The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
Sickle cell disease (SCD) is a genetic disorder that predominantly affects individuals of African descent. It is characterized by the presence of sickle hemoglobin (HbS), which polymerizes upon deoxygenation, damaging erythrocytes and potentially leading to vaso-occlusion, multi-organ damage, and early death. Painful vaso-occlusive crises (VOCs), also known as sickle cell pain crises, are the hallmark of SCD and are the primary cause of hospitalization in SCD. VOCs cause pain in the extremities, back, abdomen or chest, and can vary in intensity from mild to excruciating. Patients with SCD and frequent VOCs may experience problems with low self-esteem, anxiety, depression, dissatisfaction with body image, poor school performance, social isolation, decreased participation in normal daily activities, and poor peer and family relationships.
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 (eg, 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 age 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, aged 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).
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)
I. Prior to therapy initiation, member must meet ALL of the following:
1. Hemoglobin is > 4.0g/dL
2. Member is NOT planning to undergo an exchange transfusion during duration of treatment or is on a chronic transfusion program (this does NOT include occasional, episodic transfusions on an as needed basis)
3. Member is NOT receiving chronic anticoagulation (e.g., warfarin, heparin) therapy other than aspirin (this does NOT include NSAIDs or prophylactic doses of anticoagulation)
4. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. hematologist) or has consulted with a specialist in the area of the patient’s diagnosis
[INFORMATIONAL NOTE: Based on the FDA labeled package insert, Adakveo (crizanlizumab-tmca) has the potential to cause fetal harm when administered to a pregnant woman. There are insufficient human data on Adakveo (crizanlizumab-tmca) use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus. Adakveo (crizanlizumab-tmca) should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the fetus.]
II. Adakveo (crizanlizumab-tmca) is medically necessary to reduce the frequency of vaso-occlusive crises in adults and pediatric patients aged 16 years and older with sickle cell disease who meet the following criteria:
III. When Adakveo (crizanlizumab-tmca) is considered medically necessary, therapy will be approved for 6 months at the following dosing:
- Confirmed medical history or diagnosis of SCD (including HbSS, HbSC, HbSB0-thalassemia, HbSB+-thalassemia patients); AND
- Member has experienced at least 2 sickle cell pain crises (SCPC) within the preceding 12 months as determined by medical documentation (e.g. SCPC should include the occurrence of appropriate symptoms, a visit to a specific medical facility and/or health care professional, and receipt of pain medication); AND
- Member has tried and failed generic hydroxyurea; AND
- Adakveo is prescribed as monotherapy or concomitantly with hydroxyurea; AND
- If member is concomitantly receiving hydroxyurea, must have been prescribed for the preceding 6 months and be dose stabilized for at least 3 months prior to initiation of therapy; AND
- If member is concomitantly receiving erythropoietin, must have been prescribed for the preceding 6 months and be dose stabilized for at least 3 months prior to initiation of therapy; AND
- Member is not concomitantly receiving Oxbryta (voxelotor) tablets; AND
- Member is not concomitantly receiving Endari (L-glutamine oral powder)
- Administer Adakveo 5 mg/kg by intravenous infusion over a period of 30 minutes at Week 0, Week 2, and every 4 thereafter.
[INFORMATIONAL NOTE: Based on the FDA labeled package insert, if Adakveo is administered within 2 weeks after the missed dose, continue dosing according to the patient's original schedule. If Adakveo is administered more than 2 weeks after the missed dose, continue dosing every 4 weeks thereafter weeks thereafter. Adakveo should be prepared and administered by a healthcare professional. Calculate the dose (mg) and the total volume (mL) of Adakveo solution required, and the number of Adakveo vials needed based on the patient’s actual body weight. Prepare 5 mg of Adakveo per kg of actual body weight. Calculate the volume of Adakveo to be used according to the following equation: Volume (mL) = patient's body weight (kg) X prescribed dose [5mg/kg] / concentration of Adakveo [10mg/ml]]
IV. Continuation of Adakveo (crizanlizumab-tmca) will be approved annually if the member meets the following:
- Member continues to meet the criteria in section I: AND
- There is documentation showing a decrease in the amount of sickle cell pain crises from baseline; AND
- There is documentation showing a decrease in use of other sickle cell pain medications such as decrease in opioid use; AND
- Absence of unacceptable toxicity from the drug (e.g. infusion-related reactions).
V. Other uses of Adakveo (crizanlizumab-tmca) including but not limited to, sickle cell disease in pediatric patients less than age 16, and myelofibrosis are considered investigational.
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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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.
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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.
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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. AdakveoŽ (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.
22. Novartis. Medial Information Request. Adakveo - Anticoagulation. Inquiry number: FMAV-04149366. January 22, 2020.
23. Novartis. Medial Information Request. Adakveo - Transfusion. Inquiry number: FMAV-04147655. January 22, 2020.
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.
The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy