Hypoplastic Myelodysplastic Syndrome Research Articles

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms.

Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome are paradigms of autoimmune hematopoietic failure (AHF). Myelodysplastic syndrome and acute myeloid leukemia are unequivocal myeloid neoplasms (MNs). Currently, AA is also known to be a clonal hematological disease. Genetic aberrations typically observed in MNs are detected in approximately one-third of AA patients. In AA patients harboring MN-related genetic aberrations, a poor response to immunosuppressive therapy (IST) and an increased risk of transformation to MNs occurring either naturally or after IST are predicted. Approximately 10%-15% of patients with severe AA transform the disease phenotype to MNs following IST, and in some patients, leukemic transformation emerges during or shortly after IST. Phenotypic transformations between AHF and MNs can occur reciprocally. A fraction of advanced MN patients experience an aplastic crisis during which leukemic blasts are repressed. The switch that shapes the disease phenotype is a change in the strength of extramedullary inflammation. Both AHF and MNs have an immune-active bone marrow (BM) environment (BME). In AHF patients, an inflamed BME can be evoked by infiltrated immune cells targeting neoplastic molecules, which contributes to the BM-specific autoimmune impairment. Autoimmune responses in AHF may represent an antileukemic mechanism, and inflammatory stressors strengthen antileukemic immunity, at least in a significant proportion of patients who have MN-related genetic aberrations. During active inflammatory episodes, normal and leukemic hematopoieses are suppressed, which leads to the occurrence of aplastic cytopenia and leukemic cell regression. The successful treatment of underlying infections mitigates inflammatory stress-related antileukemic activities and promotes the penetration of leukemic hematopoiesis. The effect of IST is similar to that of treating underlying infections. Investigating inflammatory stress-powered antileukemic immunity is highly important in theoretical studies and clinical practice, especially given the wide application of immune-activating agents and immune checkpoint inhibitors in the treatment of hematological neoplasms.

Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

Overall Survival and Erythroid Response in Patients with Low-Risk Myelodysplastic Neoplasms after First-Line Treatment in a Low-Middle Income Country

Introduction Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of clonal disorders characterized by ineffective hematopoiesis and an increased risk of transformation to acute myeloid leukemia (AML). Current standard risk stratification model, the Revised International Prognostic Scoring System (IPSS-R), classifies patients into lower (≤3.5 points) or higher risk MDS. Lower-risk MDS (LR-MDS) treatment is based on the prevailing cytopenia and intends to improve symptomatic burden and minimize transfusion dependency. Anemia is present in 80-90% of patients with MDS. Throughout most of the course of the disease, patients with MDS have a hemoglobin < 10 g/dL, which leads to a decreased quality of life. Also, 50% of patients with MDS will eventually need red blood cell transfusions. Current options for the active treatment of anemia in LR-MDS are limited and vary among countries. Although erythropoiesis stimulating agents (ESAs) are considered standard of care in the absence of del5q, immunosuppressive therapy (IST) and androgens are still used in low income countries. The present study aims to evaluate whether erythroid responses and overall survival differ in patients with LR-MDS, based on their first-line treatment. Methods This is a retrospective study in patients with LR-MDS at Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, a tertiary care center in Mexico City. Eligible patients were diagnosed between January 2002 and December 2022 according to World Health Organization (WHO) 2016 criteria. Response was assessed according to International Working Group (IWG) 2018 criteria. We defined erythroid response (HI-E) as the sum of the responses achieved within different transfusion burden categories. First line therapy included ESAs, IST (cyclosporine ± eltrombopag), and androgens (mesterolone, danazol). These were compared through bivariate analysis, Kaplan-Meier curves and log-rank test. Results Until December 2022, 109 LR-MDS patients were considered for inclusion. Among them, 29 patients were lost to follow-up, and 25 patients were solely observed without any further therapy. Also, 7 patients who received other therapies were excluded. Ultimately, 48 patients were included in this analysis, 56.3% (n=27) were female, mean age was 62.8 (±15.9) years. Based on WHO 2016 classification, MDS with uni- and multilineage dysplasia was present in 58.3% (n=28) of the patients, while 29.2% (n=14) had hypoplastic MDS. Anemia was present in 89.6% (n=43) of the patients. When evaluating transfusion burden, 37.5% (n=18) of patients were non-transfusion dependent (NTD), 31.3% (n=15) low-transfusion burden (LTB), and another 31.3% (n=15) high-transfusion burden (HTB). ESAs and IST were the most frequently used frontline therapies, each accounting for 41.7% (n=20) of the patients; the remaining 16% (n= 8) received androgens. When comparing baseline characteristics between treatment arms, we found lower hemoglobin values and a greater proportion of severe anemia in ESA-treated patients (p= 0.039, p= 0.036), however, no differences in transfusion burden was observed (p= 0.212). Erythroid response rates were 25% (n=5), 20% (n=4) and 62.5% (n=5) among those treated with ESAs, IST and androgens, respectively (p= 0.071). When assessing HI-E by transfusion burden, no differences were observed between treatment arms except in HTB patients (p= 0.023). Neither time to response, nor duration of response were significantly different between treatment groups ( Table 1). Importantly, 3 of the 4 responders in the IST group received cyclosporine monotherapy, also 50% were hypoplastic MDS. After a median follow up of 47 months (IQR:22.5-85.5), the median overall survival(OS) for the entire cohort was not reached. The 3-year-OS rates for IST, ESA and androgens were 94%, 54% and 50%, respectively (p= 0.018) ( Figure 1). Conclusions In spite of the bias and limitations in the retrospective nature of this study, IST seems to be a valid option in frontline therapy for LR-MDS, since HI-E rates are similar to those observed with ESAs. Additionally, IST group showed a better OS. Results obtained with androgens merit further study and should be interpreted with caution because of the sample size.

