Aplastic Anemia & Myelodysplastic Syndromes
Aplastic Anemia
 Aplastic Anemia – a pancytopenia with bone marrow hypocellularity (<25% cellular)
o Severe AA – very low cell counts, usually indicate a non-spontaneous regression of disease
o Bone marrow – required for Dx of AA
 Pancytopenia etiology – not just AA! Also MDS, neoplasm, toxins, nutritional, genetic, infection, HSM
 AA Classification – include idiopathic, secondary, & inherited
o Idiopathic AA – aplastic anemia is primary disease
o Secondary AA – AA 2o to radiation, chemotherapy, toxins (benzene), drugs, infection
o Inherited AA – such as Fanconi’s anemia
 Diagnosis – blood counts, reticulocyte count, bone marrow biopsy shows loss of cellularity, work-up to rule out other causes
 Grading
o Non-Severe – marrows cellularity <30%, absence of severe pancytopenia, depression of at least 2 blood elements
o Severe – marrow cellularity < 25% or <50% w/ fewer than 30% hematopoietic cells and 2 of the following: ANC <
0.5 X 10^9, platelets < 20 X 10^9, retic count < 40 X 10^9
o Very Severe – as above but ANC < 0.2 X 10^9
 Pathophysiology – damage/destruction/suppression of HSC  depletion of stem cell pool  bone marrow failure  AA
o Direct insult – toxicity of hematopoietic stem cell (HSC) to radiation, chemotherapy, benzene
o Immune-mediated injury – T cells inhibit HSC colony formation; cytotoxins released in marrow
 Treatment – either matched sibling donor transplant (<20, 20-45 if healthy) or immunosuppression (otherwise):
o Non-idiopathic – treat underlying condition
o Supportive care
 Tranfusions – may become refractory, or if multiple needed may need iron chelation
 Antibiotics – to prevent neutropenic infection
 Growth factor support – GCSF, EPO
 Androgens – can stimulate hematopoiesis
o Transplant – allogenic HSC transplantation; cyclophosphamide + ATG immunosuppress, prophylax for GVHD
with MTX/cyclosporine; 88% 4-yr survival; complications are graft failiure, GVHD, secondary malignancy
o Immunosuppression – give anti-thymocyte (T-cell) Ig’s + cyclosporine; stop T-cell inhibition  70% response;
may take 3-4 months to see response, relapse is common but can respond to re-treatment; complications of serum
sickness, renal failure (cyclosporine), HTN, late malignancies (MDS/AML)
Myelodysplastic Syndrome
 MDS – acquired bone marrow failure syndromes, due to production of dysfunctional dysplastic clonal blood cells
 Heterogenous – MDS has many varying subtypes with many varying prognoses
 Bone marrow – usually hypercellular, but producing dysfunctional blood cells
 Dx – made through a morphological review of blood & marrow smears
o Dyserythropoiesis – RBC anisopoikilocytosis, megaloblastic maturation and dysmorphic nuclei
o Dysgranulopoiesis – Pelger-Huet cells (2 lobed nuclei vs. 5/6 nl) and hypogranularity
o Dysplastic platelets – huge platelets
o Dysmegakaryopoiesis – multiple separate nuceli and unilobulate megakaryocytes
 Presentation – cytopenia Sx (anemia symptoms, neutropenic infections, thrombocytopenic hemorrhage)
 Cytogenetics – involves DNA changes acquired in bone marrow only; rarely inherited
o Abnormalities – various chromosomal abnormalities can be important for prognosis/Tx
o Deletion 5q Syndrome – F predominance, 68 yo median, macrocytic anemia, nl-high platelets, erythroid
hyperplasia, hypolobulated megakaryocytes, blasts < 20%, good prognosis, if no other mutations
o Complex karyotypes – more than 3 abnormalities  poor prognosis
 Prevalence – most common in elderly men
 Classification – includes FAB and IPSS:
o French-American-British – classify by amount of blasts in blood/marrow (more = worse)
o International Prognostic Scoring System – risk scores by blasts and karyotyping & cytopenias
o WHO Classification – newest classification system…
 Blast percentage – less blasts  longer survival and decreased conversion to leukemia
 Age – older had lower survival rates even in low-risk IPSS classes
Treatment-Related MDS
 Chemotherapy – treatment for some marrow diseases, but has negative outcomes:
o Alkylating agents – include cyclophosphamide, can put patient at risk for MDS & AML
o Radiation exposure
o MDS Recurrence – can occur 4-5 years after treatment, has poor prognosis
o Genetics – deletion or loss of chromosome 5 and/or 7 and complex karyotypes are common; poor prognosis
MDS Treatment
 Stem Cell Transplant – bone marrow transplant can help cure disease, more successful in young patients
o Eligibility – young, no existing co-morbidities, available donor
o Early low-risk MDS – delay transplant until disease progresses (still have good QOL now)
o Later high-risk MDS – proceed to transplant ASAP
 Erythropoietin Therapy – give EPO to low/int-1 risk pts that are tranfusion dependent
o Refractory – give ESA + GCSF
 Immunosuppressive – clonal amplification of T cells suppresses hematopoiesis so give ATG +/- cyclosporine
Epigenetic Therapy
 Epigenetics – idea that genes can be turned off without destroying them
o Promoter methylation – promoter region of genes can by methylated “off” by cytosine residues
o Methyltransferase – methylates promoter region
o Drug inhibition – azacitidine/decitabine can inhibit methyltransferase  turn on genes again
 Azacitidine – methyltransferase inhibitor, leads to better blood counts & survival and decreased progression to AML in
patients with MDS
 Decitabine – same deal as azacitidine…
 Lenalidomide – oral drug, stops MDS clone, sensitizes cells to EPO, decreases apoptotic cytokines
o Inhibits MDS clone – will slow down MDS clone replication, also signal T-cell attack of clone
o Promotes better growth – sensitizes cells to EPO (more RBCs), decreases apoptosis
o Deletion 5q Syndrome – showed immensely positive response to lenalidomide
Treatment Summary
 Calculate IPPS and cytogenetic analysis
 Trial of ESA if anemic
 Low/int-1 risk dz and del(5q), lenalidomide trial
 Azacitidine or decitabine for symptomatic MDS
 Allogeneic stem cell transplant for high-risk, young, healthy and available donor patients