Myelodysplastic neoplasms (MDS) with ring sideroblasts (RS) are diagnosed via bone marrow aspiration in the presence of either (i) ≥15% RS or (ii) 5-14% RS and an SF3B1 mutation. In the MEDALIST trial and in an interim analysis of the COMMANDS trial, lower-risk MDS-RS patients had decreased transfusion dependency with luspatercept treatment. A total of 6817 patients with suspected hematologic malignancies underwent molecular testing using a next-generation-sequencing-based genetic assay and 395 MDS patients, seen at our centre from 1 January 2018 to 31 May 2023, were reviewed. Of these, we identified 39 evaluable patients as having lower-risk MDS with SF3B1 mutations: there were 20 (51.3%) males and 19 (48.7%) females, with a median age of 77 years (range of 57 to 92). Nineteen (48.7%) patients had an isolated SF3B1 mutation with a mean variant allele frequency of 35.2% +/- 8.1%, ranging from 7.4% to 46.0%. There were 29 (74.4%) patients with ≥15% RS, 6 (15.4%) with 5 to 14% RS, one (2.6%) with 1% RS, and 3 (7.7%) with no RS. Our study suggests that a quarter of patients would be missed based on the morphologic criterion of only using RS greater than 15% and supports the revised 2022 definitions of the World Health Organization (WHO) and International Consensus Classification (ICC), which shift toward molecularly defined subtypes of MDS and appropriate testing.

OBJECTIVE: To investigate and characterize JAK2 mutations in myelodysplastic syndrome (MDS), we present three cases with diverse JAK2 mutations and review the literature.
METHODS: The institutional SoftPath software was used to find MDS cases between January 2020 and April 2022. The cases with a diagnosis of a myelodysplastic/myeloproliferative overlap syndrome including MDS/MPN with ring sideroblasts and thrombocytosis were excluded. The cases with molecular data by next generation sequencing looking for gene aberrations commonly seen in myeloid neoplasms were reviewed for the detection of JAK2 mutations including variants. A literature review on the identification, characterization, and significance of JAK2 mutations in MDS was performed.
RESULTS: Among 107 cases of the MDS reviewed, a JAK2 mutation was present in three cases, representing 2.8% of the overall cases. A JAK2 V617F mutation was found in one case representing slightly less than 1% of all the MDS cases. In addition, we found JAK2 R564L and JAK2 I670V point mutation variants to be associated with a myelodysplastic phenotype.
CONCLUSIONS: JAK2 mutations in MDS are rare and represent less than 3% of cases. It appears that JAK2 variant mutations in MDS are diverse and further studies are needed to understand their role in the phenotype and prognosis of the disease.

The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes.
We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects.
The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16%; PR was 6%; Median OS was 16.4 months; median DOR was 10.1 months; median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%.
The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS.

BACKGROUND: Patients with higher-risk myelodysplastic syndromes (HR-MDS), if left untreated, have lower overall survival and increased economic burden.
OBJECTIVE: This systematic literature review (SLR) identified comprehensive evidence on the economic burden of disease among patients with low-to-high-risk MDS.
METHODS: Literature search of English publications from 2011-2021 was conducted in Embase®, MEDLINE® and MEDLINE-In-process, including relevant conference proceedings to identify economic burden of MDS that fulfilled pre-defined inclusion criteria. Data on study characteristics, patient demographics and economic burden were extracted.
RESULTS: A total of 20 studies fulfilled the eligibility criteria for economic burden of MDS. Overall, costs were greater among patients with high-risk versus low-risk MDS. Costs were higher in first year of diagnosis (mean [SD], $17,337 [$19,696]) versus second year (mean [SD]: $12,976 [$14,135]), with chemotherapy and supportive care being key cost drivers. Additionally, hospitalization, comorbidities, transfusions, and use of hypomethylating agents (HMAs) were main cost drivers for high-risk MDS. Transfused patients incurred significantly higher mean costs than non-transfused patients ($88,824 versus $29,519; p<0.001); transfusions alone lead to an approximately 50% increase in monthly costs. The mean (95%CI) number of transfusions over 4 years were highest for very-high-risk groups 171 (135-200) and lowest for very-low-risk groups 25 (20-32). The median (IQR) number of hospitalizations were higher in transfusion-dependent 6 (4-9) than non-transfusion-dependent patients 2 (1-4). Patients who did not persist with their HMA therapy were associated with increased total healthcare costs and resource use.
CONCLUSIONS: Overall, costs were greater with high-risk versus low-risk MDS. Transfusion and HMAs were prominent cost drivers. HMAs are the first therapeutic choice for MDS; however, their usage is limited owing to lack of durable response. There exists an unmet need for appropriate therapies focusing on improving survival and reducing economic burden of MDS. These findings are suggestive, as majority of data was available from the US. More studies are needed from across geographies to draw more meaningful conclusions.