Chronic neutrophilic leukemia preceded by myelodysplastic syndromes.

Chronic neutrophilic leukemia (CNL) is primarily diagnosed by excluding myelodysplastic syndromes (MDS). We report the case of a patient who developed secondary CNL 3years after hypoplastic MDS. We used droplet digital polymerase chain reaction mutation detection assay to analyze genomic alterations during the progression from MDS to CNL. At the time of MDS diagnosis, U2AF1 Q157P and SETBP1 D868N were dominant and additional mutation of ASXL1 1934_insG was observed. CSF3R T618I and SETBP1 D868N were increasing at the time of CNL diagnosis. We revealed the accumulation of multiple gene mutations during CNL development from MDS. This suggests that CNL was clonally developed from the founding clone of MDS and CSF3R mutation contributes to the development of CNL in the present case. These findings provide insights into the pathology of CNL.

Hypoplastic form of myelodysplastic neoplasm.

Hypoplastic myelodysplastic neoplasm (MDS-h) is a rare hematopoietic disorder characterized by peripheral cytopenia, hypoplasia (cellularity ≤ 25%) and dysplastic changes in the bone marrow. Compared to normo- /hypercellular MDS, in addition to hypocellularity, MDS-h patients have more profound neutropenia and thrombocytopenia, a lower percentage of blasts, and less frequent abnormal karyotype. It is difficult to distinguish MDS-h from aplastic anemia in differential diagnosis. Abnormal karyotype is found in 15-50% of MDS-h patients and the most common chromosomal aberrations include -5/del (5q), -7/del (7q), +8, 17pLOH, del (20q), UPD at 4q, 11q, 13q, and 14q. Approximately 35% of MDS-h patients harbour somatic mutations that are most often detected in PIGA, TET2, DNMT3A, RUNX1, NPM1, ASXL1, STAG2, and APC genes. An autoimmune destruction of hematopoietic stem cells (HSCs) or hematopoietic progenitor cells (HPCs) mediated by abnormally activated T cells plays a key role in the pathophysiology of MDS-h. Expanded T cells overproduce proinflammatory cytokines (IFN- g and TNF-a), which inhibit proliferation and induce apoptosis of HSC/HPCs. The antigens that trigger the immune response are not known, but potential candidates have been suggested such as WT1 protein and HLA class I molecules. MDS-h does not represent a phenotypically homogeneous subtype of MDS, but rather it is a mixed entity comprising both patients showing features similar to myelodysplastic neoplasm and patients with features of non-malignant bone marrow failure. Determining the prevailing phenotype in MDS-h is important for choosing the optimal treatment and prognosis prediction. The aim of this article is to point out an interesting hypoplastic MDS, the diagnosis of which is difficult, and to provide an overview of its main clinical-pathological features, genetic background, and mechanisms of aberrant immune response.

Assessment and validation of the molecular international prognostic scoring system for myelodysplastic syndromes.

The Molecular International Prognostic Scoring System (IPSS-M) is a novel risk stratification model for myelodysplastic syndromes (MDS) that builds on the IPSS and IPSS-R by incorporating mutational data. The model showed improved prognostic accuracy over the IPSS-R across three endpoints: overall survival (OS), leukemia-free survival (LFS) and leukemic transformation. This study aimed to validate the findings of the original in a large cohort of MDS patients, as well as assess its validity in therapy-related and hypoplastic MDS. We retrospectively reviewed clinical, cytogenetic and molecular data for 2355 MDS patients treated at the Moffitt Cancer Center. Correlative analysis between IPSS-R and mean IPSS-M scores and outcome predictions was performed on LFS, OS and leukemic transformation. Using the IPSS-M, patients were classified as Very Low (4%), Low (24%), Moderate-Low (14%), Moderate-High (11%), High (19%) and Very-High risk (28%). Median OS was 11.7, 7.1, 4.4, 3.1, 2.3, and 1.3 years from VL to VH risk subgroups. Median LFS was 12.3, 6.9, 3.6, 2.2, 1.4, and 0.5 years respectively. For patients with t-MDS and h-MDS the model retained its prognostic accuracy. Generalized use of this tool will likely result in more accurate prognostic assessment and optimize therapeutic decision-making in MDS.

