International Working Group Criteria Research Articles

Polymorphisms of Monocyte-Activating Cytokine/Chemokine Genes Affect the Susceptibility to, and Severity of Chronic ITP

Introduction: Immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by the production of platelet antibodies, resulting in the destruction of platelets and inhibition of their production. A shift toward Th1 and Th17 cells together with impaired Tregs has been reported using quantitative RT-PCR and flow cytometry method. Further, recent reports have shown that CD16 (+) monocytes in ITP patients are polarized to secrete the Th1 cytokine IL-12, promoting Th1 responses. Enhanced phagocytosis of splenic macrophages was also observed in ITP patients. Thus, monocytes/macrophages are also involved in the pathogenesis of ITP. However, it remains unclear whether genetic factors of cytokines/chemokines activating monocytes increase the risk of chronic ITP. We investigated the impact of monocyte-related gene polymorphisms: TNF-α -857C/T, IFN-γ +874T/A, and MCP1+2518G/A on the susceptibility and clinical feature of chronic ITP (cITP) and Th1/Th2 ratio in peripheral blood of cITP patients,Patients and methods: In this study, 126 Japanese cITP patients (92 females and 34 males with a median age of 47.7 [range: 2.4-82.3] years), as well as 202 race-matched healthy subjects were examined. The diagnosis of cITP was defined according to International Working Group criteria. Genotyping of the polymorphisms was determined by PCR based technique and direct sequencing. We evaluated Th1/Th2 ratio in peripheral blood of 15 normal donors and 25 ITP patients. Intracellular IL-4 (Th2 cytokine) and IFN-γ (Th1 cytokine) production was assessed in CD4+ T lymphocytes activated by phorbol 12-myristate 13-acetate and ionomycin by flow cytometry.This study was approved by the Institutional Review Board of Gunma University Hospital.Results: The platelet count ranged from 1×109/L to 98×109/L with a mean count of 32×109/L at the initial diagnosis. Steroid treatment was given to 86 patients (58.1%), and splenectomy was performed in only 18 patients (12.2%). The genotype distributions of these three polymorphisms in healthy subjects were similar to those observed in previous studies of Japanese populations. Patients with cITP had a significantly higher frequency of the TNF-α -857 TT genotype (high producer type) and MCP1+2518 G allele (high-producer type) compared to healthy controls (14.0% vs 5.4%, p < 0.01; 67.6% vs. 60.6%, P < 0.01). However, no significant difference in the genotype frequencies of IFN-γ was observed between cITP patients and healthy controls. Thus, it was suggested that the TNF-α and MCP-1 polymorphisms shifted toward monocyte activation in cITP patients. We examined the association between these polymorphisms and the clinical characteristics of cITP patients. cITP patients with IFN-γ +874 non-AA genotype (high expression type) showed a lower minimum platelet count than those with an AA genotype (12.9 × 109/L ± 10.7 ×109/L vs 19.4×109/L ± 18.9 ×109/L, P < 0.05). We also examined the association between these polymorphisms and Th1/Th2 ratio in both normal donors and cITP patients. The median Th1/Th2 ratio in patients with cITP was significantly higher than that of healthy controls (31.4, range 0.6-98.8 vs. 17.8, range, 2.2-52.5, P < 0.001). Patients with the IFN-γ +874 non-AA genotype (high expression type) had a significantly higher Th1/Th2 ratio compared to those with the IFN-γ +874 AA genotype (low expression type) (71.5, range 29.4-92.8 vs. 27.5, range 0.6-98.8, P < 0.05). However, there was no significant association between the Th1/Th2 ratio and other polymorphism in cITP patients.Conclusion: These findings suggested that the high expression type of monocyte-activating cytokine/chemokine genes increased the susceptibility to, and severity of chronic ITP DisclosuresMurakami:Ono: Honoraria; BMS: Honoraria; Fujimoto: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Celgene: Honoraria.

Outcome of Myelodysplastic Syndrome Patients with TP53 Mutation Treated with Hypomethylating Agents

▪IntroductionMyelodysplastic syndrome (MDS) patients (pts) with TP53 gene mutation (MT) have poor outcome. Recent studies suggested higher response rates to hypomethylating agents (HMA) among TP53 MT MDS pts. Those studies were limited by small number of TP53 MT. We compared the outcomes in a large cohort of TP53 MT MDS patients to those with wild type TP53 (WT) treated with HMA.MethodsWe identified MDS patients who underwent next generation sequencing (NGS) for TP53 MT who received hypomethylating agents in our MDS database. NGS included a panel of up to 54 genes with VAF threshold of 5% and minimum depth of coverage was 500X. We compared baseline characteristics between pts with TP53 MT and WT; chi square was used for categorical variables and t-test for continuous variables. Patients with low or intermediate-1 risk International prognostic scoring system (IPSS) were categorized as lower risk MDS (LR-MDS) and those with intermediate-2 or high risk IPSS as higher risk MDS (HR-MDS). The best response rate to HMA treatment was reported utilizing international working group criteria (IWG 2006); overall response was reported as HI+ which included complete response (CR), marrow CR, partial response and hematological improvement. Kaplan Meier estimates were used for overall survival (OS) where median OS was calculated from time of diagnosis, log rank test was used for comparison and cox regression analysis for multivariable analysis.ResultsWe identified 508 pts who underwent testing for TP53 MT and were treated with azacitidine or decitabine, 102 pts had TP53 MT. Table-1 summarizes baseline characteristics between the two groups. Among TP53 MT pts, 97 (95%) received azacitidine and 5 (5%) pts had decitabine as the first line HMA compared to 374(92%) treated with azacitidine and 32 (8%) with decitabine in TP53 WT pts as the first HMA (p= .3).Best response to HMA (HI+) was 41% (CR 18%) and 32% (CR 9%) among pts with TP53 MT and WT, respectively (p =.06). Among pts with LR-MDS the best response rates were 32% vs 25% (p=0.4) and in pts with HR-MDS the best response rates were 44% and 41% respectively in TP53 MT and WT (p=0.7). Median OS was 14 mo for TP53 MT MDS pts compared to 41 mo for TP53 WT pts (p<.005). The median OS was 45 and 65 mo. respectively in LR-MDS TP 53 MT and WT pts (p= 0.3). Among HR-MDS pts the median OS was 12 and 21 mo, respectively (p< .005).The median OS was 15 mo and 41 mo among pts with TP53 MT and WT who achieved CR, respectively (p <.005).For pts who underwent allogeneic hematopoietic stem cell transplant (AHSCT) the median OS was 16 mo for TP53 MT and 74 mo for TP53 WT (p=.008).After adjusting for age, R-IPSS, complex karyotype TP53 MT was independently associated with worse overall survival in HMA treated patients, HR 1.4 (p = .048).ConclusionsWe observed a trend for higher response rates among MDS pts with TP53 MT treated with HMA compared to TP53 WT. The median OS was inferior among TP53 MT MDS patients. The benefit of AHSCT among TP53 MT pts is not clear. The value of TP53 allele burden reduction and clearance with treatment and prior to AHSCT should be further investigated. [Display omitted] DisclosuresKomrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria. Sallman:Celgene: Research Funding. Padron:Incyte: Honoraria, Research Funding. Sweet:Ariad: Consultancy, Speakers Bureau; Otsuka: Consultancy; Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Research Funding. Lancet:Boehringer Ingelheim: Consultancy; Jazz Pharmaceuticals: Consultancy; Janssen: Consultancy; Erytech: Consultancy; Celgene: Consultancy; BioSight: Consultancy; Pfizer: Other: Institutional research funding, Research Funding; Bio-Path Holdings: Consultancy; Novartis: Consultancy.

