scholarly journals Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria

Blood ◽  
2020 ◽  
Vol 136 (1) ◽  
pp. 36-49
Author(s):  
Lova Sun ◽  
Daria V. Babushok
Keyword(s):  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clonal Selection ◽  
Bone Marrow Failure ◽  
Prognostic Significance ◽  
Increased Risk ◽  
Secondary Myelodysplastic Syndrome ◽  
Somatic Alterations ◽  
Secondary Mds

Abstract Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are pathogenically related nonmalignant bone marrow failure disorders linked to T-cell–mediated autoimmunity; they are associated with an increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately 15% to 20% of AA patients and 2% to 6% of PNH patients go on to develop secondary MDS/AML by 10 years of follow-up. Factors determining an individual patient’s risk of malignant transformation remain poorly defined. Recent studies identified nearly ubiquitous clonal hematopoiesis (CH) in AA patients. Similarly, CH with additional, non-PIGA, somatic alterations occurs in the majority of patients with PNH. Factors associated with progression to secondary MDS/AML include longer duration of disease, increased telomere attrition, presence of adverse prognostic mutations, and multiple mutations, particularly when occurring early in the disease course and at a high allelic burden. Here, we will review the prevalence and characteristics of somatic alterations in AA and PNH and will explore their prognostic significance and mechanisms of clonal selection. We will then discuss the available data on post-AA and post-PNH progression to secondary MDS/AML and provide practical guidance for approaching patients with PNH and AA who have CH.

scholarly journals Idiopathic aplastic anemia vs hypocellular myelodysplastic syndrome

Hematology ◽  
2019 ◽  
Vol 2019 (1) ◽  
pp. 97-104 ◽  
Author(s):  
Jibran Durrani ◽  
Jaroslaw P. Maciejewski
Keyword(s):  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Somatic Mutations ◽  
Chromosomal Abnormalities ◽  
Bone Marrow Failure ◽  
Bone Marrow Failure Syndromes ◽  
Cytogenetic Aberrations ◽  
Risk Of Progression ◽  
Secondary Mds

Abstract Proper diagnostic distinction of bone marrow failure syndromes can often be challenging. In particular, for older patients with idiopathic aplastic anemia (AA), differential diagnosis includes myelodysplastic syndrome (MDS), which can atypically present in a hypocellular form. In addition to blasts and overt dysplasia, the presence of chromosomal abnormalities and a spectrum of somatic mutations may be revealing. Both clonal cytogenetic aberrations and somatic mutations most typically correspond to a clonal myelodysplasia, but clonal somatic mutations have also recently been found in AA. True driver myeloid mutations are uncommon in AA. Marrow hypocellularity in AA and occasionally in MDS patients points toward a similar immune mechanism responsible for deficient blood cell production and indicates that cytopenias in early hypocellular MDS might be treated with immunosuppressive modalities. Primary hypocellular MDS has to be distinguished from post-AA secondary MDS, most commonly associated with del7/7q. Post-AA MDS evolves at the rate of about 10% in 10 years, but recent observations suggest that widespread use of eltrombopag may influence the risk of progression to MDS. This complication likely represents a clonal escape, with founder hits occurring early on in the course of AA. A similar mechanism operates in the evolution of paroxysmal nocturnal hemoglobinuria (PNH) in AA patients, but PNH clones are rarely encountered in primary MDS.

scholarly journals Clinical implications of somatic mutations in aplastic anemia and myelodysplastic syndrome in genomic age

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 66-72 ◽  
Author(s):  
Jaroslaw P. Maciejewski ◽  
Suresh K. Balasubramanian
Keyword(s):  
Stem Cell ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Cell Biology ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Somatic Mutations ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Clonal Diversity ◽  
Clinical Aspects

AbstractRecent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution.

