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Palifermin (Kepivance)

Number: 0851



Policy

Aetna considers palifermin (Kepivance) medically necessary to prevent and treat severe oral mucositis in members with hematologic malignancies undergoing high-dose chemotherapy requiring hematopoietic cell transplantation, using preparative regimens predicted to result in World Health Organization (WHO) grade 3 or 4 oral mucositis in the majority of patients (see Table 4 in Appendix).

Aetna considers palifermin experimental and investigational for the following indictions: (not an all-inclusive list)

  • Inhibition of graft-versus-host disease in persons undergoing hematopoietic stem cell transplantation
  • Mitigation of dysphagia in persons with lung cancer patients treated with concurrent chemoradiotherapy
  • Treatment of caustic esophageal burns
  • Treatment of alimentary/gastrointestinal mucositis
Background

Effective oral hygiene, appropriate analgesia, oral cryotherapy, infection management and parenteral nutrition are considered to be standard of care for oral mucositis.

Kepivance has been approved by the Food and Drug Administration (FDA) to decrease the incidence and duration of severe oral mucositis in patients with hematologic malignancies receiving myelotoxic therapy requiring hematopoietic stem cell support (HSCT).  Kepivance is indicated as supportive care for preparative regimens predicted to result in approximaetly World health organization (WHO) Grade 3 mucositis in the majority of patients.  The FDA labeling states that the safety and efficacy of Kepivance have not been established in patients with non-hematologic malignancies.  The labeling states that Kepivance is not recommended for use with melphalan 200 mg/m2 as a conditioning regimen.

Guidelines from the European Society for Medical Oncology (Peterson et al, 2011) stated that palifermin is recommended in a dose of 60 ug/kg/day for 3 days before conditioning treatment and for 3 days post-transplant for the prevention of oral mucositis in patients with hematological malignancies receiving high-dose chemotherapy (HDC) and total body irradiation (TBI) with autologous stem cell transplantation.

Guidelines from the American Society for Clinical Oncology (ASCO, 2008) stated that palifermin is recommended for use in patients undergoing autologous stem-cell transplantation for a hematologic malignancy with a TBI conditioning regimen to decrease the incidence of severe mucositis.  The ASCO guidelines stated that there are insufficient data to recommend the routine use of palifermin for patients undergoing autologous stem-cell transplantation for a hematologic malignancy where the conditioning regimen is chemotherapy only.  The ASCO guidelines also stated that palifermin may be considered for use in patients undergoing myeloablative allogeneic hematopoietic stem-cell transplantation with a TBI-based conditioning regimen; there are insufficient data to recommend its use in myeloablative conditioning regimens consisting of chemotherapy alone in this setting.  The ASCO guidelines stated that palifermin should be administered intravenously at 60 ug/kg daily for 3 days preceding the start of the conditioning regimen and 60 ug/kg daily for 3 days beginning on the day of stem-cell infusion; it should not be administered within 24 hours of the initiation of the conditioning regimen.

ASCO guidelines stated that there are insufficient data to recommend the use of palifermin in the non–stem-cell transplantation setting, or for use in the treatment of solid tumors.

Bradstock et al (2014) noted that gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukemia (AML) and contributes substantially to treatment-related mortality.  In a placebo-controlled randomized trial, these investigators evaluated the effectiveness of palifermin (given intravenously at 60 μg/kg per/day for 3 days before and after chemotherapy) for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high-dose cytarabine and etoposide.  Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study end-point) between the 2 treatment arms (3 in palifermin arm (4 %), 8 in placebo arm (10 %; p = 0.21); however, when considering the severity of oral mucositis (WHO grade 0 to 4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (p = 0.0007, test for trend).  There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21 % versus 44 % in placebo arm; p = 0.003), mainly due to a reduction in severe diarrhea (8 % palifermin, 26 % placebo; p = 0.01).  The authors concluded that palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy.

The Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO)s clinical practice guidelines on “The management of mucositis secondary to cancer therapy” (Lalla et al, 2014) recommended that palifermin be used to prevent oral mucositis (at a dose of 60 µg/kg per day for 3 days prior to conditioning treatment and for 3 days after transplant) in patients receiving HDC and TBI, followed by autologous stem cell transplantation, for a hematological malignancy.

Alimentary/Gastrointestinal Mucositis:

Herbers et al (2014) reported that the matched-control study failed to show a clinical relevant impact of palifermin on intestinal mucositis, although there was a reduced inflammatory response and less febrile neutropenia among patients who had no bacteremia.

