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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-J2000-07

Original Effective Date: 03/15/14

Reviewed: 07/13/16

Revised: 12/15/16

Subject: Obinutuzumab (Gazyva®) Injection

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:

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a mature B-cell lymphoma and comprises approximately 7% of newly diagnosed cases of Non-Hodgkin’s Lymphoma (NHL). CLL and SLL are different manifestation of the same disease and are managed in much the same way. The main difference is that in CLL the abnormal lymphocytes are found in bone marrow and blood, while in SLL they are predominately found in the lymph nodes and bone marrow. I. Treatment options have changed drastically in the last several decades; the introduction of immunotherapeutic agents such as monoclonal antibodies that target cell surface antigens (e.g., CD20, CD52) have led to the development of new and effective regimens that incorporate drugs with different mechanisms of action.

Obinutuzumab (Gazyva®) is a humanized monoclonal antibody that binds specifically to the CD20 molecule located on pre B- and mature B-lymphocytes, resulting in cell lysis independent of BCL-2, which potentially circumvents resistance. Obinutuzumab was approved by the U.S. Food and Drug Administration (FDA) in October 2013 for the treatment of previously untreated chronic lymphocytic leukemia (CLL) in combination with chlorambucil. Gazyva was previously granted orphan designation for the treatment of CLL in February 2012. Gazyva also has orphan designations for the treatment of follicular lymphoma (April 2015) and splenic marginal zone lymphoma (June 2015). In February 2016, Gazyva was FDA approved for the treatment of follicular lymphoma in patients who relapsed after or are refractory to a rituximab-containing regimen, in combination with bendamustine followed by obinutuzumab monotherapy.

Obinutuzumab’s safety and effectiveness in CLL were evaluated in a 3-arm, open-label trial of patients (n=356; median age: 73 years; 76% with coexisting medical conditions; 68% with CrCl<30 mL/min) with previously untreated CD20+ CLL. Patients were randomly assigned to receive randomized to chlorambucil only, obinutuzumab plus chlorambucil, or rituximab plus chlorambucil. Obinutuzumab 1000 mg IV infusion was administered on days 1, 8, and 15 of the first 28-day cycle and on day 1 of cycles 2 to 6. Chlorambucil 0.5 mg/kg orally was administered on day 1 and day 15 of all six 28-day cycles. Rituximab IV infusion was administered on day 1 of each 28-day cycle with 375 mg/m2 for cycle 1 and 500 mg/m2 for cycles 2 to 6. At a median follow-up of 14.2 months, median PFS was significantly improved with obinutuzumab plus chlorambucil compared with chlorambucil alone (23 vs 11.1 months; HR: 0.16; 95% CI: 0.11-0.24; p<0.0001); there were also improvements in overall response rate (75.9% vs 32.1%), complete responses (27.8% vs 0.9%), and median duration of response (15.2 vs 3.5 months). Results for obinutuzumab plus chlorambucil compared with rituximab plus chlorambucil were not reported.

National Comprehensive Cancer Network (NCCN) Guidelines for CLL/SLL (Version 1.2017) list obinutuzumab, either in combination with chlorambucil (category 1 recommendation) or as monotherapy (category 2B), as first-line therapy for CLL/SLL in all patients without a del(17p) mutation except those age less than 65 years without significant comorbidities. Alternative first-line treatments are recommended for patients less than 65 years without significant comorbidities. Obinutuzumab monotherapy (category 2A) is also listed as a treatment option in relapsed or refractory CLL/SLL for all patients without a del(17p) mutation regardless of age or comorbidities. Obinutuzumab is not recommended for CLL/SLL with a del(17p) mutation. The NCCN Guidelines for Non-Hodgkin’s Lymphomas (Version 3.2016) gives a 2B recommendation for the use of obinutuzumab maintenance therapy for rituximab-refractory disease in patients with indications for treatment as second-line extended dosing up to 12 total cycles.

