Subject:
Inotuzumab Ozogamicin (Besponsa)
Description:
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IMPORTANT NOTE:
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.
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Inotuzumab ozogamicin (BesponsaTM), a human CD22-directed antibody- drug conjugate, was FDA approved for the treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). The treatment received Orphan Drug and Breakthrough Therapy designations.
Acute lymphoblastic leukemia is a malignant disorder that originates in a single B- or T-lymphocyte progenitor. The proliferation of blast cells in the marrow results in suppression of hematopoiesis, leading to anemia, thrombocytopenia, and neutropenia. In adults, this disease is less common than AML, with approximately 1000 new cases each year. 20-40% of adults with ALL are cured with current treatment regimens. Each year in the United States approximately 840 patients relapse from a first remission or are refractory to front-line therapy. 55% of patients will relapse a second time or be refractory to second-line therapy, with worsening prognosis, decreased survival, and a need for a third line of therapy.
The safety and efficacy of BesponsaTM was evaluated in the INO-VATE ALL. This was a randomized, open-label, international, multicenter study in patients with relapsed or refractory ALL. Eligible patients were 18 > years of age with Philadelphia chromosome- negative or positive relapsed or refractory B-cell precursor ALL. Patients had Eastern Cooperative Oncology Group (ECOG) performance scores ranging from 0 to 2, bone marrow involvements with > 5% blasts, adequate liver function (total serum bilirubin < 1.5 X ULN), and SCr < 1.5 X ULN. Exclusion criteria included extramedullary relapse, Burkett’s or mixed lineage leukemia, active central nervous system leukemia, prior chemotherapy within < 2 weeks before randomization, prior monoclonal antibodies or prior allogeneic hematopoietic stem cell transplant or other anti-CD22 immunotherapy < 4 months before randomization, peripheral lymphoblasts > 10,000 uL, known systemic vasculitides, primary or secondary immunodeficiency, current or chronic hepatitis B or C infection, unstable or severe uncontrolled medical conditions, concurrent active malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix or localized prostate cancer treated with radiation or surgery, LVEF less than 45%, active heart disease, QTcF > 470 msec, MI within 6 months of randomization, history of ventricular arrhythmia, history of chronic liver disease, history of hepatic veno-occlusive disease, live vaccines 6 weeks before randomization, uncontrolled current serious active infection, and previous allergic reaction to monoclonal antibodies . Patients received a total dose of 1.8 mg/m2 of BesponsaTM; on day 1 they would receive 0.8 mg and 0.5 mg on day 8 and 15. Cycle 1 was 21 days; the subsequent 5 cycles lasted 28 days. When a patient achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi) , the dose on day 1 was reduced to 0.5 mg. BesponsaTM was compared to standard-therapy. The primary endpoint, CR+CRi, showed a statistically significant improvement (80.7% vs 29.4%, P<0.001). BesponsaTM had CR in 35.8% of patients for a median of 8 months, with 89.7% of patients being negative for minimal residual disease. Meanwhile, the standard of care arm had CR in 17.4% of patients for a median 4.9 months, with 31.6% of patients being negative for minimal residual disease. Hematologic adverse events were the most common during the trial. Febrile neutropenia was the most frequently reported serious adverse effect in both groups. Liver related adverse events were more common in the BesponsaTM group than in the standard of care group. Cases of veno-occlusive disease occurred for up to 2 years post randomization, and occurred more frequently in the BesponsaTM group (11% vs 1%).
BesponsaTM carries a black box warning for hepatotoxicity, which includes veno-occlusive disease or sinusoidal obstruction syndrome. The medication also causes an increased risk of post hematopoietic stem cell transplant non-relapse mortality.
[INFORMATIONAL NOTE: BesponsaTM packaging includes the following BLACK BOX WARNINGS:
· Hepatotoxicity, including fatal and life-threatening VOD occurred in patients who received BesponsaTM
· A higher post-HSCT non-relapse mortality rate occurred in patients receiving BesponsaTM
As per the FDA approved labeling, mid-cycle modifications are only recommended for non-hematologic toxicities. If the dose is reduced due to BesponsaTM toxicities, the dose is not to be re-escalated. Toxicities include:
· Modify doses if the following hematologic issues arise prior to BesponsaTM treatment:
o ANC > 1X 109/L
o Platelets > 50 X 109/L
o ANC < 1X 109/L and Platelets < 50 X 109/L
· Modify doses for the following non-hematologic toxicities
o Veno-occlusive disease or other severe liver toxicity
o Total bilirubin > 1.5 ULN AND AST/ALT >2.5 X ULN
o Infusion related reactions
o Non-hematologic toxicity > Grade 2
· Modifications due to non-hematologic toxicities depends on the duration of dose interruption.]
Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance)
The requirements of the Horizon BCBSNJ Inotuzumab Ozogamicin (Besponsa) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).
I. Inotuzumab ozogamicin (BesponsaTM) is considered medically necessary based on the FDA approved indication for patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).
- Member is 18 years of age or older
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- Member has CD22 positive disease
- Besponsa is to be used as a single agent
- Regardless of Philadelphia chromosome status (positive or negative), members must have received 1 or 2 previous induction chemotherapy regimens for ALL (including but not limited to regimen with daunorubicin, vincristine, prednisone, pegaspargase, and cyclophosphamide or Hyper CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone])
- Members with Philadelphia chromosome-positive B-cell precursor ALL must have also failed treatment with at least 1 tyrosine kinase inhibitor (including but not limited to imatinib, dasatinib, ponatinib.)
