Sickle Cell Disease Presentation PDF

Sicle Cell Disease PHAR 5367 – Integrated Hematology/Oncology Module Onye Ononogbu, PharmD, BCOP Jan 17th 2024 Objectives • Understand etiology and pathophysiology of sickle cell disease • Identify signs and symptoms as well as acute and chronic complications of sickle cell disease • Select an ap...

Sicle Cell Disease PHAR 5367 – Integrated Hematology/Oncology Module Onye Ononogbu, PharmD, BCOP Jan 17th 2024 Objectives • Understand etiology and pathophysiology of sickle cell disease • Identify signs and symptoms as well as acute and chronic complications of sickle cell disease • Select an appropriate care plan and supportive care management of patients with sickle cell disease Epidemiology • Sickle cell disease (SCD) affects millions throughout the world: • Ancestors from Sub-Saharan Africa • Spanish-speaking regions (Central American, the Caribbean and South America) • Saudi Arabia • India • Mediterranean Countries (Turkey, Greece, and Italy) • The number of people living with SCD is unknown however it is estimated: • Approx. 100,000 individuals are living with SCD in the US • 1 in 365 African-American births • 1 in 16,300 Hispanic-American births Kavanagh PL, Fasipe TA, Wun T. Sickle Cell Disease: A Review. JAMA. 2022;328(1):57-68. doi:10.1001/jama.2022.10233 cdc.gov/sicklecell Screening and Diagnosis Blood Test & Genetics • High-performance liquid chromatography (HPLC) • Genetic testing to confirm blood test • Genetic testing can tell if you have one or two copies of the sickle hemoglobin gene Highperformance Prenatal Screening • Can diagnose before the baby is born • Samples from amniotic fluid or tissue from the placenta • Early as 8-10 weeks into pregnancy Pecker LH, Lanzkron S. Sickle Cell Disease. Annuals of Internal Medicine. 2021: 174(1); 1-16. doi:10.7326/AITC202101190. Newborn Screening • Blood test via baby’s heel • Blood is tested in the lab • State newborn screening team will send results in the mail Etiology HbAS HbAS HbSS HbSS Pathophysiology A. HbS Polymerization • • • B. Endothelial Dysfunction • • C. Doxygenation Monomer → Polymer ↑Cellular rigidity → distortion of RBC → sickling Hemolysis →Cell-free Hb disrupts nitric oxide (NO) balance NADPH oxidase, XO, and eNOS generate free radicals → endothelial dysfunction Vaso-Occlusion (VO) • • Sickled cells bind to neutrophils, endothelium, and platelets via selectin proteins Causes impaired RBC flow → IRI D. Sterile Inflammation • • VO causes IRI → DAMP release DAMP promotes the release of proinflammatory cytokines Sundd P, Gladwin MT, Novelli EM. Pathophyiology of Sickle Cell Disease. Annu Rev Pathol. 2019; 14:263-292. GAG → GTG Fetal Hemoglobin • • • Fetal Hemoglobin (HbF) is a type of hemoglobin that is prevalent in our blood as children. As we become adults, HbF decreases to < 1%. • In sickle cell anemia (SCA) HbF levels range from 5% - 8% • In SCA, F-cells last longer than non-F cells Increased levels of HbF, prevents the HbS polymerization process by reducing the HbS concentration HbS Polymerization Hemolysis Sickling Akinsheye I, Asultan A, Solovieff N, et al. Blood. 2011 Jul 7; 118(1): 19–27. doi: 10.1182/blood-2011-03-325258 Sickle Cell Disease Overview Hemoglobin Type Disease Hemoglobin (g/dL) MCV (fL) Clinical Severity S (%) F (%) C (%) A (%) SS >90 <10 0 0 6-9 >80 Very Severe SC 50 0 50 0 10-15 75-85 Mild to Moderate Sβ+ >60 <20 0 10-30 9-12 <75 Mild to Moderate Sβ0 >80 <20 0 0 6-9 <70 Moderate to severe Sridhar A, Idowu M. Hemoglobin Electrophoresis in Sickle Cell Disease: A Primer for the Clinician. Hematology.org SCD Treatment SCD Treatment Timeline SCD was first reported by a physician, James Harrick Hydroxyurea approved for SCD 1984 1910 Hydroxyurea approved for use in children Jul 2017 1998 First reported bone marrow transplant in SCD patient who was diagnosed with AML 1. 