Relationship between Complete Remission and Overall Survival in Acute Myeloid Leukemia: A Report from Daco-016 and Daco-017

The correlation between complete remission (CR) and overall survival (OS) is not well defined for patients with AML who are not eligible for intensive chemotherapy (ICT). With the introduction of hypomethylating agents (HMAs), outcomes have improved compared to low-dose cytarabine or best supportive care, however, there is a need to understand whether patients who achieve a CR following treatment with HMAs experience a longer OS compared to those patients who don't achieve a CR. This retrospective analysis of CR and OS is based on data from two clinical trials of decitabine, DACO-0161 and DACO-0172. The dose schedule of decitabine in both studies was 20 mg/m2 intravenously for 5 consecutive days of continuous 4-week cycles. In DACO-016, the control arm was Treatment Choice (TC; supportive care or cytarabine 20 mg/m2 per day as a subcutaneous injection for 10 consecutive days every 4 weeks). DACO-017 was a single arm study. Morphologic CR was based on the modified 2003 International Working Group criteria. OS was measured from the date of randomization (N=485) in DACO-016 and the date of starting decitabine treatment (N=55) in DACO-017, with patients last known to be alive censored at the last date of contact. OS stratified by CR was estimated using the Kaplan-Meier method and tested using the log-rank test. In DACO-016, 15.7% (N=38) of patients treated with decitabine achieved CR. The median OS for decitabine treated patients who achieved a CR was 19.1 months (95% confidence interval (CI): 15.2-24.2). 97.4% of CRs (N=37) occurred at or after the fourth cycle of decitabine. The median OS for patients who did not achieve a CR with decitabine was 5.7 months (CI: 4.6-7.1) (Figure 1). In contrast, only 7.4% (N=18) of patients treated with TC achieved a CR. In the TC arm, the median OS for patients who achieved a CR was 25.0 months (CI: 16.3-37.0) and 4.5 months (CI: 3.8-5.5) for patients who did not achieve a CR. In DACO-017, the median OS for patients who achieved a CR was 21.6 months (CI: 7.1-24.7). For patients who did not achieve a CR, the median OS was 6.1 months (CI: 3.1-8.1). The median time to CR for decitabine treated patients was 4.6 months. Both studies showed that the median OS of patients who achieved a CR was more than twice that of patients who did not achieve a CR. This analysis demonstrates the prognostic value of CR in relation to OS in patients with AML regardless of treatment and thus the importance of treating patients with decitabine for a minimum of 4 cycles to before evaluating response to treatment. While CR has been shown to be an imperfect surrogate for OS, in this analysis of patients with AML who were ineligible for ICT, achieving a CR remains associated with improved OS benefits vs. not achieving a CR.

Stanozolol for the treatment of anemic lower-risk myelodysplastic syndromes without del(5q) after failure of epoetin alfa: findings from a retrospective study.

Options for anemic lower-risk myelodysplastic syndromes (MDS) without del(5q) after failure of erythropoiesis-stimulating agents (ESAs) are very limited. The effectiveness of second-line treatments is uncertain. We retrospectively reviewed the clinical effectiveness and overall survival (OS) of lower-risk MDS without del(5q) patients exclusively treated with stanozolol (STZ) after failure of epoetin alfa. The response was defined according to the 2006 International Working Group (IWG) criteria. Fifty-six patients were included. The median follow-up time was 55 months (range: 5-156 months). Twenty-seven patients (48.2%) achieved hematologic improvement-erythroid response (HI-E). Higher response rates were observed in patients with lower IPSS-R scores (≤3.5, P = 0.008) and hypocellular bone marrow (P = 0.002). In univariate Cox analysis, HI-E was the strongest factor associated with better OS (P = 0.0003). In multivariate Cox, HI-E, age ≤ 50, and transfusion independence (TI) at the onset of STZ were factors associated with better OS. The estimated 5-year OS was 88.6% (68.7-96.2%) and 33.8% (14.9-54.0%) in responders and non-responders (P < 0.01), respectively. The most common side effects included masculinization and liver damage, but they were manageable with supportive measures and dose adjustments. STZ may be considered an alternative treatment in lower-risk MDS after failure of epoetin alfa.

