Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes

Abstract Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.

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Effect of natural killer cells on syngeneic bone marrow: in vitro and in vivo studies demonstrating graft failure due to NK cells in an identical twin treated by bone marrow transplantation

Blood ◽

10.1182/blood.v66.5.1043.bloodjournal6651043 ◽

1985 ◽

Vol 66 (5) ◽

pp. 1043-1046

Author(s):

GD Goss ◽

MA Wittwer ◽

WR Bezwoda ◽

J Herman ◽

A Rabson ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Aplastic Anemia ◽

Nk Cells ◽

Natural Killer ◽

Marrow Transplantation ◽

Bone Marrow Failure ◽

Cell Activity ◽

High Dose

Bone marrow transplantation for severe idiopathic aplastic anemia was undertaken in a patient, using his monozygotic twin brother as the donor. In spite of the use of syngeneic bone marrow, failure of engraftment occurred on two occasions. In vitro studies demonstrated that natural killer (NK) cells from the recipient markedly inhibited the growth of donor bone marrow granulocyte progenitor cells. On a third attempt, successful bone marrow engraftment was achieved following high-dose cyclophosphamide, which has previously been shown to be inhibitory to NK cells. We conclude that NK cell activity may play an important role in bone marrow failure as well as being responsible for at least some cases of aplastic anemia.

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Significance of p53 overexpression in bone marrow biopsies from patients with bone marrow failure: aplastic anemia, hypocellular refractory anemia, and hypercellular refractory anemia

Annals of Hematology ◽

10.1007/s002770050455 ◽

1998 ◽

Vol 77 (6) ◽

pp. 261-264 ◽

Cited By ~ 19

Author(s):

M. T. Elghetany ◽

S. Vyas ◽

G. Yuoh

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Bone Marrow Failure ◽

Refractory Anemia ◽

P53 Overexpression ◽

Bone Marrow Biopsies

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Myelodysplastic syndromes/myeloproliferative overlap neoplasms

Oxford Specialist Handbook: Myeloproliferative Neoplasms ◽

10.1093/med/9780198744214.003.0012 ◽

2020 ◽

pp. 191-203

Author(s):

Eric Padron ◽

Tariq I. Mughal ◽

David Sallman ◽

Alan F. List

Keyword(s):

Bone Marrow ◽

Clinical Trials ◽

Stem Cell ◽

Myelodysplastic Syndromes ◽

Peripheral Blood ◽

Myeloproliferative Neoplasms ◽

Bone Marrow Failure ◽

Disease Outcomes ◽

Genomic Landscape ◽

Bone Marrow Dysplasia

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are haematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) that display a paradoxical bone marrow phenotype hallmarked by myeloid proliferation in the context of bone marrow dysplasia and ineffective haematopoiesis. The unfolding MDS/MPN genomic landscape has revealed numerous mutations in signalling genes, such as CBL, JAK2, NRAS, KRAS, CSF3R, and others involving the spliceosome complex. These observations suggest that comutation of genes involved in dysplasia and bone marrow failure along with those of cytokine receptor signalling may, in part, explain the dual MDS/MPN phenotype. The respective MDS/MPN diseases are identified by the type of myeloid subset which predominates in the peripheral blood. Currently there are no standard treatment recommendations for most patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic endpoints and standardized response criteria for clinical trials.

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Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

Blood Advances ◽

10.1182/bloodadvances.2020001541 ◽

2020 ◽

Vol 4 (21) ◽

pp. 5540-5546

Author(s):

Laurent Schmied ◽

Patricia A. Olofsen ◽

Pontus Lundberg ◽

Alexandar Tzankov ◽

Martina Kleber ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Driver Mutations ◽

Leukemic Transformation ◽

Hematopoietic Stem ◽

Bone Marrow Failure Syndromes ◽

Proinflammatory Responses ◽

Stem And Progenitor Cells

Abstract Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

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