- Eastern cooperative oncology group performance status 0-2.
- Bone marrow involvement > 5% lymphoblasts.
- Total serum bilirubin < 1.5 X ULN and AST / ALT < 2.5 X ULN.
- If abnormality due to tumor, total serum bilirubin must be < 2 X ULN.
- Serum creatinine < 1.5 X ULN or any serum creatinine associated with a calculated creatinine clearance of > 40 mL/min.
- Member may NOT have the following:
- History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS).
- History of liver disease (e.g. cirrhosis) or suspected alcohol abuse.
- QTc interval > 470 msec based on average of 3 consecutive ECGs.
- Pregnant patients, breastfeeding females.
[INFORMATIONAL NOTE: ECOG Performance Status:
- Grade 0: Fully active, able to carry on all pre-disease performance without restriction
- Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
- Grade 2: Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours]
II. When inotuzumab ozogamicin (BesponsaTM) is medically necessary, therapy will be approved for a period of 24 weeks at the following FDA-approved doses:
· Cycle 1 of treatment is 21 days in duration and consists of a total dose of 1.8 mg/m2 per cycle administered as 3 divided doses.
o Administer 0.8 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and 15.
o Cycle 1 may be extended to 4 weeks if the patient achieves CR or complete remission with incomplete hematologic recovery (CRi), or to allow recovery from toxicity.
· Subsequent cycles 2-6 are 28 days in length.
o If the patient has a CR or CRi the total dose is 1.5 mg/m2 per cycle administered as 3 divided doses.
§ Administer 0.5 mg/m2 on day 1, 8, and 15.
o If the patient has not achieved a CR or CRi, the total dose is 1.8 mg/m2 per cycle administered as 3 divided doses.
§ Administer 0.8 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and 15.
· If a patient is proceeding to hematopoietic stem cell transplant, BesponsaTM is recommended for up to 3 cycles.
· Cycle 1 of treatment is 21 days in duration and consists of a total dose of 1.8 mg/m2 per cycle administered as 3 divided doses.
o Administer 0.8 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and 15.
· Cycle 2 of treatment is 28 days in length.
o If the patient has a CR or CRi the total dose is 1.5 mg/m2 per cycle administered as 3 divided doses.
§ Administer 0.5 mg/m2 on day 1, 8, and 15.
o If the patient has not achieved a CR or CRi, the total dose is 1.8 mg/m2 per cycle administered as 3 divided doses.
§ Administer 0.8 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and 15.
· Cycle 3 may be administered if patient still has not achieved CR or CRi and minimal residual disease (MRD) negativity after 2 cycles.
o The total dose is 1.8 mg/m2 administered as 3 divided doses.
§ Administer 0.8 mg/m2 on day 1 and 0.5 mg/m2 on day 8 and 15.
[INFORMATIONAL NOTE: As per the FDA approved package insert, pre-medicate with a corticosteroid, antipyretic, and an antihistamine is recommended prior to dosing. Observe patients for 1 hour after the end of an infusion. If the patient has circulating lymphoblasts, recommend cyto-reduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast of < 10,000/mm3 prior to first dose.]
III. Inotuzumab ozogamicin (BesponsaTM) is considered medically necessary for the following off-label uses:
- Pediatric acute lymphoblastic leukemia
- Single agent therapy for relapsed/refractory Philadelphia chromosome-negative B-ALL
- Single agent therapy for relapsed/refractory Philadelphia chromosome-positive tyroskine kinase inhibitor intolerant/refractory B-ALL
IV. Inotuzumab ozogamicin (BesponsaTM) beyond 6 cycles is considered investigational.
V. Inotuzumab ozogamicin (BesponsaTM) is investigational for all other indications, including but not limited to non-hodgkin lymphoma, follicular lymphoma, diffused large cell lymphoma.
Medicare Coverage
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 Policy.
Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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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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Index:
Inotuzumab Ozogamicin (Besponsa)
Besponsa (Inotuzumab Ozogamicin)
References:
1. BesponsaTM Prescribing information. Pfizer. New York City, NY. March 2018.
2. Kantarjian HM, Deangelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. N Engl J Med. 2016;375(8):740-53.
3. Mulhay N. FDA approves Inotuzumab Ozogamicin (BesponsaTM) for ALL. Medscape . http://www.medscape.com/viewarticle/884434. Published August 17, 2017. Accessed August 28, 2017.
4. NCCN Clinical Practice Guidelines in Oncology. Acute Lymphoblastic Leukemia. Version 2.2019. May 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed October 2019.
5. ClinicalTrials.gov. Besponsa. Available at https://clinicaltrials.gov/ct2/results?cond=&term=besponsa&cntry=&state=&city=&dist=. Accessed October 2019.
6. National Comprehensive Cancer Network. NCCN Drugs & Biologics Compendium. Besponsa. Available at https://www.nccn.org/professionals/drug_compendium/content/. Accessed October 2019.
7. NCCN Clinical Practice Guidelines in Oncology. Pediatric Acute Lymphoblastic Leukemia. Version 1.2020. May 2019. Available at: https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf. Accessed October 2019.
Codes:
(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*
HCPCS
* CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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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.
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