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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-J1000-89

Original Effective Date: 03/15/13

Reviewed: 02/08/17

Revised: 03/15/17

Subject: Ponatinib (Iclusig®) 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:

Ponatinib (Iclusig®) is an oral multi-tyrosine kinase inhibitor (TKI) approved by the US Food and Drug Administration (FDA) in December 2012 for the treatment of adult persons with chronic myelogenous leukemia (CML) (chronic phase, accelerated phase, or blast phase) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) for whom no other inhibitor TKI therapy is indicated (i.e., imatinib [Gleevec®], dasatinib [Sprycel®], nilotinib [Tasigna®], and bosutinib [Bosulif®]). The approval was based on results from a pivotal phase II, single-arm, open-label clinical trial. The FDA granted orphan designation status for ponatinib in 2009 for treatment of both CML and Ph+ ALL. In October 2013, ponatinib was withdrawn from the market by the manufacturer at the request of the FDA due to the risk of life-threatening blood clots and severe narrowing of blood vessels. In December 2013, after implementing an FDA-required Risk Evaluation and Mitigation Strategy (REMS) program that included a communication plan to healthcare providers regarding the serious risk of vascular occlusion and thromboembolism associated with treatment, the manufacturer once again began marketing ponatinib to appropriate patients. In addition, the FDA-approved indication was modified to include treatment of adult patients with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive Ph+ ALL.

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. CML occurs in three different phases (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 3-5 years. Prior to the development of small molecule TKIs, treatment of CML was limited to nonspecific agents including busulfan, hydroxyurea, and interferon-alfa. Despite efficacy shown with interferon-alpha, multiple toxicities associated with interferon-alpha therapy limits its utility. Although allogeneic stem cell transplantation is a curative option, it is associated with significant morbidity and mortality and is not an option for persons with poor performance status. Furthermore, it requires an appropriate stem cell donor. The introduction of small molecule TKIs changed the treatment armamentarium and this “targeted” approach has dramatically altered the natural history of the disease and improved 10-year overall survival from approximately 20% to 80-90%.

The efficacy of CML therapy is assessed by monitoring hematologic, cytogenetic, and molecular responses. Cytogenetic monitoring is widely used and a complete cytogenetic response (CCyR) within 12 months of initiation of a first-line TKI therapy (i.e., imatinib, dasatanib, nilotinib) is considered optimal. Risk score, age, tolerance of adverse effects, and comorbid conditions may affect initial choice of treatment. For example, nilotinib may be preferred in patients prone to fluid retention; dasatinib may be preferred in patients with liver disease. Despite positive outcomes seen with TKIs in the treatment of CML, drug resistance has been observed. One of the most common mechanisms of resistance involves point mutations in the kinase domain of BCR-ABL, which impairs the activity of TKIs, including imatinib, dasatinib, nilotinib and bosutinib (Bosulif). One important mutation, the T315I, is known as the “gatekeeper” mutation, as it displays resistance to all TKIs, with the exception of ponatinib. Current 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).

Acute lymphoblastic leukemia (ALL) is a heterogeneous hematologic disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. The long-term prognosis for adults with ALL remains poor, with cure rates of only 30% to 40%. The treatment approach to ALL represents one of the most complex and intensive programs in cancer therapy. In general, treatment phases can be largely grouped into induction, consolidation, and maintenance. During the past decade, the advent of novel agents targeted to specific genetic abnormalities, such as those associated with Ph+ ALL, or to specific cell antigens, has contributed to improvements in outcomes in some subtypes of ALL. These agents include BCR-ABL selective TKIs for Ph+ ALL (e.g., imatinib, dasatinib, and nilotinib). Although TKIs have improved the prognosis for adults with ALL, resistance has been observed and is attributed, at least partly, to the presence of point mutations (e.g., T315I, V299L, and F317L mutations) with the ABL kinase domain. Second generation TKIs, specifically, dasatinib and nilotinib, have shown greater potency in inhibiting BCR-ABL compared with imatinib and retention of anti-leukemic activity in cells with certain imatinib-resistant ABL mutations. However, both agents are rendered inactive in persons with a T315I mutation. In the pivotal phase II study, ponatinib showed substantial activity in subjects with Ph+ leukemias resistant or intolerant to second-generation TKIs, including in heavily pretreated subjects with the T315I mutation.

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 ponatinib (Iclusig) 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 bosutinib) or omacetaxine mepesuccinate (Synribo®) concurrently with ponatinib.

2. Member is receiving treatment for EITHER of the following conditions:

a. Chronic-, accelerated-, or blast-phase Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) (including post-transplant relapse),

OR

b. Philadelphia-chromosome positive acute lymphoblastic leukemia (ALL).