2. 3. Crizanlizumab (Adakveo) approved for use in SCD 2017 Dec 2017 L-Glutamine approved for use in children and adults First report of a patient being cured by Gene Therapy (studies ongoing) CRISPR-based gene therapy (Casgevy) and Lentiviral vector gene therapy (Lyfgenia) approved by FDA Nov 2019 Nov 2019 December 2023 Voxelotor (Oxbryta) approved for use in SCD FDA. FDA approved L-glutamine powder for the treatment of sickle cell disease. US Food and Drug Administration. Content Updated 8/18/2017. Retrieved: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approved-l-glutamine-powder-treatment-sickle-cell-disease FDA. FDA approves voxelotor for sickle cell disease. US Food and Drug Administration. Content Updated: 11/25/2019. Retrieved: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-voxelotor-sickle-cell-disease FDA. FDA approves crizanlizumab-tmca for sickle cell disease. US Food and Drug Administration. Content Updated: 11/15/2019. Retrieved: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-crizanlizumab-tmca-sickle-cell-disease Hydroxyurea (Siklos®) When to Use First line Mechanism of Action Increases HbF, reduces red cell adhesion, reduces white blood cells and platelets Indication HbSS and HbSβ0-thal Patient Population All SCD patients ≥ 9 months Dosing Initial: 15-20 mg/kg per day Maintenance: 20-35 mg/kg per day, max 2500mg daily CrCl < 60 mL/min: 10mg/kg/day Generic tablets come in 500mg Dosing should be adjusted based on CBC (neutrophils, platelets, retic count) Adverse Effects Myelosuppression and infections Comments Do not use if Pregnancy or breastfeeding Main treatment effect Patients taking hydroxyurea vs placebo had a decrease in painful events, increase in HbF, and decrease in hospitalizations SIKLOS® (hydroxyurea) [package insert]. Rosemont, PA: ADDMEDICA, Inc.; 2007. Hydroxyurea Initiation HbSS or HbSβ0: 3 or more VOC or severe symptomatic anemia 1. Pregnancy test negative 2. Contraception for men and women 3. Monitoring of labs and med adherence Yes No Hydroxyurea 15mg/kg /day may increase up to 35 mg/kg/day Monitor CBC, HbF, Bilirubin, ALT, Creatinine, Pregnancy Test, History and PE Treatment Goals: 1.Less VOC and ACS episodes 2.Increase HbF 3. Increased Hb 4. Improved well being 5. Acceptable myelotoxicity Sickle Cell Disease (SCD), Roller LK, Baumgartner L, Desselle SP. Quick Answers: Pharmacy; 2019. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=2735&sectionid=228236205 Accessed: January 09, 2023 No Hydroxyurea L-Glutamine (Endari®) When to Use Add to, OR replace hydroxyurea, OR use as third medication Mechanism of Action (Unknown) May reduce oxidative injury by increasing NADPH Indication Reduce the frequency and severity of acute complications Patient Population Any individual with SCD ≥ 5 years old Dosing Pt weight < 30kg: 5g twice daily Pt weight 30 – 65kg: 10g twice daily Pt weight > 65kg: 15g twice daily Mix oral powder with 8oz (240 mL) of cold or room temp. beverage (i.e. water, milk, or apple juice) or 4oz to 6oz of food (i.e. applesauce or yogurt) immediately before ingestion. Adverse Effects Flatulence, constipation, abdominal pain, nausea in 20% Contraindications Pregnancy or breastfeeding Main treatment effect Patients taking L-glutamine vs placebo had a reduction in vaso-occlusive events and a reduction in hospitalizations ENDARI® (L-glutamine oral powder) [package insert]. Torrence, CA: Emmaus Medical, Inc.; 2020. Voxelotor (Oxbryta®) When to Use Add to OR replace hydroxyurea Mechanism of Action Inhibits HbS Polymerization → inhibits sickling & reduces the destruction of RBC Indication Increases Hgb Patient Population All SCD patients ≥ 4 years old Dosing 12 years and older: 1500mg a day Hepatic impairment (Child-Pugh C): 1000 mg a day Tablets come in 300mg and 500mg, oral suspension 300mg Adverse Effects Headache, diarrhea, abdominal pain, nausea, rash, and pyrexia Comments Do not use if pregnant, breastfeeding or ESRD, also may interfere with the quantification of Hb subtypes (HbA, HbS, HbF). Cost may be a barrier Main treatment effect Patients (51%) taking voxelotor compared to placebo, had an increase in Hgb ≥ 1g/dL at 24 weeks DDI Strong CYP3A4 inducers/inhibitors OXBRYTA® (voxelotor) [package insert]. South San Francisco, CA: Global Blood Therapeutics. 2022. Crizanlizumab-tmca (Adakveo®) When to Use Add to hydroxyurea, except in compound heterozygous disease, where it may be used first Mechanism of Action Binds to P-selectin on the surface of activated endothelial cells and platelets to block interactions of cell adhesion Indication Reduce the frequency and severity of vaso-occlusive crises Patient Population Any individual with SCD ≥ 16 years old Dosing Loading: 5mg/kg administered intravenously every 2 weeks for 2 doses Maintenance: 5mg/kg administered intravenously every 4 weeks Expiration: 24 hours from the time the medication is made to the end of the infusion. Adverse Effects Infusion-related reactions (nausea, pyrexia, arthralgia, abdominal pain, back pain) Contraindications Pregnancy or breast feeding DDI Anticoagulation – increased risk of bleeding ADAKVEO® (crizanlizumab-tmca) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021. The SUSTAIN Study (Safety and Efficacy of Crizanlizumab with or without Hydroxyurea Therapy in Sickle Cell Disease Patients with Sickle cell-Related Pain Crises ) Ataga KI, Kutlar A, Kanter J, et al. N Engl J Med 2017; 376:429-439 • • • • • • Exclusion Criteria Chronic transfusions or exchanges during the study Hgb < 4.0 g/dL Initiation, alteration, or termination of hydroxyurea dose Anticoagulation therapy RANDOMIZED • Inclusion Criteria SCD (HbSS, HbSC, HbSβ0-thal, HbSB+- thal) Hydroxyurea (prescribed within 6 months, stable for 3 months) 2-10 sickle cell pain crises within 12 months Experimental Group 1: High Dose • 5mg/kg crizanlizumab • IV Infusion once every 4 weeks through week 50 Experimental Group 2: Low Dose • 2.5 mg/kg crizanlizumab • IV infusion once every 4 weeks through week 50 • Placebo Group IV infusion once every 4 weeks through week 50 Primary Endpoint • Annual rate of sickle cell-related pain crises • Calculated as the total number of crises×365÷(end date−date of randomization+1) 16 The SUSTAIN Study - Results Primary Endpoint: Annual rate of sickle cell disease pain crises Variable High-dose crizanlizumab Low-dose crizanlizumab Placebo No. of patients 67 66 65 Median rate of crises/year 1.63 (0.00-3.97) 2.01 (1.00-3.98) 2.98 (1.25-5.87) P - value 0.01 0.18 -- No. of patients with 0 crises 24 12 11 Safety Profile: Adverse Events Variable High-dose crizanlizumab Low-dose crizanlizumab Placebo Pneumonia (No., %) 3 (5) 2 (3) 3 (5) Headache (No., %) 11 (17) 14 (22) 10 (16) Back Pain (No., %) 10 (15) 13 (20) 7 (11) Nausea (No., %) 12 (18) 11 (17) 7 (11) Treatment Recap Hb Polymerization Hemolysis Endothelial Dysfunction Free Heme Sickling Vaso-occlusion Sterile Inflammation Ischemia reperfusion injury Treatment Recap Voxelotor Hb Polymerization Hemolysis Sickling Hydroxyurea Voxelotor Endothelial Dysfunction Vaso-occlusion Crizanlizumab Crizanlizumab L-Glutamine Free Heme Sterile Inflammation Ischemia reperfusion injury L-Glutamine FDA-Approved Gene Therapies A. CRISPR/Cas9 (Casgevy) A. • CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut. • Modified