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APHERESIS
Protocol: OTH027 Effective Date: December 17, 2010 Table of Contents Page

COMMERCIAL COVERAGE RATIONALE......................................................................................... 1 MEDICARE & MEDICAID COVERAGE RATIONALE...................................................................... 3 BACKGROUND ...................................................................................................................................... 4 CLINICAL EVIDENCE........................................................................................................................... 5 U.S. FOOD AND DRUG ADMINISTRATION (FDA) ........................................................................ 12 APPLICABLE CODES .......................................................................................................................... 13 REFERENCES ....................................................................................................................................... 14 PROTOCOL HISTORY/REVISION INFORMATION ........................................................................ 19

INSTRUCTIONS FOR USE This protocol provides assistance in interpreting UnitedHealthcare benefit plans. When deciding coverage, the enrollee specific document must be referenced. The terms of an enrollee's document (e.g., Certificate of Coverage (COC) or Evidence of Coverage (EOC)) may differ greatly. In the event of a conflict, the enrollee's specific benefit document supersedes this protocol. All reviewers must first identify enrollee eligibility, any federal or state regulatory requirements and the plan benefit coverage prior to use of this Protocol. Other Protocols, Policies and Coverage Determination Guidelines may apply. UnitedHealthcare reserves the right, in its sole discretion, to modify its Protocols, Policies and Guidelines as necessary. This protocol is provided for informational purposes. It does not constitute medical advice.

COMMERCIAL COVERAGE RATIONALE Therapeutic apheresis or plasmapheresis is medically necessary for the following diagnoses: 1) 2) 3) 4) 5) 6) 7) ABO incompatible marrow transplant (red cell removal) (recipient: plasma exchange) Acute Guillain-Barre syndrome (plasma exchange) AIDS-related idiopathic thrombocytopenic purpura that is life-threatening (plasma exchange)* Bullous pemphigoid (plasma exchange) Coagulation factor inhibitors (plasma exchange) Chronic inflammatory demyelinating polyneuropathy (plasma exchange) Cryoglobulinemia (and other hyperviscosity syndromes including multiple myeloma, Waldenstrom's macroglobulinemia) (plasma exchange) 8) Cutaneous lymphoma (photopheresis) 9) Eaton-Lambert myasthenic syndrome (plasma exchange) 10) Erythrocytosis/polycythemia vera (phlebotomy) 11) Familial hypercholesterolemia (selective adsorption)**

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12) Goodpasture's syndrome (plasma exchange) 13) Hemolytic uremic syndrome (plasma exchange) 14) HIV related syndromes (plasma exchange) a. hyperviscosity b. polyneuropathy c. thrombotic thrombocytopenic purpura 15) Leukocytosis and thrombocytosis (cytapheresis) 16) Myasthenia gravis (plasma exchange) 17) Myeloma and paraproteinemias (plasma exchange) 18) Pemphigus vulgaris (plasma exchange) 19) Poisonings (plasma exchange) 20) Porphyria (phlebotomy) 21) Post-transfusion purpura (plasma exchange) 22) Primary/hereditary hemochromatosis (phlebotomy) 23) Rapidly progressive nephritis (without anti-GBM) (plasma exchange) 24) Raynaud's disease (plasma exchange) 25) Refsum's disease (phytanic acid) (plasma exchange) 26) Rheumatoid arthritis (immunoadsorption) 27) Sickle cell diseases (red cell exchange) 28) Systemic lupus erythematosis (plasma exchange) 29) Systemic vasculitis (plasma exchange) 30) Thrombotic thrombocytopenic purpura (plasma exchange) Photopheresis is medically necessary for the following conditions: 1. Cutaneous T-cell lymphoma (CTCL) 2. Treatment of graft vs. host disease (GVHD) under all of the following conditions: a. GVHD is medically necessary by biopsy, and b. At least 2 drugs, such as prednisone and an autoimmune drug, have been tried and have failed, and c. After photopheresis is initiated, regular skin assessments should be performed to evaluate the patient's response to treatment. Therapeutic apheresis, plasmapheresis, or photopheresis is not medically necessary for: 1. 2. 3. 4. 5. Multiple sclerosis, Hyperlipidemia in nephrotic syndrome, Hepatic conditions (hepatitis), Inflammatory bowel disease, and Diagnoses other than those listed as medically necessary in this policy.

