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Remarkable improvements in outcomes for many haematological malignancies have been driven primarily by a proliferation of novel therapeutics over the past two decades. Targeted agents, immune and cellular therapies, and combination regimens have adverse event profiles distinct from conventional finite cytotoxic chemotherapies. In 2018, a Commission comprising patient advocates, clinicians, clinical investigators, regulators, biostatisticians, and pharmacists representing a broad range of academic and clinical cancer expertise examined issues of adverse event evaluation in the context of both newer and existing therapies for haematological cancers. The Commission proposed immediate actions and long-term solutions in the current processes in adverse event assessment, patient-reported outcomes in haematological malignancies, toxicities in cellular therapies, long-term toxicity and survivorship in haematological malignancies, issues in regulatory approval from an international perspective, and toxicity reporting in haematological malignancies and the real-world setting. In this follow-up report, the Commission describes progress that has been made in these areas since the initial report.

Supplemental Table 1. Multivariate analysis of late relapse, transplant-related mortality, overall survival after HCT for each disease (AML, ALL, CML, MDS)

Purpose: Malignancy relapse remains a major obstacle for successful allogeneic hematopoietic cell transplantation (HCT). Chronic graft-versus-host disease (cGVHD) is associated with fewer relapses. However, when studying effects of cGVHD on relapse, it is difficult to separate from acute GVHD effects as most cases of cGVHD occur within the first year after transplant at the time when acute GVHD is still active.Experimental Design: This study based on CIBMTR registry data investigated cGVHD and its association with the incidence of late relapse and survival in 7,489 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS), who were leukemia free at 12 months after myeloablative allogeneic HCT.Results: Forty-seven percent of the study population was diagnosed with cGVHD at 12 months after transplant. The protective effect of cGVHD on late relapse was present only in patients with CML [RR, 0.47; 95% confidence interval (CI), 0.37–0.59; P < 0.0001). cGVHD was significantly associated with higher risk of treatment-related mortality (TRM; RR, 2.43; 95% CI, 2.09–2.82; P < 0.0001) and inferior overall survival (RR, 1.56; 95% CI, 1.41–1.73; P < 0.0001) for all diseases. In patients with CML, all organ sites and presentation types of cGVHD were equally associated with lower risk of late relapse.Conclusions: These results indicate that clinically relevant antileukemia effects of cGVHD on late relapses are present only in CML but not in AML, ALL, or MDS. Chronic GVHD in patients who are 1-year survivors after myeloablative allogeneic HCT is primarily associated with higher TRM and inferior survival. Clin Cancer Res; 21(9); 2020–8. ©2014 AACR.See related commentary by Gill, p. 1981

Supplemental Table 4. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival, overall survival in patients with AML, ALL, MDS who developed cGVHD

Supplemental Table 2. Multivariate analysis showing impact of cGVHD characteristics in CML patients on relapse

Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution.Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells.Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098–109. ©2018 AACR.

Supplemental Table 3. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival and overall survival in patients with CML who developed cGVHD

Table S1 Patients, donors, HLA-mismatches and conditioning; Table S2 Cell doses in stem cell transplant, engraftment and chimerism; Table S3 ADLI dose and timing and allostimulator source; Table S4 Patient outcomes; Figure S1 Schema for clinical study; Figure S2 Alloanergization efficiency of DLI by centre and by dose level; Figure S3 Residual alloreactivity in aDLI and occurrence of acute GvHD after T-cell depleted haploidentical HSCT and aDLI; Figure S4 Phenotype of CD4+ regulatory T-cell (Treg) in patient peripheral blood after T-cell depleted haploidentical HSCT and aDLI

Supplemental Figure 1. Cumulative incidence of cGVHD, relapse and death in patients with AML, ALL, CML, MDS

Lymphoid hematologic malignancies (HMs) and their treatment may result in secondary antibody deficiency (SAD), which is associated with an increased risk and susceptibility for recurrent and/or severe infections. Infection-related morbidity and mortality are major concerns when managing patients with HMs. The HM treatment landscape continues to evolve at a rapid pace, thereby necessitating the need for up-to-date guidance on how best to recognize, diagnose, treat, and monitor patients at risk of developing SAD. This consensus review, from a panel of international experts, aims to address this challenge by raising awareness of SAD and providing practical recommendations on SAD diagnosis and management. SAD evaluation is recommended at diagnosis of lymphoid HM in all patients, irrespective of infection history, to risk-stratify and define disease versus treatmentrelated SAD. Our recommendations promote a proactive and individualized approach to patient management to reduce infection risk and improve outcomes.