blood stem cells are transplanted back into the patient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF) B. Lentiviral Vector (Lyfgenia) B. • A manufactured Hgb (HbAT87Q)is injected into the patient’s hematopoietic stem cells and infused back into the patient after a course of chemotherapy. • A gene therapy that functions similarly to hemoglobin A is increased by decreasing expression of BCL11A, a suppressor of the γglobulin gene that encodes HbA 1.Bluebird Bio. Bluebird Bio announces FDA approval of LYFGENIA (lovotibeglogene autotemcel) for patients ages 12 and older with sickle cell disease and a history of vaso-occlusive events. [Accessed 18 December 2023] 2.Vertex Pharmaceuticals. Vertex and CRISPR Therapeutics announce US FDA approval of CASGEVY (exagamglogene autotemcel) for the treatment of sickle cell disease. [Accessed 18 December 2023] Stem Cell Transplant • • Can cure SCD Candidate status depends on: disease type, age, complications, available donor • Side effects: infection, mucositis, pulmonary, graft-vs-host disease Broder MS, Quock TP, Chang E, et al. The cost of hematopietic stem-cell transplantation in the unites states. Am Health Drug Benefits.2017;10(7): 366-374 Acute Complications of SCD Clinical Presentation Anemia Acute Pain (Vasoocclusive crises – back pain, leg pain, headaches, etc) Infection Acute Chest Syndrome Acute Kidney Injury Priapism Stroke Anemia Reduction in baseline Hgb Normal Hgb levels: • Defined by a decrease in at least 2g/dL • HbA→ Male: 13.817.2 g/dL, Female: 12.1-15.1 g/dL • HbSS and HbSβ0thal → 6-9 g/dL • HbSC and HbSβ+thal → 10-12g/dL Hematocrit Levels • Higher Hct leves lead to increased viscosity → vasoocclusive crises • Lower Hct levels lead to severe anemia and hemolysis Reticulocyte Count • Elevated • Normal RBC lifecycle → 110120 days • Sickled RBC lifecycle → 10-14 days Howard J. Sickle Cell disease: when and how to transfuse. Hematology Am Soc Hematol Educ Program. 2016; 2016(1):625-631. doi:10.1182/asheducation-2016.1.625 Anemia Management – RBC transfusion • Goal: increase oxygen carrying capacity and decrease HbS (<30%)to prevent vaso-occlusion Transfusions should be done in emergency situations for patients with SCD • Anemia should be symptomatic prior to transfusions • Every 3-4 weeks Complications • Iron overload • Alloimmunization • Hyperviscosity Simple Transfusion (acute/chronic) Exchange Transfusion (chronic) Widespread availability Limited availability Peripheral access is usual High requirement for central access Poor control of HbS% Best control of HbS% High levels of iron accumulation Low levels of iron accumulation Risk of hyperviscosity Less risk of hyperviscosity Howard J. Sickle Cell disease: when and how to transfuse. Hematology Am Soc Hematol Educ Program. 2016; 2016(1):625-631. doi:10.1182/asheducation-2016.1.625 Sickle Cell Disease Overview Hemoglobin Type Disease Hemoglobin (g/dL) MCV (fL) Clinical Severity S (%) F (%) C (%) A (%) SS >90 <10 0 0 6-9 >80 Very Severe SC 50 0 50 0 10-15 75-85 Mild to Moderate Sβ+ >60 <20 0 10-30 9-12 <75 Mild to Moderate Sβ0 >80 <20 0 0 6-9 <70 Moderate to severe Sridhar A, Idowu M. Hemoglobin Electrophoresis in Sickle Cell Disease: A Primer for the Clinician. Hematology.org Pain Crises (Vaso-occusive crises) Law of Pain (2002): • The etiology of pain is inflammation and the inflammatory response. Inflammation occurs when there is tissue or organ injury. • Inflammatory mediators activate local pain receptors and produce hypersensitivity in the area of injury Types of SCD Pain: Acute Pain – intensity varies from mild aches to severe and debilitating pain • Abrupt onset without any explanation • Can last from hours to days or even weeks if inadequately treated Chronic Pain • Pain that lasts at least 3-6 months + Mixed Pain • Acute on Chronic Pain Pain Triggers: • Hypoxia, daytime exertion, dehydration, lack of sleep, stress, cold weather, high altitude (greater than 2000 ft), infection, etc. Omoigui S. How to Manage an Acute Pain Crisis in Sickle Cell Disease: Practical Recommendations. Pract Pain Manag. 