at McGill University and a fellowship in infectious diseases and clinical epidemiology at the University of Iowa, USA. She was on faculty at the University of Iowa for several years before moving to Hopkins where she was the Hospital Epidemiologist at Johns Hopkins Hospital from 1996 to 2011 and then the Health System Epidemiologist until 2016 when she moved to UTSW. She has extensive practical and research experience in the field of healthcare associated infections and resistant and epidemiologically significant organisms and is recognized globally for her innovation and research in healthcare associated infections, antimicrobial resistance, their transmission and prevention. Because of this she helped manage international outbreaks including SARS, MERS CoV, Ebola and consults with international governments on guideline development and strategies to prevent healthcare associated and respiratory virus infections and antimicrobial resistance. An active researcher, Dr Perl has been funded by the CDC, BARDA and the Veteran's Affairs Administration over the years. She has authored or coauthored over 250 peer-reviewed articles. She actively reviews grants for the NIH.

Hyperpigmented Folliculocentric Papules in a Bone Marrow Transplant Recipient: Answer.

Hyperpigmented Folliculocentric Papules in a Bone Marrow Transplant Recipient: Answer.

In Vivo Expansion of Recipient DC Leads to Deletion of Donor Alloreactive CD8+ T Cells and Is an Alternative to Post-Transplant Cyclophosphamide for the Prevention of Graft-Versus-Host Disease after BMT

Allogeneic bone marrow transplantation (BMT) provides curative therapy for leukemia via immunological graft-versus-leukemia (GVL) effects. In practice, this must be balanced against graft-versus-host disease (GVHD) and opportunistic infection. We have investigated the role of recipient dendritic cells (DC) in the control of MHC class I restricted T cell responses after BMT. We first used the C3H.Sw → B6 miHA mismatched model of mouse BMT, with lethally irradiated B6.CD11c.DOG recipients (diphtheria toxin receptor, ovalbumin and GFP driven off the CD11c promoter) such that recipient DC can be deleted by diphtheria toxin, in combination with B6-derived MLL-AF9 induced primary acute myeloid leukemia to model clinical relapse. Depletion of recipient DC resulted in improved leukemic control (median survival 43 vs 31 days, P <0.001). The use of IRF8-/- BMT recipients (CD8α+ DC subset absent) confirmed that recipient CD8α+ DC were critical for regulating these GVL effects (median survival 43 vs 34 days, P = 0.0005). We confirmed that this accelerated relapse occurred as a consequence of recipient DC-induced donor T cell apoptosis resulting in a profound contraction of the donor T cell compartment. Using the same depletion strategies in an antigen-specific model (donor OT-I T cells, B6.CD11c.DOG x DBA/2 F1 recipients) we confirmed that recipient DC invoked effector donor CD8+ T cell hyperactivation, differentiation and apoptosis (Annexin V+ OT-I; 52.4% vs. 23.9% in DC replete vs. depleted recipients, P = 0.01).In light of the effects of recipient DC on antigen-specific donor T cell deletion, we next compared pre-transplant Flt-3L treatment (Pre-T Flt-3L; d -10 to d 0) to expand recipient CD8α+ DC (mean CD8α+ DC/spleen saline 0.14×106 vs Pre-T Flt-3L 23.6×106; P= 0.008) with post-transplant cyclophosphamide (PT-Cy at d 3,4), in a model of haploidentical BMT (B6 → B6D2F1). Consistent with our DC depletion models, Pre-T Flt-3L resulted in augmented antigen-specific donor T cell expansion 12 hours post-BMT, followed by deletion within 72 hrs (d 3 mean splenic OT-I: saline 15.94×106 vs Pre-T Flt-3L 0.01×106; P= 0.02). PT-Cy resulted in similar profound but alloantigen-independent polyclonal T cell deletion (d 7 mean splenic CD3+: saline 10.8×106 vs PT-Cy 0.8×106; P= 0.02). Pre-T Flt-3L offered better protection from GVHD than PT-Cy (median survival 36 vs 45 days, P= 0.02). In contrast, cyclosporine (CsA, administered to deliver clinically relevant serum levels of 200 - 300 ng/mL) did not result in major improvements in GVHD outcome (median survival 11 vs 13 days, P= 0.07). Both Pre-T Flt-3L and PT-Cy ablated GVL effects with relapse rates similar to corresponding TCD controls (Pre-T Flt3-L median time to relapse 11 days TCD vs 12 days BM+T; PT-Cy 22 days TCD vs 26 days BM+T). In contrast, GVL was maintained after CsA (with long-term survival seen in CsA and saline treated BM+T mice, median survival not reached; P >0.99). We confirmed that the effects with Pre-T Flt-3L were DC specific, and not related to the other populations by simultaneously deleting recipient DC (using diphtheria toxin) in Flt-3L treated recipients. This completely restored GVL effects and long-term survival to that observed in non-Flt-3L treated recipients (P >0.99). Importantly, despite effects on antigen-specific T cells, Pre-T Flt-3L facilitated the maintenance of third party CMV-specific donor T cells whereas PT-Cy did not (m38 tetramer+ cells 3 days post treatment; saline vs Pre-T Flt-3L P= 0.27; saline vs PT-Cy P= 0.028). These data highlight pre-transplant Flt-3L therapy as a potent alternative therapeutic strategy to PT-Cy to prevent GVHD, and moreover, that the effects of these strategies on attenuating GVL may have important clinical ramifications. DisclosuresLane:novartis: Consultancy; janssen: Consultancy, Research Funding.