There is insufficient evidence to conclude that apheresis, plasmapheresis, or photopheresis is beneficial for health outcomes in patients with disorders other than those listed as medically necessary.

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Additional Information For indications in which it is considered medically necessary, apheresis is clinically indicated as an adjunctive or supportive therapy when an individual has failed to respond to conventional therapy. *Clinical indications for use of extracorporeal immunoadsorption with protein A for treatment of lifethreatening AIDS-related idiopathic thrombocytopenic purpura include all of the following: 1. platelet counts below 100,000/mm3, and 2. steroid treatments have failed, and 3. splenectomy has failed. **Clinical indications for use of therapeutic apheresis to treat familial hypercholesterolemia include patients who are refractory to diet and pharmacotherapy management, and one of the following: 1. patients with homozygous familial hypercholesterolemia, or 2. heterozygous patients with coronary artery disease and LDL-C levels remaining >200 mg/dL, or 3. heterozygous patients without known coronary artery disease, but with LDL-C level remaining >300 mg/dL.

MEDICARE & MEDICAID COVERAGE RATIONALE Medicare has a National Coverage Determination for Apheresis (Therapeutic Pheresis). The National Coverage Determination is as follows: Apheresis is considered medically necessary for any of the following indications: 1. Plasma exchange for acquired myasthenia gravis; 2. Leukapheresis in the treatment of leukemia; 3. Plasmapheresis in the treatment of primary macroglobulinemia (Waldenstrom); 4. Treatment of hyperglobulinemias, including (but not limited to) multiple myelomas, cryoglobulinemia and hyperviscosity syndromes; 5. Plasmapheresis or plasma exchange as a last resort treatment of thromobotic thrombocytopenic purpura (TTP); 6. Plasmapheresis or plasma exchange in the last resort treatment of life threatening rheumatoid vasculitis; 7. Plasma perfusion of charcoal filters for treatment of pruritis of cholestatic liver disease; 8. Plasma exchange in the treatment of Goodpasture's Syndrome; 9. Plasma exchange in the treatment of glomerulonephritis associated with antiglomerular basement membrane antibodies and advancing renal failure or pulmonary hemorrhage; 10. Treatment of chronic relapsing polyneuropathy for patients with severe or life threatening symptoms who have failed to respond to conventional therapy; 11. Treatment of life threatening scleroderma and polymyositis when the patient is unresponsive to conventional therapy; 12. Treatment of Guillain-Barre Syndrome; and

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13. Treatment of last resort for life threatening systemic lupus erythematosus (SLE) when conventional therapy has failed to prevent clinical deterioration. Note: Apheresis is covered only when performed in a hospital setting (either inpatient or outpatient) or in a nonhospital setting, e.g., a physician directed clinic when all of the following conditions are met: 1. A physician (or a number of physicians) is present to perform medical services and to respond to medical emergencies at all times during patient care hours; 2. Each patient is under the care of a physician; and 3. All nonphysician services are furnished under the direct, personal supervision of a physician. Medicare has a National Coverage Determination for Extracorporeal Photopheresis. The National Coverage Determination is as follows: CMS has determined that extracorporeal photopheresis is medically necessary under the following circumstances: 1. Palliative treatment of skin manifestations of CTCL that has not responded to other therapy, or 2. Patients with acute cardiac allograft rejection whose disease is refractory to standard immunosuppressive drug treatment; or 3. Patients with chronic graft versus host disease whose disease is refractory to standard immunosuppressive drug treatment. All other indications for extracorporeal photopheresis remain not medically necessary. There are no Local Coverage Determinations for Nevada for Apheresis, Therapeutic Pheresis or Extracorporeal Photopheresis. (Accessed October, 2010) For Medicare and Medicaid Determinations Related to States Outside of Nevada: Please review Local Coverage Determinations that apply to other states outside of Nevada. http://www.cms.hhs.gov/mcd/search Important Note: Please also review local carrier Web sites in addition to the Medicare Coverage database on the Centers for Medicare and Medicaid Services Website. BACKGROUND Therapeutic apheresis or plasmapheresis is the removal of blood from the patient to remove excess antibodies or components from the blood. This is accomplished via a flexible tube placed into the patient's vein. Once the blood is removed from the patient, the plasma is separated from the cells and the cells are suspended in a plasma substitute or saline solution prior to be returned, via infusion, to the patient. Components targeted for removal in plasmapheresis may include toxins, metabolic substances, and plasma components, such as antibodies or complements. Therapeutic plasma exchange (TPE) involves the removal of large volumes of patient plasma which are then exchanged with donor plasma or a plasma substitute and then returned to the patient. This policy does not address the injection of platelets or plasma into other body parts such as bones, joints, tendons etc.

