MDS Criteria Research Articles

The Movement Disorder Society Criteria: Its Clinical Usefulness in Multiple System Atrophy.

Objective In 2022, Wenning et al. proposed the Movement Disorder Society Criteria (MDS criteria) for the Diagnosis of Multiple System Atrophy (MSA). These criteria were expected to provide useful alternatives to the second consensus statement. We examined trends in these diagnostic criteria. Methods We used patient data registered with the Hokkaido Rare Disease Consortium for Multiple System Atrophy, which has been recruiting patients with MSA through medical facilities in Hokkaido since November 2014. Patients were evaluated according to the MDS criteria based on neurological examinations and imaging findings at three separate times: the first evaluation, the time of enrollment (diagnosis), and the most recent evaluation (final evaluation). Results The MDS criteria were examined in 68 of 244 patients enrolled between November 2014 and July 2022. At the initial evaluation, the classifications were as follows: clinically established (n=27; 39.7%); clinically probable (n=13; 19.1%); possible prodromal (n=12; 17.6%); and negative [did not meet criteria (n=16; 23.5%)]. At the time of diagnosis, the classifications were as follows: clinically established (n=45; 66.2%); clinically probable (n=12; 17.6%); possible prodromal (n=4; 5.9%); and negative (n=7; 10.3%). At the final evaluation, the classifications were as follows: clinically established (n=52; 76.5%); clinically probable (n=9; 13.2%); possible prodromal (n=2; 2.9%); and negative (n=5; 7.4%). Conclusion We were able to clarify the changes in the criteria values and transition of patients due to the clarification of imaging and supportive findings in the MDS criteria.

High-dose IV ascorbic acid therapy for patients with CCUS with TET2 mutations

AbstractThis phase 2 trial assessed high-dose IV ascorbic acid in TET2 mutant clonal cytopenia. Eight of 10 patients were eligible for response assessment, with no responses at week 20 by International Working Group Myelodysplasia Syndromes/Neoplasms criteria. This trial was registered at www.clinicaltrials.gov as #NCT03418038.

Quantitative EEG in Parkinson's disease: when REM sleep behavior disorder onset really matters.

Parkinson's Disease (PD) body-first subtype is characterized by prodromal autonomic symptoms and REM sleep behavior disorder (RBD), symmetric dopaminergic degeneration, and increased risk of dementia. On the other hand, the PD brain-first subtype has fewer non-motor symptoms and a milder motor phenotype. The temporal relationship between RBD onset and motor symptoms onset may differentiate these two subtypes. We aimed to investigate electrocortical differences between brain-first and body-first PD patients. PD patients with an available routinely collected EEG were retrospectively selected. RBD was diagnosed using the RBD screening questionnaire (≥ 6). According to the onset of RBD patients were classified into PD-RBDpre (RBD onset before motor symptoms) and PD-RBDpost (RBD onset after motor symptoms). Patients without RBD were classified as PD-RBD-. Presence of Mild Cognitive Impairment (MCI) was diagnosed according to the MDS criteria. EEG Spectral analysis was performed in resting state by computing the Power Spectral Density (PSD) of site-specific signal epochs for the common frequency bands (delta, theta, alpha, beta). Thirty-eight PD-RBD-, 14 PD-RBDpre and 31 PD-RBDpost patients were recruited. Comparing both global and site-specific absolute values, we found a significant trend toward beta band reduction going from PD-RBD-, PD-RBDpost and PD-RBDpre. No significant differences were found between PD-RBDpost and PD-RBD- patients. PD-RBDpre patients may represent a different subset of patients as compared to patients without RBD, while patients with later onset have intermediate EEG spectral features. Quantitative EEG may provide new hints in PD subtyping.

A retrospective study of the MDS criteria for prodromal Parkinson’s disease in the general population

