[Diagnosis and treatment of aplastic anemia and lower-risk myelodysplastic neoplasms].

Myelodysplastic neoplasms (MDS) are clonal hematological malignancies arising from gene mutations. Immunosuppressive therapies (IST) are effective in lower-risk MDS (LR-MDS) with characteristics such as hypoplastic marrow with low blasts or low ring sideroblasts, and with a small increase of PNH clones or decrease of megakaryocytes. Differential diagnosis of these LR-MDS cases from AA can be difficult, and precise diagnosis requires careful evaluation of bone marrow cellularity and dysplasia. To decide on an appropriate treatment strategy for LR-MDS, it is important to evaluate the underlying pathology, and preferentially select IST as first-line therapy in patients with features that indicate immune-mediated bone marrow failure.

[Novel therapies for MDS and future prospects].

Myelodysplastic syndromes (MDS) are clonal diseases resulting from the accumulation of genetic mutations. In general, MDS is categorized into two risk groups, with management and treatment varying significantly based on this classification. Over the past two decades, allogeneic transplantation and hypomethylating agents (HMAs) have become the standard of care and remain crucial for higher-risk MDS. Unfortunately, no new drugs have emerged to replace HMAs as the standard of care. However, the landscape of practice and research in MDS has evolved. In 2022, the focus of diagnostic classification of MDS shifted significantly from morphology to genetic alterations. As a result, treatment strategies centered on genetic mutations are now already used internationally. Revisions made to the International Working Group (IWG) criteria for assessing treatment response in 2023 are expected to further improve accuracy. Meanwhile, interest has increased in understanding the relationship between inflammation and the development and progression of lower-risk MDS. This year, luspatercept, an anti-anemic agent targeting the TGFß pathway, became available for clinical use in Japan. Various research initiatives are currently underway to develop new medicines targeting specific molecules within innate immune and inflammasome-signaling pathways, including IL-1ß, CD33, TLR, IRAK4, and p38MAPK.

Clinical Characteristics and Diagnosis of Nonaccelerating MDS/MPN-U Patient with 5q- Karyotype.

BACKGROUND: The aim of the study was to improve the clinical cognition of nonaccelerating myelodysplastic/myeloproliferative neoplasms-unclassifiable (MDS/MPN-U) with 5q- karyotype and to avoid misdiagnosis or delayed diagnosis. METHODS: The clinical manifestations and laboratory results of a patient with nonaccelerating MDS/MPN-U with 5q- karyotype were analyzed, and related literature was reviewed. RESULTS: The patient was admitted to hospital mainly due to chest tightness and shortness of breath, aggravated for 4 days. After admission, combined with clinical manifestations, bone marrow cell morphology, immunology, multiparameter flow cytometry, cytogenetics and molecular biology, etc., the final diagnosis was MDS-MPN-U. CONCLUSIONS: Research on the correlation between MPN-U and MDS with 5q deletion is still needed. Clinically, MPN-U combined with MDS is prone to misdiagnosis. In diagnosing MPN-U patients, it is essential to not only complete routine and immunological tests but also consider clinical manifestations and laboratory results. It is crucial to be vigilant about the possibility of concurrent diseases, especially cancer, and to choose targeted examinations in a timely manner to avoid missed or incorrect diagnoses.

[Clinical characteristics and prognosis of patients with myelodysplastic syndrome with a bone marrow nucleated erythroid cell proportion of greater than or equal to 50].