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Photopheresis (also known as extracorporeal photopheresis or extracorporeal adsorption) is a therapeutic apheresis procedure in which a patient's plasma is passed over a specific adsorption column that removes constituents implicated in the disease. The treated plasma is reinfused into the patient without the addition of allogeneic plasma or albumin. This may also be referred to as componentspecific apheresis, or selective immunoadsorption. One type of affinity column (Prosorba) uses staph protein A to remove circulating immune complexes and immunoglobulins. However, the Prosorba column is no longer being marketed. Another type of column (Liposorber LA-15) selectively targets and removes LDL cholesterol from the plasma. Therapeutic apheresis or plasmapheresis and plasma exchange are usually done in an outpatient facility and usually requires several hours to complete. During acute disease, plasmapheresis may be performed daily for at least 1 week.

CLINICAL EVIDENCE The American Society of Apheresis and the American Association of Blood Banks has reviewed therapeutic apheresis outcomes and published the following practice guidelines. Disorders have been placed into four categories (Smith, 2003; Szczepiorkowski et al. 2007). Category I: Therapeutic apheresis is standard and acceptable either as primary therapy or as a first line adjunct to other therapy. Category II: Therapeutic apheresis is generally accepted in a supportive role. Category III: Therapeutic apheresis is not clearly indicated. Category IV: Therapeutic apheresis has been demonstrated to lack therapeutic efficacy.

Standard plasm`apheresis exchange protocols have yet to be established and agreed upon. Additionally, the optimal time for initiating apheresis therapy is not established. Due to the significance of adverse events associated with apheresis, the NIH recommends that the technique be limited to situations of expected major benefit (NIH, 2002). Proven Indications for Therapeutic Apheresis Bullous Pemphigoid: Two multicenter trials evaluating 141 bullous pemphigoid patients treated with conventional corticosteroid therapy or plasma exchange reached conflicting conclusions. In a study by Guillaume et al., (1993) 98 patients were randomized to prednisolone alone, prednisolone in combination with azathioprine, or prednisolone in combination with plasma exchange. A greater number of long-term remissions were achieved in the patients treated with corticosteroids alone compared with the other two treatment groups (42%, 39%, and 29%, respectively). Mortality rates were similar for the three treatment groups. It was concluded that neither azathioprine nor plasma exchange is an effective adjuvant to corticosteroids. In contrast, a trial by Roujeau et al. demonstrated that plasma exchange had a dramatic steroid-sparing effect (Roujeau, 1984). Patients treated with prednisolone alone (n=17) required higher doses of corticosteroids to control their disease compared with patients treated with a combination of corticosteroids and plasma exchange (n=24). The former study did not report the laboratory findings, and the statistical significance of the results and the results of the latter study are limited by small sample size and incomplete documentation of the results.

