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Background Sex is a major source of diversity among patients and a sex-informed approach is becoming a new paradigm in precision medicine. We aimed to describe sex diversity in myelodysplastic syndromes in terms of disease genotype, phenotype, and clinical outcome. Moreover, we sought to incorporate sex information into the clinical decision-making process as a fundamental component of patient individuality. Methods In this multicentre, observational cohort study, we retrospectively analysed 13 284 patients aged 18 years or older with a diagnosis of myelodysplastic syndrome according to 2016 WHO criteria included in the EuroMDS network (n=2025), International Working Group for Prognosis in MDS (IWG-PM; n=2387), the Spanish Group of Myelodysplastic Syndromes registry (GESMD; n=7687), or the Dusseldorf MDS registry (n=1185). Recruitment periods for these cohorts were between 1990 and 2016. The correlation between sex and genomic features was analysed in the EuroMDS cohort and validated in the IWG-PM cohort. The effect of sex on clinical outcome, with overall survival as the main endpoint, was analysed in the EuroMDS population and validated in the other three cohorts. Finally, novel prognostic models incorporating sex and genomic information were built and validated, and compared to the widely used revised International Prognostic Scoring System (IPSS-R). This study is registered with ClinicalTrials.gov, NCT04889729. Findings The study included 7792 (58middot7%) men and 5492 (41middot3%) women. 10 906 (82middot1%) patients were White, and race was not reported for 2378 (17middot9%) patients. Sex biases were observed at the single-gene level with mutations in seven genes enriched in men (ASXL1, SRSF2, and ZRSR2 p

Supplementary Methods

Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell– and T cell–dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1–refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells.Significance:Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.This article is highlighted in the In This Issue feature, p. 2659

Supplementary Figures and Figure legends

Patients with myelodysplastic syndrome and ring sideroblasts (MDS-RS) present with symptomatic anemia due to ineffective erythropoiesis that impedes their quality of life and increases morbidity. More than 80% of patients with MDS-RS harbor splicing factor 3B subunit 1 (SF3B1) mutations, the founder aberration driving MDS-RS disease. Here, we report how mis-splicing of coenzyme A synthase ( COASY ), induced by mutations in SF3B1 , affects heme biosynthesis and erythropoiesis. Our data revealed that COASY was up-regulated during normal erythroid differentiation, and its silencing prevented the formation of erythroid colonies, impeded erythroid differentiation, and precluded heme accumulation. In patients with MDS-RS, loss of protein due to COASY mis-splicing led to depletion of both CoA and succinyl-CoA. Supplementation with COASY substrate (vitamin B5) rescued CoA and succinyl-CoA concentrations in SF3B1 mut cells and mended erythropoiesis differentiation defects in MDS-RS primary patient cells. Our findings reveal a key role of the COASY pathway in erythroid maturation and identify upstream and downstream metabolites of COASY as a potential treatment for anemia in patients with MDS-RS.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with heterogeneous presentation, ranging from indolent disease courses to aggressive diseases similar to acute myeloid leukemia (AML). Approximately 90% of MDS patients harbor recurrent mutations , which - with the exception of mutated SF3B1 -have not (yet) been included into the diagnostic criteria or risk stratification for MDS. Accumulating evidence suggests their utility for diagnostic workup, treatment indication and prognosis. Subsequently, in patients with unexplained cytopenia or dysplasia identification of these mutations may lead to earlier diagnosis. The acquisition and expansion of additional driver mutations usually antecedes further disease progression to higher risk MDS or secondary AML and thus, can be clinically helpful to detect individuals that may benefit from aggressive treatment approaches. Here, we review our current understanding of somatic gene mutations, gene expression patterns and flow cytometry regarding their relevance for disease evolution from pre-neoplastic states to MDS and potentially AML.

Cardiovascular and oncological diseases represent the global major causes of death. For both, a novel and far-reaching risk factor has been identified: clonal hematopoiesis (CH). CH is defined as clonal expansion of peripheral blood cells on the basis of somatic mutations, without overt hematological malignancy. The most commonly affected genes are TET2, DNMT3A, ASXL1 and JAK2. By the age of 70, at least 20–50% of all individuals carry a CH clone, conveying a striking clinical impact by increasing all-cause mortality by 40%. This is due predominantly to a nearly two-fold increase of cardiovascular risk, but also to an elevated risk of malignant transformation. Individuals with CH show not only increased risk for, but also worse outcomes after arteriosclerotic events, such as stroke or myocardial infarction, decompensated heart failure and cardiogenic shock. Elevated cytokine levels, dysfunctional macrophage activity and activation of the inflammasome suggest that a vicious cycle of chronic inflammation and clonal expansion represents the major functional link. Despite the apparently high impact of this entity, awareness, functional understanding and especially clinical implications still require further research. This review provides an overview of the current knowledge of CH and its relation to cardiovascular and hematological diseases. It focuses on the basic functional mechanisms in the interplay between atherosclerosis, inflammation and CH, identifies issues for further research and considers potential clinical implications.