Social cognitive abilities in older adults with mild cognitive impairment and dementia

AbstractBackgroundAging is associated with changes in general cognition and social cognition. Many studies have detailed these functions in isolation, comparing young and older adults. More information is needed on how social cognition, including theory of mind (ToM), affective empathy (AE), social perception (SP), and social behavior (SB), is affected at different cognitive stages in older adults.MethodCross‐sectional study of 305 older adults from the Sydney Memory and Ageing Study. Dementia was classified based on clinical consensus using DSM‐IV criteria, while mild cognitive impairment (MCI) was classified using the International Working Group criteria. Cognitively normal (CN), MCI, and dementia participants were compared on social cognitive domains including: ToM, via the Reading the Mind in the Eyes Test (RMET) and the Interpersonal Reactivity Index – Perspective Taking subscale (IRI‐PT); AE, via the IRI – Empathic Concern subscale (IRI‐EC); and SP, via the Emotion Recognition Task (ERT). Apathy, which is related to SB, was measured via the Apathy Evaluation Scale (AES).ResultMean age 87.00 ± 4.05 years, mean education 11.89 ± 3.36 years, 60.3% female. 141 were CN, 103 had MCI, and 61 had dementia. Across cognitive groups, significant differences were observed for the RMET, ERT (specifically for the recognition of anger, disgust, and happiness), AES, IRI‐PT, and IRI‐EC. In posthoc comparisons, RMET and ERT were significantly poorer in MCI and dementia compared to CN, but not between MCI and dementia. IRI ratings and AES were poorer for dementia compared to MCI and CN, but not between MCI and CN (Table 1). In multivariable logistic regression adjusting for significant risk factors for cognitive impairment, RMET and ERT disgust performance were associated with lower risk of MCI over CN. Only AES significantly differentiated dementia from MCI (Table 2).ConclusionNeurocognitive disorders are associated with social cognition changes. ToM and SP appear to be affected in MCI relative to CN. Apathy, known to be linked to SB, appears to be affected in dementia. MCI seems to be associated with impaired ability to recognize specific social cognitive cues, while dementia may be more associated with overall worse social cognitive functioning and observed behavioral changes.

Prevalence of inflammatory back pain and radiographic axial spondyloarthritis in a semi-urban community of Lahore, Pakistan.

To determine the prevalence of inflammatory back pain (IBP) and radiographic axial spondyloarthritis (SpA) in a semi-urban community of Lahore, Pakistan. This cross-sectional household survey was designed as per the Community Oriented Program for the Control of Rheumatic Diseases (COPCORD) model. In Phase 1, the subjects were interviewed for musculoskeletal (MSK) pain in the last 7days by clinical assistants. In Phase 2, physiotherapists identified subjects with spinal/back pain and interviewed for Assessment in Spondyloarthritis International Working Group (ASAS) criteria for IBP. In Phase 3 subjects having IBP or chronic back pain (CBP) with an age at onset ≤45years, were assessed and further investigated. A total of 4922 subjects with a mean age of 35.3±14.5years, including 2770 (56%) women were surveyed in Phase 1. MSK pain in last 7days was reported by 1407 (28.6%) of whom 1034 (21%) had spinal pain. The ASAS criteria for IBP were met in 329 (6.7%, 95% CI 6.0-7.0). In Phase 3, 222 with IBP and 83 having CBP with age at onset ≤45years were evaluated. Out of this total of 305, 144 (2.9%) were confirmed to have IBP by rheumatologists as per at least 1 of the 3 criteria. ASAS criteria were met in 107 (2.2%, 95% CI 1.8-2.6). ASAS criteria for radiographic axial SpA were met in 47 (1%, 95% CI 0.7-1.3) of the surveyed population. Inflammatory back pain was reported in 6.7% by physiotherapists, confirmed in 3% by rheumatologists. The prevalence of radiographic axial SpA was 1%.

A Phase 3, Double-Blind, Placebo-Controlled, Randomized Study Evaluating Navitoclax in Combination with Ruxolitinib in Patients with Myelofibrosis (TRANSFORM-1)

Background: Myelofibrosis (MF) is a rare myeloproliferative neoplasm with poor clinical outcomes. It is characterized by bone marrow fibrosis and an array of constitutional symptoms that impair quality of life. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potential curative therapy for MF, but HSCT is only accessible to a minority of patients and is associated with high morbidity and high rates of transplant-related mortality. JAK inhibitors (JAKi), including the JAK1/2i ruxolitinib and JAK2i fedratinib, are approved for the treatment of primary and secondary MF based on reduction in splenomegaly and disease-related symptoms; however, they have little impact on bone marrow fibrosis and are not effective at managing all clinical manifestations of MF. Therefore, a substantial clinical need for novel therapies to improve the disease course of MF exists. Navitoclax is an oral, potent, small-molecule inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL-2) family proteins BCL-XL, BCL-2, and BCL-w and has demonstrated cell-killing activity in myeloproliferative neoplasm-derived cell lines and primary specimens ex vivo. Preliminary data from a Phase 2 study (NCT03222609) of ruxolitinib-experienced patients with primary or secondary MF have shown favorable spleen responses and tolerability with navitoclax plus ruxolitinib (Harrison et al. EHA 2020. EP1081). TRANSFORM-1 aims to evaluate the combination of navitoclax and ruxolitinib vs placebo and ruxolitinib in adults with primary or secondary MF who have not previously received a JAK2i. Study Design and Methods: In this Phase 3, double-blind, placebo-controlled study (NCT04472598), patients aged ≥18 years with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior treatment with JAK2i, and Eastern Cooperative Oncology Group Performance Score ≤2 will be eligible for enrollment. Candidates for allo-HSCT and those who have received prior treatment with a BH3-mimetic compound or BET inhibitor will be excluded. Patients will be enrolled across 130 sites in approximately 17 countries. Planned target enrollment is 230 patients. Patients will be randomized 1:1 to receive navitoclax or placebo, plus ruxolitinib. Randomization stratification factors include intermediate-2 vs high-risk MF and platelet count ≤200 × 109/L vs &amp;gt;200 × 109/L. Navitoclax will be administered orally at a starting dose of 200 mg (platelet count &amp;gt;150 × 109/L) or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days (platelet count ≤150 × 109/L). Ruxolitinib will be administered orally at a starting dose of 20 mg (platelet count &amp;gt;200 × 109/L) or 15 mg (platelet count 100-200 × 109/L) twice daily. Treatment may continue until the end of clinical benefit, unacceptable toxicity, or discontinuation criteria have been met. Patients who discontinue without progression will enter post-treatment follow-up; after disease progression or initiation of post-treatment cancer therapy, patients will enter survival follow-up. The primary endpoint of the study is ≥35% reduction in spleen volume from baseline (SVR35) at Week 24, as measured by magnetic resonance imaging or computed tomography, per International Working Group (IWG) criteria. Secondary endpoints include ≥50% reduction in total symptom score from baseline at Week 24 (measured by Myelofibrosis Symptom Assessment Form v4.0), duration of SVR35, change in fatigue from baseline, time to deterioration of physical functioning, anemia response per IWG criteria, SVR35 per IWG, reduction in grade of bone marrow fibrosis from baseline, overall survival, leukemia-free survival, and overall response and composite response per IWG criteria. Exploratory endpoints include progression-free survival. Safety will be assessed throughout the study via adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram variables, and clinical laboratory testing. AEs will be graded per National Cancer Institute Common Terminology Criteria for AEs v5.0. The primary statistical analysis will be conducted using a stratified Cochran-Mantel-Haenszel test, and time-to-event secondary endpoints will be analyzed using a stratified log-rank test and Kaplan-Meier methodology. Hazard ratios will be estimated using stratified Cox proportional hazards model. Disclosures Potluri: AbbVie: Current Employment, Other: may hold stock or stock options. Harb:AbbVie: Current Employment, Other: may hold stock or stock options. Masud:AbbVie: Current Employment, Other: may hold stock or stock options . Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. OffLabel Disclosure: Navitoclax is an investigational drug for the treatment of myelofibrosis