Nutritional Support from the Intestinal Microbiota Improves Hematopoietic Reconstitution after Bone-Marrow Transplantation in Mice

Bone-marrow transplantation (BMT) offers curative potential for patients with high-risk hematologic malignancies, but the post-transplantation period is characterized by profound immunodeficiency. Delayed immune reconstitution is an important contributor to transplant-related morbidity and mortality (Maury et al., Br J Haematol, 2001; Small et al., Blood, 1999). Thus, understanding the mechanisms by which the immune system reconstitutes and how environmental exposures might influence this process is an important objective in improving outcomes after BMT.The intestinal microbiota shapes both mucosal and systemic immunity and contributes to steady-state hematopoiesis (Belkaid and Hand, Cell, 2014). To determine the role of the intestinal flora in hematopoietic reconstitution following BMT, we performed syngeneic BMT after lethal irradiation in mice with an intact intestinal flora (control, C/No abx) and in mice treated with two different antibiotic (abx) regimens administered in the drinking water: ampicillin + enrofloxacin (AmpEnro/AE) or vancomycin + amikacin (VancAmik/VA). While both regimens depleted the intestinal flora 1000-fold, ampicillin and enrofloxacin are both relatively well absorbed in the intestine while vancomycin and amikacin both have poor oral bioavailability with negligible systemic effects. BMT recipients treated with either of the abx regimens had lower white blood cell (WBC) counts and, in particular, lower lymphocyte counts compared to untreated BMT recipients (Fig 1A). Fecal microbiota transfer (FMT) with an abx-resistant intestinal flora (Caballero et al., Cell Host Microbe, 2017) rescued the impaired hematopoietic reconstitution in AE-treated mice (Fig 1B). These data rule out a direct inhibitory effect of abx on hematopoietic recovery. When we examined multiple compartments of the hematopoietic cascade we observed that flora depletion significantly impaired hematopoiesis specifically in the lymphoid and myeloid compartments of the bone marrow, thymus, and peripheral blood, while the hematopoietic stem and progenitor compartment and erythroid lineage were largely unaffected. These data are summarized in a radial plot (Fig 1C) in which each compartment of the hematopoietic cascade is a spoke and the distance from the center is proportional the cell count.Treatment of mice with AmpEnro or VancAmik also reduced dietary energy uptake (Fig 1D), resulting in reduction of visceral adipose tissue (Fig 1E). The mice are normally fed a standard chow diet based on complex plant carbohydrates. To test if reduced uptake of calories in flora-depleted animals contributed to impaired hematopoiesis post-BMT, we supplemented the drinking water with 5% sucrose, a carbohydrate source that can be directly utilized by the host in the absence of microbiota metabolism. Sucrose supplementation increased peripheral WBC counts and lymphocyte counts in AE-treated mice (Fig 1F), indicating that a critical function of the intestinal microbiota in supporting hematopoiesis post-BMT is to improve dietary energy uptake.We conclude that apart from specific and direct effects of the microbiota on immuno-hematopoiesis as previously described (Balmer et al., J Immunol, 2014; Clarke et al., Nat Med, 2010; Mazmanian et al., Cell, 2005), the intestinal flora can contribute to post-transplant hematopoietic reconstitution through improved dietary energy uptake. [Display omitted] DisclosuresPeled:Seres: Research Funding. Jenq:Seres: Research Funding. van den Brink:Therakos Institute: Other: Speaking engagement; Jazz Pharmaceuticals: Consultancy; PureTech Health: Consultancy; Seres: Research Funding.

