Clinical UM Guideline


Subject:  Oprelvekin (Neumega®)
Guideline #:  CG-DRUG-30Current Effective Date:  01/14/2014
Status:NewLast Review Date:  11/14/2013

Description

Oprelvekin (Neumega, Pfizer Injectables and Wyeth BioPharma, Wyeth Pharmaceuticals Inc., Philadelphia, PA) is a subcutaneously administered synthetic recombinant humanized thrombopoietic growth factor structurally and functionally similar to endogenous human cytokine interleukin-11 (IL-11).

This document addresses the clinical indications for oprelvekin for prevention of severe thrombocytopenia (low platelet counts) and reduction of the need for platelet transfusions following myelosuppressive chemotherapy in individuals with non-myeloid malignancies at high risk of severe thrombocytopenia.

Clinical Indications

Medically Necessary:

Oprelvekin is considered medically necessary following myelosuppressive chemotherapy for non-myeloid malignancies when the following criteria are met:

  1. Individual is 18 years of age or older; and
  2. Individual is at high risk of developing severe thrombocytopenia (platelet count of less than or equal to 20,000/µL) defined as either of the following:
    1. Severe thrombocytopenia occurred following the prior chemotherapy cycle; or
    2. Individual received dose-dense or dose-intensive chemotherapy likely to cause severe thrombocytopenia.

Not Medically Necessary:

Oprelvekin is considered not medically necessary following myeloablative chemotherapy.

Oprelvekin is considered not medically necessary for all other indications when the medically necessary criteria are not met, including treatment of any of the following:

  1. Chemotherapy-related bacteremia; or
  2. Crohn's disease; or
  3. Hemophilia; or
  4. Myelodysplastic syndrome; or
  5. Refractory immune thrombocytopenic purpura (ITP); or
  6. Rheumatoid arthritis; or
  7. Von Willebrand disease.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS 
J2355Injection, oprelvekin, 5 mg
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2014]
140.0-199.2Malignant neoplasms
200.00-202.98Non-Hodgkin/Hodgkin lymphomas
203.00-204.92Multiple myeloma, immunoproliferative neoplasms and lymphoid leukemia
206.00-208.92Other nonmyeloid leukemias
209.00-209.36Malignant neuroendocrine tumors
209.70-209.79Secondary neuroendocrine tumors
V10.00-V10.61Personal history of malignant neoplasm [nonmyeloid]
V10.63-V10.9Personal history of malignant neoplasm [nonmyeloid]
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2014]
C00.0-C80.2Malignant neoplasms
C81.00-C88.9Non-Hodgkin/Hodgkin lymphomas
C90.00-C91.92Multiple myeloma, malignant plasma cell neoplasms, lymphoid leukemia
C93.00-C96.9Other nonmyeloid leukemias
Z85.00-Z85.9Personal history of malignant neoplasm
  
Discussion/General Information

Interleukin-11 (IL-11) is a thrombopoietic growth factor that directly stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production. IL-11 is a member of a family of human growth factors which includes human growth hormone, granulocyte colony-stimulating factor (G-CSF), and other growth factors. Oprelvekin, the active ingredient in Neumega, is produced in Escherichia coli (E. coli) by recombinant DNA technology. The primary hematopoietic activity of Neumega is stimulation of megakaryocytopoiesis (the production of large bone marrow cells with a lobulate nucleus that gives rise to blood platelets) and thrombopoiesis (Neumega Product Information [PI] Label, 2012).

Specific chemotherapeutic agents may cause severe thrombocytopenia as a result of damage to the bone marrow, lowering its production of platelets. Thrombocytopenia caused by chemotherapy is usually temporary. Individuals whose platelet counts drop while receiving chemotherapy may undergo dose adjustments/reductions or wait longer between chemotherapy cycles. Some individuals with low platelet counts may receive a platelet cell transfusion to prevent hemorrhage (spontaneous, heavy bleeding), while others may require multiple transfusions. Oprelvekin is indicated to help prevent severe thrombocytopenia and reduce platelet transfusion requirements following myelosuppressive chemotherapy in individuals with non-myeloid malignancies at high risk of severe thrombocytopenia.

