Allograft Research Articles

A Thrilling Case of Anemia

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that presents with triad of peripheral blood cytopenias, hemolytic anemia and thrombosis. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is due to acquired somatic mutations in phosphatidylinositol glycan class A (PIGA) gene.Terminal complement inhibition with eculizumab and allogeneic bone marrow transplantation (BMT) are the only widely effective therapies for patients with classical PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3).

10-Year Real-World Data on Acute Myeloid Leukemia:

Introduction: Despite advances in Acute Myeloid Leukemia (AML) diagnosis and treatment, the outcomes in low- and middle-income countries (LMIC) are far apart from those in high-income countries (HIC). Objective: To describe the clinical features and outcomes of AML patients in Brazil's public health system, we conducted a retrospective analysis of all cases of non-promyelocytic AML diagnosed within 10 years (2007- 2017) in northeastern Brazil, Bahia. Methodology: We analyzed the real-life outcomes of 62 patients diagnosed with non-promyelocytic AML between 2007 and 2017 at a university hospital in Northeast Brazil. We classified patients using the European LeukemiaNet 2022 guideline into favorable (n=8), intermediate (n=18), and adverse risk (n=7) groups. Twenty-nine were not otherwise classified because no cytogenetic and/or molecular tests were available at diagnosis. Results: Allogeneic bone marrow transplant (alloBMT) was performed in 16 patients (37%). Median overall survival (mOS) was seven months. Among patients receiving alloBMT, mOS was 49 months, while for the chemotherapy group, it was six months (P = 0.003). For 10-year real-life data, we found complete remission of 53%, 5-year OS of 27%, and a mortality rate during induction therapy of 27%, inferior to HIC. Conclusion: Inferior outcomes found in LMIC result from a multifactorial scenario and an unmet need in the worldwide panorama of AML.

Acquired Partial Lipodystrophy: Clinical Management in a Pregnant Patient.

Pregnancy represents an additional challenge to the complex clinical picture of lipodystrophy disorders, and the management of such conditions with related comorbidities has been underreported. This work aims to outline the risk associated with a pregnancy event for women dealing with acquired partial lipodystrophy and the need for diverse but specialized care. We report on the successful pregnancy outcome of a 28-year-old woman with an acquired partial form of lipodystrophy related to an allogenic bone marrow transplant that occurred at pediatric age. Although metabolic control was challenging, glucose levels progressively improved during the pregnancy, and triglycerides increased less than expected. The periodic monitoring of leptin levels showed a progressive increase with a peak in the third trimester (41.53 ng/mL), followed by a fast decline the day after giving birth, with a lower basal level than the prepregnancy period. However, preterm delivery occurred associated with cardiac complications in the mother. A total of 12 studies were retrieved concerning women aged 14 to 38 years with various lipodystrophy phenotypes. Diabetes and hypertriglyceridemia were the most common comorbidities. Most women had successful pregnancies despite gestational complications (including miscarriages), preterm and emergency deliveries, and newborns undergoing partum or postpartum transient or chronic complications. Lipodystrophy disorders expose both mothers and children to very high risk. Intensive monitoring and care of all potential clinical complications should be planned and carried out by a multidisciplinary team before, during, and after the pregnancy. Leptin secretion during pregnancy should be investigated more deeply in these patients.

Mineralocorticoid receptor expression and the effects of the mineralocorticoid receptor antagonist spironolactone in a murine model of graft-versus-host disease

PurposeThe topical administration of spironolactone, a mineralocorticoid receptor antagonist (MRA) improves dry eye symptoms in patients with ocular graft-versus-host disease (GVHD); however, the detailed mechanism remains unclear. This study aimed to investigate the effects of spironolactone eyedrops on the ocular surface using a chronic GVHD (cGVHD) mouse model and to determine the expression of the mineralocorticoid receptor (MR). MethodsA cGVHD mouse model was established by allogeneic bone marrow transplantation (BMT) from B10.D2 mice to BALB/c mice. Subsequently, cGVHD mice were treated with either 0.005 % spironolactone or vehicle eyedrops. The eyelids, cornea and conjunctiva of the recipients were analyzed at 4-week intervals post-BMT in both groups. ResultsSigns of ocular GVHD, such as corneal epithelial damage, depletion of meibomian glands, and inflammatory cell infiltration onto the ocular surface, were significantly decreased in cGVHD mice treated with spironolactone eyedrops. The expression of the MR NR3C2 in the corneal and conjunctival epithelia was significantly increased in cGVHD mice. HSP47+NR3C2+ MR-expressing fibroblasts, CD45+NR3C2+ MR-expressing leukocytes, and CD4+NR3C2+ MR-expressing T cells infiltrated the ocular surface tissue of cGVHD mice significantly more than that of syngeneic controls. ConclusionsMR expression is increased in epithelial cells, fibroblasts, and T cells in a murine cGVHD model, whereas MRA and spironolactone eyedrops could attenuate the severity of ocular GVHD. These findings suggest that MR signaling partially contributes to the development of ocular GVHD in this mouse model.