COVID-19 has significantly impacted the practice of hematopoietic cell transplantation (HCT) and likely affected outcomes of HCT recipients. Early reports document substantially higher case fatality rates for HCT recipients than seen in faced by the general population. Currently we do not have a clear picture of how much of this threat is present within the first year after HCT and how infection rates and outcomes vary with time after HCT. There are important because center-specific survival estimates for reporting purposes focus on 1-year post-HCT mortality. Transplantation centers have dramatically changed their practices in response to the pandemic. At many centers, quality assurance processes and procedures were disrupted, changes that likely affected team performance. Centers have been affected unevenly by the pandemic through time, location, and COVID-19 burdens. Assessment of center-specific survival depends on the ability to adjust for risk factors, such as COVID-19, that are outside center control using consistent methods so that team performance based on controllable risk factors can be ascertained. The Center for International Blood and Marrow Transplantation Research (CIBMTR) convened a working group for the 2020 Center Outcomes Forum to assess the impact of COVID-19 on both patient-specific risks and center-specific performance. This committee reviewed the factors at play and developed recommendations for a process to determine whether adjustments in the methodology to assess center-specific performance are needed.

Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N=1605) or PTCy (SibCy, N=403), and related haploidentical transplants receiving PTCy (HaploCy, N=757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2⋅14, 99% confidence interval (CI) 1⋅13-4⋅07; P=0⋅002] and inferior 2-year overall survival (HR 1⋅65, 99% CI 1⋅11-2⋅43; P=0⋅001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.

The COVID-19 pandemic has resulted in the increased use of cryopreserved grafts for allogeneic hematopoietic cell transplantation (HCT). However, information about the effect of cryopreservation on outcomes for patients receiving allogeneic donor grafts is limited. We evaluated outcomes of HCT recipients who received either fresh or cryopreserved allogeneic bone marrow (BM) or peripheral blood stem cell (PBSC) grafts reported to the Center for International Blood and Marrow Transplant Research. A total of 7397 patients were included in the analysis. Recipients of cryopreserved graft were divided into 3 cohorts based on graft source: HLA-matched related PBSC donors (n = 1051), matched unrelated PBSC donors (n = 678), and matched related or unrelated BM donors (n = 154). These patients were propensity score matched with 5514 patients who received fresh allografts. The primary endpoint was engraftment. Multivariate analyses showed no significant increased risk of delayed engraftment, relapse, nonrelapse mortality (NRM), or survival with cryopreservation of BM grafts. In contrast, cryopreservation of related donor PBSC grafts was associated with decreased platelet recovery (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.68 to 0.78; P < .001) and an increased risk of grade II-IV (HR, 1.27; 95% CI, 1.09 to 1.48; P = .002) and grade III-IV (HR, 1.48; 95% CI, 1.19 to 1.84; P < .001) acute graft-versus-host disease. Cryopreservation of unrelated PBSC grafts was associated with delayed engraftment of neutrophils (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001) and platelets (HR, 0.61; 95% CI, 0.56 to 0.66; P < .001) as well as an increased risk of NRM (HR, 1.4; 95% CI, 1.18 to 1.66; P < .001) and relapse (HR, 1.32; 95% CI, 1.11 to 1.58; P = .002) and decreased progression-free survival (HR, 1.36; 95% CI, 1.20 to 1.55; P < .001) and overall survival (OS) (HR, 1.38; 95% CI, 1.22 to 1.58; P < .001). Reasons for cryopreservation were not routinely collected; however, in a subset of unrelated donor HCT recipients, the reason was typically a change in patient condition. Products cryopreserved for patient reasons were significantly associated with inferior OS in multivariate analysis (HR, 0.65; 95% CI, 0.44 to 0.96; P = .029). We conclude that cryopreservation is associated with slower engraftment of PBSC grafts, which may be associated with inferior transplantation outcomes in some patient populations. However, the small numbers in the cryopreserved BM cohort and the lack of information on the reason for cryopreservation in all patients suggests that these data should be interpreted with caution, particularly in the context of the risks associated with unexpected loss of a graft during the pandemic. Future analyses addressing outcomes when cryopreservation is universally applied are urgently required.