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Familial hypercholesterolemia: This is an autosomal dominant disorder, which may be heterozygous or homozygous. Heterozygous hypercholesterolemia is usually successfully treated with a combination of diet and pharmacotherapy. Homozygous familial hypercholesterolemia is refractory to diet and pharmacotherapy. Typically, symptomatic coronary artery disease (CAD) develops by age 20. In the LDL Apheresis Regression Study, 30 patients, with a baseline LDL cholesterol level of 311, were treated with a combination of pharmacological and LDL-apheresis therapy (Tatami, 1992). Onethird (n=10/30) of patients showed regression of atherosclerotic disease. The Familial Hypercholesterolemia Regression Study looked at patients with heterozygous familial hypercholesterolemia and coronary artery disease (Thompson, 1995). Patients received either multidrug therapy or mono-drug therapy combined with selective apheresis with the Liposorber LA-15 system. The apheresis group experienced greater lowering of LDL (53% compared to 44% in the drugonly group). After a mean of 2.1 years of treatment, coronary angiography did not show a significant difference between the two groups. The authors concluded that LDL-apheresis should be reserved for those patients who are unresponsive to pharmacotherapy. A multicenter trial involving 120 severely hypercholesterolemic patients, refractory to diet and pharmacotherapy, was conducted over a six year period (Baumbauer, 1997). Baseline mean total serum cholesterol was 410 mg/dL and mean LDL cholesterol was 333.9 mg/dL. During weekly or twicemonthly apheresis, mean acute reduction was 52.6% for total cholesterol and 63.1% for LDL cholesterol. Time-averaged reduction in total cholesterol was 39% and in LDL cholesterol, 50%. Naganuma (1992) monitored 28 patients with symptomatic peripheral atherosclerosis. Patients received apheresis 10 times over a period of 3 months. Coldness of the legs decreased in 89.5% (n=17/19) of patients, intermittent claudication improved in 82.4% (n=14/17) of patients, foot pain at rest improved in 83.3% (n=15/18) of patients, arterial pulses strengthened in 75% (n=12/16) patients, and diminution of ulcer or necrosis occurred in 60% (n=3/5) of patients. Additionally, improvement in plethysmographic findings were observed in 100% (n=10/10) of patients and in thermographic results for 92.9% (n=13/14) of patients. Palcoux et al. (2008) evaluated 28 patients affected by familial hypercholesterolemia who had begun low-density lipoprotein (LDL) apheresis treatment before the age of 15. The two main procedures used were direct adsorption of lipoproteins and dextran sulfate cellulose adsorption. The mean age at the beginning of treatment was 8.5 years and the mean length of follow up was 12.6 years. The LDL cholesterol level before the session was lowered by 45 +/- 11% of the value at diagnosis. The LDL cholesterol reduction in a session was 72 +/- 10%. Tendinous xanthomas disappeared or diminished dramatically in 62% of the children. In 22 patients no cardiovascular event occurred during LDL apheresis treatment. Three had angina pectoris; two others had surgical management of aortic stenosis, but no clinical manifestations. Seven children had normal cardiovascular pictures while on treatment. The investigators concluded that LDL-apheresis can be recommended for the treatment of homozygous familial hypercholesterolemia with good efficiency on biological parameters, cutaneous lesions and cardiovascular events.

