PHRM 542 Sickle Cell Disease Therapeutics

Describe the inheritance pattern of sickle cell disease (SCD)

Autosomal recessive

What are the hallmark features of SCD?

Hemolytic anemia

Painful ischemic episodes of vaso-occlusion

Progressive organ failure

Describe the clinical presentation of sickle cell trait (SCT)

Generally asymptomatic

Females present with UTIs

Gross hematuria on exercise

Normal Hgb values

Describe the clinical presentation of SCD

Identifies before 2 months of age

HALLMARKS = hemolytic anemia and vaso-occlusion

What are s/sx of SCD?

Acute and chronic pain

Chronic hemolytic anemia

Splenic sequestration

Organ infarction

Infection

Growth retardation

Eyes

Cardiac enlargement

GI, GU, derm

What lab tests are consistent with SCD?

Hgb 6.0 to 9.0 g/dL

Low HgF with elevated reticulocytes, platelets, and WBCs

Presence of sickled cells on blood smears

Describe neonatal screening for SCD

Hemoglobin electrophoresis, isoelectric focusing, or DNA analysis

What are acute complications of SCD?

Fever and infection, stroke, aplastic crisis, acute chest syndrome, priapism, vaso-occlusive pain episodes, splenic sequestration, VTE

Describe vaso-occlusive pain episodes

Acute painful infarction without changed Hg

Present with deep throbbing pain often with fever and elevated WBC

What are trigger patterns associated with vaso-occlusive pain episodes?

Hypoxemia, dehydration, changes in body temperature

Describe aplastic crisis

Acute decrease in Hgb with decreased reticulocyte, transient suppression of RBC production in response to bacterial or viral infection

How are patients evaluated for aplastic crisis?

CBC, reticulocyte count, CXR, cultures, parvovirus titers

What is the treatment for aplastic crisis?

Supportive = isolation, blood transfusions

Describe acute splenic sequestration

Spleen sequesters large blood volume

Associated with bacterial/viral infections

What are signs and symptoms of acute splenic sequestration?

Rapid decrease in Hgb and Hct with elevated reticulocyte count

Hypotension and shock

Sudden onset of fatigue, dyspnea, distended abdomen, abdominal pain, splenomegaly, vomiting

How should acute splenic sequestration be evaluated?

VS, spleen size, O2 saturation, reticulocyte count, cultures, broad spectrum antibiotic coverage to include S. pneumoniae and H. influenzae

Describe acute chest syndrome

Acute lung injury with new pulmonary infiltrate involving at least one lung segment on CXR with fever and respiratory symptoms

Describe supportive care for acute chest syndrome

Oxygen, fluids, bronchodilators, pain control, incentive spirometry

Empiric antibiotics directed against S. pneumoniae and Mycoplasma pneumoniae/Chlamydia pneumoniae

How can stroke be prevented in SCD patients?

TCD screening beginning at age 2 through at least age 16 years

Chronic transfusion therapy for TCD (> 200 cm/s) results

Describe the acute management of priapism in SCD patients

Stuttering = analgesics, exercise, warm bath

Requires prompt medical attention if lasting more than 2-3 hours

How are SCD patients tested for pulmonary HTN?

Noninvasive testing through Doppler echocardiography, serum NT-proBNP

Full echo by age 8 or with pulmonary symptoms

How should CKD be treated in patients with SCD?

Screen for microalbuminuria annually starting at age 10

Treatment with ACEi

Consider renal transplant for ESKD

How should AKI be treated in patients with SCD?

Supportive care = fluids, avoid nephrotoxic drugs (e.g. NSAIDs)

What are examples of skeletal and skin complications associated with SCD?

Osteonecrosis

Osteomyelitis

Chronic leg ulcers

How should SCD patients be screened for ophthalmologic complications?

Annual eye evaluations starting at age 10 for proliferative retinopathy and vitreous hemorrhage

What are treatments for ophthalmologic complications of SCD?

Laser photocoagulation

Intravitreal injection of anti-VEGF

What are examples of hepatobiliary complications associated with SCD?

Cholelithiasis secondary to chronic hemolysis and bilirubin production leading to gallstones

Cirrhosis may develop from chronic liver occlusion, iron overload or hepatitis

What are examples of cardiac complications associated with SCD?

Left ventricular hypertrophy

Diastolic dysfunction

Heart failure

Acute MI (may be silent)

Give an overview of health maintenance in patients with SCD

Folic acid 1 mg/day

Induction of fetal hemoglobin

Chronic transfusion therapy

Transplantation

Consider gene therapy

What agent is used for induction of fetal hemoglobin?

Hydroxyurea

Why is chronic transfusion therapy used in SCD patients?

Stroke prevention in pediatrics

All patients with prior stroke

What is the goal of chronic transfusion therapy?