The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the ‘European Myelodysplastic Neoplasms Cooperative Group‘ (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response.

Many patients with hematologic malignancies receive RBC transfusion support, which often causes systemic and tissue iron toxicity. Because of their compromised bone marrow function, hematopoietic stem cell transplant (HSCT) recipients are especially vulnerable to excess iron levels. Iron toxicity may compromise transplant engraftment and eventually promote relapse by mediating oxidative and genotoxic stress in hematopoietic stem cells (HSCs) and further impairing the already dysfunctional bone marrow microenvironment in HSCT recipients. Iron toxicity is thought to be primarily mediated by its ability to induce reactive oxygen species and trigger inflammation. Elevated iron levels in the bone marrow can decrease the number of HSCs and progenitor cells, as well as their clonogenic potential, alter mesenchymal stem cell differentiation, and inhibit the expression of chemokines and adhesion molecules involved in hematopoiesis. In vivo, in vitro, and clinical studies support the concept that iron chelation therapy may limit iron toxicity in the bone marrow and promote hematologic improvement and engraftment in HSCT recipients. This review will provide an overview of the current knowledge of the detrimental impact of iron toxicity in the setting of HSCT in patients with hematologic malignancies and the use of iron restriction approaches to improve transplant outcome.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.

Heterogeneity is the disease-defining epithet of myelodysplastic syndromes (MDS), a clonal disorder of hematopoietic stem and progenitor cells. During the last decade, significant progress has been made to better understand the diversity of clinical, molecular, cellular, and immunological factors that are bound to the prognosis and outcomes of patients with MDS. Despite the rapid generation of all of this biological information, how to implement it has fallen short. Redefining clinical tools to use this new information remains a challenge. The holistic integration of novel, high-impact individual risk parameters such as patient-reported outcomes or mutational and immunological data into conventional risk stratification systems may further refine patient subgroups, improve predictive power for survival, and provide a next-generation classification and prognosis system for patients with MDS. Dichotomic treatment strategies in patients with MDS according to their patient and disease profiles highlight the importance of precise risk stratification, which may be complemented by the definition of granular cohorts of patients with myeloid neoplasms and a druggable target (ie, IDH1/2 mutations) across conventional blast thresholds.

Clinical research has resulted in an improvement of treatment options for patients with immune thrombocytopenia (ITP) over the last years. However, only few data exist on the real-life management of patients with ITP. To expand the knowledge, a multicenter, national survey was undertaken in 26 hematology practices distributed all over Germany. All patients with a diagnosis of ITP were documented using questionnaires, irrespective of the diagnosis date over a period of 2 years. Overall, data of 1023 patients were evaluated with 56% of patients being older than 60 years. Seventy-nine percent of the patients had chronic (> 12 months), 16% persistent (> 3–12 months), and 5% newly diagnosed (0–3 months) ITP. In 61% of cases, the disease lasted 3 or more years before survey documentation started. Main strategies applied as first-line therapy consisted of steroids in 45% and a “watch and wait” approach in 41% of patients. During second- and third-line strategies, treatment with steroids decreased (36% and 28%, respectively), while treatment modalities such as TPO-RAs increased (19% and 26%, respectively). As expected, patients with a low platelet count and thus a higher risk for bleeding and mortality received treatment (esp. steroids) more frequently during first line than those with a higher platelet count. Up to a third of patients were treated with steroids for more than a year. Overall, our study provides a cross-section overview about the current therapeutic treatment landscape in German ITP patients. The results will help to improve therapeutic management of ITP patients. Electronic supplementary material The online version of this article (10.1007/s00277-020-04173-5) contains supplementary material, which is available to authorized users.

