Malignant Hematological Disorders Research Articles

E039 Multiple myeloma and neurological complications: prevalence and risk factors

Abstract Background/Aims Multiple myeloma (MM) is a malignant haematological disorder with a highly variable clinical presentation. Few studies have explored the neurological complications (CN) associated with MM. The objectives of this study were to describe the neurological manifestations observed in MM and to determine predictive factors for neurological complications. Methods We collected data from 126 cases of symptomatic multiple myeloma patients followed in our department over a 30-year period (1993 - 2023). We gathered sociodemographic, clinical, and laboratory data. Neurological complications were diagnosed based on clinical findings and magnetic resonance imaging data. Results Our study included 126 patients with an average age of 65.23 ± 11.63 years [36-92], and a male-to-female sex ratio of 3.8. Bone pain was present in 92.1% (116 cases) with an average duration of 4 months. The mean erythrocyte sedimentation rate and C-reactive protein levels were 99.08 mm at H1 [3-190] and 27.74 [0-196], respectively. Hemoglobin levels were less than 10g/dl in 51.2% of cases, with an average of 9.902 ± 2.22 g/dl [5-13.9]. Calcium levels exceeded 2.75 mmol/l in 20% of cases, with an average of 2.49 ± 0.33 mmol/l. The mean creatinine level was 88.28 ± 77.9 μmol/l [36-587], with levels above 177 μmol/l observed in 15 cases (10.4%). The Durie and Salmon prognostic classification categorized our patients as follows: Stage IA (3.2%), Stage IIA (4%), Stage IIB (0.8%), Stage IIIA (72.2%), and Stage IIIB (18.3%). Neurological complications were present in 22.2% of patients (n = 28). Sixteen patients (12.7%) had spinal cord compression, with nine having dorsal involvement, six having conus medullaris involvement, and one having cervical involvement. Radicular pain affected 14 patients, with eight experiencing sciatalgia and four having cruralgia. Two patients (1.8%) had carpal tunnel syndrome. No cerebral involvement was observed in our series. In our study, only creatinine levels were significantly lower in patients who developed neurological complications (64.35 vs. 95.19, p = 0.004). However, the occurrence of neurological complications was independent of age (p = 0.696), duration of evolution (p = 0.669), erythrocyte sedimentation rate (p = 0.541), C-reactive protein (p = 0.963), hemoglobin (p = 0.076), or calcium levels (p = 0.274). No association was found between neurological complications and gender (p = 0.849) or prognostic stage (p = 0.119) Conclusion Neurological manifestations in MM are diverse and often underestimated. The diagnosis of MM should be considered in the presence of spinal or radicular compression, especially when the laboratory findings suggest it. Disclosure M. Dhifallah: None. I. Fenniche: None. A. Feki: None. S. Ben Djemaa: None. M. Kallel: None. H. Fourat: None. R. Akrout: None. S. Baklouti: None.

The paradigm of total body irradiation in acute lymphoblastic leukaemia: Therapeutic effectiveness versus the challenges of toxicity

IntroductionTotal body irradiation (TBI) is part of the myeloablative conditioning for hematopoietic stem cell transplantation (HSCT) in malignant hematologic disorders. This therapy has recently shown improved survival in acute lymphoblastic leukemia (ALL) compared to chemotherapy-based regimens. However, side effects are a significant limitation, especially in the pediatric population. Patients and methodsWe retrospectively analyzed the survival of patients with ALL who underwent an HSCT at a tertiary hospital between 1996 and 2009 (N = 69 HSCT in 57 patients). We differentiated a cohort that received TBI (N = 44) from another that did not (N = 25). Subsequently, we interviewed the survivors from the TBI group with a minimum of 10 years of follow-up (N = 18), asking about the presence of side effects. ResultsThe overall survival (OS) at 2 and 5 years was 79.1% and 65.2% respectively for the TBI group and 66.2% and 55.8% for the non-TBI group, although this difference was not significant (P=.31). The event-free survival (EFS) at 2 and 5 years was 77.3% and 63.6% respectively for the TBI group and 56% and 32% for the non-TBI group (P=.02). The probability of relapse (PR) at 2 years for those who received TBI was 10% compared to 28.6% for those who did not receive TBI (P=.005). Survivors who received TBI developed secondary neoplasms (39%), dyslipidemia (67%), cognitive impairments affecting memory (44%), recurrent respiratory infections (39%), thyroid abnormalities (45%), premature ovarian failure (89%), cataracts (22%), and psychological problems (44%). However, the quality of life, as self-assessed by the patients, was considered good for 83% of the participants.. ConclusionsPatients who received TBI had significantly higher EFS and lower PR. However, adverse effects are frequent and significant, although they do not subjectively affect quality of life.

LARYNGEAL PLASMACYTOMA IN KAHLERS DISEASE: A CASE REPORT

Multiple myeloma or Kahlers disease is a malignant hematological disorder due to a monoclonal plasma cell proliferation primarily invading the hematopoietic bone marrow. Extra-medullar involvement occurs in 18% of patients with multiple myeloma. Laryngeal Localization remains rare and has been described in a few cases after a literature review.We report the case of a 44-year-old woman who presented an inspiratory dyspnea caused by a laryngeal tumor. The pathological study and bone marrow examination confirmed the laryngeal localization of multiple myeloma. Treatment consisted of chemotherapy with good clinical outcomes over a 2-year follow-up period.