The Movement Disorder Society developed research criteria for the detection of the prodromal phase of Parkinson’s disease (PD). Accurate identification of this phase is essential for early interventions. Therefore, we investigated the diagnostic value of these research criteria in the general population. Lifelines is an ongoing cohort study of 167,000 participants from the general population of the Northern Netherlands. 160 participants self-reported to have developed PD during three rounds of follow-up of five years each. Data were available to infer six out of eleven risk markers, and six out of twelve prodromal markers. We retrospectively compared the criteria in the prodromal stage of a group of 160 ‘converters’ with 320 age- and sex-matched controls. The overall incidence rate of PD was 0.20 per 1.000 person-years (95% CI: 0.049−0.36), increasing with age and rates were higher in men. The median probability for prodromal PD in PD-converters was 1.29% (interquartile range: 0.46−2.9), compared to 0.83% (0.39−1.8) for controls (P = 0.014). The MDS set of criteria for prodromal PD had an ROC-AUC of 0.577, and was therefore not sufficient to adequately predict conversion to PD. We were unable to predict conversion to PD in the general population using a selection of the prodromal PD research criteria. Ancillary investigations are required to improve the diagnostic accuracy of the criteria, but most are precluded from large-scale use. Strategies, including olfactory tests or alpha-synuclein seeding amplification assays may improve the detection of prodromal PD in the general population.

A Systematic Literature Review of Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes.

Erythropoiesis-stimulating agents (ESAs) are the first-line treatment option for anemia in patients with lower-risk myelodysplastic syndromes (LR-MDS). A systematic literature review was conducted to identify evidence of the association between prognostic factors and ESA response/failure in LR-MDS. MEDLINE, Embase, and relevant conferences were searched systematically for studies assessing the association between prognostic factors and ESA response/failure in adult patients. Of 1566 citations identified, 38 were included. Patient risk status in studies published from 2000 onwards was commonly assessed using the International Prognostic Scoring System (IPSS) or revised IPSS. ESA response was generally assessed using the International Working Group MDS criteria. Among the included studies, statistically significant relationships were found, in both univariate and multivariate analyses, between ESA response and the following prognostic factors: higher hemoglobin levels, lower serum erythropoietin levels, and transfusion independence. Furthermore, other prognostic factors such as age, bone marrow blasts, serum ferritin level, IPSS risk status, and karyotype status did not demonstrate statistically significant relationships with ESA response. This systematic literature review has confirmed prognostic factors of ESA response/failure. Guidance to correctly identify patients with these characteristics could be helpful for clinicians to provide optimal treatment.

Protocol for a randomized, placebo-controlled, double-blind phase IIa study of the safety, tolerability, and symptomatic efficacy of the ROCK-inhibitor Fasudil in patients with Parkinson's disease (ROCK-PD).

The Rho-kinase (ROCK) inhibitor Fasudil has shown symptomatic and disease-modifying effects in Parkinson's disease (PD) models in vitro and in vivo. In Japan, Fasudil has been approved for the treatment of subarachnoid haemorrhage since 1995 and shows a favourable safety profile. To investigate the safety, tolerability, and symptomatic efficacy of ROCK-inhibitor Fasudil in comparison to placebo in a randomized, national, multicenter, double-blind phase IIa study in patients with PD. We plan to include 75 patients with at least 'probable' PD (MDS criteria), Hoehn and Yahr stages 1-3, and age 30-80 years in 13 German study sites. Patients must be non-fluctuating and their response to PD medication must have been stable for 6 weeks. Patients will be randomly allocated to treatment with the oral investigational medicinal product (IMP) containing either Fasudil in two dosages, or placebo, for a total of 22 days. As primary analysis, non-inferiority of low/high dose of Fasudil on the combined endpoint consisting of occurrence of intolerance and/or treatment-related serious adverse events (SAEs) over 22 days will be assessed in a sequential order, starting with the lower dose. Secondary endpoints will include tolerability alone over 22 days and occurrence of treatment-related SAEs (SARs) over 22 and 50 days and will be compared on group level. Additional secondary endpoints include efficacy on motor and non-motor symptoms, measured on established scales, and will be assessed at several timepoints. Biomaterial will be collected to determine pharmacokinetics of Fasudil and its active metabolite, and to evaluate biomarkers of neurodegeneration. After positive evaluation by the competent authority and the ethics committee, patient recruitment started in the 3rd quarter of 2023. ROCK-PD is registered with Eudra-CT (2021-003879-34) and clinicaltrials.gov (NCT05931575). Results of this trial can pave way for conducting extended-duration studies assessing both symptomatic efficacy and disease-modifying properties of Fasudil.

Sexual dysfunction in men with young onset Parkinson's disease.

