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The widely used alkylating agent cyclophosphamide (CY) has substantive interpatient variability in the area under the curve (AUC) of it and its metabolites. Numerous factors may influence the drug‐metabolizing enzymes that metabolize CY to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. We sought to identify endogenous metabolomics compounds (EMCs) associated with 4HCY formation clearance (ratio of 4HCY/CY AUC) using global metabolomics. Patients who undergo hematopoietic cell transplantation receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 26) and cohort 2 (n = 25) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY), and 24 h after the first dose of PT‐CY (24‐h post‐CY), which is also immediately before the second dose of CY. A total of 512 and 498 EMCs were quantitated in two cohorts, respectively. Both univariate linear regression with false discovery rate (FDR), and pathway enrichment analyses using a global association test were performed. At the pre‐CY time point, no EMCs were associated at FDR less than 0.1. At pre‐HCT, cohort 1 had one EMC (levoglucosan) survive the FDR threshold. At pre‐graft, cohort 1 and cohort 2 had 20 and 13 EMCs, respectively, exhibiting unadjusted p values less than 0.05, with the only EMCs having an FDR less than 0.1 being two unknown EMCs. At 24‐h post‐CY, there were three EMCs, two ketones, and threitol, at FDR less than 0.1 in cohort 2. These results demonstrate the potential of pharmacometabonomics, but future studies in larger samples are needed to optimize CY. [ABSTRACT FROM AUTHOR]

Introduction: Medication nonadherence continues to be challenging for allogeneic hematopoietic cell transplant (HCT) recipients. The risk and severity of chronic graft-versus-host disease (GVHD) are associated with low immunosuppressant concentrations (which can be improved with model-informed precision dosing (MIPD)) and with immunosuppressant nonadherence (which can be improved with acceptable interventions). Methods: With the goals of improving adherence and achieving therapeutic concentrations of immunosuppressants to eliminate GVHD, we characterized the feasibility of using the Medication Event Monitoring (MEMS®) Cap in adult HCT recipients. Results: Of the 27 participants offered the MEMS® Cap at the time of hospital discharge, 7 (25.9%) used it, which is below our a priori threshold of 70%. These data suggest the MEMS® Cap is not feasible for HCT recipients. The MEMS® Cap data were available for a median of 35 days per participant per medication (range: 7–109 days). The average daily adherence per participant ranged from 0 to 100%; four participants had an average daily adherence of over 80%. Conclusions: MIPD may be supported by MEMS® technology to provide the precise time of immunosuppressant self-administration. The MEMS® Cap was used by only a small percentage (25.9%) of HCT recipients in this pilot study. In accordance with larger studies using less accurate tools to evaluate adherence, immunosuppressant adherence varied from 0% to 100%. Future studies should establish the feasibility and clinical benefit of combining MIPD with newer technology, specifically the MEMS® Button, which can inform the oncology pharmacist of the time of immunosuppressant self-administration. [ABSTRACT FROM AUTHOR]

Background: Studies have suggested that acute myeloid leukemia (AML) patients with incomplete hematologic recovery undergoing allogeneic stem cell transplantation (allo‐HSCT) had inferior overall survival (OS). Study Design and Methods: This single‐center, retrospective study of AML patients evaluated the relationship between red blood cell (RBC) and platelet (PLT) transfusion requirements during the first 30 days and long‐term outcomes after allo‐HSCT through multivariate analyses. Results: A total of 692 AML patients received peripheral blood stem cells (89.2%), marrow (5.6%), or umbilical cord (5.2%) from matched related (37.4%), unrelated (49.1%), or haploidentical (8.2%) donors in 2011–2017. Transfusion requirements during the first 30 days for RBC (89.5% transfused, median 3, range 1–18 units) or PLT (98.2% transfused, median 6, range 1–144 units) were variable. By Day 30, 56.7% (95% confidence interval [CI]: 52.8–60.3%) and 86.1% (95% CI: 83.2–88.5%) had achieved RBC and PLT transfusion independence, respectively. Median follow‐up among survivors (n = 307) was 7.1 years (range: 2.7–11.8). Lack of RBC transfusion independence by Day 30 was strongly and independently associated with worse 5‐year OS (39.2% vs. 59.6%, adjusted hazard ratio [HR] 1.83, 95% CI: 1.49–2.25), leukemia‐free survival (35.8% vs. 55.5%, HR = 1.75, 95% CI: 1.43–2.14), and NRM (29.7% vs. 13.7%, HR = 2.05, 95% CI: 1.45–2.89) (p <.001). There was no difference in relapse rates among patients who achieved or did not achieve RBC (p =.34) or PLT (p =.64) transfusion independence. Conclusion: Prolonged RBC dependence predicted worse survival and NRM rates, but not increased relapse. Posttransplant surveillance of such patients should be adjusted with more attention to non‐relapse complications. [ABSTRACT FROM AUTHOR]

A polystyrene (PS)-based composite film and nonwoven fabric consisting of a photochromic spiropyran dye, 1,3,3-trimethylindolino-6′-nitrobenzopyrylospiran (6-nitro BIPS), and a photostimulable phosphor, europium-doped barium fluorochloride (BaFCl:Eu2+), were developed for the detection of X-ray exposure doses on the order of a milligray (mGy). The PS-based composite film and the nonwoven fabric were successfully prepared according to a cast method and a forcespinning method. The colours of the composite film and the nonwoven fabric were changed from white to deep blue, and a broad absorption band appeared, with a maximum at 604 nm, with X-ray exposures of 0.1 Gy and 5.6 Gy, respectively. The maximum sensitivity of 0.1 Gy of the composite film is equivalent to the radiation dose limit for workers who conduct emergency work. [ABSTRACT FROM AUTHOR]

Immunologie disparities between minor histocompatibility antigen (mHAg) genes on Y (H-Y) and X (H-X) chromosomes contribute to graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects observed in male recipients of a female donor (FtoM) hematopoietic stem cell transplant (HCT). Using in silico prediction tools, a panel of HLA-A0201 restricted H-Y peptides was synthesized. Expression of CD137 was monitored on CD8+ T cells after brief stimulation with the H-Y peptides in FtoM HLA-A0201 HCT recipients (N = 29), and control groups (HLA-A0201 MtoM[N= 18],non-HLA-A0201 FtoM [N = 14], and HLA-A0201 female volunteers [N = 25]). Specific H-Y responses were significantly greater in HLA-A0201 FtoM than controls. CD8+ T-cell responses to novel H-Y epitopes were shared among multiple patients, showing marked CD45RA+CD27 cytolytic effector profiles. These data represent a proof of concept for our in silico/ex vivo CD8+ T-cell based approach of prediction and validation of H-Y mHAgs in HCT recipients, which may facilitate prospective studies to identify targets/biomarkers of GVHD/GVL. [ABSTRACT FROM AUTHOR]