7016 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4) and FLT3. IRAK4 is critical in triggering inflammation, oncogenesis, and survival of cancer cells. Genetic mutations in the splicing factors SF3B1 and U2AF1 drive overexpression of a highly active long isoform of IRAK4 and have been associated with disease progression and poor prognosis of high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Methods: This is an open-label, phase 1/2a dose escalation and cohort expansion trial (NCT04278768). In phase 1 Dose Escalation, patients with R/R AML or HR-MDS are treated with CA-4948 monotherapy. Phase 1b includes 2 arms of combination therapy: CA-4948 + azacitidine (AZA) and CA-4948 + venetoclax (VEN). The primary objectives of this study are to assess the safety, clinical activity, and identify the Recommended Phase 2 Dose (RP2D) of CA-4948 as monotherapy or in combination with AZA or VEN in R/R AML or HR-MDS. The Phase 2a Dose Expansion includes patients for CA-4948 monotherapy: R/R AML with FLT3 mutation, or AML and HR-MDS R/R to HMA with U2AF1 or SF3B1 mutations. Results: As of December 16th, 2021, 49 patients have been treated in the phase 1 portion, of whom 43 started by September 30th, allowing 2 on-study disease assessments. The median number of prior therapies was 2 (range 1-5). Four monotherapy dose levels of CA-4948 were tested (200 to 500 mg orally BID). No dose-limiting toxicities were observed at 200 mg and 300 mg BID. No Grade 4 or 5 treatment-related AEs (TRAEs) were reported, and all the TRAEs were manageable. Reversible, manageable Grade 3 rhabdomyolysis occurred in 1/26 (4%) patients at 300 mg BID, 2/17 (12%) at 400 mg BID, and 1/3 (33%) at 500 mg BID. RP2D was determined as 300 mg BID. Of 43 patients starting before Sept 30th, 2021, 14 had SF3B1, U2AF1 or FLT3 mutations and demonstrated more promising efficacy. In the 5 evaluable AML patients with spliceosome mutations, 40% reached CR/CRh (1 CR, 1 CRh), both with study duration >6 months. In the 7 spliceosome-mutated HR-MDS patients, 57% reached marrow CR, including 1 with RBC transfusion independence and 1 proceeding to HSCT. One of the three FLT3-mutated AML reached CR, and 2 became FLT3-negative. Among the 29 patients without SF3B1/U2AF1/FLT3 mutations, 1 reached CR and 2 PR. Phase 1b and Phase 2a are ongoing. RNA-seq on selected samples showed decrease in relative expression of IRAK4-long isoforms with response to CA-4948. Conclusions: CA-4948 is well tolerated and effective in heavily pretreated AML and HR-MDS patients, especially in those with U2AF1/SF3B1/FLT3 mutations. No dose-limiting myelosuppression was reported, suggesting CA-4948 may be a candidate for combination therapy. Accrual of Phases 1b and 2a is ongoing. Clinical trial information: 04278768.

Luspatercept (Reblozyl) was recently approved for treating patients with transfusion-dependent lower-risk myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who were not eligible for erythropoiesis-stimulating agents (ESAs) or patients for whom those agents failed. Luspatercept acts as an activin receptor type IIB fusion protein ligand trap that targets the altered transforming growth factor beta pathway in MDS, which is associated with impaired terminal erythroid maturation. Treatment with luspatercept results in decreased SMAD signaling, which enables erythroid maturation by means of late-stage erythroblast differentiation and thus improves anemia. ESAs, the current standard first-line therapeutic option for anemic lower-risk patients with MDS, also improve red cell parameters mainly by expanding proliferation of early erythroid progenitor cells. However, erythropoietin (EPO) and its receptor (EPO-R) are also required for survival of late-stage definitive erythroid cells, and they play an essential role in promoting proliferation, survival, and appropriate timing of terminal maturation of primitive erythroid precursors. Thus, luspatercept joins the mechanism of ESAs in promoting erythroid maturation. Especially in the subgroup of MDS patients with RS, luspatercept showed high clinical activity for the treatment of anemia in the phase 2 (PACE-MDS) trial and subsequently in the phase 3 (MEDALIST) trial, which resulted in approval by both the US Food and Drug Administration and the European Medicines Agency in April 2020. Additional studies are needed to better understand the mechanism of action and pharmacodynamics of this novel agent in MDS.

Currently available targeted therapeutic agents may lead to prolongation of overall survival, but no cure of MDS. Therefore, HCT remains the only potential curative therapy for MDS patients, but the decision for the right candidates and the optimal moment for transplant is still a challenge. The clinical basis to recommend MDS patients for transplantation besides considering only disease-specific factors is currently provided by IPSS. Fit patients with IPSS intermediate 2 or high-risk MDS should be transplanted early in their disease course. In patients with lower-risk IPSS and without poor-risk features, HCT is usually postponed until disease progression to higher-risk disease. The introduction of reduced-intensity conditioning (RIC) regimens have extended the indication for HCT to patients with comorbidities or reduced fitness. Less toxic but intensive regimens prior HCT and further prophylactic strategies to prevent relapse are currently under clinical investigation.