SOHO State of the Art Updates and Next Questions: Treatment of Lower Risk Myelodysplastic Syndromes.

MDS is a clonal stem cell neoplasm with a spectrum from lower risk disease to short term life threatening higher risk disease. The disease risk is dictated by clinical and molecular features. Majority of MDS patients including lower risk disease unfortunately succumb from disease related complications namely cytopenia. While cytopenias may be mild early upon diagnosis and can be surveilled, ultimately treatment is required. Anemia is the hall mark of disease and most common indication to treat in lower risk MDS. Erythroid stimulating agents are used in the first line setting. Treatment can be a personalized approach as in select patient such as patients with del(5q) and those with ringed sideroblasts, lenalidomide, and luspatercept can be extremely effective respectively at improving cytopenias. Younger patients and hypoplastic MDS have also shown and improved response to immunosuppressive therapy. Hypomethylating agents can be option for patients with higher risk features or thrombocytopenia/neutropenia. Refractory cytopenias still poses frustration as options are limited and there is need to add more treatments to our armamentarium.

Deciphering Hypoplastic Myelodysplastic Syndrome and Aplastic Anemia via In-Depth Analysis of Lymphocyte Subsets

To explore the difference of lymphocyte subsets in peripheral blood (PB) between aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (hypo-MDS) patients, meanwhile to compare the clinical parameters obtained from PB and bone marrow (BM). The lymphocyte subsets in hypo-MDS (n=25) and AA (n=33) patients were investigated by flow cytometry. Meanwhile, the differences in PB cell counts, biochemical indicators, BM cell counts and abnormal chromosomes between the two groups were analyzed. The percentage of CD8+T cells in AA group was significantly higher than that in hypo-MDS group (P=0.001), while the percentage of CD4+ T cells and the CD4+/CD8+ ratio in AA group were obviously lower than those in hypo-MDS group (P=0.015 and 0.001, respectively). Furthermore, the proportion of CD4+ and CD8+ activated T (TA) cells, and memory Tregs in AA group was distinctly lower than those in hypo-MDS group (P=0.043, 0.015 and 0.024, respectively). Nevertheless, the percentage of CD8+ naive T (TN) cells in AA patients was remarkably higher (P=0.044). And hypo-MDS patients had declined lymphocyte counts (P=0.025), increased levels of total bilirubin (TBil), lactate dehydrogenase (LDH), vitamin B12 and proportion of BM blasts than AA patients (P=0.019, 0.023, 0.027 and 0.045, respectively). In this study it was confirmed that the percentages of CD4+ and CD8+ TA cells, memory Tregs and CD8+ TN cells were significantly different between AA and hypo-MDS patients, which provide an essential basis for the identification of these two diseases.

Clinical significance of clonal hematopoiesis and disease boundaries in bone marrow failure diseases

Aplastic anemia (AA) is a non-neoplastic bone marrow failure syndrome caused by the destruction of hematopoietic stem and progenitor cells by the immune system. However, in some cases of AA, a small number of specific clones with gene mutations are observed without clinical manifestations. Cases with mutated PIG-A, BCOR/BCORL1, or HLA class I allele clones respond better to immunosuppressive therapies (ISTs). Cases with MDS-related clones, such as DNMT3A or ASXL1 mutations, are at a higher risk for secondary MDS. In this review, I will focus on the clonal hematopoiesis (CH) in AA and discuss its clinical significance, including its impact on disease boundaries and transition. I will also discuss the pathophysiology and diagnosis of hypoplastic MDS, a type of MDS that responds to ISTs.