Sexual dysfunction (SD) is a common, yet under-reported non-motor symptom of PD. Common sexual symptoms among male PD patients include erectile dysfunction, premature ejaculation, and decreased sexual desire. Few research papers have examined sexual dysfunction in PD, especially in YOPD male patients, and there is no Indian research study on sexual dysfunction in YOPD. In this study, we determined the frequency of sexual dysfunction in men with YOPD, and its correlation with other motor and NMS. This prospective cross-sectional study was conducted on YOPD males who presented to the Department of Neurology, NIMHANS, Bangalore, India, from May 2021 to April 2023. The diagnosis of YOPD was made based on MDS criteria for IPD 2015. Sexual functions were evaluated by ASEX, PEDT, QUIP-RS, and sex hormone assay. The patients also underwent other motor and non-motor assessments. Statistical analysis was done using SPSS version 22.0. The study was funded by the PDMD fund. This study included 62 male YOPD patients. The mean age of cases was 44.74 ± 8.54years. The mean duration of symptoms was 8.45 ± 6.23years. 43.5% of the cases of PD were Akinetic rigid type. By ASEX Score grading, 46.8% of the cases had erectile dysfunction and 71% of the cases of YOPD had premature ejaculation by PEDT Score grading. 9.7% of the cases had hypersexuality by QUIP-RS.Duration of YOPD was a better predictor of Erectile Dysfunction and premature ejaculation when compared with other variables. SD was related to anxiety and depression and it had a negative impact on the patient's health-related quality of life (HR-QoL). SD should be investigated and treated as an integral part of the neurological assessment in YOPD.

Validation of the Composite Complete Response (cCR) Definitions in the International Working Group (IWG) 2023 Criteria in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) Treated with Hypomethylating Agents (HMA) - a Large, Multicenter, Retrospective Analysis from the Validate Database

JPB and TK are co-first authors; RK and AMZ are co-senior authors Introduction: Efficacy of therapies used in HR-MDS pts has long been assessed using IWG 2006 MDS criteria, but important limitations in clinical utility and practical application of these criteria have become apparent. The revised IWG response criteria for HR-MDS were proposed in 2023 (Zeidan et al., Blood 2023) were proposed to address these gaps. IWG 2023 re-defined CR by lowering hemoglobin (Hb) threshold from 11 to 10 g/dL and bone marrow [BM] blasts from ≤5% to <5%. Further, CR with partial hematologic recovery (CRh; <5% BM blasts, no Hb threshold, platelets ≥50 × 10 9/L; neutrophils ≥0.5 × 10 9/L; peripheral blood [PB] blasts 0%), CR with limited count recovery (CR-L; <5% BM and 0% PB blasts + PB parameters for CR met in 1 [CRuni] or 2 lineages [CRbi]), and CR equivalent (CRequ; defined for pts with baseline BM of <5%.) were all proposed as provisional endpoints. Per IWG 2023 hierarchical response assessment, if a pt met criteria for both CR-L and CRh, they would be recorded as CR-L. We sought to validate the IWG 2023 definitions of cCR (CR+CR-L+CRh+CRequ) in a large, multi-center dataset of HR-MDS pts who received HMAs. Methods: The VALIDATE database includes HR-MDS pts treated with HMA-based therapies in frontline setting from 14 specialized centers. HR-MDS was defined as IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded (N=90) if age at diagnosis was <18 years, BM blasts ≥20% or unknown at HMA initiation, or if survival status, follow-up time, HMA type or initiation date were unknown. To preserve validity of response assessments, pts also were excluded (N=290) if no BM evaluation was performed or if first BM assessment was >180 days after HMA initiation, except in cases of overt disease progression. Best responses were assessed based on IWG 2006 and 2023 criteria. Kaplan-Meier analysis estimated OS from HMA initiation, and the log-rank test was used to compare subgroups. Cox multivariable regression models identified predictors of OS. This study was supported by an independent research grant from AbbVie. Results: Of 1,223 pts in VALIDATE database, 629 were met eligibility. Median age was 68 years, 27.7% and 27.4% were red blood cell and platelet transfusion-dependent, respectively, 38.1% had TP53 mutations, and 45.3% underwent allogeneic transplantation (allo-HCT). Most pts (71.6%) received HMA monotherapy (51.7% azacitidine, 19.9% decitabine), while 28.4% received HMA-based combinations. Median duration of therapy was 4 cycles (Range: 1-94). Median OS of different subgroups pts are shown in Figure 1. Median OS for pts with IWG 2023-defined cCR (CR+CR-L+CRh+CRequ; N = 230) was 26.5 months (mo; 95% CI: 20.7 - 32.2 mo) vs 14.3 mo (95% CI: 12.5 - 16.9 mo) for pts who did not achieve cCR (p=0.002). Median OS for pts who achieved IWG 2023-defined CR (N = 90) was 29.8 (95% CI: 23.1 - 41.8) vs. 26.4 mo (95% CI: 22.0 - 41.3) for IWG 2006-defined CR (p=0.71). The 124 pts (19.7%) who achieved CR-L had a median OS of 26.4 mo (95% CI: 17.6 - 36.2 mo); of those 67 pts achieved CRbi and had a median OS of 29.1 mo (95% CI: 20.7 - not reached), while 57 pts achieved CRuni and had a median OS of 18.7 mo (95% CI: 15.5 - 54.4 mo), with no significant difference in OS between CRbi and CRuni (Hazard ratio: 1.24; 95% CI: 0.78-1.98, p=0.71). Given the hierarchical prioritization of CR-L designation over CRh in IWG 2023 if a pt meets both response definitions, only 6 pts achieved CRh which precluded a reliable estimate of their OS. Similarly, CRequ was achieved only in 10 pts limiting a reliable assessment of OS in these pts. In a multivariable Cox model that adjusted for sex, HMA type, age, allo-HCT, complex karyotype, TP53 mutation, and IPSS-M risk group, achieving a cCR per IWG 2023 criteria was statistically significantly associated with improved OS was associated with improved OS compared to those who did not achieve cCR (HR: 1.64; 95% CI: 1.30 - 2.08; p<0.001, Figure 2). Discussion: In this real-world analysis of HR-MDS pts treated with HMA-based therapy, cCR according to IWG 2023 were associated improved OS. In particular, CR and CRL (including CRbi and CR uni) were associated with improved OS, supporting their inclusion in the overall response rate in clinical trials. The number of pts who achieved CRh and CRequ was too small to reliably assess their specific association with OS. Additional pts are being added to the database and detailed analyses will be presented in the meeting.

