Aplastic anemia resident survival guide

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: ; Chetan Lokhande, M.B.B.S [2]

Definition

Aplastic Anemia is a condition where the bone marrow and the bone marrow cells are damaged. A deficiency of all the three cell types is seen which leads to pancytopenia. Decrease in red blood cells (Anemia) presents as pallor, fatigue, dyspnea and leg pain. Decrease in platelets (Thrombocytopenia) presents as mucosal bleeding, purpura and bruising. Decrease in white blood cells (Neutropenia) manifests as recurrent infection.

Causes

Drug History

• Chemotherapy

• Bone marrow suppressing drugs

• • Chloramphenicol
  • Carbamazepine
  • Felbamate
  • Phenylbutazone
  • Quinine
  • Phenytoin
  • Gold
  • Sulfonamides
  • Nifedipine

• Industrial chemicals and insecticides eg, benzene hexachloride (lindane)

Infection

• Viral Hepatitis

• Parvovirus B19 in children

Congenital /Family History

• Fanconi's Anemia ( 98 % Autosomal recessive and 2 % X-linked recessive )

• Radiation

Miscellaneous

• Thymoma
• Pregnancy
• Radiation

Investigations

Symptoms of dyspnea , fatigue , bleeding and recurrent infection

Check routine Labs, CBC and smear

Pancytopenia

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Bone Marrow Aspirate / Biopsy

1. Chest X-ray 2. Liver function tests 3. Vit B12 / Folate

Genetic / Cytology 1. Chromosomal breakpoint for Fanconi's Anemia 2. Mutational Analysis for Inherited Bone Marrow Failure Syndrome (IBMFS) 3. Flow cytometry for Paroxysmal Nocturnal Hemoglobinuria (PNH). Check CD55 and CD59 expression on RBC for PNH.

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Hypocellular Diagnostic criteria of Aplastic Anemia includes 1. Increased fat / Stroma 2. No Malignant / Fibrotic infiltration 3. Normal Residual hematopoeitic cells with megaloblastic cells Once diagnosed as Aplastic anemia rule out the common causes of Aplastic anemia.

Variable / Infiltrated / Hypercellular Causes are : 1. Myelodysplastic Syndrome 2. Leukemia 3. Hodgkins 4. Storage disorder 5. Anorexia Nervosa 6. Nutritional deficiency 7. Myelofibrosis 8. Solid tumors

Grading

Aplastic anemia

Moderate 1. Bone marrow cellularity < 30 % 2. Absence of severe pancytopenia 3. Depression of atleast 2 / 3rd blood elements

Severe 1. Bone Marrow cellularity < 25 % OR 2. Bone Marrow cellularity < 50 % out of which < 30 % cells are hematopeotic and atleast 2 out of the following : a. Absolute reticulocyte count < 40000 / ul. b. ANC < 500 / ul c. Platelet < 10,000 / ul

Very Severe Same as Severe + Absolute neutrophil count < 200 / ul

Management

Aplastic Anemia

Hematopoietic stem cell transplantation(HSCT)

Immunotherapy

Severe and very severe Aplastic anemia

Patients < 40 yrs old

HLA match

Moderate Aplastic anemia

Patients > 40 Yrs old

HLA not matched hence not a candidate for HSCT

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Drugs used in Immunotherapy

Immunotherapy in Aplastic anemia

Horse ATG ( 20 mg / kg x 4 days ) + Cyclosporine (CSA) ( 12 - 15 mg / kg in divided doses b.i.d x 6 months

Granulocyte colony-stimulating factor ( G-CSF) (5 µg / kg/ day x 90 days)

For relapsing and in countries where ATG is unavailable

Cyclophosphamide (CTX) ( 30 mg / kg IV x 4 days over 1 hr ) + Cyclosporin (CSA) (3 mg / kg / day ) Starting on day 11 to maintain trough and peak blood levels of 150 - 250 mg/ml and 700 - 1000 mg / ml respectively for 180 days

Do's

• Take detailed history of all patients presenting with anemia.
• Have a high suspicion and look for any identifiable causes.
• When treating with ATG keep the platelet count >20,000 / microL at all times. Keep platelets and leukoreduced irradiated blood products readily available.
• Secure a central line which would help in blood drawing , infusing blood products and other fluids.
• When treating with cyclosporine check levels regularly , renal function ( creatinine levels ), blood pressure and for signs of neurotoxicity. Cyclosporine should be given for six months but dosage should be tapered right from the first month to maintain levels of 200 to 250 ng/ml.
• In previously untreated adults use horse ATG instead of rabbit ATG.

Don'ts

• G-CSF should not be used as a primary therapy because that will only delay the onset of effective therapy (Immunosuppressive therapy) . There is an increased incidence of MDS/AML as well as poor outcome in relapsing patients who were treated with G-CSF.
• There is no evidence to use high dose intravenous cyclophosphamide (total dose 200 mg/kg given over four days), with or without cyclosporine in the initial treatment of severe aplastic anemia (SAA) . However, this regimen can be used in patients who did not respond to immunosuppressive therapy.