Clinical UM Guideline
|Guideline #:||CG-DRUG-30||Current Effective Date:||01/05/2016|
|Status:||Reviewed||Last Review Date:||11/05/2015|
This document addresses the clinical indications for oprelvekin (Neumega, Pfizer Injectables and Wyeth BioPharma, Wyeth Pharmaceuticals Inc., Philadelphia, PA). Oprelvekin is a subcutaneously (SQ) administered synthetic recombinant humanized thrombopoietic growth factor structurally and functionally similar to endogenous human cytokine interleukin-11 (IL-11).
Oprelvekin is considered medically necessary following myelosuppressive chemotherapy for non-myeloid malignancies when the following criteria are met:
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 but not limited to the following:
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.
|J2355||Injection, oprelvekin, 5 mg|
|C90.00-C91.92||Multiple myeloma, malignant plasma cell neoplasms, lymphoid leukemia|
|C93.00-C96.9||Other nonmyeloid leukemias|
|Z85.00-Z85.9||Personal history of malignant neoplasm|
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, 2014).
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) initially approved oprelvekin in 1997 for the prevention of severe thrombocytopenia in adults following single or repeated sequential cycles of various myelossuppressive chemotherapy. This approval 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 1 additional cycle of the same chemotherapy without dose reduction). A total of 93 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 1 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 1 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<0.05, 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 PI Label, 2014; 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 2 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; 8 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=0.04). Treatment with oprelvekin significantly reduced the total number of platelet transfusions required in the assessable subgroup (P=0.03) and the time to platelet recovery to more than 50,000/µL in the second cycle (P=0.01). 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 4 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 placebo (n=26), 25 mcg/kg/day (n=28), or 50 mcg/kg/day (n=26) of 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 of 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 3 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.
The safety and efficacy of oprelvekin was evaluated by Suliman and colleagues (2014) in a randomized, double-blind, placebo controlled trial of 40 hospitalized individuals diagnosed with DF; a mosquito-borne illness that often leads to thrombocytopenia. The outcome of interest in this study was an increase in platelet count of at least 20,000 µl over baseline at 48 hours post treatment. Of the 20 individuals who received the treatment drug (single dose of 1.5mg oprelvekin, SQ), 10 met criteria for the outcome of interest and 3 of 20 in the placebo group (P=0.047). Authors conclude that the treatment shows promise; however, the sample size was small and mild signs of bleeding spontaneously occurred later in the study period in 3 of the individuals in the treatment group (despite an increase in platelet count) and 4 in the placebo group.
Additional studies have evaluated the safety of dose escalation with oprelvekin in children and adolescents with solid tumors or lymphoma (Cairo, 2005). The efficacy of low-dose or dose adjustments of oprelvekin have also 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), hemophilia or mild von Willebrand disease (to reduce bleeding, hemorrhage, or menorrhagia) (Ragni, 2008; Ragni, 2011; Ragni, 2013), and DF (Suliman, 2014). At this time, the FDA has not approved the use of oprelvekin for any of these indications.
Warnings and Adverse Events (Neumega PI Label, 2014)
Black Box Warning:
Allergic Reactions Including Anaphylaxis
Other Warnings and Precautions
Geriatric and Pediatric Use
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.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
|Reviewed||11/05/2015||Medical Policy & Technology Assessment Committee (MPTAC) review|
|Reviewed||11/04/2015||Hematology/Oncology Subcommittee review. Updated Description/General Information, References and Website sections. Removed ICD-9 codes from Coding section.|
|Revised||11/12/2014||Hematology/Oncology Subcommittee review. Updated Description/General Information, References and Websites. Added Dengue Fever to not medically necessary criteria.|
|New||11/13/2013||Hematology/Oncology Subcommittee review. Initial document development.|