Maintain HbS < 30%

When is transplantation used in SCD patients?

HSCT mostly for children/adolescents using matched sibling donor and myoablative conditioning regimen

Describe pneumococcal prophylaxis in SCD patients

Routine childhood prophylaxis until at least age 5

Longer prophylaxis including in adults if episode of sepsis

What agents are used for pneumococcal prophylaxis in children < 3 yrs?

Oral penicillin V potassium 125 mg BID

OR

Amoxicillin 10 mg/kg PO BID

What agents are used for pneumococcal prophylaxis in children 3-5 years?

Pen VK 250 mg PO BID

What agent can be used for pneumococcal prophylaxis in children with a PCN allergy?

Erythromycin 10 mg/kg BID

What is the schedule for the pneumococcal conjugate vaccine (PCV13, Prevnar) in SCD?

4-dose schedule before 23 months of age

2, 4, and then 6 months and age 12-15 months of age at least two months after third dose

What is the schedule for the pneumococcal polysaccharide vaccine (PPSV23, Pneumovax) in SCD?

Given as 2 doses

First dose at 24 months of age and at least 8 weeks after the last PCV13 dose and second dose at 5 years of age

What is the schedule for the influenza vaccine in SCD?

Annually at start of flu season

Beginning at 6 months of age (two doses at least 4 weeks apart)

When is the live flu vaccine (LAIV3) contraindicated in SCD?

Asplenia/functional asplenia

What is the schedule for meningococcal vaccines in SCD?

Four-dose primary series of MenACWY-CRM (Menveo) at 2, 4, 6, and 12 months

Booster 3 years after primary series with MenACWY or MenACWY-D (Menactra) and repeat every 5 years

Children ≥ 10 yrs should receive serogroup B meningococcal vaccine

Why is folic acid used in SCD?

Replaces depleted folate stores to reduce anemia/symptoms

What are the MOAs of hydroxyurea?

Increases HbF levels as well as HbF-containing reticulocytes and intracellular HbF

Antioxidant that reduces neutrophils and monocytes

Increases red cell deformability due to increased intracellular water

Decreases red cell adhesion to endothelium

Increases levels of NO

Describe the onset of the effects of hydroxyurea

Up to 3 weeks for onset of effects on HbF

6 months for the prevention of vascular occlusive events

What are the goals of therapy with hydroxyurea?

Decrease acute/chronic complications, improve QOL, reduce frequency of pain crises

INCREASING HBF 15% TO 20%

What is the initial adult dose of hydroxyurea?

10-15 mg/kg daily in single oral dose

Increased by 5 mg/kg if blood counts stable and no ADEs

What is the initial pediatric dose of hydroxyurea?

20 mg/kg daily

Increased by 5 mg/kg up to 35 mg/kg in 8-week intervals

How should hydroxyurea therapy be monitored?

Blood counts every 2 weeks until stable dose then every 4-6 weeks

Describe the dosing adjustment of hydroxyurea in renal dysfunction

CrCl < 60 mL/min = initial dose of 7.5 mg/kg/day

CrCl 10-50 mL/min = reduce the daily dose by 50%

CrCl < 10 mL/min = administer 20% of the usual dose

Hemodialysis = 7.5 mg/kg/day give after dialysis

What are notable adverse effects of hydroxyurea?

TERATOGENIC = avoid breast feeding

Bone marrow suppression

How should hydroxyurea be monitored for bone marrow suppression?

Monitor CBC every 4 weeks during dose titration and every 8 weeks thereafter

When should doses of hydroxyurea be held?

Hgb < 4.5 g/dL OR

ANC < 2000 /mm^3 OR

PLT < 80,000 /mm^3

Hold until counts return to normal, then restart at a lower dose (2.5-5 mg/kg less)

What else should be monitored in patients on hydroxyurea?

Monitor SCr and LFTs

Can monitor MCV more often than HbF

What is the goal of blood transfusions?

Maintain HbS less than 30% of total to prevent neurological complications (including stroke)

What are examples of gene therapies for SCD?

Casgevy and Lyfgenia

What is the boxed warning of Lyfgenia?

Hematologic malignancy (requires long-term follow up)

What is L-glutamine used for in SCD?

Prevents complications of SSD and reduces vaso-occlusive pain in ages ≥ 5 with frequent episodes (≥ 2 in a year)

Either as an adjunct to hydroxyurea or as an alternative in patients unable to tolerate hydroxyurea

Describe the dosing of L-glutamine in SCD

< 30 kg = 5 g BID

30 to 65 kg = 10 g BID

> 65 kg = 15 g BID

How should L-glutamine be administered?

Mix each dose with 240 mL cold or room temperature beverage or with 120 to 180 mL of food

What is Adakveo used for in SCD?

Humanized, anti-P selectin monoclonal antibody that reduces sickle cell adherence to endothelium