Investigating differences in young- and late-onset progressive supranuclear palsy.

The impact of age of onset on the presentation of progressive supranuclear palsy phenotypes is not well studied. We hypothesized that there is difference in presentation and phenotype between young- and late-onset PSP. Our aim was to compare phenotypes and rate of change in disability between young-onset PSP (YOPSP) and late-onset PSP (LOPSP). Retrospective data of patients seen in the Rossy PSP Centre from March 2014 to April 2022 with clinical diagnosis of PSP as per the MDS 2017 diagnostic criteria were examined. We used cut-off age of 65years to categorize the patients into YOPSP and LOPSP. We compared the prevalence of phenotypes, presenting symptoms, and MDS core criteria between the two groups. The severity of disease between the two groups was measured using PSP-RS. We found 107 patients with clinical diagnosis of PSP as per MDS criteria, a third were defined as YOPSP. PSP speech/language (SL) phenotype was more prevalent in YOPSP (18% vs 0%, p < 0.001). Aphasia was significantly higher in YOPSP (16% vs 1.4%, p = 0.03). The speech and language dysfunction (C1) core criteria were more prevalent in YOPSP (33.3% vs 12.2%, p = 0.05). Longitudinal analysis of PSP-RS showed worsening of bulbar total score at 6months in YOPSP (t (38) = 2.87; p = 0.05). Our study revealed that YOPSP are more likely to present with a speech and language variant. Our results highlight that age of onset may predict PSP phenotypes, which holds both clinical and prognostic importance.

Influence of RBD onset on the clinical characteristics of Parkinson's disease patients: a retrospective study.

In Parkinson's disease (PD), rapid eye movement (REM) sleep behavior disorder (RBD) might either precede the appearance of motor symptoms, or develop during the disease course. PD patients with RBD are characterized by a higher burden of cognitive impairment and hallucinations. However, few studies have analyzed the clinical characteristics of PD patients according to the timeline of RBD onset. PD patients have been retrospectively enrolled. Presence and onset of probable RBD (pRBD) has been evaluated using RBD Screening Questionnaire (score ≥ 6). Presence of Mild Cognitive Impairment (MCI) at baseline has been evaluated using the MDS criteria level II. Presence of motor complications and hallucinations has been evaluated at a 5-year follow-up. A total of 115 PD patients (65 men, 56.5%; mean age 62.5 ± 9.7years; mean disease duration 3.7 ± 3.9years) have been enrolled. Out of these, 63 fulfilled the diagnosis of pRBD (54.8%) with 21 (33.3%) reporting the RBD onset before the onset of the motor symptoms (PD-RBDpre), and 42 (66.7%) after the motor symptoms (PD-RBDpost). At enrolment presence of MCI was associated with PD-RBDpre patients (OR 5.04; 95% CI 1.33-19.05; p value 0.02). At follow-up, a higher risk of developing hallucinations was also associated with PD-RBDpre (OR 4.68; 95% CI 1.24-17.63; p = 0.022). PD patients with RBD occurring before the onset of motor symptoms represent a subgroup of patients with a more severe cognitive phenotype and with a higher risk of developing hallucinations along the disease course, with significant implications in terms of prognostic stratification and therapeutic approach.

