SBJ-24 Myelodysplastic Syndromes and Aplastic Anemia crc

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Mark Fesler MDS AA

Increased, occasionally normocellular or hypocellular

BM cellularity in Myelodysplastic syndromes?

Normal or increased, <20%

If >20%, then it is an acute leukemia

% marrow blasts in Myelodysplastic syndromes?

Present, but usually abnormal, or dysplastic

Maturation in Myelodysplastic syndromes?

Usually minimal, but can vary

Maturation in acute leukemias?

By definition, >20%, except in some specific cases

% marrow blasts in acute leukemias?

MDS: cytopenia(s) typical
AML: WBC variable, usually anemia and thrombocytopenia

Blood counts in MDS vs AML?

Uncommon in both

Organomegaly in MDS vs AML?

Acute leukemia

A lot of blasts, and not a lot of normal end points

Myelodysplastic disorders
Showing:
Nucleated RBC
Large and abnormal platelet
Bilobed neutrophil

These abnormal cells are often killed via apoptosis in the BM, BM often hypercellular, and there are peripheral blood cytopenias

Dysplasia or dyspoiesis in erythroid, myeloid, and/or megakaryocytic lineages

Clonal hematopoietic stem cell neoplasm

Hypercellular bone marrow with peripheral blood cytopenias

Dysplasia or dyspoiesis in erythroid, myeloid, and/or megakaryocytic lineages

What is a myelodysplastic syndrome?

Normal RBCs
Normal neutrophil (cells have granularity in cytoplasm, which is normal)
Normal band cell

These cells are actually abnormal.
Segmented neutrophil has too few lobes, and there is not enough granularity to the cytoplasm (compare to last slide)

Dyspoietic white cell: Bilobed neutrophil. This cell also lacks granularity in its cytoplasm.
PseudoPelger-Huet anomaly

Neutrophil is much larger and has a lot of lobes (8-9 lobes). Can be a myelodysplastic syndrome, dyspoiesis or dysplasia.

Hypersegmented neutrophils are also considered to be a sign of megaloblastic anemia.

Normal megakaryocyte that has many lobed nucleus. Spinning off platelets, also seen here. Very large cell

Megakaryocyte in a myelodysplastic syndrome. Cell is still large, but nucleus is fragmented, even to the point of being in blebs out in the periphery. A lot more lobation.

Megakaryocyte in the setting of a myelodysplastic syndrome. It's actually a bit smaller, and it only has one very large nucleus out in the periphery (should be lobulated).

Normal erythroid maturation in the bone marrow
Proerythroblast
As cell matures, the cell gets smaller, chromatin condenses, etc.

Abnormal erythroid precursor in the setting of a myelodysplastic syndrome.
This has three different nuclei (should only have one).

These red cell precursors are in the process of dividing (seen here are some mitotic spindles). This is distinctly abnormal. Orthochromic normoblast.

Myelodysplastic syndrome

Cells just do not look healthy.

Ringed sideroblast
Abnormal finding, fairly specific for a myelodysplasia

Peripheral blood smear of a normal patient (top left)
vs
Blood smear of someone with a myelodysplastic syndrome that affects the RBCs. Very bizarre RBCs of both size and shape.

Evidence of ineffective hematopoiesis (anemia, neutropenia, thrombocytopenia)
Hypercellular marrow <20% blasts (may also rarely be hypocellular)
Evidence of dysplasia on BM examination (typically in more than one lineage)
Careful exclusion of "mimickers," which are diseases that may look like myelodysplasias

How to diagnose an MDS?

B12/folate deficiency
EtOH intake
Chemotherapy or growth factor (erythropoietin, G-CSF)
Viral infections (HIV, CMV, parvovirus)
Autoimmune disorders (SLE)

MDS "mimickers"

Elevated blast percentage (but <20%)
Ringed sideroblasts
Cytogenetic abnormalities

What are the three most specific bone marrow features of a myelodysplastic syndrome?

Fatigue
Symptoms are due to bone marrow failure in those who are symptomatic.

Unlike acute leukemia, symptom onset is typically subacute to chronic, with no hyperleukocytosis, TLS, DIC

Most common symptom of MDS?

Unlike acute leukemia, symptom onset is typically subacute to chronic, with no hyperleukocytosis, TLS, DIC

Major difference between symptoms of acute leukemia and MDS?

No apparent symptoms, but are diagnosed after CBC demonstrates at least one peripheral blood cytopenia. Illness is characterized by peripheral blood cytopenias: mono, bi, pan

Patients, unlike acute leukemia, will typically not present with symptoms of infiltration of organs (organomegaly rare)

Many patients present with MDS how?

Anemia 50-70%
Granulocytopenias and thrombocytopenia less common - 20-50%

Isolated neutropenia or thrombocytopenia unusual

For whatever reason, hits the erythroid lineage much more likely.

What cytopenias do patients with an MDS typical present with?

MDS: 20-30k new cases
AML: 13k new cases

Which is more common: MDS or AML?

Predominately a disease of the elderly: median age 70, incidence greater in men than in women 2:1
Increases with age (people in their 80s, highest incidence of this disease)

Who gets MDS?