A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

A Phase 1a/b Dose Escalation Study of the MYC Repressor Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

A Phase 3, Open-Label, Randomized Study Evaluating the Efficacy and Safety of Navitoclax Plus Ruxolitinib Versus Best Available Therapy in Patients with Relapsed/Refractory Myelofibrosis (TRANSFORM-2)

Background: Myelofibrosis (MF) is a rare myeloproliferative neoplasm with limited treatment options and a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure, most patients remain ineligible; other therapies, including approved JAK inhibitors (JAKi), do not control the broad array of manifestations associated with MF. Navitoclax is a potent, small molecule inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL-2) family members BCL-XL, BCL-2, and BCL-w and has been shown to potently enhance cytotoxicity of chemotherapy and radiation in cells derived from multiple tumor types. Preclinical data indicate that navitoclax may overcome JAK2 inhibitor resistance. Preliminary data from a Phase 2 study (NCT03222609) of navitoclax with ruxolitinib, a JAK1/2i, for patients with primary or secondary MF who have previously received ruxolitinib suggest favorable spleen response rates and an acceptable safety profile (Harrison et al. EHA 2020. EP1081). TRANSFORM-2 aims to evaluate the combination of navitoclax and ruxolitinib vs best available therapy (BAT) in adults with relapsed or refractory MF that is resistant to JAK2 inhibition. Study Design and Methods: This Phase 3, open-label study (NCT04468984) is designed to recruit patients aged ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly, and who are experiencing MF-related symptoms. Patients must have received a single prior JAK2i for ≥24 weeks that was stopped due to lack of efficacy or for &amp;lt;24 weeks with disease progression while on therapy. Candidates for allo-HSCT, patients who have received prior treatment with a BH3-mimetic compound or &amp;gt;1 prior JAK2i, and patients with platelets &amp;lt;100 × 109/L will be excluded. The study will be conducted at approximately 173 sites in 23 countries. The planned sample size is 330 patients. Patients will be randomized 1:1 to receive either navitoclax plus ruxolitinib, or BAT. Navitoclax will be administered orally at a starting dose of 200 mg (platelet count &amp;gt;150 × 109/L) or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days (platelet count ≤150 × 109/L); navitoclax may be increased to 300 mg once daily after Week 25 Day 1 at the investigator's discretion, based on platelet count for patients with suboptimal spleen response; ruxolitinib will be administered orally at the prior stable dose if on ruxolitinib at study entry or at a dose of 10 mg twice daily if no longer on ruxolitinib. BAT options include hydroxyurea, interferon, ruxolitinib, fedratinib, or danazol, which will be administered at standard doses. Randomization stratification will be by region (US vs Japan vs EU vs rest of world), by Dynamic International Prognostic Scoring System Plus score at randomization (intermediate-2 vs high risk), and by stable ruxolitinib dosing at randomization vs not on ruxolitinib/JAK2i. Treatment can continue until the end of clinical benefit, unacceptable toxicity, or discontinuation criteria have been met; disease assessments will be performed after 12 and 24 weeks even if discontinuing therapy, after which patients will enter posttreatment follow-up (discontinuation without progression) or survival follow-up (after progression). The primary endpoint is ≥35% reduction in spleen volume from baseline (SVR35) at Week 24, measured by magnetic resonance imaging, per International Working Group criteria. Secondary endpoints include ≥50% reduction in total symptom score from baseline at Week 24, SVR35, duration of SVR35, change in fatigue from baseline, time to deterioration of physical functioning, anemia response, overall survival, leukemia-free survival, overall response, composite response, and reduction in grade of bone marrow fibrosis from baseline. Safety will be assessed via adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram variables, and clinical laboratory testing. AEs will be graded per National Cancer Institute Common Terminology Criteria for AEs v5.0. Statistical analysis of the primary endpoint and binary secondary endpoints will be conducted using a stratified Cochran-Mantel-Haenszel test. Time-to-event secondary endpoints will be analyzed using a stratified log-rank test and Kaplan-Meier methodology. Hazard ratios will be estimated using stratified Cox proportional hazards model. Disclosures Dilley: AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Harb:AbbVie: Current Employment, Other: may hold stock or stock options. Jalaluddin:AbbVie: Current Employment, Other: may hold stock or stock options. Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. OffLabel Disclosure: Navitoclax is an investigational drug for the treatment of myelofibrosis