Background: Clonal hematopoiesis (CH) describes the presence of genetic alterations and expansion of clonal cell populations in the peripheral blood (PB) of individuals without clinical manifestation of a hematologic malignancy. CH is a common, age-related state. However, individuals carrying CH are at greater risk for hematologic cancer. It has been shown that presence of TP53- and other high-risk mutations, variant allele frequency (VAF) >10% or multiple mutations in CH carriers may confer a higher risk of preleukemic development and transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Nevertheless, further insights into the role of CH in clonal evolution towards leukemia and elaborating features that are predictive of leukemic progression are needed. Aims: We have recently shown that CH is common in individuals undergoing hip replacement surgery (Hecker, Hartmann et al., Blood 2021). Here, we compared mutational spectrum in these CH individuals to MDS and secondary AML (sAML) cohorts. Additionally, we analyzed spatial and lineage distribution of CH and longitudinally monitored CH and MDS clones over time. Methods: Samples from individuals without known hematologic disease undergoing hip replacement surgery (n=288 samples from 261 individuals), patients with MDS (n=92) or sAML (n=123) were screened for variants in 68 leukemia-associated genes using a targeted sequencing approach (VAF cut off, 1%). Follow-up (FU) PB samples were available for 21 individuals with CH and 16 untreated low-risk MDS patients, 6-24 months after screening. n=5 CH bone marrow (BM) samples carrying six ASXL1-mutations were sorted for seven different cell fractions. Results: At screening, variants were detected in 127/261 (49%) healthy individuals, 84/92 (91%) MDS and 117/123 (95%) sAML patients, with median VAFs of 2.7% (ranging from 1-44%), 18.8% (1.1-87%) and 37.1% (1-99%), respectively. Individuals with CH had a median number of 1 variant per individual, whereas median detected variants per patient increased with clonal evolution with 3 variants in the MDS and 4 variants per patient in the sAML cohort. CH, MDS and sAML showed entity-specific mutation profiles (Figure 1A). Most variants in CH affected epigenetic modifiers, while mutations in splicing factors, signaling pathways and transcription factors increased with clonal progression. During FU, untreated low-risk MDS patients more frequently gained additional mutations compared to CH individuals (7/16 vs 2/21, respectively; p=0.024). However, we did not observe significant changes in clone sizes over time. In 17 hip replacement individuals both femoral heads were removed simultaneously, allowing paired analysis of two different hematopoietic sites. CH prevalence in this subgroup was 70.6% (12/17). Ten individuals showed identical mutation patterns in BM obtained from the right and left femoral head, with little differences in VAFs (Table 1). In contrast, two other individuals showed significant differences in variant detection comparing one to the other side: ASXL1-mutations were only present in one hip sample, whereas all the other variants were detectable in both sides (p To further characterize ASXL1 mosaicism across hematopoietic lineages and differentiation stages, we sorted and sequenced n=5 CH BM samples carrying six ASXL1-mutations for seven different hematopoietic cell fractions. In all cases ASXL1-mutations were identified in CD34 +CD38 -CD90 + hematopoietic stem cells (HSC). VAFs of ASXL1-mutations were differentially distributed (p=0.0049, Kruskal Wallis test): detected VAFs were significantly higher in HSC and common myeloid progenitors (CMP) compared to VAFs in T-cells (p=0.045 and p=0.011, respectively; Dunn´s multiple comparison test; Figure 1B). Conclusions: CH, MDS and sAML show characteristic mutation profiles that remained stable over a 6-24-month period. Gains of additional variants and clonal expansion associated with disease progression. Cellular distribution analysis of ASXL1 CH variants revealed characteristic repartition patterns within the hematopoietic differentiation tree. Additionally, differences in variant detection between cellular BM compartments indicates spatial heterogeneity of CH clones warranting further investigation. J.S.H. and L.H. contributed equally. Figure 1 Figure 1. Disclosures Platzbecker: Geron: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Celgene/BMS: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Goetze: BMS/Celgene: Other: Advisory Board, Research Funding; Abbvie: Other: Advisory Board.

