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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:037
Effective Date: 02/11/2020
Original Policy Date:11/21/2005
Last Review Date:02/11/2020
Date Published to Web: 07/14/2006
Subject:
Clolar (Clofarabine)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Clolar (clofarabine) a purine nucleoside anti-metabolite, is indicated for the treatment of pediatric patients (between the ages of 1-21 years old) with relapsed or refractory acute lymphoblastic leukemia after at least two prior chemotherapy regimens. The current gold standard of treatment for acute lymphoblastic leukemia consists of 4 phases (1) induction (2) CNS prophylaxis (3) consolidation therapy (4) maintenance therapy. The use of this drug is based on the induction of complete responses.

Clolar is a prodrug inhibiting DNA synthesis by decreasing cellular deoxynucleotide triphosphate pools through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting action repair through incorporation into the DNA chain by competitive inhibition of DNA polymerase. Clolar also disrupts the integrity of the mitochondrial-membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death.

Clolar has been studied in three clinical trials in the pediatric population.
  • Phase I, open-label, dose-escalation, non-comparative study in 25 pediatric patients with refractory or relapsed hematologic malignancies. Seventeen patients had acute lymphoblastic leukemia. The recommend dose based on this study in pediatric population was 52 mg/m2/day for 5 days.
  • Phase II, nonrandomized, open-label, single arm study in 49 pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL) after two or more prior chemotherapies. All patients received a dose of 52 mg/m2 daily IV infusion for 5 days. There was no dose modification during the remission induction phase of treatment (maximum of 2 cycles). Doses could be modified (reduced/delayed) during the post-induction phase (total maximum of 12 cycles). The study endpoint included:
    • Complete Remission (CR) - defined as no evidence of circulating blasts or extramedullary disease, an M1 bone marrow (<5% blasts), and recovery of peripheral counts [platelets > 100 x 109/L and absolute neutrophil count (ANC) > 1.0 x 109/L] – 6 patients out of 49 patients (12.2%) had CR
    • Complete Remission in the Absence of Total Platelet Recovery (CRp) - defined as meeting all criteria for CR except for recovery of platelet counts to > 100 x 109/L – 4 patient out of 49 patients (8.2%) had CRp
    • Partial Response (PR) was also determined, defined as complete disappearance of circulating blasts, an M2 bone marrow (> 5% and < 25% blasts), and appearance of normal progenitor cells or an M1 bone marrow that did not qualify for CR or CRp – 5 patients out of 49 patients (10.2%) had PR
Results were that 15 patients out of 49 patients (30.6%) responded to treatment.
  • Phase II, open-label, multicenter study in 61 pediatric patients (under 21) with refractory or relapsed ALL. Patients received 52 mg/m2/day for 5 consecutive days, every 2 to 6 weeks, for up to 12 cycles. The study primary endpoint was overall remission (OR) rate, which was defined as patients who achieved a complete remission (CR) or CR without platelet recovery (CRp), defined above. Results were that the OR rate was 20% (seven CRs and five CRps). Median duration of OR was 29 weeks.

The recommended pediatric dose and schedule is 52 mg/m2 administered daily by IV infusion over 2 hours daily for 5 consecutive days. Treatment cycles are recommended approximately every 2 to 6 weeks following recovery or return to baseline organ function. The most common adverse effects included nausea, vomiting, anemia, leukopenia, thrombocytopenia, neutropenia, and infection.

The label for Clolar was updated in January 2013 to include updated dosage and administration and warnings and precautions information. There was an addition of a dose-reduction recommendation for patients with stable, moderate renal impairment. It is recommended to reduce the Clolar starting dose by 50% in patients with CrCL of 30 to 60 mL/min. There is insufficient information to make a dosage recommendation in patients with CrCL less than 30 mL/min or in patients on dialysis. Post-marketing experience was updated to include gastrointestinal disorders: gastrointestinal hemorrhage including fatalities.

Information on renal toxicity within warnings and precautions section of prescribing information was updated in October 2016. Additional information includes warning on possibility of causing renal failure and the increased risk of renal toxicity in patients with infection, sepsis, or tumor lysis syndrome.


Policy:

(Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

1. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis.

2. Clolar (clofarabine) is medically necessary for the following FDA-labeled indications:

      • Acute lymphoblastic leukemia (ALL) when the following criteria are met:
          • Member is 1-21 years of age AND
          • Member has failed at least two prior regimens

3. When clofarabine is considered medically necessary, initial therapy will be eligible up to 3 months at the FDA-recommended dose below:
      • 52 mg/m2 IV daily infusion for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2-6 weeks.
[INFORMATIONAL NOTE: Based on the Phase II clinical trial, patients had a maximum of 2 cycles for the induction phase and an overall maximum of 12 cycles. The dose is based on the patient’s height and weight before the start of each cycle. Clolar should be discontinued if a patient shows sign of SIRS (Systemic Inflammatory Response Syndrome) or capillary leak (e.g. hypotension). It should also be discontinued if hypotension develops within the 5 days of administration. Close monitoring of hepatic function and renal function is advised, because Clolar has not been studied in patients with hepatic or renal dysfunction. If substantial increases in creatinine or bilirubin are noted, physicians should immediately discontinue administration of Clolar.