Characteristics of Different Splicing Factor Mutation Hotspots in Myelofibrosis

CONTEXT: Splicing factor mutations (SRSF2, U2AF1, SF3B1, and ZRSR2) are present in ~50% of myelofibrosis (MF) patients. SRSF2 and U2AF1 Q157 are considered to be high-risk mutations, while the prognostic significance of ZRSR2 and SF3B1 has not been well established. As a group, splicing mutations are associated with cytopenias, the management of which is an area of unmet clinical need in MF. OBJECTIVE: To describe the clinical characteristics, treatment approaches, and outcomes in MF patients with splicing mutations. DESIGN: This is a single-institution, retrospective analysis of 133 MF patients with splicing mutations who presented to our institution between 2006 and 2019. PMF, post-ET MF, and post-PV MF were defined according to the World Health Organization and International Working Group criteria, respectively. Baseline variables were compared between patients harboring different splicing factor mutations and different mutations within the same splicing gene. Median overall survival (OS) was measured from time of diagnosis to date of death or censored at last follow up or date of transplant. Kaplan-Meier plots were created to compare LFS and OS among treatment cohorts, and differences were assessed using Log-rank tests. RESULTS: Among 133 MF patients with a splicing mutation, SRSF2 mutations were most common (n = 48), followed by U2AF1 (n = 36), SF3B1 (n = 27) and ZRSR2 mutations (n = 24). Most SRSF2 mutations occurred at P95 (90%). Thirty (83%) U2AF1 mutations occurred at Q157, with 5 (14%) at S34. Fourteen (63%) SF3B1 mutations occurred K666, with 9 (33%) at K700. Thirteen (54%) ZRSR2 mutations were in-frame insertions/deletions, 4 (17%) frameshift mutations, 3 (13%) nonsense mutations and 4 (17%) missense. All frameshift/nonsense ZRSR2 mutations occurred in males. Spliceosome mutations were mutually exclusive but for 2 cases (one had U2AF1 and SRSF2 mutations and the other had SF3B1 and ZRSR2 mutations). Baseline characteristics were similar between splicing mutations. The presence of a U2AF1 mutation correlated with lower hemoglobin (p 0.018) and U2AF1 Q157 mutations were associated with thrombocytopenia p=0.051) and higher DIPSS-plus scores (p=0.006). Severe thrombocytopenia (platelets &amp;lt; 50 x 109/L) was present in 20 (17%) patients and enriched in those with U2AF1 mutations (n = 9). ASXL1 mutations rarely occurred in conjunction with SF3B1 mutations (p = 0.007). Among all patients with splicing mutations, median OS was 60.6 months. Median OS was decreased in patients with SRSF2 mutations (33 vs 106 months, p=0.001) compared to those with other splicing mutations. Median OS was increased in patients with SF3B1 mutations compared to patients with other splicing mutations (181 mo vs 42 mo, p = 0.002). Median OS for patients with U2AF1 and ZRSR2 mutations was 44 and 106 months, respectively. Among patients with U2AF1 mutations, the presence of severe thrombocytopenia was associated with inferior survival (13.9 mo vs not reached, p = 0.045). The presence of an SRSF2 mutation was associated with an increased risk of leukemic transformation (24% vs 3%, p = 0.002). Among patients with SRSF2 mutations, median OS in those with documented leukemic transformation was 32.9 mo compared to 48.7 mo in those without (p = 0.17). CONCLUSIONS: Splicing mutations in MF have unique phenotypic and prognostic correlations. While SRSF2 mutations appear detrimental, SF3B1 mutations correlate with favorable outcomes. While U2AF1 and SRSF2 mutations are considered high-risk in MF, the impact appears driven by cytopenias in the former and leukemic transformation in the latter. This may hold relevance when considering therapeutic approaches in these patients. Disclosures Talati: AbbVie: Honoraria; Jazz: Speakers Bureau; Astellas: Speakers Bureau; BMS: Honoraria; Pfizer: Honoraria. Sallman:Celgene, Jazz Pharma: Research Funding; Agios, Bristol Myers Squibb, Celyad Oncology, Incyte, Intellia Therapeutics, Kite Pharma, Novartis, Syndax: Consultancy. Sweet:Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Stemline: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Padron:Incyte: Research Funding; Kura: Research Funding; BMS: Research Funding; Novartis: Honoraria. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. Komrokji:Geron: Honoraria; Novartis: Honoraria; Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding.

Results of a Phase II Study of PD-1 Inhibition in Advanced Myeloproliferative Neoplasms

