clinical update: sickle cell disease
TRANSCRIPT
Clinical Update:Sickle Cell Disease
JUSTIN ARNALL, PHARMD, BCOP
SPECIALTY PHARMACY SERVICES, ATRIUM HEALTH
CHARLOTTE, NC
DisclosuresI have nothing to disclose.
ObjectivesReview the pathophysiology and common complications of sickle cell disease
Identify standard and novel treatment approaches to managing sickle cell disease
Apply optimized disease modifying and supportive therapies to the care of sickle cell patients
Sickle Cell Disease (SCD)A collection of inherited blood disorders that feature the propensity for erythrocytes to change into crescent/sickle shapes
◦ Mediterranean descent – “malaria hypothesis”
Sickle cell anemia is the most common monogenic disorder and SCD variant (homozygosity for the sickle hemoglobin, HbS, gene)
◦ Estimated 100,000 persons with sickle cell anemia in the United States
◦ Newborn estimates suggest ~300,000 babies born annually internationally
Survival and quality of life have dramatically improved in recent years◦ In developed countries, median survival now >60 years
Ware RE et al. Lancet 2017; 390: 311-23.Piel FB et al. NEJM 2017; 376:1561-1573.
SCD in North CarolinaSCD affects ~3,000 patients and their families in NC
◦ 39% younger than 18 years; 29% 18-35 years; 32% 35+ years (2008)
◦ ~80 infants diagnosed by newborn screening annually
Comprehensive Sickle Cell Medical Centers of NC◦ Atrium Health
◦ Duke University
◦ East Carolina University School of Medicine
◦ University of NC – Chapel Hill
◦ Wake Forest University School of Medicine
◦ Mission Hospital (Pediatric Only)
Accessed from: https://www.ncsicklecellprogram.org/Documents/OtherDocuments/SC-DiseaseInNC-Providers.pdf on 6/30/20.
Pathophysiology: HemoglobinTetrameric structure that transports O2 from lungs to tissues
During first year of post-natal life, γ globin synthesis nadirs as β globin levels rise to adult levels
◦ Corresponding drop in HbF levels with rise of HbA levels
Normal adult hemoglobin electrophoresis◦ HbA = α2β2 = ~97% ; HbA2 = α2δ2 = ~2%; HbF = α2γ2 = ~1%
Accessed from: https://askhematologist.com/abnormal-hemoglobins/ on 7/1/20.Schechter AN. Blood 2008; 112(10):3927-3938.
Pathophysiology: Sickle CellGenetic disorder of hemoglobin, involving single base substitution of valine for glutamine in β chain
◦ Different forms of SCD with specific hemaglobinopathies◦ Results in malformed erythrocytes (HbS; a variant of HbA) that are stiff and have
difficulty navigating through microvasculature leading to vaso-occlusive crises (VOC) and hemolysis
Deoxygenated HbS polymerizes, damaging the erythrocyte and causing loss of cations and water
◦ Damaged cells have abnormalities in rheologic features and expression of adhesion molecules resulting in hemolytic anemia and blockage of small blood vessels
Genotype Nomenclature Comments
HbSS Sickle cell anemia Typically more severe
HbSβ°thal Sickle cell disease Phenotypically similar to HbSS
HbSC, HbSβ+thal Sickle cell disease Typically less severe phenotypes
HbAS Sickle cell trait NOT disease
Ware RE et al. Lancet 2017; 390: 311-23.Piel FB et al. NEJM 2017; 376:1561-1573.
SCD ComplicationsADHESION
Typically causes acute complications, including ischemic tissue damage, resulting in severe pain or organ failure
Acute chest syndrome is a typical example of organ failure and a leading cause of hospitalization and death among patients
Leads to vascular-endothelial dysfunction, functional nitric oxide deficiency, inflammation, oxidative stress and reperfusion injury, hypercoagulability, neutrophil adhesiveness, platelet activation
HEMOLYSIS
Breakdown of red blood cells results in free hemoglobin
◦ Decreases the availability of nitric oxide
Causes widespread pathologic consequences, including pulmonary hypertension
Regular hemolysis leads to anemia as the body is unable to keep up with RBC turnover and production demands
Ware RE et al. Lancet 2017; 390: 311-23.Piel FB et al. NEJM 2017; 376:1561-1573.