AK+NG eq. cont. Introduction Management of multiple myeloma (MM) improved dramatically in the last decade. However, prognosis is still poor for high-risk MM patients experiencing early relapse (ER) within 12 months after primary diagnosis. While some patients achieve long lasting remission with first-line triple combinations including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) followed by high dose therapy plus autologous stem cell transplantation (ASCT), ER has been recognized as an independent risk factor of resistance to rescue treatments and shorter overall survival (OS). Individual treatment response duration is influenced by several disease-specific and patient-related features. Despite the availability of several MM prognostic scores, the prediction and prevention of ER in MM is still challenging. Our goal was to construct a holistic MM ER prediction model based on machine learning (ML) algorithms. Methods In this study, we applied ML algorithms to sociodemographic, clinical, and cytogenetic data associated with MM ER collected by the Multiple Myeloma Research Foundation (MMRF) CoMMpass consortium. Our model included the following covariates at baseline: gender, age, BMI, ECOG, creatinine, hemoglobin, platelets, neutrophils, calcium, beta-2-microglobuline, albumin, first-line therapy classification (doublet versus triplet, IMiD- versus PI-based versus combination), ASCT within the first year of primary diagnosis, high-risk cytogenetics as well as best response during first year of therapy. Our core patient characteristics in relation to ER are summarized in Table 1. Only complete case documentations were included in the data set (N = 563). To reduce dimensionality and overfitting, continuous data was converted to ordinal data bins according to standard clinical reference ranges (e.g. American Board of Internal Medicine (ABIM) reference ranges for laboratory tests). To ensure that only relevant patient characteristics are used for ER prediction, the Boruta algorithm (version 7.0.0) was used for feature selection using R 4.0.2. Feature independence was assessed by the calculation of correlation between the selected features using the Spearman correlation coefficient for nominal features and the point-biserial correlation coefficient for the comparison of nominal and dichotomous features. Because only few patients experienced ER, the Synthetic Minority Oversampling Technique (SMOTE) was used to correct for imbalance in the target variable. For classification, 14 different ML algorithms were evaluated with the PyCaret 2.0.0 package for Python 3.8.6, using 70% (N=394) of the data as the training set and 30% (N=169) for testing. Hyperparameter tuning and final evaluation was performed for the model with the highest accuracy. Results The feature selection algorithm identified four features as relevant to predict ER in newly diagnosed MM patients enrolled in the MMRF CoMMpass study (Figure 1). Interestingly, factors that usually guide first-line treatment decision like ECOG and kidney function as well as type of induction therapy had no significant impact on risk for ER. The four most important features selected were ´first year best response´, followed by ´ASCT during first year of diagnosis´, ´age´ and ´beta-2-microglobuline´. To rule out bias that might have been introduced by e.g. selecting fitter patients for more intensive regimen, feature independency was assessed as described above. No correlation was identified between the selected features except a weak correlation between age and ASCT with a point-biserial correlation coefficient of -0.35 (Figure 2). The best performing model to predict ER considering the reported relevant features was Gradient Boosting Classification. The final model resulted in an accuracy of 73%, whereas 82% and 69% of the patients in the test data were correctly classified regarding ER and non-ER, respectively. The corresponding AUROC curve is displayed in Figure 3. Conclusions Based on ML algorithms, we identified four features associated with ER in patients with newly diagnosed MM. Our results contribute to the early identification of patients with high risk of ER and thus will guide treatment decision in the future. Moreover, our presented features underline the importance of depth of response to first-line treatment and the role of ASCT to prevent ER even in the era of novel agent-based induction therapies. Figure 1 Figure 1. Disclosures Hochhaus: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; Takeda: Honoraria; Geron: Honoraria. Merz: Sanofi: Honoraria; Takeda: Honoraria; BMS: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Hexal: Honoraria; GSK: Honoraria; Janssen: Honoraria; onkowissen.de: Honoraria.

Using a range of health-related quality of life (HRQoL) instruments, most - but not all - studies of myelodysplastic syndromes (MDS) have reported that lower hemoglobin levels and red blood cell transfusion dependency are associated with worse HRQoL. In addition, some MDS treatments may significantly improve HRQoL, particularly among those patients who respond to therapy; however, the majority of these studies were underpowered for this secondary endpoint. Furthermore, decreased HRQoL has been associated with worse survival outcomes, and HRQoL scores can be used to refine classical prognostic systems. Despite the subjective nature of HRQoL, the importance and validity of measuring it in trials and clinical practice are increasingly being recognized, but properly validated MDS-specific instruments are required. We describe what is currently known about HRQoL in patients with MDS, and the limitations of measuring HRQoL, and we provide some recommendations to improve the measurement of this outcome in future trials.