3. Member has tested positive for the T315I BCR-ABL kinase domain mutation (lab documentation must be submitted),

OR

Member meets any of the following in reference to TWO or more TKI therapies (i.e., imatinib, dasatinib, nilotinib, or bosutinib):

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

4. Dosage of ponatinib does not exceed 45 mg daily and will be achieved using the fewest number of tablets per day.

Approval duration: 6 months

Continuation of ponatinib (Iclusig®) 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’s disease has not progressed during treatment with ponatinib.

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

4. Dosage of ponatinib does not exceed 45 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 test. 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: ponatinib is indicated for the treatment of adults with chronic phase, accelerated phase, or blast phase chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) for whom no other TKI therapy is indicated. It is also approved for use in the treatment of adults with T315I-positive CML or T315I Ph+ALL. These indications are based on response rate and there are no clinical studies verifying an improvement in disease-related symptoms or increased survival time. The recommended starting dose is 45 mg orally once daily with or without food. However, 68% of the patients required dose reductions to 30 mg or 15 mg once daily during the course of therapy. Consider reducing the dose for CP-CML and AP-CML patients who have achieved a major cytogenetic response. The optimal dose of ponatinib has not been identified. Consider discontinuing if response has not occurred by 3 months (90 days).Tablets should be swallowed whole. To reduce the risk of tumor lysis syndrome, adequate hydration and correction of elevated uric acid levels should be achieved prior to ponatinib initiation.

Dose Modifications

Concomitant Use with Strong CYP3A Inhibitors: Reduce dose to 30 mg once daily when administering ponatinib with strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin).

Hepatic Impairment: The recommended starting dose is 30 mg once daily in patients with hepatic impairment (Child-Pugh A, B, or C)

Toxicity: Dose adjusts for toxicity (i.e., myelosuppression and non-hematologic adverse reactions) are depicted in tables 1-3.

Table 1

Suggested dose adjustments for Myelosuppression

 

Occurrence

Re-initiation dose†

ANC less than 1000 cells/mm3

OR

Platelet count less than 50,000 cells/mm3

1st

45 mg

2nd

30 mg

3rd

15 mg

† Once ANC is greater than 1500 cells/mm3 and platelet count is greater than 75,000 cells/mm3

ANC, absolute neutrophil count

Table 2

Recommended dose adjustments for Hepatic toxicity

 

Dose at Occurrence

Action

Elevation of AST or ALT greater than 3 x ULN (Grade 2 or higher)

45 mg

• Interrupt therapy and monitor hepatic function

• Resume at 30 mg after ALT and AST is less than 3 x ULN (Grade 1 or less)

30 mg

• Interrupt therapy and monitor hepatic function

• Resume at 15 mg after ALT and AST is less than 3 x ULN (Grade 1 or less)

15 mg

Discontinue

Elevation of AST or ALT 3 x ULN or greater (Grade 2 or higher) AND elevation of bilirubin greater than 2 x ULN AND alkaline phosphatase less than 2 x ULN

Discontinue therapy

ULN, upper limit of normal for lab performing test

Table 3

Table 3: Recommended dose adjustments for pancreatitis and lipase elevations

 

Dose at Occurrence

Action

Asymptomatic Grade 1 or Grade 2 elevation of serum lipase

ANY

Consider therapy interruption or dose reduction

Asymptomatic Grade 3 or 4 elevation (greater than 2xULN) or Grade 2 pancreatitis (asymptomatic radiologic pancreatis)

45 mg

• Interrupt therapy

• Resume at 30 mg once recovery to Grade 1 or less

30 mg

• Interrupt therapy

• Resume at 15 mg once recovery to Grade 1 or less

15 mg

Discontinue therapy

Grade 3 pancreatitis

45 mg

• Interrupt therapy

• Resume at 30 mg once complete resolution of symptoms and recovery to Grade 1 or less

30 mg

• Interrupt therapy

• Resume at 15 mg once complete resolution of symptoms and recovery to Grade 1 or less

15 mg

Discontinue therapy

Symptomatic Grade 4 pancreatitis

Discontinue therapy

ULN, upper limit of normal for laboratory performing test

Drug Availability: ponatinib is available as 15, 30, and 45 mg tablet.

PRECAUTIONS:

CONTRAINDICATIONS

• None

BOXED WARNINGS

Arterial Occlusion: Arterial occlusions have occurred in at least 35% of ponatinib -treated patients. Some patients experienced more than 1 type of event. Events observed included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of arterial occlusion. Interrupt or stop ponatinib immediately for arterial occlusion. A benefit-risk consideration should guide a decision to restart ponatinib therapy.