Background: Myelofibrosis (MF) is a hematopoietic stem cell neoplasm characterized by abnormal JAK-STAT signaling, increased inflammation, and evolution to acute myeloid leukemia. Most patients harbor a phenotypic driver mutation- JAK2, CALR or MPL. In the last decade, two JAK2 inhibitors have been approved, however, outside of hematopoietic stem cell transplantation (HSCT), there are no medications that meaningfully modify MF disease biology. Thus, additional treatments are needed. We previously demonstrated the presence of multiple immunosuppressive mechanisms in MPN patients, including expanded myeloid derived suppressor cell (MDSC) populations and elevated expression of immune checkpoint receptors, particularly PD1, on T cells from MPN patients compared to healthy donors (Cimen Bozkus, Cancer Discovery 2019). Therefore, we conducted a multi-center, open-label, phase 2, single-arm study of pembrolizumab in patients with primary, post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) (NCT03065400). Methods: Patients with intermediate-2/high DIPSS MF, ineligible for or previously failed ruxolitinib were eligible. Pembrolizumab was administered at the FDA-approved dose of 200 mg every 3 weeks for 6 cycles. The study was a Simon two-stage design, 9 patients enrolled in the first arm. The study was terminated after completion of this arm due to the lack of responses. Response assessment was conducted after 6 cycles utilizing the International Working Group (IWG-MRT) criteria. In addition, patients with accelerated or blast phase (MPN-AP/BP) could enroll as a separate, ten patient, exploratory cohort. Results: 9 patients enrolled in the MF cohort and 1 in the BP cohort between 6/2017 and 3/2020. Baseline characteristics are summarized in Table 1. Median weeks on treatment were 14.7 (range 4-20). All 9 MF patients were evaluable for response as they received at least 1 dose of pembrolizumab. Of the 9 patients who were evaluable for response, all had SD, 4 (44%) patients discontinued therapy prior to the end of cycle 6. Reasons for discontinuation were adverse events (n=1), patient decision (n=1), physician decision (n=2). Grade 3/4 AEs included anemia (n=3), thrombocytopenia (n=2), leukopenia (n=1), hyperglycemia (n=2), hyperuricemia (n=1), dyspnea (n=1), headache (n=1). No grade 3/4 immune related AEs occurred (Table 2). The effects of pembrolizumab on the immune suppressive milieu observed in MPN were analyzed. PD-1 was detected on peripheral blood T cells by flow cytometry at baseline, but not post-treatment, likely due to receptor occupancy by pembrolizumab. In all patients analyzed, the levels of soluble PD1 in the plasma by Olink assay were significantly higher post-treatment. Other soluble factors associated with T cell activation such as class I-restricted T cell-associated molecule (CRTAM) and CD27 were also elevated after pembrolizumab administration. Furthermore, ARG1, a molecule that mediates T-cell suppression by MDSC, was significantly reduced in the plasma of treated patients. An increase in peripheral blood T cell frequencies was observed in a subset of patients after two cycles. Discussion: Pembrolizumab did not demonstrate clinical activity in this phase 2 trial. The relevance of the preliminary correlative findings will be further confirmed by in situ gene profiling of immune cells and their microenvironment. The complete results will be available at the meeting. These results suggest that pembrolizumab may promote a phenotypical and soluble signature suggestive of a restored immune response. The fact that these molecular changes were not associated with clinical responses indicate that pembrolizumab alone may not be sufficient to reverse the multifactorial causes of immune tolerance in MPN. Disclosures Hobbs: Constellation: Honoraria, Research Funding; Bayer: Research Funding; Jazz: Honoraria; Incyte: Research Funding; Novartis: Honoraria; Merck: Research Funding; Celgene/BMS: Honoraria. Stone:Syndax: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Astellas: Consultancy; Takeda: Other: DSMB; Syntrix: Other: DSMB; Arog: Consultancy, Research Funding; Jazz: Consultancy; Trovagene: Consultancy; Syros: Consultancy; Abbvie: Consultancy, Research Funding; Biolinerx: Consultancy; Argenix: Other; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Other; Agios: Consultancy, Research Funding; Gemoab: Consultancy; Janssen: Consultancy; Stemline: Consultancy; Pfizer: Consultancy; Aztra-Zeneca: Consultancy; Macrogenics: Consultancy; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.

Myelodysplastic Syndromes with 20q Deletion: Incidence, Prognostic Value and Impact on Response to Azacitidine of ASXL1 Chromosomal Deletion and Genetic Mutations

Introduction : The 20q deletion [del(20q)] is a recurrent chromosomal aberration in myelodysplastic syndromes (MDS) and, as a single abnormality, is associated according to the Revised International Prognostic Scoring System (IPSS-R) with a favorable outcome. However, the breakpoint of del(20q) is very heterogeneous and may cause deletion of the ASXL1 gene (20q11.21). This gene is an important epigenetic regulator of hematopoiesis and its mutations have been associated in MDS with a shorter overall survival (OS) and a lower response to azacitidine (AZA). Aim: To assess the incidence, prognostic value and impact on response to AZA of ASXL1 chromosomal alterations and genetic mutations in MDS patients with del(20q). Methods: We studied 153 patients diagnosed with MDS and del(20q) as a sole abnormality (n=93), with an additional chromosomal abnormality (n=27) or in a complex karyotype (n=33). Response to AZA therapy was assessed using the 2006 International Working Group (IWG) criteria. Analysis of ASXL1 chromosome alterations was performed by FISH (Empire Genomics probe). Samples with ASXL1 alterations by FISH were analyzed using the Agilent SurePrint G3 Human CGH 8x60K Microarray. Mutations of ASXL1 were detected by Sanger sequencing. SF3B1, SRSF2, U2AF1, DNMT3A, IDH1, IDH2, TP53, RUNX1, and SETBP1 mutations were screened by high-resolution melting and positives were confirmed by Sanger sequencing. An in vitro assay of the response to AZA in HAP1 and HAP1 ASXL1 knockout cell lines (Horizon) was also performed. The association of the clinical characteristics with the molecular findings was analyzed with the SPSS statistical program (v.20.0) and P values &amp;lt;0.05 were considered as statistically significant. Results: Main patient characteristics are shown in Table 1.ASXL1 chromosomal alterations were detected by FISH in 44 patients (29%; Fig. 1): 34 patients (22%) with gene deletion (ASXL1DEL) and 10 cases (6.5%) with additional gene copies (ASXL1GAIN). All 44 cases were analyzed by microarray, and alterations in centromeric KIF3B gene (20q11.21) were also identified in 24 patients (16%). Patients with ASXL1DEL showed a lower platelet count (median, 68x109/L vs. 103x109/L, P=0.046), a poorer response to AZA (response, 9% vs. 43%, P= 0.040) and a trend towards a lower OS (34 vs. 65 months, P=0.057). ASXL1 and KIF3B chromosomal gains were associated with complex karyotypes (ASXL1GAIN, 80% vs. 23%, P&amp;lt;0.001; KIF3BGAIN, 80% vs. 25%, P=0.011). Patients with ASXL1GAIN had a similar OS and response to AZA than ASXL1nonDEL/ASXL1nonMUT patients (OS, 51 vs. 73 months, P=0.86; response, 60% vs. 44%, P=0.43). Seventy patients (46%) in the series had ≥1 genetic mutation (Fig. 1). ASXL1 mutations (ASXL1MUT; 22/153, 14%) were mostly frameshift (n=17, 77%) or nonsense (n=4, 18%) and were associated with a lower hemoglobin level (median, 8.3 vs. 10.3 g/dL; P=0.007), a higher ferritin level (median, 691 vs. 286 ng/mL, P=0.014), a higher number of mutations (23% vs. 0% ≥3 mutations, P&amp;lt;0.001) and a lower OS (22 vs. 62 months, P=0.016). U2AF1 mutations were associated with a deeper neutropenia (median, 1.17x109/L vs. 1.83x109/L, P=0.026) and TP53 mutations were associated with acute myeloid leukemia (AML) transformation (55% vs. 16%, P=0.005) and a lower OS (24 vs. 57 months, P=0.037). In the global series, patients with ASXL1 altered either by chromosomal deletion or mutation (ASXL1DEL/ASXL1MUT) had a poorer response to AZA (13% vs. 47%, P=0.020) and a lower OS (32 vs. 70 months, P=0.005; Fig. 2) than the remaining patients. In the analysis of isolated del(20q) subgroup (n=93), ASXL1DEL/ASXL1MUT patients also showed a lower OS (37 vs. 80 months, P=0.026) and ASXL1DEL was associated with a higher risk of progression to AML (33% vs. 11%, P=0.029), despite 64% of patients were clustered in lower-risk categories of the IPSS-R. In the in vitro assay performed at 2 μM AZA, HAP1 ASXL1 knockout cells showed less growth inhibition (26% vs. 46%, P=0.003), lower cell apoptosis (17% vs. 34%, P&amp;lt;0.001) and less cell cycle arrest in G0/G1 phase (6% vs. 23%, P=0.009), compared to HAP1 cells. Conclusion: In MDS patients with del(20q), the alteration of ASXL1 by chromosome deletion or somatic mutation was associated with adverse clinical features and a poorer response to AZA. Its detection at diagnosis would allow the rapid identification of a subgroup of MDS patients with a poor prognosis that could benefit of earlier and more effective therapies. Disclosures Sanz: Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; LaHoffman Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Helsinn: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Ltd.: Membership on an entity's Board of Directors or advisory committees. Tormo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; MSD: Honoraria; Daiichi Sankyo: Honoraria; Servier: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees.