Hypoplastic MDS: Validation of the New World Health Organization 2022 Proposal

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic neoplasms that is characterized by ineffective hematopoiesis. The morphological diagnosis is essential and reveals a subset of patients with hypoplastic marrow, referred to as hypoplastic MDS (MDS-h) that is more recently being proposed as a distinct entity in the World Health Organization (WHO) 2022 proposal for myeloid neoplasms. MDS-h shares several features with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH), thus, it needs a careful diagnostic approach, but also, the natural history of the disease is distinct than those with non-hypoplastic MDS (MDS-nh) warranting consideration for further subclassification. Here, we aim to study the characteristics and molecular profiling of MDS-h as opposed to the (MDS-nh), in addition to treatment and disease outcomes, and overall survival. Methods: We conducted a retrospective analysis of all patients diagnosed with MDS at the H. Lee Moffitt Cancer Center & Research Institute from our MDS database. Patients were divided into two groups: those with MDS-h, defined as bone marrow cellularity of less than 30%, and those with MDS-nh, with cellularity greater than 30%. We further subdivided patients based on the marrow blasts (<5% vs >=5%). Patients with MDS/MPN were excluded. Results: A total of 4037 patients with MDS were identified, of those, 403 (10%) were MDS-h. The median age at diagnosis was 65 and 68 for MDS-h and MDS-nh respectively (P= 0.03). In females, MDS-h was observed more compared to MDS-nh (41% vs 35%, P= 0.008). There was no difference in terms of IPSS-R, LGL clones, PNH clones, and history of autoimmune diseases. MDS-RS was more observed in MDS-nh. Interestingly, therapy-related MDS (t-MDS) was more observed in MDS-h (29% vs 20%, P <0.005). Patients with MDS-h had more thrombocytopenia, neutropenia and were more likely to be platelet transfusion dependent (31% vs 23% P=0.001). The following somatic mutations were found more frequently in MDS-nh compared to MDS-h: SF3B1 (P<0.005), SRSF2 (P<0.005), TET2 (P=0.004), and ASXL1 (P=0.02). There was a better response to ATG/CSA among MDS-h compared to MDS-nh (46% vs 21% P=0.019). On the contrary patients with MDS-nh were more likely to respond to lenalidomide when compared to patients with MDS-h (46% vs 22% P=0.001). There was no statistically significant difference in response to hypomethylating agents. The median overall survival (OS) for MDS-h was 41.6 months compared to 35 months in patients with MDS-nh (P=0.05). The HR for OS was 0.88 (P =0.057) adjusted for IPSS-R. There was no difference in the rate of AML transformation. Then, we further categorized patients based on the marrow blasts. Among MDS-h, 43% (170/400) had myeloblasts >=5% (MDS-EB), The median OS was 53 months for MDS-h with < 5% blasts (n=231) compared to 27 months for those with >= 5% blasts (n=170) (P < 0.005). Among all patients with MDS-EB, those with MDS-h (n= 170) had median OS of 27 month compared to 19 months for MDS-EB with MDS-nh (n=1465) (P=0.02). Conclusions: In summary, we conclude that MDS-h accounted for 10% of MDS cases. The OS for MDS-h is better than MDS-nh. Additionally, MDS-h tended to have lower frequency of splicing and epigenetic somatic mutations. Among MDS-h, patients with marrow myeloblasts >=5% clearly had inferior outcomes compared to those MDS-h with blasts <5%. Therefore, our findings support the new WHO 2022 proposal for MDS-h as a distinct entity with restriction to patients with marrow cellularity of <30% and marrow myeloblasts <5%.

Assessment of the Molecular International Prognostic Scoring System (IPSS-M) Risk Stratification Model in Hypoplastic Myelodysplastic Syndromes

Assessment of the Molecular International Prognostic Scoring System (IPSS-M) Risk Stratification Model in Hypoplastic Myelodysplastic Syndromes

MDS Classification - Do We Still Have to Count Blasts?

Background: Since the definition of MDS their classification relied on cytomorphology determining dysplasia, cytopenia and blast count. The revised 4th edition of the WHO classification encompasses only one genetically defined entity (MDS with isolated del(5q)). In the 5th edition of the WHO classification 2 additional entities are defined by genetics: MDS with low blasts and SF3B1 mutation and MDS with biallelic TP53 inactivation. All other are classified still based on morphology into i) hypoplastic MDS, ii) MDS with low blasts and iii) MDS with increased blasts. Aim: As blast counting is subjective and the boundary between low and elevated blasts is arbitrary, we set out to propose a classification for MDS based solely on genetic abnormalities obviating the need for blast counting. Patients and Methods: The cohort comprised 735 de novo MDS. The diagnosis was established following WHO classifications. In all cases chromosome banding analysis and WGS (100x, 2x151bp, NovaSeq) were performed. Variants were called with Strelka2, Manta and GATK using a tumor w/o normal pipeline. For all cases overall survival data was available (median follow-up: 9.3 years). Results: We categorized our cohort 1) according to WHO revised 4th edition, 2) 5th edition, 3) according to blast count (<5%, 5 to <10%, 10 to <20%), and 4) according to numbers of mutations. For all 4 categorizations prognostic differences between subgroups was confirmed. Next, we performed cluster analyses to identify genetic abnormalities associated with blast count. While SF3B1 mutations and isolated del(5q) were associated with low blast count, mutations in ASXL1 and RUNX1 were associated with higher blast count (for all p<0.0001). Further, we evaluated the genomic landscape for associations of genetic parameters. RUNX1 mutations and ASXL1 mutations were highly associated with spliceosome mutations. 49/62 (79%) RUNX1mut MDS and 97/153 (63%) ASXL1mut MDS harbored also spliceosome mutations. On the other hand RUNX1mut, ASXL1mut and spliceosome mutations rarely co-occurred with biallelic TP53 inactivation or complex karyotype (only 5/41 cases and 19/78 cases). 102/735 (14%) cases harbored neither a del(5q), a complex karyotype, biallelic TP53 inactivation nor a mutation in SF3B1, SRSF2, U2AF1, ZRSR2, DNMT3A, TET2, RUNX1 or ASXL1. In 20 of these at least one mutation was found in 21 additional genes known to be mutated in MDS. Based on these data 9 genetically defined non-overlapping hierarchical subgroups (definitions of the respective prior subgroups are exclusion criteria for the following ones) are proposed: 1. biallelic TP53 inactivation 2. complex karyotype, 3. RUNX1 mutated, 4. ASXL1 mutated, 5. del(5q), 6. SF3B1 mutated, 7. mutated DNMT3A, TET2, U2AF1, SRSF2, and/or ZRSR2, 8. presence of at least one mutation in one of 21 other genes recurrently mutated in MDS, 9. none of the genetic markers present that define any of the previous entities. Survival analyses revealed marked differences between these biologically defined entities (figure 1). In univariate cox regression analyses including all 9 genetic categories and blast count the categories biallelic TP53 inactivation, complex karyotype, RUNX1mut, ASXL1mut, SF3B1mut, none of the genetic markers and blast count <5% vs ≥5% and <10% vs ≥10% were significantly associated with OS (for all p<0.002). In multivariate analyses both blast count cut offs did not show a significant impact, while the categories biallelic TP53 inactivation, complex karyotype, RUNX1mut, ASXL1mut, SF3B1mut were independently associated with OS (for all p<0.05). In figure 2 the relationship of classification according to the 4th revised, the 5th edition of the WHO and the purely genetically based classification as proposed here is depicted. Conclusions: Based on karyotype and mutation status of 9 genes complemented by 21 genes in 10-15% of cases, MDS can be separated into 9 biologically distinct subgroups, reflecting biology better than blast counts. These are associated with significant differences in overall survival. RUNX1 and ASXL1 define distinct subgroups within spliceosome mutated MDS potentially driving progression. Given the poor survival of the MDS subgroups with biallelic TP53 inactivation, complex karyotype and RUNX1 mutation it has to be further evaluated whether or not these MDS subtypes should be combined with AML harboring the respective genetic abnormalities for treatment approaches. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Myelodysplastic Syndromes in Latin-America - Results from a Novel International Registry: Re-Glam

