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•Germ line ERG LOF variants predispose to cytopenias and HMs.•Somatic genetic rescue of ERG pathogenic variants in hematopoietic tissues impacts diagnosis, disease severity, and potential for correction.

•Allogeneic HCT quickly and durably resolved disease manifestations in patients with CGD, with excellent survival.•HCT should be considered early for CGD before comorbidities affect the performance status.

•Fractionated compared with single-dose gemtuzumab increased response depth across most AML molecular groups without increasing toxicity.•Older patients with AML receiving fractionated gemtuzumab had improved survival when induction was consolidated by allograft.

•Cell-free mtDNA is elevated in the peripheral blood and BM of patients with myeloma compared with those of healthy controls.•Myeloma-derived mtDNA remodels the BM microenvironment through its effect of STING activation in myeloma-associated macrophages.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651.

Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs), and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. Here, using experimental models that use the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase mixed lineage leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein, “coagulopathy-related factors”) in noninfected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon alfa (IFN-α), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NF-κB/RelA–mediated transcription of these coagulation-related factors and identify a context-dependent, MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant, and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to noninfected and healthy controls. We also observed elevated plasma PLAU and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting CAC and inflammation.

Following allogeneic hematopoietic cell transplantation (allo-HCT), the gastrointestinal (GI) tract is frequently affected by acute graft-versus-host disease (aGVHD), the pathophysiology of which is associated with a dysbiotic microbiome. Since microbial composition varies along the length of the GI tract, the authors hypothesized that microbiome features correlate with the pattern of organ involvement after allo-HCT. We evaluated 266 allo-HCT recipients from whom 1303 stool samples were profiled by 16S ribosomal gene sequencing. Patients were classified according to which organs were affected by aGVHD. In the 20 days prior to disease onset, GVHD patients had lower abundances of members of the class Clostridia, lower counts of butyrate producers, and lower ratios of strict-to-facultative (S/F) anaerobic bacteria compared with allograft recipients who were free of GVHD. GI GVHD patients showed significant reduction in microbial diversity preonset. Patients with lower GI aGVHD had lower S/F anaerobe ratios compared with those with isolated upper GI aGVHD. In the 20 days after disease onset, dysbiosis was observed only in GVHD patients with GI involvement, particularly those with lower-tract disease. Importantly, Clostridial and butyrate-producer abundance as well as S/F anaerobe ratio were predictors of longer overall survival; higher abundance of butyrate producers and higher S/F anaerobe ratio were associated with decreased risk of GVHD-related death. These findings suggest that the intestinal microbiome can serve as a biomarker for outcomes of allo-HCT patients with GVHD.

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at <3.5 months of age (91.6% vs 68% if ≥3.5 months, P = .02). Active infection at the time of HCT (regardless of ERT) decreased 5-year EFS (33.1% vs 68.2%, P < .01) and OS (64.7% vs 82.3%, P = .02). Five-year EFS (90.5%) and OS (100%) were best for matched sibling and matched family donors (MSD/MFD). For patients treated after the year 2000 and without active infection at the time of FDCT, no difference in 5-year EFS or OS was found between HCT using a variety of transplant approaches and ERT-GT. This suggests alternative donor HCT may be considered when MSD/MFD HCT and GT are not available, particularly when newborn screening identifies patients with ADA-SCID soon after birth and before the onset of infections. This trial was registered at www.clinicaltrials.gov as #NCT01186913 and #NCT01346150.

Patients lacking functional adenosine deaminase activity have severe combined immunodeficiency (ADA SCID), which can be treated with ADA enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplantation (HSCT), or autologous HSCT with gene-corrected cells (gene therapy [GT]). A cohort of 10 ADA SCID patients, aged 3 months to 15 years, underwent GT in a phase 2 clinical trial between 2009 and 2012. Autologous bone marrow CD34+cells were transduced ex vivo with the MND (myeloproliferative sarcoma virus, negative control region deleted, dl587rev primer binding site)–ADA gammaretroviral vector (gRV) and infused following busulfan reduced-intensity conditioning. These patients were monitored in a long-term follow-up protocol over 8 to 11 years. Nine of 10 patients have sufficient immune reconstitution to protect against serious infections and have not needed to resume ERT or proceed to secondary allogeneic HSCT. ERT was restarted 6 months after GT in the oldest patient who had no evidence of benefit from GT. Four of 9 evaluable patients with the highest gene marking and B-cell numbers remain off immunoglobulin replacement therapy and responded to vaccines. There were broad ranges of responses in normalization of ADA enzyme activity and adenine metabolites in blood cells and levels of cellular and humoral immune reconstitution. Outcomes were generally better in younger patients and those receiving higher doses of gene-marked CD34+cells. No patient experienced a leukoproliferative event after GT, despite persisting prominent clones with vector integrations adjacent to proto-oncogenes. These long-term findings demonstrate enduring efficacy of GT for ADA SCID but also highlight risks of genotoxicity with gRVs. This trial was registered at www.clinicaltrials.govas #NCT00794508.