Novel Treatment of Multiple System Atrophy in the Era of the New MDS Criteria

As our understanding of the pathogenesis of multiple system atrophy (MSA) continues to advance, significant research has focused on the development of disease-modifying therapies. In addition to inhibiting the aggregation of α-synuclein (αS) protein, a major culprit of MSA pathogenesis, disease-modifying drugs have been developed to mitigate cell-to-cell transmission of aggregated αS, thereby suppressing subsequent neuroinflammation, and release of trophic factors. However, most of these therapies have been unsuccessful. The diagnostic criteria for MSA have recently been revised to allow for earlier and more reliable diagnosis. In addition, clear criteria for prodromal MSA have been established, which is expected to narrow the translational gap.

New MDS Criteria for the Diagnosis of Multiple System Atrophy: An Autonomic Viewpoint

We reviewed the autonomic dysfunction in multiple system atrophy (MSA) with reference to the new MDS criteria. MSA is a major neurodegenerative disorder that presents with autonomic and motor dysfunctions (cerebellar ataxia and/or parkinsonism). Autonomic dysfunction in MSA affects urinary, cardiac, gastrointestinal, otorhinolaryngologic, and respiratory functions. Therefore, autonomic dysfunction in MSA should be recognized, collaborating with each faculty for the treatment and care of the patients. Moreover, it is highly recommended that neurologists request for an ultrasound measurement of the post-void residual urine volume. MSA has no cure; hence, active participation in the treatment and care of autonomic dysfunction in MSA patients is warranted.

New MDS Criteria for the Diagnosis of Multiple System Atrophy: Overview and Genetic Viewpoint

A new diagnostic criteria for multiple system atrophy, "The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy (MSA)", has been proposed. Under the new criteria, new categories of "clinically established MSA," "clinically probable MSA," and "possible prodromal MSA" have been introduced. The new diagnostic criteria is expected to facilitate early and accurate diagnosis of MSA in clinical practice for MSA patients and clinical trials for MSA. In the diagnostic criteria, "A sporadic, progressive adult (>30 years) onset disease" is described as an "essential feature of MSA," and thus attention to familial occurrence of MSA is not included. Familial occurrence of MSA, however, was recognized first in Japan, and later in the world. We have witnessed discoveries of numerous genes underlying other neurodegenerative diseases, including Parkinson disease, and therefore application of molecular genetics research for MSA is highly expected to contribute to elucidating the molecular basis of MSA. Although the new diagnostic criteria is designed to facilitate early and accurate diagnosis of sporadic MSA, we simultaneously need to pay attention to familial occurrence of MSA and promotion of molecular genetics research of MSA.

New MDS Criteria for the Diagnosis of Multiple System Atrophy: How to Use in Clinical Practice and Clinical Trials

The newly revised diagnostic criteria for multiple system atrophy (MSA) have reduced the criteria for diagnosing orthostatic hypotension compared to the conventional diagnostic criteria, but require tests such as MRI and residual urine measurement. Under the new diagnostic criteria, cases that were previously classified as possible MSA with low diagnostic accuracy may become clinically established with higher diagnostic accuracy. However, examination of the cohort treated in our establishment showed that there were cases in which the diagnostic criteria could not be applied when the symptoms and test items necessary for diagnosis were not confirmed. In clinical trials, clinically established or clinically probable MSA are targeted for interventional studies, and possible prodromal MSA are considered to be more important for observational studies. In the future, it will be necessary to confirm the diagnostic accuracy pathologically, accumulate evidence from various clinical tests that are listed as supportive biomarkers, and to develop more useful diagnostic criteria.

