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Date Printed: August 23, 2017: 06:02 AM

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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-J1000-84

Original Effective Date: 02/15/13

Reviewed: 02/08/17

Revised: 03/15/17

Subject: Bosutinib (Bosulif®) Tablets

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:

Bosutinib (Bosulif®) is a second-generation dual tyrosine kinase inhibitor (TKI) and exerts is therapeutic effects by inhibiting the BCR-ABL kinase that promotes chronic myelogenous leukemia (CML) and Src-family kinases. Bosutinib has demonstrated activity against many of the BCR-ABL kinase domain mutations resistant to imatinib (Gleevec®), dasatinib (Sprycel®), and nilotinib (Tasigna®), except V299L and T315I. Bosutinib was given orphan designation status in 2009 for the treatment of CML and was approved by the US FDA in September 2012 for the treatment of adults with chronic phase, accelerated phase, or blast phase Philadelphia (Ph) chromosome-positive CML (CP-CML, AP-CML, and BP-CML, respectively) demonstrating resistance or intolerance to prior TKI therapy. The approval was based principally on a single-arm multicenter phase I-II study that enrolled a total of 570 adult subjects diagnosed with CP-CML, AP-CML, or BP-CML. All subjects were previously treated with one prior TKI (imatinib) or more than one TKI (imatinib followed by dasatinib and/or nilotinib) and were imatinib resistant or intolerant. The primary endpoint was major cytogenetic response (MCyR) at 24 weeks for subjects with CP-CML and complete hematologic response (CHR) by 8 weeks for subjects with AP-CML and BP-CML. In the cohort of CP-CML subjects previously treated with imatinib alone, 31% achieved MCyR at 24 weeks. In the cohort of CP-CML subjects who were pretreated with more than one TKI, 32% achieved MCyR at 24 weeks. Additionally, 61% of subjects with AP-CML and BP-CML achieved CHR by 8 weeks. The efficacy and safety of bosutinib as first-line therapy was evaluated in a phase III randomized study (the BELA trial). There was no statistically significant difference in CCyR at 12 months in bosutinib-treated patients vs. imatinib-treated patients (70% vs 68%). However, discontinuation of therapy due to adverse events occurred in more patients in bosutinib arm (19% vs. 6%) and bosutinib was associated with more grade 3 or 4 diarrhea (11% vs. 1%), vomiting (3% vs. 0%) and elevated ALT (22% vs. 3%) compared with imatinib, respectively. As such, bosutinib is not recommended as first-line therapy in persons with CP-CML.

Chronic myelogenous leukemia is a hematopoietic stem cell disease characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia chromosome. The median age of disease onset is 67 years, but CML occurs in all age groups. CML occurs in three different phases (i.e., chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase disease in 3 to 5 years. The National Comprehensive Cancer Network (NCCN) CML guidelines provide treatment recommendations for all three phases. The efficacy of CML therapy is assessed by monitoring hematologic, cytogenetic, and molecular responses. The National Comprehensive Cancer Network (NCCN) guidelines for CML (Version 2.2017) list imatinib, nilotinib, or dasatinib (Sprycel) as category 1 options for the treatment of chronic phase CML in patients with a low-risk Sokal or Hasford score. For patients with an intermediate- or high-risk score, the three TKIs are all listed as category 2A options; however, dasatinib and nilotinib are labeled as preferred. Age, tolerance of adverse effects, and comorbid conditions also may affect initial choice of treatment.Individuals who do not respond to first-line therapy should be switched to an alternate second-generation TKI.

NCCN CML guidelines also discuss the role of allogeneic hematopoietic stem cell transplant (HSCT). Although allogeneic HSCT is a potentially curative treatment for persons with CML, the excellent results observed with TKI therapy have challenged its role as a first-line therapy. Although the guideline no longer recommends allogeneic HSCT as a first-line treatment option for CP-CML, it is a potential option for persons with the T315I mutation, since this mutation is associated with resistance to TKI therapy, and for those who present with blast phase at diagnosis. It is also a viable option in individuals with disease progression to accelerated or blast phase on TKI therapy. In this group, treatment with a course of alternate TKI (not received before) will be beneficial as a “bridge” to transplantation. TKIs may also play a role in persons who relapse following allogeneic HSCT.

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 bosutinib (Bosulif®) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is NOT taking another tyrosine kinase inhibitor (TKI) (i.e., imatinib, dasatinib, nilotinib, or ponatinib) or omacetaxine mepesuccinate (Synribo®) concurrently with bosutinib.

2. Dosage of bosutinib does not exceed 600 mg daily and will be achieved using the fewest number of tablets per day.

3. Member does NOT have a T315I or V299L mutation (only applicable if a BCR-ABL kinase domain mutation analysis has been performed).