Development of Bone Marrow Transplantation Strategies

The use of alternative stem cell sources, the growth of supportive healthcare facilities, and the expansion of indications for bone marrow transplantation (BMT) as well as partially matched donors from the same family are all continuing evolutionary trends as the use of BMT has been developed and expanded to include donors who are not related by blood but have Partial histocompatibility antigen compatibility. Although the outcomes of these transplants are not as good as those performed with first-degree siblings, patients with leukemia, aplastic anemia, and immunodeficiency disorders who cannot receive treatment otherwise they can receive it now. Patients suffering from diseases such as acute myeloid leukemia, acute lymphoblastic leukemia, and Hodgkin lymphoma also show success with autologous bone marrow transplants. Furthermore, bone marrow or blood stem cell support is used after intensive chemotherapy. Patients with stage II, III, and IV breast cancer can benefit from treatment with bone marrow cells found in peripheral blood. In this review, the most important developments in autologous and allogeneic bone marrow transplantation, the control of infectious diseases, and the use of gene therapy to alter genetic disorders that are transmitted from parents to their offspring through bone marrow or peripheral blood infusions are outlined.

Primary Conjunctival Molluscum Contagiosum in a Patient With Ocular Graft-Versus-Host Disease.

Primary conjunctival molluscum contagiosum (MC) is rare and usually reported in patients with acquired immunodeficiency syndrome. In this study, we present a case of bilateral primary conjunctival MC in a patient with ocular graft-versus-host disease (oGVHD). This is a case report study. Clinical evaluation, in vivo confocal microscopy imaging, and histopathology were used to confirm the diagnosis. A 38-year-old woman with a history of allogeneic bone marrow transplant and secondary chronic oGVHD presented with ocular discomfort, redness, and dryness. On examination, clusters of white gelatinous nodular lesions, stained with fluorescein and Lissamine green, were observed on the bulbar conjunctiva, along with similar solitary nodular lesions in all quadrants of both eyes. In vivo confocal microscopy revealed nests of epithelial cells with bright inclusions measuring approximately 30-35 μm. Excisional biopsy confirmed the diagnosis of MC. A 6-month post-operative follow-up showed healed conjunctiva with no recurrence and improved ocular comfort. Molluscum contagiosum should be considered in the differential diagnosis of conjunctival lesions in patients with impaired immunity such as oGVHD. In diagnosing MC lesions, in vivo confocal microscopy proves to be valuable. In the absence of topical antiviral treatment, surgical excision is warranted.

CT-424 Evaluation of Elderly Patients Undergoing Allogeneic Bone Marrow Transplantation: Brazilian Single-Center Outcomes

CT-424 Evaluation of Elderly Patients Undergoing Allogeneic Bone Marrow Transplantation: Brazilian Single-Center Outcomes

Quality of Life in 74 Recipients of Allogeneic Bone Marrow Transplantation

Quality of Life in 74 Recipients of Allogeneic Bone Marrow Transplantation

Evaluation of Elderly Patients Undergoing Allogeneic Bone Marrow Transplantation: Brazilian Single-Center Outcomes

Evaluation of Elderly Patients Undergoing Allogeneic Bone Marrow Transplantation: Brazilian Single-Center Outcomes

HLA alleles, haplotypes frequencies, and their association with hematological disorders: a report from 1550 families whose patients underwent allogeneic bone marrow transplantation in Egypt.

