Myelodysplastic Research Articles

Artificial intelligence-based Myelodysplastic Syndromes Score, 2022 classifications, and the Molecular International Prognostic Scoring System : a perfect match.

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Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.

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Pediatric Myelodysplastic Syndrome.

Myelodysplastic syndromes (MDSs) are rare in children and have unique clinical manifestations and implications. To review the clinical features, pathogenesis, and classification of pediatric MDS. Published literature and personal experience. Pediatric MDS vastly differs from adult MDS. Evaluation for the presence of an underlying germline predisposition syndrome is critical for optimal classification and management. Because of the rarity of cases, resources to aid with the recognition, diagnosis, and management of pediatric MDS are limited, and multi-institutional collaborative studies are needed for the future.

Umbilical Amniotic Tissue Graft as an Alternative Approach for Eyelid Reconstruction After Necrotizing Fasciitis Debridement

A 54-year-old female with myelodysplastic syndrome on chemotherapy presented with 10 days of periocular erythema and edema worsening on oral antibiotics. Computed Tomography scan showed periorbital soft tissue swelling without postseptal extension or abscess. Intravenous broad-spectrum antibiotics were administered. However, she developed necrosis of the upper eyelid requiring aggressive debridement. Nine days after debridement, the defect measuring 5.5 × 3 cm was covered using an umbilical amniotic tissue graft (AmnioGuard, BioTissue, Miami, FL). At postoperative week 4, 5-fluorouracil was injected to prevent the shortening of anterior lamella. At postoperative week 20, the graft had dissolved and been replaced by regenerated skin. Final eyelid exam demonstrated normal eyelid elevation and minimal lagophthalmos. Herein, we present a case of umbilical amniotic membrane as a substrate graft to support the healing of the eyelid defect by secondary intention.

Cytogenetic-Phenotypic Profile of Filipinos with Myelodysplastic Syndrome in Makati Medical Center: A 10-Year Review

Hematologic malignancies remained to be a significant contributor in the Global Burden of Disease. Myelodysplastic syndrome is one of the hematologic malignancies and has remained to be underestimated, underreported, and underdiagnosed. It is a group of hematologic malignancies that proves a challenge in diagnosis and is characterized by clonal hematopoiesis, with one or more cytopenias. Data on Prevalence of Myelodysplastic syndrome globally is scarce, moreso, not available in the Philippines. This is the first clinical profile study in Myelodysplastic Syndrome in the Philippines. This 10-year study has shown that 240 patients were diagnosed to have Myelodysplastic syndrome but only 35 had the MDS Fluorescent-in-Situ Hybridization test done. The most common reasons for hematologic referral, chief complaint, signs, cytogenetic test are anemia, low hemoglobin, pallor and fatigue, del7q31 which belongs to the Good risk cytogenetic category respectively. The most common CBC findings were hemoglobin of 8 and above, ANC of above 800 and Platelets of 50 and higher. There was no noted significant difference in the clinical profile of patients with MDS based on FISH study results

Myelodysplasia Rehabilitation in Children: a Review

INTRODUCTION. 1.5 thousand children with myelodysplasia (MD) are born in Russia every year. To improve the quality of life, most of them need lifelong medical supervision and rehabilitation. The topic of medical rehabilitation in MD in children is poorly covered. AIM. To search and analysis published data on the rehabilitation of children with MD identify the most effective methods. MATERIALS AND METHODS. The collection and analysis of publications on this topic from the PubMed and eLibrary databases published from 2014 to 2024 was carried out. Earlier fundamental works on secondary disorders in myelodysplasia and Spina bifida were also included in the review. A total of 512 publications in PubMed and 1096 publications in eLibrary were analyzed, 584 of them were unique. Publications of reviews, systematic reviews and clinical observations were included. RESULTS AND DISCUSSION. Rehabilitation for MD in children is multidisciplinary in nature, a violation of the structure of the nervous system entails, already in utero, the formation of deformities of the musculoskeletal system, combined changes in the functioning of the lower urinary tract and intestines. It is known that rehabilitation started from an early age helps to master motor skills in a timely manner, contributes to the prevention of metabolic syndrome, contractures, pressure sores, urodynamic disorders and constipation. There are different approaches regarding the intensity of physical activity during the day and week, following the recommendations of the World Health Organization (WHO), children should exercise for more than 60 minutes a day. Physical exercises should be carried out from the perspective of the concept of neuroplasticity and enhanced by the influence of magnetic stimulation, low-intensity laser, electromyostimulation, vibration therapy. It will be possible to effectively use acupuncture and massage. In addition, it is important to include urological and orthopedic care in medical rehabilitation from an early age. CONCLUSION. Due to the high disability, there is a question of effective methods for improving rehabilitation potential and improving the standard of living. Among the described methods, physiotherapy is distinguished, including therapeutic exercises, magnetic stimulation, low-intensity laser therapy, electromyostimulation, and ergotherapy. It is necessary to continue to study the effectiveness of the use of various physical factors in children with MD.

