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SICKLE CELL DISEASE:

PREVENTING A CRISISRachel Dyke PharmD

PGY2 Pediatric ResidentThe University of Iowa Stead Family

Children’s Hospital

Rachel reports she has no actual or potential conflict of interest in relation to this presentation

Off label use of medications will not be discussed

DISCLAIMER

Hemoglobin

Disease state review Sickle cell

Thalassemias

Pathophysiology and treatment

Prophylaxis

Iron chelation

In the pipeline

PRESENTATION OVERVIEW

Goal: To appreciate the l imited treatment and prophylactic therapies available for sickle cell disease

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Pharmacists

Understand the pathophysiology of sickle cell disease

Compare thalassemiasand sickle cell diseases

Identify and differentiate between iron chelation therapies

Use the guidelines to direct evidenced based management of sickle cell disease

Technicians

Understand the pathophysiology of sickle cell disease

Compare thalassemia and sickle cell diseases

Communicate the role of specialty pharmacies for iron chelation medications

OBJECTIVES

BLOOD

https://upload.wikimedia.org/wikipedia/commons/6/69/Hematopoiesis_(human)_diagram.png

Metalloprotein tetramer located within erythrocytes that serves as an oxygen transporter 4 subunits

HEMOGLOBIN

http://higheredbcs.wiley.com/legacy/college/tortora/0470565101/hearthis_ill/pap13e_ch19_illustr_audio_mp3_am/simulations/figures/rbc.jpg

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Metalloprotein tetramer located within erythrocytes that serves as an oxygen transporter 4 ferrous iron (Fe2+) binding sites

HEMOGLOBIN

http://higheredbcs.wiley.com/legacy/college/tortora/0470565101/hearthis_ill/pap13e_ch19_illustr_audio_mp3_am/simulations/figures/rbc.jpg

Metalloprotein tetramer located within erythrocytes that serves as an oxygen transporter 4 heme sites to bind oxygen

HEMOGLOBIN

https://www.quora.com/How-is-the-heme-molecule-attached-to-the-globin-protein

Globins α, β, γ, δ, ε, ζ

Hemoglobin A 2 α, 2 β chains

Fetal hemoglobin 2 α, 2 γ chains

Hemoglobin A2

2 α, 2 δ chains

Other hemoglobin variants Hb D-Punjab, Hb G-Philadelphia, Hb Hasharon, etc.

HEMOGLOBIN TYPES AND COMPONENTS

Blood 2011 118:19-27. http://the-healthcare.org/wp-content/uploads/2014/06/Normal-Hemoglobin-Variants-and-Subunits1.png

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GLOBIN CHANGES

Blood. 2008; 112: 3927-3938.

Hereditary diseases of hemoglobin Sickle cell disease Variation in structure

Thalassemia Underproduction

Combination Sickle cell + thalassemia

HEMOGLOBINOPATHY

National Coalition for Health Professional Education in Genetics.. 2013.

Autosomal recessive mutation in the beta globin Hemoglobin S replacement

Iowa newborn screen

SICKLE CELL DISEASE

Iowa Newborn Screening Program. IDPH. http://ww.wefightwewin.org/wp-content/uploads/2013/08/Cells.png, http://evolution.berkeley.edu/evolibrary/article/mutat

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Sickle cell trait (HbαS) One abnormal gene, one abnormal chain

Sickle cell anemia (HbSS)

Two abnormal genes, two abnormal chains

AKA: sickle cell disease

Combination diseases One beta globin replace with hemoglobin S, one replaced with

abnormal variant

Hb SC, Hb SD, Hb SE

Thalassemia Decreased production of alpha or beta chains

TERMINOLOGY

CDC. Thalassemia. 2016; NHLBI. Health Topics: Sickle Cell Disease 2016.

Autosomal recessive or autosomal dominant mutation resulting in unusually low amounts of beta-globin

Beta Types Major (Cooley’s anemia)

Intermedia

β0 thalassemia: absence of beta-globin

β+ thalassemia: reduced amount of beta-globin Severity is not dictated by type “zero vs plus”

BETA THALASSEMIAS

CDC. Thalassemia. 2016; NIH. Genetics Home Reference: Beta Thalassemia 2017.

Autosomal recessive mutation resulting in unusually low amounts of alpha-globin Deletions of HBA1 or HBA2 genes

4 alleles

Alpha Types Silent carrier

Alpha thalassemia trait

HbH: milder form

Hb Bart syndrome Loss of all 4 alpha-globin alleles

ALPHA THALASSEMIAS

CDC. Thalassemia. 2016; NIH. Genetics Home Reference: Alpha Thalassemia 2017.