Short-term substitution of calcineurin inhibitors (CNI) with recombinant humanized anti-CD25 monoclonal antibody (Basiliximab) as aGVHD prophylaxis in CNI intolerant patients after allogeneic hematopoietic stem cell transplantation

Objectives: To investigate the efficacy of short-term substitution of recombinant humanized anti-CD25 monoclonal antibody (Basiliximab) as acute GVHD (aGVHD) prophylaxis in calcineurin inhibitors (CNI) intolerant patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT) . Methods: This study included 17 patients with refractory malignant hematological disorders who underwent salvage allo-HSCT at the Bone Marrow Transplantation Department of Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital from August 2021 to August 2022 and were treated with Baliximab to prevent aGVHD due to severe adverse reactions to CNI. There were seven men and ten women, with a median age of 43 years (18-67). Following the discontinuation of CNI, Basiliximab was administered at a dose of 1 mg/kg once weekly until CNI or mTOR inhibitors were resumed. Results: Basiliximab was started at an average of 5 (1-32) days after HSCT. The median duration of substitution was 20 (7-120) days. All had neutrophil engraftment within a median of 12 (10-17) days. Thirteen patients had platelet engraftment after a median of 13 (11-20) days. Four patients did not develop stable platelet engraftment. Eight patients (47.1% ) developed Grade Ⅱ-Ⅳ aGVHD, while four (23.6% ) developed Grade Ⅲ/Ⅳ aGVHD. Only one patient died from aGVHD. Before the end of the followup period, seven of 17 patients died. The longest followup period of the survivors was 347 days, and the median survival rate was not met. The overall survival (OS) rate at six months was 62.6%. Among the 17 patients, 13 (76.4% ) experienced cytomegalovirus reactivation, 7 (41.2% ) experienced EB virus activation, and no cytomegalovirus disease was observed. Conclusions: When CNI intolerance occurs during allo-HSCT, short-term replacement with Baliximab can be used as an alternative to prevent aGVHD.

A machine learning approach to identify groups of patients with hematological malignant disorders

Background and ObjectiveVaccination against SARS-CoV-2 in immunocompromised patients with hematologic malignancies (HM) is crucial to reduce the severity of COVID-19. Despite vaccination efforts, over a third of HM patients remain unresponsive, increasing their risk of severe breakthrough infections. This study aims to leverage machine learning's adaptability to COVID-19 dynamics, efficiently selecting patient-specific features to enhance predictions and improve healthcare strategies. Highlighting the complex COVID-hematology connection, the focus is on interpretable machine learning to provide valuable insights to clinicians and biologists. MethodsThe study evaluated a dataset with 1166 patients with hematological diseases. The output was the achievement or non-achievement of a serological response after full COVID-19 vaccination. Various machine learning methods were applied, with the best model selected based on metrics such as the Area Under the Curve (AUC), Sensitivity, Specificity, and Matthew Correlation Coefficient (MCC). Individual SHAP values were obtained for the best model, and Principal Component Analysis (PCA) was applied to these values. The patient profiles were then analyzed within identified clusters. ResultsSupport vector machine (SVM) emerged as the best-performing model. PCA applied to SVM-derived SHAP values resulted in four perfectly separated clusters. These clusters are characterized by the proportion of patients that generate antibodies (PPGA). Cluster 1, with the second-highest PPGA (69.91%), included patients with aggressive diseases and factors contributing to increased immunodeficiency. Cluster 2 had the lowest PPGA (33.3%), but the small sample size limited conclusive findings. Cluster 3, representing the majority of the population, exhibited a high rate of antibody generation (84.39%) and a better prognosis compared to cluster 1. Cluster 4, with a PPGA of 66.33%, included patients with B-cell non-Hodgkin's lymphoma on corticosteroid therapy. ConclusionsThe methodology successfully identified four separate patient clusters using Machine Learning and Explainable AI (XAI). We then analyzed each cluster based on the percentage of HM patients who generated antibodies after COVID-19 vaccination. The study suggests the methodology's potential applicability to other diseases, highlighting the importance of interpretable ML in healthcare research and decision-making.

The Impact of Pretransplant Use of Tyrosine Kinase Inhibitors on Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia-A Single-institution Retrospective Study.

Objective Chronic myeloid leukemia (CML) is a malignant hematological disorder, and allogeneic stem cell transplantation (allo-SCT) was its only curative treatment until the introduction of tyrosine kinase inhibitors (TKIs). Allo-SCT is still considered for CML patients who are resistant to TKIs and in an advanced phase. Currently, second- and third-generation (2/3 G) TKIs are typically incorporated into the first-line treatment of CML. However, the impact of 2/3 G TKIs on subsequent allo-SCT remains unclear. We therefore evaluated the effect of 2/3 G TKIs on allo-SCT. Methods We retrospectively evaluated the effect of pretransplant therapy with TKIs on the outcome of allo-SCT for CML using clinical data at our institution. Patients or Materials Thirty-two CML patients who received their first allo-SCT procedure at our institute from 2001 to 2020 were included. We divided the patients into three subgroups based on TKI treatment before allo-SCT. Patients receiving no TKIs, only imatinib (IM), and 2/3 G TKIs were classified into the Non-TKI, IM, and 2/3 G TKI groups, respectively. Results In a univariate analysis, the pretransplant use of 2/3 G TKIs was significantly associated with a higher 5-year overall survival (91.7%) and relapse-free survival (75.0%) than the use of IM (37.5% and 12.5%) in patients presenting with or progressing to the advanced phase. In addition, pretransplant use of 2/3 G TKIs did not increase the incidence of graft-versus-host disease (GVHD). Conclusions We demonstrated that the pretransplant use of 2/3 G TKIs was safe and improved the outcome of CML patients who presented with or progressed to the advanced phase without increasing the frequency of GVHD.