Severe bleeding events among critically ill patients with haematological malignancies

BackgroundBleeding events are common complications in critically ill patients with haematological malignancies. The objective of this study was to assess the incidence and identify determinants of ICU-acquired severe bleeding events in critically ill patients with haematological malignancies. We conducted a single-center retrospective study including all adult patients with a history of haematological malignancy requiring unplanned ICU admission over a 12-year period (2007–2018). The primary endpoint was the occurrence of ICU-acquired (i.e. after the first 24 h in the ICU) severe bleeding events, as defined as grades 3 or 4 of the World Health Organization classification.ResultsA total of 1012 patients were analysed, mainly with a diagnosis of lymphoma (n = 434, 42.9%) and leukaemia or myelodysplastic syndrome (n = 266, 26.3%). Most patients were recently diagnosed (n = 340, 33.6%) and under active cancer treatment within the last 3 months (n = 604, 59.7%). The main cause for admission was infection (n = 479, 47.3%), but a significant proportion of patients were admitted for a primary haemorrhage (n = 99, 10%). ICU-acquired severe bleeding events occurred in 109 (10.8%) patients after 3.0 days [1.0–7.0] in the ICU. The main source of bleeding was the gastrointestinal tract (n = 44, 40.3%). Patients experiencing an ICU-acquired severe bleeding event displayed prolonged in-ICU length of stay (9.0 days [1.0–6.0] vs. 3.0 [3.5–15.0] in non-bleeding patients, p < 0.001) and worsened outcomes with increased in-ICU and in-hospital mortality rates (55% vs. 18.3% and 65.7% vs. 33.1%, respectively, p < 0.001). In multivariate analysis, independent predictors of ICU-acquired severe bleeding events were chronic kidney disease (cause-specific hazard 2.00 [1.19–3.31], p = 0.008), a primary bleeding event present at the time of ICU admission (CSH 4.17 [2.71–6.43], p < 0.001), non-platelet SOFA score (CSH per point increase 1.06 [1.01–1.11], p = 0.02) and prolonged prothrombin time (CSH per 5-percent increase 0.90 [0.85–0.96], p = 0.001) on the day prior to the event of interest.ConclusionsMajor bleeding events are common complications in critically ill patients with haematological malignancies and are associated with a worsened prognosis. We identified relevant risk factors of bleeding which may prompt closer monitoring or preventive measures.