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Matsuzaki et al. and Koga et al. each conducted controlled, nonrandomized studies in which patients with familial hypercholesterolemia were treated with LDL apheresis plus medication or with medication alone. In the study by Matsuzaki et al., coronary artery plaques were measured by angiography at baseline and after one year of treatment. The group treated with LDL apheresis (n=11) had a significant remission of plaques; the group receiving medication only (n=7) did not (Matsuzaki, 2002). In the study by Koga et al., carotid artery plaques were measured by ultrasound at baseline and after seven years of treatment (Koga, 1999). The annual progression rate of mean maximum intimamedia thinkness in the common carotid artery was significantly lower in the LDL apheresis group than the control group. In summary, though the evidence is indirect, and there are components of related physiology that are not completely understood, the pathophysiological model reasonably supports efforts to maintain acceptable serum cholesterol levels as widely accepted by the clinical community. Circumstantial evidence particularly supports this effort with the increased cardiovascular risk present in patients with hypercholesterolemia refractory to dietary and pharmacotherapeutic management. Therapeutic apheresis has been demonstrated to be relatively safe, and effective in lowering LDL cholesterol. Guillain-Barre Syndrome: A total of 1719 patients with acute or severe Guillain-Barre syndrome (GBS) underwent extracorporeal apheresis therapy in 10 trials. Six of the studies were randomized controlled trials and four were controlled trials. Plasma exchange was the test treatment in nine of the studies and plasmapheresis was tested in one study. The results of the studies suggest that plasma exchange or plasmapheresis is effective treatment for GBS. Plasma exchange compares favorably with intravenous immunoglobulin, and combining the two treatments provides no extra benefit. Pemphigus Vulgaris: Two trials evaluating corticosteroid therapy and plasma exchange for the treatment of pemphigus reached conflicting conclusions. In a study by Guillaume et al., (1988) all 34 patients were treated with low-dose corticosteroids, while a subset of patients (n=19) underwent plasma exchange. Both treatments were equally efficacious at controlling pemphigus. The cumulative corticosteroid dose required to control the disease and the resultant serum antibody titers were also similar. Tan-Lim and Bystryn (1990) treated 22 patients with high-dose corticosteroids, 11 of which also underwent immunosuppressive therapy combined with plasmapheresis. The average serum antibody titers decreased by 18% in patients treated with high-dose corticosteroids alone compared with an 83% reduction in patients treated with concurrent corticosteroids, immunosuppressives, and plasmapheresis. Rheumatoid arthritis: In a prospective, multi-center, randomized, double-blinded and placebocontrolled clinical trial of 109 patients, patients were randomized to receive either 12 sham procedures (plasmapheresis without the use of the column) or 12 active treatments with the Prosorba protein-A immunoadsorptive column once weekly for 12 weeks (Felson, 1999). The patient was then followed for at least 8 weeks. Efficacy results were reported on these 99 patients. For patients completing 12 weeks of treatment and measured at weeks 19/20, 41.7% showed a response to treatment with Prosorba versus 15.6% response with placebo (P<.003). For tender and swollen joint count, and patient global assessment, the average responder exceeded 50% improvement. Health Assessment Questionnaire scores showed 30% improvement. Mean duration of response was 37 weeks, with a general response to therapy within 9-13 weeks. For the open-label, continuation phase, efficacy was evident in 33% of the active-treatment group compared with 9% of the sham-treated patients.
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Roth (2004) reported on a study of 91 patients with refractory rheumatoid arthritis who underwent 12 treatments with Prosorba column apheresis. At 24 weeks the response to treatment was a 52% improvement in joint tenderness, 40% improvement in swelling, 42% improvement in pain, 38% improvement in patient's global response, and 48% improvement in physician's global scores. Thrombocytopenic Purpura: Two studies compared plasma exchange with plasma infusion in the treatment of a total of 165 patients with thrombotic thrombocytopenic purpura (TTP) (Rock, 1991; Shumak, 1995). Plasma exchange was associated with a significantly greater treatment success and lower mortality rate than plasma infusion. Shumak et al. determined that 18% of plasma exchange patients are expected to relapse within 4 years and 36% within 10 years of initial treatment. In a randomized, active-controlled trial by Mintz et al. (2006), 35 patients with TTP were compared utilizing standard plasma exchange or plasma exchange with photochemical inactivation of pathogens in the exchanged plasma. The authors found that both treatments (18 plasma exchange and 17 plasma exchange with photochemically treated plasma) were equally effective at inducing remission in patients. Contraindications for extracorporeal apheresis include low granulocyte, hemoglobin, or platelet counts; clotting disorders; significant cardiac problems; and uncontrolled hypertension or hypotension. These conditions are contraindicated for a treatment, such as plasmapheresis, in which blood volume could be altered. In addition, due to the necessity for venous access, patients with clotting factor abnormalities would be at risk for serious complications (Hayes, 2007). Not Medically Necessary Indications for Therapeutic Apheresis Multiple sclerosis: The rationale for the use of plasmapheresis for treatment of MS is that there may be plasma-soluble factors that contribute to the disease: these factors include antimyelin antibodies, nonantibody demyelinating factors, immunostimulating cytokines, circulating immune complexes, and neuroelectric blocking factors (Khatri, 1999). Eight studies met the criteria for detailed review for this report, five randomized controlled trials, two crossover controlled trials, and a retrospective observation study. All of these studies except Weinshenker et al. evaluated plasmapheresis as an adjunct to steroid and immunosuppressant drug treatment for multiple sclerosis (MS) (Weinshenker, 1999). In addition, all of the studies were single-or double-blinded and most involved sham treatment for the control group in which plasma was returned to the patient rather than being replaced. Two of the reviewed studies enrolled patients whose symptoms were consistent with relapsing-remitting MS (RRMS). However, only one of these studies stated how many patients were diagnosed with RRMS and 35% of the patients enrolled in this study had chronic progressive MS (CPMS). Although the other reviewed studies primarily evaluated plasmapheresis for CPMS, a study by the Canadian Cooperative MS Study Group also included patients with relapsing-progressive MS. In a retrospective study by Keegan et al., 19 patients were treated with therapeutic plasma exchange (TPE) for an attack of fulminant CNS inflammatory demyelinating disease (Keegan, 2005). Patients were divided by pattern: pattern I (n=3), pattern II (n=10), and pattern III (n=6). All patients with pattern II (n=10), but none with pattern I (n=3) or pattern III (n=6), achieved moderate to substantial functional neurological improvement after TPE. The authors therefore concluded that patients with multiple sclerosis with pattern II pathology are more likely to respond favourably to TPE than are patients with patterns I or III.
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While the studies provide limited evidence that plasmapheresis used in conjunction with immunosuppressive drugs may provide short-term improvements in symptoms, there is no evidence of long-term benefit and no evidence of a reduction in brain lesion size or amelioration of the underlying pathology of MS. American Academy of Neurology (AAN)/MS Council for Clinical Practice: In 2002, the Therapeutics and Technology Assessment Subcommittee of the AAN and the MS Council for Clinical Practice Guidelines issued a report on disease-modifying therapies in MS. The subcommittee concluded that "on the basis of consistent class I, II, and III studies, plasma exchange is of little or no value in the treatment of progressive MS" (Goodin, 2002). Hepatic Conditions (Hepatitis): The utility of plasma exchange for conditions of the liver was tested in two studies. He et al. conducted a comparison study of plasma exchange, hemoperfusion adsorption, and a combination of both treatments in 75 patients who had severe chronic viral hepatitis (He, 2004). Liver function was significantly improved in all groups, but prothrombin time and activity were significantly improved only for the two groups treated with plasma exchange. The study results were limited by the relatively small sample size, and the treatment allocation method and inclusion and exclusion criteria were not reported. In the other study, by Nakae et al. (2002), plasma exchange was compared with plasma exchange plus continuous hemodiafiltration in 26 patients with acute hepatic failure by any cause. Total bilirubin was significantly lowered in both groups; however, plasma levels of tumor necrosis factor and interleukin-8 were significantly decreased after the combination treatment but not plasma exchange alone. The study results are limited by the very small sample size, diverse causes of liver failure, and method of allocating patients to the treatment groups was not reported. Hyperlipidemia in nephrotic syndrome: With the exception of one small randomized, controlled trial, the reported studies were small case series and isolated case reports. All of the studies involved very small numbers of subjects. Many of the subjects in the studies were concurrently receiving steroids or lipid-lowering drug therapy without the standardization of regimens or control of this confounding variable. Temporal variation in length of each apheresis episode, duration of treatment, and frequency of treatment was also prevalent. Patient selection criteria varied widely in the studies reviewed. Well-designed studies are necessary to determine its value in the treatment of this disorder (Brunton, 1999; Derfler, 1997; Muso, 1994; Yokoyama, 1998; Faucher, 1997; Ideura, 2000). Inflammatory Bowel Disease: Review of clinical trials by Schwartz and Ferguson on current pharmacologic treatment paradigms for inflammatory bowel disease and the potential role of granulocyte/monocyte apheresis showed that remission rates are consistent with those of currently available pharmacologic therapies for IBD (Schwartz, 2007). The majority of these trials enrolled only small numbers of patients, were largely open-label, and were of limited duration; therefore, wellcontrolled, large-scale clinical trials are needed to confirm these findings. Sands et al. (2008) evaluated the efficacy of granulocyte/monocyte apheresis in a randomized, doubleblind, sham-controlled trial in patients with active moderate-to-severe ulcerative colitis. Granulocyte/monocyte apheresis with the Adacolumn Apheresis System (JIMRO, Ltd, Takasaki, Japan) or sham apheresis in a 2:1 ratio was used for 9 weeks of treatment in a North American pivotal study (n = 168) and in a smaller, companion study of identical design conducted in Europe and Japan