Abstract: We studied the morphological behavior of two-dimensional (2D) structures fabricated by two-photon excitation of silver nitrate in poly(N-vinylpyrrolidone) (PVP) matrix. The 2D structures at two different positions toward depth direction were fabricated on a microscope stage. Obtained structures were investigated using an atomic force microscopy (AFM), a scanning electron microscopy (SEM), an energy dispersive X-ray spectrometry (EDX), and an X-ray photoelectron spectroscopy (XPS). AFM measurement showed the photo-induce structure on a cover slip. EDX and XPS measurements showed that the silver ion was photo-reduced and the photo-reduced silver was interacted with PVP, respectively. [Copyright &y& Elsevier]

Abstract: We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II–IV acute GVHD was 35.4%; grade III–IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD; of these 35 were extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result. [Copyright &y& Elsevier]

Patients receiving allogeneic hematopoietic stem cell transplant may experience graft-versus-host disease (GVHD) in which donor immune cells cause an immune reaction in host tissues. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are highly effective in prevention of severe coronavirus-2019 (COVID-19) disease, but the vaccine can result in immune activation and GVHD. Herein, we report 4 cases of oral manifestations that may have been stimulated by COVID-19 or vaccination with Pfizer or Moderna vaccines. We believe this study is the first to report oral changes driven by an inflammatory/immune mechanism leading to oral symptomatic cGVHD. The clinical impact of this study is early recognition and appropriate management of oral symptomatic cGVHD following COVID-19 disease or SARS-CoV-2 vaccination. [ABSTRACT FROM AUTHOR]

Abstract: Peripheral blood stem cells (PBSC) have been increasingly used in the matched unrelated donor (MUD) transplant setting, but the impact of CD34+ cell dose on outcomes in this setting have not been well characterized. We analyzed 181 consecutive patients who underwent MUD-PBSC transplantation at the City of Hope between August 2000 to December 2004. Patients were conditioned with either full-intensity regimen or reduced-intensity regimen. There was a significant inverse relationship between higher CD34+ cell dose and faster neutrophil engraftment (r = −0.16, P = .035). By univariate analysis, a CD34+ cell dose ≥4.2 × 106/kg (above the lowest quartile) was associated with significantly lower relapse risk (hazard ratio [HR] = 0.67, P = .0126), with a trend for corresponding improvement for disease-free survival (HR = 0.84, P = .12) but not overall survival (HR = 0.91, P = .46). The impact of the CD34+ cell dose remained significant in multivariate analysis. The higher CD34+ cell dose was significantly associated with faster recovery of absolute lymphocyte counts on day +30 posttransplant. Subset analysis demonstrated that the higher CD34+ cell dose was associated with (1) greater reduction in relapse in myeloid malignancies than that in lymphoid malignancies, (2) greater reduction in reduced-intensity conditioning than in full-intensity conditioning, (3) greater reduction in relapse when there is a inhibitory killer-cell immunoglobulin-like receptor ligand (iKIRL)-mismatch in the gravft-versus-host (GVH) direction, and (4) greater reduction in relapse when there is a lack of iKIRL, suggesting that the protective effect of CD34+ cell dose against relapse may be immune-mediated, possibly through NK cell recovery. [Copyright &y& Elsevier]

Numerous clinical studies link cytomegalovirus (CMV) infection with incomplete posttransplantation T-cell recovery. We hypothesized that the inability of transplant recipients to handle CMV reactivation might correlate with a defective graft-versus-leukemia response and increased posttransplantation morbidity. Between May 1995 and August 2001, 82 patients who were CMV seropositive and survived the first 100 days after transplantation were identified for a day 100 landmark analysis of the effect of CMV reactivation patterns on eventual transplantation outcome. All patients underwent a myeloablative HLA-identical sibling donor T cell-depleted stem cell transplantation with scheduled donor T-cell add-back on day 45. Median follow-up was 1032 days. Forty-two patients who had either no reactivation or only 1 positive test with quick clearance were designated as a CMV immune competent group. Forty patients designated as CMV immune deficient (ID) had at least 2 positive tests. Apart from younger age (33 versus 38 years; P = .05) in the ID group, the 2 groups were balanced for clinical characteristics. In multivariate analysis, ID patients had a significantly higher incidence of leukemia relapse (58% versus 21%; P = .03) and worse disease-free survival (31% versus 66%; P = .04). There was no significant difference in week 1 to 14 posttransplantation lymphocyte counts between the 2 groups. In 67 patients tested 3 to 6 months after transplantation, a proliferative response to CMV antigen (stimulation index ≥2) occurred in 27 of 36 immune competent patients compared with 15 of 31 ID patients (P = .006). These results show that recurrent CMV reactivation in the first 100 days after transplantation predicts for reduced disease-free survival and increased leukemic relapse beyond 100 days and correlates with inferior proliferative responses to CMV. The higher relapse rate may reflect poor immune reconstitution in ID patients or an adverse effect of prolonged antiviral treatment. [Copyright &y& Elsevier]

We sought to optimize and standardize stem cell and lymphocyte doses of T cell-depleted peripheral blood stem cell transplants (T-PBSCT), using delayed add-back of donor T cells (DLI) to prevent relapse and enhance donor immune recovery. Fifty-one patients with haematological malignancies received a T-PBSCT from an HLA-identical sibling, followed by DLI of 1 × 107 and 5 × 107 CD3+ cells/kg on d +45 and +100 respectively. Twenty-four patients were designated as standard risk and twenty-seven patients with more advanced leukaemia were designated as high risk. Median recipient age was 38 years (range 10–56). Median (range) of CD34+ and CD3+ cell transplant doses were 4·6 (2·3–10·9) × 106/kg and 0·83 (0·38–2) × 105/kg respectively. The cumulative probability of acute GVHD was 39%. No patient died from GVHD or its consequences. The probability of developing chronic GVHD was 54% (18% extensive). The probability of relapse was 12% for the standard-risk patients and 66% for high-risk patients. In multivariate analysis, the risk factors for lower disease-free survival and overall survival were high-risk disease, CD34+ dose < 4·6 × 106/kg and CD3+ dose < 0·83 × 105/kg. Predictive factors for chronic GVHD were a T-cell dose at transplant > 0·83 × 105 CD3+ cells/kg. These results further define the impact of CD34 and CD3 cell dose on transplant outcome and show that careful dosing of stem cells and lymphocytes may permit the control and optimization of transplant outcome. [ABSTRACT FROM AUTHOR]