SCD ComplicationsAcute Complications Chronic Complications
Vaso-occlusive (pain) crises Chronic pain
Acute chest syndrome Pulmonary hypertension
Splenic sequestration Nephropathy
Stroke Hepatopathy
Priapism Cardiomyopathy
Aplastic crisis Depression
Cholelithiasis Avascular necrosis
Ware RE et al. Lancet 2017; 390: 311-23.Piel FB et al. NEJM 2017; 376:1561-1573.
Progress in SCD Management
Vichinsky E. Blood 2008; Accessed from https://www.hematology.org/about/history/50-years/milestones-sickle-cell-disease on 6/30/2020.
1983Penicillin
prophylaxis (PROPS)
1996BMT curative for
children
1995Hydroxyurea
2006Transfusions for
stroke prevention
2001 – 2010sGene therapy
trials in animals and humans
1998Doppler
ultrasonography screening
SCD ManagementRoutine Care
Functional asplenia◦ Penicillin prophylaxis (at least to 5 years of age)
◦ Vaccinations (pneumococcal every 5 years starting 2 years of age)
Eye exams
Transcranial Doppler imaging
Folate supplementation, multivitamin without iron, calcium/vitamin, ACE-inhibitors for microalbuminemia
Pediatric consideration for hematopoietic stem cell transplant (curative option)
Pain management◦ Multifactorial pain – psychologic and
hematologic considerations
◦ Opiates & opiates use disorder
◦ Simple Transfusions
Hydroxyurea◦ Induces production of HbF and decreases
expression of adhesion molecules to reduce VOC
◦ Decreases incidence of pain crises, acute chest syndrome, and transfusions
◦ Limitations: carcinogen, bone marrow suppression
Chronic RBC transfusions◦ Simple and/or exchange transfusions
◦ For patients with frequent crises, failed hydroxyurea therapy, high stroke risk (primarily)
◦ Limitations: alloimmunization, health care utilization, iron overload (not always with exchange)
Yawn BP et al. JAMA 2014; 312: 1033-48.Ware RE et al. Lancet 2017; 390: 311-23.Piel FB et al. NEJM 2017; 376:1561-1573.
Case for Audience Response 1TS is a 13 YO AAM with sickle cell homozygous SS disease who has a history of 3-4 transfusions (no alloantibodies), and experiences 2-3 vaso-occlusive events per year. These are generally short-lived and managed at home. He has no history of strokes.
CBC shows WBC 14.1 x103/mm3, Hgb 8.3 g/dL, platelets 502 x103/mm3, reticulocytes 9.4%, ferritin of 74 ng/mL.
Hemolysis markers are also elevated with LDH 672 IU/L, total bilirubin 2.8 mg/dL.
Vaccination history appears to be up to date and he is currently taking folic acid 1mg daily and no other medications.
Audience Response 1Which of the following is the most appropriate intervention to consider to optimize the patient’s SCD management?
A) Penicillin V 250mg twice daily
B) Hydroxyurea 30mg/kg/day
C) Simple blood transfusions every 4 weeks, target HbS <30%
D) Ibuprofen 200-400mg every 6 hours as needed for pain crises to resolution
text SallyBarbour693 to 22333 www.pollev.com/sallybarbour693
Progress in SCD Management
Vichinsky E. Blood 2008; Accessed from https://www.hematology.org/about/history/50-years/milestones-sickle-cell-disease on 6/30/2020.
1983Penicillin
prophylaxis (PROPS)
1996BMT curative for
children
1995Hydroxyurea
2019Crizanlizumab
2019Voxelotor
2006Transfusions for
stroke prevention
2001 – 2010sGene therapy
trials in animals and humans
2017L-glutamine
1998Doppler
ultrasonography screening
L-glutamineIndication: Prevention/ reduction of acute complications of SCD in adult and pediatric (≥ 5 years old) patients
Mechanism: NAD+ and its reduced form NADH, regulate and prevent oxidative damage; L-glutamine may improve the NAD redox potential in sickle RBCs through increasing the availability of reduced glutathione
Dosing: 5g twice daily for patients <30kg; 10g twice daily for patients 30-65kg; 15g twice daily for patients >65kg
Administration: Each dose should be mixed with 8 oz. (240 mL) of cold or room temperature beverage or 4 – 6 oz. of food before ingestion
◦ Provided as 5 gram oral powder/ packet
Dose adjustments: No dosage adjustments recommended in hepatic or renal impairment
Endari® [package insert]. Torrence, CA: Emmaus Medical, Inc; 2017.