POSITION STATEMENT:

Initiation of obinutuzumab (Gazyva®) meets the definition of medical necessity for EITHER of the following indications when ALL associated criteria are met:

1. Member is diagnosed with follicular lymphoma

a. Member meets EITHER of the following (i or ii):

i. Member has experience a disease relapse after treatment with a rituximab-containing regimen for their follicular lymphoma

ii. Member is refractory to a rituximab-containing regimen for their follicular lymphoma

b. Obinutuzumab will be used initially in combination with bendamustine for the first 6 cycles, followed by monotherapy with obinutuzumab as maintenance treatment

c. The dosage does not exceed ANY of the following:

i. Cycle 1 (first 28 days): 3,000 mg

ii. Cycles 2 to 6: 1,000 mg every 28 days

iii. After cycle 6: 1,000 mg every 60 days

2. Member is diagnosed with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)

a. Member meets EITHER of the following (i or ii):

i. ALL of the following:

• Treatment is for relapsed/refractory CLL/SLL.

• Member does NOT have a del (17p) mutation.

• Obinutuzumab is used a monotherapy for the member’s CLL/SLL treatment.

ii. ALL of the following:

• Member has not received previous therapy for CLL/SLL (i.e., member is treatment naïve and is receiving first-line treatment)

Member does NOT have a del (17p) mutation

• Obinutuzumab is used as monotherapy, or in combination with chlorambucil

b. The dose dosage not exceed ANY of the following

i. Cycle 1 (first 28 days): 3,000 mg

ii. Cycles 2 to 6: 1,000 mg every 28 days

iii. No more than 6 total treatment cycles

Approval duration: 180 days

The continuation of obinutuzumab (Gazyva®) meets the definition of medical necessity when ALL of the following criteria are met:

1. Authorization/reauthorization for obinutuzumab has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of follicular lymphoma, OR the member previously met ALL indication-specific initiation criteria [see initiation criteria for CLL/SLL treatment.].

2. The member did NOT have disease progression during treatment with obinutuzumab

3. Dosage does not exceed the following:

a. Cycles 2 to 6: 1,000 mg every 28 days

b. Cycle 6 to 12: 1,000 mg every 60 days

4. Member has not received more than 12 total cycles of treatment during their current line of therapy

Approval duration: 1 year

Obinutuzumab (Gazyva®) meets the definition of medical necessity when BOTH of the following are met for the orphan indication of splenic marginal zone lymphoma:

1. The member has failed previous first-line chemotherapy

2. The dose does not exceed ALL of the following:

a. Cycle 1 (first 28 days): 3,000 mg

b. Cycles 2 to 6: 1,000 mg every 28 days

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: obinutuzumab is a CD-20 directed antibody and is indicated, in combination with chlorambucil, for the treatment of individuals with treatment-naïve chronic lymphocytic leukemia (CLL). It is also indicated for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen in combination with bendamustine followed by obinutuzumab monotherapy. Obinutuzumab should be administered as an intravenous (IV) infusion; do not administer as an IV push or bolus. Individuals should receive pre-medication (i.e., glucocorticoid, acetaminophen, and an anti-histamine) prior to each obinutuzumab infusion. See the package insert for additional details on infusion rates and rate adjustments.

The recommended dosage for members with CLL/SLL is as follows (1 cycle = 28 days):

• 100 mg on day 1, Cycle 1

• 900 mg on day 2, Cycle 1

• 1,000 mg on day 8 and 15 of Cycle 1

• 1,000 mg on day 1 of Cycles 2 to 6

The recommended dosage for member with follicular lymphoma is as follows (1 cycle = 28 days):

• The first 6 cycles are given in combination with bendamustine

o 1,000 mg on day 1, Cycle 1

o 1,000 ng on day 8, Cycle 1

o 1,000 mg on day 15, Cycle 1

o 1,000 mg on day 1 of Cycles 2 to 6

• After cycle 6 obinutuzumab is given as monotherapy

o 1,000 mg every 2 months

Dose Adjustments: Monitor blood counts at regular intervals. Consider treatment interruption if infection, Grade 3 or 4 cytopenia, or Grade 2 or great non-hematologic toxicity occurs.

Drug Availability: obinutuzumab is supplied as a 1,000 mg/40 mL single-use vial.

PRECAUTIONS:

Boxed Warning

• Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in persons treated with anti-CD-20 antibodies such as obinutuzumab. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment. Discontinue obinutuzumab and concomitant medications in the event of HBV reactivation.

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in persons treated with obinutuzumab.

Contraindications:

• None

Precautions/Warnings

• Infusion reactions: Premedicate members with glucocorticoid, acetaminophen and anti-histamine. Monitor members closely during infusions. Interrupt or discontinue infusion for reactions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms. Two thirds of patients experienced a reaction to the first 1,000 mg infused.