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PATHOPHYSIOLOGY OF VASO-OCCLUSIVE EVENTS

AND TREATMENT

RBCs sickle with deoxygenation Increased adhesion

Decreased flexibility

Leads to microvascular occlusions & ischemia

Common sites of aggregation Lungs

Spleen

Kidneys

Liver

Bones

Brain

Penis

VASCULAR OCCLUSION

NEJM. 1999; 340 (13): 1021-1030. http://www.newsworks.org/images/stories/flexicontent/l_sickle-cell.jpg

Anemia

Fatigue

Pain

Dactylitis

Frequent infections

Stunted growth

End organ damage

Iron accumulation

COMPLICATIONS

Dactylitis

Bone infarcts

NEJM. 1999; 340 (13): 1021-1030. http://medical-photographs.com/images/infectious%20diseases/genetic-blood-dyscrasias/2.jpg. http://www.radiologyassistant.nl/data/bin/a509797a3920b8_Schermafbeelding-2010-02-23.jpg

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Acute chest syndrome

Splenic sequestration

Priapism

Stroke

SICKLE EMERGENCIES

APON. Sickle Cell Disease. 2012.

Mild-moderate pain: oral or parenteral NSAIDs

Severe pain: parenteral opioids NSAID adjuvant

Non-pharmacologic: Heating pad

Distraction

Hydration

Oxygen

ACUTE PAIN CRISIS TREATMENT

NHLBI: Sickle Cell Disease. Expert Panel Report 2014. https://cdn.sicklecellanemianews.com/wp-content/uploads/2015/02/shutterstock_89193115.jpg

Sickled cells become trapped inside the lung

Etiology: generally infection mediated Viral

Bacterial: chlamydia, mycoplasma

Post operative complication

Insidious

Treatment: supportive care, antibiotics! IV cephalosporin + oral macrolide

Oxygen, bronchodilators, analgesia, fluids

ACUTE CHEST SYNDROME

NHLBI: Sickle Cell Disease. Expert Panel Report 2014. Pediatr Rev. 2012; 33(5): 195-204. https://pedsinreview.aappublications.org/content/33/5/195

New pulmonary infiltrates

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Short & long acting opioids for pain not managed by non-opioids NSAID adjuvant

Bowel regimen

Encourage pain agreement 2-4 week prescriptions

Non-pharmacologic: Deep tissue/pressure massage

Muscle relaxation therapy

Self-hypnosis

Hydration

CHRONIC PAIN MANAGEMENT

NHLBI: Sickle Cell Disease. Expert Panel Report 2014

Counseling point:Patients should have a bowel regimen!

Clinical Pearl:Due to chronic pain and frequent exposure, patients may be on extremely high doses of opioids

TREATMENT

Bone marrow transplant Replace sickle erythrocyte progenitors with normal ones

Gene therapy Emerging

Blood transfusions Leukoreduced erythrocytes

THIS IS IT…

NHLBI: Sickle Cell Disease. Expert Panel Report 2014

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IRON CHELATION THERAPY

Transfusion dependent patients are exposed to large amounts of iron over their lifetime 1ml erythrocytes=1 mg iron

Deposits in target organs Liver, pancreas, heart especially vulnerable

Diagnostic gold standard Liver biopsy

Treatment: iron chelation

IRON ACCUMULATION

Clinical Pearl:All iron chelators are specialty medications with limited distribution

NHLBI: Sickle Cell Disease. Expert Panel Report 2014

Binds ferric iron (3:1 binding affinity) from thalassemic and sickle cell RBCs

Dosing (adult data) 25mg/kg PO TID Tablets: 500mg May take with food

Adverse ef fects [BBW] agranulocytosis Arthralgias Nausea Liver toxicity

Monitoring ANC, CBC LFTs

DEFERIPRONE (FERRIPROX®)

Counseling Point:Oral iron chelators should be separated from polyvalent cations

Deferiprone. TruvenHealth. 2017. Deferiprone. WoltersKluwer. 2016; Guidelines for the Management of Transfusion Dependent Thalassaemia. 3rd Ed. 2014.

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100mg deferoxamine binds 8.5mg elemental Fe Complexes ferric iron (Fe3+) in vascular space to form

ferrioxamine Chronic treatment dosing 20-40 mg/kg (max 1-2 g) SQ over 8 hrs 5-7 days/week

Adverse effects Infusion reaction Auditory toxicity Ocular toxicity

Monitoring Audiometry Funduscopy, slit-lamp examination

DEFEROXAMINE (DESFERAL®)

Deferoxamine. TruvenHealth. 2017; Deferoxamine. WoltersKluwer. 2016; Guidelines for the Management of Transfusion Dependent Thalassaemia. 3rd Ed. 2014.