Peripheral blood stem cells (PBSCs) have been increasingly used for allogeneic hematopoietic cell transplantation instead of bone marrow stem cells. Current National Marrow Donor Program policy recommends 5 days of daily filgrastim, followed by either 1 or 2 days of apheresis for unrelated donors, depending on collection center choice. To date, there are no published studies comparing the differences in donor experience between 1 day and 2 days of apheresis. We examined 22,348 adult unrelated donor collections in 184 centers between 2006 and 2016. Of these 22,348 donors, 20,004 (89.5%) had collection on 1 day, and the other 2344 (9.5%) had collection over 2 days. Information on why donors underwent apheresis in 1 day or 2 days was not available. Donors who underwent apheresis in 1 day were more likely to be male (67% versus 46%; P 30, 30% versus 22%; P

Objective/background: Clinical predictors of delayed engraftment following autologous hematopoietic cell transplantation (AHCT) are poorly described in the literature. The purpose of this study was to identify pretransplant characteristics contributing to delayed engraftment (DE) following AHCT. Methods: A retrospective, single institution study of 1162 consecutive patients undergoing AHCT from January 1996 to August 2016 was studied for DE. DE was defined as platelet count ≤ 50,000/µl, hemoglobin ≤ 8 g/dL, or absolute neutrophil count ≤ 1000/mm3. Results: Of the 1162 AHCT recipients, 263 (22.6%) were identified as having DE at 30-days post-AHCT with 80.0% being solely due to delayed platelet engraftment. Patients with Non-Hodgkin lymphoma (NHL) represented 18% of the original cohort, but accounted for 45% of those with DE, whereas multiple myeloma patients represented 59% of the initial cohort, but only 29% of those that had DE. At 3 months post-AHCT, transfusion dependence (p = .0083) prior to AHCT, low-infused CD34+ cell dose

The use of hematopoietic cell transplantation (HCT) has been increasing in older patients. However, the levels if distress, psychosocial functioning, and health-related quality of life (HRQOL) among older HCT survivors remains largely unknown. In this secondary analysis using data from 2 randomized controlled trials, we analyzed baseline Cancer and Treatment Distress (CTXD) and Confidence In Survivorship Information (CSI) surveys of HCT survivors who were age ≥60 years at the time of transplantation and alive and disease-free ≥1 year post-autologous or -allogeneic HCT. We analyzed associations of these parameters with the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-Item Short Form Survey (SF-12) and a healthcare adherence (HCA) scale, after adjusting for transplantation and patient demographic factors. A total of 567 patients were included. The median patient age at HCT was 65 years, and 68% of the patients underwent autologous HCT. The median CTXD score was .7 (mild), and the greatest distress was reported in the "health burden" subscale. The median CSI score was 1.4 (moderate-high), with the lowest confidence reported in the "late effects" subscale. We found negative Spearman correlations between CTXD score and SF-12 PCS (P = -.59) and MCS (P = -.54) and positive Spearman correlations between CSI score and SF-12 PCS (P = .23) and MCS (P = .30). The median HCA scale score was high at .8. Male sex, autologous HCT, increased distress level, and worse CSI score were associated with lower use of preventive care. Older survivors experienced a low level of distress and moderate-high level of CSI at ≥1 year post-HCT. As lower distress and higher CSI were associated with improved HRQOL and optimized preventive HCA, CTXD/CSI measures can be used to individualize the care of older adult HCT survivors.