Safety and efficacy of eculizumab in paroxysmal nocturnal hemoglobinuria evolving from patients with myelodysplastic syndrome and aplastic anemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7033-7033
Author(s):  
R. A. Brodsky ◽  
P. Hillmen ◽  
J. Schubert ◽  
L. Luzzatto ◽  
G. Socié ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Rank Test ◽  
Point Increase ◽  
Signed Rank ◽  
Signed Rank Test ◽  
History Of

7033 Background: Myelodysplastic syndrome (MDS) and aplastic anemia (AA) have been reported to be associated with the development of the acquired clonal hemolytic and bone marrow failure disorder, paroxysmal nocturnal hemoglobinuria (PNH). Two recent phase 3 clinical studies have demonstrated significant benefit of the complement inhibitor eculizumab (Soliris) in a heterogeneous population of patients with PNH (n=140). Methods: To investigate whether eculizumab was safe and effective in PNH patients with a history of MDS or AA (n=37), efficacy parameters were examined in the MDS/AA patient subpopulation. Results: Intravascular hemolysis, as assessed by plasma levels of the enzyme lactate dehydrogenase (LDH), was reduced from a mean of 1871 ± 159 U/L at baseline to 300 ± 21 U/L at week 26 in patients with a history of MDS or AA (p<0.001, signed rank test; normal range 103–223 U/L). Anemia was improved as packed RBC transfusion requirements were substantially reduced with eculizumab in these patients from a median of 8 units per patient in the 6 months before treatment to 0 units per patient during eculizumab treatment (p<0.001, signed rank test). Despite history of bone marrow failure, eculizumab treatment markedly improved fatigue with an 11.6 point increase over baseline using the FACIT-Fatigue instrument (p<0.001, signed rank test; a 3 or more point increase in this instrument has been shown to be clinical meaningful). Fatigue was similarly improved with the fatigue scale of the EORTC QLQ-C30 instrument (p<0.001, signed rank test). Eculizumab appeared to be well tolerated when administered to PNH patients with a history of MDS or AA. The significant clinical improvements in hematologic and quality of life outcomes with eculizumab treatment in PNH patients with a history of MDS or AA were similar to the clinical improvements demonstrated the overall PNH patient population. Conclusions: These analyses show that eculizumab treatment may provide important clinical benefit when administered to PNH patients with a history of bone marrow failure. No significant financial relationships to disclose.

Paroxysmal Nocturnal Hemoglobinuria and Pregnancy: The French Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1984-1984
Author(s):  
Sophie de Guibert ◽  
Régis Peffault de Latour ◽  
Nathalie Varoqueaux ◽  
Hélène Labussiere ◽  
Bernard Rio ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Hemolytic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Post Partum ◽  
Bone Marrow Failure ◽  
Mortality Rates ◽  
Maternal Complications ◽  
Foetal Mortality ◽  
Increased Risk ◽  
Prophylactic Anticoagulation

