Description
The most common SCD genotype is homozygous hemoglobin S (HbSS) which, along with sickleB0-thalassemia (HbSB0), is generally considered to be the most clinically severe. Less severe genotypes include sickle hemoglobin C disease (HbSC) and sickleB+-thalassemia (HbSB+), and a number of rare genotypes are also known (e.g., sickle-deltaB-thalassemia). There is a high degree of phenotypic variability within each SCD genotype, and all can experience frequent VOCs. Polymerization of deoxygenated HbS distorts the shape of erythrocytes, and leads to the “sickle” appearance associated with SCD. Erythrocytes containing HbS can adhere to vascular endothelial cells, which become activated by circulating free heme and inflammatory stimuli inherent to the pathophysiology of SCD and promote further inflammation and leukocyte adherence to the endothelium. Activated platelets can also adhere to leukocytes and sickled erythrocytes, forming aggregates. These interactions with the endothelium lead to altered hemodynamics, vascular obstruction, acute vaso-occlusion, and tissue ischemia, causing VOCs.The initiation of a VOC is a complex event involving a multitude of molecules. One of the molecules involved is P-selectin, a cell adherence molecule that is rapidly and chronically expressed on the surface of endothelial cells and platelets when activated. Leukocytes are initially captured on the endothelium via P-selectin and its ligand P-selectin glycoprotein ligand1 (PSGL-1). The expression of PSGL-1 by leukocytes also causes activated platelets to adhere to the leukocyte, leading to aggregate formation. Although PSGL-1 is not present on normal erythrocytes, sickled red blood cells (RBCs) are known to have glycoproteins on their cell surface that can mimic the P-selectin ligand and mediate adherence to activated endothelial cells expressing P-selectin.

On November 15, 2019, the U.S. Food and Drug Administration (FDA) approved Novartis’ drug Adakveo (crizanlizumab-tmca), a treatment to reduce the frequency of vaso-occlusive crisis — a common and painful complication of sickle cell disease that occurs when blood circulation is obstructed by sickled red blood cells — for patients ages 16 years and older. This is the first targeted therapy to treat patients with this painful complication of sickle cell disease. This drug was given priority review, breakthrough therapy designation and orphan drug designation.

Adakveo (crizanlizumab-tmca) is a humanized IgG2 kappa monoclonal antibody that binds to P-selectin and blocks interactions with its ligands, including P-selectin glycoprotein ligand 1.

The approval was based on the results of a randomized, double-blind, placebo-controlled, phase II clinical trial (SUSTAIN study) enrolling 198 patients with sickle cell disease with a history of vaso-occlusive crisis. Patients either received low-dose crizanlizumab (2.5 mg/kg; n = 66), high dose crizanlizumab (5.0 mg/kg; n = 67) or placebo (n = 65). Patients received 14 doses over a course of 52 weeks. Eligible patients included those with sickle cell disease, ages 16 to 65 years and who had 2 to 10 sickle cell-related pain crises in the 12 months before trial enrollment. Patients were permitted to receive concomitant hydroxyurea therapy. Patients receiving long-term red-cell transfusion therapy were excluded. Eligible patients participated in a 30-day screening phase, followed by a 52-week treatment phase and a 6-week follow-up evaluation phase. Patients received 2 doses of crizanlizumab or placebo 2 weeks apart (loading dose) and then received a dose every 4 weeks (maintenance dosing) through week 50 for a total of 14 doses administered. Each dose was given intravenously (IV) over 30 minutes.

The primary efficacy endpoint, the annual rate of sickle cell-related pain crises, was significantly lower in the high-dose crizanlizumab group compared to placebo (1.63 vs 2.98; 45.3% lower rate; P = .01). The patients treated with Adakveo (crizanlizumab-tmca) experienced fewer health care visits for vaso-occlusive crisis annually (median annual rate of 1.63 visits), compared to patients who received a placebo (median annual rate of 2.98 visits). In addition, 36 percent of patients who received Adakveo (crizanlizumab-tmca) did not experience vaso-occlusive crisis during the study, and it delayed the time that patients first experienced vaso-occlusive crisis after starting treatment from 1.4 months to 4.1 months.

Common side effects for patients taking Adakveo (crizanlizumab-tmca) were back pain, nausea, pyrexia (fever) and arthralgia (joint pain). As per the approved FDA package insert, health care professionals are advised to monitor patients for infusion-related reactions and to discontinue Adakveo (crizanlizumab-tmca) for severe reactions. Patients who receive Adakveo (crizanlizumab-tmca) should be monitored for interference with automated platelet counts or platelet clumping (platelet counts reported may be much lower than the actual count in the blood). Health care professionals are advised to run tests as soon as possible or use citrate tubes (a practice to avoid platelet activation).