2021;21(3). Pain Crises (Vaso-occusive crises) Vaso-occlusive crisis is the #1 cause of ER visits and hospitalizations for SCD patients Treatment Goals: • Provide RAPID and ADEQUATE pain management Pertinent Information : • Get a good patient history and determine what has caused the pain crises • Get a good medication history • Utilization of care plan pathways and protocols can help guide providers and pharmacists to adequately treat patients Management: • Hydration • Treat underlying cause • Start pain management Omoigui S. How to Manage an Acute Pain Crisis in Sickle Cell Disease: Practical Recommendations. Pract Pain Manag. 2021;21(3). Pain Crises – Outpatient (Non-Opioids) Drug Name Strength and Dose Acetaminophen 1,000 mg Ibuprofen 600 mg Ketorolac (IV) 15-30 mg Instructions Take 1 tablet by mouth every 8-12 hours as needed for mild pain Take 1 tablet by mouth every 6-8 hours as needed for moderate pain Infuse over 1 hour Pain scale Max dose 1-3 3,000 mg/day 4-6 2,400 mg/ day 6-10 120 mg/day Pain Crises – Outpatient (Opioids) Drug Name Norco (HydrocodoneAcetaminophen) Strength and Dose 5-325; 7.5-325; 10-325 mg Oxycodone-Acetaminophen 2.5-325; 5-325; 7-325; 10325 mg Oxycodone IR 5;10;15;20;30 mg Oxycodone ER 10;15;20;30;40;60;80 mg Hydromorphone (Dilaudid) 1; 2; 3; 4 mg Instructions Take 1 tablet by mouth every 4-6 hours / 6-8 hours / 8-12 hours as needed for severe pain Take 1 tablet by mouth every 4-6 hours / 6-8 hours / 8-12 hours as needed for severe pain Take 1 tablet by mouth every 4-6 hours / 6-8 hours / 8-12 hours as needed for severe pain Take 1 tablet by mouth every 4-6 hours / 6-8 hours / 8-12 hours as needed for severe pain Take 1 tablet by mouth every 4-6 hours / 6-8 hours / 8-12 hours as needed for severe pain Pain scale Max dose *** if taking with acetaminophen, do not exceed more than 4 grams today*** 7-10 7-10 7-10 7-10 7-10 Example: If taking 1,000 mg every 12 hours of Acetaminophen, only take an additional 3 tablets of Hydrocodone-Acetaminophen in the same day Opioid Reversal Drug Name Naloxone (Narcan) Strength and Dose 4 mg Instructions Use 1 spray in each nostril. May repeat every 2-3 minutes until medical assistance arrives Pain scale Max dose - The purpose of this medication is to prevent accidental opioid overdose. It works to reverse the effects of opioids, and it is being given for your safety. Please educate your family members on where they can find this medication and how to use it. Pain Crises (Vaso-occusive crises) - Inpatient Moderate-to-Severe Pain • PO, IV, or PCA Opioids should be utilized – dose dependent on patient history • Oxycodone-acetaminophen 5-325mg po q4hrs • Morphine IV 0.1 -0.15 mg/kg IV q2-4hrs (for a 70 kg pt = 7-10.5 mg q2-4hrs) • Hydromorphone PCA 0.015-0.02 mg/kg IV q3-4hrs (for a 70 kg pt = 1.05-1.4 mg q3-4 hrs) • Ketamine infusions (for opioid refractory patients) • 0.1 to 0.3 mg/kg per hour IV with a max of 1 mg/kg per hour Omoigui S. How to Manage an Acute Pain Crisis in Sickle Cell Disease: Practical Recommendations. Pract Pain Manag. 