L-glutamine Phase 3 trial
Primary efficacy endpoint: number of pain crises through week 48
Secondary end points: number of hospitalizations for SCD-related pain, number ED visits for SCD-related pain, changes in hematologic measures from baseline
2:1
L-glutamine (pharmaceutical grade) (n=152)Oral administration twice daily0.3 g/kg body weight per dose (rounded to 10g, 20g, 30g [maximum dose] per day)
Placebo powder (100% maltodextrin) (n=78)
Patient Population• ≥ 5 years old• HbSS or HbSβ°-
thalassemia (SCA)• ≥2 pain crises during
the previous year• ± hydroxyurea if on a
stable dose ≥ 3 months
Planned treatment period of 48 weeks
Niihara Y. NEJM 2018; 379:226-235.
L-glutamine Phase 3 trialPrimary outcome: mean 3.2 ± 2.24 pain crises in glutamine group vs 3.9 ±2.54 pain crises in placebo group, p = 0.005
◦ Median 2 hospitalizations in L-glutamine group vs 3 with placebo (p = 0.005)
◦ Median time to first pain crisis 84 days with L-glutamine vs 54 days with placebo (p=0.02)
◦ Significantly fewer occurrences of acute chest syndrome and less cumulative number of days hospitalized
Consistent outcomes seen across all subgroups favoring use of L-glutamine◦ Mean corpuscular volumes consistent with hydroxyurea adherence in both
groups
More adverse events reported in placebo group than with L-glutamine◦ Most common adverse effects: nausea, arm/leg pain, back pain
Overall noncompletion rate of 32% (withdrawal of consent or “other”)
Niihara Y. NEJM 2018; 379:226-235.
L-glutamine pearlsMay be mixed in either drink or food
◦ Well tolerated, adverse events mild and infrequent
Adherence an ongoing consideration◦ NAD/NADH levels in RBCs not measured
◦ Demonstrated adherence to hydroxyurea suggestive of relatively adherent patient population
◦ Patients in phase 3 trial contacted by telephone every week between monthly visits to encourage adherence
Therapy considerations:◦ All patients with sickle cell anemia, particularly useful for patients unable to take
hydroxyurea
◦ Continuation in the acute setting (no obvious acute benefit if initiated in crisis setting)
Cieri-Hutcherson NE et al. Pharmacotherapy 2019; 39(11): 1095-1104.Endari® [package insert]. Torrence, CA: Emmaus Medical, Inc; 2017.
VoxelotorIndication: treatment of SCD in adults and pediatric patients ≥12 years of age (accelerated approval based on increase in hemoglobin)
Mechanism: HbS polymerization inhibitor, reversibly binds to hemoglobin to stabilize the oxygenated hemoglobin state
Dosing: 1500 mg once daily
Administration: oraly, with/without food
Dose adjustments:◦ Severe hepatic impairment (CP-C) – 1000 mg once daily
◦ Strong CYP3A4 inhibitors – 1000 mg once daily
◦ Strong/moderate CYP3A3 inducers – 2500 mg once daily
OxbrytaTM [package insert]. South San Francisco, CA: Global Blood Therapeutics; 2019.
Voxeletor Phase 3 (HOPE) trial
Primary efficacy endpoint: % participants who had a hemoglobin response (increase from baseline >1 g/dL) at week 24
Secondary endpoints: change in hemoglobin level from baseline to week 24, laboratory markers associated with hemolysis, annualized incidence rate of vaso-occlusive crisis
1:1:1
Voxelotor 1500 mg (n=90)
Voxelotor 900 mg (n=92)
Patient Population• 12-65 years of age• Any SCD variant• Hgb level 5.5 – 10.5 g/dL during
screening• 1 – 10 vaso-occlusive crises in past 12
months• ± hydroxyurea on stable dose ≥ 3
months• No regular RBC transfusions, transfusion
in past 60 days, hospitalized for vaso-occlusive crisis within 14 days of consent
Placebo (n=92)
Planned treatment period of up to 72 weeks
Vichinsky E et al. NEJM 2019; 381:509-519.
Voxeletor Phase 3 trialPrimary outcome: 51% patients with Hb increase >1 g/dL at week 24 from baseline in 1500 mg voxelotor group vs 7% in placebo group (p<0.001) (33% in 900 mg voxelotor group)
◦ Hb improvement greater with voxelotor regardless of hydroxyurea use or baseline anemia severity
◦ Hb change at 24 weeks 1.1 g/dL in 1500 mg voxelotor group (p<0.001), 0.6 g/dL in 900 mg voxelotor group
No differences seen in vaso-occlusive crises between groups◦ Trend over time towards reduction in VOC with voxelotor
◦ Improved VOC rate with 1500 mg voxelotor in those who had experienced ≥2 VOC events the year prior
Most common (≥ 20%) adverse events: diarrhea, headache◦ Primarily grade 1 & 2 events, grade 3 events occurred similarly across groups
Vichinsky E et al. NEJM 2019; 381:509-519.