Albinism can be divided into oculocutaneous albinism (OCA) and ocular albinism (OA). In the differential diagnostics these can be distinguished from rarer syndromes with partial albinism, which are frequently associated with susceptibility to infections and neurological symptoms. The OCA is an autosomal recessive inherited disease of melanin biosynthesis, which leads to complete or partial loss of melanin in the skin, hair follicles and eyes. Of the seven currently known subtypes (OCA 1-7), four are well-characterized (OCA 1-4). These are based on gene mutations, which code for tyrosinase, a key enzyme in melanin synthesis and for further proteins. These play an important role in the catalytic activity of tyrosinase and the structure and function of melanosomes. In the presence of these subtypes, the clinical symptoms and the course of the disease show a pronounced variability, especially in the type and extent of pigmentation of the skin and hair as well as the severity of eye involvement, which makes the phenotypic classification difficult. Treatment priorities are a consistent protection from UV light for prophylaxis against skin cancer and regular preventive investigations. The ocular alterations typical for albinism necessitate timely diagnostics and care by institutions specialized in ophthalmology. Novel strategies for systemic treatment of subtypes of albinism are in preclinical testing. The OA without skin involvement shows X‑linked inheritance, is much rarer and is characterized by reduced pigmentation of the retina and iris, nystagmus and macular hypoplasia, sometimes with substantial loss of visual acuity. The typical ocular symptoms of OA can be manifested to a varying extent in all forms of OCA.

*AK, PP shared first-, UP, HM, LA shared senior authors Introduction: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndrome (HR-MDS) or acute myeloid leukemia (AML), not eligible for intensive chemotherapy or allogeneic stem cell transplantation. However, the majority of patients do not respond to these agents. Patients failing HMA therapy still have a dismal outcome with very limited treatment options available. Bemcentinib (BEM) is a selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor mediating resistance to chemotherapeutic agents and decreased antitumor immune response. AXL is overexpressed on leukemic cells, especially in the stem cell compartment, and represents a potential novel target in patients with MDS and AML. Methods: The multicenter phase 2 BERGAMO trial evaluated the safety and efficacy of BEM in patients with HR-MDS or AML, refractory to or relapsing after at least six or four cycles of either azacitidine (AZA) or decitabine (DAC), respectively. Patients received an initial loading dose of 400mg BEM orally administered on d1-3 of cycle 1 and a maintenance dose of 200mg BEM on d4-28 of cycle 1 as well as on d1-28 in subsequent 28-day cycles. The primary endpoint was overall response rate (CR, CRi, PR or SD) assessed after 4 treatment cycles. All patients who achieved CR, CRi, PR or SD after 4 cycles of BEM were considered as responders and allowed to continue treatment for a total of up to 9 cycles. Non-responding patients stopped treatment after 4 cycles. Secondary endpoints of the trial included a translational project evaluating the role of biomarkers and response. Results: Between 2018 and 2020, 58 patients in 10 European centers were screened (MDS=27/AML=31) with a median age of 78 years (range, 62-86 years). 45 patients (MDS=21, AML=24) received at least one cycle of BEM and were eligible for safety and efficacy analysis after the first 4 months of treatment. Thirty six (80%) out of 45 patients were considered relapsed after a response to HMA, 8 (18%) had primary resistance and 1 patient (2%) had HMA intolerance. The median number of prior AZA or DAC cycles was 13. In addition, 18 patients (40%) (MDS=9/AML=9) were red blood cell transfusion-dependent. Treatment with BEM was generally well tolerated with only low rates of grade 3-4 hematologic toxicities (n=7). Forty-seven serious adverse events (SAE) occurred in 22 patients (MDS=9/AML=13), mostly due to infectious complications (n=12), hematological toxicity (n=4) or gastrointestinal disturbance (n=6). Until the first 4 months of BEM treatment, the median number of BEM treatment cycles received was 1.5 (range, 0.5-4). During study, 9 patients (20%) died due to infection (MDS=1/AML=3), deterioration of general condition (MDS=1/AML=2) and progressive disease (MDS=0/AML=2). BEM treatment is currently ongoing in four patients (MDS=3/AML=1). The primary endpoint was met in 9 of 45 patients (20.0%). Within the MDS cohort 33.3% achieved a response (n=7/21; CR=1, CRi= 3, SD=3), while 8.3% of patients (n=2/24) with AML achieved stable disease(SD). The 4 MDS patients achieving CR/CRi had a normal karyotype and a median baseline IPSS-R score of 4 (range 3-5). Among the MDS non-responders 4 patients had a complex karyotype, median IPSS-R score was 5 (range 3-5). Median baseline bone marrow blast count was 15% vs. 13% and median pretreatment hemoglobin-, platelet- and WBC levels were 9.2 g/dl (range 7.9-11.8 g/dl), 51 G/L(range 26-120 G/L) and 1.9x109/l (range 1.18-8.9 x109/l) vs. 9.6 g/dl (range 7.9-11.3 g/dl), 35 G/L (range 0-167 G/L) and 1.45x109/l (range 0.82-6.97 x109/l) comparing MDS responders (CR/CRi) vs MDS non-responders, respectively. Preliminary data evaluating soluble AXL (sAXL) in blood plasma at baseline showed that 66.6 % (n=2/3) of MDS patients achieving CR/CRi displayed sAXL levels below a defined threshold, while this was only seen in 20% (n=2/10) of MDS non-responders. Conclusion: These results of the prospective phase II BERGAMO trial confirm, that single agent BEM is generally safe and well tolerated in this patient population with an unmet medical need. Importantly, BEM showed clinical efficacy in a subgroup of MDS patients. These encouraging clinical results are being further explored by an in depth translational research program aiming to identify additional molecular and biological prognostic factors associated with response. Disclosures Kubasch: Celgene: Research Funding; Shire: Research Funding; Novartis: Research Funding. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Research Funding. Teipel:janssen: Honoraria. Jentzsch:Novartis: Honoraria; JAZZ Pharmaceuticals: Honoraria. Giagounidis:Novartis: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees. McPherson:BerGenBio ASA: Current Employment. van de Loosdrecht:novartis: Honoraria; celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Platzbecker:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding. Medyouf:Bergenbio: Consultancy, Research Funding. Ades:Celgene/BMS: Research Funding; novartis: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding. OffLabel Disclosure: Bemcentinib is currently undergoing Phase II clinical trials for non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), acute myeloid leukemia /myelodysplastic syndrome (AML/MDS), melanoma and metastatic pancreatic cancer. In 2019, FDA have granted fast track designation to bemcentinib for the treatment of elderly patients with acute myeloid leukemia (AML) whose disease has relapsed.