The U.S. Food and Drug Administration (FDA, 1997) approval of oprelvekin for the prevention of severe thrombocytopenia in adults following single or repeated sequential cycles of various myelossuppressive chemotherapy was based on results of two randomized, double-blind, placebo-controlled trials.

Use of Oprelvekin in Individuals with Prior Chemotherapy-Induced Thrombocytopenia

The first Phase II trial evaluated the efficacy of oprelvekin in eliminating the need for platelet transfusions in adults who had recovered from an episode of severe chemotherapy-induced thrombocytopenia (defined as a platelet count of less than or equal to 20, 000/µL, and were to receive one additional cycle of the same chemotherapy without dose reduction). Ninety-three participants with various underlying non-myeloid malignancies (lymphomas or solid tumors) who were undergoing dose-intensive chemotherapy with a variety of regimens were randomized to receive oprelvekin at a dose of 25 mcg/kg or 50 mcg/kg, or placebo, once daily for 14 to 21 days beginning one day after chemotherapy. Five participants withdrew from the study prior to receiving the drug; 88 participants were included in a modified intent-to-treat (mITT) analysis. The primary endpoint was whether a participant required one or more platelet transfusions in the subsequent chemotherapy cycle. The placebo group included one person who underwent chemotherapy dose reduction and avoided platelet transfusions. The primary endpoint established the statistically significant efficacy of oprelvekin 50 mcg/kg/day dose, but not the 25 mcg/kg/day dose; more participants in the oprelvekin 50 mcg/kg group (8 of 27; 30%) than in the placebo group (1 of 27; 4%) did not require a platelet transfusion(s) (p<.05, Fisher's exact test). The difference in the proportion of participants avoiding platelet transfusions in the oprelvekin 50 mcg/kg and placebo groups was 21% (95% confidence interval [CI], 2% to 40%) (Neumega Product Information [PI] Label, 2012; Tepler, 1996).

Use of Oprelvekin in Individuals Receiving Dose-Intensive Chemotherapy

The second Phase II trial evaluated the efficacy of oprelvekin in eliminating platelet transfusions over two dose-intensive chemotherapy cycles in women with advanced breast cancer who had not previously experienced severe chemotherapy-induced thrombocytopenia. All participants received the same chemotherapy regimen of cyclophosphamide and doxorubicin and concomitant filgrastim (G-CSF) in all cycles. Participants were stratified by whether or not they had received prior chemotherapy and then randomized to receive oprelvekin 50 mcg/kg/day or placebo for 10 to 17 days after the first two chemotherapy cycles. The primary endpoint was whether a participant required one or more platelet transfusions in the two study cycles. Thirteen of the 77 randomized participants failed to complete both study cycles; eight of these had insufficient data to be evaluated for the primary endpoint. In the ITT population, oprelvekin significantly decreased the requirement for platelet transfusions; 27 of 40 (68%) participants who received oprelvekin did not require transfusions, compared to 15 of 37 (41%) in the placebo group (p=.04). Treatment with oprelvekin significantly reduced the total number of platelet transfusions required in the assessable subgroup (p=.03) and the time to platelet recovery to more than 50,000/µL in the second cycle (p=.01). Open-label treatment with oprelvekin was continued for up to four consecutive chemotherapy cycles without evidence of any adverse effect on the rate of neutrophil recovery or red blood cell transfusion requirements. Some individuals continued to maintain platelet nadirs greater than 20,000/µL for at least four sequential cycles of chemotherapy without the need for transfusions, chemotherapy dose reduction, or changes in treatment schedules. Most adverse events associated with oprelvekin were reversible, mild to moderate in severity, and likely related to fluid retention (Isaacs, 1997).

Other Uses of Oprelvekin

Use of Oprelvekin in Individuals Following Myeloablative Chemotherapy

Oprelvekin has not received FDA approval for use in individuals following myeloablative chemotherapy. In a randomized, double-blind, placebo-controlled, Phase II trial conducted in 80 women with high-risk breast cancer who received 0 (n=26), 25 mcg/kg/day (n=28), or 50 mcg/kg/day (n=26) oprelvekin following myeloablative chemotherapy and autologous bone marrow transplantation, the incidence of platelet transfusions and time to neutrophil and platelet engraftment were similar in the oprelvekin and placebo-treated arms. In addition, this study showed a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia in participants receiving oprelvekin compared to placebo. In long-term follow-up, the distribution of survival and progression-free survival times was similar between participants randomized to oprelvekin therapy and those randomized to receive placebo (Neumega PI Label, 2012). Severe or fatal adverse reactions have been reported in post-marketing use oprelvekin in individuals following bone marrow transplantation, including fluid retention or overload (facial edema, pulmonary edema), capillary leak syndrome, pleural and pericardial effusion, papilledema and renal failure.