Recent advancements in hematopoietic stem cell transplantation in Taiwan.

Hematopoietic stem cell transplantation (HSCT) can cure malignant and nonmalignant hematological disorders. From 1983 to 2022, Taiwan performed more than 10,000 HSCT transplants. The Taiwan Blood and Marrow Transplantation Registry collects clinical information to gather everyone's experience and promote the advances of HSCT in Taiwan to gather everyone's experience and promote advances of HSCT in Taiwan. Compared with matched sibling donors, transplants from matched unrelated donors exhibited a trend of superior survival. In Taiwan, transplant donors showed remarkable growth from unrelated (24.8%) and haploidentical (10.5%) donors. The number of older patients (17.4%; aged ≥61 years) who underwent transplantation has increased markedly. This review summarizes several significant developments in HSCT treatment in Taiwan. First, the use of Anti-thymocyte globulin (ATG) and intravenous busulfan regimens were important risk factors for predicting hepatic sinusoidal obstruction syndrome. Second, a new, machine learning-based risk prediction scoring system for posttransplantation lymphoproliferative disorder has identified five risk factors: aplastic anemia, partially mismatched related donors, fludarabine use, ATG use, and acute skin graft-versus-host disease. Third, although the incidence of idiopathic pneumonia syndrome was low (1.1%), its mortality rate was high (58.1%). Fourth, difficult-to-treat mantle cell and T-cell lymphomas treated with autologous HSCT during earlier remission had higher survival rates. Fifth, treatment of incurable multiple myeloma with autologous HSCT showed a median progression-free survival and overall survival of 46.5 and 70.4 months, respectively. Sixth, different haploidentical transplantation strategies were compared. Seventh, caution should be taken in administering allogeneic HSCT treatment in older patients with myeloid leukemia with a Charlson Comorbidity Index ≥3 because of a higher risk of nonrelapse mortality.

Adoption value of support vector machine algorithm-based computed tomography imaging in the diagnosis of secondary pulmonary fungal infections in patients with malignant hematological disorders.

This study aimed to assess the feasibility of diagnosing secondary pulmonary fungal infections (PFIs) in patients with hematological malignancies (HM) using computerized tomography (CT) imaging and a support vector machine (SVM) algorithm. A total of 100 patients with HM complicated by secondary PFI underwent CT scans, and they were included in the training group. Concurrently, 80 patients with the same underlying disease who were treated at our institution were included in the test group. The types of pathogens among different PFI patients and the CT imaging features were compared. Radiomic features were extracted from the CT imaging data of patients, and a diagnostic SVM model was constructed by integrating these features with clinical characteristics. Aspergillus was the most common pathogen responsible for PFIs, followed by Candida, Pneumocystis jirovecii, Mucor, and Cryptococcus, in descending order of occurrence. Patients typically exhibited bilateral diffuse lung lesions. Within the SVM algorithm model, six radiomic features, namely the square root of the inverse covariance of the gray-level co-occurrence matrix (square root IV), the square root of the inverse covariance of the gray-level co-occurrence matrix, and small dependency low gray-level emphasis, significantly influenced the diagnosis of secondary PFIs in patients with HM. The area under the curve values for the training and test sets were 0.902 and 0.891, respectively. Therefore, CT images based on the SVM algorithm demonstrated robust predictive capability in diagnosing secondary PFIs in conjunction with HM.

Chronic GVHD: review advances in prevention, novel endpoints, and targeted strategies.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative therapy for many malignant and non-malignant hematologic disorders. Chronic graft-versus-host (cGVHD) disease remains a significant hurdle for long-term survival in patients post allo-HCT, and it remains the leading cause of late non-relapse mortality. The risk factors for development of cGVHD include degree of human leukocyte antigen (HLA) disparity, increasing recipient age, use of peripheral blood stem cells as a source, myeloablative conditioning regimens, prior acute GVHD (aGVHD), and female donor to male recipient. Our biological understanding of cGVHD is mostly derived from transplantation mouse models and patient data. There are three distinct phases in the development of cGVHD. Approaches to prevent GVHD include pharmacologic strategies such as calcineurin inhibitors (cyclosporine, tacrolimus) combined with methotrexate or mTOR inhibitors (sirolimus), and IMP dehydrogenase inhibitors (mycophenolate mofetil). Increasingly, posttransplant cyclophosphamide is emerging as a promising strategy for GVCHD prevention especially in a setting of reduced intensity conditioning. Other approaches include serotherapy (ATG, Campath) and graft manipulation strategies. A significant obstacle to evaluating the response of novel GVHD-directed therapies has been standardized response assessments. This has functioned as a barrier to designing and interpreting clinical trials that are structured around the treatment of cGVHD. Novel endpoints including failure-free survival, Graft-versus-host disease-free, relapse-free survival (GRFS), and current GVHD-free, relapse-free survival (CGRFS) may create a clearer picture for post-HCT outcomes. Targeted therapies including Bruton's tyrosine kinase inhibition, JAK1/2 inhibition, and ROCK2 inhibitors have improved cGVHD therapy, especially in the steroid refractory setting. Continued improvement in prophylactic strategies for cGVHD, identification of accurate cGVHD treatment endpoints, and access to novel therapeutic agents are expected to improve cGVHD outcomes.