The expression of ZAP-70 in a subset of chronic lymphocytic leukemia (CLL) patients strongly correlates with a more aggressive clinical course, although the exact underlying mechanisms remain elusive. The ability of ZAP-70 to enhance B-cell receptor (BCR) signaling, independently of its kinase function, is considered to contribute. We used RNA-sequencing and proteomic analyses of primary cells differing only in their expression of ZAP-70 to further define how ZAP-70 increases the aggressiveness of CLL. We identified that ZAP-70 is directly required for cell survival in the absence of an overt BCR signal, which can compensate for ZAP-70 deficiency as an antiapoptotic signal. In addition, the expression of ZAP-70 regulates the transcription of factors regulating the recruitment and activation of T cells, such as CCL3, CCL4, and IL4I1. Quantitative mass spectrometry of double–cross-linked ZAP-70 complexes further demonstrated constitutive and direct protein-protein interactions between ZAP-70 and BCR-signaling components. Unexpectedly, ZAP-70 also binds to ribosomal proteins, which is not dependent on, but is further increased by, BCR stimulation. Importantly, decreased expression of ZAP-70 significantly reduced MYC expression and global protein synthesis, providing evidence that ZAP-70 contributes to translational dysregulation in CLL. In conclusion, ZAP-70 constitutively promotes cell survival, microenvironment interactions, and protein synthesis in CLL cells, likely to improve cellular fitness and to further drive disease progression.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day −1. All patients received T-cell–replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P= .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P= .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P= .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P= .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P= .56), and overall survival was 79% vs 71% (P= .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) is a preferred regimen for HIV-non-Hodgkin lymphomas (HIV-NHLs), which are frequently Epstein-Barr virus (EBV) positive or human herpesvirus type-8 (HHV-8) positive. The histone deacetylase (HDAC) inhibitor vorinostat disrupts EBV/HHV-8 latency, enhances chemotherapy-induced cell death, and may clear HIV reservoirs. We performed a randomized phase 2 study in 90 patients (45 per study arm) with aggressive HIV-NHLs, using dose-adjusted EPOCH (plus rituximab if CD20+), alone or with 300 mg vorinostat, administered on days 1 to 5 of each cycle. Up to 1 prior cycle of systemic chemotherapy was allowed. The primary end point was complete response (CR). In 86 evaluable patients with diffuse large B-cell lymphoma (DLBCL; n = 61), plasmablastic lymphoma (n = 15), primary effusion lymphoma (n = 7), unclassifiable B-cell NHL (n = 2), and Burkitt lymphoma (n = 1), CR rates were 74% vs 68% for EPOCH vs EPOCH-vorinostat (P = .72). Patients with a CD4+ count <200 cells/mm3 had a lower CR rate. EPOCH-vorinostat did not eliminate HIV reservoirs, resulted in more frequent grade 4 neutropenia and thrombocytopenia, and did not affect survival. Overall, patients with Myc+ DLBCL had a significantly lower EFS. A low diagnosis-to-treatment interval (DTI) was also associated with inferior outcomes, whereas preprotocol therapy had no negative impact. In summary, EPOCH had broad efficacy against highly aggressive HIV-NHLs, whereas vorinostat had no benefit; patients with Myc-driven DLBCL, low CD4, and low DTI had less favorable outcomes. Permitting preprotocol therapy facilitated accruals without compromising outcomes. This trial was registered at www.clinicaltrials.gov as #NCT0119384.

Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.

Introduction:Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for adults with relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Blinatumomab is a CD19-directed bispecific T-cell engager that is also approved for r/r B-ALL, and often used as early salvage therapy. Data in the pediatric/AYA population suggest that patients who did not respond to blinatumomab may have inferior outcomes to CD19-directed CAR-T products compared to those who have achieved a response to blinatumomab or were blinatumomab-naïve (Myers et al. J Clin Oncol 2022). In this study, we evaluate the response to blinatumomab and subsequent response to brexu-cel in adults with r/r B-ALL.