HLA alleles are representative of ethnicities and may play important roles in predisposition to hematological disorders. We analyzed DNA samples for HLA-A, -B, -C, -DRB1, and -DQB1 loci, from 1550 patients and 4450 potential related donors by PCR-SSO (Polymerase chain reaction sequence-specific oligonucleotides) and estimated allele frequencies in donors and patients from 1550 families who underwent bone marrow transplantation (BMT) in Egypt. We also studied the association between HLA allele frequencies and incidence of acute myeloid leukemia, acute lymphoblastic leukemia, and severe aplastic anemia. The most frequently observed HLA class I alleles were HLA- A*01:01 (16.9%), A*02:01 (16.1%), B*41:01 (8.7%), B*49:01 (7.3%), C*06:02 (25.1%), and C*07:01 (25.1%), and the most frequently observed class II alleles were HLA-DRB1*11:01 (11.8%), DRB1*03:01 (11.6%), DQB1*03:01 (27.5%), and DQB1*05:01 (18.9%). The most frequently observed haplotypes were A*33:01~B*14:02 ~ DRB1*01:02 (2.35%) and A*01:01~B*52:01~DRB1*15:01 (2.11%). HLA-DRB1*07:01 was associated with higher AML odds (OR, 1.26; 95% CI, 1.02-1.55; p = 0.030). Only HLA-B38 antigen showed a trend towards increased odds of ALL (OR, 1.52; 95% CI, 1.00-2.30; p = 0.049) HLA-A*02:01, -B*14:02, and -DRB1*15:01 were associated with higher odds of SAA (A*02:01: OR, 1.35; 95% CI, 1.07-1.70; p = 0.010; B*14:02: OR, 1.43; 95% CI, 1.06-1.93; p = 0.020; DRB1*15:01: OR, 1.32; 95% CI, 1.07-1.64; p = 0.011). This study provides estimates of HLA allele and haplotype frequencies and their association with hematological disorders in an Egyptian population.

Use of HSC-targeted LNP to generate a mouse model of lethal α-thalassemia and treatment via lentiviral gene therapy

Abstractα-Thalassemia (AT) is one of the most commonly occurring inherited hematological diseases. However, few treatments are available, and allogeneic bone marrow transplantation is the only available therapeutic option for patients with severe AT. Research into AT has remained limited because of a lack of adult mouse models, with severe AT typically resulting in in utero lethality. By using a lipid nanoparticle (LNP) targeting the receptor CD117 and delivering a Cre messenger RNA (mRNACreLNPCD117), we were able to delete floxed α-globin genes at high efficiency in hematopoietic stem cells (HSC) ex vivo. These cells were then engrafted in the absence or presence of a novel α-globin–expressing lentiviral vector (ALS20αI). Myeloablated mice infused with mRNACreLNPCD117–treated HSC showed a complete knock out (KO) of α-globin genes. They showed a phenotype characterized by the synthesis of hemoglobin H (HbH; also known as β-tetramers or β4), aberrant erythropoiesis, and abnormal organ morphology, culminating in lethality ∼8 weeks after engraftment. Mice infused with mRNACreLNPCD117–treated HSC with at least 1 copy of ALS20αI survived long term with normalization of erythropoiesis, decreased production of HbH, and amelioration of the abnormal organ morphology. Furthermore, we tested ALS20αI in erythroid progenitors derived from α-globin–KO CD34+ cells and cells isolated from patients with both deletional and nondeletional HbH disease, demonstrating improvement in α-globin/β-globin mRNA ratio and reduction in the formation of HbH by high-performance liquid chromatography. Our results demonstrate the broad applicability of LNP for disease modeling, characterization of a novel mouse model of severe AT, and the efficacy of ALS20αI for treating AT.

Socio-economic burden of chronic graft-versus-host disease after allogenic bone marrow transplantation

Aim. Chronic graft-versus-host disease (crGVHD) socio-economic burden assessment in the Russian Federation.Materials and methods. The assessment was performed in children aged 12–18 years and adults aged over 18 years. The payer's position is "Government". The modeling horizon is 5 years. Direct medical (costs of crGVHD drug therapy; prevention of complications of crGVHD therapy and their treatment in case of occurrence) are taken into account; the cost of visits with the symptoms of crGVHD), as well as direct non-medical costs and indirect costs due to the patient’s disability or disability of their relatives.Results. The total costs for the population of patients with crGVHD aged 12–18 years ranged from 498,120,490 rubles to 1,487,918,739 rubles, in adults — from 969,019,644 rubles to 3,290,898,722 rubles from a five-year perspective, depending on the simulated population size and the choice of the 3rd line therapy regimen. A one-sided sensitivity analysis demonstrated that the main changes in the size of the overall economic burden were observed in the case of changes in the size of the target population, as well as in the cost of therapy.Conclusions. The conducted clinical and economic analyses demonstrated that significant losses of both the health system and the state as a whole were associated with crGVHD after allogeneic bone marrow transplantation, which requires the development of new prevention strategies.