Abstract A016: Novel LEF1 gene structural variants in T-cell acute lymphoblastic leukemia Patient-Derived Xenografts models

Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by uncontrolled proliferation of immature T-cell precursors. LEF1 (Lymphoid Enhancer-Binding Factor 1) is a transcription factor that plays a crucial role in the development of T-cells. Recent studies have shown that LEF1 can affect the expression of MYC, a proto-oncogene that is frequently dysregulated in cancer. The highly expressed LEF1 gene and potentially its variants (K86E and P106L) stimulate cell growth by upregulating the expression of MYC. In T-ALL, MYC is often overexpressed, the abnormal expression of MYC propels the advancement of T-ALL and sustains the function of leukemia stem cells. The interaction between LEF1 and MYC in T-ALL is complex and involves multiple regulatory pathways, particularly the Wnt/β-catenin signaling pathway. Several studies have revealed a significant correlation between the inactivation of LEF1 and the overexpression of MYC in T-ALL. Therefore, understanding the role of LEF1 in T-ALL pathogenesis may provide new insights into the development of novel therapeutic strategies for this aggressive disease. This study shows that the novel structural variants (SVs) found in the LEF1 gene could be associated with the decreased expression of MYC. Methods: Leukemia cells derived from 6 patients with T-ALL were inoculated intravenously into immunodeficient mice tails. The burden of tumor was monitored within the peripheral blood (hCD45+), and the leukemia cells were collected once human CD45 was above 80%. Optical Genome Mapping (OGM, Bionano Genomics) and Whole Genome Sequencing (WGS) techniques were used to detect SVs and mutations. The findings were subsequently validated using polymerase chain reaction (PCR). Results: Of the 6 T-ALL models that were analyzed, two of them had SVs in the LEF1 gene. Although the expression of the LEF1 gene did not show significant changes, the expression of MYC was observed to be downregulated. The OGM analysis revealed that the second and third exons of the LEF1 gene, which are located in the β-catenin binding region, were deleted at the DNA level. The lack of complete identity between the sequences at the breakpoints could be attributed to DNA repair mechanisms. At the RNA level, the two models had distinct LEF1 mutations - E60K and P106L. Conclusion: In two of the six T-ALL models, novel SVs were found in the LEF1 gene that may decrease MYC expression compared to control samples. Further research is required to understand the relationship between LEF1 deletion and the regulation of MYC expression, as well as the role of this phenomenon in the development of T-ALL. Targeting LEF1 has emerged as a potential therapeutic strategy for the treatment of T-ALL. Citation Format: Yueying Wang, Wubin Qian, Mengting Qin, Xiaobo Chen, Jia Xue, Sheng Guo. Novel LEF1 gene structural variants in T-cell acute lymphoblastic leukemia Patient-Derived Xenografts models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A016.

Interindividual HLA Evolutionary Divergence in Single HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation for Malignant Hematological Disorders: A Report on Behalf of the Cellular Therapy and Immunobiology Working Party of the EBMT