Effect of Pembrolizumab (Pembro) Monotherapy Versus Brentuximab Vedotin (BV) on Patients (Pts) with Relapsed/Refractory Classical Hodgkin Lymphoma (R/R cHL): Exploratory Analysis of the Randomized, Phase 3 Keynote-204 Study By Prior Lines of Therapy

Effect of Pembrolizumab (Pembro) Monotherapy Versus Brentuximab Vedotin (BV) on Patients (Pts) with Relapsed/Refractory Classical Hodgkin Lymphoma (R/R cHL): Exploratory Analysis of the Randomized, Phase 3 Keynote-204 Study By Prior Lines of Therapy

TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia

TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Patients with Relapsed/Refractory Marginal Zone Lymphoma in the MAGNIFY Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance

Patients with Relapsed/Refractory Marginal Zone Lymphoma in the MAGNIFY Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance

AML-221: Liposomal Annamycin Overcomes MDR and Has No Cardiac Toxicity in Two Clinical Trials for the Second-Line Treatment of R/R AML

Context This study is determining the lack of any cardiotoxicity and efficacy of L-Annamycin for the second-line treatment of R/R AML. Objective To demonstrate the safety and efficacy of L-Annamycin leading to its approval as the only approved therapy for most patients with R/R AML agnostic of mutational status. Design Two new phase Ib/IIa clinical trials were started in both the U.S. and Europe in 2018 using L-Annamycin for the second-line treatment of R/R AML. These are ongoing proof-of-concept studies that will hopefully lead to accelerated approval for this indication. All patients have received 3 days of intravenous L-Annamycin over 2 hours. Patients are being evaluated for efficacy using the International Working Group response criteria. For the efficacy analysis, 21 subjects will be evaluated and compared to historical controls. All patients will be followed, and OS, as well as subsequent therapies if any (including SCT) will be captured. An update to these results will be presented. Setting All patients are being treated in tertiary care academic medical centers specializing in hematological malignancies and hematopoietic SCT in both Poland and the U.S. Patients Patients who have primarily refractory AML or who have relapsed with AML are eligible for the study. The EF must be >50% to receive therapy. The study is a 3+3 dose escalation followed by an expansion cohort to evaluate safety, toxicity, and efficacy. Two cohorts have been completed in the U.S., and the study met its primary endpoint of safety. There were no SAEs or DLTs, and no patients were withdrawn because of adverse events. In Poland, the first four cohorts have finished, again without any SAEs or DLTs, and no patients were withdrawn because of adverse events. Intervention L-Annamycin IV over 2 hours qd × 3d Main outcome measures 1. Safety; 2. PR and CR according to International Working Group criteria for AML; 3. Assessment of any cardiotoxicity as determined by 3D echocardiography with strain analysis and cardiotoxicity biomarkers, including troponins levels. Results To date, the U.S. study has met its primary endpoint of safety. There were no SAEs or DLTs. No patient was withdrawn due to toxicity. There was one CRi and one PR in the six patients treated. The Polish study has enrolled the first four cohorts and the first patient in the fifth cohort. Of the 13 patients, 7 had relapsed AML, and 6 had primarily refractory AML. As in the U.S., there have been no SAEs, DLTs, or patients withdrawn. There have been no decreases in EF, and all cardiotoxicity markers have remained normal. Dose escalation continues to reach a therapeutic dose. Conclusions Absolutely no cardiotoxicity has been seen, along with preliminary evidence of efficacy. The investigational agent has received fast track and orphan designation in the U.S. A meeting with the FDA has been scheduled to ask for a single-arm phase 2 study for accelerated approval. If successful, this will be the first approved therapy for all patients with R/R AML agnostic of mutational status. Funding The study is supported by funding from the sponsor, Moleculin Biotech, LLC.