Abstract Abstract 1984 Poster Board I-1006 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired stem cell disorder characterized by hemolytic anemia, bone marrow failure and venous thromboembolism. PNH and pregnancy is associated with an increased risk of complications for both mother and foetus with high maternal and foetal mortality rates (around 10%, Fieni et al, Obst and Gynecol survey, 2006). However, the literature about PNH and pregnancy is scarce. We took advantage of the French PNH registry to systematically review all cases of pregnancy between 1978 and 2008. We thus identified 27 pregnancies occurring in 22 patients. The median age was 21 years (17-41) at PNH diagnosis and 27 years (21-38) at pregnancy. Pregnancy occurred mainly in women who were already diagnosed with PNH (n=20) with a median time of 70.4 months (1-192) between PNH diagnosis and pregnancy. The PNH diagnosis was also made during pregnancy for 4 patients (2 cytopenias and 2 hemolytic anemia). For the remaining 3 cases, PNH diagnosis was made after pregnancy with strong evidence of PNH history during pregnancy. Among the 27 pregnancies, 2 ended in therapeutic abortion and one was complicated by severe intrauterine foetal growth restriction leading to foetal death at 27 weeks of amenorrhea. Twenty four pregnancies gave birth to live newborns. The foetal mortality was 4%. Delivery was preterm in 29% of cases and therapeutically induced in 70% (half cases delivered by caesarean section). Birth weight was less than 3 kg in 53% of cases with one case of high prematurity. During pregnancy, minor maternal complications (not requiring hospitalization and/or intensive care) occurred in all but one of the 22 documented cases and consisted mostly in cytopenias requiring transfusions (14/22). Anemia (Hb<10 g/dl) occurred in 18/22 cases (82%) with 10 patients requiring red blood cell transfusions. Thrombocytopenia (<80.000/mm3) was observed in 16/21 cases (76%), with 10 patients requiring platelet transfusions. Arterial hypertension and diabetes occurred in 6/24 and in 1/24 women, respectively. Major maternal complications during pregnancy were observed in 8% of the patients (n=2/25, aplastic anemia). In one case, the onset of aplastic anemia allowed the diagnosis of PNH at 5 months of pregnancy while in the other case, it was a relapse of a previously treated disease. We did not observe any thrombotic events during pregnancy. Most severe complications appeared in the immediate post partum (PP) period with an incidence rate of 32%. Three thrombotic events were recorded (12.5%): 2 cerebral venous thromboses occurred in the first month of PP, one associated with maternal death. One patient experienced a Budd-Chiari syndrome leading to death at one month PP. Maternal mortality rate in post partum was 8.3%. Other maternal major complications during post partum were hemorrhagic delivery (n=2), febrile neutropenia (n=1), HELLP syndrome (n=1) and hemolysis (n=1). After delivery, two patients experienced late major thrombotic events at 7 and 9 months PP (mesenteric venous thrombosis and cerebral thrombotic event). Concerning thrombosis prophylaxis, 13/24 pregnancies (54%) were accompanied by prophylactic anticoagulation with half of them started during the first or second trimester. In all documented cases, anticoagulation was continued during at least 1 month PP. The 3 post partum thrombotic events appeared in 3 patients whom at least 1 was anticoagulated (one without anticoagulation, one unknown). In conclusion, we confirmed that pregnancy during PNH is associated with an increased risk of complications for both mother and foetus with maternal and foetal mortality rates of 8.3% and 4%, respectively. However, those rates are lower than those previously described in the literature probably because of the preferentially report of selective dramatic cases. Thrombotic events are still the main fatal complication in this context, occurring preferentially during the post partum period. Young women patients with PNH must be informed about the high risk of complications during and after pregnancy. Prophylactic anticoagulation should be started from the sixth month and continued at least until six weeks post partum. Anticoagulation is not always enough to prevent thrombotic complications raising the potential role of Eculizumab in this situation. Disclosures: No relevant conflicts of interest to declare.

Molecular Classification of Bone Marrow Failure Syndromes: Protein Signatures As Surrogate Biomarker for Accurate Diagnosis of Severe Aplastic Anemia, Hypoplastic Myelodysplastic Syndrome and Paroxysmal Nocturnal Hemoglobinuria Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2414-2414
Author(s):  
Ayodele Alaiya ◽  
Hazza A Alzahrani ◽  
Zakia Shinwari ◽  
Tarek Owaidah ◽  
Fahad Al Mohareb ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Accurate Diagnosis ◽  
Bone Marrow Failure Syndrome ◽  
Bone Marrow Failure Syndromes ◽  
Disease Specific

Abstract Background/Purpose: Bone marrow failure syndrome is an example of disease entity where accurate diagnosis of Severe Aplastic Anemia (SAA), Paroxysmal Nocturnal Hemoglobinuria (PNH) and Hypoplastic Myelodysplastic Syndrome (MDS) is very challenging. The aim of this study was to identify panels of disease-specific /disease-associated proteins biomarkers to be used for more objective diagnosis and better prediction of disease prognosis of patients presenting with features of bone marrow failure syndromes. Methodology: Bone marrow plasma (MBP) and peripheral blood plasma (PBP) samples from 20 patients with bone marrow hypoplasia; including AA/MDS/PNH were subjected to expression proteome analysis using label-free quantitative liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Results: Approximately 300 unique protein species were identified of which 107 and 218 were significantly differentially expressed (> 2- ∞- fold change & p < 0.05) in BMP and PBP respectively. These protein fingerprints independently discriminates patients into three distinct clusters; AA/MDS/PNH. Furthermore, only approx. 25% of the proteins were common between the two datasets from BMP and PBP. Some of the identified proteins were filtered and mapped using Ingenuity Pathway Analysis, and were associated with five different networks. The top two of these networks involved cell-to-cell signaling interaction, hematological system development and function, and immune cell trafficking. Only three of the differentially expressed proteins were uniquely expressed in SAA and MDS but absent in PNH, thus making these proteins potential biomarkers. The probable diagnostic utility of these proteins would be validated in large archival clinical samples. Our data indicates the utility of multivariate analysis of quantitative proteome data as a means of discovery of disease related or disease specific biomarkers for bone marrow syndromes. Conclusions: We have identified protein signatures capable of objective classification of bone marrow failure syndromes patients. Our expression proteomics strategy is very promising for identification of clinically useful biomarkers. These proteins once validated, on a larger cohort of patients, might be valuable to complement the currently existing parameters for reliable and objective disease diagnosis, monitoring treatment response and clinical outcome of bone marrow failure syndrome patients. Disclosures Owaidah: King abdulaziz city for science, Novo Nordisk, Bayer: Honoraria, Research Funding.

scholarly journals Hypoplastic Myelodysplastic Syndromes: Just an Overlap Syndrome?