8203 A Solitary Fibrous Tumor Mimicking a Non-functional Pituitary Macroadenoma

Abstract Disclosure: L. Bernacet Rivera: None. S. Omay: None. A. Huttner: None. S.E. Inzucchi: None. Background: A solitary fibrous tumor (SFT), also known as hemangiopericytoma (HPC), is a rare subset of soft tissue tumors of mesenchymal origin. This type of tumor tends to have aggressive behavior and a high risk of recurrence. Approximately less than 1% of central nervous system (CNS) tumors have been identified as part of this subtype. Case Presentation: A 73-year-old female with medical history of primary hypothyroidism, myelodysplastic syndrome (MDS), and IgM kappa MGUS initially presented to her primary care physician for evaluation of progressive visual loss over several weeks, accompanied by worsening headaches. Ophthalmologic exam revealed bitemporal hemianopsia which prompted urgent imaging. Pituitary MRI with IV contrast revealed a solid sellar mass with suprasellar extension measuring 1.8 x 1.3 x 1.9 cm. The lesion was noted to superiorly displace the optic chiasm as well as to cause mild impingement of the anterior cerebral arteries. Patient was urgently referred to neurosurgery and endocrinology for further evaluation. Initial neuroendocrine laboratory assessment, performed at 8 am, revealed a cortisol 16.5 ug/dL, free T4 1.2 ng/dL, TSH 0.77 mIU/L, prolactin 9.9 ng/mL, IGF-1 17 ng/mL, the latter value consistent with adult growth hormone deficiency. Her LH and FSH were 4.3 mIU/mL and 12.6 mIU/mL, respectively, lower than expected for a post-menopausal woman. She underwent a transnasal transsphenoidal resection of the sellar lesion. Surgery was difficult due to the fibrous nature of the tumor, for which complete resection was not achieved. Post-operative course was complicated by thrombocytopenia due to MDS. Hormonal workup following surgery was consistent with central adrenal insufficiency, hypogonadotropic hypogonadism, and central hypothyroidism. Pathology showed densely cellular spindle cell neoplasm with a collagenous background consistent with hemangiopericytoma. She underwent fractionated radiotherapy and tumor has since remained stable in size. Her visual symptoms resolved quickly following surgery. Discussion: SFT is an aggressive mesenchymal tumor which rarely appears in the sellar region. There are no identified brain MRI findings that would suggest the nature of this tumor. As a result, endocrinologists should be aware of this rare condition while evaluating pituitary neoplasms. Presentation: 6/3/2024

Midostaurin added to 10-day decitabine, for patients unfit for intensive chemotherapy with AML and higher risk MDS, irrespective of FLT3 mutational status, does not improve outcome.

The treatment of older patients with acute myeloid leukemia (AML) considered unfit for receiving intensive chemotherapy is challenging. Based on the hypothesis that addition of the broad tyrosine kinase inhibitor (TKI) midostaurin could improve the response to hypomethylating agents, irrespective of FLT3 gene mutational status, we conducted a randomized phase II multicenter study to assess the tolerability and efficacy of the addition of midostaurin to a 10-day schedule of decitabine in unfit (i.e. Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) ≥ 3) AML and higher risk myelodysplasia (MDS) patients (HOVON155 trial). In total, 140 eligible patients were randomly (1:1) assigned to treatment with 10-days of decitabine alone (N = 70) or combined with midostaurin (50mg bid;starting the day following the last dose of decitabine), (N = 70). Addition of midostaurin was well tolerated and the number of AEs was comparable for both treatment arms. Early death rates (< 30 days) were similar as well (10%). In the decitabine plus midostaurin arm 24% reached CR/CRi, the median OS was 4.8 months and 1-yrs OS was 31% which compared with 34% CR/CRi, median OS of 7.4 months and 1-yrs OS of 37% for the decitabine alone group (NS). Thus, while the addition of midostaurin appears safe, it does not enhance therapeutic efficacy of decitabine in unfit AML patients.

