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The Coronavirus Disease 2019 pandemic, caused by the severe acute respiratory syndrome-associated coronavirus (SARS-CoV-2), is having devastating effects on every country around the world. SARS-CoV-2 can be fatal in patients with described risk factors. A question remains as to whether other immunosuppressed populations are at risk for severe complications. There is limited data on the impact of COVID-19 in young patients with bone marrow failure syndromes (BMFs). 29 institutions, from the NAPAAC consortium, reported 4 with BMFs diagnosed with SARS-CoV-2. These patients presented with relatively mild clinical courses, raising questions as to why this apparently low morbidity and mortality

For patients with bone marrow failure syndromes (BMFS) who may tolerate gradual donor engraftment and achieve adequate disease control with stable mixed chimerism, RIC regimens may be preferable to myeloablative regimens. We performed a retrospective analysis of outcomes for patients who underwent HSCT at our institution between 2009 and 2017 for BMFS using an irradiation-free RIC regimen. Fourteen pediatric patients with BMFS received fludarabine (30 mg/m2 IV daily × 3), thiotepa (5 mg/kg IV every 12 hours × 2), and melphalan (70 mg/m2 IV daily × 2) prior to HSCT. Our cohort included the following diagnoses: SAA (n = 7), CAMT (n = 4), SCN (n = 1), DBA (n = 1), and non-Fanconi congenital BMF (n = 1). Seven patients underwent a MSD transplant; seven underwent an unrelated donor transplant. All patients are alive with median follow-up of 1112 days (range 455-2549 days). The median time to neutrophil engraftment was 16 days (range 10-26 days). All were transfusion independent by day + 100. The highest grade of aGVHD was grade 2; 8 (57%) did not develop aGVHD. Four (28.5%) developed extensive cGVHD, 4 (28.5%) developed limited cGVHD, and 6 (43%) did not develop cGVHD. No patients developed SOS. None died from GVHD or infectious complications. HSCT with RIC with fludarabine, thiotepa, and melphalan for BMFS was effective with a tolerable safety profile. Probability of OS at 100 days and 1 year was 100%.

Inherited bone marrow failure syndromes (IBMFS) are a heterogenous group of disorders characterized by cytopenia, systemic abnormalities, and predisposition to hematologic and solid tumor malignancies. These disorders have a variable clinical presentation, even within members of the same family, and some may not present until adulthood. Cytopenias, either uni-lineage or multi-lineage are a common feature at presentation. Early recognition, diagnosis and referral to a hematopoietic stem cell transplantation center is key to achieving long-term survival. Patients with IBMFS have a predisposition to myelodysplastic syndromes, acute leukemia, and solid tumors, which poses specific challenges in their management.

Purpose Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS). Methods We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months–21 years). Results With a median follow-up of 26 months (range 7 months–9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III–IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%. Conclusion This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS. Trial registration ClinicalTrials.gov Identifier: NCT04232085

ObjectivesAt a discussion on molecular/cytogenetic education for hematopathology fellows at the 2018 Society for Hematopathology Program Directors Meeting, consensus was that fellows should understand basic principles and indications for and limitations of molecular/cytogenetic testing used in routine practice. Fellows should also be adept at integrating results of such testing for rendering a final diagnosis. To aid these consensus goals, representatives from the Society for Hematopathology and the Association for Molecular Pathology formed a working group to devise a molecular/cytogenetic curriculum for hematopathology fellow education.Curriculum SummaryThe curriculum includes a primer on cytogenetics and molecular techniques. The bulk of the curriculum reviews the molecular pathology of individual malignant hematologic disorders, with applicable molecular/cytogenetic testing for each and following the 2017 World Health Organization classification of hematologic neoplasms. Benign hematologic disorders and bone marrow failure syndromes are also discussed briefly. Extensive tables are used to summarize genetics of individual disorders and appropriate methodologies.ConclusionsThis curriculum provides an overview of the current understanding of the molecular biology of hematologic disorders and appropriate ancillary testing for their evaluation. The curriculum may be used by program directors for training hematopathology fellows or by practicing hematopathologists.