Factors Affecting Platelet Transfusion Response Following Haploidentical Stem Cell Transplant

A mainstay of therapy for certain hematologic malignancies and non-malignant disorders is allogeneic stem cell transplant. One known complication is post-transplant thrombocytopenia which results in a significant bleeding risk. Although prophylactic platelet transfusions reduce the severity of thrombocytopenia, refractoriness to transfusions often develops. Several studies have examined clinical and laboratory factors that are associated with poor platelet response in the general hematologic malignancy and hematopoietic stem cell transplant population, which include lymphocytotoxic antibodies, bleeding, medications and infection. Only a few detailed studies have examined factors which specifically affect platelet transfusion response in patients who have undergone haploidentical stem cell transplant (HI SCT).This was a single center retrospective analysis of 721 platelet transfusions from 110 HI SCT patients to determine risk factors associated with platelet refractoriness. During the Jefferson 2-step HI SCT, the recipient receives myeloablative or reduced intensity conditioning followed by donor lymphocyte product infusion (DLI). Cyclophosphamide is given 2-3 days after DLI for tolerization, followed in 2 days by CD34+ stem cell product infusion. Patient-specific, transplant-specific and transfusion-specific data were collected and analyzed within 28 days following the 2-step HI SCT. Patient- and transplant-specific data included patient age, gender, body surface area, indication for transplant, conditioning regimen, date of transplant, pre-transplant CMV antibody status, pre-transplant anti-HLA antibodies, number of prior pregnancies, history of splenectomy or splenomegaly, and patient co-morbidities according to the Hematopoietic Cell Transplantation-Specific Co-morbidity Index. Transfusion-specific data included major ABO or Rh mismatch between bone marrow transplant (BMT) recipient and platelet product, major ABO or Rh mismatch between BMT donor and platelet product, age of platelet product at the time of transfusion, pre- and post-transfusion platelet count, and time from BMT to transfusion.Corrected count increments (CCI) were calculated according to standard formula, CCI=(post-transfusion - pre-transfusion platelet count) x body surface area / number of platelet transfused. The date and time of each platelet transfusion were recorded along with pre- and post-transfusion counts. CCI measures were modeled as a function of time from BMT using a linear mixed effects model allowing for the patient-specific trajectories by incorporating random effects in the intercept and slope for time from BMT.Our analysis identified significant associations with recipient gender, splenomegaly, coronary artery disease/congestive heart failure (CAD/CHF) and time from BMT to transfusion. CCI was on average lower by 23% in male compared to female recipients (95%CI: 13%, 33%; p<0.001), and by 40% in patients with splenomegaly (95%CI: 29%, 49%; p<0.001). When assessing CCI trends over time, transfusions further out from BMT were shown to have improved CCI versus those closer to BMT with significant improvement in patients without CAD/CHF (average 2.8% CCI improvement per day in non-CAD/CHF patients versus 0.8% in CAD/CHF patients; p=0.034). The effect of pre-transplant class 1 anti-HLA antibodies was not significant (p=0.510).This study confirms results from prior studies which indicate that male gender and splenomegaly are important contributors to post-transplant platelet transfusion refractoriness. Previous findings indicating the impact of anti-HLA antibodies in the pre-transplant setting were not confirmed by this study. We hypothesize that the marked increase in sensitivity that characterizes current-generation anti-HLA antibody testing may have lowered the predictive value of this test. Associations between platelet responsivity, CAD/CHF and time from transplant are novel findings and will require confirmation in future studies. DisclosuresNo relevant conflicts of interest to declare.