In allogeneic hematopoietic cell transplantation (allo-HCT), alloreactive T-cell responses (graft versus leukemia - GvL and graft versus host disease - GvHD) are mediated by the interaction between recipient antigens and donor lymphocytes via human leukocyte antigen (HLA) molecules. HLA evolutionary divergence (HED) is a metric recently implemented as a functional proxy for the structural variability between two homologous HLA alleles at their peptide binding sites, mirroring quantitative differences in pathogen and cancer-related immunopeptidomes ( A). 1 Here, we hypothesize that differences in and between donor and recipient HEDs at given loci may modulate the direction and the intensity of alloreactivity, informing on post-transplant outcomes. We tested this hypothesis in onco-hematologic patients undergoing allo-HCT from a single HLA-A, -B, -C, -DRB1, or -DQB1 (9/10) mismatched unrelated donor (MMUD) at EBMT centers. We included patients with selected hematological malignancies, receiving a thymoglobulin-based T cell depletion, for whom complete clinical and HLA information was available in the EBMT database. We deployed individual locus-specific recipient/donor HED (HED-R, HED-D) metrics as previously described 1, and conceptualized two novel interindividual HED scores accounting for functional differences at the mismatched HLA loci ( A). The latter were considered as: 1) DeltaHED, quantifying the relative directional difference between HED-D and HED-R and informing on differences in immunopeptidome sizes, potentially capturing the direction and the intensity of the alloreactive response (GvH or HvG); 2) HEDmismatch, describing the HED of the mismatched locus as a proxy for the qualitative differences in immunopeptidomes between donor and recipient ( B). Using multivariable Cox regression (cause-specific) models adjusted for relevant clinical variables, we investigated the associations of HED-R, DeltaHED and HEDmismatch, analyzed as continuous variables, with relapse free survival (RFS), overall survival (OS), non-relapse mortality (NRM), relapse and grade II-IV acute and chronic GvHD. For each outcome and in each mismatched subgroup, we built separate models for these immunogenetic parameters and checked for proportional hazards assumption (PHA). To account for multiple comparisons, only p-values <0.01 were considered significant. Overall, 4639 adult patients, with available HLA data, received a 9/10 MMUD allo-HCT between 2010 and 2019 for acute leukemia (N=3853, 83%), myelodysplastic syndromes or myeloproliferative neoplasms (N=786, 17%). Median recipient age was 53.5 (IQR 40.2-61.9) with a male/female ratio of 1.28, whilst median donor age was 33.1 (IQR 24.5-40). Majority of patients (90%) received peripheral blood stem cells and were mismatched with their donors for locus A (33%), followed by C (21%), B (15%), DQB1 (14%) and DRB1 (6%). When analyzing the impact of HED-related parameters in each model, we observed that most recurrent associations with outcomes occurred with DRB1-related metrics. In the DRB1-mismatched subgroup (N=276), a time-varying association was found for HEDmismatch of DRB1 locus with higher HEDmismatch leading to worse RFS [HR:1.25 at t=0, (95% CI 1.1-1.42), p<0.001] and lower OS [HR:1.23 at t=0, (95%CI 1.08-1.41), p=0.002]. The strength of this associations declined over time for both endpoints (respectively RFS: HR:0.91, 95% CI 0.86-0.97, p=0.005 and OS: HR:0.93, 95% CI 0.88-0.98, p=0.013). The (directional) DeltaHED DRB1 measure instead did not display any impact on outcomes. In the same subgroup, higher HED-R in the locus C showed also a time-varying association with NRM at transplant [HR:1.89, (95% CI 1.29-2.85), p=0.002], progressively declining over time (HR:0.77, 95% CI 0.65-0.92, p=0.003). Furthermore, DRB1 HED-R modulated the probability of survival in B-mismatched subgroup, being higher scores associated with reduced OS [HR:1.03, (95%CI 1.01-1.06), p=0.009]. Here, we provide an immunogenetic benchmark to explore donor-recipient interactions in MMUD allo-HCT, demonstrating how different HLA configurations within the mismatched loci, in particular for DRB1 genes, can influence post-transplant outcomes. Given the peculiar associations observed, HED may have a role in driving early GvL effects, informing on future donor selection strategies in high-risk patients.

Full Body Screening Computed Tomography Prior to Allogeneic Hematopoietic Stem Cell Transplantation: A Single Institution Experience from an Academic Center

Background: The extent of pretransplant workup for allogeneic hematopoietic stem cell transplant (HSCT) differs considerably among transplant centers. Current practice at the University of Wisconsin is for all recipients to undergo screening CT (computed tomography) of the sinuses, chest, abdomen, and pelvis prior to HSCT which can reveal several incidental radiographic findings. Here, we examined the impact of this procedure on discovery of clinically meaningful incidental findings, on time to transplant, on detecting post-COVID-19 infection related complications and on overall clinical outcomes post-HSCT in the current era of novel treatments for malignant hematologic disorders. Methods: After IRB approval, all consecutive patients > age 18 years at the University of Wisconsin who underwent full body screening CT prior to HSCT, from January 2019 to August 2022 were studied. Imaging abnormalities were defined as any finding reported by the radiologist apart from isolated mucosal thickening on sinus CT scans. Post-transplant pulmonary complications were defined as abnormal chest CT scans within 6 months post-transplant. Patient and disease characteristics were tabulated, and descriptive statistics are reported. Progression free survival (PFS) is defined as the time from transplant to first identification of relapsed disease. Results: Table 1 shows clinical characteristics of the study cohort. Median follow up is 22.55 months (95% CI 12.04-34.78). A total of 205 patients underwent 577 screening CT scans prior to HSCT, of which 82% (n=169) had at least one abnormal finding and 52% (n=107) had an incidental finding. Of the patients with incidental findings, 53% (n=57) received no additional workup or intervention while 47% (n=50) underwent further workup, yet only 18% (n=19) had a change in management as depicted in figure 2. Therapeutic interventions included treatment with antifungals (n=11), antibiotics (n=5), thoracentesis (n=1), thoracotomy (n=1) and anticoagulation (n=1). Although 50% of all chest CT scans identified an abnormality, only 5% revealed an incidental finding that influenced management including pulmonary nodules (n=7), bronchiolitis (n=1) and pulmonary emboli (n=1), compared to just 3% for both sinus and abdominal CT scans including sinusitis (n=4), periapical abscesses (n=3) and abdominopelvic masses of the bladder (n=1), iliac fossa (n=1), pancreas (n=1) and ovary (n=1). Post-HSCT complications were identified in 23% (n=21) vs 16% (n=15) in those with abnormal and normal pre-HSCT chest CT, respectively. In the subset of patients who underwent therapeutic interventions resulting from abnormal screening chest CT, 28% (n=5) still experienced post-transplant complications. Finally, the incidence of post-transplant pulmonary complications was similar, 27% (n=4), in patients with and without documented COVID infection prior to transplant. Median time to HSCT after scan completion was similar in patients with normal vs abnormal imaging without additional workup at 23 days (range 11-47), compared to 24 days (range 8-62), respectively. In contrast, median time to HSCT was longer at 30 days (range 11-173) and 48 days (range 13-208) for those who received additional work up and a therapeutic intervention, respectively (p=0.0001). One year post HSCT non-relapse mortality was 9% and 12 % among patients with normal screening CT, and those with at least one abnormal finding, respectively. 2-year PFS was similar in patients with abnormal vs normal screening chest CT scans at 60% vs 58% respectively (p=0.98). Conclusions: We observed high rates of incidental findings leading to additional work up in over 40% of patients, though less than half of them led to changes in management. As expected, we noted a substantial risk of delay to HSCT in most recipients needing intervention. Chest CT scans had the highest prevalence of clinically significant incidental findings and meaningful impact on management, whereas routine sinus and abdomen-pelvic CT showed lower clinical benefit. No additional advantage of CT chest was found in asymptomatic patients who had a COVID-19 infection pre-HSCT. Our findings provide basis to re-evaluate current practice of pre HSCT screening, and identify at-risk patients who would benefit from screening. Additional analyses are needed to minimize risks of unnecessary interventions, delays and burden on patients and healthcare utilization.