Background Myelodysplastic syndromes (MDS) represent a group of clonal hematopoietic stem cell disorders that commonly progress to acute myeloid leukemia (AML). The diagnostics, prognostics, and treatment of adult MDS are established but do not directly translate to children and adolescents. Pediatric MDS is a rare disease, characterized by unique cytogenetics and histology compared with adult MDS, and often arises secondary to germline predisposition or cytotoxic exposures. Our objective was to highlight aspects of diagnosis/management that would benefit from further systematic review toward the development of clinical practice guidelines for pediatric MDS. Procedure The North American Pediatric Aplastic Anemia Consortium (NAPAAC) is composed of collaborative institutions with a strong interest in pediatric bone marrow failure syndromes and hematologic malignancies. The NAPAAC MDS working group developed a national survey distributed to 35 NAPAAC institutions to assess data on (1) clinical presentation of pediatric MDS, (2) diagnostic evaluation, (3) criteria for diagnosis, (4) supportive care and treatment decisions, and (5) role of hematopoietic stem cell transplantation (HSCT). Results Twenty-eight of 35 institutions returned the survey. Most centers agreed on a common diagnostic workup, though there was considerable variation regarding the criteria for diagnosis. Although there was consensus on supportive care, treatment strategies, including the role of cytoreduction and HSCT, varied across centers surveyed. Conclusions There is lack of national consensus on diagnosis and treatment of pediatric MDS. This survey identified key aspects of MDS management that will warrant systematic review toward the goal of developing national clinical practice guidelines for pediatric MDS.

Long thought to be too big and too ubiquitous to fail, we now know that human cells can fail to make sufficient amounts of ribosomes, causing a number of diseases collectively known as ribosomopathies. The best characterized ribosomopathies, with the exception of Treacher Collins syndrome, are inherited bone marrow failure syndromes, each of which has a marked increase in cancer predisposition relative to the general population. Although rare, emerging data reveal that the inherited bone marrow failure syndromes may be underdiagnosed on the basis of classical symptomology, leaving undiagnosed patients with these syndromes at an elevated risk of cancer without adequate counselling and surveillance. The link between the inherited ribosomopathies and cancer has led to greater awareness that somatic mutations in factors involved in ribosome biogenesis may also be drivers in sporadic cancers. Our goal here is to compare and contrast the pathophysiological mechanisms underpinning ribosomopathies to gain a better understanding of the mechanisms that predispose these disorders to cancer.

Clonal hematopoiesis as a hallmark of myelodysplastic syndrome (MDS) is mediated by the selective advantage of clonal hematopoietic stem cells in a context-specific manner. Although primary MDS emerges without known predisposing cause and is associated with advanced age, secondary MDS may develop in younger patients with bone marrow failure syndromes or after exposure to chemotherapy, respectively. This article discusses recent advances in the understanding of context-dependent clonal hematopoiesis in MDS with focus on clonal evolution in inherited and acquired bone marrow failure syndromes.

This review summarizes the pathophysiology, genetic background and clinical symptoms of anemias belonging to the group of inherited bone marrow failure syndromes with unilineage failure of erythropoiesis. It sums up the current knowledge of three diseases: Diamond-Blackfan anemia, congenital dyserythropoietic anemia and Fanconi anemia whose pathophysiology was elucidated in detail during the last decade, owing to the rapid development of new molecular-genetic techniques, especially next-generation sequencing. Fanconi anemia is included in this overview because of macrocytosis and/or anemia detected in the majority of the patients before they develop bone marrow failure. The paper also aims at pointing out typical associated anomalies in these diseases which might be overlooked and which can lead to early diagnosis. Unfortunately, the correct diagnosis is often established later in adulthood and, in some cases, as late as at the time of manifestation of malignant disease. Accurate and timely diagnosis of these conditions is extremely important for the determination of appropriate treatment approach, diagnosis of affected family members (especially in the process of bone marrow donor search), and genetic counselling, which can substantially influence the prognosis of these diseases. Key words: congenital dyserythropoietic anemia - Diamond-Blackfan anemia - DNA repair - dyserythropoiesis - Fanconi anemia - inherited bone marrow failure - ribosomopathies.