Wardill et al (2014) stated that chemotherapy-induced alimentary (gastrointestinal) mucositis is an extremely common condition that is caused by a breakdown of the mucosal barrier.  It occurs in between 40 to 100 % of cancer patients depending on the treatment regimen.  Symptoms typically include pain from oral ulceration, vomiting and diarrhea.  Alimentary mucositis often necessitates chemotherapy reductions or treatment breaks, overall potentially compromising survival outcomes.  Consequently, alimentary mucositis creates a burden not only on patients' quality of life (QOL) but also on healthcare costs.  Despite this, currently, there is no clinically effective localized/pharmacological therapy intervention strategy to prevent alimentary mucositis.  Over recent years, a number of novel pharmacotherapy agents have been trialed in various pre-clinical and clinical settings.  These researchers provided an overview of emerging pharmacotherapies for the treatment of alimentary mucositis following chemotherapy with particular emphasis on studies published in the last 2 years.  A PubMed literature search was conducted to identify eligible articles published before November 30, 2013 and each article was reviewed by all authors.  All articles were written in English.  The authors concluded that currently, there is no clinically effective localized therapeutic intervention strategy to prevent the condition.  New emerging areas of research have recently been proposed to play key roles in the development of alimentary mucositis and these areas may provide researchers and clinicians with new research directions.  Hopefully this will continue, and evidence-based informed guidelines can be produced to improve clinical practice management of this condition.

Caustic Esophageal Burns:

Numanoglu et al (2014) noted that current treatment strategies against the development of corrosive esophageal strictures remain unsatisfactory.  These researchers investigated the effectiveness of palifermin for the prevention of stricture development following esophageal caustic injuries in a rat model.  A total of 32 female Wistar albino rats were divided into 4 groups, which included the control (C), burn (B), steroid (S) and steroid plus palifermin (S/P) groups.  An experimental corrosive esophageal burn model was established in the B, S and S/P groups.  Weight gain was recorded and histopathological evaluation was performed for each group.  Weight gain in the S and B groups was compared with the control group and statistically significant differences were observed.  In addition, statistically significant differences in weight gain were observed between the S/P group and the B group.  Histopathologically, statistically significant differences were identified with regard to submucosal collagen deposition, muscularis mucosa and tunica muscularis damage when comparing the B group with the C group.  In addition, statistically significant differences were observed when comparing the S and S/P groups with the B group.  Furthermore, significant submucosal collagen deposition and tunica muscularis damage were observed in the S group when compared with the S/P group.  The stenosis indexes in the C and S groups were significantly lower compared with the B group.  In addition, the stenosis index in the S/P group was significantly lower compared with the S group.  The authors concluded that the present study was the first to investigate the effect of palifermin on corrosive esophageal burns.  The addition of palifermin to the corrosive esophageal burn standard treatment regimen was found to reduce the degree of fibrosis and ameliorate histopathological damage in an experimental model of corrosive esophagitis in rats.

Other Experimental Indications:

Vadhan-Raj et al (2013) noted that mucositis is one of the most significant toxicities in cancer patients undergoing cytotoxic treatment.  It can have a negative impact on both QOL and health economics.  Severe oral mucositis can contribute to hospitalization, need for narcotic analgesics, total parenteral nutrition, suboptimal delivery of anti-neoplastic treatment, and morbidity and mortality.  Palifermin is the first active agent approved by the FDA for the prevention of severe oral mucositis in patients undergoing HSCT.  Several studies have also shown significant reduction in the incidence, severity and/or duration of oral mucositis in other high-risk settings such as concurrent chemoradiotherapy (CT/RT) for patients with head and neck cancer, and use of mucotoxic chemotherapeutic agents such as doxorubicin in sarcoma and fluorouracil for the treatment of colorectal cancer.  The reduction in mucositis has translated into amelioration of symptoms and improvement in daily functioning as measured by patient-reported outcome in multiple studies.  The clinical response to palifermin appears to be related in part to epithelial proliferation and mucosal thickening.  Palifermin also has other potential clinical applications including the acceleration of immune reconstitution and inhibition of graft-versus-host disease in patients undergoing HSCT, and mitigation of dysphagia in lung cancer patients treated with concurrent CT/RT.  Palifermin is generally well-tolerated with mild-to-moderate skin and oral adverse events.  The authors concluded that future studies may expand the use of palifermin into other areas that would benefit from its cyto-protective and regenerative effects.