Restrictive Versus Liberal Red Blood Cell Transfusion Strategies for Patients with Hematologic Malignancies Receiving Intensive Chemotherapy

Background: It is estimated that one-quarter to one-half of people diagnosed with hematologic malignancies experience anemia and red blood cell (RBC) transfusion plays an essential supportive role in their management. There are different strategies for RBC transfusions to treat anemia. A restrictive transfusion strategy seeks to maintain a lower hemoglobin level (usually between 70 g/L to 90 g/L with a trigger for transfusion when the hemoglobin drops below 70 g/L), whereas a liberal transfusion strategy aims to maintain a higher hemoglobin (usually between 100 g/L to 120 g/L, with a threshold for transfusion when hemoglobin drops below 100 g/L). The most effective and safest strategy is unknown in people with hematological malignancies. Objectives: To determine the efficacy and safety of a restrictive versus liberal RBC transfusion strategies for people diagnosed with hematological malignancies treated with intensive chemotherapy, radiotherapy, or both, with or without a hematopoietic stem cell transplant (HSCT). Methods: Review was completed using Cochrane standard methodological procedures. We included randomized controlled trials RCTs and prospective non-randomized studies NRS that evaluated a liberal compared with a restrictive RBC transfusion strategy in children or adults with malignant hematological disorders receiving intensive chemotherapy/radiotherapy or undergoing HSCT. We searched for RCTs and NRS in MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials, and eight other databases and three trial registries to 21 March 2023. For dichotomous outcomes such as mortality, results were presented as a risk ratio (RR) with 95% confidence interval (CI) to compare restrictive versus liberal transfusion strategies. For continuous outcomes using the same scale, we assessed the mean difference (MD) with 95% CI. Where outcome measures were heterogenous, a narrative synthesis was used. Review Manager Web was used to meta-analyze the data. GRADE rating methodology was used for the overall certainty of evidence from included studies. Main Results: Nine studies were included: eight RCTs and one NRS. 644 participants were included in analyses from six completed RCTs (n=560) and one completed NRS (n=84). Two ongoing RCTs consisting of 294 participants (260 adult and 34 pediatric) are pending inclusion. One completed RCT included children receiving HSCT (n=6) and five RCTs only included adults (n=239 with acute leukemia receiving chemotherapy and n=315 with a hematological malignancy receiving HSCT). The restrictive strategies varied from 70 g/L to 80 g/L and liberal strategies from 80 g/L to 120 g/L. A restrictive strategy was found to result in a reduction in the number of RBC units per participant compared to a liberal strategy (Four studies; 457 participants; MD: -2.39, 95%CI -3.38 to -1.39, P = <0.00001). No difference was seen in bleeding between strategies although there was high concern for bias in included trials. Effects were reported in the summary of findings tables for RCTs (Table 1) which included results from adults only to reduce indirectness as a result of limited information from the single published pediatric RCT which was terminated early. Overall, a restrictive RBC transfusion strategy may result in little to no difference in the risk of death at 31 to 100 days compared to a liberal transfusion strategy (three studies; 382 participants; RR 0.74, 95% CI 0.13 to 4.09, P= 0.73; I 2=28%; low-certainty evidence). Two outcomes (mortality at 31 to 100 days and clinically significant bleeding) were reported from the one NRS (Table 2). The evidence is very uncertain whether there is a difference in mortality and clinically significant bleeding between the transfusion strategies based on the very low-certainty evidence. Conclusions: A restrictive transfusion strategy demonstrated a reduction in RBC usage, while there may be no impact on mortality. Definite conclusions are challenging given the relatively few studies with low numbers of included participants, concern for bias, heterogeneity of intervention and outcome reporting and overall certainty of evidence. There is a need for larger and methodologically better designed and executed studies. There is insufficient evidence to answer this review's primary outcome. Further RCTs are required overall, particularly trials inclusive of pediatric participants.