Background: It is very well known that information provided by clinical records and organized system platforms (registries) offer a holistic view of MDS patients' characteristics and therapeutic aspects in real-life. The primary objective of this study was to analyze data from a novel MDS Latin-American Registry. Methods: The registry started in April 2022. From April to July, patients with MDS or CMML diagnosed since January 2014 were reported from Argentina, Brazil, Colombia, Mexico, and Uruguay. The Research Electronic Data Capture (REDCap) platform was used, consisting of 298 fields to describe patient demographics; their biological characteristics; clinical manifestations; comorbidities; laboratory features; bone marrow studies; risk classification; treatments, and outcomes. According to the Ethics Committee, all subjects had to sign an inform consent. Descriptive statistics were used to summarize demographic, and clinical data, as well as treatment characteristics - overall and by risk groups. Results: A total of 231 patients were included in this analysis. The mean age was 62.8 ± 16.9 years and the male to female ratio was 1.1:1. Baseline characteristics are described in Table 1. According to WHO's 2016 classification, the following categories were reported: MDS-SLD 4.4%; MDS-RS 1.3%; MDS-MLD 34.5%; MDS-RS-MLD 4.4%; MDS-EB 24.9%; MDS with isolated del(5q) 2.2%; unclassifiable MDS 0.4%; therapy-related MDS 7.0%; CMML 10.9%; MDS-U 1.3%; MDS/MPN-RS-T 0.4%; aCML 0.4%; other 7.9%. The IPSS-R was: 3.4% Very Low; 62.3% Low; 17.9% Intermediate; 10.1% high-risk; and 6.3% very high-risk. The majority of patients had de novo MDS (95.2%), and 8.6% had hypoplastic MDS. The mean BM blast count was 3.5±4.3%. Iron staining was performed in 28.1%. BM biopsies were performed at the moment of diagnosis in 77.5% of cases, reported as hypercellular in 90.0% of them and with fibrosis (> grade 1) in 32%. Immunohistochemistry was performed in 53.7% and flow cytometry in 47.8% of patients. Cytogenetics was performed in 93.9% and FISH in 26.9%. Abnormal karyotype was detected in 38.2%. An NGS panel was performed in 35 (15.2%) patients. Low-risk MDS accounts for the majority of patients in our registry (58%). Erythropoietin was given in 73 (69.5%) and growth factor therapy in 13 (11%) patients. Red blood cell transfusion was given to 59 (50%) patients. 31 (26%) of them received second-line treatment: 29 with HMA, and 2 with lenalidomide. 5 (4.2%) underwent allogenic transplant. 16 (13.7%) progressed to AML. The median overall survival was 4.19 (2.7-6.40) years. High-risk MDS was reported in 42% of patients. Regarding treatment, 69 (80.2%) received HMA (AZA=65 and DEC=4), 4 (4.6%) chemotherapy, and 8 (9.3%) of them were administered a venetoclax-based therapy. Fifteen (17.4%) were transplanted and 46 (53.4%) progressed to AML. The median overall survival was 1.5 (1.2-2.0) years. Conclusions: This novel and international registry showed preliminary MDS data from Latin-America. Our results revealed younger age at diagnosis, high number of patients undergoing allogenic transplant and OS according to literature. The expansion of this registry certainly improves our clinical practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