Appendix

Table 1: Routine Oral Hygiene Care

  • Toothbrushing [Note: Electric and ultrasonic toothbrushes are acceptable if the patient is capable of using them without causing trauma]

  • Soft Nylon-Bristled Brush (2 to 3 rows)

    • Brush 2 to 3 times daily with Bass sulcular scrub method
    • Rinse frequently
    • Foam toothbrushes:

      • Use only when use of a regular toothbrush is not feasible
      • Use with anti-microbial rinses when possible
      • Brush teeth and mucosal surfaces 2 to 3 times a day
      • Rinse frequently
  • Dentifrice:

    • Patient preference as tolerated
    • Fluoride recommended
    • Use 0.9 % saline or water if toothpaste causes irritation
  • Flossing:

    • Once daily
    • Atraumatic technique with modifications as needed
  • Bland Rinses:

    • Varieties:

      • 0.9 % saline
      • Sodium bicarbonate solution
      • 0.9 % saline plus sodium bicarbonate solution
    • Use 8 to 12 oz of rinse, hold and expectorate; repeat every 2 to 4 hours or as needed for pain

  • Fluoride:

    • 1.1 % neutral sodium fluoride gel
    • 0.4 % stannous fluoride gel
    • Brush on gel for 2 to 3 minutes
    • Expectorate and rinse mouth gently
    • Apply once a day
  • Topical Anti-Microbial Rinses:

    • 0.12 % to 0.2 % chlorhexidine oral rinse
    • Povidone iodine oral rinse
    • Rinse, hold 1 to 2 minutes, expectorate
    • Repeat 2 to 4 times a day depending on severity of periodontal disease  

Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy

  • Minimize denture use during first 3 to 4 weeks post-transplant

    • Wear dentures only when eating
    • Discontinue use at all other time
       
  • Clean twice a day with a soft brush and rinse well
  • Soak in anti-microbial solutions when not being worn
  • Perform routine oral mucosal care procedures 3 to 4 times a day with the oral appliances out of the mouth
  • Leave appliances out of mouth when sleeping and during periods of significant mouth soreness
  • Dentures may be used to hold medications needed for oral care (e.g., anti-fungals).
  • Discontinue use of removable
  • Discontinue use of removable appliances until oral mucositis has healed

Remove orthodontic appliances (e.g., brackets, wires, retainers) prior to conditioning.

Table 2: Mucositis Management

Bland Rinses:

  • 0.9 % saline solution
  • Sodium bicarbonate solution
  • 0.9 % saline/sodium bicarbonate solution

Topical Anesthetics:

  • Lidocaine: viscous, ointments, sprays
  • Benzocaine: sprays, gels
  • 0.5 % or 1.0 % dyclonine hydrochloride (HCl)
  • Diphenhydramine solution

Mucosal Coating Agents:

  • Amphojel
  • Kaopectate
  • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin)
  • Cyanoacrylate mucoadherent film.

Analgesics:

  • Benzydamine HCl topical rinse (not approved in the United States)
  • Opioid drugs: oral, intravenous (IV) (e.g., bolus, continuous infusion, patient-controlled analgesia [PCA]), patches, transmucosal.

Table 3: Summary of Clinical Practice Guidelines for Care of Patients with Oral Mucositis

Basic Oral Care and Good Clinical Practices

  1. The panel suggests multi-disciplinary development and evaluation of oral care protocols, and patient and staff education in the use of such protocols to reduce the severity of oral mucositis from chemotherapy and/or radiation therapy (Level III evidence, grade B suggestion).  As part of the protocols, the panel suggests the use of a soft toothbrush that is replaced on a regular basis.  Elements of good clinical practice should include the use of validated tools to regularly assess oral pain and oral cavity health.  The inclusion of dental professionals is vital throughout the treatment and follow-up phases.
  2. The panel recommends patient-controlled analgesia with morphine as the treatment of choice for oral mucositis pain in patients undergoing HSCT (Level 1 evidence, grade A recommendation).  Regular oral pain assessment using validated instruments for self-reporting is essential.

Radiotherapy: Prevention

  1. The panel recommends the use of midline radiation blocks and 3-dimensional radiation treatment to reduce mucosal injury.  (Level 2 evidence, grade B recommendation)
  2. The panel recommends benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy.  (Level I evidence, grade A recommendation)
  3. The panel recommends that chlorhexidine not be used to prevent oral mucositis in patients with solid tumors of the head and neck who are undergoing radiotherapy.  (Level II evidence, grade B recommendation)
  4. The panel recommends that anti-microbial lozenges not be used for the prevention of radiation-induced oral mucositis.  (Level II evidence, grade B recommendation)

Radiotherapy: Treatment

  1. The panel recommends that sucralfate not be used for the treatment of radiation-induced oral mucositis.  (Level II evidence, grade A recommendation)

Standard-Dose Chemotherapy Prevention

  1. The panel recommends that patients receiving bolus 5-fluorouracil (5-FU) chemotherapy undergo 30 minutes of oral cryotherapy to prevent oral mucositis.  (Level II evidence, grade A recommendation)
  2. The panel suggests the use of 20 to 30 minutes of oral cryotherapy to decrease mucositis in patients treated with bolus doses of edatrexate.  (Level IV evidence, grade B suggestion)
  3. The panel recommends that acyclovir and its analogues not be used routinely to prevent mucositis.  (Level II evidence, grade B recommendation)