As the sister group to bilaterians, cnidarians stand in a unique phylogenetic position that provides insight into evolutionary aspects of animal development, physiology, and behavior. While cnidarians are classified into two types, sessile polyps and free-swimming medusae, most studies at the cellular and molecular levels have been conducted on representative polyp-type cnidarians and have focused on establishing techniques of genetic manipulation. Recently, gene knockdown by delivery of short hairpin RNAs into eggs via electroporation has been introduced in two polyp-type cnidarians, Nematostella vectensis and Hydractinia symbiolongicarpus, enabling systematic loss-of-function experiments. By contrast, current methods of genetic manipulation for most medusa-type cnidarians, or jellyfish, are quite limited, except for Clytia hemisphaerica, and reliable techniques are required to interrogate function of specific genes in different jellyfish species. Here, we present a method to knock down target genes by delivering small interfering RNA (siRNA) into fertilized eggs via electroporation, using the hydrozoan jellyfish, Clytia hemisphaerica and Cladonema paciificum. We show that siRNAs targeting endogenous GFP1 and Wnt3 in Clytia efficiently knock down gene expression and result in known planula phenotypes: loss of green fluorescence and defects in axial patterning, respectively. We also successfully knock down endogenous Wnt3 in Cladonema by siRNA electroporation, which circumvents the technical difficulty of microinjecting small eggs. Wnt3 knockdown in Cladonema causes gene expression changes in axial markers, suggesting a conserved Wnt/β-catenin-mediated pathway that controls axial polarity during embryogenesis. Our gene-targeting siRNA electroporation method is applicable to other animals, including and beyond jellyfish species, and will facilitate the investigation and understanding of myriad aspects of animal development. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing autologous hematopoietic cell transplantation (HCT) have a >2‐fold risk of developing cardiovascular disease (CVD; heart failure, myocardial infarction, and stroke), compared to the general population. Coronary artery calcium (CAC) is predictive of CVD in nononcology patients but is not as well studied in patients who underwent HCT and survivors of HCT.The objective of this study was to examine the association between CAC and CVD risk and outcomes after HCT in patients with lymphoma. Methods: This was a retrospective cohort study of 243 consecutive patients who underwent a first autologous HCT for lymphoma between 2009 and 2014. CAC (Agatston score) was determined from chest computed tomography obtained <60 days from HCT. Multivariable Cox regression analysis was used to calculate hazard ratio (HR) estimates and 95% confidence intervals (CIs), adjusted for covariates (age, conventional risk factors [e.g., hypertension and dyslipidemia], and cancer treatment). Results: The median age at HCT was 55.7 years (range, 18.5–75.1 years), 59% were male, and 60% were non‐Hispanic White. The prevalence of CAC was 37%. The 5‐year CVD incidence for the cohort was 12%, and there was an incremental increase in the incidence according to CAC score: 0 (6%), 1–100 (20%), and >100 (32%) (p =.001). CAC was significantly associated with CVD risk (HR, 3.0; 95% CI, 1.2–7.5) and worse 5‐year survival (77% vs. 50%; p <.001; HR, 2.0; 95% CI, 1.1–3.4), compared to those without CAC. Conclusions: CAC is independently associated with CVD and survival after HCT. This highlights the importance of integrating readily available imaging information in risk stratification and decision‐making in patients undergoing HCT, which sets the stage for strategies to optimize outcomes after HCT. Hematopoietic cell transplantation (HCT) survivors have an increased risk of cardiovascular disease (CVD) compared to the general population, and therefore thorough assessment of cardiovascular risk before HCT is essential. This study showed that the coronary artery calcium (CAC) score, obtained from routine pretransplant imaging, is significantly associated with CVD posttransplant and is a useful addition to traditional cardiovascular risk factors. Further prospective studies are needed to understand how CAC screening should be formally incorporated into pretransplant workup, cardiovascular risk assessment, and clinical decision‐making and its effect on posttransplant outcomes. [ABSTRACT FROM AUTHOR]

Intensive care physicians may assume the primary care of patients with transplant-associated thrombotic microangiopathy (TA-TMA), an uncommon but potentially critical complication of hematopoietic stem cell transplants (HSCTs) and solid organ transplants. TA-TMA can have a dramatic presentation with multiple organ dysfunction syndrome (MODS) associated with high morbidity and mortality. The typical presenting clinical features are hemolytic anemia, thrombocytopenia, refractory hypertension, proteinuria and worsening renal failure. Intestinal involvement, with abdominal pain, nausea and vomiting, gastrointestinal bleeding, and ascites are also common. Cardiopulmonary involvement may develop from various causes including pulmonary arteriolar hypertension, pleural and pericardial effusions, and diffuse alveolar hemorrhage. Due to other often concurrent complications after HSCT, early diagnosis and effective management of TA-TMA may be challenging. Close collaboration between ICU and transplant physicians, along with other relevant specialists, is needed to best manage these patients. There are currently no approved therapies for the treatment of TA-TMA. Plasma exchange and rituximab are not recommended unless circulating factor H (CFH) antibodies or thrombotic thrombocytopenic purpura (TTP; ADAMTS activity < 10%) are diagnosed or highly suspected. The role of the complement pathway activation in the pathophysiology of TA-TMA has led to the successful use of targeted complement inhibitors, such as eculizumab. However, the relatively larger studies using eculizumab have been mostly conducted in the pediatric population with limited data on the adult population. This review is focused on the role of intensive care physicians to emphasize the clinical approach to patients with suspected TA-TMA and to discuss diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Background Early CMV reactivation remains a significant cause of morbidity/mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine based on an HLA-A0201-restricted immune-dominant peptide (pp65 495-503). In a randomized Phase 1b trial, CMVPepVax (given on days 28 & 56 post-HCT) demonstrated safety, immunogenicity, and reduced CMV reactivations (Lancet Haem 2017). In the current study, we assessed the detailed phenotypes and time-courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. Patients (pts)/methods Of 18 pts in the vaccine arm (VA) and 18 in the observation arm (OA), 12 VA and 8 OA pts were included for the current study as they developed levels of CMV-specific T cells evaluable for memory phenotyping. Eleven of the 12 VA pts did not reactivate CMV during the 6-month while 5 OA and 1 VA pts developed viremia requiring antiviral treatment. The differentiation status of CMV-specific CD3+CD8+ T cells, identified by pp65 495-503 dextramers, was determined based on CD28/CD45RA expression using polychromatic flow cytometric panels. CD137 expression assay was used to evaluate T cell responses to pp65 or IE1 peptide library. Results The VA pts more often achieved ³0.2% levels of pp65 495-503 -specific CD8 T cells in the absence of clinically detectable CMV viremia (10 non-reactivating pts of 17 in the VA vs. 1 non-reactivating pts of 12 in the OA, p=0.008). Phenotype proportions are displayed in Figure 1. In contrast, when T cells were stimulated with pp65 or IE1 peptide libraries encoding T cell epitopes specific for a variety of HLA alleles, the T cell responses measured by CD137 expression in both VA and OA pts did not significantly differ. These results suggest that the enhanced pp65 495-503 response measured in the VA pts (without viremia) was likely driven by PepVax. When the differentiation status was analyzed, pp65 495-503 -specific T cells in viremic OA pts had a median % of effector phenotype profiles of 91% (range: 31-99%), similar to those of the evaluable non-viremic VA patients, for whom the median % of effector phenotype profiles was 93% (range: 13-100%). Importantly, 2 weeks after the 2nd PepVax vaccination, >80% of pp65 495-503 -specific T cells were TEM and TEMRA in 9 out of the 10 evaluable VA pts. Thus, in these HCT recipients who did not develop CMV viremia, PepVax rapidly expanded CMV-specific T cells with substantial EM profiles. Figure 2 depicts longitudinal dynamic of pp65 495-503 -specific CD8 T cells and their memory profiles. Conclusion Collectively, our analysis indicates that, in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated effector memory CD8 T cells specific to the vaccine epitope of pp65 495-503 early post-HCT, which may have been key to the favorable outcomes of the CMVPepVax clinical trial. [ABSTRACT FROM AUTHOR]