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(n = 47). In the pivotal study, clinical remission rates were 17% and 11% for the granulocyte/monocyte apheresis (n = 112) and sham-treatment groups, respectively (n = 56). Clinical response was observed in 44% and 39% of patients, respectively. Similar changes were observed for the apheresis- and shamtreatment groups for endoscopic remission and response, and changes in Mayo and quality-of-life scores. The companion study and pooled data from both studies also yielded similar results. The investigators concluded that granulocyte/monocyte apheresis was well tolerated but did not demonstrate efficacy for induction of clinical remission or response in patients with moderate-tosevere ulcerative colitis. Photopheresis Cutaneous T-Cell Lymphoma: Studies evaluating the clinical response of patients to extracorporeal photopheresis (ECP) monotherapy, comparing ECP monotherapy with a combination of ECP and adjuvant therapy, and evaluating ECP as adjuvant therapy with the primary therapy under study met the criteria for review; all were nonrandomized, uncontrolled or poorly controlled trials, and involved small study populations. All of the reviewed studies employed the UVAR photopheresis system (Hayes, 2006). ECP monotherapy (combined n=195): In the studies evaluating ECP monotherapy for treatment of cutaneous T-cell lymphoma (CTCL) , 40% to 50% of patients had a positive response, positive response being most often defined as between 50% and 100% improvement in lesions and/or histopathological parameters for 1 to 3 months after treatment. An effect on disease-free or overall survival was less clear; most studies did not document a clear impact of ECP on survival rates, although the effect was difficult to evaluate in studies that did not provide a contemporary control or comparison group, and not all studies provided data on survival. (Hayes 2006) Evans et al., (2001) reported positive findings for ECP monotherapy in 23 patients with Sezary syndrome; 13 patients (57%) achieved > 25% reduction in skin scores. In their 7-year experience, Knobler et al. (2002) retrospectively reviewed the charts of 20 patients with biopsy-proven CTCL who had received ECP. An overall response rate of 50% was observed. ECP versus ECP plus adjuvant therapy (combined n=135): Of the four small studies that compared the efficacy and safety of ECP monotherapy with that of ECP in combination with adjuvant therapy, one was prospective, and three were retrospective. Adjuvants varied among the studies, and results were conflicting. Two of the retrospective studies suggested an improvement in response to combination therapy compared with response to ECP alone, although Suchin et al. (2002) failed to find a significant effect of combination therapy. Two studies evaluated survival in the two experimental arms; neither clearly demonstrated a significant improvement in survival among patients who received ECP in combination with adjuvant therapy, compared with ECP alone (Hayes, 2006). Richardson et al. (2006) evaluated the clinical response rate of 28 patients with Sazary syndrome (SS) to multimodality immunomodulatory therapy consisting of extracorporeal photopheresis in combination with 2 or more systemic biologic response modifiers (interferon-, interferon-, retinoids, and/or sargramostim) and psoralen plus UV-A. An overall clinical response of 89% was achieved with multimodality immunomodulatory therapy. Sixty-one percent exhibited a partial response. Eleven percent of patients were nonresponders. The investigators concluded that multimodality