Inherited bone marrow failure syndromes (IBMFS) represent a heterogeneous group of multisystem disorders that typically present with cytopenia in early childhood. Efforts to understand the underlying hematopoietic stem cell (HSC) losses have generally focused on postnatal hematopoiesis. However, reflecting the role of many of the involved genes in core cellular functions and the diverse nonhematologic abnormalities seen in patients at birth, studies have begun to explore IBMFS manifestations during fetal development. Here, I consider the current evidence for fetal deficits in the HSC pool and highlight emerging concepts regarding the origins and unique pathophysiology of hematopoietic failure in IBMFS.

THE BRAZILIAN SOCIETY FOR BLOOD AND MARROW TRANSPLANTATION (SBTMO) PRESENTS THE BRAZILIAN GUIDELINES ON HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR ACQUIRED APLASTIC ANEMIA AND INHERITED BONE MARROW FAILURE SYNDROMES

Background: An inflammatory bone marrow microenvironment with unchecked immune activation mediated by cytotoxic T cells and defective T regulatory cells contribute to acquired bone marrow failure (BMF) syndromes, including aplastic anemia (AA), myelofibrosis (MF) and hypoplastic myelodysplasia (MDS). Adoptive therapy with allogeneic cord blood (CB) T-regulatory (Treg) cells has shown safety in humans and clinical benefit in graft vs. host disease. Derived from CB, these Treg cells enjoy immune privilege, demonstrate high proliferative index, lack plasticity, and have been shown to consistently suppress inflammation. Therefore, we hypothesized that adoptive therapy with CB Tregs can be utilized as treatment for the inflammatory BMF disorders. Study Design and Methods: This is a phase I clinical trial examining the role of a single infusion of CK0801, an allogeneic, fresh CB Treg product for the treatment of BMF. CK0801 was produced utilizing novel process development that consists of well-defined qualification criteria for the starting material (CB units), parameters for manufacturing and culture-expansion; and well-defined analytic testing and lot release criteria. Three dose-levels were examined: i) 1x10 6 cells/kg; ii) 3x10 6 cells/kg and iii) 10x10 6 cells/kg (NCT03773393). No immune suppression or lymphodepletion was administered. Patients were allowed to continue their ongoing treatment at stable doses. The study followed a 3+3 phase dose-escalation design. Patients aged ≥ 18 yrs with AA, MDS or MF, and available (HLA 3 out of 6) matched CB units were eligible. The primary endpoint is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the Treg infusion defined as any of the following 3 events: i) severe (grade 3 or 4) infusion toxicity within 24 hours (NCI-CTCAE V4.0), ii) regimen related death within 30 days, or iii) severe (grade 3 or 4) cytokine release syndrome (CRS) within 30 days. Secondary endpoints include exploration of efficacy, PB and BM immune reconstitution, and inflammatory cytokines. Results: Nine patients (Pts) have been treated, with a median age of 57 (range, 20-74) with a diagnosis of MF (n=4); AA (N=4) and hypoplastic MDS (n=1). Overall, the patients had received a median of 4 prior therapies (range, 1-5). There were no infusion related reactions and no DLTs in any of the patients. The patient characteristics and day 30 response are summarized in Table 1. The median time to best response was 3 months (range, 1-6) with complete response (n=1); partial response (n=2); symptom response (n=2); anemia response (n=1); stable disease (n=2) and no response (n=1) (Figure 1). The median duration of response was 6 months (range, 1-12). Of the 5 transfusion dependent pts, transfusion independence was reported in 3 pts (AA = 2; MF= 1). Improvement in transfusion requirement was seen in 2 pts (AA=1; hypoplastic MDS = 1). All AA pts continued their immunosuppressive therapies and the 2 MF patients continued their Ruxolitinib. Decrease in inflammatory biomarker levels as well as lower Th17 cells were observed post CK0801 infusion. No impact on the anti-viral activity of the normal CD4+ and CD8+ T cells was observed (data will be presented later). Conclusion: A single infusion of allogeneic CB derived Treg cells (CK0801) is well tolerated, feasible, and may be associated with clinical improvement in patients with immune related bone marrow disorders. Clinical response appears to correlate with a decrease in inflammatory biomarkers. Expansion of the study, including multiple repeated Treg dosing in BMF is planned. Figure 1 Figure 1. Disclosures Kadia: Jazz: Consultancy; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Astellas: Other; AstraZeneca: Other; Novartis: Consultancy; Liberum: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support. Pemmaraju: Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; CareDx, Inc.: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Affymetrix: Consultancy, Research Funding; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; Springer Science + Business Media: Other; Aptitude Health: Consultancy; Plexxicon: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Daver: Novartis: Consultancy; Trovagene: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; ImmunoGen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Hanmi: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Parmar: Cellenkos Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Mukherjee: Vor Biopharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: coinventor on issued and pending patent applications licensed to Vor Biopharma. S.M. has equity ownership and is on the Scientific Advisory Board of Vor Biopharma., Research Funding. Sadeghi: Cellenkos Inc.: Current Employment. DiNardo: Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding. Issa: Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Kura Oncology: Consultancy, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; GSK: Consultancy. Jain: Bristol Myers Squibb: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Beigene: Honoraria; AstraZeneca: Honoraria, Research Funding; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Pfizer: Research Funding; TG Therapeutics: Honoraria; Janssen: Honoraria; Fate Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Verstovsek: Celgene: Consultancy, Research Funding; Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Roche: Research Funding; CTI BioPharma: Research Funding; Genentech: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Background: Small populations of paroxysmal nocturnal hemoglobinuria (PNH)-type cells ( Methods: Patients diagnosed with PNH, AA, MDS or indistinguishable BMF without malignant diseases were prospectively recruited to the study between April 1 st, 2016 and December 31 st, 2019 in Japan. Participants were excluded from the study if treated with eculizumab or ravulizumab. Peripheral blood samples were obtained with informed consent and sent to the single laboratory every 12months (mos) for 36 mos. A high-resolution flow cytometry assay known as OPTIMA method (Ann Hematol 97(12):2289-2297) was used to precisely detect a small population of GPI(-) cells, which defines ≥0.003% PNH-type granulocytes (Gran) and ≥0.005% erythrocytes as an abnormal increase. The quality of life (QOL) of the pts was assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) instruments. All other lab data and clinical information were obtained at each participating institute or hospital on sample collection, and were accumulated by the Japan PNH Study Group for analysis. Results: Total 1,985 pts were registered and 1,813 pts were eligible for analysis. Median age was 67 with 50.5% male patients. PNH-type cells were positive in 50.4% (235/466) of AA, 19.7% (70/355) of MDS, 22.3% (61/273) of suspected PNH, and 33.9% (232/685) of undiagnosed BMF. PNH-type cells were increased in nearly 30% of the pts with RCUD, RCMD, MDS-U, and 5q-, but not in RARS, RAEB-1, or RAEB-2. Time-course data of the size of PNH-type cells were available in 651 pts at 12mos and in 210 pts at 36mos. Small ( Conclusion: PNH-type cells were detected exclusively in AA and low-risk MDS, supporting the hypothesis that the increase of PNH-type cells in BMF underpin the benign immune-mediated feature of the disease. The presence of PNH-type cells predicts a better response to IST in BMF, which is consistent with previous reports. Detection of subclinical PNH-type cells was associated with an improvement of QOL scores in multiple items at 36mos. Those small populations of PNH-type cells stayed subclinical in most of the cases, but caution should be exercised in monitoring the sizes as some may evolve into clinical PNH. Figure 1 Figure 1. Disclosures Ueda: Chugai Pharmaceutical: Consultancy, Honoraria, Research Funding; Alexion Pharma: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Yonemura: Alexion Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Novartis Pharma: Honoraria. Obara: Novartis Pharma: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Alexion Pharma: Honoraria, Research Funding. Ando: Novartis: Honoraria; Kyowa Kirin: Research Funding; Chugai Pharmaceutical: Research Funding; Celgene: Honoraria; Astellas Pharma: Honoraria; Takeda Pharmaceutical: Research Funding. Kawaguchi: Alexion Pharma: Honoraria. Nishimura: Alexion Pharma: Consultancy; Chugai Pharmaceutical: Consultancy; Novartis Pharma: Consultancy; Roche: Consultancy; apellis pharmaceuticals: Consultancy; Biocryst: Consultancy; Sanofi: Consultancy. Nakao: Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Symbio: Consultancy; Alexion Pharma: Research Funding.