• The incidence of AML relapse is reduced with CMV reactivation. • NK cells are involved in CMV-associated protection from AML relapse. • CMV infection trigger/enhance a response by NK expressing activating KIRs. Multiple retrospective studies have demonstrated an association between cytomegalovirus (CMV) reactivation and reduced risk of AML relapse. However, the potential mechanism explaining this association remains elusive. We investigated a homogeneous cohort of 288 adult patients with AML in remission who received allogeneic hematopoietic stem cell transplantation (HCT) from matched sibling/unrelated donors between 1995 and 2011. The 5-year cumulative incidence of relapse was greater in patients without CMV reactivation compared with those with reactivation (30.2% vs. 12.1%, p = 0.001) in a landmark analysis. In multivariate analyses CMV reactivation was independently associated with reduced relapse risk (HR: 0.49 [0.25-0.95], p = 0.036) and increased non-relapse mortality (26.5% vs. 13.1%, p = 0.002) resulting in similar 5-year overall survival (64.5% vs. 59.1%, p = 0.8). In further subgroup analyses the protective effect of CMV reactivation was significant in patients who received HCT from donors with KIR Bx compared to KIR AA (11.7% vs. 29.5%, p = 0.01). Likewise, the protective effect of CMV reactivation was more significant when the donors had 2DS1 activating KIR (11.5% vs. 30.7%, p = 0.05) compared with those without 2DS1 (14.3% vs. 27.5%, p = 0.12). Our data independently confirmed the association between CMV reactivation and AML relapse, suggesting the involvement of donor KIR genotypes and NK cell-mediated graft-versus-leukemia effect. [ABSTRACT FROM AUTHOR]

Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35–298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation. [ABSTRACT FROM AUTHOR]

We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS. [ABSTRACT FROM AUTHOR]

Background: Allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients often require substantial but variable transfusion support.Study Design and Methods: This single-center, retrospective study evaluated the red blood cell (RBC) and platelet (PLT) transfusion data of first-time allo-HSCT recipients transplanted in 2011 to 2017. Multivariate analyses were performed to assess the associations between patient and transplant-related factors and transfusion requirements.Results: The study included 1762 patients who received peripheral blood stem cells (88.2%), marrow (7.0%), or umbilical cord (4.8%) from matched related (38.3%), unrelated (49.2%), or haploidentical (7.8%) donors. Almost all patients required RBCs (88.3%) or PLTs (97.4%) during the first 30 days, with medians of 3 (range, 1-37) RBC and 6 (range, 1-144) PLT units transfused. Fewer patients required RBC (43.8%) or PLT (27.3%) transfusions during Days 31 to 100, but the median (range) numbers of RBC and PLT units remained high at 3 (1-36) and 6 (1-116) among transfused patients. RBC and PLT transfusion independence was reached in medians of 24 (95% confidence interval [CI], 22-26) and 12 (95% CI, 11-12) days, respectively. Haploidentical donor, cord graft, and requiring RBC transfusions in the 10 days before HSCT were the most significant independent factors predictive of increased transfusion requirements. Advanced disease, diagnosis, ABO incompatibility, conditioning intensity, CD34+ cell dose, presence of severe acute graft-vs-host disease, and changes in recommended transfusion triggers were also shown to independently impact transfusion requirements.Conclusions: This study provided for the first time quantitative and comparative transfusion data on a large contemporary cohort of HSCT recipients, including haploidentical and cord graft recipients, and identified factors predictive of increased transfusions. [ABSTRACT FROM AUTHOR]

Background: The volume of haploidentical hematopoietic stem cell transplant (haplo-HSCT) has increased dramatically in recent years. However, the associated higher risk of delayed engraftment may increase patient transfusion requirements.Study Design and Methods: The post-HSCT RBC and platelet transfusions of 195 haplo-HSCT recipients were evaluated. Patient and transplant-related factors potentially impacting the number of products transfused and time to transfusion independence were assessed.Results: Nearly all (98.4%) patients were transfused in the first 30 days, and 59.2% were transfused between days 31 and 100. Among the transfused patients, medians of 5 units (interquartile range [IQR] = 3-8) of RBCs and 11 units (6-20) platelets were given in the first 30 days, and medians of 3 units (IQR = 1-7) of RBCs and 6 units (2-18) of platelets were transfused between days 31 and 100. Median times for achieving RBC and platelet transfusion independence were 34 (95% CI: 28-40) and 25 (95% CI: 23-27) days, respectively. Multivariable analyses showed that RBC transfusions in the 10 days before HSCT were associated with significantly increased and sustained RBC and platelet transfusion requirements. Major ABO incompatibility led to increased RBC transfusions. Advanced disease was associated with increased transfusions during the first 30 days, whereas GVHD increased platelet transfusions between days 31 and 100. Effects of age, sex, CD34+ cell dose, stem cell source, and conditioning regimen were limited or insignificant.Conclusions: This study for the first time provided quantitative transfusion data on a large cohort of haplo-HSCT recipients and identified factors predictive of increased transfusions. [ABSTRACT FROM AUTHOR]