Cancers ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 132
Author(s):  
Bruno Fattizzo ◽  
Fabio Serpenti ◽  
Wilma Barcellini ◽  
Chiara Caprioli
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Clonal Selection ◽  
Cytotoxic T Cells ◽  
Immunosuppressive Treatment ◽  
Young Patients ◽  
Suppressor Cells ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Increased Risk

Myelodysplasias with hypocellular bone marrow (hMDS) represent about 10–15% of MDS and are defined by reduced bone marrow cellularity (i.e., <25% or an inappropriately reduced cellularity for their age in young patients). Their diagnosis is still an object of debate and has not been clearly established in the recent WHO classification. Clinical and morphological overlaps with both normo/hypercellular MDS and aplastic anemia include cytopenias, the presence of marrow hypocellularity and dysplasia, and cytogenetic and molecular alterations. Activation of the immune system against the hematopoietic precursors, typical of aplastic anemia, is reckoned even in hMDS and may account for the response to immunosuppressive treatment. Finally, the hMDS outcome seems more favorable than that of normo/hypercellular MDS patients. In this review, we analyze the available literature on hMDS, focusing on clinical, immunological, and molecular features. We show that hMDS pathogenesis and clinical presentation are peculiar, albeit in-between aplastic anemia (AA) and normo/hypercellular MDS. Two different hMDS phenotypes may be encountered: one featured by inflammation and immune activation, with increased cytotoxic T cells, increased T and B regulatory cells, and better response to immunosuppression; and the other, resembling MDS, where T and B regulatory/suppressor cells prevail, leading to genetic clonal selection and an increased risk of leukemic evolution. The identification of the prevailing hMDS phenotype might assist treatment choice, inform prognosis, and suggest personalized monitoring.

scholarly journals Apoptosis Resistance of Blood Cells From Patients With Paroxysmal Nocturnal Hemoglobinuria, Aplastic Anemia, and Myelodysplastic Syndrome

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2716-2722 ◽  
Author(s):  
Kentaro Horikawa ◽  
Hideki Nakakuma ◽  
Tatsuya Kawaguchi ◽  
Norihiro Iwamoto ◽  
Shoichi Nagakura ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clinical Manifestations ◽  
Interferon Γ ◽  
Apoptosis Resistance ◽  
Molecular Events ◽  
Cd34 Cells ◽  
Factor Α

Bone marrow (BM) hypoplasia is a major cause of death in paroxysmal nocturnal hemoglobinuria (PNH). However, little is known about the molecular events leading to the hypoplasia. Considering the close pathologic association between PNH and aplastic anemia (AA), it is suggested that a similar mechanism operates in the development of their BM failure. Recent reports have indicated apoptosis-mediated BM suppression in AA. It is thus conceivable that apoptosis also operates to cause BM hypoplasia in PNH. If this is the case, PNH clones need to survive apoptosis and show considerable expansion leading to clinical manifestations. We report here that granulocytes obtained from 11 patients with PNH were apparently less susceptible than those from 20 healthy individuals to both spontaneous apoptosis without any ligands and that induced by anti-FAS (CD95) antibody in vitro. The patients' BM CD34+ cells were also resistant to apoptosis induced by treatment with tumor necrosis factor-α, interferon-γ, and subsequently with anti-FAS antibody. In lymphocytes, the pathologic resistance was not discriminated from inherent resistance to apoptosis. Granulocytes from 13 patients with AA and 12 patients with myelodysplastic syndrome (MDS) exhibited similar resistance to apoptosis. CD34+ cells from MDS-BM also showed similar tendency. Thus, the comparative resistance to apoptosis supports the pathogenic implication of apoptosis in marrow injury of PNH and related stem cell disorders.