Clinicopathological Features of Isolated Thrombocytopenia Associated with SRSF2 Mutations: A Case Series

Introduction: Mutations of SRSF2, a gene involved in RNA splicing, are identified across a heterogenous group of myeloid neoplasms including MDS, CMML, and MPN. SRSF2 mutations have been associated with thrombocytopenia in MDS, but not in the case of MDS/MPN overlap conditions. When co-mutated with TET2, SRSF2 is associated with monocytosis and a myeloproliferative phenotype. SRSF2 mutations are also identified in normal individuals and in those with clonal cytopenias of undetermined significance (CCUS). Studies have examined genotype-phenotype correlations in myeloid malignancies, but similar analysis of the heterogeneity amongst patients with CCUS are lacking. Although dysplasia is not a defining feature of CCUS, sub-diagnostic dysplasia can be seen in CCUS and this subset notably had a higher proportion of spliceosome mutations. Here we describe the clinical and pathological features of a series of CCUS patients with prolonged, isolated thrombocytopenia and a SRSF2 mutation. Methods: We conducted a retrospective review of the electronic medical records of patients seen in the outpatient Hematology Clinic at the University of Southern California Norris Comprehensive Center between May 2014 and December 2021. Patients with persistent (> 6 months) isolated thrombocytopenia, a SRSF2 pathogenic mutation identified on a myeloid molecular panel, and absence of WHO-defined dysplasia or hematologic neoplasm on initial bone marrow biopsy were included. A work-up for alternative etiologies of thrombocytopenia was completed based on the clinical judgment of the treating physician. Bone marrow biopsies were reviewed by 2 independent hematopathologists. This study was approved by the Institutional Review Board of the University of Southern California. All patients signed informed consent. Results: Five patients met criteria for inclusion. All patients were male. Median age at diagnosis of thrombocytopenia was 61 years (56-74). Two patients were Asian and 3 were Caucasian. The median time from diagnosis of thrombocytopenia to the identification of a mutation on a myeloid molecular panel was 4 years (3-12). No patients had a family history of hematologic malignancy. Initial bone marrow biopsies did not meet WHO-defined thresholds for morphologic dysplasia. However, all patients had megakaryocytic hyperplasia and megakaryocytes with hyperchromasia and high nuclear-cytoplasmic ratio in 20% of megakaryocytes (Figure 1). Two patients who had CD34 staining showed positive staining in 30% of megakaryocytes. Four patients had normal cytogenetics and 1 patient had monosomy 7. Median bone marrow cellularity was 65% (30-80%). Two patients had intermittent peripheral monocytosis but did not meet the diagnostic criteria for CMML. No monocyte proliferation or immature monocytes were seen on bone marrow. SRSF2 mutations were P95H in 3 patients and P95L in 2 patients. Average variant allele frequency was 37.3% (range 28 - 50.2). Four patients had a co-occurring TET2 mutation; other co-mutated genes included RUNX1 (3 pts.), ASXL1 (1 pt.), DNMT3A (1 pt.), and NF1 (1 pt.). Median number of co-occurring mutations was 2 (0-3). Three patients were treated empirically for immune thrombocytopenia and had no response to IVIG and/or steroids. Three patients were treated with thrombopoietin receptor agonists (2 eltrombopag, 1 romiplostim) and had minimal transient platelet count increases not meeting the IWG MDS criteria for response. One patient was treated with hypomethylating agents for 4 months before progressing to MDS or AML. Four patients required as-needed platelet transfusions. To date, 4 have progressed to MDS or AML with a median time from diagnosis to progression of 6.3 years (range 5-10). Three patients have received allogeneic hematopoietic stem cell transplant. Conclusion: This series describes a subset of CCUS patients with isolated thrombocytopenia associated with SRSF2 mutations. We also describe atypical megakaryocytic findings which do not meet current WHO diagnostic criteria for dysmegakaryopoiesis; however, the uniform presence of these findings in this cohort suggests an association with thrombocytopenia and CCUS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Predictors of Erythropoiesis-Stimulating Agent Failure in Lower-Risk Myelodysplastic Syndromes: Systematic Literature Review