Hematopoietic stem cell transplantation (HSCT) represents a curative option for those afflicted with numerous hematologic malignancies and bone marrow failure syndromes. Advances and refinement of the HSCT process have resulted in increasing number of transplants performed on older patients in the recent years. Pre-transplant assessments (PTA) function to risk stratify patients prior to undergoing HSCT in an effort to predict those at higher risk of treatment-related toxicity, to inform risk/benefit assessments and to aid clinical decision making. Traditionally used risk stratification parameters such as chronologic age, comorbidity and performance status may not fully capture physical function, physiologic fitness, highlighting a need for improvement in PTA. Incorporation of frailty measurements in pre-HSCT assessments, particularly in elderly transplant candidates, may result in improving predictive ability of existing tools such as the Hematopoietic Cell Transplantation Comorbidity Index and Karnofsky performance status. Here, we review existing pre-HSCT assessment tools, measures of frailty that may aid in risk stratification for patients undergoing HSCT and directions for future research using frailty in the pre-HSCT setting.

Acquired bone marrow failure syndromes (aBMFS) encompass a wide range of diseases. A study to investigate WT1 expression in BM was conducted in 387 patients with aBMFS in China. The WT1 level in patients with aplastic anemia (AA) was significantly lower than that in patients with paroxysmal nocturnal hemoglobinuria (PNH, p = .023) and myelodysplastic syndrome (MDS, p

The Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes has been conducting prospective registration, central review, and follow-up study for patients with aplastic anemia and myelodysplastic syndrome (MDS) since 2006. Using this database, we retrospectively analyzed the prognosis of patients with MDS. As of May 2016, 351 cases were registered in this database, 186 of which were eligible for the present study. Kaplan–Meier analysis showed that overall survival (OS) curves of the five risk categories stipulated by the revised international prognostic scoring system (IPSS-R) were reasonably separated. 2-year OS rates for the very low-, low-, intermediate-, high-, and very high-risk categories were 95, 89, 79, 35, and 12%, respectively. In the same categories, incidence of leukemic transformation at 2 years was 0, 10, 8, 56, and 40%, respectively. Multivariate analysis revealed that male sex, low platelet counts, increased blast percentage (>2%), and high-risk karyotype abnormalities were independent risk factors for poor OS. Based on these data, we classified Japanese MDS patients who were classified as intermediate-risk in IPSS-R, into the lower risk MDS category, highlighting the need for careful assessment of treatments within low- and high-risk treatment protocols.

Keywords: STAT3, mTOR, Bone Marrow Failure Syndromes, lymphocytes

Inherited bone marrow failure is caused by mutations in genes that are critical for normal cell development or intrinsic cell function. Because of the protean effects of the mutations, multi-organ involvement is common. Compromised growth and early senescence drive strong selective pressure to acquire oncogenic somatic abnormalities. Thus, testing should be performed on non-hematopoietic cells such as fibroblasts.

Inherited bone marrow failure syndromes (BMFS) are rare, distressing, inherited blood disorders of children. Although the genetic origin of these pathologies involves genes with different functions, all are associated with progressive haematopoietic impairment and an excessive risk of malignancies. Defects in energy metabolism induce oxidative stress, impaired energy production and an unbalanced ratio between ATP and AMP. This assumes an important role in self-renewal and differentiation in haematopoietic stem cells (HSC) and can play an important role in bone marrow failure. Defects in energetic/respiratory metabolism, in particular in FA and SDS cells, have been described recently and seem to be a pertinent argument in the discussion of the haematopoietic defect in BMFS, as an alternative to the hypotheses already established on this subject, which may shed new light on the evolution of these diseases.