scholarly journals Paroxysmal Nocturnal Hemoglobinuria Clones Are Infrequent in Hepatitis-Associated Aplastic Anemia at the Time of Diagnosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5016-5016
Author(s):  
Wenrui Yang ◽  
Xin Zhao ◽  
Guangxin Peng ◽  
Li Zhang ◽  
Liping Jing ◽  
...  
Keyword(s):  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Conflicts Of Interest ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Extrinsic Factors ◽  
Clone Size ◽  
Hematopoietic Stem ◽  
Over Time ◽  
Pnh Clone

Aplastic anemia (AA) is an immune-mediated bone marrow failure, resulting in reduced number of hematopoietic stem and progenitor cells and pancytopenia. The presence of paroxysmal nocturnal hemoglobinuria (PNH) clone in AA usually suggests an immunopathogenesis in patients. However, when and how PNH clone emerge in AA is still unclear. Hepatitis associated aplastic anemia (HAAA) is a special variant of AA with a clear disease course and relatively explicit immune pathogenesis, thus serves as a good model to explore the emergence and expansion of PNH clone. To evaluate the frequency and clonal evolution of PNH clones in AA, we retrospectively analyzed the clinical data of 90 HAAA patients that were consecutively diagnosed between August 2006 and March 2018 in Blood Diseases Hospital, and we included 403 idiopathic AA (IAA) patients as control. PNH clones were detected in 8 HAAA patients (8.9%,8/90) at the time of diagnosis, compared to 18.1% (73/403) in IAA. Eight HAAA patients had PNH clone in granulocytes with a median clone size of 3.90% (1.09-12.33%), and 3 patients had PNH clone in erythrocytes (median 4.29%, range 2.99-10.8%). Only one HAAA patients (1/8, 12.5%) had a PNH clone larger than 10%, while 24 out of 73 IAA patients (32.9%) had larger PNH clones. Taken together, we observed a less frequent PNH clone with smaller clone size in HAAA patients, compared to that in IAAs. We next attempted to find out factors that associated with PNH clones. We first split patients with HAAA into two groups based on the length of disease history (≥3 mo and < 3mo). There were more patients carried PNH clone in HAAA with longer history (21.4%, 3/14) than patients with shorter history (6.6%, 5/76), in line with higher incidence of PNH clone in IAA patients who had longer disease history. Then we compared the PNH clone incidence between HAAA patients with higher absolute neutrophil counts (ANC, ≥0.2*109/L) and lower ANC (< 0.2*109/L). Interestingly, very few VSAA patients developed PNH clone (5%, 3/60), while 16.7% (5/30) of non-VSAA patients had PNH clone at diagnosis. We monitored the evolution of PNH clones after immunosuppressive therapy, and found increased incidence of PNH clone over time. The overall frequency of PNH clone in HAAA was 20.8% (15/72), which was comparable to that in IAA (27.8%, 112/403). Two thirds of those new PNH clones occurred in non-responders in HAAA. In conclusion, PNH clones are infrequent in HAAA compared to IAA at the time of diagnosis, but the overall frequency over time are comparable between the two groups of patients. In SAA/VSAA patients who are under the activated abnormal immunity, longer clinical course and relatively adequate residual hematopoietic cells serve as two important extrinsic factors for HSCs with PIGA-mutation to escape from immune attack and to expand. Disclosures No relevant conflicts of interest to declare.

scholarly journals STAT3 mutations indicate the presence of subclinical T-cell clones in a subset of aplastic anemia and myelodysplastic syndrome patients

Blood ◽  
2013 ◽  
Vol 122 (14) ◽  
pp. 2453-2459 ◽  
Author(s):  
Andres Jerez ◽  
Michael J. Clemente ◽  
Hideki Makishima ◽  
Hanna Rajala ◽  
Ines Gómez-Seguí ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Myelodysplastic Syndrome ◽  
Aplastic Anemia ◽  
Somatic Mutation ◽  
Bone Marrow Failure ◽  
Cell Clones ◽  
Key Points ◽  
Stat3 Mutations

Key PointsSTAT3+ T cells are found not only in detected concomitant LGL-BMFs, but in cases in which an LGL expansion was not suspected. Transformation via acquisition of a somatic mutation in T cells may be a mechanism of immune, mainly hypoplastic, bone marrow failure.

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