Objective: To analyze the clinical characteristics and prognosis of patients with myelodysplastic syndrome (MDS) with a bone marrow nucleated erythroid cell proportion of greater than or equal to 50% (MDS-E) . Methods: The clinical characteristics and prognostic factors of patients with MDS-E were retrospectively analyzed by collecting the case data of 1 436 newly treated patients with MDS diagnosed in the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences from May 2014 to June 2023. Results: A total of 1 436 newly diagnosed patients with complete data were included in the study, of which 337 (23.5%) patients with MDS-E had a younger age of onset and lower neutrophil and platelet counts compared with those in patients with an erythroid cell proportion of less than 50% (MDS-NE) (all P<0.05). The proportion of MDS cases with ring sideroblasts (MDS-RS) was higher in the MDS-E group than in the MDS-NE group, and multi-hit TP53 mutations were more enriched in the MDS-E group than in the MDS-NE group (all P<0.05). Among patients with MDS-RS, the frequency of complex karyotypes and the TP53 mutation rate were significantly lower in the MDS-E group than in the MDS-NE group (0 vs 11.9%, P=0.048 and 2.4% vs 15.1%, P=0.053, respectively). Among patients with TP53 mutations, the frequencies of complex karyotypes and multi-hit TP53 mutations were significantly higher in the MDS-E group than in the MDS-NE group (87.5% vs 64.6%, P=0.003 and 84.0% vs 54.2%, P<0.001, respectively). Survival analysis of patients with MDS-RS found that the overall survival (OS) in the MDS-E group was better than that in the MDS-NE group [not reached vs 63 (95% CI 53.3-72.7) months, P=0.029]. Among patients with TP53 mutations and excess blasts, the OS in the MDS-E group was worse than that in the MDS-NE group [6 (95% CI 2.2-9.8) months vs 12 (95% CI 8.9-15.1) months, P=0.022]. Multivariate analysis showed that age of ≥65 years (HR=2.47, 95% CI 1.43-4.26, P=0.001), mean corpuscular volume (MCV) of ≤100 fl (HR=2.62, 95% CI 1.54-4.47, P<0.001), and TP53 mutation (HR=2.31, 95% CI 1.29-4.12, P=0.005) were poor prognostic factors independent of the Revised International Prognostic Scoring System (IPSS-R) prognosis stratification in patients with MDS-E. Conclusion: Among patients with MDS-RS, MDS-E was strongly associated with a lower proportion of complex karyotypes and TP53 mutations, and the OS in the MDS-E group was longer than that in the MDS-NE group. Among patients with TP53 mutations, MDS-E was strongly associated with complex karyotypes and multi-hit TP53 mutations, and among TP53-mutated patients with excess blasts, the OS in the MDS-E group was shorter than that in the MDS-NE group. Age of ≥65 years, MCV of ≤100 fl, and TP53 mutation were independent adverse prognostic factors affecting OS in patients with MDS-E.

The Histopathology of Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic Syndrome: Report of 12 Skin Biopsies From 6 Patients.

ABSTRACT: We present the histopathology of 12 skin biopsies from 6 patients with vacuoles, enzyme E1, X-linked, autoinflammatory, somatic syndrome and review the literature. The age of these 6 men ranges from 62 to 83 years (median of 70 years). UBA1 mutation was documented in all 6 patients. Multiple organ systems were involved with constitutional symptoms noted in 4 of 6 patients (67%), cutaneous involvement in 6 of 6 patients (100%), hematologic abnormalities in 6 of 6 patients (100%), pulmonary involvement in 4 of 6 patients (67%), musculoskeletal abnormalities in 3 of 6 patients (50%), vascular thrombosis in 2 of 6 patients (33%), ocular involvement in 2 of 6 patients (33%), and gastrointestinal involvement in 5 of 6 patients (83%). Of the 6 presented patients, neutrophilic dermatosis was seen in 3 biopsies, histiocytoid neutrophilic dermatosis in 1 biopsy, neutrophilic dermatosis with vasculitis in 1 biopsy, neutrophilic and granulomatous dermatitis in 2 biopsies, septal panniculitis consistent with erythema nodosum in 2 biopsies, and nonspecific patterns in 3 biopsies. In summary, neutrophilic dermatosis, small-vessel vasculitis, and panniculitis are frequent histopathologic patterns noted in decreasing frequency in skin biopsies of the patients with vacuoles, enzyme E1, X-linked, autoinflammatory, somatic syndrome. However, the histopathologic findings can be diverse, nonspecific in some instances, and varied among different biopsies obtained from the same patient.

Anti-synthetase and myelodysplastic syndromes with deep morphea: an example of shared immunopathogenesis? A case-based review.

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient.

Molecular pathophysiology of germline mutations in acute myeloid leukemia.

Germline (GL) predisposition to acute myeloid leukemia (AML) has been established as an independent disease entity in the latest World Health Organization classification. Following the American College of Medical Genetics and Genomics guidelines, GL variants were interpreted as causal if they were classified as "pathogenic." GL predisposition can be divided into three groups with different phenotypes, and play an important role in the pathogenesis of adult-onset AML. The clinical course and age of onset of myeloid neoplasms varied considerably for each gene. For example, patients with GATA2 GL variants develop AML before the age of 30 along with bone marrow failure, whereas those with DDX41 GL variants tend to develop AML after the age of 50 without any preceding hematological abnormalities or organ dysfunction. A comprehensive analysis of adult-onset myelodysplastic syndromes in transplant donors showed a 7% frequency of pathogenic GL variants, with DDX41 being the most frequent gene mutation at approximately 3.8%. Future research on GL predisposition at any age of myeloid neoplasm onset will assist in early and accurate diagnosis, development of effective treatment strategies, and selection of suitable donors for stem cell transplantation.

Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications.

Two new diagnostic classifications of acute myeloid leukemia (AML) were published in 2022 to update current knowledge on disease biology. In previous 2017-edition categories of AML with myelodysplasia-related changes, AML was not otherwise specified, but AML with mutated RUNX1 experienced profound changes. We performed whole exome sequencing on a cohort of 69 patients with cytogenetic intermediate-risk AML that belonged to these diagnostic categories to correlate their mutational pattern and copy-number alterations with their new diagnostic distribution. Our results show that 45% of patients changed their diagnostic category, being AML myelodysplasia-related the most enlarged, mainly due to a high frequency of myelodysplasia-related mutations (58% of patients). These showed a good correlation with multilineage dysplasia and/or myelodysplastic syndrome history, but at the same time, 21% of de novo patients without dysplasia also presented them. RUNX1 was the most frequently mutated gene, with a high co-occurrence rate with other myelodysplasia-related mutations. We found a high prevalence of copy-neutral loss of heterozygosity, frequently inducing a homozygous state in particular mutated genes. Mild differences in current classifications explain the diagnostic disparity in 10% of patients, claiming a forthcoming unified classification.

TRANSFORMATION OF MYELODYSPLASTIC SYNDROME INTO ACUTE MYELOBLASTIC LEUKEMIA (CLINICAL CASE).

Despite the availability of modern methods for diagnosing and treating myelodysplastic syndrome (MDS) in the arsenal of a hematologist, even with an adequate treatment strategy, it is not always possible to predict the timing of transformation of the disease into acute myeloid leukemia. The clinical case we presented demonstrates the rapid transformation of MDS into acute myeloid leukemia in a relatively young patient whose prognosis turned out to be poorly predictable despite a change in therapy.

Clonal hematopoiesis: malignant implications, extrahematologic manifestations, and management.

As individuals age, their hematopoietic stem cells can sporadically acquire genetic mutations, known as clonal hematopoiesis. Although most of these genomic aberrations are of little consequence, particular changes in certain contexts can lead to the development of hematologic malignancies, such as myelodysplastic syndromes and acute myeloid leukemia. Owing to its pervasive extrahematologic interactions, clonal hematopoiesis is a recognized risk factor for and is causally implicated in the development of several chronic diseases of aging and/or inflammation, such as atherosclerotic cardiovascular disease. Here, we provide a review of the diagnosis and clinical implications of clonal hematopoiesis, as well as evolving management strategies in the absence of formal consensus guidelines.

Screening of Myelodysplastic Syndromes Using Research Parameters of Complete Blood Count: Automated Detection of Dysplasia.

Myelodysplastic syndromes (MDS) present with polymorphic and non-specific diagnostic features Research parametersfrom hematology analyzers may be useful to discriminate MDS-related cytopenia.Parameters such as Neu X (related to the cytoplasmic complexity) and Neu Y (related to nucleic acid content) show promise to detect dysplasia of MDS and aid to recognize MDS from cytopenias of other etiologies.

Myeloid sarcoma in JAK2-positive myelodysplastic neoplasms with fibrosis: a case report and literature review.

Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease.

[Clinical Characteristics and Prognosis of Myelodysplastic Syndromes Patients with RUNX1 Gene Mutation].

