PHRM 542 Aplastic Anemia Therapeutics

Define aplastic anemia

Syndrome of chronic hematopoietic failure from injury leading to diminished or absent hematopoietic precursors in bone marrow leading to pancytopenia

What are notable causes of aplastic anemia?

Autoimmune mechanisms

Direct injury to hematopoietic stem cells

Viral infection

Clonal and genetic disorders

What are signs and symptoms of aplastic anemia?

Anemia-progressive weakness, pallor, dyspnea, neutropenia, thrombocytopenia

What labs are consistent with a diagnosis of aplastic anemia?

Macrocytic normochromic anemia with reticulopodia, neutropenia and thrombocytopenia

No cytologic abnormalities suggesting underlying malignancy

What test is notable for being used for aplastic anemia diagnosis?

Bone marrow biopsy

Describe a bone marrow biopsy consistent with aplastic anemia

Bone marrow hypocellularity with 2 or more cytopenias

Define bone marrow hypocellularity

Markedly hypocellular and devoid of marrow progenitors

Fat cells and fibrotic stroma replace bone marrow

What is considered a cytopenia?

Absolute reticulocyte cont < 60,000

Neutropenia (severe = ANC < 500)

Thrombocytopenia < 20,000

What are the two classifications of aplastic anemia?

Severe = < 25% bone marrow cellularity

Very severe = severe criteria plus neutropenia < 200

Define absolute neutrophil count (ANC)

The sum of segmented cells and bands in peripheral blood

Measures the percentage of neutrophils in WBC

What is the formula for ANC?

WBC x [(%PMNs + %bands) / 100]

What are supportive treatments for aplastic anemia?

Transfusions

Infection prevention

What is the ideal treatment for severe aplastic anemia?

Allogenic HCT (matched sibling donor) within 6-8 weeks

Done in medically fit patients with no co-morbid diseases with severe disease (usually < 40 years old)

What is the treatment for an AA patient with no matched donor or if they are not physically fit to undergo HCT?

TPO-RA plus IST = triple therapy!

Ex: eltrombopag, ATG, and cyclosporine

What is the dose of eltrombopag for AA?

150 mg orally daily starting on day 1 and continued for 6 months

What is the dose of antithymocyte globulin equine for AA?

40 mg/kg daily for 4 consecutive days

What is the dose of cyclosporine A in AA?

6 mg/kg orally daily in 2 divided doses x 2 years

What is the target trough concentration of cyclosporine?

200-400 ng/mL for first month

200-250 ng/mL for 5 months

When should the initial dose of eltrombopag be dose reduced by 50% (75 mg PO daily)?

Patients with East/Southeast Asian ancestry

Mild, moderate, or severe hepatic impairment

What are boxed warnings of eltrombopag?

Hepatotoxicity

Laboratory test interference

What are notable adverse effects of eltrombopag?

Rash

Skin discoloration/hyperpigmentation

Fetal harm

Cataracts

How can fetal harm from eltrombopag be avoided?

Use contraceptive methods which result in < 1% pregnancy during and for at least 7 days after stopping

Can patients on eltrombopag breast feed?

No

How can cataracts be prevented in patients on eltrombopag?

Baseline ocular exam and after therapy or with s/sx

What other test should be performed in patients with eltrombopag?

Check for clonal abnormalities in bone marrow at baseline and periodically during treatment

When should eltrombopag not be initiated?

Do not initiate if ALT or AST levels are ≥ 5x ULN

How should LFTs be monitored in patients on eltrombopag?

Measure ALT, AST, and bilirubin prior to initiation, every other day while hospitalized for hATG therapy, then every 2 weeks during treatment

When should eltrombopag be dose adjusted?

To maintain AST/ALT ≤ 6x ULN

To maintain platelet count > 50K

Dose reduce when PLT > 200-400K

When should eltrombopag be held?

Hold dose when platelets > 400K

Describe the DDI between eltrombopag and polyvalent cations

Chelation occurs resulting in reduced absorption of eltrombopag

What does eltrombopag inhibit?

OATP1B1/1B3

BCRP/ABCG2

UGT

Which medications should be avoided with eltrombopag?

Deferiprone (eltrombopag increases concentrations)

Lorazepam ER (eltrombopag increases concentrations)

What medication's dose should be reduced by 50% when being used with eltrombopag?

Rosuvastatin

How should eltrombopag be taken?

Take on an empty stomach or with a low calcium meal

Take 2 hours before or 4 hours after other medications

How should eltrombopag tablets be taken?

Swallow tablets whole

Do not split, chew, or crush

Do not mix with food or liquids

How should eltrombopag suspensions be taken?

Reconstitute with cool or cold water only

Discard any unused within 30 min

Do not reuse any oral dosing syringes

Store at room temp

How should hATG be administered and monitored?

Requires hospitalization and close monitoring for allergic reactions

Administered via high flow in central vein

Describe the serum sickness-like reaction that can occur from hATG

Nonhuman proteins present in ATG stimulate the production of antibodies (except IgD)

Type III hypersensitivity = formation or deposition of Ag:Ab complexes in vessels/tissues

Usually occurs after about 10-15 days

Describe skin testing prior to hATG administration

Prick with undiluted hATG

If no wheal within 10 min, then prick with diluted hATG intradermal, if still no wheal, administer

Describe pre-medication prior to hATG administration

Prednisone for serum sickness

Diphenhydramine and acetaminophen in general

What are other adverse reactions of hATG?

Thrombocytopenia, leukopenia, urticaria, pruritus

Nausea

Chest pain

Bradycardia

How should patients be counseled while taking hATG?

Do not get live vaccines during treatment

Counsel to report signs of infection

Describe monitoring during hATG treatment

Frequent VS during administration

Daily CBC