Background: Patients undergoing hematopoietic cell transplantation (HCT) are at high risk of chronic health complications, including frailty and physical dysfunction. Conventional exercise programs have been shown to improve frailty in other cancer populations, but these have largely been based out of rehabilitation facilities that may act as geographic and logistical barriers. There is a paucity of information on the feasibility of implementing telehealth exercise interventions in long-term HCT survivors. Methods: We conducted a pilot randomized trial to assess the feasibility of an 8-week telehealth exercise intervention in 20 pre-frail or frail HCT survivors. Participants were randomized to either a telehealth exercise (N = 10) or delayed control (N = 10). We administered a remote physical function assessment at baseline, followed by an 8-week telehealth exercise intervention (30-60 min/session, 3 sessions/week), and post-intervention. The primary endpoint was feasibility as determined by 1) > 70% of participants completing all remote physical functional assessments, and 2) > 70% of participants in the exercise group completing > 70% (17/24) of the prescribed exercise sessions. Exploratory outcomes included changes in gait speed, handgrip strength, and short physical performance battery. Results: The mean [standard deviation] age at study enrollment was 64.7 [9.1] years old. Twelve had undergone allogenic and 8 had undergone autologous HCT at an average of 17 years from study enrollment. Both feasibility criteria were achieved. Nineteen patients (95%) completed all remote study outcome assessments at baseline and post-intervention, and nine participants in the exercise group completed > 70% of prescribed exercise sessions. Overall, no significant group x time interaction was observed on handgrip strength, fatigue, body mass index, and short physical performance battery test (P < 0.05). However, there were significant within-group improvements in four-meter gait speed (+ 13.9%; P = 0.004) and 5-minute gait speed (+ 25.4%; P = 0.04) in the exercise group whereas non-significant changes in four-meter gait speed (-3.8%) and 5-minute gait speed (-5.8%) were observed after 8 weeks. Conclusion: Implementing an 8-week telehealth exercise intervention for long-term HCT survivors was feasible. Our findings set the stage for innovative delivery of supervised exercise intervention that reduces the burden of frailty in HCT survivors as well as other at-risk cancer survivors. Trial registration: The protocol and informed consent were approved by the institutional IRB (IRB#20731) and registered (ClinicalTrials.gov NCT04968119; date of registration: 20/07/2021). [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) microstructures with micron scale are fabricated in photoresist using two-photon direct laser writing with an infrared femtosecond laser at 800 nm. The positive photoresist of Novolak/diazonaphthoquinone (DNQ) is used for the fabrication of line structures and 3D microstructures. Linewidths of line structures are fabricated with laser power ranging from 1 to 15 mW and scanning speeds ranging from 5 to 50 μm s. The obtained linewidth is analyzed using an exposure kinetics model of DNQ for two-photon absorption. Both 3D inversed woodpile structures and helical structures are fabricated. Graphical abstract: Two-photon direct laser writing is used to fabricate microstructures in positive photoresist. Microstructures with helical and inversed woodpile shapes were fabricated with positive photoresist Novolak/DNQ using two-photon direct laser writing. [ABSTRACT FROM AUTHOR]

This study reports the incidence of chronic graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplant (alloHCT) recipients who received SARS-CoV2 vaccination. The overall rates of new and worsening chronic GvHD combined were 14%, with median time from vaccination to GVHD being approximately three to four weeks. A majority of the cases were of mild to moderate severity and primarily localized to either the skin, mouth, or joints. Prior chronic GVHD and recent transplant were associated with higher GVHD rates following COVID-19 vaccination. More prospective studies are needed to provide a definitive mechanism for the impact of SARS-CoV2 vaccination on alloHCT patients. [ABSTRACT FROM AUTHOR]

Rearrangements of I lysine [K] methyltransferase 2 A i ( I KMT2A i ) gene, previously known as the I MLL i gene, occur in 3 to 7% of adult patients with de novo AML and are enriched in therapy-related disease, particularly after treatment with topoisomerase II inhibitors [[1]]. Response and survival of patients with KMT2A rearranged acute myeloid leukemia (AML) receiving venetoclax in combination with hypomethylating agent therapy (HMA). The inferior prognosis of KMT2A rearranged AML patients undergoing alloSCT presents an opportunity for post-transplant maintenance trials with therapies targeting KMT2A. [Extracted from the article]

Biomarker‐guided dosing may improve the efficacy and toxicity of cyclophosphamide (CY); however, clinical studies evaluating their association with the area under the plasma concentration–time curve (AUC) of CY and its metabolites are time‐ and resource‐intensive. Therefore, we sought to identify lipidomic biomarkers associated with the time‐varying differences in CY formation clearance to 4‐hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Hematopoietic cell transplant (HCT) patients receiving post‐transplant CY (PT‐CY) were enrolled, cohort 1 (n = 25) and cohort 2 (n = 26) donating longitudinal blood samples before they started HCT (pre‐HCT), before infusion of the donor allograft (pre‐graft), before the first dose of PT‐CY (pre‐CY) and 24 h after the first dose of PT‐CY (24‐h post‐CY) which is also immediately before the second dose of CY. A total of 409 and 387 lipids were quantitated in the two cohorts, respectively. Associations between lipids, individually and at a class level, and the ratio of 4HCY/CY AUC (i.e., 4HCY formation clearance) were evaluated using linear regression with a false discovery rate <0.05. There were no individual lipids that passed control for false discovery at any time point. These results demonstrate the feasibility of lipidomics, but future studies in larger samples with multiple omic tools are warranted to optimize CY dosing in HCT. [ABSTRACT FROM AUTHOR]