• Tumor Lysis Syndrome: Anticipate tumor lysis syndrome; premedicate with anti-hyperuricemics and adequate hydration especially for persons with high tumor burden and/or high circulating lymphocyte count. Correct electrolyte abnormalities, provide supportive care, and monitor renal function and fluid balance.

• Neutropenia: Monitor for infection.

• Thrombocytopenia: Monitor platelet counts and for bleeding. Management of hemorrhage may require blood product support.

• Immunization: Do not administer live virus vaccines prior to or during treatment with obinutuzumab.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J9301

Injection, obinutuzumab, 10 mg

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/15)

C82.00 – C82.09

Follicular lymphoma grade I

C82.10 – C82.19

Follicular lymphoma grade II

C82.20 – C82.29

Follicular lymphoma grade III, unspecified

C82.30 – C82.39

Follicular lymphoma grade IIIa

C82.40 – C82.49

Follicular lymphoma grade IIIb

C82.50 – C82.59

Diffuse follicle center lymphoma

C82.60 – C82.69

Cutaneous follicle center lymphoma

C82.80 – C82.89

Other types of follicular lymphoma

C82.90 – C82.99

Follicular lymphoma, unspecified

C83.00 – C83.09

Small cell B-cell lymphoma

C83.50 – C83.59

Lymphoblastic (diffuse) lymphoma

C83.87

Other non-follicular lymphoma, spleen

C91.10

Chronic lymphocytic leukemia of B-cell type not having achieved remission

C91.11

Chronic lymphocytic leukemia of B-cell type in remission

C91.12

Chronic lymphocytic leukemia of B-cell type in relapse

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 the last guideline review date.

DEFINITIONS:

Chronic lymphocytic leukemia (CLL): an indolent (slow-growing) cancer in which too many immature lymphocytes (white blood cells) are found mostly in the blood and bone marrow. Sometimes, in later stages of the disease, cancer cells are found in the lymph nodes and the disease is called small lymphocytic lymphoma.

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01
Autologous Bone Marrow and Stem Cell Transplantation, 02-38241-01

Bendamustine (Treanda), 09-J2000-40

Ibrutinib (Imbruvica), 09-J2000-09

Idelalisib (Zydelig), 09-J2000-23

Interferons for Oncology Use, 09-J1000-37

Lenalidomide (Revlimid), 09-J0000-80

Procarbazine (Matulane), 09-J1000-59

Rituximab (Rituxan), 09-J0000-59

OTHER:

None

REFERENCES:

  1. Cartron G, de Guibert S, Dilhuydy MS, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016 [cited 2016 June 10]. Available from: http://www.clinicalpharmacology.com/. .
  3. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2016 Jun 10]. Available from: http://www.thomsonhc.com/.
  4. Gazyva (Obinutuzumab) [package insert]. Genentech, Inc. South San Francisco (CA): March 2016.
  5. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 2014;370(12):1101-1110.
  6. Merli M, Ferrario A, Basilico C, et al. Novel agents in indolent lymphomas. Ther Adv Hematol. 2013 Apr;4(2):133-48.
  7. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 6/10/16.
  8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 1.2017. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Available at https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf. Accessed 11/02/16.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2016. Non-Hodgkin’s Lymphoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed 11/02/16.
  10. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016 Jun 10]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index
  11. Radford J, Davies A, Cartron G, et al. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000). Blood. 2013 Aug 15;122(7):1137-43. Epub 2013 Jul 10.
  12. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016 Jun 23. pii: S1470-2045(16)30097-3.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 07/13/16.

GUIDELINE UPDATE INFORMATION:

3/15/2014

New Medical Coverage Guideline.

01/01/15

Review and revision to guideline; consisting of annual HCPSC coding update

08/15/15

Review and revision to guideline; consisting of description, position statement, precautions, billing/coding information, related guidelines, and references.

11/01/15

Revision: ICD-9 Codes deleted.

08/15/16

Review and revision to guideline consisting of updating the description section, position statement, dosage/administration section, related guidelines, and references.

12/15/16

Revision to guideline consisting of updating the description section, position statement, and references based on updated NCCN guidelines for CLL/SLL.

Date Printed: June 28, 2017: 11:42 PM