6728 Bilateral Adrenal Hemorrhage: Cause Or Consequence?

Abstract Disclosure: M.N. Rayan: None. R. Horner: None. A. Valenciaga: None. L.E. Ryan: None. Introduction: Before the advent of the CT scan, bilateral adrenal hemorrhage was primarily discovered post-mortem in patients who had succumbed to sepsis, burns, or anticoagulant therapy. Today, non-traumatic hemorrhage is recognized as an infrequent, yet potentially lethal diagnosis causing clinical deterioration in acutely ill patients. Clinical Case: Our patient is a 64-year-old-male with a medical history of Myelodysplastic Syndrome initially presented to an external ED with abdominal pain. CT abdomen revealed hepatomegaly, splenomegaly, and new bilateral adrenal masses—absent in an MRI conducted a year earlier. He was treated conservatively and subsequently discharged. Two weeks later, he returned to the hospital with severe right sided flank pain. His hemoglobin and platelet counts dropped from 11.5 g/dL and 309 K/uL during the previous ED visit to 7.7 g/dL and 80 K/uL, respectively. Additionally, his PT/INR, PTT, fibrinogen, and D-Dimer levels were elevated. A repeat CT scan indicated a significant enlargement of the right adrenal mass, raising suspicion of adrenal hemorrhage. He was appropriately transfused, and a BM biopsy was performed to evaluate for acute transformation of underlying MDS. Cortisol levels were monitored daily for adrenal insufficiency. A complicated hospital course ensued marked by worsening anemia, thrombocytopenia, and coagulopathy, accompanied by high fevers and new-onset atrial fibrillation. Mixing studies showed absence of a factor inhibitor ruling out acquired forms of Hemophilia. Infectious workup including fungal and viral serologies returned negative. A PET scan revealed several small hypermetabolic hypodense liver lesions, and hypermetabolic activity diffusely in the spleen, and adrenal glands leading to suspicion of metastasis. Results of the BM biopsy returned revealing hypercellularity, with aggregates of hemosiderin-laden macrophages replacing the bone marrow space with associated necrosis. Worsening abdominal pain with hematochezia prompted an endoscopy, confirming a diagnosis of metastatic melanoma. Concurrently, seizure activity and altered mentation led to a head CT, revealing new metastatic lesions that confirmed the rapid progression of the disease. Subsequently, the patient was transitioned to comfort care and passed away. Clinical Lesson: It is crucial to review the various causes of adrenal hemorrhage, understand the challenges associated with interpreting adrenal imaging, emphasize the need to monitor adrenal function, and consider the occasional necessity for tissue sampling. In this clinical scenario, metastases with hemorrhage were the most likely etiology. The causes of adrenal hemorrhage are not always apparent; in this presentation, the consequence of the underlying disease state ultimately led to the initial presenting symptom of abdominal pain. Presentation: 6/2/2024

Measurable residual disease assessment prior to allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromes: a 20-year monocentric study.

Patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) who undergo allogeneic hematopoietic stem-cell transplantation (alloHSCT) can have divergent survival outcomes while all in morphological complete remission (CR). Techniques of measurable residual disease (MRD) have allowed us to refine their prognosis in two categories: MRD-positive and MRD-negative patients. We conducted a monocentric retrospective study (01/2000-12/2020) to assess the prognosis of pretransplant MRD status measured by multiparametric flow cytometry (MFC) and molecular biology assessed by PCR. 192 patients were included. The median follow-up period was 77months. Among patients undergoing alloHSCT in CR, overall survival (median-OS: 130.6 vs. 16.0months, P < 0.001), disease-free survival (median-DFS: 109.6 vs. 7.1months, P < 0.001) and cumulative incidence of relapse (12-month CIR: 7.3% vs. 33.7%, P < 0.0001) were significantly different between MRD-negative and MRD-positive patients. Patients with discordant intermethod results had intermediate DFS. MRD-negative patients according to molecular PCR-based techniques, WT1 overexpression and MFC had longer median-DFS, compared to MRD-positive patients (P = 0.001, P < 0.001, P < 0.001, respectively). Looking into subgroups, MRD-positive patients among the ELN2017 adverse-category (P < 0.0001), myeloablative and reduced-intensity conditioning regimens (P < 0.0001, P = 0.005), < 60-year patients (P < 0.001) and AML patients (P < 0.001) were associated with lower DFS. This difference was not found in ≥ 60-year patients (P = 0.27) and MDS patients (P = 0.70). MRD-positive patients within the favorable/intermediate ELN2017 category trended toward lower DFS (P = 0.05). We confirmed that MRD status prior to alloHSCT is a strong prognostic factor for OS, DFS and CIR. Combining MFC and molecular-PCR techniques to assess MRD seems primordial as inter-method discordance can be consequential.

Multicentral Retrospective Analysis of Venetoclax-Based Treatments in AML and MDS: A Real-World Study by the Turkish Hematology Network Group.