Voxelotor pearlsWell tolerated with adverse events mild and transient
◦ Patients may express feeling improvement within first month of therapy
CYP3A4 interactions should be accounted for
May interfere with measurement of Hb subtypes (HbA, HbS, and HbF)◦ Discontinue oxbryta 5 days prior to subtype measurement
Therapy considerations:◦ Patients with hemolytic SCD phenotype may find particular benefit
◦ SCD patients with chronic severe anemia, who may have concomitant chronic kidney disease – seeking to minimize RBC transfusions
◦ Limited insight into the efficacy and safety of combination therapies
◦ Continuation in the acute setting (no obvious acute benefit if initiated in crisis setting)
Han J et al. Pharmacotherapy 2020; 40(6): 525-534.OxbrytaTM [package insert]. South San Francisco, CA: Global Blood Therapeutics; 2019.
Crizanlizumab drug infoIndication: reduce the frequency of vaso-occlusive crises in adults and pediatric patients ≥16 years of age with sickle cell disease
Mechanism: binds to P-selectin and blocks interactions with its ligands including P-selectin glycoprotein ligand 1
◦ Binding P-selectin on surface of the activated endothelium and platelets blocks interactions between endothelial cells, platelets, RBCs, and leukocytes
Dosing: 5 mg/kg actual body weight at weeks 0, 2, and every 4 weeks thereafter
Administration: intravenous infusion over 30 minutes
Dose adjustments: N/A
Adakveo® [package insert]. East Hanover, NJ: Novartis; 2019.
Crizanlizumab Phase 2 (SUSTAIN) trial
Primary efficacy endpoint: annual rate of SCD-related pain crises
Secondary endpoints: annual rate of days hospitalized, times to first & second crises, annual rate of uncomplicated crises, annual rate of acute chest syndrome, Brief Pain Inventory questionnaire
1:1:1
Low-dose crizanlizumab (2.5 mg/kg) (n=66)
High-dose crizanlizumab (5 mg/kg) (n=67)
Patient Population• Any SCD subtypes• 16 – 65 years of age• 2 – 10 SCD-related pain crises in 12
months prior to enrollment• ± hydroxyurea if taking for ≥ 6 months,
including the most recent 3 months on a stable dose (not allowed dose alterations during 52-week treatment phase)
Placebo (n=65)
Planned treatment 14 total doses including loading doses and maintenance dosing
Ataga KI et al. NEJM 2017; 376:429-439.
Crizanlizumab Phase 2 (SUSTAIN) trialPrimary outcome: annual rate of VOCs reduced from 2.98/year in placebo to 2.01/year with low-dose crizanlizumab (p=0.18) and 1.63/year with high-dose crizanlizumab (p=0.01)
◦ Reductions with high-dose compared with placebo regardless of concurrent hydroxyurea, prior history of VOC frequency, or SCD genotype
◦ Median time to first VOC event 4.07 months with high-dose vs 1.38 months placebo (p=0.001)
◦ Lower annual rate of uncomplicated VOC with high-dose vs placebo (1.08 vs 2.91, p=0.02)
No significant differences in quality of life identified
Common (≥10%) adverse events: headache, back pain, nausea, arthralgia, pain in extremity, urinary tract infection, upper respiratory infection, pyrexia, diarrhea, musculoskeletal pain
Ataga KI et al. NEJM 2017; 376:429-439.
Crizanlizumab pearlsInfusion-related reactions were observed in 2 (3%) patients
◦ Monitor for signs/symptoms including fever, chills, nausea, vomiting, fatigue, dizziness, pruritus, urticaria, sweating, shortness of breath or wheezing
Adherence could be improved with crizanlizumab on a monthly schedule at an infusion center
Therapy considerations:◦ Blocking P-selectin may decrease leukocyte recruitment and increase
infection risk – should be considered in post marketing pharmacovigilance
◦ Alternative therapy for patients who have failed or developed an intolerance to hydroxyurea or L-glutamine, as well as adjunctive therapy
Han J et al. Pharmacotherapy 2020; 40(6): 535-543.Adakveo® [package insert]. East Hanover, NJ: Novartis; 2019.