PSAT341 Hashimoto's Thyroiditis After Allogenic Bone Marrow Transplantation

Abstract Introduction Hashimoto's thyroiditis or chronic lymphocytic thyroiditis is a common autoimmune-mediated thyroid disease triggered by an inappropriate T and B cells response. We present a case of a female without personal or family history of autoimmune disease, who developed Hashimoto's thyroiditis with severe hypothyroidism after undergoing bone marrow transplant (BMT). Clinical Case A 57-year-old woman with hypoplastic myelodysplastic syndrome (MDS) was initially started on immunosuppressive therapy, complicated by autoimmune hemolytic anemia and thrombocytopenia. Three years after diagnosis, she underwent allogenic BMT from a matched unrelated donor. A year later, she presented with weight gain, fatigue, cold intolerance, insomnia, eye puffiness and lower extremity weakness, developed over a month. Exam was notable for periorbital edema and delayed DTRs. Laboratory workup revealed an elevated TSH at 302 µIU/mL (0.27-4.2) with undetectable free T4 and total T4 levels and elevated anti-thyroglobulin antibodies of 2698 IU/mL (0-40) and antiTPO antibodies of 90 IU/mL (0-35). Cortisol was normal at 14 µg/dL. TSH was normal prior to the BMT. Thyroid ultrasound revealed a normal-sized thyroid with a slightly heterogeneous echotexture, suggestive of thyroiditis without distinct nodules. Myxedema coma was ruled out at the time of diagnosis. The patient was started on levothyroxine and noticed a significant improvement of her symptoms within few weeks. Our patient does not have a personal or family history of thyroid disease or other autoimmune disorders. She did not receive radiation treatment or steroid treatment prior to her hypothyroidism diagnosis. She had an RSV upper respiratory infection two months prior to the diagnosis of hypothyroidism without associated neck pain. The clinical and biochemical picture suggest that her hypothyroidism could be related to her allogenic BMT. The presumed mechanism for the autoimmune thyroid dysfunction noted in this patient is the transfer of autoantibodies and donor lymphocytes during BMT. Conclusion Adoptive autoimmune hypothyroidism can occur post-BMT, especially if the donor has genetic susceptibility. It is now accepted that autoimmune thyroiditis can be transferred from donors to recipients during BMT. Reference Buxbaum NP, Pavletic SZ. Autoimmunity Following Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol. 2020 Aug 25;11: 2017. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

MDS-504 Mutation Profiling and Characteristics of Hypoplastic MDS

Myelodysplastic syndromes (MDS) are heterogenous spectrum of myeloid neoplasms. A subset of patients with MDS have hypoplastic marrow (h-MDS) and is being recognized more as a separate entity in the upcoming 2022 WHO classification. We aim to study characteristics and the molecular profiling of hypoplastic (h-MDS) in comparison with normo-/hypercellular MDS (n-MDS). This was a retrospective analysis of all patients diagnosed with MDS from Moffitt Cancer Center MDS database. Patients were divided into two groups: those with h-MDS, defined as cellularity less than 30%, and those with n-MDS, cellularity greater than 30%. Individuals with MDS/MPN were excluded. A total 4037 patient with MDS were identified, 403 (10%) were h-MDS. The median age at diagnosis was 65 and 68 for h-MDS and n-MDS respectively (P=0.03); h-MDS was observed more in females compared to n-MDS (41% vs 35%, P=0.008). There was no difference in terms of IPSS-R, LGL PNH clones, and history of autoimmune diseases. MDS-RS was more observed in n-MDS. Interestingly, t-MDS was more observed in h-MDS (29% vs 20%, P<0.005). Patients with h-MDS had more thrombocytopenia, neutropenia and were more likely to be platelet transfusion dependent. The following somatic mutations were detected more frequently in n-MDS compared to h-MDS: SF3B1 (P<0.005), SRSF2 (P<0.005), TET2 (P=0.004), and ASXL1 (P=0.02). There was a better response to ATG/CSA among h-MDS 46% compared to 21% for n-MDS (P=0.019). On the contrary, patients with n-MDS were more likely to respond to lenalidomide 46% when compared to patients with h-MDS in which 22% responded (P=0.001). There was no statistically significant difference in response to hypomethylating agents. The median overall survival (OS) for h-MDS was 41.6 months compared to 35 months in patients with n-MDS (P=0.05). The HR for OS was 0.88 (P=0.057) adjusted for IPSS-R. There was no difference in rate of AML transformation. h-MDS accounted for 10% of MDS cases. The OS for h-MDS is better than n-MDS, which tended to have more frequency of splicing and epigenetic somatic mutations.