Background Patients receiving chemotherapy for acute myeloid leukemia (AML) are at high risk for invasive fungal disease (IFD). Diagnosis of IFD is challenging, leading to interest in fungal biomarkers. The objective was to define the utility of surveillance testing with Platelia Aspergillus galactomannan (GM) enzyme immunoassay (EIA) and Fungitell β-d-glucan (BDG) assay in children with AML receiving antifungal prophylaxis. Methods Twice-weekly surveillance blood testing with GM EIA and BDG assay was performed during periods of neutropenia in the context of a randomized trial of children, adolescents, and young adults with AML allocated to fluconazole or caspofungin prophylaxis. Proven or probable IFD was adjudicated using blinded central reviewers. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for Platelia and Fungitell assays alone and in combination for the outcomes of proven and probable invasive aspergillosis (IA) or invasive candidiasis (IC). Results Among 471 patients enrolled, 425 participants (209 fluconazole and 216 caspofungin) contributed ≥1 blood specimen. In total, 6103 specimens were evaluated, with a median of 15 specimens per patient (range 1–43). The NPV was >99% for GM EIA and BDG assay alone and in combination. However, there were no true positive results, resulting in sensitivity and PPV for each assay of 0%. Conclusions The GM EIA and the BDG assay alone or in combination were not successful at detecting IA or IC during periods of neutropenia in children, adolescents, and young adults with AML receiving antifungal prophylaxis. Utilization of these assays for surveillance in this clinical setting should be discouraged.

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the TET2, IDH1/2, ASXL1, and EZH2 genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients.

Hematopoietic cell transplantation (HCT) survivors have a complex and multiphase recovery period. Health care delivery and psychosocial interventions for HCT survivors are challenging because many HCT recipients live great distances from the facility where they had their HCT. Therefore identifying factors associated with a patient's capability to self-manage symptoms is a significant focus of survivorship research. A patient's self-efficacy may be important for the successful management of major stressors associated with treatments and recovery. Here, we aimed to evaluate the impact of perceived self-efficacy on distress, quality of life (QoL), depression, and fatigue and identify the factors associated with lower self-efficacy. This cross-sectional study analyzed baseline data from a randomized controlled trial INSPIRE (NCT01602211) in adult (age 18 and older) survivors 2 to 10 years after HCT. Patients with recurrence or subsequent malignancy requiring cancer treatment during the 2 years before enrollment, inability to read and understand English, and lack of access to email and the Internet were excluded. Data included medical records and patient-reported outcomes including Cancer and Treatment Distress (CTXD) with 6 subscales, Patient Health Questionnaire depression scale (PHQ-8), Short Form 12 Health Survey (SF-12) physical function and mental function scores, Brief Fatigue Inventory (BFI) and Self-Efficacy. Pearson correlations were used to test bivariate associations for self-efficacy of CTXD, SF-12, BFI, and PHQ-8. General linear models were used to test the independent associations for CTXD and SF-12 outcomes with self-efficacy, controlling for selected sociodemographic and treatment covariates. Tenability of statistical model assumptions were examined, and no remediation was necessary. A total of 1078 HCT survivors were included in the analysis. Participants were 19 to 85 years (mean age 58), 53% male, and over 90% White and non-Hispanic. Only 16% reported living in a rural area. A majority received an autologous HCT (55%) and were less than 5 years from their first HCT (54%). Among the allogeneic HCT recipients, more than half (55%) had active chronic Graft-versus-Host (cGVHD) and nearly 40% were on active systemic treatment. The mean self-efficacy score was 3.01 (SD = 0.49). Female sex (P = .014), younger age at HCT, younger age at cGVHD presentation (P = .031), moderate to severe currently active cGVHD (P = .003) and household income less than $40,000 (P.001) were associated with lower self-efficacy. In bivariate analyses, self-efficacy was negatively correlated with mean total distress (CTXD, r = -.5, P.001) and each of the CTXD subscales. HCT survivors with higher self-efficacy also reported better physical (r 0.48, P.001) and mental function on the SF-12 (r = 0.57, P.001). Moreover, self-efficacy was negatively correlated with symptoms such as fatigue (r = -.44, P.001) and depression (r = -.48, P.001). In a regression model investigating the impact of self-efficacy on CTXD controlled for demographics and disease characteristics, lower self-efficacy was independently associated with higher distress (CTXD, β = -.232; 95% CI [-.294, -.169], P.001). Moreover, there was a significant positive relationship between self-efficacy and both mental (β = 4.68; 95% CI [3.82, 5.54]; P.001) and physical (β = 2.69; 95% CI [1.74, 3.64]; P.001) components of QoL. Our study demonstrates that lower levels of self-efficacy reported by HCT survivors were independently associated with higher levels of symptoms such as fatigue and depression, lower QoL, and more cancer-related distress. Furthermore, self-efficacy was more likely to be impaired in females, younger adults, those with lower incomes, and survivors with active cGVHD. These findings support the value of self-management interventions focused on improving self-efficacy as having the potential to improve multiple symptoms and QoL in HCT survivors.