BACKGROUND

Cytarabine (also known as ara-C) has been the mainstay of AML chemotherapy for both pediatric and adult patients (pts) since 1970s, and when given in combination with anthracycline it induces remission in ~60% of adult and 80% of pediatric pts. However, almost ~40% of pts relapse. Cytarabine is a prodrug requiring activation to ara-CTP for its antileukemic effect. Our group has been investigating the relevance of cytarabine pharmacogenomics and recently reported a pharmacogenomics-based polygenic score (ACS10) that includes 10 SNPs spanning 9 genes within metabolic pathway of cytarabine. ACS10 is predictive of intracellular levels of ara-CTP as well as outcome in pediatric AML pts enrolled in multiple clinical trials led by St Jude Children's Research Hospital and Children's Oncology Group (Elsayed et al, JCO2022;40:772-3). Overall, pediatric AML pts with ACS10 low(≤0), had inferior outcomes compared with ACS10 highpts. Thus far, the ACS10 score has not been tested for its performance in adult AML, especially adolescent and young adult (AYA) AML pts. We hypothesized that ACS10 might be predictive of chemotherapy resistance in this defined pt population that is commonly treated with intensive induction therapy. Moreover, as several SNPs included in ACS10 show ancestry-enrichments, we speculated whether this might help explain the high resistance to treatment recently observed in Black AYA AML pts.

Introduction:

A growing body of evidence from preclinical and human epidemiology studies of multiple cancer types indicate that physical activity can delay or avert the outgrowth of cancer, in a mechanistic process that may involve exercise-induced alterations to anti-cancer immunity. Many Chronic Lymphocytic leukaemia (CLL) patients present with asymptomatic, early-stage disease that is monitored until disease progression. Thus, exercise may be an effective way to manage disease burden and delay progression in treatment naïve CLL. The primary objective of this pilot study was to investigate the safety and feasibility of an exercise programme in people with treatment naïve CLL, and preliminarily explore the effects of exercise training on CLL counts, body composition, cardiorespiratory fitness, and immune cell phenotypes including T-cells.

Background:Outcomes for pediatric acute myeloid leukemia (AML) remain disappointing, particularly for patients with poor risk cytogenetic/molecular genetic abnormalities and those who fail to achieve complete remission following course 1 of induction chemotherapy. Despite upfront allogeneic hematopoietic stem cell transplantation (HSCT) for these patients, high rates of relapse persist. The optimal approach to chemotherapy intensification and timing of HSCT for high risk (HR) patients remains unknown, with variable approaches employed by cooperative trial groups.

Background

Introduction

Introduction:

Introduction:Racial and ethnic disparities in survival outcomes exist in pediatric acute myeloid leukemia (AML), but the role of relapse and its potential contribution to outcome disparities is unknown. We sought to examine differences in relapse-free survival (RFS) and clinical characteristics at the time of relapse by race and ethnicity using a real-world multi-institution cohort of pediatric AML patients.

Transfusion-related acute lung injury (TRALI) is potentially life-threatening and has been ranked as the leading cause of transfusion-related fatalities since its description in the 1980s. With a 5 to 14% mortality rate, symptoms range from mild dyspnea, cough and fever to full-blown respiratory failure and severe hypoxemia, which usually occurs within 6 hours from the transfusion. To date, the pathogenesis is not fully understood, but it appears that TRALI requires two hits in order to be initiated; the first-hit is the patient's clinical condition often reflected by a state of inflammation while the second hit is the transfusion itself. Several published articles have shown that mitochondrial damage-associated molecular patterns (mtDAMPs) including extracellular mitochondria and mitochondrial DNA (mtDNA) are elevated in stored transfusion products that have been linked to adverse transfusion reactions. Using an in vivo murine model of TRALI where injection of a monoclonal anti-MHC class I antibody (34-1-2s) into LPS-primed BALB/c mice causes significant lung edema, we explored the possibility of whether mitochondria and mtDAMPs could act as first hits in TRALI induction. Mitochondria were prepared from mouse livers by differential centrifugation and purified on a density gradient. Intravenous injections of only mitochondria (2.5 x 10 8per mouse) prior to injection with 34-1-2s caused TRALI characterized by significantly elevated lung wet/dry ratios (Figure 1A), temperature loss and lung neutrophil accumulation. In contrast, however, intraperitoneal injections of mitochondria did not prime as a first hit for 34-1-2s-induced TRALI suggesting that the route of the mitochondrial first hit is important in determining whether TRALI proceeds (Figure 1A.). Using a TLR9 agonist (ODN2395) to mimic mtDNA as a first hit, we also observed 34-1-2s-induced TRALI induction, and this could be prevented by the administration of a specific TLR9 antagonist (ODN4084F) 2h before the ODN2395 injection (Figure 1B). Of interest, the TLR9 antagonist was not sufficient to prevent TRALI induced by the iv whole mitochondria first hit, indicating that other mtDAMPS are also involved in the priming of the mice for TRALI. This study suggests that mitochondria and at least mtDNA can act as a first hit in antibody-mediated TRALI via stimulation of recipient TLR9 and that the first hit route maybe important in stimulating TRALI. Further investigations are underway to identify other mtDAMPS (such as N-formyl peptides) or a combination of DAMPs that are important for the first hit. Inhibition of mitochondrial DAMPS may be a potential therapy for transfusion recipients suffering from TRALI.