BACKGROUND: Patients with higher-risk myelodysplastic syndromes (HR-MDS), if left untreated, have lower overall survival (OS), progress to acute myeloid leukemia (AML), and increased burden.
OBJECTIVE: This systematic literature review (SLR) identified comprehensive evidence of clinical burden of disease among patients with lower to HR-MDS.
METHODS: Literature search of English publications from 2011-2021 was conducted in Embase®, MEDLINE® and MEDLINE®-In-process to identify relevant studies fulfilling pre-defined inclusion criteria. Data on study characteristics, patient demographics and clinical burden were extracted.
RESULTS: A total of 67 studies fulfilled the eligibility criteria. Patients with HR-MDS had lower OS and were four-times less likely to survive compared with lower-risk MDS (LR-MDS) over 85 months (HR, 4.46; CI, 2.8-7.1; p<0.001). Presence of comorbidities, karyotyping and transfusion dependency were predictive of low survival with HR-MDS. Progression to AML was time-dependent and significantly associated with decreased survival (HR, 1.80; CI, 1.27-2.55; p<0.001). Patients with HR-MDS had a high propensity and took less time for AML transformation than patients with LR-MDS. The AML transformation rate increased by 1.5-fold among HR-MDS patients, from first to second year of MDS diagnosis. Cardiovascular disorders and diabetes were common comorbidities, while anemia, thrombocytopenia and neutropenia constituted a major symptom burden. The impact of IPSS-R categories on EuroQoL-5D scoring, was only marginal, and varied per age, gender, comorbidities and transfusion requirement (p<0.001). Among patients with HR-MDS, blood transfusion led to reduction in symptoms of anemia and fatigue (p=0.016). Low quality of life (QoL) was associated with reduced survival. Age, gender, comorbidities and blood transfusion (p<0.001) significantly impacted QoL.
CONCLUSIONS: There is a substantial clinical burden with MDS; age, gender, cytogenetics, comorbidities and blood transfusion being the predominant factors that predict survival and QoL among these patients. A significant proportion of patients with MDS transform to AML. Thus, there is a clearly identified need for more frontline therapies focusing on improving symptoms and OS, particularly among patients with HR-MDS.

BACKGROUND: Myelodysplastic syndromes (MDS) are orphan, rare diseases with an incidence rate of 4.6 (US) per 100,000; 75% are low-risk MDS (LR-MDS). Approximately 50% of LR-MDS patients develop transfusion-dependent (TD) anemia irrespective of ring sideroblasts (RS) status. There are no approved treatments for RS-LR-MDS.
OBJECTIVE: To identify the burden of illness, treatment patterns, and costs for ESA-refractory or relapsed (ESA-r/r) LR-MDS by conducting real-world evidence (RWE), economic, and HRQoL systematic literature reviews (SLRs).
METHODS: SLRs conducted following PRISMA guidelines, supplemented with conference proceedings (ASCO, EHA, ISPOR, ESMO, ASH).
METHODS: ESA-r/r, TD, LR-MDS patients.
METHODS: ESAs, HMAs, lenalidomide, luspatercept, imetelstat, rigosertib.
METHODS: Overall survival (OS), hematological improvement (HI), transfusion independence (TI), HRQoL, costs, hospitalization.
RESULTS: 9/28 RWE studies included ESA-r/r populations; two studies reported lower OS compared with responding patients. 6/28 RWE studies contained a TD population; in three, HI was worse in TD patients compared to TI populations. No RWE studies reported an RS+, TD population; however, while RS status did not impact TI, OS was significantly longer in RS+ populations (2.8 vs. 2.1 years, p<0.01; US SEER Medicare-linked database). 5/14 HRQoL studies found TD LR-MDS subjects had lower HRQoL than TI subjects (EQ-5D, FACT-An, EORTC-QLQ-C30). Evidence from the MDS-CAN registry suggested that transfusion burden negatively affects HRQoL in RS+ LR-MDS. In the MEDALIST trial, ESA-r/r, RS+, LR-MDS patients had a higher disease burden (physical functioning, role functioning, social functioning, fatigue, dyspnea) relative to the general population. RS+, TD populations are associated with 3-fold higher costs compared to TI populations, increased risk of hospitalization (OR 1.3 95% CI 1.15 - 1.46), and lower HRQoL in France and Canada. Transfusion-related costs were the largest contributor to the economic burden of LR-MDS in these two studies (US, 2008-2013; France, 2012-2013).
CONCLUSIONS: While TI is not well-defined or commonly reported in RWE, ESA-r/r, TD LR-MDS populations (RS+/-) have worse outcomes with RS- status significantly reducing survival. The continued use of ESAs and HMAs in ESA-r/r LR-MDS demonstrates a high unmet need. New therapies that reduce transfusions and improve durability across RS status may improve HRQoL and outcomes.
BACKGROUND: Nishan Sengupta, Geron Corporation.