*UP, LA contributed equally Introduction A significant proportion of lower risk (LR)-MDS patients present with thrombocytopenia, being associated with shortened survival and higher risk of progression to acute myeloid leukemia (AML). Treatment options for patients with LR-MDS and severe thrombocytopenia remain limited apart from transfusion support. Romiplostim (ROM), a thrombopoietin receptor agonist (TPO-RA) has shown safety and efficacy dependent on endogenous TPO levels as well as platelet transfusion history in a poorly defined subset of LR-MDS patients (Giagounidis et al. Cancer 2014, Sekeres et al. BJH 2014). Methods The multicenter phase 2 EUROPE trial investigated potential biomarkers of response (e.g. TPO levels, molecular markers) to single agent ROM in LR-MDS patients with severe thrombocytopenia. Patients were eligible if platelet counts were ≤30 G/L or ≤50 G/L in case of bleeding history. The primary efficacy endpoint was the rate of hematologic improvement of platelets (HI-P, according to IWG 2006 criteria) lasting for at least 8 weeks after 16 weeks of ROM (750µg SC qw) treatment. At the time of screening, patients were assigned into 3 different cohorts based on their previous platelet transfusion events (PTE) as well as centrally assessed TPO serum levels (A: TPO Results From 2015 to 2019, a total of 79 patients were included at 29 trial sites in Germany, France and the Czech Republic. Patients' median age was 74 years (range 42-93), median baseline platelet count was 25.5 G/L (range 3-50 G/L) and they were stratified into cohort A (n=51) or B+C (n=28), respectively. The primary endpoint was met with 34 out of 79 (43%) patients responding (HI-P), with response being markedly higher in cohort A (49%, n=25) vs. cohort B and C (32%, n=9) (p=0.145). Ten (13%) and eight (10%) patients had additional neutrophil (HI-N) and erythroid (HI-E) responses, respectively. During treatment, six patients had transient increases in peripheral blasts to more than 10% and one patient progressed to AML after one month of ROM. Although a higher number of responders was observed in group A, neither TPO level at screening (p=0.21), nor number of pretreatment PTE (p=0.12) were significantly associated with response to ROM treatment. Thus, our findings do not confirm that baseline TPO levels and number of pretreatment PTE alone allow reliable prediction of response to ROM. With the aim to identify new molecular patterns correlating with response, we performed a targeted NGS analysis for somatic variants in 54 candidate genes in 75 patients at baseline and in 44 patients after 16 weeks of ROM. Responders (R) more frequently exhibited mutations like SRSF2 (R=39%, NR=17%), RUNX1 (R=24%, NR=14%) and TET2 (R=30%, NR=29%), whereas non-responders (NR) exhibited mutations like DNMT3A (R=12%, NR=21%), U2AF1(R=9%, NR=14%) or ASXL1 (R=6%, NR 17%) more frequent. The percentages of patients with a response to ROM were similar regardless of total number of baseline somatic mutations. Comparing responders vs. non-responders, we found no significant changes of variant allelic burden of variants detected pre- and post-ROM (Fig. 1). We identified the presence of a SRSF2 mutation as a significant predictor of response to ROM treatment (p=0.031, logistic regression). Mutated SRSF2 was significantly more frequent in responders (39%) compared to non-responders (17%) (p=0.036, Fisher's exact test) (Fig. 2A,B). We used logistic regression with stepwise backward selection to assess the influence of the presence of ASXL1, DNMT3A, RUNX1, TET2 and SRSF2 mutations on response. Our final regression model excludes the non-significant ASXL1, DNMT3A, RUNX1 and TET2 mutations and includes the significant SRSF2 mutation, resulting in an overall accuracy of 64.0% for a correct ROM response prediction in this patient cohort. Conclusion: This prospective study did not confirm a significant association between response to ROM, pretreatment PTE burden and endogenous TPO levels. Instead, patients with a mutated SRSF2 displayed a significantly higher response to ROM treatment. This may allow personalized treatment approaches in patients with LR-MDS and severe thrombocytopenia. In this study, extended treatment with ROM did not lead to a significant increase in AML cases. Disclosures Kubasch: Shire: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Giagounidis:AMGEN: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Götze:Celgene: Research Funding. Cony-Makhoul:Novartis: Consultancy; Pfizer: Consultancy; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; BMS: Speakers Bureau. Laribi:takeda: Research Funding; novartis: Honoraria, Research Funding; amgen: Research Funding; abbvie: Honoraria, Research Funding. Park:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Other: Travel expenses. Metzeler:Astellas: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Schlenk:PharmaMar: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Roche: Research Funding; AstraZeneca: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Fenaux:Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Platzbecker:Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Geron: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Ades:Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; novartis: Research Funding; Celgene/BMS: Research Funding; jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Romiplostim is a thrombopoietin receptor agonist indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP). Limitations of Use: Romiplostim is not indicated for the treatment of thrombocytopenia due to myelodysplastic syndrome (MDS) or any cause of thrombocytopenia other than chronic ITP.