Infection-Related Mortality in Adults and Children Undergoing Allogeneic Hematopoietic Cell Transplantation: An Australian Registry Report

Infection-related mortality (IRM) is the most common non-relapse-related cause of death reported after allogeneic hematopoietic cell transplantation (HCT). Information on the incidence and timing of specific infective organisms and the risk factors for IRM is essential to developing prevention strategies. This report provides the first account of IRM in adults and children undergoing HCT in Australia. Between 2013 and 2018, 2705 adult and 689 pediatric first HCTs were identified from the Australasian Bone Marrow Transplant Recipient Registry database, associated with 1075 (39.7%) total overall deaths in adults and 134 (19.4%) in children. Demographics and causes of death, including infectious etiology and causative organisms, were extracted from the database for adults and children for analysis. At day +100 and 1 year post-HCT, IRM was the leading cause of early post-HCT mortality in adults, accounting for 6.2% and 9.8%, respectively; in children, IRM was the leading cause of post-HCT mortality at day +100 at 2.5% and the second highest cause of post-HCT mortality at 1 year post-HCT at 4.9%, following relapse at 5.8%. In adults, older age, transplantation not in a first complete remission (non-CR1), the use of antithymocyte globulin (ATG) or alemtuzumab, donor-positive/recipient-negative cytomegalovirus (CMV) serostatus, and acute graft-versus-host disease were significant risk factors for IRM. However, in children, age >5 years, acute lymphocytic leukemia as the primary disease, and mismatched unrelated or haploidentical donor source were predictive of IRM. Of the deaths in which an infectious etiology was reported in adults (52.4%), 49.3% were attributed to bacteria, 25.3% to fungus, 21.7% to viruses, and 3.6% to post-transplantation lymphoproliferative disorder (PTLD). The most common organisms were Pseudomonas spp, Enterococcus spp, Candida spp, Aspergillus spp, and CMV. In children where an infectious etiology was reported (64%), 13% were attributed to bacteria, 26% to fungus, 45% to viruses, and 16% to PTLD. This report highlights that IRM was the leading cause of death early post-HCT in Australia. Strategies to reduce IRM, such as individualized pre-transplantation infection risk assessment, rapid diagnostics, and prevention management strategies should be explored to determine whether these outcomes can be improved. In addition, improving the completeness and accuracy of reported data, particularly for infectious pathogens, could assist in directing management strategies to reduce IRM in HCT.

Antioxidant Fusion Protein SOD1-Tat Increases the Engraftment Efficiency of Total Bone Marrow Cells in Irradiated Mice.

Total body irradiation is a standard procedure of bone marrow transplantation (BMT) which causes a rapid increase in reactive oxygen species (ROS) in the bone marrow microenvironment during BMT. The increase in ROS reduces the engraftment ability of donor cells, thereby affecting the bone marrow recovery of recipients after BMT. In the early weeks following transplantation, recipients are at high risk of severe infection due to weakened hematopoiesis. Thus, it is imperative to improve engraftment capacity and accelerate bone marrow recovery in BMT recipients. In this study, we constructed recombinant copper/zinc superoxide dismutase 1 (SOD1) fused with the cell-penetrating peptide (CPP), the trans-activator of transcription (Tat), and showed that this fusion protein has penetrating ability and antioxidant activity in both RAW264.7 cells and bone marrow cells in vitro. Furthermore, irradiated mice transplanted with SOD1-Tat-treated total bone marrow donor cells showed an increase in total bone marrow engraftment capacity two weeks after transplantation. This study explored an innovative method for enhancing engraftment efficiency and highlights the potential of CPP-SOD1 in ROS manipulation during BMT.

Considerations for immunotherapy in patients with cancer and comorbid immune dysfunction.

Immune checkpoint inhibitors have been widely incorporated for cancer treatment in a variety of solid and hematologic malignancies. Multiple clinical trials have demonstrated the efficacy of PD-1/PD-L1 and CTLA-4 axis inhibition in the metastatic and adjuvant settings. Due to the risks of autoimmune toxicity with these agents, stringent inclusion/exclusion criteria were employed in those initial clinical trials. These criteria led to exclusion or underrepresentation of a variety of patient populations with underlying immune dysfunction. These populations included patients with preexisting autoimmune diseases, solid organ or bone marrow transplant recipients, patients with HIV or viral hepatitis infections, patients receiving concurrent chronic steroid therapy, as well as patients who were elderly, pregnant, or had poor performance status. Thus, established guidelines on the use of immune checkpoint inhibitors in these patients are lacking, and evidence to support efficacy or toxicity are overall limited to retrospective studies and case series. Fortunately, ongoing clinical trials are now including these patients and are shedding light on whether these underrepresented populations can also safely benefit from immune checkpoint inhibitor therapies. In this review, we summarize the most clinically relevant available data on the use of checkpoint inhibitors in immunocompromised patient groups with a primary focus on safety.