Background and Objectives: Acute myeloid leukemia and myelodysplastic syndrome are both clonal hematologic malignancies that primarily affect older adults. Current treatments for AML/MDS are both limited in number and efficacy. This study aims to evaluate venetoclax-based therapies in AML/MDS, focusing on overall survival and recurrence-free survival rates, and to expand real-world data on its use. Materials and Methods: Clinical and laboratory data on patients with AML/MDS aged 18≥ treated with venetoclax between January 2019 and July 2022 were included. Survival analysis was calculated based on the period from 2019 to December 2023. Results: A total of 161 AML and 40 patients with MDS were included. The median age was 63.53 ± 15.30 years for AML and 70.12 ± 10.21 years for MDS. In both groups, over 55% are male. A total of 77.6% of patients with AML and 75% of patients with MDS received treatment prior to venetoclax. Venetoclax was administered in combination with azacitidine to 84.5% of AML and 67.5% of MDS. The relapse rate in AML is approximately 15%. Overall, the 2-year survival rate is 46% and 18.73 months. The overall CR/CRi rate for patients with AML is 49.1%, while for patients with MDS, it is 50%. The 2-year survival rate for patients with MDS is 52.7%. The 2-year RFS rate was 75.5% for AML and 90.9% for MDS. The relapse rate in AML is approximately 15%. The percentage of adverse events leading to treatment discontinuation among those with grade 3-4 toxicity is low; 26.7% for AML (n = 43) and 15% for MDS (n = 6). Conclusions: Our real-world data demonstrate that venetoclax has the potential to improve overall survival rates when used in combination with HMAs and supports its use in patients with AML/MDS.

Recurrent, multisystem angioedema induced by 5-azacitidine.

5-azacitidine is a hypomethylating agent (HMA) used for treating myelodysplastic syndrome (MDS) and certain myeloproliferative neoplasms (MPNs). Common side effects include myelosuppression, nausea and injection site reactions. Serious allergic reactions are rare with this class of agents. We describe a 71-year-old man with MDS/MPN who developed repeated episodes of angioedema after starting treatment with subcutaneous 5-azacitidine. Angioedema involved multiple body areas including the neck, genitalia, lower back and gastrointestinal system. Causality assessment linked this entity to 5-azacitidine via the Naranjo nomogram questionnaire, by scoring 9. 5-azacitidine was discontinued due to recurrent episodes of angioedema that occurred even after dose reduction. Steroids were helpful in terms of reversing this reaction. Afterwards, no further episodes of angioedema have been documented. The patient's thrombocytosis is currently well-controlled with low dose hydroxyurea. We report herein a unique case of recurrent, multisystem angioedema likely related to 5-azacitidine. The exact mechanism of azacitidine-induced angioedema is not currently known. Symptoms, clinical findings and timing of presentation are not always clear-cut, and it may take more than one cycle of 5-azacitidine before the diagnosis is made. Supportive and symptomatic treatment will be provided based on the severity of the reaction. Future studies may offer more insights into the mechanism underlying this rare and serious, yet intriguing side effect.

B-214 Mutational Landscapes of Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Database-Driven Comprehensive Myeloid Panel Analysis of DNA Variants and Gene Fusions