Clinical, biological, electrophysiological and therapeutic profile of patients with anti-MAG neuropathy according to MYD88L265P and CXCR4 mutations and underlying haemopathy.

Anti-MAG neuropathies are associated with an IgM monoclonal gammopathy of undetermined significance (MGUS) or with a malignant haemopathy. Our objective was to determine whether the presence of a haemopathy or somatic mutations of MYD88 and CXCR4 genes influences disease presentation and response to rituximab (RTX). We included 79 patients (mean age 74years, disease duration 9.68years) who had a bone marrow aspiration with morphologic and immunophenotypic analysis. MYD88L265P and CXCR4 mutations were analysed in peripheral B cells. Information collected included: inflammatory neuropathy cause and treatment sensory sum score (ISS), MRC testing, overall neuropathy limitation scale (ONLS), Rash-built Overall Disability Score (RODS), ataxia score, anti-MAG titres, peak IgM dosage, neurofilament light chain levels, motor and sensory amplitudes, motor unit index (MUNIX) and motor unit size index (MUSIX) sum scores. Efficacy of RTX was evaluated at 12months in 26 patients. Malignant haematological disorders were discovered in 17 patients (22%): 13 Waldenstrom macroglobulinemia, 3 marginal zone lymphoma and one mantle cell lymphoma. MYD88L265P mutation was detected in 29/60 (48%) patients and CXCR4 in 1 single patient. Disease severity, biological and electrophysiological data and response to RTX were comparable in patients with MGUS/lymphoma and patients with/without MYD88L265P mutation. ISS was lower and MUSIX higher in patients improved by RTX. MYD88L265P mutation and underlying haemopathies are not predictive of a more severe disease. However, in cases of resistant and progressive neuropathy, they provide an opportunity to prescribe newly available drugs such as Bruton tyrosine kinase inhibitors.

Blastic Plasmacytoid Dendritic Cell Neoplasm Presenting as a Mammary Gland Tumor in a Pediatric Patient: A Case Report.

Emanating from a discrete category within the lympho-hematopoietic tumor system, as established by the World Health Organization in 2008, the blastic plasmacytoid dendritic cell neoplasm constitutes an uncommon malignant hematological disorder. It is routinely misidentified on account of its conspicuous dermatological manifestation, yet may insidiously permeate bone marrow and lymph nodes, involving peripheral blood and diverse extra-nodal tissues. Instances of mammary gland encroachment are extraordinarily infrequent. The current document delineates a case of a 14-year-old female patient contending with blastic plasmacytoid dendritic cell neoplasm, whose primary symptom was a mammary nodule, and whose breast and bone marrow/blood involvement were synchronous, in attempt to increase clinical vigilance.

Insights into highly engraftable hematopoietic cells from 27-year cryopreserved umbilical cord blood

Umbilical cord blood transplantation is a life-saving treatment for malignant and non-malignant hematologic disorders. It remains unclear how long cryopreserved units remain functional, and the length of cryopreservation is often used as a criterion to exclude older units. We demonstrate that long-term cryopreserved cord blood retains similar numbers of hematopoietic stem and progenitor cells compared with fresh and recently cryopreserved cord blood units. Long-term cryopreserved units contain highly functional cells, yielding robust engraftment in mouse transplantation models. We also leverage differences between units to examine gene programs associated with better engraftment. Transcriptomic analyses reveal that gene programs associated with lineage determination and oxidative stress are enriched in high engrafting cord blood, revealing potential molecular markers to be used as potency markers for cord blood unit selection regardless of length of cryopreservation. In summary, cord blood units cryopreserved for extended periods retain engrafting potential and can potentially be used for patient treatment.

Automated bone marrow cell classification through dual attention gates dense neural networks.

The morphology of bone marrow cells is essential in identifying malignant hematological disorders. The automatic classification model of bone marrow cell morphology based on convolutional neural networks shows considerable promise in terms of diagnostic efficiency and accuracy. However, due to the lack of acceptable accuracy in bone marrow cell classification algorithms, automatic classification of bone marrow cells is now infrequently used in clinical facilities. To address the issue of precision, in this paper, we propose a Dual Attention Gates DenseNet (DAGDNet) to construct a novel efficient, and high-precision bone marrow cell classification model for enhancing the classification model's performance even further. DAGDNet is constructed by embedding a novel dual attention gates (DAGs) mechanism in the architecture of DenseNet. DAGs are used to filter and highlight the position-related features in DenseNet to improve the precision and recall of neural network-based cell classifiers. We have constructed a dataset of bone marrow cell morphology from the First Affiliated Hospital of Chongqing Medical University, which mainly consists of leukemia samples, to train and test our proposed DAGDNet together with the bone marrow cell classification dataset. When evaluated on a multi-center dataset, experimental results show that our proposed DAGDNet outperforms image classification models such as DenseNet and ResNeXt in bone marrow cell classification performance. The mean precision of DAGDNet on the Munich Leukemia Laboratory dataset is 88.1%, achieving state-of-the-art performance while still maintaining high efficiency. Our data demonstrate that the DAGDNet can improve the efficacy of automatic bone marrow cell classification and can be exploited as an assisting diagnosis tool in clinical applications. Moreover, the DAGDNet is also an efficient model that can swiftly inspect a large number of bone marrow cells and offers the benefit of reducing the probability of an incorrect diagnosis.

Bone marrow transplant: A two-decade single centre hematology experience

BackgroundBone Marrow Transplant (BMT) is a curative form of therapy for many hematological disorders in both the adult and pediatric patients. The availability of BMT in the AFMS at AHRR for the last 02 decades has been a game changer for the patients. MethodsWe reviewed our BMT data since the inception of the program till Feb 2023. ResultsOver 700 patients with more than 23 different types of hematological disorders have undergone this procedure 58%% patients underwent an Autologous BMT and 42% an allogenic BMT. Autologous BMT for Multiple Myeloma and Allogenic BMT for Aplastic Anemia and Acute Leukemias have been the most common indications. 73% patients were adults, and 27% patients were of the pediatric age group. The male: female ratio was 2:1. The spectrum of allogenic Hematopoietic Stem Cell Transplant (HSCT) has expanded from Matched Sibling Donor (MSD) transplants to Matched Unrelated Donor (MUD) Transplants and Haploidentical Donor Transplants. 93% of our Allogenic BMT patients underwent a MSD BMT, 1% MUD BMT and 06% Haploidentical BMT. Today no patient with a malignant hematological disorder requiring a BMT is denied the procedure due to the lack of an HLA donor due to the availability of haploidentical BMT. ConclusionThe evolution of a BMT program has a long learning curve and the expanded pool of eligible donors has led to a situation of “transplant for all”. Haploidentical HSCT for nonmalignant hematological disorders is an unmet need. CART cell therapy and Cellular therapies need to be prioritized for future inclusion.

Risk Factors, Prevalence, and Outcomes of Invasive Fungal Disease Post Hematopoietic Cell Transplantation and Cellular Therapies: A Retrospective Monocenter Real-Life Analysis.

(1) Background: Autologous, allogeneic hematopoietic cell transplantation (HCT) and other cellular therapies, including CAR T cell and gene therapy, constitute a cornerstone in the management of various benign and malignant hematological disorders. Invasive fungal infections (IFD) remain a significant cause of morbidity and mortality in HCT recipients. Therefore, we investigated the prevalence and risk factors of IFD following HCT and other cellular therapies in an era of novel antifungal prophylaxis. (2) Methods: In this study, we retrospectively enrolled adult HCT recipients who were treated at our JACIE-accredited center according to standard operating procedures over the last decade (2013-2022). (3) Results: 950 patients who received cellular therapies were studied. None of the 19 CAR T cell and neither of the two gene therapy recipients developed IFD whereas 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Overall, 11 patients who received allogeneic HCT experienced probable IFD, possible IFD was found in 31/473, and IFD was proven in 10/473. A second IFD episode was present in three patients. Four-year OS was significantly lower in proven compared to probable IFD (p = 0.041) and was independently associated with HCT-CI (p = 0.040) and chronic GVHD (p = 0.045). (4) Conclusions: In this real-world cohort, the prevalence of proven and probable IFD in an era of novel antifungal prophylaxis was found to be relatively low. However, IFDs were associated with poor outcomes for patients who received allogeneic HCT.

152-LB: Implementing a Pilot Clinic for Steroid-Induced Hyperglycemia in Graft vs. Host Disease

Introduction: Malignant hematologic disorders are often treated with hematopoietic stem cell transplantation. This can be complicated by graft versus host disease (GVHD). Treatment is high dose corticosteroids, which often leads to steroid induced hyperglycemia (SIH). Uncontrolled hyperglycemia is associated with increased morbidity and mortality. Despite evidence favoring glycemic control in this population, there are no formal protocols or clinics in place to achieve this. Methods: The University of Kansas Blood and Marrow Transplant Program collaborated with the Department of Endocrinology to establish a pilot clinic for patients with GVHD who have SIH. Over 12 months, patients were referred to a physician assistant specializing in diabetes. They were seen at 1-4 week intervals based on acuity and glycemic control. Data was collected on blood glucose, hemoglobin A1c, fructosamine, steroid doses, insulin doses, hospitalizations, infections, and death. Results: 64 patients were referred to this clinic. 24 were excluded due to lack of hyperglycemia or declined being seen. Median time to index visit from referral was 20.5 days (IQR 8.25-29). Median A1c at index visit was 5.9 (IQR 5.4-7.2) and at 3 months was 5.3 (IQR 4.6-6.3). Median highest glucose within the first 3 months was 230 mg/dL (IQR 183-362) and at 3-6 months was 161 mg/dL (IQR 119.8-247, p-value = 0.0025). Median lowest glucose at 3 months was 86 mg/dL (IQR 78.5-103) and at 6 months was 87 mg/dL (IQR 75-115.8). There were 20 patients who were hospitalized and 9 patient deaths. Conclusions: Managing SIH is complex and requires a multidisciplinary approach. Patients who were seen had reduced episodes of hyperglycemia without increased episodes of hypoglycemia. A1c is an unreliable measurement in this patient population due to high cell turnover and frequent transfusions. Future studies using continuous glucose monitors could be investigated to assess the efficacy and feasibility of this pilot clinic. Disclosure D. Pham: None. K. Grdinovac: None. J. Leal: None. L. Rodriguez: None. A. Salva: None. W. Wesson: None. J. McGuirk: None.