In utero and early-life exposure to thirdhand smoke causes profound changes to the immune system.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Thirdhand smoke (THS) is the residual tobacco contamination that remains after the smoke clears. We investigated the effects of THS exposure in utero and during early life in a transgenic Cdkn2a knockout mouse model that is vulnerable to the development of leukemia/lymphoma. Female mice, and their offspring, were exposed from the first day of pregnancy to weaning. Plasma cytokines, body weight and hematologic parameters were measured in the offspring. To investigate THS exposure effects on the development of leukemia/lymphoma, bone marrow (BM) was collected from control and THS-exposed mice and transplanted into BM-ablated recipient mice, which were followed for tumor development for 1 year. We found that in utero and early-life THS exposure caused significant changes in plasma cytokine concentrations and in immune cell populations; changes appeared more pronounced in male mice. Spleen (SP) and BM B-cell populations were significantly lower in THS-exposed mice. We furthermore observed that THS exposure increased the leukemia/lymphoma-free survival in BM transplantation recipient mice, potentially caused by THS-induced B-cell toxicity. A trend towards increased solid tumors in irradiated mice reconstituted with THS-exposed BM stimulates the hypothesis that the immunosuppressive effects of in utero and early-life THS exposure might contribute to carcinogenesis by lowering the host defense to other toxic exposures. Our study adds to expanding evidence that THS exposure alters the immune system and that in utero and early-life developmental periods represent vulnerable windows of susceptibility for these effects.

Immature platelet fraction as a predictor of platelet count recovery following allogeneic bone marrow transplantation

The immature platelet fraction (IPF) is a marker of increased platelet production. An increase in IPF is associated with increased marrow production; therefore, a subsequent increase in a bone marrow transplant recipient during the pancytopenic phase may correlate with platelet recovery and engraftment. We performed a retrospective cohort study and evaluated 32 patients who underwent allogeneic bone marrow transplantation. Patients had platelet count, neutrophil count, platelet transfusion and IPF recorded over a period extending from stem cell infusion, day 0, to day 30. The outcomes analysed were platelet count versus time and IPF versus time to establish the predictive ability of the IPF to determine platelet count recovery. Further analysis was performed to confirm the strength of the correlation and the sensitivity of the IPF in predicting a platelet count greater than 50 at day 30. The IPF was shown to rise 5 days prior to platelet count increase. An IPF rise was also shown to correlate with higher average platelet counts at day 30 of transplant. The utility of the IPF in predicting a platelet count of over 50 at day 30 was strongest between days 11 and 15 with an area under the curve (AUC) of 0.79. An IPF of 2.0 or above had 69% sensitivity and 85% specificity for predicting a platelet count of greater than 50 by day 30. In allogeneic bone marrow transplantation, the IPF is a reliable predictor of platelet recovery. The mean IPF between day 11 and day 15 is the most sensitive in predicting a robust platelet count of greater than 50 by day 30.

Australia and New Zealand (ANZ) outcomes of high-dose chemotherapy and stem cell transplantation for relapsed or refractory germ cell tumors (GCT) from 1999 to 2019: Multicenter registry-based study with ABMTRR.

382 Background: High dose chemotherapy (HDCT) with autologous stem-cell transplant (ASCT) is effective in advanced germ cell tumours (GCT) that are refractory to, or progress after, first-line therapies. Five-year overall survival in North American and European series range from 48-60%1,2,3. This study aimed to assess ANZ outcomes for quality assurance. Methods: Retrospective multi-centre audit of all male patients with GCT who underwent HDCT and ASCT from 1999-2019. Patients were identified from the Australasian Bone Marrow Transplant Recipient Registry. Primary outcomes included overall and progression- free survival (OS, PFS). Results: 111 patients were identified at 13 centres, each treating a median (range) of 7 (1-27) patients. Median (range) age was 30 (14-68) years. 88 (79%) had testicular primary. 16% were pure seminoma. Median time from first diagnosis to first stem cell cycle was 11 months (range 3 months-38 years). Prior to ASCT, 35% had primary refractory disease and 65% had relapsed. IPFSG risk score was very low in 5%, low in 13%, intermediate in 36%, high in 25%, and very high in 21%. HDCT regimen was CE in 78% (as part of TI-CE regimen in 38%), Carbop-EC-T in 6%, ICE in 6%, CEC in 5% and other in 4%. 89% completed all planned HDCT and ASCT cycles. Five treatment related deaths occurred. Progressive disease on treatment occurred in 14%. At median follow-up time 4.4 years (95% CI: 2.9 to 6.0), 51% were disease-free, 13% alive with disease, 34% deceased. 3 patients displayed late progression over 2 years after ASCT. The estimated 1, 2 and 5-year PFS rates were 62%, 57% and 52% respectively and OS rates were 73%, 65% and 61%. Survival by IPFSG and IGCCG risk categories are displayed in the table below. Conclusions: This is the first registry-based audit of HDCT for metastatic GCT from ANZ, which has demonstrated our outcomes are comparable with best international practice.