Tumor lysis syndrome

TLS stands for what?

Reviewed

Lower risk: RA, RARS
RCUD, RCMD
MDS-U, MDS del(5q)
IPSS low, Int-1 (0-1.0)

Higher risk:
RAEB (-1,-2)
IPSS Int-2, high (>=1.5)

Review the common subtypes, but do not memorize

Percentage of blasts in the bone marrow (the more blasts, the worse prognosis)
Certain karyotypes
Cytopenias (the more cytopenias, the worse the prognosis)

PRognostic indicators of MDS

Normal
-y
del(5q)
del(20q)

Cytogenetic features associated with good prognosis of MDS?

Chromosome 7 abnormality
Complex (greater than or = 3 abn)

Cytogenetic features associated with poor prognosis of MDS?

Development of AML

High risk MDS is associated with what, in addition to bad survival curves?

Not too aggressive:
Growth factors (EPO, G-CSF)
Immunomodulatory agents such as Lenalidomide specific for the 5q subtype of MDS

Treatment of lower risk MDS?

MDS with a del(5q), which is a lower risk MDS. Results in improvement of anemia, and decrease in transfer requirement

Lenalidomide useful to treat what?

Allogeneic stem cell transplant
Methyltransferase inhibitors, such as Azacytidine, Decitabine

Treatment of higher risk MDS?

Pre-leukemia

Myelodysplastic syndrome is basically what?

Patient is bleeding
Platelet count <10,000/ul

Indications for a platelet transfusion for an MDS patient?

Ferritin levels. If Ferritin >2500 ng/ml, aim to decrease to <1000

How to measure the need for iron chelation in an MDS patient receiving many transfusions?

G-CSF or GM-CSF

Not recommended for routine infection prophylaxis, but use if recurrent infections happen.

MDS patients who are neutropenic might be treated with what?

Lenalidomide

Usually this will relieve their symptomatic anemia

MDS with a del(5q) should be treated with what?

Symptomatic anemia

Patients with an MDS due to del (5q) usually have what?

Methyltransferase inhibitors (e.g. azacytidine, decitabine)

If a patient has a high risk MDS and is not a stem cell candidate, what is the treatment of choice?

ATG (antithymocyte globulin)

MDS low risk that is hypoplastic: treatment of choice?

EPO
MTIs afterward

MDS low risk with a low erythropoietin level?

Azacytidine
Decitiabine (deoxy derivative of Azacytidine)

In the setting of MDS, these prevent the methylation of promoter regions that control the transcription of genes needed for normal maturation.

What are the methyltransferase inhibitors?

Allogeneic hematopoietic stem cell transplant

MDS cure?

Not a blood cancer, an autoimmune disease

0.2/100,000 per year (vs 2-3/100,000 for MDS)

Aplastic anemia: incidence

Younger people:

Slightly more males than females

Aplastic anemia: who gets this?

Drugs
Benzene
Hepatitis
Pregnancy
Eosinophilic fasciitis

Unknown in close to 2/3 of cases, however.

Known causes of aplastic anemia?

Bone marrow failure

Aplastic anemia: how is it characterized, how does it present?

Low platelets: ecchymoses, petechiae, etc. This is due to aplastic anemia

Medication-related
MDS
Deficiencies of B12, folate
AML or ALL
Non-Hodgkin or Hodgkin lymphoma
Aplastic anemia
Myelofibrosis
Viral infectiosn (HIV, CMV, EBV, parvo)
Paroxysmal nocturnal hemoglobinuria
Metastatic carcinomas
Chronic infections (TB, histo)

Bone marrow failure: differential diagnoses?

Autoreactive CD8+ T cells undergo clonal expansion and attack hematopoietic stem cell and progenitor cell.

Aplastic anemia: root cause?

Normal bone marrow aspirate in a middle aged individual. Dark areas are spicules

Bone marrow aspirate in aplastic anemia. Basically purple stromal cells are gone, with fat cells remaining. Hypocellular aspirate.

Bone marrow core normal

Bone marrow core in aplastic anemia

Absolute Neutrophil Count (ANC) <500/uL
Absolute Reticulocyte Count (ARC) <40,000/uL
Platelets <20,000/uL

2 out of 3 criteria

Definition of severe aplastic anemia

ANC <200/uL

Definition of very severe aplastic anemia?

Diagnosis of chronic MAA requires persistently mdoerately depressed counts >3 months

Definition of chronic moderate AA?

Periodic observation via CBC. Don't require treatment necessarily.

Treatment of moderate AA?

Treatment of an autoimmune disease

Treatment scheme for severe AA should follow what?

Bone marrow transplant. These patients do very well.
Cyclosporine (CsA) taper over 6 months

Treatment of severe AA in a patient <35 yo with an HLA matched sibling?

Immunosuppressive therapy (horse ATG + CsA)

Prognosis is still a lot better than MDS or AML.

Treatment of severe AA in a patient >35 yo, or no HLA matched sibling?

Most are pancytopenic at diagnosis

CBC of a patient with aplastic anemia?

Not very common
Prognosis is very bad (usually fatal).

Prognosis and incidence of evolution from AA to MDS, AML?

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