OBJECTIVE: To investigate the clinical characteristics and survival analysis of myelodysplastic syndromes (MDS) with RUNX1 gene mutation. METHODS: Clinical data of 177 newly diagnosed MDS patients admitted to the Department of Hematology, the Second Affiliated Hospital of Air Force Military Medical University from October 1, 2015 to October 31, 2022 were retrospectively analyzed. Gene mutation detection was performed by second-generation sequencing technology, and clinical characteristics and prognosis of patients with RUNX1 gene mutation were analyzed. RESULTS: A total of 30 cases (16.95%) of RUNX1 gene mutations were detected, including 15 missense mutations (50.0%), 9 frameshift deletion mutations (30.0%), 4 splice site mutations (13.3%), 1 insertion mutation (3.3%), and 1 nonsense mutation (3.3%). Patients with RUNX1 mutations had a median age of 68.5 years at diagnosis (range: 62.25-78.50 years old). There were no significantly differences between RUNX1 mutations and wild type patients in age distribution, gender, peripheral blood white blood cell count, hemoglobin level, bone marrow and peripheral blood blasts ratio, IPSS-R cytogenetics, IPSS-R stage, etc. (P >0.05). However, there were statistically significant differences in platelet count and whether complicated karyotype. Compared with patients without RUNX1 gene mutation, patients with RUNX1 gene mutation had lower platelet count (P =0.018), and were less likely to have complicatedkaryotype at initial diagnosis (P =0.01). Cox proportional hazards model analysis showed that when other covariates remained unchanged, the higher the platelet count, the better the survival of patients (HR=0.995, 95%CI : 0.990-0.999, P =0.036); In the IPSS-M prognostic stratification, keeping other covariates unchanged, the risk of progression or death of myelodysplastic syndrome was significantly lower in the medium to high-risk and low-risk groups compared with the high-risk group (HR=0.149, 95%CI : 0.031-0.721, P =0.018; HR=0.026, 95%CI : 0.003-0.234, P =0.001). Survival analysis showed that MDS patients with RUNX1 gene mutation had worse overall survival time (P < 0.001). Patients with RUNX1 mutation had worse OS than non-mutation patients in the early WHO group. RUNX1 mutation and IPSS-M risk stratification mean OS and mean LFS were worse in low-risk patients than in non-mutated patients. CONCLUSION: RUNX1 gene mutation is an adverse prognostic factor in MDS patients, especially in the IPSS-M prognosis stratification group of low-risk, medium-low risk, medium-high risk and WHO classification of early patients.

Myelodysplasia cutis and VEXAS syndrome initially diagnosed as histiocytoid Sweet syndrome: A diagnostic pitfall.

Histiocytoid Sweet syndrome (H-SS) is a histopathological variant of Sweet syndrome (SS) defined by cutaneous infiltration of immature myeloid cells morphologically resembling histiocytes. The association of H-SS with underlying malignancy, particularly myelodysplastic syndromes, is well-established. Myelodysplasia cutis (MDS-cutis) has been proposed to describe cases historically diagnosed as H-SS but characterized by shared clonality of the myeloid infiltrate in skin and bone marrow. Therefore, identifying patients who might have MDS-cutis is critical for the management of the associated hematologic malignancy. VEXAS syndrome, an adult-onset autoinflammatory disease, should also be included in the histopathologic differential diagnosis of H-SS, as it shares clinical and pathologic features with MDS-cutis. Through the presentation of two cases, we aim to highlight the defining features and key clinical implications of MDS-cutis and VEXAS syndrome.

Update on Recommendations for Surveillance for Children with Predisposition to Hematopoietic Malignancy.

Children harboring certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in children with other HM. For some hematopoietic malignancy predispositions (HMP), specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by a hematopoietic stem cell transplantation specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions.

Flow cytometry in the differential diagnosis of myelodysplastic neoplasm with low blasts and cytopenia of other causes.

Background: Myelodysplastic neoplasms (MDS) are characterized by cytopenia, morphologic dysplasia, and genetic abnormalities. Multiparameter flow cytometry (FCM) is recommended in the diagnostic work-up of suspected MDS, but alone is not sufficient to establish the diagnosis. Our aim was to investigate the diagnostic power of FCM in a heterogeneous population of patients with cytopenia, excluding cases with increased blast count. Methods: We analyzed bone marrow samples from 179 patients with cytopenia (58 MDS, 121 non-MDS) using a standardized 8-color FCM method. We evaluated the sensitivity, specificity, and accuracy of several simple diagnostic approaches, including Ogata score, extended Ogata score, the WHO and ELN iMDSFlow recommended "3 aberrations in two cell compartments method," and the combination of the Ogata score and "3 aberrations in two cell compartments method." The patients were followed until the diagnosis was confirmed, with a median follow-up of 2 months (range 0.2-27). Results: The combination of Ogata score and "3 aberrations in two cell compartments method" achieved the highest diagnostic accuracy (78%) with sensitivity and specificity 61% and 86%, respectively. When using only the "3 aberrations in two cell compartments method," the accuracy was 77% with a sensitivity of 72% and a specificity of 79%. The most frequently observed etiologies among the false positive cases were substrate deficiencies, inflammation/infection, or toxic effects. MDS can be excluded in all these cases after a thorough clinical evaluation and a relatively short follow-up. Conclusion: FCM remains an important but supplementary part in an integrated diagnostic process of MDS with low blasts. The combination of the Ogata score and the "3 aberrations in two cell compartments method" slightly improves accuracy compared to the detection of "3 aberrations in two cell compartments method" alone.