Barriers to careInsufficient payer coverage/ medication expenses
Lack of pharmacies that stock novel agents
Lack of provider awareness of novel therapies and their application
Patient fears and/or intolerance of undesirable side effects
Drug regimen complexity and adherence◦ Daily/twice daily dosing, recommended supplemental therapies (zinc,
vitamin B12, chlorophyll, iron, folic acid)
Integration of novel therapies into holistic care plans
Masese RV et al. PLoS ONE 14(5): e0216414.
Cost of careMedication WAC Estimated cost per year
Crizanlizumab $2,357.14 per 10 mL (100 mg) vial
$107,700
Voxelotor $10,417.00 per 90 packages
$104,357
Pharmaceutical grade L-glutamine
$18.50 per 5gm package $26,082
WAC per Redbook accessed December 17, 2019
Hydroxyurea may be expected to cost ~$100/month, generally well-covered
Providers will need to work with payers to obtain prior authorization and work with institutional and payer-preferred dispensing specialty pharmacies
Accessed from: https://icer-review.org/announcements/scd_evidence_report/ on 6/29/20.
AdherenceAccumulating evidence to support safety, efficacy, and cost effectiveness of using hydroxyurea in pediatric and adult SCD patients
◦ Hydroxyurea utilization and adherence are suboptimal
◦ Barriers to hydroxyurea adherence include forgetfulness, fear of side effects, limited knowledge of benefits, inability to obtain refills, misperceptions of SCD severity
◦ Improved adherence at thresholds associated with improved outcomes
Adherence is a multi-factorial process influenced by parental and patient perceptions and/or SCD severity
Clinical trials with novel agents included aggressive adherence measures - practical adherence measures should be investigated
Candrilli SD et al. Am J Hematol 2011; 86(3): 273-7.
Continued Case for Audience Response 2TS (SCD HbSS) is now 17 YO (70 kg) and has a history of infrequent follow up. He has possible evidence of end organ damage with hypoxia at rest and elevated protein/creatinine on random urine.
Patient and parents state that he developed a rash on hydroxyurea, initially and on retrial, and discontinued with no interest in restarting. (Presentation similar as before)
Audience Response 2Which of the following novel therapies would you recommend initiating for this patient?
A) L-glutamine 15g twice daily
B) Voxelotor 1500mg daily
C) Crizanlizumab 350mg IV
D) None of the above are appropriate
text SallyBarbour693 to 22333 www.pollev.com/sallybarbour693
Case for Audience Response 3MR is a 49 YO AAM with sickle cell homozygous HbSSdisease.
He has pulmonary hypertension and hepatic cirrhosis, with persistent anemia on epoetin alfa and as needed exchange transfusions, with chelation therapy for iron overload.
Other medications include hydroxyurea, sertraline Suboxone, torsemide, spironolactone, gabapentin, valsartan, folic acid, and trazodone.
The patient’s hematologist would like to initiate L-glutamine and voxelotor.
Audience Response 3Which of the following are appropriate considerations?
A) Patient may expect gastrointestinal disturbance on initiation of therapies
B) There is limited data on combination therapy with novel SCD agents
C) Adherence is crucial to maximize expected benefits of therapy
D) All of the above
text SallyBarbour693 to 22333 www.pollev.com/sallybarbour693
SCD and COVID-19Aside from specific COVID-19-related morbidities, infections in patients with SCD can provoke painful vaso-occlusive crisis and life-threatening acute chest syndrome
French registry study inclusive of 83 patients did not identify particular risks with COVID-19 in SCD patients, though patients ≥45 years may have poorer outcomes
Importance of hydroxyurea adherence to reduce transfusion needs◦ Especially in areas with severe blood shortages to decrease acute VOC pain
and ACS events in the absence of regular blood transfusion therapy
Education on at-home (early) VOC management
Consideration of novel agents
Chowdhury SF, Anwar S. Front Med 2020; 7:306Arlet JB et al. Lancet Haematol 2020; epub.
Audience Response 4Have you managed COVID-19 positive sickle cell patients? And/or has your institution established SCD-specific COVID-19 protocols?
A) Yes
B) No
text SallyBarbour693 to 22333 www.pollev.com/sallybarbour693
ConclusionSickle cell disease is a hemglobinopathy with multiple variants, the most severe of which is associated with significant morbidity and early mortality if not effectively managed
Standard of care for sickle cell disease includes the use of penicillin prophylaxis, hydroxyurea, and blood transfusions to prevent and mitigate complications
With recent therapeutic options including L-glutamine, crizanlizumab, and voxelotor there is opportunity for pharmacists to optimize care