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies., Using more stringent consensus diagnostic definitions for Invasive Aspergillosis, more than 20% of cases in hematopoietic cell transplant and hematologic malignancies patients that met earlier definitions no longer meet diagnostic criteria. This has important implications for antifungal prevention trials.

BACKGROUND: Cytomegalovirus (CMV) is a complication of allogeneic haematopoietic cell transplantation (allo-HCT). ASP0113, a DNA-based vaccine, contains two plasmids encoding human CMV glycoprotein B and phosphoprotein 65 (pp65). We assessed ASP0113 in CMV-seropositive allo-HCT recipients. METHODS: In this phase 3, randomised, placebo-controlled study, CMV-seropositive allo-HCT recipients were randomly assigned (1:1) via interactive response technology to receive five injections of 1 mL of 5 mg/mL ASP0113 or placebo. The pharmacist and designated staff were unblinded. Masked syringes maintained the blind for patients and study personnel. Efficacy and safety analyses included patients who received ≥1 dose of ASP0113/placebo. The primary efficacy endpoint was the proportion of allo-HCT recipients with composite all-cause mortality and adjudicated CMV end-organ disease (EOD) by 1 year post-transplant. ClinicalTrials.gov: NCT01877655 (not recruiting). FINDINGS: Patients were recruited between Sept 11, 2013 and Sept 21, 2016. Overall, 501 patients received ≥1 dose of ASP0113 (n = 246) or placebo (n = 255). The proportion of patients with composite all-cause mortality and adjudicated CMV EOD by 1 year post-transplant was 35.4% (n = 87) with ASP0113 and 30•2% (n = 77) with placebo (odds ratio 1.27; 95% confidence interval: 0.87 to 1.85; p = 0.205). Incidence of injection site-related treatment-emergent adverse events (TEAEs) was higher with ASP0113 than placebo. Overall incidence and severity of other TEAEs was similar between groups. T-cell response to pp65 increased over time and was greater with placebo than ASP0113 (p = 0.027). INTERPRETATION: ASP0113 did not reduce overall mortality or CMV EOD by 1 year post-transplant. Safety findings were similar between groups. FUNDING: Astellas Pharma Global Development, Inc . ispartof: ECLINICALMEDICINE vol:33 ispartof: location:England status: published