Venous Thromboembolism: Venous occlusive events have occurred in 6% of ponatinib -treated patients. Monitor for evidence of venous thromboembolism. Consider dose modification or discontinuation of Iclusig in patients who develop serious venous thromboembolism.

Heart Failure: Heart failure, including fatalities, occurred in 9% of ponatinib-treated patients. Monitor cardiac function. Interrupt or stop ponatinib for new or worsening heart failure.

Hepatotoxicity: Hepatotoxicity, liver failure, and death have occurred in ponatinib-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

WARNINGS

Hypertension: monitor for high blood pressure and treat as clinically indicated.

Neuropathy: Monitor for symptoms of peripheral and cranial neuropathy.

Ocular toxicity: Conduct comprehensive eye exams at baseline and periodically during treatment

Pancreatitis: monitor serum lipase monthly; elevations may require dose interruption or discontinuation.

Hemorrhage: interrupt dosing for serious or severe hemorrhage

Fluid retention: monitor for signs and symptoms of fluid retention. May require interruption, reduction, or discontinuation of therapy.

Cardiac arrhythmias: monitor for symptoms of arrhythmia

Myelosuppression: thrombocytopenia, neutropenia, and anemia may require dose interruption or reduction. Monitor complete blood counts (CBC) every 2 weeks for 3 months and then monthly and as clinically indicated. Refer to dosage and administration section for recommended dose adjustments

Tumor Lysis Syndrome: ensure adequate hydration and correct elevated uric acid levels prior to therapy initiation.

Reversible posterior leukoencephalopathy syndrome (RPLS): interrupt and resume treatment only once the event is resolved and if the benefit of continued treatment outweighs the risk of RPLS

Compromised wound healing and gastrointestinal perforation: temporarily interrupt therapy in members undergoing major surgical procedures.

Pregnancy category D: can cause fetal harm.

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

C91.00

Acute lymphoblastic leukemia not having achieved remission

C91.01

Acute lymphoblastic leukemia, in remission

C91.02

Acute lymphoblastic leukemia, in relapse

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 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:

Acute lymphoblastic leukemia: an aggressive (fast-growing) type of leukemia (blood cancer) in which too many immature white blood cells are found in the blood and bone marrow. Also called acute lymphocytic leukemia and ALL.

Chronic myelogenous leukemia: 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

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-positive metaphases are detectable), BCR-ABL1 transcript levels >1%, or cytogenetic relapse at 12 months

Ph+ ALL complete response criteria to induction chemotherapy:

1. No circulating blasts or extramedullary disease

2. Trilineage hematopoiesis (TLH) and less than 5% blasts

3. ANC greater than 1,000/microL

4. Platelet count greater than 100,000/microL

5. No recurrence for 4 weeks

Philadelphia chromosome or Philadelphia translocation: is a specific chromosomal abnormality that is associated CML or ALL.

Relapse: the return of a disease or the signs and symptoms of a disease after a period of improvement.

Refractory: cancer that does not respond to treatment; the cancer may be resistant at the beginning of treatment or it may become resistant during treatment. Also called resistant cancer.

RELATED GUIDELINES:

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

Bosutinib (Bosulif) Tablets, 09-J1000-84

Cytogenetic Studies (Chromosomal Studies), 05-82000-18

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

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

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

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

OTHER:

None applicable.

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: www.clinicalpharmacilogy-ip.com. Accessed 1/19/17.
  2. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88.
  3. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96.
  4. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. PACE: A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant of dasatinib or nilotinib, or with the T315I mutation. J Clin Oncol 2012;30:6503.
  5. Iclusig (ponatinib) [package insert]. ARIAD Pharmaceuticals, Inc. Cambridge (MA): November 2016.
  6. Lipton JH, Bryden P, Sidhu MK, et al. Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors. Leuk Res. 2014 Nov 1. pii: S0145-2126(14)00327-0. doi: 10.1016/j.leukres.2014.10.005. [Epub ahead of print]
  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 Version2.2017. 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:

03/15/13

New Medical Coverage Guideline.

12/15/13

No Longer Review

3/15/14

Review and revision to guideline; consisting of revising position statement, updating dosage/administration, precautions, and references.

02/15/15

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

11/01/15

Revision: ICD-9 Codes deleted.

03/15/16

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

03/15/17

Review and revision to guideline consisting of removal of the age requirement in the position statement, and updates to description section, precautions section, and references.

Date Printed: October 17, 2017: 04:15 PM