The efficacy of oprelvekin was evaluated in a dose escalation study of 76 individuals with active Crohn's disease (Sands, 1999). The results suggested that short-term treatment of three weeks of oprelvekin significantly improved clinical response compared with placebo; however, Herrlinger and colleagues (2006) found that oprelvekin was inferior to prednisolone in achieving induction of remission in a randomized controlled trial involving 51 individuals with active Crohn's disease.

Additional studies have evaluated the safety of dose escalation with oprelvekin in children and adolescents with solid tumors or lymphoma (Cairo, 2005); and, the efficacy of low-dose or dose adjustments of oprelvekin has been studied in individuals with active rheumatoid arthritis (Moreland, 2001), hematological malignant disease undergoing chemotherapy (prevention of bacteremia) (Ellis, 2003), bone marrow failure or myelodysplastic syndrome (Kurzrock, 2001; Montero, 2006), refractory ITP (Bussel, 2001), and hemophilia or mild von Willebrand disease (to reduce bleeding, hemorrhage, or menorrhagia) (Ragni, 2008; Ragni, 2011; Ragni, 2013). At this time, the FDA has not approved the use of oprelvekin for any of these indications.

Warnings and Adverse Events (Neumega PI Label, 2012)

Black Box Warning:

Allergic Reactions Including Anaphylaxis

Contraindications

Other Warnings and Precautions

Drug Interactions

Geriatric and Pediatric Use

Definitions

Chemotherapy: Medical treatment of a disease, particularly cancer, with drugs or other chemicals.

Dose-dense chemotherapy: A chemotherapy treatment plan in which drugs are given with less time (increased frequency) between treatments than in a standard chemotherapy treatment plan.

Dose-intensive chemotherapy: A chemotherapy treatment plan in which drugs are given at a higher (increased) dose than in a standard chemotherapy treatment plan.

Hematopoiesis: The formation of new blood cells.

Hematopoietic stem cell: An immature cell that can develop into all types of blood cells, including white blood cells, red blood cells, and platelets. Hematopoietic stem cells are found in the peripheral blood and the bone marrow.

Myeloablative chemotherapy: High-dose chemotherapy that kills cells in the bone marrow, including cancer cells, and is usually followed by a bone marrow or stem cell transplant to rebuild the bone marrow.

Myeloid leukemias: A type of cancer that starts in the cells that are supposed to mature into different types of blood cells; can be acute (acute myelogenous leukemia [AML]) or chronic (chronic myelogenous leukemia [CML]).

Non-myeloid malignancies (cancers): All types of cancer other than myeloid leukemias, including lymphomas, lymphocytic leukemias (such as acute lymphocytic [lymphoblastic] leukemia [ALL] and chronic lymphocytic leukemia [CLL]), melanoma, multiple myeloma, and sarcoma.

Platelet: A tiny piece of cell that is made by breaking off of a large cell in the bone marrow. Platelets are found in the blood and spleen, help form blood clots to slow or stop bleeding, and to help wounds heal; also called a thrombocyte.

Thrombocytopenia: A condition in which there is a lower-than-normal number of platelets in the blood. It may result in easy bruising and excessive bleeding from wounds or bleeding in mucous membranes and other tissues.