To the editor: We read with great interest the recent letter in Blood , by Gansner et al, on the topic of pregnancies in patients with an inherited bone marrow failure syndrome (IBMFS).[1][1] We agree that these rare patients have reduced numbers and complicated pregnancies, and we think that our

Myelodysplastic syndromes (MDS) are a diverse group of clonal disorders of hematopoietic stem or progenitor cells that represent the most common class of acquired bone marrow failure syndromes in adults. Despite significant improvement in the pathologic insight into this group of disorders, therapeutic options remain limited and allogeneic hematopoietic stem-cell transplantation is the only treatment that can induce long-term remission in patients with MDS. The goals of therapy for MDS are based on disease prognostication, with a focus of minimizing transfusion dependence and preserving quality of life in low-risk groups and preventing progression of disease to acute myeloid leukemia in high-risk groups. Given the dearth of approved treatment options, there is a marked need for novel therapies across the board, and there are several novel agents currently in the pipeline.Among the promising agents with preclinical and early phase efficacy in higher risk MDS, apoptosis targeting with BCL-2 inhibitors have been a standout. There is also a keen interest in immunotherapy, and targeted agents (genetic, signaling pathways, bispecific antibodies, antibody-drug conjugates, and others described in this review).In this review, we will highlight some of the promising new agents currently under investigation for the management of MDS.

Acute myeloid leukemia or myelodysplastic syndrome in the setting of inherited (germline) mutations or inherited bone marrow failure syndromes.

Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of rare blood disorders due to hematopoiesis impairment, with different clinical presentations and pathogenic mechanisms.