International audience; Myelodysplastic syndromes (MDS) with ring sideroblasts are hematopoietic stem cell disorders with erythroid dysplasia and mutations in the SF3B1 splicing factor gene. Patients with MDS with SF3B1 mutations often accumulate excessive tissue iron, even in the absence of transfusions, but the mechanisms that are responsible for their parenchymal iron overload are unknown. Body iron content, tissue distribution, and the supply of iron for eryth-ropoiesis are controlled by the hormone hepcidin, which is regulated by erythroblasts through secretion of the erythroid hormone erythroferrone (ERFE). Here, we identified an alternative ERFE transcript in patients with MDS with the SF3B1 mutation. Induction of this ERFE transcript in primary SF3B1-mutated bone marrow erythroblasts generated a variant protein that maintained the capacity to suppress hepcidin transcription. Plasma concentrations of ERFE were higher in patients with MDS with an SF3B1 gene mutation than in patients with SF3B1 wild-type MDS. Thus, hepcidin suppression by a variant ERFE is likely responsible for the increased iron loading in patients with SF3B1-mutated MDS, suggesting that ERFE could be targeted to prevent iron-mediated toxicity. The expression of the variant ERFE transcript that was restricted to SF3B1-mutated erythroblasts decreased in lenalidomide-responsive anemic patients, identifying variant ERFE as a specific biomarker of clonal erythropoiesis.

Systemic iron overload (SIO) is a common challenge in patients with hematological diseases and develops as a result of ineffective erythropoiesis, multiple red blood cell (RBC) transfusions and disease-specific therapies. Iron homeostasis is tightly regulated as there is no physiological pathway to excrete iron from the body. Excess iron is, therefore, stored in tissues like liver, heart and bone marrow and can lead to progressive organ damage. The presence of free iron in the form of non-transferrin bound iron (NTBI) is especially detrimental. Reactive oxygen species can also cause stromal damage in the bone marrow and promote leukemic cell growth in vitro. In acute leukemias and myelodysplastic syndromes outcome is worse in patients with SIO compared to patients without. Especially in patients undergoing allogeneic HSCT presence of NTBI before or during transplant has been shown to negatively affect non-relapse mortality and overall survival. Although the mechanisms, of how these effects are mediated by SIO are not very well understood monitoring of iron status by serum markers and imaging techniques is, therefore, mandatory especially in these patients. Whether peri-interventional iron chelation may improve outcome of these patients is part of current clinical research.

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn's disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn's disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn's disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn's disease patients with "bone pain" and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.