Survey of HCMV in allogenic and autologous stem cell transplantation by real-time PCR in Kermanshah, west of Iran

IntroductionHuman Cytomegalovirus (HCMV) is the most important viral pathogen in people undergoing bone marrow transplantation (BMT). HCMV detection in the early stages makes is possible to save the patients’ lives through immediate and timely treatment. The aim of this study was to investigate the status of HCMV using the real-time PCR method in BMT patients in Kermanshah, west of Iran.MethodsHCMV monitoring was done in 120 patients who underwent BMT, 38 allogeneic cases and 82 autologous cases, using the ELISA serology test before transplantation. The participants were followed up 100 days after transplantation for HCMV detection in blood samples using real-time PCR. Preemptive therapy started with Ganciclovir and Foscarnet when the viral load was > 200 HCMV DNA copies/ml.ResultsDespite preemptive therapy, infection recurred in less than 1 month. HCMV recurred more frequently in patients undergoing allogenic transplation versus those receiving autologous transplantation. Recurrence was seen in 5 patients receiving allogenic transplantation. HCMV recurrence occurred in five patients with allogeneic transplantation. Twelve patients undergoing allogeneic or autologous transplantation (83%) and a virus load of > 1000 copies/ml showed HCMV-related symptoms. Three patients died, two due to HCMV-related pneumonia and the other one due to a fungal infection.ConclusionReal-time PCR may be a useful method for quantification and monitoring of HCMV recurrence and may be helpful in choosing more efficient HCMV preemptive treatment in BMT recipients.

375 - The Incidence of Viral Upper Respiratory Tract Infection in Allogeneic Bone Marrow Transplant Recipients during the COVID Pandemic

375 - The Incidence of Viral Upper Respiratory Tract Infection in Allogeneic Bone Marrow Transplant Recipients during the COVID Pandemic

489 - Trends and Outcomes in Australia and New Zealand in Autologous Stem Cell Transplantation in Older Patients with Multiple Myeloma: An Australasian Bone Marrow Transplant Recipient Registry Study

489 - Trends and Outcomes in Australia and New Zealand in Autologous Stem Cell Transplantation in Older Patients with Multiple Myeloma: An Australasian Bone Marrow Transplant Recipient Registry Study

483 - Allogeneic Haematopoietic Cell Transplantation for Mantle Cell Lymphoma Can Achieve Durable Remission and Myeloablative Conditioning Is Associated with Inferior Survival: An Australasian Bone Marrow Transplant Recipient Registry Study

483 - Allogeneic Haematopoietic Cell Transplantation for Mantle Cell Lymphoma Can Achieve Durable Remission and Myeloablative Conditioning Is Associated with Inferior Survival: An Australasian Bone Marrow Transplant Recipient Registry Study

142 - Improvement in Non-Relapse Mortality Following Allogeneic Transplantation for Chronic Lymphocytic Leukaemia in Australia and New Zealand: An Australasian Bone Marrow Transplant Recipient Registry Study

142 - Improvement in Non-Relapse Mortality Following Allogeneic Transplantation for Chronic Lymphocytic Leukaemia in Australia and New Zealand: An Australasian Bone Marrow Transplant Recipient Registry Study

482 - Allogeneic Stem Cell Transplantation for Diffuse Large B Cell Lymphoma Can Achieve Durable Remissions: An Australasian Bone Marrow Transplant Recipient Registry Study

482 - Allogeneic Stem Cell Transplantation for Diffuse Large B Cell Lymphoma Can Achieve Durable Remissions: An Australasian Bone Marrow Transplant Recipient Registry Study