Essentials
A bone marrow biopsy is hyper cellular but the pt has anemia and neutropenia? How does this make sense?
MDS is characterized by ineffective hematopoiesis, mutated precursors mature abnormally and many die within the marrow. The marrow can be packed with developing cells while too few healthy mature cells enter the blood, producing cytopenias.
Anemia in MDS causes fatigue an dyspnea; neutropenia increases risk of what ____
thrombocytopenia increases risk of _____
Infection; bleeding/bruising
Extra: dominant clinical burden of MDS is decreased functional mature blood cells. RBC deficits reduce oxygen delivery, neutrophil deficits impair antibacterial defense, and platelet deficits impair primary hemostasis
What can MDS evolve into, and how does a rising marrow blast count change this concern?
Acute myeloid leukemia (AML); increasing blasts suggest progression and a higher likelihood of transformation.
Extra: Broadly speaking in bone marrow MDS without increased blasts: is blasts less than 5% and less than 1% in peripheral blood. For MDS with excess blasts its 5 - <20% blasts in bone marrow and 1- 19% in blood.
Cytopenias worsen as MDS progresses
Two patients have hypercellular marrow. Patient A has thrombocytosis from megakaryocyte proliferation. Patient B has anemia, neutropenia, and dysplastic precursors. Which patient most likely has MDS, who has MPN, Why???
Both diseases have high marrow cellularity but their major functional difference is whether excess proliferation produces circulating cells effectively (MPN) or results in defective maturation and intramedullary death (MDS).
Extra: However! MPN can be cytopenic too in severe cases (Early to spent phase of PMF)
Examine this blood smear. What's characteristic of MDS.
neutrophil Pseudo-Pelger–Huët anomaly (hypolobated/bilobed nuclei) with cytoplasmic hypogranulation.
Extra: MDS-associated granulocytic dysplasia produces neutrophils with decreased nuclear segmentation and reduced granules
One of MDS associated mechy (mechanism of action) is abnormal DNA methylation? Which drug class counteracts this mechy how?
Hypomethylating agents (DNA methyltransferase inhibitors), such as azacitidine or decitabine. They are cytidine analogs that can become incorporated into nucleic acids - their DNA-directed activity traps DNA methyltransferase that comes to methylate it, reducing its availability for abnormal methylation and potentially allowing previously silenced genes involved in differentiation and tumor suppression to be expressed.
MDS versus classic nutritional megaloblastic anemia: what findings favor MDS?
Multilineage dysplasia beyond megaloblastic RBC + not a DNA synthesis failure but an expression issue due to abnormal silencing (DNA methylation + histone deacetylation)
Extra: Common mutations driving MDS:
Epigenetic/chromatin and DNA methylation regulation - RNA-splicing machinery - cell-cycle/transcriptional/cohesin regulation.
Ring sideroblasts on Prussian blue stain, defective mitochondrial iron utilization/incorporation into heme cuz of nonfunctional RBC (erythroblasts)
A 66-year-old pt with MDS develops transfusion-dependent anemia, recurrent infections from neutropenia, and increasing marrow blasts. Supportive treatment has been exhausted and they are sick of the temporary relief from the drugs what is a possible definitive therapy?
Allogeneic hematopoietic stem cell transplantation. This is the same for Myeloproliferative neoplasms, it is the only definitive therapy cure at this time.