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Date Printed: December 17, 2017: 04:38 PM

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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J2000-90

Original Effective Date: 11/15/17

Reviewed: 10/11/17

Revised: 00/00/00

Next Review: 11/14/18

Subject: Enasidenib Mesylate (Idhifa®) Tablet

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates    
           

DESCRIPTION:

Enasidenib mesylate (Idhifa) is an oral isocitrate dehydrogenase-2 (IDH2) inhibitor first approved by the Food and Drug Administration (FDA) in August 2017 for the treatment of adult patients with relapsed or refractory acute myelogenous leukemia (AML) with an IDH2 mutation as detected by an FDA-approved test. It is the first FDA approved drug to target the IDH2 pathway. Enasidenib was previously granted orphan designation by the FDA for the treatment of AML in June 2014. Enasidenib targets mutant IDH2 variants resulting in increased myeloid differentiation, increased mature myeloid cell count, and reduced blast counts in IDH2-mutated AML. In vitro, enasidenib inhibits the mutant IDH2 enzyme at approximately 40-fold lower concentrations than the wild-type enzyme.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults, and accounts for the largest number of annual deaths from leukemia in the US. The median age of diagnosis is 67 years. A diagnosis is typically made based on the presence of 20% myeloid blast in the marrow or peripheral blood. Assessment of molecular abnormalities (IDH1/2, FLT3, NPM1, CEBPA, and other mutations) has become important for risk assessment, prognostication, and treatment selection. Isocitrate dehydrogenase-2 (IDH2) mutations have been reported in 8 to 12% of patient with AML, with a higher frequency of 19% among those with NK-AML. Reports on the prognostic effect of IDH2 mutations have been inconsistent. Some studies have reported the lack of prognostic value of IDH2 mutation whereas others have reported favorable outcomes with IDH2 mutations. Treatment of AML is divided into induction chemotherapy and postremission (e.g., consolidation) therapy. Initial treatment decisions are primarily based on age (<60 or ≥60), history of prior myelodysplasia or cytotoxic therapy, and performance status. Candidates for intensive remission induction therapy typically receive a regimen based on a backbone of cytarabine plus an anthracycline (daunorubicin or idarubicin). Up to two courses of inpatient induction therapy may be attempted to induce a complete response. If a complete response is achieved, consolidation therapy normally consists of cytarabine for 3 or 4 cycles (inpatient or outpatient). An allogeneic hematopoietic stem cell transplantation (HSCT) can be considered for induction failures and as a consolidation option for patient with unfavorable-risk cytogenetics and/or molecular abnormalities. For relapsed disease, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for AML (Version 3.2017) enrollment in a clinical trial in the strongly preferred option. Other options include chemotherapy followed by allogenic stem cell transplant if remission is achieved. Most chemotherapy regimens are purine analog-based (e.g., fludarabine, cladribine) and generally have remission rates of 30 to 45%. Best supportive care is recommended for patients who cannot tolerate or do not wish to pursue further intensive treatment.

The safety and efficacy of enasidenib was evaluated in an open-label, single-arm, multicenter, two-cohort clinical trial (Study AG221-C-001) of 199 adult patients with relapsed or refractory AML and an IDH2 mutation. Cohort 1 included 101 patients and Cohort 2 included 98 patients. IDH2 mutations were identified by a local diagnostic test and retrospectively confirmed by the Abbott RealTime IDH2 assay, or prospectively identified by the Abbott RealTime IDH2 assay, which is the FDA-approved test for selection of patients with AML for treatment. Enasidenib was given orally at starting dose of 100 mg daily until disease progression or unacceptable toxicity. Dose reductions were allowed to manage adverse events. Efficacy was established on the basis of the rate of complete response (CR)/complete response with partial hematologic recovery (CRh), the duration of CR/CRh, and the rate of conversion from transfusion dependence to transfusion independence.