The p53 protein is mostly studied for its capacity to prevent the proliferation of cells with damaged genome. However, while studying p53Δ31/Δ31 mice that express a hyperactive p53 protein, our laboratory uncovered an unexpected role of p53 in the regulation of telomere metabolism. These mice model dyskeratosis congenita (DC), an inherited bone marrow failure syndrome (IBMFS) caused by defects in telomere maintenance. My PhD project combined analyses of mouse models and human cell lines to extend the study of this new function for p53 and to understand the role of the p53 pathway in the development of IBMFS.By extending our analysis of the p53Δ31 mouse model, we revealed that the p53Δ31/Δ31 cells exhibit decreased expression levels for 12 genes mutated in Fanconi anemia (FA), another IBMFS closely related to DC. Furthermore, these cells display a reduced capacity to repair DNA inter-strand crosslinks, a typical feature of FA cells. Our study suggests that a sustained activation of p53 might actually contribute to the clinical overlap between both syndromes. Importantly, we identified the mechanism used by p53 to downregulate telomere metabolism and the FA DNA repair pathway. This regulatory mechanism is indirect, via p21 and E2F4, and largely conserved between mice and humans. In fact, the p53Δ31/Δ31 cells constitute a powerful tool to find p53 target genes downregulated through this regulatory pathway. Accordingly, they were useful to show that two genes essential for centromere structure are also downregulated by p53.p53 activation is clearly involved in the final stages of bone marrow failure, but to-date, the role of p53 hyperactivation in the initiation of IBMFS remains controversial. Indeed, an inactivating mutation of the PARN gene, encoding a ribonuclease, was found in patients with DC. This protein was proposed to destabilize the p53 mRNA while promoting the maturation of the telomerase RNA, so that the consequences of PARN inactivation remain poorly understood. During my thesis, I also studied new mouse models and established human cellular models to determine the contribution of p53 activation in initiating IBMFS in humans. The current results, which are particularly promising, should notably determine the impact of Parn deficiency on the p53 regulatory pathway.In conclusion, we demonstrated that a sustained activation of p53 leads to phenotypes mainly associated with IBMFS. In addition, we showed that p53 suppresses many genes involved in genome maintenance, which may seem surprising in view of the concept of "guardian of the genome" commonly attributed to p53, leading us to revisit this concept. Hence, the results obtained during my thesis should help to better understand the mechanisms involved in bone marrow failure, tumor suppression and aging.; La protéine p53 est surtout étudiée pour sa capacité à empêcher la prolifération de cellules dont le génome est endommagé. Toutefois, en analysant les souris p53Δ31/Δ31 qui expriment une protéine p53 hyperactive, notre laboratoire a découvert un rôle inattendu de p53 dans la régulation du métabolisme des télomères. Ces souris modélisent la dyskératose congénitale (DC), un syndrome d’insuffisance médullaire héréditaire (SIMH) causé par un dysfonctionnement télomérique. Mon projet de thèse a combiné les analyses de modèles murins et de lignées cellulaires humaines afin d’approfondir l'étude de cette nouvelle fonction de p53 et de mieux comprendre le rôle de la voie p53 dans le développement des SIMH.En poursuivant notre analyse du modèle murin p53Δ31, nous avons montré que les cellules p53Δ31/Δ31 présentent une diminution d’expression de 12 gènes mutés dans l’anémie de Fanconi (AF), un autre SIMH étroitement lié à la DC. De plus, ces cellules montrent une capacité réduite à réparer les ponts inter-brins de l’ADN, une caractéristique typique de l’AF. Notre étude suggère que l’activation soutenue de p53 pourrait ainsi contribuer aux similitudes cliniques entre ces deux syndromes. Par ailleurs, nous avons identifié par quel mécanisme p53 régule négativement le métabolisme des télomères et la voie Fanconi de réparation de l’ADN. Ce mécanisme de régulation indirect, via p21 et E2F4, est très conservé entre la souris et l’Homme. De fait, les cellules p53Δ31/Δ31 constituent un outil puissant pour identifier de nouvelles cibles de p53 réprimées par ce mécanisme. Ainsi, elles nous ont permis de montrer que deux gènes essentiels pour la structure des centromères sont réprimés par p53.L’activation de p53 est clairement impliquée dans les étapes ultimes d’une insuffisance médullaire, mais le rôle d’une suractivation de p53 dans l’initiation d’un SIMH chez l'Homme reste, à ce jour, controversé. En effet, une mutation inactivatrice de la ribonucléase PARN a été trouvée chez des patients atteints de DC. Il a été proposé que cette protéine déstabilise l’ARNm de p53 tout en favorisant la maturation de l’ARN de la télomérase, si bien que les conséquences d’une inactivation de PARN restent mal comprises. Au cours de ma thèse, j'ai également étudié de nouveaux modèles murins et établi des modèles cellulaires humains pour déterminer l’implication d’une activation de p53 dans l’initiation d’un SIMH chez l’homme. Les résultats en cours, particulièrement prometteurs, devraient notamment déterminer l’impact d’une déficience en Parn sur la voie de régulation de p53.En conclusion, nous avons montré qu’une activation soutenue de p53 conduit à des phénotypes principalement associés aux SIMH. Par ailleurs, nous avons montré que p53 réprime de nombreux gènes impliqués dans la maintenance du génome, ce qui peut sembler surprenant au regard du concept de « gardien du génome » communément attribué à p53, et nous a amené à rediscuter ce concept. Ainsi, les résultats obtenus pendant ma thèse devraient permettre de mieux comprendre les mécanismes impliqués dans l’insuffisance médullaire, la suppression tumorale et le vieillissement.

Hematopoietic stem cell transplants (HSCTs) are used to treat a variety of conditions, including hematologic malignancies, bone marrow failure syndromes, and immunodeficiencies. Over 60,000 HSCTs are performed annually worldwide, and the numbers continue to increase. Indeed, as new conditioning regimens develop, more and more individuals, including those of older age, will be eligible for transplants. Nevertheless, although HSCTs are clearly a life-saving and necessary treatment for thousands of patients per year, there is still substantial morbidity and mortality associated with the procedure. Of note, skin eruptions in the post-HSCT period are frequent and often significantly reduce quality of life in recipients. Moreover, these cutaneous findings sometimes herald an underlying systemic condition, presenting possible opportunities for timelier intervention. Dermatologists therefore play a vital role in distinguishing life-threatening conditions from benign issues and prompting recognition of critical complications earlier in their course. This article aims to review the major dermatologic conditions occurring in the early post-HSCT period.