References

Peer Reviewed Publications:

  1.  Bussel JB, Mukherjee R, Stone AJ. A pilot study of rhuIL-11 treatment of refractory ITP. Am J Hematol. 2001; 66(3):172-177.
  2. Cairo MS, Davenport V, Bessmertny O, et al. Phase I/II dose escalation study of recombinant human interleukin-11 following ifosfamide, carboplatin and etoposide in children, adolescents and young adults with solid tumours or lymphoma: a clinical, haematological and biological study. Br J Haematol. 2005; 128(1):49-58.
  3. Ellis M, Zwaan F, Hedström U, et al. Recombinant human interleukin 11 and bacterial infection in patients with [correction of] haematological malignant disease undergoing chemotherapy: a double-blind placebo-controlled randomised trial. Lancet. 2003; 361(9354):275-280.
  4. Herrlinger KR, Witthoeft T, Raedler A, et al. Randomized, double blind controlled trial of subcutaneous recombinant human interleukin-11 versus prednisolone in active Crohn's disease. Am J Gastroenterol. 2006; 101(4):793-797.
  5. Isaacs C, Robert NJ, Bailey FA, et al. Randomized placebo-controlled study of recombinant human interleukin-11 to prevent chemotherapy-induced thrombocytopenia in patients with breast cancer receiving dose-intensive cyclophosphamide and doxorubicin. J Clin Oncol. 1997; 15(11):3368-3377.
  6. Kurzrock R, Cortes J, Thomas DA, et al. Pilot study of low-dose interleukin-11 in patients with bone marrow failure. J Clin Oncol. 2001; 19(21):4165-4172.
  7. Montero AJ, Estrov Z, Freireich EJ, et al. Phase II study of low-dose interleukin-11 in patients with myelodysplastic syndrome. Leuk Lymphoma. 2006; 47(10):2049-2054.
  8. Moreland L, Gugliotti R, King K, et al.  Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis. Arthritis Res. 2001; 3(4):247-252.
  9. Ragni MV, Jankowitz RC, Chapman HL, et al. A phase II prospective open-label escalating dose trial of recombinant interleukin-11 in mild von Willebrand disease. Haemophilia. 2008; 14(5):968-977.
  10. Ragni MV, Jankowitz RC, Jaworski K, et al. Phase II prospective open-label trial of recombinant interleukin-11 in women with mild von Willebrand disease and refractory menorrhagia. Thromb Haemost. 2011; 106(4):641-645.
  11. Ragni MV, Novelli EM, Murshed A, et al. Phase II prospective open-label trial of recombinant interleukin-11 in desmopressin-unresponsive von Willebrand disease and mild or moderate haemophilia A. Thromb Haemost. 2013; 109(2):248-254.
  12. Sands BE, Bank S, Sninsky CA, et al. Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease. Gastroenterology. 1999; 117(1):58-64.
  13. Smith JW 2nd. Tolerability and side-effect profile of rhIL-11. Oncology (Williston Park). 2000; 14(9 Suppl 8):41-47.
  14. Tepler I, Elias L, Smith JW 2nd, et al. A randomized placebo-controlled trial of recombinant human interleukin-11 in cancer patients with severe thrombocytopenia due to chemotherapy. Blood. 1996; 87(9):3607-3614.

Government Agency, Medical Society, and Other Authoritative Publications:

  1.  American Hospital Formulary Service® (AHFS). AHFS Drug Information 2013®. Bethesda, MD: American Society of Health-System Pharmacists®, 2013.
  2. NCCN Clinical Practice Guidelines in Oncology™. © 2013 National Comprehensive Cancer Network, Inc.  For additional information, visit the NCCN website: http://www.nccn.org/index.asp.  Accessed on September 11, 2013.
  3. Neumega. [Product Information], Pfizer Injectables; Wyeth Pharmaceuticals Inc. [Pfizer Inc], Philadelphia, PA; October 2012. Available at: http://labeling.pfizer.com/showlabeling.aspx?id=500. Accessed on September 11, 2013.
  4. Oprelvekin. In: DrugPoints System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated September 22, 2011. Available at: http://www.micromedexsolutions.com. Accessed on September 11, 2013.
  5. U.S. Food and Drug Administration (FDA). MedWatch: The FDA Safety Information and Adverse Event Reporting Program. Safety Information. Neumega (Oprelvekin). August 24, 2001. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm172749.htm. Accessed on September 11, 2013.
Web Sites for Additional Information
  1. American Cancer Society. Available at: http://www.cancer.org/. Accessed on September 11, 2013.
  2. National Cancer Institute (NCI). Dictionary of cancer terms. Available at: http://www.cancer.gov/. Accessed on September 11, 2013.
History

Status

Date

Action

New11/14/2013Medical Policy & Technology Assessment Committee (MPTAC) review.
New11/13/2013Hematology/Oncology Subcommittee review. Initial document development.