The median age of the patients was 68 years, 48% of patients had relapsed AML while the other 52% had refractory AML, median time to initial AML diagnosis was 11.3 months, and the median number of prior therapies was two. Most patients (79%) were transfusion depended at baseline and only 13% had had a prior stem cell transplant for their AML. The median follow-up was 6.6 months (range, 0.4 to 27.7 months). Among both cohorts, 37 patients (19%) achieved a complete remission (CR) with median duration of response of 8.2 months, and 9 patients (4%) achieved a complete remission with partial hematological recovery (CRh) with median duration of response of 9.6 months. This resulted in a combined CR/CRh of 46 patients (23%) with a median duration of response of 8.2 months. For patients who achieved a CR/CRh, the median time to first response was 1.9 months (range, 0.5 to 7.5 months) and the median time to best response of CR/CRh was 3.7 months (range, 0.6 to 11.2 months). Of the 46 patients who achieved a best response of CR/CRh, 39 (85%) did so within 6 months of initiating treatment. Among the 157 patients who were dependent on red blood cell (RBC) and/or platelet transfusions at baseline, 53 (34%) became independent of RBC and platelet transfusions during any 56-day post baseline period. Of the 42 patients who were independent of both RBC and platelet transfusions at baseline, 32 (76%) remained transfusion independent during any 56-day post baseline period. The most common adverse reactions (≥20%) of any grade were nausea, vomiting, diarrhea, elevated bilirubin and decreased appetite. Serious adverse reactions were reported in 77.1% of patients. The most frequent serious adverse reactions (≥2%) were leukocytosis (10%), diarrhea (6%), nausea (5%), vomiting (3%), decreased appetite (3%), tumor lysis syndrome (5%), and differentiation syndrome (8%). Differentiation syndrome events characterized as serious included pyrexia, renal failure acute, hypoxia, respiratory failure, and multi-organ failure. Overall, 92 of 214 patients (43%) required a dose interruption due to an adverse reaction; the most common adverse reactions leading to dose interruption were differentiation syndrome (4%) and leukocytosis (3%). Thirty-six of 214 patients (17%) permanently discontinued treatment due to an adverse reaction; the most common adverse reaction leading to permanent discontinuation was leukocytosis (1%).

POSITION STATEMENT:

Comparative Effectiveness

The FDA has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

Initiation of enasidenib mesylate (Idhifa) meets the definition of medical necessity when ALL of the following criteria are met (“1”, “2”, “3”, “4”, and “5”):

1. Member has a confirmed diagnosis of relapsed or refractory acute myelogenous leukemia (AML)

2. Member meets ANY of the following criteria regarding their relapsed or refractory disease (“a”, “b” , “c”, or “d”):

a. Member is refractory to initial induction or re-induction chemotherapy

b. Member had a relapse at any time following an allogeneic stem cell transplant

c. Member had a relapse occurring within 1 year of initial treatment AND does not have favorable-risk status according to NCCN Guidelines

d. Member had two or more relapses following chemotherapy treatment

3. Member has IDH2 (isocitrate dehydrogenase-2) mutation-positive disease – laboratory documentation of the IDH2 mutation must be submitted

4. Enasidenib will be used a single-agent therapy for AML (i.e., not used in combination with other chemotherapy)

5. The dosage of enasidenib does not exceed 100 mg once daily, and will be obtained using the fewest number of tablets possible

Approval duration: 6 months

Continuation of enasidenib mesylate (Idhifa) meets the definition of medical necessity when ALL of the following criteria are met (“1”, “2”, “3”, and “4”):

1. The member has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of IDH2-positive AML, OR the member has previously met ALL indication-specific criteria.

2. The member has not experienced disease progression during treatment with enasidenib

3. Enasidenib is being used a single-agent therapy for AML (i.e., not used in combination with other chemotherapy)

4. The dosage of enasidenib does not exceed 100 mg once daily, and will be obtained using the fewest number of tablets possible

Approval duration: 12 months

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

• For the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test.

• The recommended starting dose is 100 mg taken orally once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response.

Dose Adjustments

• Baseline hepatic impairment: Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Treatment-related hepatic impairment: For a bilirubin level of greater than 3-times the upper limit of normal (ULN) that persists for 2 weeks or longer without elevated transaminases or other hepatic disorders, decrease the enasidenib dose to 50 mg PO once daily; may increase to 100 mg PO once daily if the bilirubin level decreases to 2-times the ULN or less.

• Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

• See the package insert for additional dosage adjustments for drug toxicity and the management of differentiation syndrome

Drug Availability

• 50 and 100 mg tablets in 30-count bottles

PRECAUTIONS:

Boxed Warning

• WARNING: DIFFERENTIATION SYNDROME

Patients treated with enasidenib have experienced symptoms of differentiation syndrome, which can be fatal if not treated. Symptoms may include fever, dyspnea, acute respiratory distress, pulmonary infiltrates, pleural or pericardial effusions, rapid weight gain or peripheral edema, lymphadenopathy, bone pain, and hepatic, renal, or multi-organ dysfunction. If differentiation syndrome is suspected, initiate corticosteroid therapy and hemodynamic monitoring until symptom resolution.

Contraindications

• None

Precautions/Warnings

Differentiation Syndrome: In the clinical trial, 14% of patients treated with enasidenib experienced differentiation syndrome, which may be life-threatening or fatal if not treated. Differentiation syndrome is associated with rapid proliferation and differentiation of myeloid cells. While there is no diagnostic test for differentiation syndrome, symptoms in patients treated with enasidenib included acute respiratory distress represented by dyspnea and/or hypoxia (68%) and need for supplemental oxygen (76%); pulmonary infiltrates (73%) and pleural effusion (45%); renal impairment (70%); fever (36%); lymphadenopathy (33%); bone pain (27%); peripheral edema with rapid weight gain (21%); and pericardial effusion (18%). Hepatic, renal, and multi-organ dysfunction have also been observed. Differentiation syndrome has been observed with and without concomitant hyperleukocytosis and as early as 10 days and at up to 5 months after enasidenib initiation. If differentiation syndrome is suspected, initiate oral or intravenous corticosteroids (e.g., dexamethasone 10 mg every 12 hours) and hemodynamic monitoring until improvement. Taper corticosteroids only after resolution of symptoms. Symptoms of differentiation syndrome may recur with premature discontinuation of corticosteroid treatment. If severe pulmonary symptoms requiring intubation or ventilator support, and/or renal dysfunction persist for more than 48 hours after initiation of corticosteroids, interrupt enasidenib until signs and symptoms are no longer severe. Hospitalization for close observation and monitoring of patients with pulmonary and/or renal manifestation is recommended.

• Embryo-Fetal Toxicity: Enasidenib can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with enasidenib and for at least 1 month after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with enasidenib and for at least 1 month after the last dose. Advise of the potential risk to a fetus.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8999

Prescription drug, oral, chemotherapeutic, Not Otherwise Specified

ICD-10 Diagnoses Codes That Support Medical Necessity

C92.00 – C92.02

Acute myeloblastic leukemia

C92.50 – C92.52

Acute myelomonocytic leukemia

C92.60 – C92.62

Acute myeloid leukemia with 11q23-abnormality

C92.A0 – C92.A2

Acute myeloid leukemia with multilineage dysplasia

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of guideline creation.

DEFINITIONS:

Refractory AML: Inability to achieve a complete response (CR) following induction chemotherapy.

Relapsed AML: Following a complete response the reappearance of leukemic blasts in the peripheral blood or the finding of more than 5% blasts in the bone marrow, not attributable to another cause.

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01

Azacitidine (Vidaza) Injection, 09-J0000-84

Granulocyte Colony Stimulating Factors, 09-J0000-62

Midostaurin (Rydapt), 09-J2000-86

Rasburicase (Elitek), 09-J2000-43

Sorafenib (Nexavar) Tablets, 09-J1000-50

Topotecan HCl (Hycamtin) Injection and Capsule, 09-J1000-02

OTHER:

None

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: www.clinicalpharmacilogy-ip.com. Accessed 9/18/17.
  2. ClinicalTrials.gov. Phase 1/2 Study of AG-221 in Subjects With Advanced Hematologic Malignancies With an IDH2 Mutation. NCT01915498. Available at: https://clinicaltrials.gov/ct2/show/NCT01915498. Accessed: 9/27/17.
  3. FDA Orphan Drug Designations and Approvals [Internet]. Washington, D.C. [cited 2017 September 18]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/.
  4. Idhifa (enasidenib) tablet package insert. Summit, NJ: Celgene Corporation; 2017 Aug.
  5. Micromedex Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 9/18/17.
  6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines). Acute Myeloid Leukemia (Version 3.2017 – June 6, 2017) [cited 2017 September 18]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.
  7. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2017 [cited 2017 September 18]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 10/11/17.

GUIDELINE UPDATE INFORMATION:

11/15/17

New Medical Coverage Guideline.

Date Printed: December 17, 2017: 04:38 PM