Introduction: Patients with lower-risk myelodysplastic syndromes (LR-MDS) commonly experience chronic progressive anemia, which is initially treated with erythropoiesis-stimulating agents (ESAs). However, many patients do not respond to ESAs, thereby putting them at risk of earlier disease progression, which can require invasive and/or costly treatments, including blood transfusions or hypomethylating agents. A systematic literature review (SLR) was conducted to assess quantitative associations between prognostic factors and response to treatment with ESAs in patients with LR-MDS. Methods: An electronic search for relevant literature was conducted on February 25, 2022, across Embase and MEDLINE via OvidSP. Also, proceedings from the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, Academy of Managed Care Pharmacy, and European Society for Medical Oncology meetings from 2019 to 2022 were searched via OvidSP or manually if not indexed in databases. Articles written in languages other than English were excluded. Adult patients with LR-MDS were included in the analysis. Studies reporting measures of effect between prognostic factors and ESA response were included, as were studies reporting quantitative data pertaining to differences in patient characteristics between ESA responders and non-responders. Studies reporting both univariate and multivariate analyses were included. No geographic or temporal limits were applied to the search strategy, except for congress proceedings, which were limited to 2019 onwards. Results: In total, 38 studies were eligible for inclusion in this SLR, and 8 prognostic factors of interest were most frequently reported: baseline serum erythropoietin (EPO), hemoglobin (Hb), transfusion independence, bone marrow blast count, ferritin levels, International Prognostic Scoring System (IPSS) risk status, age, and karyotype status. Regarding study design, most were retrospective cohort studies (N = 15) or single-arm trials (N = 12), and were conducted in Europe (N = 24). Within the identified publications, ESA response was often assessed using the International Working Group (IWG) MDS 2000 or 2006 criteria in publications after 2000. Studies published prior to 2000 did not use a standardized method of refining response, but still classified patients according to changes in Hb levels or transfusion requirements. The literature available in LR-MDS demonstrated statistically significant relationships suggesting that patients with low serum EPO levels (vs higher EPO levels), high Hb levels (vs lower levels), and transfusion independence (vs transfusion dependent) are more likely to respond to ESA treatment (Table). This relationship was consistent across both univariate and multivariate analyses. The evidence for bone marrow blasts and ferritin levels was inconclusive, but could potentially be influenced in the future by the publication of studies with larger patient populations. There was no published evidence that ESA response was related to IPSS risk status, age, and karyotype status. The associated data for these prognostic factors in responders versus non-responders showed similar patterns. Conclusion: All studies assessing quantitative associations between ESA response and prognostic factors were published after 2000, hence ESA response was assessed according to IWG 2000 or 2006 criteria. The studies demonstrate a clear link between response to ESA treatment and lower serum EPO levels, higher Hb levels, and transfusion independence. The other prognostic factors were either not significant or inconclusive, and more research is needed to clarify whether they have a prognostic impact on ESA response in patients with LR-MDS. Some of the studies comparing prognostic factors for responders versus non-responders to ESA treatment were published before 2000 and did not use standardized methods to describe response. Due to changes in ESA treatment response definitions over time, some patients in the included studies may be classified differently with a more recent version of the IWG MDS criteria. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MDS-110 SELECT-MDS-1 Trial in Progress: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Tamibarotene/Azacitidine Versus Placebo/Azacitidine in Newly Diagnosed Adult Patients Selected for RARA-Positive Higher-Risk MDS

A novel genomically defined subset of higher-risk myelodysplastic syndrome (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive by a blood-based biomarker test (Vigil 2017). Tamibarotene is an oral selective RARα agonist with potential for clinical benefit in RARA-positive HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA-positive relapsed/refractory HR-MDS showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene/azacitidine led to a CR/CRi rate of 61% with rapid onset of response in RARA-positive newly diagnosed (ND) unfit AML patients, including those with low blast count (≤30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/azacitidine was generally well tolerated with no increase in myelosuppression compared with azacitidine alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and low blast count AML (Estey 2022) supports further development of tamibarotene/azacitidine in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). To characterize and compare the CR rate of tamibarotene/azacitidine to placebo/azacitidine in RARA-positive ND HR-MDS patients. Secondary objectives include comparisons of overall response rate, event-free survival, overall survival, transfusion independence, and safety. Global, Phase 3, randomized, double-blind, placebo-controlled trial (NCT04797780). Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms. The included patients will be RARA-positive based on investigational assay and ND with HR-MDS by WHO classification (Arber 2016) with an IPSS-R risk category of very high, high, or intermediate and a blast count >5% at baseline. Patients with prior treatment for MDS with any HMA, chemotherapy, or transplant are excluded. Azacitidine will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. Response is assessed per the modified IWG MDS criteria (Cheson 2006).

