DRAFT Name of Blue Advantage Policy: Mylotarg® (gemtuzumab ozogamicin) Policy #: 679 Effective Date: June 1, 2018 Category: Pharmacology Latest Review Date: March 2018 Background: Blue Advantage medical policy does not conflict with Local Coverage Determinations (LCDs), Local Medical Review Policies (LMRPs) or National Coverage Determinations (NCDs) or with coverage provisions in Medicare manuals, instructions or operational policy letters. In order to be covered by Blue Advantage the service shall be reasonable and necessary under Title XVIII of the Social Security Act, Section 1862(a)(1)(A). The service is considered reasonable and necessary if it is determined that the service is: 1. Safe and effective; 2. Not experimental or investigational*; 3. Appropriate, including duration and frequency that is considered appropriate for the service, in terms of whether it is: • Furnished in accordance with accepted standards of medical practice for the diagnosis or treatment of the patient’s condition or to improve the function of a malformed body member; • Furnished in a setting appropriate to the patient’s medical needs and condition; • Ordered and furnished by qualified personnel; • One that meets, but does not exceed, the patient’s medical need; and • At least as beneficial as an existing and available medically appropriate alternative. *Routine costs of qualifying clinical trial services with dates of service on or after September 19, 2000 which meet the requirements of the Clinical Trials NCD are considered reasonable and necessary by Medicare. Providers should bill Original Medicare for covered services that are related to clinical trials that meet Medicare requirements (Refer to Medicare National Coverage Determinations Manual, Chapter 1, Section 310 and Medicare Claims Processing Manual Chapter 32, Sections 69.0-69.11). Page 1 of 7 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Blue Advantage Medical Policy #679 Description of Procedure or Service: Gemtuzumab ozogamicin is a CD33-directed antibody-drug conjugate (ADC). The antibody portion (hP67.6) recognizes human CD33 antigen. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumor cells, followed by internalization of the ADC- CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death. Hepatoxicity, including severe or fatal hepatic veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), has been reported in association with the use of Mylotarg as a single agent, and as part of a combination chemotherapy regimen. Monitor frequently for signs and symptoms of VOD after treatment with Mylotarg. Policy: Effective for dates of service on and after June 1, 2018: Blue Advantage will treat Mylotarg® (gemtuzumab ozogamicin) as a covered benefit for the treatment of CD33-positive acute myeloid leukemia (AML) when the following criteria are met: • Used in combination with daunorubicin and cytarabine for newly-diagnosed de novo acute myeloid leukemia in adults 18 years of age and older; or • Used as a single agent for newly diagnosed acute myeloid leukemia; or • Used as a single agent for relapsed or refractory AML in adults and children 2 years and older. Blue Advantage will treat Mylotarg® (gemtuzumab ozogamicin) as a covered benefit for the treatment of acute promyelocytic leukemia (APL) in high-risk individuals who are ineligible for treatment with anthracycline. Blue Advantage does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. Blue Advantage administers benefits based on the members' contract and medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination. Page 2 of 7 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Blue Advantage Medical Policy #679 Key Points: Acute Myeloid Leukemia AML, sometimes called acute non-lymphocytic leukemia (ANLL), is a malignancy arising from a myeloid precursor in the bone marrow. It is the most common form of leukemia among older persons. AML incidence rates increase dramatically among people who are over the age of 40. It is most prevalent in the sixth, seventh and eighth decades of life. The American Cancer Society estimates that in 2018 there will be about 19,520 new cases of AML and 10,670 deaths from AML. APL is a subtype of AML and usually occurs in middle-aged adults. Effective treatment of AML requires the control of bone marrow and systemic disease and specific treatment of CNS disease, if present. There are currently four types of standard therapy generally used to treat adults with AML: chemotherapy, radiation therapy, stem cell transplant and other drug therapy. Typically, there are two treatment stages for adult AML: remission induction therapy (to attain remission) and post-remission therapy (to maintain remission). In May 2000, gemtuzumab ozogamicin was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed CD33 positive AML in individuals over 60 years of age unable to receive other chemotherapy. This approval was based on a response rate of approximately 30% observed in phase II trials. Results from the required post- approval study of the addition of gemtuzumab to standard induction therapy (daunorubicin and cytosine arabinoside) as first-line therapy for AML in individuals less than 61 years of age showed significantly greater fatal induction toxicity and no improvement in survival compared to chemotherapy alone. Due to safety and efficacy concerns raised by the post-approval study, gemtuzumab ozogamicin was voluntarily withdrawn from the U.S. market on June 21, 2010. However, clinical trials evaluating the safety and efficacy of the agent continued. In light of the current availability of additional clinical trial data, the regulatory status of gemtuzumab ozogamicin was re-evaluated. In January 2017, a Biologics License Application (BLA) for gemtuzumab ozogamicin was accepted for filing by the FDA. This FDA submission was based on additional data from a phase III randomized, open-label study (ALFA-0701) and a large meta- analysis. Castaigne and colleagues (2012) evaluated the addition of gemtuzumab ozogamicin to standard induction chemotherapy using an alternative fractionated dosing schedule. This phase III randomized, open label trial was performed between January, 2008 and November, 2010 at 26 French hematology centers. Subjects aged 50-70 years with normal cardiac function were eligible if they had previously untreated, locally confirmed AML. Exclusion criteria included previous myeloproliferative/myelodysplastic syndrome; previous exposure to chemotherapy or radiotherapy; CNS involvement, severe uncontrolled infection; or liver or kidney dysfunction. A total of 280 individuals were randomly assigned with a 1:1 ratio to a standard treatment (control group, n=140) or a gemtuzumab ozogamicin group (n=140). In each group, 139 of the 140 subjects were analyzed. The primary endpoint was event-free survival (EFS) and secondary endpoints were relapse-free survival (RFS), overall survival (OS), and safety. Endpoints (EFS, RFS, and OS) were significantly improved in the gemtuzumab ozogamicin group at 2 years. Complete response with or without incomplete platelet recovery to induction was 104 (75%) in the control group and 113 (81%) in the gemtuzumab ozogamicin group. EFS at 2 years was estimated as 17.1% (10.8-27.1) in the control group versus 40.8% (32.8-50.8) in the gemtuzumab Page 3 of 7 Proprietary Information of Blue Cross and Blue Shield of Alabama An Independent Licensee of the Blue Cross and Blue Shield Association Blue Advantage Medical Policy #679 ozogamicin group (hazard ratio 0.58, 0.43-0.78; p=0.0003), OS was 41.9% (33.1-53.1) versus 53.2% (44.6-63.5), respectively (0.69, 0.49-0.98; p=0.0368), and RFS 22.7% (14.5-35.7) versus 50.3% (41.0-61.6), respectively (0.52, 0.36-0.75; p=0.0003). Hematological toxicity was more frequent in the gemtuzumab ozogamicin group than in the control group; however, there was not an increase in the risk of death from toxicity. Hills and colleagues (2014) performed a large meta-analysis of 3325 subjects (median age 58) from five randomized phase III trials (including ALFA-0701) of gemtuzumab ozogamicin added to intensive induction chemotherapy for AML (excluding acute promyelocytic leukemia [APL]) in adults. All trials with data available as of May 1, 2013 were included. Overall results demonstrated that adding gemtuzumab ozogamicin to intensive induction chemotherapy did not increase the remission rates, with or without complete peripheral count recovery. However, the addition of gemtuzumab ozogamicin significantly reduced the risk of relapse, and improved OS at 5 years. The absolute survival benefit was particularly noted in subjects at 6 years with favorable cytogenetics, but was also seen in those with intermediate characteristics. Doses of 3 mg/m2 and 6 mg/m2 had equal efficacy; however, doses of 3 mg/m2 were associated with fewer early deaths. Subjects with adverse karyotypes treated with gemtuzumab ozogamicin did not benefit within any trial, or overall. In 2013, Amadori and colleagues reported the results of a randomized phase III clinical trial that evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin and standard chemotherapy in 472 individuals aged 61-75 years with newly diagnosed AML.