Abstract Background Myeloid malignancies, including Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS), are characterized by a complex spectrum of genetic mutations. These mutations play a critical role in the pathogenesis of the diseases and are essential for accurate diagnosis, prognosis, and the development of personalized treatment strategies. This study aimed to compare the molecular profiles of AML and MDS by analyzing a database of comprehensive NGS myeloid panel results, which concurrently evaluates DNA variants and gene fusions, to identify distinct mutational patterns and differences between these conditions. Methods A retrospective analysis was conducted on a de-identified dataset from myeloid panel tests applied at the time of diagnosis for myeloid malignancies during 2023. Cases indicated for AML and MDS testing were identified, and relevant demographic, specimen, and test outcome data were retrieved from the database. The dataset was compiled from data obtained using the AmpliSeq for Illumina Myeloid Panel, performed on the MiSeq system (both from Illumina). This panel targets 40 DNA genes (17 full-length, 23 hotspots) and 29 RNA fusion genes, covering 629 potential fusions, with a limit of detection at a 5% allele frequency. Variants were classified according to the CAP/ASCO/AMP guidelines on the Frankling (Genoox) platform. Demographic, specimen, and test outcome data—including gene fusions, mutated genes grouped by biological function (epigenetic regulators, signaling and kinase pathway genes, tumor suppressors, transcription factors, and RNA spliceosome), and DNA variants (limited to tiers 1 and 2)—were analyzed and compared using the Mann-Whitney U test or chi-square test, as appropriate. Results A total of 106 cases were evaluated, comprising 53 AML (31 females) and 53 MDS (25 females). The average age was 56.15±21.62 years for AML and 64.79±18.18 years for MDS (p=0.026). Blood sample distribution was 26 for AML and 33 for MDS (p=0.24). Fusion genes, found exclusively in AML, appeared in 34% (18/53) of cases (p&amp;lt;0.0001), with the most common being CBFB::MYH11 (50%, 9/18) and RUNX1::RUNX1T1 (22%, 4/18). Somatic DNA variants were more prevalent in AML cases at 87% (46/53) compared to 64% (34/53) in MDS cases (p=0.012). There were 87 Tier 1/2 DNA variants in AML and 53 in MDS, with a median (min-max) of 2 (1-7) variants per case for AML and 1 (1-5) for MDS (p=0.02). For AML versus MDS, the distribution of DNA variants by mutated gene biological function was as follows: epigenetic regulators [29.88% (26/87) versus 33.96% (18/53), p=0.75], signaling and kinase pathway genes [31.03% (27/87) versus 5.66% (3/53), p=0.0008], tumor suppressors [16.09% (14/87) versus 11.32% (6/53), p=0.59], transcription factors [17.24% (15/87) versus 20.75% (11/53), p=0.76], and RNA spliceosome [5.75% (5/87) versus 28.30% (15/53), p=0.0005]. Conclusions Our study underscored distinct molecular profiles for AML and MDS when both DNA variants and gene fusions are analyzed. AML cases were younger, displayed a higher frequency of gene fusions, and a greater diversity of DNA variants compared to MDS. AML cases also showed a higher prevalence of mutations in signaling and kinase pathway genes. MDS was characterized by a higher prevalence of mutations in RNA spliceosome genes.

Experience with luspatercept therapy in patients with transfusion-dependent low-risk myelodysplastic syndromes in real-world clinical practice: exploring the positive effect of combination with erythropoietin alfa.

Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

A-156 Comparison of blast and variant lymphocyte flagging between the Alinity hq from Abbott and XN-1000 from Sysmex

Abstract Background Blast cells are immature white blood cells (WBC). The presence of blasts in the peripheral blood may be associated with certain diseases such as myelodysplastic syndrome and acute myelogenous leukemia. Variant lymphocytes (i.e., reactive lymphocytes, atypical lymphocytes) are WBCs produced by the immune system in reaction to infections caused by pathogens such as Epstein-Barr virus, cytomegalovirus, etc. It is clinically useful that the automated hematology analyzer is capable of flagging these cells. In this study, the blast (shown as ‘BLAST’ on the Alinity hq and ‘Blast/Abn Lympho?’ or ‘Blast?’ on XN-1000) and variant lymphocyte (shown as ‘VAR LYM’ on the Alinity hq, and ‘Atypical Lympho?’ on XN-1000) flagging was compared between the Alinity hq from Abbott and XN-1000 from Sysmex. Alinity hq has different sensitivity settings available for BLAST and VAR LYM flagging. In this study, the default setting for Alinity hq was used. For XN-1000, the Q-Flag default setting is 100. In this study, the setting was 120 for ‘Blast/Abn Lympho’ and 100 for “Atypical lympho?’. Methods Blood specimens were tested on the Alinity hq and XN-1000 analyzers. Two smears per specimen were made manually or by the Alinity hs slide maker stainer and read by two independent readers. The specimens showing any of the following flagging were included in the analysis: ‘BLAST’ on Alinity hq, ‘VAR LYM’ on Alinity hq, ‘Blast/Abn Lympho?’ or ‘Blast?’ on XN-1000, ‘Atypical lympho?’ on XN-1000. The flagging reports of these samples from both analyzers were compared to the smear review to determine if each analyzer's blast and variant lymphocyte flagging were true positive, false positive, true negative, or false negative. Results A total of 520 specimens were tested, yielding 41 specimens for blast flagging analysis and 80 specimens for variant lymphocyte flagging analysis. Due to the scarce availability of true positive samples from the manual review, true positive and false negative rate were not compared. For blast flagging using smear results of &amp;gt;=1% or &amp;gt;=5% as the positive criterion, Alinity hq yielded a 9.8% (=4/41) false positive rate and 87.8% (=36/41) true negative rate. XN-1000 yielded a 75.6% (=31/41) false positive rate and 22.0% (=9/41) true negative rate. For variant lymphocyte flagging using smear results of &amp;gt;=5% as the positive criterion, Alinity hq yielded a 6.3% (=5/80) false positive rate and 92.5% (=74/80) true negative rate. XN-1000 yielded a 91.3% (=73/80) false positive rate and 7.5% (=6/80) true negative rate. Conclusions This study demonstrated that Alinity hq achieved a much lower false positive rate and much higher true negative rate for both blast and variant lymphocyte flagging when compared to the XN-1000. Manual blast and variant lymphocyte morphology classification is laboratory- and technician-dependent. Both analyzers allow different sensitivity/specificity levels to flag blasts and variant lymphocytes. Each individual laboratory should evaluate and choose the setting that is most suitable for their specific patient populations to obtain the desired flagging rate.

Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.

Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.

A-152 Enhancing PNH Diagnosis with Multicolor Flow Cytometry Immunophenotyping Protocol in a Medical Center in Taiwan

Abstract Background Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder resulting from mutations in the X-linked PIG-A gene, leading to an inability to produce GPI-anchored proteins on RBCs and WBCs. PNH presents in three variants: classic (hemolytic), associated with specified bone marrow disorders, and subclinical. Flow cytometric analysis stands as the gold standard for PNH detection, crucial in diagnosis, monitoring, and clinical management. Recognizing potential variations in PNH testing among labs, it is essential to establish a precise and consistent protocol for accurate diagnosis and patient management. This report aims to demonstrate the effectiveness of a PNH immunophenotyping protocol adhering to ICCS/ESCCA PNH consensus guidelines. Methods A total of 501 samples were analyzed from Jan 1st, 2021 to Dec 31st, 2023. All the acquisitions were accomplished by a 3-laser and 10-PMT Navios EX (Beckman Coulter) flow cytometry. A typical combination of anti-CD235a-FITC (clone KC16) and anti-CD59-PE (clone MEM43) antibodies were adopted to identify the PNH clone size in the RBC tube. To achieve higher sensitivities in PNH granulocyte and PNH monocyte detection, a single tube, 6-color mixture of FLAER, monoclonal antibodies including CD14-APC, CD24-PE, CD33-APC-H7, CD15-PacB, and CD45-KrO, to immunostaining simultaneously was developed. An unstained control was run after the full-stained tube to determine the position of threshold for positivity, and to exam the potential carryover into the test sample. Results RBC and granulocyte assays can detect PNH phenotypes at the 0.009% level or higher with more than 50,000 cells of gated cells acquired, while the monocyte assay can detect at &amp;gt;=0.069% with at least 20,000 cells acquired. Analysis was conducted on five hundred and one patients to investigate potential PNH clones in their blood cells. Among them, 45 patients were identified as having classic PNH, while PNH clones were not detected in 168 cases, constituting 33.5% of total cases. Minor PNH clone (&amp;lt;1.0%) in single cell lineage were observed in 144 cases, making up 28.7% of all cases. Minor PNH clones found in more than one cell lineages were found in 155 cases (30.9% of 501). Additionally, minor PNH clones were identified across RBCs, granulocytes, and monocytes, with percentages of 32.9%, 23.8%, and 43.9%, respectively of all patients. Notably, monocyte clones exceeded granulocyte clones in 23.0% of cases with WBC PNH clones, irrespective of clone sizes. Furthermore, we investigated seven patients exhibiting persistent minor PNH clones in 2 to 3 cell lineages. Among them, five had aplastic anemia or myelodysplastic syndromes, while one underwent evaluation for young stroke and one was investigated for venous thromboembolism. Conclusions Flow cytometry labs aim not only to identify classic PNH patients but also to consistently detect minor or small clones in individuals with bone marrow disorders or subclinical conditions. Our findings are compatible with international reports, underscoring the importance of routinely examining patients with minor clones. Such assays serve as essential tools for ongoing monitoring, facilitating PNH diagnosis and management by physicians.