Counseling Point:All iron chelators can cause red-orange tinted urine

10mg/kg/day excretes 0.119 mg Fe/kg/day Binds ferric iron (2:1 binding affinity) Low affinity for zinc and copper Excreted through feces

Adverse Effects [BBW] Renal failure [BBW] Hepatic failure [BBW] GI hemorrhage Nausea

Monitoring Infusion reaction Audiometry Funduscopy, slit-lamp examination

Interactions 3A4 inducer, 1A2 & 2C8 inhibitor

DEFERASIROX

Deferasirox. TruvenHealth. 2017; Deferasirox. WoltersKluwer. 2016; Guidelines for the Management of Transfusion Dependent Thalassaemia. 3rd Ed. 2014.

20mg/kg PO QD Tablet for oral solution:

125mg, 250mg, 500mg Take on empty stomach

at least 30 minutes before meal

14mg/kg PO QD

Tablets: 90mg, 180mg, 390mg

Take on empty stomach or with l ight meal

DEFERASIROX

Deferasirox. TruvenHealth. 2017; Deferasirox. WoltersKluwer. 2016

http://www.exjade.com/images/caplets.jpg http://www.multivu.com/players/English/7440151-novartis-jadenu-fda-approval/gallery//image/761bfd65-adac-4f1c-a96a-8ca2873ef93f.jpg

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PROPHYLAXIS

Increases production of fetal hemoglobin

Increases water content of erythrocytes

Decreases circulating leukocytes and reticulocytes

HYDROXYUREA: PROPHYLAXIS AND TREATMENT

Evidence Lower annual rate of pain crises

Longer time to 1st & 2nd crisis

Lower incidence of ACS

Reduced need for transfusion

Increased total hemoglobin

Lower cost for pain hospitalization

No difference on mortality or stroke outcomes

Benefits limited to those with consistently increased fetal hemoglobin

HYDROXYUREA: THE DATA

Blood. 2008; 112: 3927-3938. NHLBI: Sickle Cell Disease. Expert Panel Report 2014.

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Indications All pediatric patients Adults 3+ pain crises per year, symptomatic anemia, interference with daily life

Dosing Infants/children: 20mg/kg/day Adults: 15mg/kg/day Maximum: 35mg/kg/day

Adverse effects: [BBW] Bone marrow suppression Secondary malignancies N/V/D/C

Monitoring CBC + differential Reticulocyte count Fetal hemoglobin

HYDROXYUREA

Blood. 2008; 112: 3927-3938. NHLBI: Sickle Cell Disease. Expert Panel Report 2014.

Counseling Point:Contraception is needed for all patients taking hydroxyurea. Continue for 1 year after therapy cessation

Penicillin VK Early infancy to at least age 5

Discontinue at 5 yrs unless splenectomy or invasive pneumococcal infection <3 years: 125mg PO BID

≥ 3 years: 250mg BID

ANTIBIOTICS

NHLBI: Sickle Cell Disease. Expert Panel Report 2014. http://www.pneumogen.net/gps/img/strep_sanger.jpg

Pneumococcus

H. influenzae (Hib)

Pneumococcal PCV13, PPSV23

Meningococcal

Influenza

IMMUNIZATIONS

NHLBI: Sickle Cell Disease. Expert Panel Report 2014.https://jnswire.s3.amazonaws.com/jns-media/67/be/67541/Child-Vaccination-Immunization.jpg

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WHAT’S COMING AROUND THE BEND?

THERE’S A “MAB” FOR THAT

Humanized monoclonal antibody against p-selectin blocking interaction with p-selectin glycoprotein ligand 1 (PSGL-1) Decreases adhesion of sickle erythrocytes and leukocytes to the

endothelium

NEJM. 3 Dec 2016. DOI: 10.1056/NEJMoa1611770

Primary end pointAnnual rate

of pain crises

1.63 vs 2.98

p=0.01

THE FUTURE OF PREVENTION?

All statistics cited as medians between high-dose and placeboNEJM. 3 Dec 2016. DOI: 10.1056/NEJMoa1611770

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Sickle cell disease and thalassemia are chronic disease with long term consequences including immunosuppression, pain, and iron overload

Prophylactic treatment is the most important aspect of managing sickle cell disease

Hydroxyurea is an effective option for most sickle cell patients

Multiple unique iron chelators are available but have many side effects and have a heavy administration burden

Additional treatment options are needed!

TAKE HOME POINTS: PREVENTING A CRISIS

Antibiotics!

Pain control!!

Supportive care!!!

TAKE HOME POINTS: BUT WHAT IF YOU ARE ALREADY IN A CRISIS?

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