    Prophylactic steroids to prevent signs and symptoms of SIRS or capillary leak, or prophylactic anti-emetic medication may be considered.]

4. Continued therapy will be eligible up to maximum of 12 treatment cycles at the FDA-recommended dose below if there is stabilization of disease or decrease in tumor size/tumor spread AND no unacceptable toxicities:
      • 52 mg/m2 IV infusion daily for 5 consecutive days. Treatment cycles are repeated following recovery or return to baseline organ function, approximately every 2-6 weeks.

5. Clolar (clofarabine) is considered medically necessary for the following off-label indications:
      • Acute Lymphoblastic Leukemia (ALL) as:
          • Therapy for relapsed or refractory Philadelphia chromosome-negative B-cell ALL
            · As a single agent
            · As a component of clofarabine-containing regimens (e.g. clofarabine, cyclophosphamide, and etoposide)
          • Therapy for relapsed or refractory Ph-negative B-ALL, or in combination with dasatinib or imatinib for relapsed/refractory Ph-positive B-ALL as a component of clofarabine-containing regimens (e.g. clofarabine, cyclophosphamide, and etoposide)
      • Acute Myeloid Leukemia (AML) as:
          • Therapy for relapse or refractory disease:
            • As a component of repeating the initial successful induction regimen if late relapse (≥12 months)
            • In combination with cytarabine and granulocyte colony-stimulating factor (G-CSF) or in combination with idarubicin
            • In combination with cytarabine, G-CSF, and idarubicin
          • For treatment induction in patients age ≥60 years as part of an alternative non-anthracycline-containing regimen (eg, clofarabine-based regimen) in candidates for intensive remission induction therapy who exceed anthracycline dose or have cardiac issues but are still able to receive aggressive therapy
6. Other uses of Clolar are considered investigational including, but are not limited to, myelodysplastic syndrome, chronic myeloid leukemia, chronic lymphocytic leukemia - blast phase, chronic lymphocytic leukemia, solid tumors, adult acute lymphoblastic leukemia, refractory Langerhans cell histiocytosis and Non-Hodgkin’s lymphoma, refractory juvenile xanthogranuloma, refractory Rosai-Dorfman disease, relapsed or refractory acute lymphocytic leukemia, and allogeneic stem cell transplant conditioning in combination with busulfan.

[INFORMATIONAL NOTE: There is limited information available for the use of Clolar in the above mentioned indications. Genzyme, the manufacturer of Clolar, recently announced that the early stages of 3 clinical trials are planned to determine the use of Clolar in adult patients with AML. The studies include a randomized, double-blind, controlled study of Clolar in combination with cytarabine versus cytarabine alone, in over 376 patients aged 60 and older previously treated with one or two prior induction regimens; a separate phase II trial using Clolar in previously untreated patients who are unlikely to respond to standard therapy; and a phase III trial using Clolar as first line therapy in untreated patients who are considered suitable for standard therapy.
In November 2008, Genzyme filed a supplemental New Drug Application with the FDA for the use of Clolar as a single agent in previously untreated adults aged 60 years or older with AML who have at least one unfavorable prognostic factor. A phase 2 study examining clofarabine monotherapy in adults >60 years in AML with unfavorable prognosis showed a 46% overall remission rate. Patients received 30mg/m2 for 5 days as induction therapy with 28 days between cycles up to a maximum of 5 cycles. As of February 2015, the approval for this indication has not been determined. Clolar is also being developed for the treatment of adult AML, earlier-line pediatric ALL, and myelodysplastic syndromes (MDS). http://www.bloodjournal.org/content/112/5/1638.long?sso-checked=true]

Medicare Coverage

There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this drug. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ medical policy.

Medicaid Coverage

For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Clolar (Clofarabine)
Clofarabine (Clolar)

References:

1. Clolar (clofarabine) Prescribing Information. Genzyme Corporation. October 2016.

2. DiPiro JT, Talbert RL, Yee GC, et al. ed. Pharmacotherapy: A Pathophysiologic approach. 5th Ed. New York: McGraw-Hill, 2002.

3. Jeha S, Gandhi V, Chan KW, et al. Clofarabine, novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood 2004; 103 (3): 784-789.

4. Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacological study of clofarabine in patients with solid and hematologic cancers. Journal of Clinical Oncology 2003; 21 (6): 1167-1173.

5. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacological study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 2003; 102 (7): 2379-2389.

6. Faderi S, Gandhi V, O’Brien Susan, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-c) in relapsed and refractory acute leukemias. Blood 2005; 105(3): 940-947.