Hyponatremia as acute adrenal insufficiency in patients with type 1 diabetes mellitus and kidney transplantation cause end-stage chronic kidney disease

Diabetes mellitus type 1 (DM1) and chronic adrenal insufficiency (CAF) are among the most common autoimmune endocrine diseases that develop both isolated and in combination with each other and with other diseases of autoimmune origin, as part of various syndromes. At the same time, type 1 diabetes is quite often the first component of a systemic autoimmune lesion and acts as a predictor of the development of congenital disorder, which, in turn, against the background of type 1 diabetes, acquires a mild, sometimes atypical course, which complicates the diagnosis and prescription of therapy. The clinical case describes a patient with type 1 diabetes and end-stage chronic kidney disease (CKD), kidney allotransplantation (ART), who was on triple immunosuppressive therapy, who developed CHN, which was manifested by severe hyponatremia and the occurrence of frequent hypoglycemic conditions.

Reconstituted CD74+ NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation

Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74− NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.

NFS-01. EXTREMELY RARE CASE OF CHILDREN WITH NIJMEGEN BREAKAGE SYNDROME AND MEDULLOBLASTOMA – A THERAPEUTIC CHALLENGE

Abstract BACKGROUND Nijmegen Breakage Syndrome (NBS) is an autosomal recessive inherited disorder characterized by DNA repair abnormalities. It manifests with heightened sensitivity to radiotherapy (RT) and predisposes individuals to neoplastic diseases. Antineoplastic treatment in NBS patients is particularly challenging due to concurrent immune disorders, intense toxicities, and contraindications for RT. Hematologic disorders, especially lymphomas, are among the most prevalent malignancies in NBS patients. Solid tumors in NBS are extremely rare, with only two pediatric cases documented in the literature, both succumbing due to severe complications of treatment. METHODS A review and analysis of the medical documentation of a child with NBS and MB treated at the Department of Pediatrics, Hematology, and Oncology, Gdansk, Poland, were conducted. RESULTS A genetically confirmed NBS girl displaying typical phenotypic features presents symptoms at the age of 2 years, such as headaches, reluctance to walk, and drowsiness. Imaging confirmed a tumor in the left cerebellar hemisphere, measuring 40x33x30mm, displaying radiological features consistent with Medulloblastoma (MB). The patient underwent gross total resection of the tumor. The pathology revealed a desmoplastic type of MB with SHH activation, TP53 wild type, and ongoing molecular analysis. Postoperative imaging confirmed clinical remission, and cerebrospinal fluid examination was negative. Considering the substantial toxicities of chemotherapy in NBS patients and the contraindications for RT, the patient received chemotherapy with reduced cytostatic doses. Treatment was complicated by profound and prolonged myelosuppression and infections. Currently, after completing six cycles of chemotherapy, the patient is still in remission. To maintain remission and address NBS, the patient will receive allogeneic bone marrow transplantation from a 9/10 HLA-matched unrelated donor. CONCLUSIONS Managing patients with NBS, complicated by neoplastic diseases, is exceptionally demanding and necessitates an individualized multidisciplinary approach. Modern diagnostic and therapeutic methods enhance the prospects of reducing the toxicity of oncologic treatment, improving quality of life, and extending overall survival.

Antioxidant Activity and Oxidative Damage Associated with Seeding Surgery for Pearl Culture in the Winged Pearl Oyster Pteria sterna.