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immunomodulatory therapy is an exceptionally effective treatment for SS. The durability of response and impact on overall survival remains to be determined. ECP plus other primary therapy versus other primary therapy alone (combined n=251): Three studies evaluated ECP as an adjunct to another primary therapy for CTCL; two were prospective and one was retrospective (Hayes, 2006). The studies by Wilson et al. reported significantly greater overall survival in the patient group that received ECP immediately before or during total skin electron beam treatment, with the greatest benefit observed in patients with advanced-stage tumors (Wilson, 1995; Wilson, 2000). Quaglino et al. (2004) reported a significant improvement in response rate but not survival in patients who received ECP in combination with fludarabine, compared with the study group that received fludarabine alone. Graft vs. Host Disease: Flowers et al. (2008) compared the safety and efficacy of extracorporeal photopheresis (ECP) used with standard therapy and standard therapy alone in 95 patients with cutaneous manifestations of graft versus host disease that could not be adequately controlled by corticosteroid treatment. Patients were randomized to either ECP with standard therapy (n = 48) or standard therapy alone (n = 47). The median percentage improvement in total skin score (TSS) at week 12 was 14.5% for the ECP arm and 8.5% for the control arm. The proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease from baseline in TSS was 8.3% in the ECP arm at week 12 and 0% in the control arm. The nonblinded investigator assessment of skin complete or partial responses revealed a significant improvement in favor of ECP. ECP was generally well tolerated. These results suggest that ECP may have a steroid-sparing effect in the treatment of graft versus host disease. Other Disorders Extracorporeal photopheresis (ECP) has also been investigated for disorders such as scleroderma, multiple sclerosis, and type I diabetes. There is little evidence that photopheresis is beneficial for these conditions. Many studies are small pilot studies that demonstrate minor improvement in patient status during the course of therapy. A study by Rook et al. (1992) reported on 79 patients with systemic sclerosis with skin involvement who were randomized to receive treatment with extracorporeal photopheresis or D-penicillamine. The study demonstrated improved skin symptoms in patients who received extracorporeal photopheresis. However, the study was of short duration, and a large number of patients were lost to follow-up. Knobler et al. (2006) compared ECP and sham pheresis treatment in a randomized controlled trial demonstrated an improvement in skin scores and joint involvement in patients receiving ECP compared to baseline scores. Comparison of skin scores between the two study arms did not achieve statistical significance because of small sample size of the study arms. This study lacked sufficient statistical power to determine any effect when ECP was compared with sham treatment. Rostami et al. (1999) performed a randomized controlled trial of monthly ECP for the treatment of clinically definite multiple sclerosis. ECP did not significantly alter the course of chronic progressive multiple sclerosis.