PURPOSE OF REVIEW Anaemia is a common haematological presentation in patients with bone marrow failure, yet a challenging condition to treat. As anaemia has a direct impact on the patient's symptoms, managing anaemia in the common bone marrow failure conditions, such as myelodysplastic syndrome will help to improve the quality of life. This review discusses the available treatment options and the benefit of improving the haemoglobin level. RECENT FINDINGS Managing anaemia effectively has shown to improve the patient outcome, yet treatment option remain limited. Recently, activin inhibitors such as Luspatercept have shown to be effective in patients' refractory to ESAs and further clinical trials are ongoing to explore this further. SUMMARY Transfusion still remains the mainstay of treatment in patients not suitable, lost response or refractory to erythropoiesis-stimulating agents (ESAs). Majority of these patients are not suitable for definite treatment options such as bone marrow transplantation. The aim of treatment remains improving the quality of life and newer therapeutic options may offer better and more sustained response.

International audience; The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia. This downregulation is largely conserved in human cells, which suggests that our findings could be relevant to better understand processes involved in bone marrow failure as well as aging and tumor suppression.

Congenital dyserythropoietic anemias (CDAs) are inherited disorders hallmarked by chronic hyporegenerative anemia, relative reticulocytopenia, hemolytic component and iron overload. They represent a subtype of the inherited bone marrow failure syndromes, characterized by impaired differentiation and proliferation of the erythroid lineage. Three classical types were defined by marrow morphology, even if the most recent classification recognized six different genetic types. The pathomechanisms of CDAs are different, but all seem to involve the regulation of DNA replication and cell division. CDAs are often misdiagnosed, since either morphological abnormalities or clinical features can be commonly identified in other clinically-related anemias. However, differential diagnosis is essential for guiding both follow up and management of the patients.

Hypoproliferative anemia results from the inability of bone marrow to produce adequate numbers of red blood cells. The list of conditions that cause hypoproliferative anemia is long, starting from common etiologies as iron deficiency to rarer diagnoses of constitutional bone marrow failure syndromes. There is no perfect diagnostic algorithm, and clinical data may not always clearly distinguish “normal” from “abnormal”, yet it is important for practicing clinicians to recognize each condition so that treatment can be initiated promptly. This review describes diagnostic approaches to hypoproliferative anemia, with particular emphasis on bone marrow failure syndromes.

Background Androgens have been used to treat bone marrow failure syndromes such as aplastic anaemia (AA) since the 1970s, and are currently used as adjuvants to other treatment regimens. Objective To determine the efficacy and response time of androgens in the treatment of AA. Materials and methods A retrospective, analytical-observational nested study in a cohort of patients with AA. The study was conducted from January 2006 to December 2013. Results A total of 63 patients with a mean age of 47 (18–83) years were included in the study. Out of 27 patients in full remission, 17 received some type of immunosuppressant combined with androgens. The use of more than 2 immunosuppressants did not significantly improve response times ( p = 0.311, 95% CI). Mean response time was 725 (331–1119) days; 4-year survival rate was 86%. Conclusions Improved immunosuppressant response rates with adjuvant androgens were mainly observed in patients with severe AA.

Diamond Blackfan anemia (DBA) is an inherited bone marrow failure syndrome. As with the other rare inherited bone marrow failure syndromes, the study of these disorders provides important insights into basic biology and, in the case of DBA, ribosome biology; the disruption of which characterizes the disorder. Thus DBA serves as a paradigm for translational medicine in which the efforts of clinicians to manage DBA have informed laboratory scientists who, in turn, have stimulated clinical researchers to utilize scientific discovery to provide improved care. In this review we describe the clinical syndrome Diamond Blackfan anemia and, in particular, we demonstrate how the study of DBA has allowed scientific inquiry to create opportunities for progress in its understanding and treatment.