To evaluate the antioxidant activity and oxidative damage by relaxing, wounding, and seeding of a saibo of different origin on Pteria sterna hosts, five oyster treatments were included: (1) relaxed (REL) but neither wounded nor seeded; (2) relaxed and wounded (WOU) but not seeded; (3) relaxed, wounded, and seeded with an allograft (ALL); (4) relaxed, wounded, and seeded with an autograft (AUT); and (5) unrelaxed, unwounded, and unseeded as control (CTR). Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and thiobarbituric acid (TBARS) activity were quantified between 3 and 24 h post-seeding. Compared to the CTR oysters, which did not suffer oxidative stress, SOD activity significantly decreased in the gonad and digestive gland in all treatments and decreased in mantle tissue in AUT oysters; this indicates that the entire process of preparing oysters for pearl culture (relaxing, wounding, and seeding) generates oxidative stress in the host. CAT was not a sensitive enzyme for measuring the short-term response of oysters to the wounding-seeding processes but rather a more prolonged or chronic stress. Similar to SOD, the lowest GPx and TBARS activity in seeded oysters evidenced their susceptibility to oxidative stress and damage, particularly in the WOU treatment. Evidence from this study indicates that SOD is a more sensitive enzyme for measuring the short-term response of the host oyster to the wounding and seeding of a saibo. It is also clear that the host undergoes stress at all stages of the pearl culture process, mostly during gonad wounding and regardless of the origin of saibo.

CD155 blockade enhances allogeneic natural killer cell-mediated antitumor response against osteosarcoma.

Allogeneic bone marrow transplant (alloBMT) is curative for hematologic malignancies through the graft-versus-tumor (GVT) effect but has been ineffective for solid tumors like osteosarcoma (OS). OS expresses CD155 which interacts strongly with inhibitory receptors TIGIT and CD96 but also binds to activating receptor DNAM-1 on natural killer (NK) cells. CD155 has never been targeted after alloBMT. Combining adoptively transferred allogeneic NK (alloNK) cells with CD155 blockade after alloBMT may enhance a GVT effect against OS. Murine NK cells were activated and expanded ex vivo with soluble IL-15/IL-15Rα. AlloNK and syngeneic NK (synNK) cell phenotype, cytotoxicity, cytokine production, and degranulation against CD155-expressing murine OS cell line K7M2 were assessed in vitro. Mice bearing pulmonary OS metastases underwent alloBMT and alloNK cell infusion with anti-CD155 either before or after tumor induction, with select groups receiving anti-DNAM-1 pretreated alloNK cells. Tumor growth, GVHD and survival were monitored, and differential gene expression of lung tissue was assessed by RNA microarray. AlloNK cells exhibited superior cytotoxicity against CD155-expressing OS compared to synNK cells, and this activity was enhanced by CD155 blockade. CD155 blockade increased alloNK cell degranulation and interferon gamma production through DNAM-1. In vivo, CD155 blockade with alloNK infusion increased survival when treating OS that relapsed after alloBMT. No benefit was seen for treating established OS before alloBMT. Treatment with combination CD155 and anti-DNAM-1 pretreated alloNK ameliorated survival and tumor control benefits seen with CD155 blockade alone. RNA microarray showed mice treated with alloNK and CD155 blockade had increased expression of cytotoxicity genes and the NKG2D ligand H60a, whereas mice treated with anti-DNAM-1 pretreated alloNK cells resulted in upregulation of NK cell inhibitory receptor genes. Whereas blocking DNAM-1 on alloNK abrogated cytotoxicity, blocking NKG2D had no effect, implying DNAM-1:CD155 engagement drives alloNK activation against OS. These results demonstrate the safety and efficacy of infusing alloNK cells with CD155 blockade to mount a GVT effect against OS and show benefits are in part through DNAM-1. Defining the hierarchy of receptors that govern alloNK responses is critical to translating alloNK cell infusions and immune checkpoint inhibition for solid tumors treated with alloBMT. Allogeneic bone marrow transplant (alloBMT) has yet to show efficacy in treating solid tumors, such as osteosarcoma (OS). CD155 is expressed on OS and interacts with natural killer (NK) cell receptors, such as activating receptor DNAM-1 and inhibitory receptors TIGIT and CD96 and has a dominant inhibitory effect on NK cell activity. Targeting CD155 interactions on allogeneic NK cells could enhance anti-OS responses, but this has not been tested after alloBMT. CD155 blockade enhances allogeneic natural killer cell-mediated cytotoxicity against OS and improved event-free survival after alloBMT in an in vivo mouse model of metastatic pulmonary OS. Addition of DNAM-1 blockade abrogated CD155 blockade-enhanced allogeneic NK cell antitumor responses. These results demonstrate efficacy of allogeneic NK cells combined with CD155 blockade to mount an antitumor response against CD155-expressing OS. Translation of combination adoptive NK cell and CD155 axis modulation offers a platform for alloBMT treatment approaches for pediatric patients with relapsed and refractory solid tumors.

Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes.

Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as "AML with mutated TP53". Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease.

CS12192: A novel selective and potent JAK3 inhibitor mitigates acute graft-versus-host disease in bone marrow transplantation

BackgroundDespite the significant role of JAK3 in various autoimmune diseases, including graft-versus-host disease (GVHD), there has been a lack of potent and selective JAK3 inhibitors specifically studied for GVHD. In our preclinical investigations, we evaluated a novel JAK3 inhibitor called CS12192, which is already undergoing clinical investigation in autoimmune diseases. MethodsWe evaluated the efficacy of CS12192 in GVHD through mixed lymphocyte reaction (MLR) in both mouse and human cells, as well as allogeneic bone marrow transplantation (BMT) in a murine model. ResultsCS12192, starting at a concentration of 0.5 μM, dose-dependently reduced the intracellular positivity for cytokines TNF-α and IFN-γ in CD4+ T cells (p < 0.05 to p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001) during mouse allogeneic MLR assays. This effect was observed for both single and double positivity of the cytokines. Moreover, In MLR assays with three different human donors, CS12192 also demonstrated a dose-dependent reduction in the proportion of IFN-γ positive CD4+ T cells (p < 0.0001) and CD8+ T cells (p < 0.01 to p < 0.0001). Additionally, it suppressed T cell proliferation in the mouse MLR (p < 0.05 to p < 0.0001), but this effect was observed in only one human donor (p < 0.001 to p < 0.0001). Furthermore, the administration of CS12192 at 40 and 80 mg/kg BID significantly improved the survival rate in the BMT model, resulting in cumulative 62-day survival rates of 88.89% (p < 0.01) and 100% (p < 0.001), respectively, compared with prednisolone (p < 0.05). ConclusionsCS12192 is a novel, potent and selective JAK3 inhibitor demonstrating great potential to mitigate acute GVHD.

Health disparities in acute myeloid leukemia: A decade-long analysis of Afro-Caribbean patients in a safety net New York City hospital.

e18515 Background: Acute Myeloid Leukemia (AML) in the Afro-Caribbean population is associated with poor outcomes due to disparities in health insurance and access to healthcare resources, among other factors, when compared to survival data in the national SEER database. This study reviews clinical characteristics and treatment outcomes of a cohort of 51 Afro-Caribbean patients who were diagnosed with AML and treated in the past 10 years in a urban safety net hospital in Brooklyn, New York. Methods: This is a retrospective review of patients diagnosed and treated for AML at New York City Health and Hospitals/Kings County from 2012 to 2022. Electronic Health Data was reviewed for clinicopathologic data and treatment outcomes. Analysis was performed through descriptive statistics with specific focus on insurance status and survival outcomes. Results: Our AML patient cohort had a mean age of 66, with 84% of patients identifying as Afro-Caribbean, and 51% being female. In this cohort, the AML risk stratification distribution based on 2022 European LeukemiaNet Risk classification includes 21 (41%) patients in the adverse-risk group, 23 (45%) patients in the intermediate-risk group, and 7 (14%) patients in the favorable-risk group. Of the 36 patients with molecular analysis data, 9 (25%) harbored a mutation in FLT3-ITD. Healthcare disparities are evident in insurance coverage, as 58% of patients lacked medical insurance, 19% had Medicare/Medicaid, and 23% had private insurance. At the time of this retrospective chart review, 35% of patients lacked any follow-up information, including appointments or status updates regarding their condition, vital status, or engagement with healthcare, possibly due to missed appointments, transfers, mortality, or other reasons. Of the 27 patients who were deemed transplant eligible, three (11%) successfully completed allogeneic bone marrow transplant. Reasons for non-transplantation include lack of a compatible donor, inadequate social support, insurance-related challenges, or patient refusal. Patients who completed induction and consolidation treatment with documented follow-up had a 23% survival rate at the five-year mark, compared to 31.7% overall survival rate reported in SEER data from 2013 to 2019. Conclusions: Our study highlights persistent healthcare disparities in Afro-Caribbean AML patients leading to poor survival outcomes. Despite treatment advancements, challenges related to insurance coverage, social support, follow-up care, and access to restricted, advanced care remain. Addressing these disparities calls for targeted interventions to enhance access and support systems for this vulnerable population.