2021;21(3). Patient Example Step 1: Step 2: Calculate parenteral (IV or SC) opioid dosing based on patients home oral dose. Administer parenteral opioids Reassess pain and readminister opioids, if necessary for continued severe pain every 15-30 min until patient reports pain is under control Step 5: Step 6: Opioid sparing medication (Ketamine) may be utilized to decrease amount of opioids required as well decrease side effects Consider IV hydration at no more than maintenance rate in patients who are unable to drink fluids and who are euvolemic Step 3: Step 4: Maintain or escalate dose by 25% until pain is controlled Reassess after each dose for pain relief and side effects Step 7: Step 8: Monitor excessive sedation in patients being treated with opioids Gradually titrate down parenteral opioids as VOC resolves Omoigui S. How to Manage an Acute Pain Crisis in Sickle Cell Disease: Practical Recommendations. Pract Pain Manag. 2021;21(3). Conversion Ratios Total daily oral MME dose >50 mg is one factor that can help identify patients who may be at higher risk for overdose Drug Approximate equivalent oral dose Approximate equivalent IV or SC dose Conversion ratio to determine daily total ORAL morphine milligram equivalent (MME) Morphine 30 mg 10 mg IV Morphine to Oral Morphine 1:3 Fentanyl Not available 0.1 mg (100mcg) IV Fentanyl to Oral Morphine 1:300 Hydromorphone 7.5 mg 1.5 mg Oral Hydromorphone to Oral Morphine 1:4 IV Hydromorphone to Oral Morphine 1:20 Oxycodone 20 mg Not available Oral Oxycodone to Oral Morphine 1: 1.5 National Comprehensive Cancer Network. Adult Cancer Pain, Version 2.2021. Lexicomp Online. Copyright © 1978-2023 Lexicomp, Inc. All Rights Reserved. Infection and Immunizations Spleen • SCD patients are at risk for infections because sickle cell damages organs starting in the first year of life. • The spleen is a major organ that protects by filtering old blood and removing damaged blood. The spleen also helps make antibodies to fight off infections. • However, sickled blood pools in the spleen and damages it causing patients to lose their spleen by the age of 5 years old leaving SCD patients at risk for bacteremia, sepsis, respiratory infections, etc. Harmful Bacteria • Streptococcus pneumoniae – a common cause of pneumonia • Neisseria meningitidis – the number one cause of bacterial meningitis • Haemophilus influenzae type b – prior to vaccinations this used to be the number one cause of meningitis in children • Influenza – patients that end up with the flu most likely will be hospitalized, which may also cause lung complications Centers for Disease Control and Prevention. Infections and sickle cell disease. Chenou F, Azevedo J, Leal HF, Gonçalves MD, Reis JN. Hematol Transfus Cell Ther. 2020;42:139-44. doi:10.1016/j.htct.2019.06.006 Immunizations Age Vaccine 0-18 years 19 years + Pneumococcal 13 valent (PCV13) • • • Pneumococcal 23 valent (PPSV23) • Haemophilus influenza (Hib) • • MenACWY & Meningococcal B *Booster doses, every 5 years Influenza Should be administered prior to PPSV23 4 dose series at 2, 4 and 6 months and at 12-15 months Persons ≥2 years should receive 2 doses of PPSV23 separated by 5 years beginning at least 8 weeks after completing PCV13 2 or 3 dose series at 2 and 4 months of age OR at 2, 4, 6 months of age Booster dose: 12-15 months • • • If 19 years and older and no PCV13 dose, give 1 dose of PCV13 If 19 years and older and no PPSV23 dose, give 2 doses 5 years apart If 65 years and older, give 1 PPSV23 dose –this will be the final dose If no previous Hib dose give 1 dose of Hib Menveo® • Initiating at 8 weeks give a 4-dose series: 2,4,6 and 12 months • Initiating at 7-23 months give 2 doses 12 weeks apart • Initiating at 24 months, give 2 doses 8 weeks apart Menactra® • Only administer to 2 years or older, give 2 doses 8 weeks apart MenB • 10 years and older give 2 doses 1 month apart (Bexsero®) or 3 doses 0,1-2, and 6 months (Trumenba®) • If