PB1921: A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAMIBAROTENE/AZACITIDINE VERSUS PLACEBO/AZACITIDINE IN NEWLY DIAGNOSED ADULT PATIENTS SELECTED FOR RARA-POSITIVE HR-MDS (SELECT-MDS-1)

Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). This RARA positivity enables biologically targeted therapy with tamibarotene (formerly SY-1425), an oral selective RARα agonist with potential to provide clinical benefit for HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial Phase 2 clinical data in RARA+ relapsed/refractory HR-MDS patients treated with single agent tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) demonstrated high complete response rates with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene plus aza was generally well tolerated with no increase in myelosuppression compared to single agent aza (de Botton 2020). HR-MDS and AML have common cytogenetic abnormalities and gene mutations present in the blast populations in each condition. The historical precedent demonstrating similar clinical outcomes among patients with HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of the combination of tamibarotene plus aza in the HR-MDS population, with the opportunity to improve upon the clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Aims: This is a global Phase 3, multi-center, randomized, double-blind, placebo-controlled study comparing the activity of tamibarotene plus aza, to placebo plus aza in RARA+ patients with ND HR-MDS. The primary objective is to compare the complete remission rate of tamibarotene plus aza vs. placebo plus aza, with secondary objectives to compare objective response rate, event-free survival, overall survival, transfusion independence rate, time to and duration of initial and complete responses, and safety. Methods: Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a bone marrow blast count > 5% at study entry. Patients suitable for allogeneic HSCT at the time of screening, or who received prior treatment for MDS with any HMA, chemotherapy or allogeneic HSCT are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or days 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per the modified IWG MDS criteria (Cheson 2006). Results: Approximately 190 patients will be randomized 2:1 and stratified by IPSS-R risk group and geographic region, providing 90% power to detect the difference in CR rates between the experimental and control arms, respectively, with one-sided alpha of 0.025. Summary/Conclusion: The SELECT-MDS-1 trial opened to enrollment in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe (NCT04797780).

A randomized, double-blind, placebo-controlled study of tamibarotene/azacitidine versus placebo/azacitidine in newly diagnosed adult patients selected for RARA+ HR-MDS (SELECT-MDS-1).

TPS7075 Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). Biologically targeted therapy with tamibarotene, an oral selective RARα agonist, has potential to provide clinical benefit for RARA+ HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA+ R/R HR-MDS patients treated with tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) showed high complete response rates (CR) with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/aza was generally well tolerated with no increase in myelosuppression compared to aza alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of tamibarotene/aza in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Methods: This Phase 3, multi-center, randomized, double-blind, placebo-controlled study will compare activity of tamibarotene/aza to placebo/aza in RARA+ patients with ND HR-MDS. The primary objective is to characterize and compare the CR rate of tamibarotene/aza vs placebo/aza, with secondary objectives to characterize ORR, EFS, OS, transfusion independence rate, time to and duration of initial and complete responses, and safety. Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms, with a one-sided alpha of 0.025. Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a blast count &gt; 5% at study entry. Patients suitable for transplant at screening, or with prior treatment for MDS with any HMA, chemotherapy or transplant are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per modified IWG MDS criteria (Cheson 2006). The SELECT-MDS-1 trial opened in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe. Clinical trial information: NCT04797780.

Challenges in Clinico-Genetic Correlations in Parkinson’s disease (PD). The Role of Copy Number Variants (CNV)

Parkinson’s disease (PD) represents the second most common neurodegenerative disease and remains incurable. Mutations in multiple genes have been linked to monogenic PD (gPD); these monogenic forms, however, represent a small number of cases while in most instances PD appears as idiopathic (iPD). These findings raise the question of whether genetic and idiopathic parkinsonisms constitute the same disease. Nevertheless, monogenic-PD phenotypes and iPD both fulfill MDS criteria for PD, and show evidence of alpha-synuclein aggregates in both conditions. Distinct genetic loci in rare Mendelian forms have been identified as causal mutations, others as possible disease-causing genes, and genome-wide association studies have reported several risk loci, many of them located in the genes associated with the dominant mutations. Not only single-nucleotide polymorphisms (SNPs), but other kinds of DNA molecular defects as well have been spotted as significant disease-causing mutations, including large chromosomal structural rearrangements and copy number variations (CNVs). As their size varies, and detection methodologies have different sensitivity and resolution, CNVs pose a special challenge in genetic studies, and there currently is a debate on the pathogenetic or susceptibility impact of specific CNVs on PD. In this review, through multiple instances of experimental evidence, we analyze the impact on histopathology of the different mutational mechanisms involved in the genesis and etiology of PD. We believe that increasing our knowledge about the changes and implications at tissue level produced by each of those mechanisms will allow to develop much more suitable and personalized potential therapeutic strategies, biomarker identification, as well as disease modeling, agreeing with the precision medicine concept.