4. The member is receiving treatment for EITHER of the following conditions:

A. Chronic-, accelerated- or blast-phase Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML),

AND

ONE of the following:

1) Member is being treated for a relapse following allogeneic hematopoietic stem cell transplant (HSCT)

2) Member meets ANY of the following in reference to at least ONE first-line TKI (i.e., imatinib, nilotinib, or dasatinib):

a) Did not achieve recommended treatment goals defined by NCCN as ANY of the following:

§ BCR-ABL1 transcript levels >10% or lack of partial cytogenetic response (i.e., >35% Ph-positive metaphases) at 3 or 6 months

§ Lack of a complete response (i.e., Ph-postive metaphases are detectable), BCR-ABL1 transcript levels >1%, or cytogenetic relapse at 12 months

b) Had persistent intolerable adverse effects despite appropriate dose modification (the specific adverse effect must be provided)

c) Has documented genetic resistance (lab documentation of E255K/V, F317L/V/I/C, F359V/C/I, T315A, or Y253H mutation must be submitted)

d) Has an FDA-labeled contraindication (the specific contraindication must be provided)

Approval duration: 6 months

Continuation of bosutinib (Bosulif®) meets the definition of medical necessity when ALL of the following criteria are met:

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

2. Member does NOT have a T315I or V299L mutation (only applicable if a BCR-ABL kinase domain mutation analysis has been performed).

3. Member’s disease has not progressed during treatment with bosutinib.

4. Member is NOT taking another TKI (i.e., imatinib, dasatinib, nilotinib, or ponatinib) or omacetaxine concurrently.

5. Dosage of bosutinib does not exceed 600 mg daily and will be achieved using the fewest number of tablets per day.

Approval duration: 1 year

NOTE: Quest Diagnostics® can perform the BCR-ABL kinase domain mutation analysis. Current NCCN guidelines recommend checking mutational analysis in the following situations: if there is inadequate initial response, any sign of loss of response, and in disease progression to accelerate-phase or blast-phase CML (CML-AP and CML-BP, respectively).

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: bosutinib is indicated for the treatment of adult patients with chronic, accelerated, or blast phase Ph+ CML with resistance or intolerance to prior therapy. The recommended dose and schedule of bosutinib is 500 mg orally once daily with food. Continue treatment with bosutinib until disease progression or member intolerance. If a dose is missed beyond 12 hours, the member should skip the dose and take the usual prescribed dose on the following day.

Consider dose escalation to 600 mg once daily with food in members who do not reach complete hematological response (CHR) by week 8 or a CCyR by week 12, who did not have Grade 3 or higher adverse reactions, and who are currently taking 500 mg daily.

Dose Modifications

Hepatic Impairment: In patients with pre-existing mild, moderate, and severe hepatic impairment, the recommended dose of bosutinib is 200 mg daily.

Renal Impairment: In patients with pre-existing moderate renal impairment (CrCl 30 to 50 mL/min), the recommended dose of bosutinib is 400 mg daily. In patients with pre-existing severe renal impairment (CrCl less than 30 mL/min), the recommended dose of bosutinib is 300 mg daily.

• Toxicity:

o Elevated liver transaminases: If elevations in liver transaminases greater than 5×institutional upper limit of normal (ULN) occur, withhold bosutinib until recovery to less than or equal to 2.5×ULN and resume at 400 mg once daily thereafter. If recovery takes longer than 4 weeks, discontinue treatment. If transaminase elevations greater than or equal to 3×ULN occur concurrently with bilirubin elevations greater than 2×ULN and alkaline phosphatase less than 2×ULN (Hy's law case definition), discontinue treatment.

o Diarrhea: For NCI CTCAE Grade 3-4 diarrhea (increase of greater than or equal to 7 stools/day over baseline/pretreatment), withhold bosutinib until recovery to Grade less than or equal to 1. Treatment may be resumed at 400 mg once daily.

o For other clinically significant, moderate or severe non-hematological toxicity, withhold bosutinib until the toxicity has resolved, then consider resuming treatment at 400 mg once daily. If clinically appropriate, consider re-escalating the dose to 500 mg once daily.

o Neutropenia and thrombocytopenia: ANC less than 1,000×106/L or platelets less than 50,000×106/L: Withhold bosutinib until ANC greater than or equal to1,000×106/L and platelets greater than or equal to 50,000×106/L. Resume treatment at the same dose if recovery occurs within 2 weeks. If blood counts remain low for greater than 2 weeks, upon recovery, reduce dose by 100 mg and resume treatment. If cytopenia recurs, reduce dose by an additional 100 mg upon recovery and resume treatment. Doses less than 300 mg/day have not been evaluated.

Drug Availability: bosutinib is supplied as 100- or 500-mg tablets.

PRECAUTIONS:

CONTRAINDICATIONS

• Hypersensitivity to bosutinib.

WARNINGS

Concomitant Use With CYP3A Inhibitors and Inducers: Avoid the concomitant use of bosutinib with strong or moderate CYP3A inhibitors OR strong or moderate CYP3A inducers

o Strong CYP3A inhibitors - ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone and conivaptan

o Moderate CYP3A inhibitors - fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, grapefruit products and ciprofloxacin

o Strong CYP3A inducers - rifampin, phenytoin, carbamazepine, St. John's Wort, rifabutin and phenobarbital

o Moderate CYP3A inducers - bosentan, nafcillin, efavirenz, modafinil and etravirine

Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain occur with bosutinib treatment. Monitor and manage members using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. Withhold dose, dose reduce or discontinue bosutinib as necessary.