no previous MenACWY doses give 2 doses 8 weeks apart and boost with MenACWY every 5 years • • Given in divided doses from 6 months to 1 year old, then annually Centers for Disease Control and Prevention. Immunization Schedule. • For Menactra, do not administer PCV13 at the same time. Wait 4 weeks before giving Menactra • MenB: if no complete Men B series, give 2 doses 1 month apart (Bexsero®) or 3 doses 0,1-2, and 6 months (Trumenba®) – use all the same products! Annually Acute Chest Syndrome (ACS) Defined as a new infiltrate on chest imaging plus any 2 of the following: SCD patients may present with ACS due to: Can Lead to: infection (i.e. pneumonia) Respiratory failure may also develop 3 to 4 days after an acute pain episode due to a fat embolism, sickling, or thromboembolism Death (one of the leading causes of death in SCD) Pleuritic chest pain Hypoxemia Tachypnea Fever Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of acute chest syndrome in sickle cell disease. N Engl J Med. 2000; 342(25): 1855-1865. Acute Chest Syndrome (ACS) Goals of therapy • Prevent respiratory collapse • Decrease the proportion of sickle red cells Treatment • Oxygen supplementation • If O2 sat < 90% despite supplementation – Blood transfusions or exchange tranfusions • This will increase oxygen affinity of blood in SC patients • Control chest pain with analgesics • Incentive spirometry • Antibiotics • Rehydration with IV fluids Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of acute chest syndrome in sickle cell disease. N Engl J Med. 2000; 342(25): 1855-1865. Priapism Ischemic priapism is a common but underrecognized morbidity affecting about 33% of adult men with sickle cell disease (SCD). The onset of priapism occurs in the prepubertal period and tends to be recurrent with increasing age. Priapism is associated with an unrecognized high burden of mental duress and sexual dysfunctions. The burden of severe erectile dysfunction is 2.5-fold higher among men with SCD compared with men without SCD and about 5-fold higher among those with a history of priapism. There are two major categories of Priapism: Low flow / ischemic priapism: Major episode: Episodes lasting ≥ 4 hrs Recurrent or stuttering Priapism: Last for few minutes for up to 3 hrs. High flow / non-ischemic priapism: is typically not painful and may resolve spontaneously with minimal complications. Priapism Treatment Supportive measures If no response after 4 to 6 hours If the above does not work Oral fluids Intravenous fluids Urgent shunting between the corpora cavernosa and the glans of the penis may be needed Warm showers Walking Analgesia Local injection of sympathomimetics 2022 ASH Guidelines Epidemiology and treatment of priapism in sickle cell disease: Three controlled trials using stilbestrol, ephedrine, etilefrine, and sildenafil have shown inconclusive evidence for secondary priapism prevention. Observational data support the strategy of chronic low morning dosing with PDE-5 inhibitors for prevention of priapism recurrences. Currently two-phase II clinical trials are ongoing to provide evidence for using Crizanlizumab (SPARTAN) and Hydroxyurea with tadalafil (PIN) for secondary prevention of priapism recurrences in SCD. Chronic Complications of SCD Chronic Complications Chronic Complication Screening Follow - up Pain • • • Pain is considered chronic if it lasts > 3 months • Chronic pain of unclear etiology • Chronic pain in specific tissue or organ • Neuropathic pain • Breakthrough pain Assess for pain annually or more often as needed using a numerical rating scale • • Treatment options include: • NSAIDs • Opioids • Antidepressants Nonpharmacological approaches include: • Acupuncture • Mild