Background Risk of nonrelapse mortality (NRM) after hematopoietic cell transplantation (HCT) is high. Patient-level clinical prediction models such as the HCT–comorbidity index (HCT-CI) help identify those at increased risk for NRM, but the independent contribution of social determinants of health on HCT outcomes is not well characterized. Methods This study included 1602 patients who underwent allogeneic HCT between 2013 and 2019 at City of Hope. Census tract–level social vulnerability was measured using the social vulnerability index (SVI). Fine-Gray multivariable regression evaluated the association between SVI and 1-year NRM. Subgroup analysis examined risk of NRM across combined SVI and HCT-CI categories and by race and ethnicity. Results Cumulative incidence of 1-year NRM after HCT was 15.3% (95% confidence interval [CI] = 13.6% to 17.1%). In multivariable analysis, patients in the highest SVI tertile (highest social vulnerability) had a 1.4-fold risk (subdistribution hazard ratio [sHR] = 1.36, 95% CI = 1.04 to 1.78) of NRM compared with individuals in the lower tertiles; patients in the highest SVI tertile who also had elevated (≥3) HCT-CI scores had the highest risk (sHR = 1.81, 95% CI = 1.26 to 2.58) of 1-year NRM (reference: lower SVI tertiles and HCT-CI < 3). High social vulnerability was associated with risk of 1-year NRM in Asian (sHR = 2.03, 95% CI = 1.09 to 3.78) and Hispanic (sHR = 1.63, 95% CI = 1.04 to 2.55) but not non-Hispanic White patients. Conclusions High social vulnerability independently associated with 1-year NRM after HCT, specifically among minority populations and those with a high comorbidity burden at HCT. These findings may inform targeted approaches for needs assessment during and after HCT, allowing for timely interventions to improve health outcomes in at-risk patients. [ABSTRACT FROM AUTHOR]

Abbreviations CIBMTR Center for International Blood in Marrow Transplant Research CMWP Chronic Malignancies Working Party EBMT European Society for Blood and Marrow Transplantation Chronic neutrophilic leukaemia (CNL) is a rare, frequently aggressive Philadelphia (Ph)-negative myeloproliferative neoplasm (MPN). The disease status at allo-HCT was reported to be no response/stable disease in 11 (38%) patients and complete remission (CR) in four (14%) patients. In the case series from Japan, two patients received cord blood grafts and one patient received a related haploidentical donor marrow graft. [Extracted from the article]

Patients with acute leukemia who undergo allogenic hematopoietic cell transplantation with active disease have high rates of relapse and poor overall survival (OS) post-transplant compared to patients undergoing HCT in remission. Here, we report the long-term outcomes in 32 patients who received a high-intensity conditioning regimen comprising fractionated total body irradiation (FTBI; 1200 cGy) with pharmacokinetic (PK) dosing of intravenous Busulfan (IV BU) targeted to first dose area under curve (AUC) of 700–900 µM/min and etoposide (30 mg/kg) in a prospective phase 2 clinical trial. The median age of the patients at the time of HCT was 37 years (range: 18–50) presenting with high-risk (n = 6) and relapsed/refractory(r/r) acute leukemias (n = 26). All but one patient underwent HCT using peripheral blood stem cells from matched sibling donors. At a median follow-up of 17.3 years (range 14.4–19.0), 11 patients remained alive. The disease-free survival and OS at 15 years was 34% (versus 40% at 5-years post-HCT). The 15-year cumulative incidence of relapse was 26% and non-relapse mortality (NRM) was 38% (95% CI: 21–54%) and the cumulative incidence of chronic GVHD at 15 years was 33% using a prophylactic regimen of cyclosporine A and mycophenolate mofetil. The most common life-threatening late effects were secondary malignancies, metabolic, or cardiac complications with a cumulative incidence of 6.6%, 6.6%, and 13.3%, respectively. No unusual late effects or patterns of relapse were noted on longer followed on patients treated with intensified myeloablative condition regimen. Results from this study supports continued development of intensive conditioning regimens in patients with r/r acute leukemias to improve leukemia free (LFS) and OS in this high-risk population. [ABSTRACT FROM AUTHOR]

This study attempted to visualize reversible X-ray radiation by using a poly-(l-lactic acid) (PLLA) composite fiber with an average diameter of 150 μm. The fiber contains photostimulable phosphor (PSP) BaFCl:Eu2+ particles that are subsequently dyed with the photochromic spiropyran dye (1,3,3-trimethylindolino-6′-nitrobenzopyrylospiran) (6-nitro BIPS). [ABSTRACT FROM AUTHOR]

Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and s irolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There w as no difference in the probability of day 114 grades 2 -4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .0 0 1 ; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393. (Blood. 2014;124(8):1372-1377) [ABSTRACT FROM AUTHOR]

The 1-year OS for HCT patients (21 patients) was 85% (95% CI 61-95%) compared to 41% (95% CI 16-65%) in non-HCT patients in cCR (14 patients). The 1-year LFS in patients who underwent HCT (21 patients) was 67% (95% CI 41-84%) I versus i 33% (95% CI 10-57%) in non-HCT patients in cCR (14 patients). [Extracted from the article]

Background: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease–positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19– disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. Methods: This study retrospectively reviewed the outcomes of adult patients with B‐cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013‐2021) and analyzed factors associated with treatment response and EMD failure. Results: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P =.049) and no history of previous EMD (P =.019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P =.005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P =.012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. Conclusions: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. Lay Summary: Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia.A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites.Most extramedullary failure cases retain CD19 expression. Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) from human leukocyte antigen (HLA) matched related donor (MRD) and matched unrelated donors (MUD) produces similar survival for patients with acute myelogenous leukemia. Whether these results can be extended to patients with myelodysplastic syndromes (MDS) is unknown. Therefore, analysis of post-HCT outcomes for MDS was performed. Outcomes of 701 adult MDS patients who underwent HCT between 2002 and 2006 were analyzed (MRD [n = 176], 8 of 8 HLA-A, -B, -C, -DRB1 allele matched MUD [n = 413], 7 of 8 MUD [ n = 112]). Median age was 53 years (range, 22-78 years). In multivariate analyses, MRD HCT recipients had similar disease free survival (DFS) and survival rates compared with 8 of 8 MUD HCT recipients (relative risk [RR] 1.13 [95% confidence interval (CI) 0.91-1.42] and 1.24 [95% CI 0.98-1.56], respectively), and both MRD and 8 of 8 MUD had superior DFS (RR 1.47 [95% C11.10-1.96] and 1.29 [95% C11.00-1.66], respectively) and survival (RR 1.62 [95% CI 1.21-2.17] and 1.30 [95% CI 1.01-1.68], respectively) compared with 7 of 8 MUD HCT recipients. In patients with MDS, MRD remains the best stem cell source followed by 8 of 8 MUD. Transplantation from 7 of 8 MUD is associated with significantly poorer outcomes [ABSTRACT FROM AUTHOR]