Renal dysfunction is a recognized risk factor for mortality after allogeneic hematopoietic cell transplantation (alloHCT), yet our understanding of the effect of different levels of renal dysfunction at time of transplantation on outcomes remains limited. This study explores the impact of different degrees of renal dysfunction on HCT outcomes and examines whether the utilization of incremental degrees of renal dysfunction based on estimated glomerular filtration rate (eGFR) improve the predictability of the hematopoietic cell transplantation comorbidity index (HCT-CI). The study population included 2 cohorts: cohort 1, comprising patients age ≥40 years who underwent alloHCT for treatment of hematologic malignancies between 2008 and 2016 (n = 13,505; cohort selected given a very low incidence of renal dysfunction in individuals age40 years), and cohort 2, comprising patients on dialysis at the time of HCT (n = 46). eGFR was measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method. The patients in cohort 1 were assigned into 4 categories-eGFR ≥90 mL/min (n = 7062), eGFR 60 to 89 mL/min (n = 5264), eGFR 45 to 59 mL/min (n = 897), and eGFR45 mL/min (n=282)-to assess the impact of degree of renal dysfunction on transplantation outcomes. Transplantation outcomes in patients on dialysis at the time of alloHCT were analyzed separately. eGFR60 mL/min was associated with an increased risk for nonrelapse mortality (NRM) and requirement for dialysis post-HCT. Compared with the eGFR ≥90 group, the hazard ratio (HR) for NRM was 1.46 (P = .0001) for the eGFR 45 to 59 mL/min group and 1.74 (P = .004) for the eGFR45 mL/min group. Compared with the eGFR ≥90 mL/min group, the eGFR 45 to 59 mL/min group (HR, 2.45; P.0001) and the eGFR45 mL/min group (HR, 3.09; P.0001) had a higher risk of renal failure necessitating dialysis after alloHCT. In addition, eGFR45 mL/min was associated with an increased overall mortality (HR, 1.63; P.0001). An eGFR-based revised HCT-CI was also developed and shown to be predictive of overall survival (OS) and NRM, with predictive performance similar to the original HCT-CI. Among 46 patients on dialysis at alloHCT, the 1-year probability of OS was 20%, and that of NRM was 67%. The degree of pretransplantation renal dysfunction is an independent predictor of OS, NRM, and probability of needing dialysis after alloHCT. An eGFR-based HCT-CI is a validated index for predicting outcomes in adults with hematologic malignancies undergoing alloHCT. The outcomes of alloHCT recipients on dialysis are dismal; therefore, one should strongly weigh the significant risks of being on hemodialysis as a factor in determining alloHCT candidacy.

Aspergillus fumigatus is an opportunistic mold that infects patients who are immunocompromised or have chronic lung disease, causing significant morbidity and mortality in these populations. While the factors governing the host response to A. fumigatus remain poorly defined, neutrophil recruitment to the site of infection is critical to clear the fungus. Galectin-3 is a mammalian β-galactose-binding lectin with both antimicrobial and immunomodulatory activities, however the role of galectin-3 in the defense against molds has not been studied. Here we show that galectin-3 expression is markedly up-regulated in mice and humans with pulmonary aspergillosis. Galectin-3 deficient mice displayed increased fungal burden and higher mortality during pulmonary infection. In contrast to previous reports with pathogenic yeast, galectin-3 exhibited no antifungal activity against A. fumigatus in vitro. Galectin-3 deficient mice exhibited fewer neutrophils in their airways during infection, despite normal numbers of total lung neutrophils. Intravital imaging studies confirmed that galectin-3 was required for normal neutrophil migration to the airspaces during fungal infection. Adoptive transfer experiments demonstrated that stromal rather than neutrophil-intrinsic galectin-3 was necessary for normal neutrophil entry into the airspaces. Live cell imaging studies revealed that extracellular galectin-3 directly increases neutrophil motility. Taken together, these data demonstrate that extracellular galectin-3 facilitates recruitment of neutrophils to the site of A. fumigatus infection, and reveals a novel role for galectin-3 in host defense against fungal infections., Author summary The environmental mold Aspergillus fumigatus commonly causes lung infections in people with impaired immunity or those suffering from a chronic lung disease. While neutrophils are a key cell type necessary for the eradication of this infection, the precise mechanism of their recruitment to the site of infection remains incompletely understood. Here we show that the secreted mammalian protein galectin-3 plays an important role in helping neutrophils reaching the fungus within the airways. We found that both mice and humans produce galectin-3 when infected with A. fumigatus, and mice lacking galectin-3 were more susceptible to infection than normal mice. Galectin-3-deficient mice had impaired neutrophil recruitment to the site of infection. In the absence of galectin-3, neutrophils exhibited reduced motility in mouse lungs and in tissue culture. Our study offers insights into the mechanisms underlying the recruitment of neutrophils to the airways during A. fumigatus infection and reveals a new role for galectin-3 in increasing neutrophil motility.