Standard-Dose Chemotherapy: Treatment

  1. The panel suggests that chlorhexidine not be used to treat established oral mucositis.  (Level III evidence, grade C recommendation)

High-Dose Chemotherapy With or Without Total Body Irradiation Plus HCST: Prevention

  1. In patients with hematologic malignancies who are receiving HDC and TBI with autologous stem cell transplantation, the panel recommends the use of keratinocyte growth factor-1 (palifermin) in a dose of 60 micrograms/kg per day for 3 days prior to conditioning treatment and for 3 days post-transplantation for the prevention of oral mucositis.  (Level 1 evidence, grade A recommendation)
  2. The panel suggests the use of cryotherapy to prevent oral mucositis in patients receiving high-dose melphalan.  (Level II evidence, grade A recommendation)
  3. The panel does not recommend the use of pentoxifylline to prevent mucositis in patients undergoing HSCT.  (Level II evidence, grade B recommendation) 
  4. The panel suggests that granulocyte macrophage colony-stimulating factor (GM-CSF) mouthwashes not be used for the prevention of oral mucositis in patients undergoing HSCT.  (Level II evidence, grade C recommendation)
  5. The panel suggests the use of low-level laser therapy (LLLT) to reduce the incidence of oral mucositis and its associated pain in patients receiving HDC or chemoradiotherapy before HSCT if the treatment center is able to support the necessary technology and training, because LLLT requires expensive equipment and specialized training.  Because of inter-operator variability, clinical trials are difficult to conduct, and their results are difficult to compare; nevertheless, the panel is encouraged by the accumulating evidence in support of LLLT.  (Level II evidence, grade B recommendation)

Key: HSCT: hematopoietic stem cell transplantation; 5-FU: 5-fluorouracil; TBI: total-body irradiation; LLLT: low-level laser therapy.

Table 4: WHO Classification of Oral Mucositis

Grade 0                  No oral mucositis

Grade 1                  Soreness +/- erythema

Grade 2                  Erythema and ulcers

Grade 3                  Extensive erythema, ulcers and inability to swallow solid food

Grade 4                  Mucositis that prevents any form of alimentation, including swallowing liquids

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
Other CPT codes related to the CPB :
38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241     autologous transplantation
38242     HPC boost
HCPCS codes covered if selection criteria are met:
J2425 Injection, palifermin, 50 micrograms
ICD-10 codes covered if selection criteria are met:
C81.00 - C88.9 Malignant neoplasm of lymphatic and hematopoietic tissue [in members with hematologic malignancies undergoing high-dose chemotherapy requiring hematopoietic cell transplantation, using preparative regimens predicted to result in WHO grade 3 or 4 oral mucositis]
K12.31 Oral mucositis (ulcerative) due to antineoplastic therapy


The above policy is based on the following references:
    1. Kepivance Prescribing Information. Amgen, Inc. January 2010.
    2. National Cancer Institute, Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ®), webpage. Accessed 3/15/10. (http://www.cancer.gov/cancertopics/pdq/supportivecare/oralcomplications/HealthProfessional)
    3. Spielberger R, Stiff P, Bensinger W, et al. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med. 2004;351(25):2590-2598.
    4. American Society of Clinical Oncology 2008 clinical practice guideline update summary: Use of chemotherapy and radiation therapy protectants. JOP. 2008;4(6):277-279.
    5. Peterson DE, Bensadoun R-J, Roila F. Management of oral and gastrointestinal mucositis: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22 (Suppl 6): vi78-vi84.
    6. Numanoglu KV, Tatli D, Bektas S, Er E. Efficacy of keratinocyte growth factor (palifermin) for the treatment of caustic esophageal burns. Exp Ther Med. 2014;8(4):1087-1091.
    7. Vadhan-Raj S, Goldberg JD, Perales MA, et al. Clinical applications of palifermin: Amelioration of oral mucositis and other potential indications. J Cell Mol Med. 2013;17(11):1371-1384.
    8. Bradstock KF, Link E, Collins M, et al; Australasian Leukaemia and Lymphoma Group. A randomized trial of prophylactic palifermin on gastrointestinal toxicity after intensive induction therapy for acute myeloid leukaemia. Br J Haematol. 2014;167(5):618-625.
    9. Herbers AH, van der Velden WJ, de Haan AF, et al. Impact of palifermin on intestinal mucositis of HSCT recipients after BEAM. Bone Marrow Transplant. 2014;49(1):8-10.
    10. Wardill HR, Bowen JM, Gibson RJ. New pharmacotherapy options for chemotherapy-induced alimentary mucositis. Expert Opin Biol Ther. 2014;14(3):347-354.
    11. Lalla RV, Bowen J, Barasch A, et al; Mucositis Guidelines Leadership Group of the MASCC/ISOO [trunc]. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. 2014;120(10):1453-1461.


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