7. Faderi S, Ferrajolil A, Wierda W, et al. Phase I study of clofarabine plus idarubicin and clofarabine plus idarubicin plus cytarabine (ara-c) in patients with relapsed and primary refractory acute myeloid leukemia, myelodysplastic syndrome, and myeloid blast phase of chronic myeloid leukemia. 46th ASH Annual Meeting and Exposition, Dec 4-7, 2004; San Diego, CA: 1809. (Poster)

8. Federi S, Gandhi V, Verstovsek S, et al. Clofarabine is active in newly diagnosed patients ≥ age 50 with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 46th ASH Annual Meeting and Exposition, Dec 4-7, 2004; San Diego, CA: 875. (Poster)

9. Burnett AK, Russell N, Kell JW, et al. A phase 2 evaluation of single agent clofarabine as first line treatment for older patients with AML who are not considered fit for intensive chemotherapy. 46th ASH Annual Meeting and Exposition, Dec 4-7, 2004; San Diego, CA: 889. (Poster)

10. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. Journal of Clinical Oncology 2006;24:1917-1923.

11. Federi S, Gandhi V, Keating MJ, et al. The role of clofarabine in hematologic and solid malignancies—development of a next-generation nucleoside analog. Cancer 2005;103(10):1985-1995.

12. Kolitz, J. Current therapeutic strategies for acute myeloid leukaemia. British Journal of Haematology 2006; 134:555-572.

13. Genzyme Corporation. Press Release: Genzyme Begins Phase 3 Pivotal Study of Clolar® in Adult Acute Myelogenous Leukemia. [Available at http://www.genzyme.com/corp/media/GENZ%20PR-090606.asp (Last accessed 09/13/2006)].

14. Kantarjian HM, Gandhi V, Kozuch P et al: Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol 2003a;21(6):1167-1173.

15. Faderl S, Gandhi V, Giles F et al: Clofarabine plus cytarabine (ara-C) is an active induction regimen for newly diagnosed patients (pts) greater than or equal to 50 with acute myeloid leukemia (AML) and high- risk myelodysplastic syndrome (MDS) (abstract 6609). Presented at the ASCO Annual Meeting; June 5-8, 2004; New Orleans, LA, USA.

16. Gandhi V, Kantarjian H, Faderl S et al: Pharmacokinetics and pharmacodynamics of plasma clofarabine and cellular clofarabine triphosphate in patients with acute leukemias. Clin Cancer Res 2003;9:6335-6342.

17. Micromedex. Clofarabine update. [Available at http://www.micromedex.com/products/updates/drugdex updates/de/clofarabine.html].

18. Burnett A, Baccarani M, Johnson P, et al. Effectiveness of clofarabine in elderly AML patients with adverse cytogenetics unfit for intensive chemotherapy.Blood 2006 108:Abstract 1985.

19. Faderl S, Verstovsek S, Cortes J, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older. Blood 2006;108:45-51.

20. Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood 2008;112(5):1638-45.

21. Genzyme Corporation. Press Release: Genzyme seeks U.S. Approval for Clolar to Treat Adult AML. Available from: [http://www.genzyme.com/corp/media/GENZ%20PR-112408.asp (last accessed March 19, 2009)].

22. Gandhi V, Plunkett W, Bonate P, et al. Clinical and Pharmacokinetic Study of Clofarabine in Chronic Lymphocytic Leukemia: Strategy for Treatment. Clin Cancer Res 2006;12(13):4011-17.

23. Kantarjian H, Jeha S, Gandhi V, et al. Clofarabine: Past, present, and future. Leukemia & Lymphoma 2007; 48(10): 1922-30.

24. Genzyme Corporation. Press Release: FDA Advisory Committee recommends randomized trial to support proposed indication for Clolar in adult AML. [Available at www.genzyme-latinoamerica.com/corp/news/all_news/GENZ%20PR-090109.asp].

25. Jeha S, Razzouk B, Rytting M, Rheingold S, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute myeloid leukemia. J Clin Oncol. 2009 Sep 10; 27(26): 4392-4397.

26. Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008 Sep 1; 112(5): 1638-1645.

27. Advani AS, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study S0530: a phase II trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia. Br J Haematol. 2010 Dec; 151(5):430-4.

28. National Comprehensive Cancer Network (NCCN) Drugs and Biologics Compendium. Clofarabine. [Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=357 (accessed January 16, 2020).]

29. Simko SJ, Tran HD, Jones J, et al. Clofarabine salvage therapy in refractory multifocal histiocytic disorders including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosia-Dorfman disease. Pediatr Blood Cancer. 2014;61(3):479-487.

30. Chevallier P, Labopin M, Socie G, et al. Results from a clofarabine-busulfan-containing, reduced-toxicity conditioning regimen prior to allogeneic stem cell transplantation: The phase 2 prospective CLORIC trial. Haematologica. 2014;99(9):1486-1491.

31. Kantarjian HM, Erba HP, Claxton D, et al. Phase II study of clofarabine monotherapy in previously untreated older adults with acute myeloid leukemia and unfavorable prognostic factors. J Clin Oncol. 2010 Feb 1;28(4):549-555.

32. National Comprehensive Cancer Network. Acute Lymphoblastic Leukemia (Version 1.2020). https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed January 29, 2020.


Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

    J9027

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.


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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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