P834: REAL-WORLD EVIDENCE OF SAFETY AND EFFECTIVENESS OF ECULIZUMAB AND SWITCH TO RAVULIZUMAB IN A SWISS PATIENT POPULATION WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Background: Eculizumab (ECU) a complement component 5 (C5) inhibitor, is the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH). Ravulizumab (RAV) is engineered from ECU with the main advantage of having an extended 8-week (vs 2-week with ECU) dosing interval, which decreases treatment burden markedly. Hence, RAV is expected to become the new standard of care to treat PNH. In Switzerland, RAV was approved for PNH treatment in 2020. Aims: The objective of this study was to evaluate data from the PNH Swiss Soliris and Ultomiris Reimbursement Registry (SSURR) to assess key parameters for safety and effectiveness of ECU and to assess the adoption of RAV for PNH treatment by physicians under real-world conditions. Methods: The SSURR was designed in 2012 as a prospective, longitudinal, multi-center registry study in Switzerland. Patients were recruited and followed in 9 centers. Health-related data were collected at the first consultation (baseline) and during follow-up visits. In this report, results are based on data collected from 23 February 2012 to 30 September 2021. Data were summarized using descriptive analysis. Ethics approval was obtained. All participants provided written informed consent. Results: In total, 56 patients with a median age of 51 (range 20-84) years were enrolled in the Registry, 52% were female. For 42 patients, the 12-month follow-up (FU) was available: 39 patients on ECU and 3 on RAV (switched from ECU). Median FU was 27 (range 12-108) months. Hemoglobin (Hb) mean was 63 ± 47 g/L at baseline (n=41), and Hb mean was 105 ± 25 g/L (n=26) at the last visit. The lactate dehydrogenase (LDH) decreased from a mean 1457 ± 706 U/L (baseline, n=42) to 403 ± 212 U/L after 12 months FU (n=40; 65% of patients < 1.5 × upper limit of normal [ULN]), and was for 88% of the patients < 1.5 × ULN at their last visit (n=24). Thrombosis events (TE) were reported in 33% of patients prior to treatment start (n=42) and 3 (7%) had thrombosis during FU of which 2 patients had no prior history of TE. Within 12 months prior to treatment start, 21 patients (50%) received one or more red blood cell (RBC) transfusions. At 12 months of FU, 91% (n=42) were RBC transfusion-free. RBC transfusions remained reduced (82%; n=27 at last visit). After 12 months FU, 19% (n=8) of the patients had withdrawn from the registry due to allogenic bone marrow transplantation, low PNH clone size, transformation to hypoplastic MDS, and 5 non-disease related reasons. Eight patients from the 56 enrolled received RAV as initial treatment. They were all C5-inhibitor treatment-naïve with a mean LDH level of 1481 ± 1432 U/L at inclusion, which decreased to 230 ± 62 U/L at the 6-month visit (n=4; all below 1.5 × ULN). Of the 56 enrolled patients with PNH, 43% were switched from ECU to RAV. These patients (58% female) had a median age of 55 (range 26-85) years and 75% of them had LDH < 1.5 × ULN at their last LDH measurement on ECU before RAV administration. There were 7 patients with a 6-month FU after switching at which 6 of them had a LDH below 1.5 × ULN. Summary/Conclusion: The current analysis provides real world evidence for the safety and effectiveness of ECU in the Swiss PNH patient population, demonstrated by pronounced reduction in LDH, low need for RBC transfusion and stable hemoglobin as well as reduced occurrence of thrombosis. The fast adoption of RAV demonstrates RAV may likely become the new standard of care for patients with PNH. In time, more data will become available for safety and effectiveness of RAV under real-world conditions.

Exclusive diagnosis of aplastic anemia

As an independent disease, aplastic anemia (AA) has been recognized for more than a century. When AA is diagnosed, other non-AA bone marrow failures should be excluded. It is termed as exclusive diagnosis of AA. The exclusive diagnosis of AA is helplessly based on that there is no parameter by which AA can be sensitively and specifically diagnosed now. So further searching for the meaningful diagnostic parameters of AA should be carried on to establish a direct diagnostic protocol of this disease and make it possible to differentiate it clearly from other bone marrow failure disease such as congenenital bone marrow failure, hypoplastic myelodysplastic syndromes, AA-paroxysmal nocturnal hemoglobinuria syndromes, large granules lymphocyte leukemia, clonal cytopenia of undetermined significance, immunorelated pancytopenia, acute hemopoietic arresting and idiopathic cytopenia of undetermined significance. The new markers and technologies being helpful for distinguishing AA from other bone marrow failures should be used in diagnosing AA. Correct understanding and application of exclusive diagnosis is not only related to the correctness of diagnosis and treatment of excluded diseases, but also to the quality of AA diagnosis, treatment and research.

Hypoplastic myelodysplastic syndrome and acquired aplastic anemia: Immune‑mediated bone marrow failure syndromes (Review)