BACKGROUND: AML is an orphan hematological disease. Epidemiology, and data on genetic subgroups that impact prognosis, improves understanding of global disease burden.
OBJECTIVE: Identify and consolidate incidence, prevalence, and mortality data in adult AML/MDS patients through targeted literature review (TLR).
METHODS: TLR of published data from the past 5 years. Sources included PubMed, ISPOR, ASH, ASCO, AACR, EHA, ESMO, and SOHO.
METHODS: Newly diagnosed (ND), relapsed/refractory (R/R) AML or MDS.
METHODS: Incidence, prevalence, mortality.
RESULTS: Fifty-two publications were identified. Studies reported AML, MDS, or both, including ND and R/R. US 5-year age-adjusted AML incidence was 4.1 per 100,000, with a 2019 prevalence of 69,700. MDS incidence ranged from 2.9 per 100,000 cases in Sweden to 7.81 per 100,000 in US Caucasians; the US age-adjusted prevalence was 58,835 in 2019. SEER reported 5-year age-adjusted mortality for AML of 2.7 per 100,000; MDS was not reported. AML and MDS mortality increase with age: the lowest 5-year relative survival rates were in patients over 75, 3.2% for AML and 30.6% for MDS (all IPSS taken together). OS in patients with MDS was reported per IPSS score. Novel treatments target IDH, FLT3, and NPM1 alterations. Fourteen studies reported genetic variants in AML; 2 in MDS. Genetic mutations impacted OS and relapse risk: IDH2+ve patients had lower OS than wild-type (23 vs. 72 months, P=0.0093), and FLT3-ITD indicated poorer survival in patients <60 years (P=0.00003), whereas IDH2/DNMT3A co-mutation conferred a higher relapse risk (100% vs. 48%, P=0.0063). In AML, 2-year mortality was higher in Black patients (39%) than in White (28%) or Hispanic patients (27%). In MDS, racial differences in mutation rates were NPM1: 1% (White), 3% (Hispanic), 8% (Black) (P=0.004), and IDH2: 3% (Hispanic), 5% (White), 8% (Black) (P=0.013), and there were OS differences: median OS was 35, 31, and 52.5 months for White, Black, and Hispanic patients, respectively (P=0.01). Genetic differences in patients with MDS may link to different OS in racial subgroups.
CONCLUSIONS: AML and MDS are rare diseases, and clinical outcomes are impacted by cytogenetics that vary with race. There remains a high unmet need for patients with AML and MDS; novel treatments are needed to improve patient outcomes.

Evidence-based recommendations for the optimal duration and sequencing of temozolomide-based treatments in advanced neuroendocrine neoplasms are lacking. Here, we conducted a systematic review of the literature for a descriptive analysis of temozolomide-associated myelodysplasias and leukemias to guide treatment planning. A database search of PubMed and Embase was conducted to identify case reports and/or case series reporting secondary myelodysplasias or leukemias in the setting of temozolomide therapy. Key data items extracted from the studies were the temozolomide dose and duration, latency to hematological disorder, type of secondary malignancy and cytogenetics. Reported cases were summarized graphically. A total of 16 studies with 27 patient cases of therapy-related hematologic neoplasms were identified, all of which were case reports or case series. The median treatment duration and cumulative dose were 19 months and 18,000 mg/m2 , respectively. Most patients (21/27) were diagnosed on, or after, 12 months, while only one patient was diagnosed before 6 months of treatment. Most of the patients were diagnosed, while still on treatment with temozolomide. Graphically, cases clustered around a cumulative dose of 10,000 to 30,000 mg/m2 and a latency period of 10 to 40 months which translates to an approximate treatment duration of 12.5 to 37.5 months. Taken together, most reported treatment-related hematological neoplasms appear to develop on or beyond the 12-month mark, while patients are still on treatment with temozolomide. For patients with neuroendocrine neoplasms, where sequencing of multiple therapies is important, we suggest an approach to optimizing treatment duration by establishing disease response at 6 months before continuing further treatment and restricting treatment to or establishing closer vigilance beyond 12 months.

ANKRD26 is a highly conserved gene located on chromosome 10p12.1 which has shown to play a role in normal megakaryocyte differentiation. ANKRD26-related thrombocytopenia, or thrombocytopenia 2, is an inherited thrombocytopenia with mild bleeding diathesis resulting from point mutations the 5\'UTR of the ANKRD26 gene. Point mutations in the 5\'UTR region have been shown to prevent transcription factor-mediated downregulation of ANKRD26 in normal megakaryocyte differentiation. Patients with ANKRD26-related thrombocytopenia have a predisposition to developing hematological malignancies, with acute myeloid leukemia and myelodysplastic syndrome most commonly described in the literature. We review the clinical features and biological mechanisms of ANKRD26-related thrombocytopenia and summarize known cases in the literature.

Therapy-related myeloid neoplasms (t-MN) are a distinct subgroup of myeloid malignancies with a poor prognosis that include cases of therapy-related myelodysplastic syndrome (t-MDS), therapy-related myeloproliferative neoplasms (t-MPN) and therapy-related acute myeloid leukemia (t-AML). Here, we report a series of patients with clinical features consistent with juvenile myelomonocytic leukemia (JMML), an overlap syndrome of MDS and myeloproliferative neoplasms that developed after treatment for another malignancy.