DNA methylation inhibitors adverse reaction characteristic analysis: a descriptive analysis from WHO-VigiAccess.

DNA methylation inhibitors (azacitidine, decitabine) have revolutionized the treatment dilemma of myelodysplastic syndromes (MDS), a group of malignant hematopoietic disorders. This study evaluates the adverse drug reactions (ADRs) following the use of DNA methylation inhibitors in the World Health Organization (WHO) VigiAccess database and compares the characteristics of ADRs between the two drugs to select the drug with the minimum individualized risk for patients. This study employed a retrospective descriptive analysis method. We compiled ADR reports for two marketed DNA methylation inhibitors for the treatment of MDS from WHO-VigiAccess. Data collected included demographic data such as age groups, gender, and regions of global patients covered by ADR reports, as well as data on the disease systems and symptoms caused by ADRs recorded in the annual reports and reports received by WHO. By calculating the proportion of ADRs reported for each drug, we compared the similarities and differences in ADRs between the two drugs. Overall, 23,763 adverse events (AEs) related to the two DNA methylation inhibitors were reported in VigiAccess. The results showed that the top 10 most common AEs were febrile neutropenia, bone marrow suppression, neutropenia, anemia, pancytopenia, leukopenia, thrombocytopenia, bone marrow failure, agranulocytosis, and hematotoxicity. The top five common types of DNA methylation inhibitor AEs were blood and lymphatic system disorders (11,178 cases, 47.0%), cardiac organ diseases (1,488 cases, 6.3%), various congenital familial genetic diseases (49 cases, 0.2%), ear and labyrinth diseases (100, 4.2%), and endocrine system diseases (57, 2.4%). There is no Strong correlation between DNA methylation inhibitors and ADRs. Current comparative observational studies of these inhibitors show that there are common and specific adverse reactions in the ADR reports received by WHO for these drugs. Clinicians should improve the rational use of these drugs based on the characteristics of ADRs.

Superior Survival After Unrelated Allogeneic Stem Cell Transplantation With Low-Dose ATG Compared to Low-Dose TBI in Myeloablative Fludarabine/Busulfan-Based Regimen for MDS on Behalf of the Adult MDS Working Group of the JSTCT

The fludarabine/intravenous busulfan 12.8 mg/kg (FB4) regimen is an effective conditioning regimen in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome (MDS); however, limited data is available on the prognostic impact of FB4 with low-dose anti-thymoglobulin (ATG ≤ 5 mg/kg) or low-dose total body irradiation (TBI ≤ 4 Gy). Therefore, we retrospectively evaluated the outcomes in 280 adults with de novo MDS who underwent their first transplantation from an unrelated donor between 2009 and 2018. Median age was 61 years (range, 16 to 70 years). In the FB4 alone (FB4), FB4 plus ATG (FB4-ATG), and FB4 plus TBI (FB4-TBI) groups, 3-years overall survival (OS) rates were 39.9%, 64.8%, and 43.7%; 3-years nonrelapse mortality (NRM) were 32.1%, 22.1%, and 27.1%; and 3-years relapse incidences were 34.7%, 21.2%, and 28.9%, respectively. The multivariate analyses showed that FB4-ATG group significantly correlated with better OS (hazard Ratio [HR], 0.51; 95% confidence interval [CI], 0.27 to 0.95; P = .032) than FB4 group. FB4-ATG group tended to correlate with lower NRM (HR, 0.36; 95% CI, 0.13 to 1.06; P = .063) than FB4 group. In comparison with FB4-TBI group, FB4-ATG group showed better OS (HR 0.52, 95% CI 0.27 to 0.99, P = .049) and NRM (HR 0.034, 95% CI 0.11 to 0.92, P = .034). No significant differences were observed in OS and NRM between the FB4-TBI and FB4 groups. The present study demonstrated that the FB4 plus low-dose ATG regimen improved OS and NRM, but FB4 plus low-dose TBI regimen had no clear benefit over FB4 alone, in MDS patients who used unrelated donors.