Highlights • Transplant clinicians expect significant changes in the practice of hematopoietic cell transplantation over the next few years • There are considerable variations in practice predictions among adult and pediatric transplant clinicians • The degree of equipoise in the community about the relative efficacy of therapies being studied does not seem to affect accrual to current BMT CTN trials, Background Research priorities are best determined by the most pressing scientific questions, in the context of current knowledge. However, definitive research studies take time while real-world experience accumulates. Adoption of new practices before adequate comparison to current treatments threaten successful study conduct and may expose patients to what is ultimately learned to be inferior treatment. We conducted a survey to understand the Hematopoietic Cell Transplant (HCT) community's predictions about (a) future practice trends in the HCT field and (b) results of ongoing Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials to gauge how the HCT community views the treatments being studied. Method The survey was distributed between February and March 2019 to an electronic mailing list maintained by the Center for International Blood and Marrow Transplant Research (CIBMTR) of HCT clinicians practicing in the United States. Results Of 986 clinicians surveyed, 315 responded (32%). They predicted an increase in the number of HCTs performed for malignant hematologic diseases and benign diseases such as sickle cell, autoimmune and genetic disorders. The majority (63%) predicted that matched related donors (MRD) will remain the preferred donor source for adult HCT recipients in 2023 but 21% predicted haploidentical (Haplo) and 17% predicted matched unrelated donors (MUD) would be the preferred donors. Most respondents (65%) predicted a decrease in the use of umbilical cord blood (UCB) as a graft source for HCT. Most respondents also predicted that calcineurin-based graft-versus-host disease (GVHD) prophylaxis would be replaced by post-transplant cyclophosphamide (PTCy) (55%), biomarker use would become standard practice to guide GVHD therapy (73%), and steroids would be combined with other agents for first line therapy for newly diagnosed acute and (53%) chronic GVHD (54%). In ongoing BMT CTN trials where outcomes are not yet known, 60% to 92% of respondents had an opinion about which arm they thought would be superior. However, not all respondents predicted the same outcome with a range of 44% to 88% choosing the same arm. There was not a clear relationship between the proportion predicting the same arm would win and accrual to the trial. Conclusion Survey respondents are optimistic about growth in the volume of transplant procedures, and they also expect significant changes in the practice of HCT over the next few years including wider adoption of PTCy GVHD prophylaxis, increased use of biomarkers to guide GVHD therapy, and decreased use of UCB HCT. The degree of equipoise in the community about the relative efficacy of therapies being studied did not seem to affect accrual to current BMT CTN trials but this is an area that needs further investigation.

The current COVID-19 pandemic, caused by SARS-CoV-2, has impacted many facets of hematopoietic cell transplantation (HCT) in both developed and developing countries. Realizing the challenges as a result of this pandemic affecting the daily practice of the HCT centers and the recognition of the variability in practice worldwide, the Worldwide Network for Blood and Marrow Transplantation (WBMT) and the Center for International Blood and Marrow Transplant Research's (CIBMTR) Health Services and International Studies Committee have jointly produced an expert opinion statement as a general guide to deal with certain aspects of HCT, including diagnostics for SARS-CoV-2 in HCT recipient, pre- and post-HCT management, donor issues, medical tourism, and facilities management. During these crucial times, which may last for months or years, the HCT community must reorganize to proceed with transplantation activity in those patients who urgently require it, albeit with extreme caution. This shared knowledge may be of value to the HCT community in the absence of high-quality evidence-based medicine. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.