Cellular Immunotherapies: Late Phase and Commercially Available Therapies

Introduction:

Introduction: Computerized tomography (CT) scans of the sinus, chest, abdomen, and pelvis are often performed in children prior to hematopoietic stem cell transplantation (HSCT) to evaluate for occult infections. Identification of infectious abnormalities could allow for pre- or post-HSCT infection prophylaxis to reduce morbidity or mortality. However, the association of abnormal pre-HSCT and adverse outcomes post-HSCT has not been previously examined. Additionally, routine imaging may identify incidental non-infectious findings, potentially necessitating additional diagnostic workup and unnecessary radiation exposure. In this study, we sought to investigate the prevalence of abnormal findings on CT scans in children undergoing HSCT and their association with post-HSCT length of stay (LOS) and early non-relapse mortality (NRM).

Introduction: Ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor (BTKi), is recommended as first-line (1L) treatment for patients with chronic lymphocytic leukemia (CLL). Dosing flexibility with ibrutinib allows patients to adjust their daily dose to help prevent recurrence or worsening of adverse events, while maintaining efficacy by allowing patients to stay on treatment and benefit from long-term treatment outcomes. The current study aimed to compare time to next treatment (TTNT) in CLL patients initiating 1L single-agent ibrutinib at 420mg/day and staying on this dose versus those having a dose adjustment (DA) within 3-12 months.

Background

Introduction:Daratumumab, lenalidomide, and dexamethasone (DRd) and bortezomib, lenalidomide, and dexamethasone (VRd) are the only two regimens that are considered as preferred per the National Comprehensive Care Network for transplant ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). While there are no head-to-head studies comparing clinical outcomes of DRd and VRd in this population, an indirect comparison (PEGASUS study [Durie et al., 2020]) has shown that DRd was associated with significantly lower risk of disease progression or death compared with VRd and Rd. This study aims at supplementing this information by comparing real-world time-to-next-treatment (TTNT) or death between NDMM TIE patients treated with front-line (FL) DRd or VRd.

Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by abnormally short telomeres. There are at least 15 genes associated with TBD including ACD, CTC1, DKC1, NHP2, NOP10, PARN, POT1, RTEL1, STN1, TERC, TERT, TINF2, WRAP53 NAF1and ZCCHC8, which can be inherited in autosomal dominant (AD), autosomal recessive (AR), or X-linked recessive patterns. Genetic anticipation has been described in some families with more severe symptoms appearing in each successive generation. We report two patients that presented with bone marrow failure, who were subsequently identified to have short telomeres and variants of uncertain significance (VUS) in two different telomere genes inherited from their parents. These cases suggest a potential for digenic inheritance of TBD.

Background:Persistent thrombocytopenia following allogeneic stem cell transplantation (alloHSCT) leads to an increase in morbidity and mortality. Causes of severe thrombocytopenia following HSCT include poor graft function, graft-versus-host disease (GVHD), infections, drug toxicities, underlying autoimmune diseases and relapse of underlying disease. Treatments can include thrombopoietin receptor agonists (TPO-RA), immunomodulators, and stem cell boost. Avatrombopag is a second generation TPO-RA approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients with poor response to standard treatments or in patients with chronic liver disease (CLD) associated thrombocytopenia requiring surgical interventions. Phase III clinical trials have shown greater platelet responses in chronic ITP and reduced transfusion needs in patients with CLD. Avatrombopag differs from other TPO-RA medications due to majority of elimination occurring in the gut, thus avoiding hepatic toxicity. Additionally, it does not require dietary restrictions. As there is limited literature in pediatric patients following alloHSCT, we describe the use of avatrombopag in a pediatric patient with chronic severe thrombocytopenia (<10 x10 3/uL) post HSCT.