Stress hyperglycemia and acute graft- versus-host disease (GVHD), the major early complication of hematopoietic stem cell transplantation (HSCT), are both associated with excessive release of inflammatory cytokines. We investigated whether new-onset hyperglycemia immediately after HSCT predicts acute GVHD. We studied nondiabetic adult recipients of human leukocyte antigen-matched HSCT (peripheral blood stem cells) for acute leukemia. Using mean morning serum glucose on Days 1-10, we classified hyperglycemia as: mild (6.11-8.33 mmol/L), moderate (8.34-9.98), and severe (minimum of 9.99). Subjects who were GVHD-free on Day 10 were followed during Days 11-100 for grades II-IV acute GVHD or competing event. Evaluation utilized cumulative incidence-based proportional hazards regression. Subjects ( n = 328) were age 18-74, median of 49 years. Per body mass index (BMI)-25.0 % were obese (BMI, 30-48), 33.8 % overweight (25 to <30), 30.8 % normal weight (21 to <25), and 10.4 % lean (18 to <21). Mild, moderate, or severe hyperglycemia occurred during Days 1-10 in 50.0, 21.3, and 16.8 % of subjects, respectively. Cumulative incidence on Day 100 was 44.8 (±2.8) % acute GVHD and 7.9 (±1.5) % competing event. Among normal-to-overweight subjects ( n = 212), severe hyperglycemia developed in 14.2 % ( n = 30) and more than doubled the risk of acute GVHD (hazards ratio, 2.71; 95 % CI, 1.58-4.65-adjusted for donor/recipient characteristics, prophylactic regimen, and mucositis). In contrast, among obese subjects ( n = 82), severe hyperglycemia developed in 30.5 % ( n = 25) but did not significantly affect risk of GVHD. (No lean subjects ( n = 34) developed severe hyperglycemia.) Hyperglycemia that was less than severe had an effect indistinguishable from normoglycemia. In nondiabetic patients, severe hyperglycemia immediately after allogeneic HSCT indicates increased likelihood of acute GVHD. This association is absent in obese patients, who may be primed by obesity-induced inflammation to develop severe hyperglycemia even without experiencing the cytokine storm that is essential to GVHD pathogenesis. [ABSTRACT FROM AUTHOR]

IL-22 has been shown to support intestinal mucosa after damage through multiple mechanisms, including promotion of epithelial survival and regeneration as well as induction of innate antimicrobial molecules such as REG3. In experimental murine models, aGVHD resulted in elimination of host-derived IL-22-producing cells, IL-22 deficiency increased GVHD mortality and GI pathology, and early initiation of treatment with exogenous IL-22 reduced GI pathology and improved survival. We thus tested if the addition of IL-22 to corticosteroids could promote healing of GI tract injury and improve treatment response in patients with lower GI aGVHD. We conducted a 27-patient open-label, single-cohort, multicenter prospective phase 2 study between 05/16 and 05/19. Eligible pts were ≥ 18 yrs old and had new onset biopsy-proven grade II-IV lower GI aGVHD following an allo-HCT. Pts received F-652 once weekly at a dose of 45 μg/kg x 4 weeks in combination with standard corticosteroid treatment. Primary endpoints included PK, safety, and day 28 lower GI aGVHD response. Additional endpoints included day 56 treatment response, evaluation of changes in gut microbiota by 16S sequencing, and plasma GVHD biomarkers. The study was powered to distinguish between an unpromising response rate of 35% and a promising response rate of 60%. The 27 pts (median age 55 yrs, mostly PBSC recipients) had predominantly stage 2-4 lower GI GVHD (17/27, 63%), with 6/27 (22%) pts having stage 3 and 6/27 (22%) pts having stage 4 disease. All pts had detectable F-652 levels. Overall, 19/27 achieved a day 28 response (70%, 90%CI: 56-79, Fig 1A). Response to treatment based on Ann Arbor Risk, evaluable in 20 pts, was 7/12 (58%) with high, 3/4 (75%) with intermediate, and 4/4 (100%) with low risk biomarkers (Fig 1B). At day 56, 16 pts (59%) remained treatment responders. 3 pts had repeat GI biopsy after treatment and demonstrated improvement in GI epithelial injury (Fig 2). Additionally, in a subset of 17 pts with stool samples collected, microbial diversity and relative abundance of protective commensal Blautia appeared increased in pts with a clinical response to F-652 (p = 0.082 and 0.048, respectively, Fig 3A-B). Serious TEAEs were observed in 11 pts (40%) including enterocolitis (n = 1), pyrexia (n = 1), infection (2 sepsis, 1 device-related, 1 pneumonia, 1 sinusitis), musculoskeletal (n = 2), and respiratory (n = 1). One patient was diagnosed with squamous cell carcinoma 8 months after F-652 treatment. IL-22 in combination with corticosteroids was well tolerated and the 70% lower GI aGVHD response rate met the primary efficacy endpoint. These findings support further development of this approach and provide a proof-of-concept for combining standard immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa, promote microbial health, and improve GVHD treatment response. [ABSTRACT FROM AUTHOR]

Blinatumomab is a bispecific T cell‐engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%‐50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single‐nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients' archived DNA samples. With a median duration of 9.5 months (range: 1‐37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE‐0.43, P =.01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078‐0.92, P =.034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis‐generated data suggest a potential role for IL‐17 and IL‐2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B‐ALL. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of studies describing the incidence and risk factors for late‐occurring (≥1 year) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). Methods: This was a retrospective cohort study of 641 1‐year survivors of HCT, transplanted between 2010 and 2013 as adults, and in remission from their primary disease. Standardized definitions were used to characterize viral, fungal, and bacterial infections. Cumulative incidence of infections was calculated, with relapse/progression considered as a competing risk event. Fine‐Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained, adjusted for relevant covariates. Results: Median age at HCT was 55.2 years (range 18.1–78.1 years); 54.0% were survivors of allogeneic HCT. The 5‐year cumulative incidence of a late‐occurring infection for the entire cohort was 31.6%; the incidence of polymicrobial (≥2) infections was 10.1%. In survivors who developed at least one infection, the 5‐year incidence of a subsequent infection was 45.3%. Among allogeneic HCT survivors, patients with acute lymphoblastic (HR = 1.82 95% CI [1.12–2.96]) or myeloid (HR = 1.50 95% CI [1.02–2.20]) leukemia, and those with an elevated HCT‐Comorbidity index score (HR = 1.09 95% CI [1.01–1.17]) were more likely to develop late‐occurring infections; there was an incremental risk associated with severity of graft versus host disease (GVHD) at 1‐year post‐HCT (mild: HR = 2.17, 95% CI [1.09–4.33]; moderate/severe: HR = 3.78, 95% CI [1.90–7.53]; reference: no GVHD). Conclusions: The burden of late‐occurring infections in HCT survivors is substantial, and there are important patient‐ and HCT‐related modifiers of risk over time. These findings may help guide personalized screening and prevention strategies to improve outcomes after HCT. [ABSTRACT FROM AUTHOR]