Hypoplastic myelodysplastic syndrome (hMDS) and aplastic anemia (AA) are rare hematopoietic disorders characterized by pancytopenia with hypoplastic bone marrow (BM). hMDS and idiopathic AA share overlapping clinicopathological features, making a diagnosis very difficult. The differential diagnosis is mainly based on the presence of dysgranulopoiesis, dysmegakaryocytopoiesis, an increased percentage of blasts, and abnormal karyotype, all favouring the diagnosis of hMDS. An accurate diagnosis has important clinical implications, as the prognosis and treatment can be quite different for these diseases. Patients with hMDS have a greater risk of neoplastic progression, a shorter survival time and a lower response to immunosuppressive therapy compared with patients with AA. There is compelling evidence that these distinct clinical entities share a common pathophysiology based on the damage of hematopoietic stem and progenitor cells (HSPCs) by cytotoxic T cells. Expanded T cells overproduce proinflammatory cytokines (interferon-γ and tumor necrosis factor-α), resulting in decreased proliferation and increased apoptosis of HSPCs. The antigens that trigger this abnormal immune response are not known, but potential candidates have been suggested, including Wilms tumor protein 1 and human leukocyte antigen class I molecules. Our understanding of the molecular pathogenesis of these BM failure syndromes has been improved by next-generation sequencing, which has enabled the identification of a large spectrum of mutations. It has also brought new challenges, such as the interpretation of variants of uncertain significance and clonal hematopoiesis of indeterminate potential. The present review discusses the main clinicopathological differences between hMDS and acquired AA, focuses on the molecular background and highlights the importance of molecular testing.

Inherited bone marrow failure presenting as hypoplastic myelodysplastic syndrome

Inherited bone marrow failure presenting as hypoplastic myelodysplastic syndrome

Real-World Outcomes with Immunosuppressive Therapy for Aplastic Anemia in Patients Treated at the University of Michigan

IntroductionAplastic anemia is a challenging disease to treat due to its rarity and severity. The current standard of care for severe and very severe aplastic anemia includes consideration of frontline allogeneic stem cell transplant (ASCT) in patients who are under 40 years of age and have an HLA-matched sibling. For patients who do not meet this criteria, immunosuppressive therapy (IST) consisting typically of horse antithymocyte-globulin (ATG) and cyclosporine (CsA) is considered, with recent data supporting the addition of eltrombopag. The main risks of IST are infusion reactions, serum sickness, kidney injury, and infection. While it is generally well tolerated in younger patients, older patients have historically been treated with transfusion support alone due to concerns for higher complications. Unfortunately, data to support clinical decisions regarding these concerns is limited, with small studies showing that reduced dosing or attenuated doses of ATG with or without CsA is safe and can be effective. At the University of Michigan, we have been treating older patients with attenuated doses of ATG +/- CsA since the late-2000s and have recently added eltrombopag to our standard of care. Herein, we present the results of our experience using IST to treat aplastic anemia, specifically presenting our outcomes in patients over 60 years old at the time of initiation of IST.MethodsWe used the Electronic Medical Record Search Engine (EMERSE) to query patients with aplastic anemia who were treated at the University of Michigan between 1995 and 2021. Patients included in our analysis were diagnosed with idiopathic aplastic anemia or hepatitis-associated aplastic anemia, were 18 years or older at the date of initiating IST, were treated with IST first-line, had adequate physician follow up at the University of Michigan, and were reported as being complaint with IST. Patients diagnosed or with high concern for hypoplastic myelodysplastic syndrome (MDS) were excluded in addition to those who received treatment for paroxysmal nocturnal hemoglobinuria (PNH). Statistical analysis was performed using SPSS Statistics v.27 (IBM, 2020).ResultsWe identified 62 patients aged 18 - 60 and 54 patients over 60 years old who met inclusion criteria. Descriptive statistics of the two cohorts are available in Table 1. All patients in our study received horse ATG in addition to cyclosporine. 63% of patients over 60 received full dose horse ATG (20mg/kg for 5 days) and 37% received attenuated horse ATG (20mg/kg for 5 days), while 46% received eltrombopag as part of their IST. OS was superior in patients 18-60 receiving IST with median OS NR vs. 2760 days (Figure 1; p=0.009). In patients over 60, no difference in OS was observed in those who received attenuated (3646 days) vs. full dose IST (2760 days) (Figure 2, p=0.83). Lastly, no difference in median OS was seen in patients > 60 years old who received eltrombopag compared to those who did not (2821 vs 2760 days, Figure 3, p=0.795).Using a Chi-squared test, no statistically significant differences in rates of PR at 12 months, CR at 12 months, primary refractory disease, febrile neutropenia within 6 months of IST, bacterial infections within 6 months IST, and viral infections within 6 months of IST were noted between those who received dose attenuated ATG and those who received full dose ATG in patients > 60. PR in older patients was 48% (12) and 36% (9) at 3 and 12 months with eltrombopag, compared to 40% (10) and 36% (9) without. CR in older patients was 12% (3) and 16% (4) with eltrombopag at 3 and 12 months, compared to 12% (3) and 12% (3) without. In patients > age 60 who received dose attenuated IST, the addition of eltrombopag did not affect OS (Figure 4). A trend toward better OS was seen in patients 18-60 who received eltrombopag, but this was not statistically significant (Figure 5).DiscussionIn conclusion, we present our experience using IST to treat aplastic anemia at the University of Michigan. Dose attenuated IST has been proposed as a potential option for elderly patients, but we found no significant difference in OS, rates of response, or rates of infection between patients who received full dose and those who did not. There was also a trend toward improved survival with the addition of eltrombopag in younger patients, but additional follow up time is needed. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.