to moderate exercise • Aqua therapy • Occupational therapy Let patients' response guide treatment Retinopathy Refer to an ophthalmologist beginning at age 10 for a dilated eye exam If the eye exam is normal, re-screen at 1–2-year intervals If retinopathy Pulmonary Complications Assess for respiratory problems (asthma, COPD, sleep apnea, restrictive lung disease) by patient history Check tricuspid regurgitant velocity (TRV), if elevated ≥ 2.5m/sec via ECHO, consult pulmonary hypertension specialist Renal Complications Screen annually for microalbuminuria and proteinuria beginning at age 10 • • Stroke In children, screen annually with Transcranial Doppler ultrasound between ages 2-16. • • If microalbuminuria or macroalbuminuria is identified, consult a nephrologist Adults may be started on an ACE inhibitor even in the presence of normal blood pressure Chronic RBC transfusions for high-risk patients Consider switching to hydroxyurea after a year or if transfusions are not possible National Heart, Lung, and Blood Institute’s Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014, available at www.nhlbi.nih.gov/guidelines Iron Overload Caused by intermittent transfusions throughout a lifetime Diagnosed by liver biopsy or liver MRI • Screening every 1-2 years Ferritin Levels Treatment • Screen levels annually • Normal: 25-300 ug/l • Moderate: 800-1700 ug/l • High: 1700 + • Start Chelation therapy >1000 ug/l • Iron chelation therapy • Exchange transfusions Coates TD, Wood JC. Br J Haematol. 2017; 177(5): 703-716. doi:10.1111/bjh.14575 Iron Overload Drug Dose/Route Excretion Deferoxamine (Desferal®) • 20-50 mg/kg/day SC BID • Urine/fecal at higher or TID or continuous doses infusion over 24 hours • Can be used with (5 to 7 times a week) decreased renal function Retinal damage; hearing loss, growth retardation, increase infection risk Deferasirox (Exjade®, Jadenu®) • 20-40 mg/kg/day (Exjade) – Oral Dispersible tablet or suspension - daily • 14-28 mg/kg/day (Jadenu)- oral filmcoated tablet – daily • Fecal • Nephrotoxic – should not be used unless totally dialysis dependent Moderate GI toxicity (diarrhea, nausea, vomiting), skin rashes, increase in serum creatinine Deferiprone (Ferriprox®) • 75-100 mg/kg/day – oral tablet or solution – TID • Urine • Can be used with decreased renal function Transient transaminitis, GI toxicity, agranulocytosis, arthralgias, neutropenia Coates TD, Wood JC. Br J Haematol. 2017; 177(5): 703-716. doi:10.1111/bjh.14575 Adverse Effects Other Considerations • Supportive Care • Vitamin D – has been shown to improve bone health, reduce chronic pain, and improve quality of life in SCD patients. • Drink water and less caffeine • Live a healthy lifestyle ( diet, mild exercise) • Pregnancy Considerations • Folic acid 1 mg – should be taken by all women of childbearing age • Medications should be reviewed before conceiving – hydroxyurea cannot be initiated during pregnancy • Preeclampsia is the most common complication in SCD patients that are pregnant • Cardiac function can be compromised due to chronic hypoxemia and anemia • Pain episodes may increase during pregnancy Conclusions Sickle cell disease is very complex and involves multiple organ systems Mainstays of therapy include blood transfusions, SCD disease-modifying drugs (hydroxyurea, voxelotor, crizanlizumab, and L-glutamine), iron chelation therapy, and pain management Pharmacists can play a role in helping to customize medication regimens to adequately treat patients in crisis; counseling, education, and adherence monitoring are key to keeping the disease under control. Case THANK YOU PHAR 5367 – Integrated Hematology/Oncology Module Onye Ononogbu, PharmD, BCOP Jan 17th 2024