Introduction

Introduction

Introduction

Chronic Lymphocytic Leukaemia (CLL) is characterised by the proliferation and accumulation of clonal B cells (B-CLL cells) and is often treated with anti-CD20 monoclonal antibody immunotherapies, including rituximab. One of the mechanism-of-action of rituximab is antibody-dependent cellular cytotoxicity (ADCC) which occurs when natural killer (NK) cells detect rituximab bound to CD20 +target cells. Rituximab often fails to induce stringent disease eradication, due in part to the diffuse distribution of clonal cells across multiple lymphoid and non-lymphoid tissues where NK cell frequency can be low. It is well established that an individual bout of aerobic exercise induces a transient relocation of lymphocytes - including NK cells and B cells - into peripheral blood. We hypothesised that this exercise-induced lymphocytosis could be harnessed to enhance the efficacy of rituximab in CLL by relocating both target and effector cells together with rituximab into blood.

Background

Transfusion-related acute lung injury (TRALI) is a leading cause of transfusion-related fatalities with a 5 to 14% mortality rate. Symptoms range from mild dyspnea, cough, fever to full-blown respiratory failure and severe hypoxemia within 6 hours from the transfusion. To date, the pathogenesis is not fully understood, but it appears that TRALI requires two hits in order to be initiated; the first-hit is the patient's clinical condition often reflected by a state of inflammation while the second hit is the transfusion itself (often containing anti-donor antibodies). Several reports have described platelet involvement in antibody-mediated TRALI, however, there are significant controversies that have arisen as to whether intact platelets actually play a role or not. On the other hand, platelet extracellular vesicles (PEV) have been found to accumulate in stored platelet units and are positively correlated with significant adverse transfusion reactions. Furthermore, in a murine antibody-independent model of TRALI, it was recently demonstrated that PEV increase in stored murine platelet concentrates and are associated with TRALI-induction via excess ceramide production. We have used an in vivomurine model of TRALI where liposaccharide (LPS)-primed BALB/c mice are injected with a murine monoclonal anti-MHC class I antibody (34-1-2s). This antibody-mediated TRALI model exhibits severe acute lung injury that closely mimics the human condition. We attempted to understand what role recipient PEV may play in antibody-dependent TRALI. Male BALB/c mice were administered LPS ip (0.1 mg/kg) 18 hrs prior to initiating TRALI. At time zero, the mice are injected iv with 34-1-2s (1 mg/kg) and subsequently, TRALI manifestations were monitored every 30 min, and at 90 min post-injection, blood and lungs were harvested for the indicated measurements. Results show that compared with isotype-control treated mice, animals administered 34-1-2s had significantly elevated lung Wet/Dry (W/D) ratios (measure of lung edema, Figure 1a) and pulmonary neutrophil accumulation. The TRALI mice had significant thrombocytopenia and elevated levels of PEV in their plasma as detected by High-sensitivity Flow Cytometry (Hs-FCM). To determine the role of in vivo generated PEV in antibody-mediated TRALI, mice were first administered amitriptyline (AMI), a potent inhibitor of PEV formation. AMI treatment significantly reduced plasma PEV levels, but after administration of 34-1-2s, TRALI responses (lung edema) were significantly enhanced in the AMI-treated mice (Figure 1). To determine if this effect was due to PEV-derived serotonin, mice were next treated with Prozac to deplete platelet/PEV stores of serotonin. Prozac-treated mice had normal levels of PEV after 34-12s administration and TRALI induction was not affected. Our results suggest that in antibody-mediated TRALI, recipient generated PEV play a suppressive role that is independent of serotonin. Further studies are underway to determine the mechanism(s) of PEV-mediated TRALI suppression. Thus, modulating PEV formation in recipients may be an effective therapy for reducing TRALI reactions.

Background: Sickle cell disease (SCD) is among the most common monogenic disorders and causes lifelong complications, including vaso-occlusive events (VOEs) and decreased quality of life (QOL). Gene therapy (GT) has emerged as a potential curative therapy for SCD, but its impact on patients' QOL remains underexplored. We previously reported preliminary safety and efficacy data on 6 patients who received autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector (Esrick et al., NEJM, 2021). Here, we report the first results of parent- and patient-reported outcomes (PROs) for 10 patients treated with BCH-BB694 up to 24 months post-infusion.

Introduction