PURPOSE: Thirty-day unplanned readmission is one of the key components in measuring quality in patient care. Risk of readmission in oncology patients may be associated with a wide variety of specific factors including laboratory results and diagnoses, and it is hard to include all such features using traditional approaches such as one-hot encoding in predictive models. METHODS: We used clinical embeddings to represent complex medical concepts in lower dimensional spaces. For predictive modeling, we used gradient-boosted trees and adopted the shapley additive explanation framework to offer consistent individualized predictions. We used retrospective inpatient data between 2013 and 2018 with temporal split for training and testing. RESULTS: Our best performing model predicting readmission at discharge using clinical embeddings showed a testing area under receiver operating characteristic curve of 0.78 (95% CI, 0.77 to 0.80). Use of clinical embeddings led to up to 23.1% gain in area under precision-recall curve and 6% in area under receiver operating characteristic curve. Hematology models had more performance gain over surgery and medical oncology. Our study was the first to develop (1) explainable predictive models for the hematology population and (2) dynamic models to keep track of readmission risk throughout the duration of patient visit. CONCLUSION: To our knowledge, our study was the first to develop (1) explainable predictive models for the hematology population and (2) dynamic models to keep track of readmission risk throughout the duration of patient visit. [ABSTRACT FROM AUTHOR]

CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted. [ABSTRACT FROM AUTHOR]

• The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (VEN-HMA) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) is associated with favorable HCT outcomes. • VEN-HMA could allow more patients of older age to proceed to potentially curative alloHCT. • AlloHCT outcomes are particularly good in patients who undergo HCT in complete remission after VEN-HMA therapy. The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML. [ABSTRACT FROM AUTHOR]

Background: Long-term mortality after hematopoietic cell transplantation (HCT) is conventionally calculated from the time of HCT, ignoring temporal changes in survivors' mortality risks. Conditional survival rates, accounting for time already survived, are relevant for optimal delivery of survivorship care but have not been widely quantified. We estimated conditional survival by elapsed survival time in allogeneic HCT patients and examined cause-specific mortality.Methods: We calculated conditional survival rates and standardized mortality ratio for overall and cause-specific mortality in 4485 patients who underwent HCT for malignant hematologic diseases at a large transplant center during 1976-2014. Statistical tests were two-sided.Results: The 5-year survival rate from HCT was 48.6%. After surviving 1, 2, 5, 10, and 15 years, the subsequent 5-year survival rates were 71.2%, 78.7%, 87.4%, 93.5%, and 86.2%, respectively. The standardized mortality ratio was 30.3 (95% confidence interval [CI] = 29.2 to 35.5). Although the standardized mortality ratio declined in longer surviving patients, it was still elevated by 3.6-fold in survivors of 15 years or more (95% CI = 3.0 to 4.1). Primary disease accounted for 50% of deaths in the overall cohort and only 10% in 15-year survivors; the leading causes of nondisease-related mortality were subsequent malignancy (26.1%) and cardiopulmonary diseases (20.2%). We also identified the risk factors for nondisease-related mortality in 1- and 5-year survivors.Conclusion: Survival probability improves the longer patients survive after HCT. However, HCT recipients surviving 15 years or more remain at elevated mortality risk, largely because of health conditions other than their primary disease. Our study findings help inform preventive and interventional strategies to improve long-term outcomes after allogeneic HCT. [ABSTRACT FROM AUTHOR]

Only 1 (3%) patient, a CAR-T therapy recipient for diffuse large B-cell lymphoma, treated with bamlanivimab for mild COVID-19 progressed to severe disease requiring ICU care. To the Editor - We read with interest the article by Ganesh et al regarding monoclonal antibody (mAb) therapy for coronavirus disease 2019 (COVID-19) in high-risk patients [[1]]. Coronavirus (COVID-19) update: FDA authorizes monoclonal antibodies for treatment of COVID-19. 2020. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-monoclonal-antibody-treatment-covid-19. [Extracted from the article]

• Impact of iron overload (serum ferritin [SF] >2000 ng/mL) on umbilical cord blood hematopoietic cell transplantation (HCT) outcomes was examined. • Overall survival rate at 2 years was significantly lower in patients with higher pre-HCT SF levels (P =.005). • Nonrelapse mortality was significantly higher in patients with higher SF (P =.02). • Significantly faster engraftment was seen in patients with lower SF levels. • Iron overload is a strong adverse prognostic factor for cord blood transplant. The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P =.005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P =.025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P =.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P =.044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic cell transplantation (HCT) is a curative option for a growing number of patients with hematologic diseases and malignancies. However, HCT-related factors, such as total body irradiation used for conditioning, graft-versus-host disease, and prolonged exposure to immunosuppressive therapy, result in very high risk for melanoma and non-melanoma skin cancer (NMSC). In fact, skin cancer is the most common subsequent neoplasm in HCT survivors, tending to develop at a time when survivors' follow-up care has largely transitioned to the primary care setting. The goal of this study is to increase skin cancer screening rates among HCT survivors through patient-directed activation alone or in combination with physician-directed activation. The proposed intervention will identify facilitators of and barriers to risk-based screening in this population and help reduce the burden of cancer-related morbidity after HCT.Methods/design: 720 HCT survivors will be enrolled in this 12-month randomized controlled trial. This study uses a comparative effectiveness design comparing (1) patient activation and education (PAE, N = 360) including text messaging and print materials to encourage and motivate skin examinations; (2) PAE plus primary care physician activation (PAE + Phys, N = 360) adding print materials for the physician on the HCT survivors' increased risk of skin cancer and importance of conducting a full-body skin exam. Patients on the PAE + Phys arm will be further randomized 1:1 to the teledermoscopy (PAE + Phys+TD) adding physician receipt of a portable dermatoscope to upload images of suspect lesions for review by the study dermatologist and an online course with descriptions of dermoscopic images for skin cancers.Discussion: When completed, this study will provide much-needed information regarding strategies to improve skin cancer detection in other high-risk (e.g. radiation-exposed) cancer survivor populations, and to facilitate screening and management of other late effects (e.g. cardiovascular, endocrine) in HCT survivors.Trial Registration: ClinicalTrials.gov, NCT04358276 . Registered 24 April 2020. [ABSTRACT FROM AUTHOR]