KEYNOTE-204: Randomized, open-label, phase III study of pembrolizumab (pembro) versus brentuximab vedotin (BV) in relapsed or refractory classic Hodgkin lymphoma (R/R cHL).

8005 Background: PD-1 blockade via pembro monotherapy showed antitumor activity in R/R cHL. KEYNOTE-204 (NCT02684292) was a randomized, international, open-label, phase III study of pembro vs BV in R/R cHL. Methods: Patients (pts) were aged ≥18 y, were post−autologous stem cell transplant (auto-SCT) or ineligible for auto-SCT, and had measurable disease and ECOG PS 0 or 1. BV-naive and BV-exposed pts were eligible. Pts were randomized 1:1 to pembro 200 mg IV Q3W or BV 1.8 mg/kg IV Q3W and stratified by prior auto-SCT (yes vs no) and status after 1L therapy (primary refractory vs relapsed &lt;12 mo vs relapsed ≥12 mo after end of 1L therapy). Primary end points: PFS by blinded independent central review (BICR) per International Working Group (IWG) criteria including clinical and imaging data after auto-SCT or allogeneic SCT (allo-SCT) and OS. Key secondary end points: PFS excluding clinical and imaging data after auto-SCT or allo-SCT (PFS-secondary), and ORR by BICR per IWG, PFS by investigator review per IWG, and safety. Exploratory end point: DOR by BICR per IWG. Results: 304 pts were randomized and 300 were treated (148, pembro; 152, BV); 256 discontinued. Median (range) follow-up: 24.7 (0.6-42.3) mo. 15 pts were BV exposed. Median (range) time on treatment was 305.0 (1-814) and 146.5 (1-794) days with pembro and BV, respectively. Statistically significant improvement was observed with pembro vs BV for primary PFS analysis (HR 0.65 [95% CI 0.48-0.88; P =0.00271]; median 13.2 vs 8.3 mo); 12-mo PFS rates were 53.9% vs 35.6%, respectively. Benefit was observed in all subgroups tested, including pts with no auto-SCT (HR=0.61), primary refractory disease (HR=0.52), prior BV (HR=0.34) and BV naive (HR=0.67). Significant improvement in PFS-secondary was observed with pembro vs BV (HR 0.62 [95% CI 0.46-0.85]; median 12.6 vs 8.2 mo). Per investigator assessment, PFS was longer with pembro vs BV (HR 0.49 [95% CI 0.36-0.67]; median 19.2 vs 8.2 mo). ORR was 65.6% for pembro and 54.2% for BV; CR rates were 24.5% and 24.2%, respectively. Median (range) DOR was 20.7 mo (0.0+ to 33.2+) for pembro and 13.8 mo (0.0+ to 33.9+) for BV. Grade 3-5 TRAEs: 19.6% of pts with pembro and 25.0% with BV. One death due to TRAE occurred with pembro (pneumonia). Conclusions: In pts with R/R cHL, pembro was superior to BV and demonstrated statistically significant and clinically meaningful improvement in PFS across all subgroups, with safety consistent with previous reports. Pembro monotherapy should be standard of care for this pt population with R/R/cHL. Clinical trial information: NCT02684292 .

Mannuronic Acid in Low‐Risk and Intermediate‐1‐Risk Myelodysplastic Syndromes

The discovery of hematologic improvement and bone marrow modification by the drug β-D mannuronic acid (M2000) during treatment of rheumatoid arthritis in phase 1/2/3 clinical trials prompted us to design a new trial to target hematologic deficits in myelodysplastic syndromes (MDS). In this open-label, randomized phase 2 clinical trial, the potential effect and tolerability of drug M2000 was assessed in patients with low- and intermediate-1-risk MDS. The primary efficacy end point was hematologic improvement after 12 weeks of β-D-mannuronic acid therapy. Among 34 enrolled patients, half received their conventional therapy plus β-D-mannuronic acid, and the other half received only conventional drugs. In the conventional + β-D mannuronic acid treatment group, hematologic improvement and development of transfusion independence and/or reduction in transfusion requirements were seen in 12 patients (92.3%) and 1 patient (7.7%), respectively. Moreover, 5 patients (38.5%), 2 patients (15.4%), and 1 patient (7.7%) in the β-D-mannuronic acid-treated group showed hematologic improvement of the major parameters of erythroid, neutrophil, and platelet responses, respectively, based on the International Working Group criteria), whereas in the conventional treatment group as control, no hematologic improvements including erythroid, neutrophil, and platelet response was seen. In this trial, the addition of β-D mannuronic acid to conventional treatment showed promising results in MDS patients with low and intermediate-1 risk with effects on hematologic improvements without significant adverse effect.

Mild Cognitive Impairment in the Migrant Population Living in Europe: An Epidemiological Estimation of the Phenomenon.

Background:The construct of mild cognitive impairment (MCI) is triggering growing clinical and research interest. The detection of MCI may be affected by diverse ethno-cultural determinants possibly influencing the personal and social perception of the individual cognitive functioning as well as the reliability of objective cognitive assessment. These challenges may acquire special relevance in subjects with a migration background and composing ethnic minority groups.Objective:The present study is aimed at providing an estimate of the number of MCI cases occurring in the migrant population living in the extended European Union (EU) in 2018.Methods:The number of MCI cases in older migrants living in Europe and in each of the 32 considered countries was estimated by multiplying the number of migrants, provided by Eurostat, with the age-specific prevalence rates, derived by the harmonized data produced by the COSMIC collaboration and based on different operational definitions of MCI.Results:Nearly 686,000 cases of MCI were estimated in the extended EU by applying age-specific prevalence rates based on the International Working Group criteria. Higher figures were obtained when the Clinical Dementia Rating- and the Mini Mental State Examination-based criteria were applied. The proportion of MCI cases in migrant subjects ranged from 1.1% (Romania) to 54.1% (Liechtenstein) (median: 8.4%; IQR: 4.7%–14.2%).Conclusions:MCI represents and will increasingly constitute a relevant issue in the migrant population living in Europe. The present data reinforce the need of developing approaches and models of care that may be diversity-sensitive and inclusive for a culturally variegated population.