Policy 
Crizanlizumab-tmca (Adakveo) is considered MEDICALLY NECESSARY when the following criteria is met: 

1. Patient has the diagnosis of sickle cell disease, identified by any genotype (e.g. HbSS, HbSC, HbS/beta0-thalassemia, or HbS/beta+-thalassemia)
2. Patient is 16 years of age or greater 
3. Documentation of 2 vaso-occlusive events that required medical facility visits and treatments in the past 12 months (e.g., sickle cell crisis, acute pain episodes, acute chest syndrome, hepatic sequestration, splenic sequestration, priapism)
4. Trial and failure, contraindication, or intolerance to all of the following:
   • Hydroxyurea
   • L-glutamine (i.e., Endari)
5. Prescribed by or in consultation with one of the following:
   • Hematologist/oncologist
   • Specialist with expertise in the diagnosis and management of sickle cell disease 

Crizanlizumab-tmca (Adakveo) is considered investigational and/or unproven for all other uses and is therefore considered NOT MEDICALLY NECESSARY.  

Initial Approval: Six Months 

Continuation: Approval 1 year

• Patient must meet initial criteria
• Documentation of decreased sickle cell crisis
• Documentation of decreased use of sickle cell pain medications (opioids, hydroxyurea, etc.) 

References 

1. Ashley-Koch A, Yang Q, Olney RS. Sickle hemoglobin (Hb S) allele and sickle cell disease: a HuGE review. Am J Epidemiol. 2000;151:839-845.
2. Piel FB, Steinberg MH, Rees DC. Sickle cell disease. N Engl J Med. 2017;376:1561-1573.
3. Ballas SK, Gupta K, Adams-Graves P. Sickle cell pain: a critical reappraisal. Blood. 2012;120:3647-3656.
4. Jacob E. The pain experience of patients with sickle cell anemia. Pain Manag Nurs. 2001;2:74-83.
5. Ramirez JF, Frei-Jones M. Essential of sickle cell disease management. In: Ulualp S, ed. Recent Advances in Pediatric Medicine; Synopsis of Current General Pediatrics Practice. United Arab Emirates: Bentham Science Publishers; 2017:231-247.
6. Habara A, Steinberg MH. Minireview: genetic basis of heterogeneity and severity in sickle cell disease. Exp Biol Med (Maywood). 2016;241:689-696.
7. Browning JA, Staines HM, Robinson HC, et al. The effect of deoxygenation on whole-cell conductance of red blood cells from healthy individuals and patients with sickle cell disease. Blood. 2017;109:2622-2629.
8. Zhang D, Xu C, Manwani D, Frenette PS. Neutrophils, platelets, and inflammatory pathways at the nexus of sickle cell disease pathophysiology. Blood. 2016;127:801-809.
9. Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013;122:3892-3898.
10. Wun T, Paglieroni T, Tablin F, Welborn J, Nelson K, Cheung A. Platelet activation and platelet-erythrocyte aggregates in patients with sickle cell anemia. J Lab Clin Med. 1997;129:507-516.
11. Zarbock A, Polanowska-Grabowska RK, Ley K. Platelet-neutrophil-interactions: linking hemostasis and inflammation. Blood Rev. 2007;21: 99-111.
12. Gutsaeva DR, Parkerson JB, Yerigenahally SD, et al. Inhibition of cell adhesion by anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood. 2011;117:727-735.
13. Kutlar A, Embury SH. Cellular adhesion and the endothelium. P-selectin Hematol Oncol Clin North Am. 2014;28:323-339.
14. Wagner DD, Frenette PS. The vessel wall and its interactions. Blood. 2008;111:5271-5281.
15. Matsui NM, Borsig L, Rosen SD, Yaghmai M, Varki A, Embury SH. P-selectin mediates the adhesion of sickle erythrocytes to the endothelium. Blood. 2001;98:1955-1962.
16. Matsui NM, Varki A, Embury SH. Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin. Blood. 2002;100:3790-3796.
17. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376:429-439.
18. Platt OS. Hydroxyurea for the treatment of sickle cell anemia. N Engl J Med. 2008;358:1362-1369.
19. Adakveo (crizanlizumab-tmca) [Prescribing information]. Novartis. November 2019.
20. AMCP Formulary Dossier Version 4.0. Adakveo® (crizanlizumab-tmca). Version date: November 2019. Novartis Pharmaceuticals; East Hanover NJ.
21. Clinicaltrials.gov. Study to Assess Safety and Impact of SeIG1 With or Without Hydroxyurea Therapy in Sickle Cell Disease Patients with Pain Crisis (SUSTAIN). NCT01895361.

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each Policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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