Aplastic Anemia and Myelodysplastic Disorders

Hematopoietic stem cell disorders are a group of disorders that result from alterations in the most primitive hematopoietic precursor cells and result in abnormal production in mature blood cells. Can be congenital or acquired. blood cell production can be Ý or ß . Bone marrow can be hypoplastic or hyperplastic.

Clinical manifestations are variable, but generally result form the absence of normal blood cells and /or proliferation of abnormal immature cells.

May transform from one clinical syndrome to another with a variable tendency to transform into acute leukemia

4 Major Categories of Myelodysplastic Disorders:

(1) Aplastic - loss of stem cell pools

(2) Dysplastic - qualitative stem cell abnormalities

(3) Proliferative - uncontrolled stem cell proliferation

(4) Leukemia - malignant transformation of stem cells

Aplastic Anemia

Stem cell disorder characterized by fatty replacement of hematopoietic tissue and pancytopenia. Incidence: 2-25/10⁶ population/year. Occurs in all age groups, 25% of cases before age 20.

Clinical presentation: Bleeding, Infection, Pallor. Slow marrow destruction Þ failure of RBCs

Labs: Pancytopenia Þ Reticulocyte count < 1%, Granulocytes < 500 /mm³, Platelets < 20,000 /mm³. Hypocellular bone marrow

Karyotype – see chromosomal gaps and breaks (not translocations) indicating something wrong with DNA repair.

Etiology:

Congenital – Fanconi’s Anemia (disorder of DNA repairÞ marrow failure with mental retardation, skeletal probs, renal probs).

Acquired – Physical agents (Ionizing radiation), Chemical agents (Organic solvents, benzene), Meds (Chloramphenicol), Infections (Viral hepatitis), Idiopathic.

Pathophysiology: Proliferative defect of hematopoietic precursor cells, Immune reaction against hematopoietic tissue

Therapy:

(1) Supportive care
(2) Immunosuppression
(3) Myelostimulatory therapy
(4) Bone marrow transplantation (only effective treatment)

Myelodysplastic Disorders

acquired clonal disorders of the hematopoietic stem cell (disordered maturation of one or more cell lines) characterized by peripheral blood cytopenias (decreased numbers of circulating RBCs, WBCs or platelets), bone marrow hyperplasia with disordered maturation, and a variable tendency to terminate in acute leukemia.

Clinical presentation: Anemia, leukopenia, thrombocytopenia, macrocytosis. Primarily disease of elderly (50% >70y/o).

Blood smear: dimorphic RBCs (both microcytes and macrocytes), Pelger-huet cells (bilobed PMN with hypogranulation), variable platelet size, monocytosis and/or circulating blasts. Bone marrow: hyperplastic, Ý cellularity for patient’s age (differentiates from aplastic anemia), abnormal megakaryocytes. Aspirate: too many immature cells (nulcear cytoplasmic dysynchrony) in RBC and granulocyte lines. Ringed-sideroblasts

Etiology and Pathophysiology: Etiology is unknown, may be related to toxins, benzene, and alkylating agents used for other malignancies. Myelodysplastic disorders show Clonal proliferation of altered hematopoietic stem cell. Abnormality of genes controlling hematopoietic cell growth and differentiation (ex: Loss of 5q chromosome containing genes for GM-CSF, PDGFR, M-CSF, FMS, IL-3, IL-4, IL-5). Altered genetic make-up of cells leads to abnormalities in the controls of growth and differentiation as well as to a proliferative advantage over normal stem cells. The progenitor cells show ineffective hematopoiesis (increased proliferation in marrow with defective maturation and premature cell death). Mature cells which are produced are functionally defective. As the disease progresses further mutations occur ultimately resulting in loss of capacity to differentiate Þ acute leukemia.

Classification of myelodysplastic disorders:

Myelodysplastic syndromes:

(1) Refractory anemia – benign disorder
(2) Refractory anemia with ringed Sideroblasts
(3) Refractory anemia with excess blasts
(4) Refractory anemia with excess blasts in transformation
(5) Chronic myelomonocytic leukemia

5q- syndrome – refractory macrocytic anemia, abnormal megakaryocytes, thrombocytosis, interstitial deletion of long arm of chromosome 5 (5q^-).

Paroxysmal Nocturnal Hemoglobinuria (PNH) – acquired clonal disorder of hematopoietic stem cell, occurs in young adults, clinical features: intravascular hemolysis, defective hematopoiesis, thrombotic tendency. PNH may arise from aplastic anemia after immunosuppressive therapy, and transform into acute leukemia. Defect is in a single enzyme system responsible for the attachment of phosphoinosital-linked proteins to the cell surface. The sensitivity to hemolytic complement results from failure to express decay activating factor (DAF).

Therapy: Supportive care, differentiating agents, antileukemic chemotherapy, hematopoietic cell growth factors, bone marrow transplantation.