Myelosuppression: Thrombocytopenia, anemia and neutropenia occur with bosutinib treatment. Members with CML who are receiving bosutinib should have a complete blood count performed weekly for the first month and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue bosutinib as necessary.

Hepatic Toxicity: Perform at least monthly hepatic enzyme tests for the first three months of treatment with bosutinib and as clinically indicated thereafter. In members with transaminase elevations, monitor liver enzymes more frequently. Withhold, dose reduce, or discontinue bosutinib as necessary.

Renal Toxicity: An on-treatment decline in estimated glomerular filtration rate (eGFR) has occurred in patients treated with bosutinib. Monitor patients for renal function at baseline and during therapy.

Fluid Retention: Fluid retention occurs with bosutinib and may manifest as pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. Monitor and manage members using standards of care. Interrupt, dose reduce or discontinue bosutinib as necessary.

Embryofetal toxicity: May cause fetal harm. Females of reproductive potential should avoid becoming pregnant while being treated.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

J8999

Prescription drug, oral, chemotherapeutic, nos

ICD-10 Diagnoses Codes That Support Medical Necessity

C92.10

Chronic myeloid leukemia, bcr/abl-positive, not having achieved remission

C92.11

Chronic myeloid leukemia, bcr/abl-positive, in remission

C92.12

Chronic myeloid leukemia, bcr/abl-positive, 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 Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

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

DEFINITIONS:

Accelerated Phase CML: is a phase of chronic myelogenous leukemia in which the disease is progressing.

Blast Phase CML: is the final phase in the evolution of CML, and behaves like an acute leukemia, with rapid progression and short survival.

Chronic Phase CML: approximately 85% of members with CML are in the chronic phase at the time of diagnosis. During this phase, members are usually asymptomatic or have only mild symptoms of fatigue, left side pain, joint and/or hip pain, or abdominal fullness.

Chronic Myelogenous Leukemia (CML): also known as chronic granulocytic leukemia (CGL), is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.

Cytogenetic: is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH).

Inadequate chronic-phase CML treatment response: BCR-ABL1 transcript levels >10% or lack of partial cytogenetic response (i.e., >35% Ph-positive metaphases) at 3 or 6 months; or lack of a complete response (i.e., Ph-postive metaphases are detectable), BCR-ABL1 transcript levels >1%, or cytogenetic relapse at 12 months.

Induction Chemotherapy: the use of drug therapy as the initial treatment for patients presenting with advanced cancer that cannot be treated by other means.

Philadelphia chromosome or Philadelphia translocation: is a specific chromosomal abnormality that is associated with chronic myelogenous leukemia (CML).

RELATED GUIDELINES:

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

Dasatinib (Sprycel®) Tablets, 09-J1000-43

Imatinib Mesylate (Gleevec®) Tablets, 09-J1000-46

Immune Globulin Therapy, 09-J0000-06

Nilotinib (Tasigna®) Capsules, 09-J1000-48

Omacetaxine (Synribo®) Injection, 09-J1000-87

Ponatinib (Iclusig®) Tablet, 09-J1000-89

OTHER:

None applicable.

REFERENCES:

  1. Bosulif (bosutinib) [package insert]. Pfizer, Inc. New York (NY): December 2016.
  2. Brümmendorf TH, Cortes JE, de Souza CA, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2015 Jan;168(1):69-81. doi: 10.1111/bjh.13108. Epub 2014 Sep 8.
  3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2015. Available at: www.clinicalpharmacilogy-ip.com. Accessed 1/19/17.
  4. Cortes JE, Kantarjian HM, Brümmendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76.
  5. Kantarjian HM, Cortes JE, Kim DW, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18.
  6. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12.
  7. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 1/19/17.
  8. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 1/19/17.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 2.2016. Acute Lymphoblastic Leukemia. Available at http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf Accessed 1/25/17.
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 2.2017..Chronic Myelogenous Leukemia. Available at http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed 1/25/17.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 02/08/17.

GUIDELINE UPDATE INFORMATION:

02/15/13

New Medical Coverage Guideline.

03/15/14

Review and revision to guideline; consisting of reformatting position statement, updating dosage/administration, references, program exceptions, and related guidelines.

03/15/15

Review and revision to guideline; consisting of revising position statement and decision tree, and updating the description, dosage/administration, and references.

11/01/15

Revision: ICD-9 Codes deleted.

03/15/16

Review and revision to guideline consisting of description, position statement, definitions, and references.

03/15/17

Review and revision to guideline consisting of removal of the age requirement and acute lymphoblastic leukemia (ALL) indication in the position statement, and updates to description section, dosage/administration section, precautions section, billing/coding section, definitions, and references.

Date Printed: August 23, 2017: 06:02 AM