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Gandhi et al. (2008) performed a systematic review and meta-analysis to determine the efficacy of non-antigen based immunotherapies, including ECP, in the treatment of patients with type I diabetes mellitus. The meta-analysis found a small-to-moderate improvement in beta cell function with immunotherapy vs. placebo. Jonson et al. (2008) evaluated 20 children with type 1 diabetes who received photopheresis 8methoxypsoralen + extracorporeal photopheresis (ECP) or placebo + sham pheresis. Over time, expression of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and transforming growth factor (TGF)-beta decreased with a parallel reduction of glutamic acid decarboxylase (GAD) 65-peptide and phytohaemagglutinin (PHA)-simulated TGF-beta expression. The investigators concluded that ECP maintains regulatory T cell-associated activity in recent-onset type 1 diabetes. Additional Search Terms photoimmune therapy, photoimmunotherapy

U.S. FOOD AND DRUG ADMINISTRATION (FDA) Devices for plasmapheresis are regulated by the FDA as Class II or III devices depending on whether they rely on centrifugation or filtration of blood. Devices that separate blood cells from plasma by filtration are Class III devices that are subject to the most extensive regulations enforced by the FDA. The FDA rules state that photopheresis for treatment of graft vs. host disease (GVHD) may be indicated after the following: GVHD is proven by biopsy, all other options of treatment have been exhausted.

If photopheresis is initiated, the FDA mandates the following: regular skin assessments be performed to evaluate the patient's response to treatment.

Additional information, regarding product code LKN, can be obtained from the U.S. Food and Drug Administration (FDA) [website]: Center for Devices and Radiological Health at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm. Accessed July 2009. Additional devices have been approved under the 510K Product Codes DXN, LLZ, and DQY. The THERAKOS UVAR Photopheresis System and updated models (UVAR XTS are approved by the FDA, along with associated products, such as the TPS102 Photoceptor Activation Chamber, the TPS101 Photopheresis blood tubing set, and the UVADEX Solution, which is a sterile liquid formulation of 8-methoxypsoralen (8-MOP).

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Additional information may be obtained directly from the U.S. Food and Drug Administration (FDA) [website]. Center for Devices and Radiological Health (CDRH). Search premarket approval (PMA) database (product code LNR and MNR). Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm. Accessed July 2009. Additional Medical Products Haemonetics Therapeutic Plasma Exchange Set; Fresenius P1r Plasma Treatment Set, Cobe Spectra Blood Component Separator, Plasma Separation System, Heparin-Induced Extracorporeal Lipoprotein Precipitation (H.E.L.P.) System, Liposorber LA-15 System, LDL-Therasorb, Prosorba APPLICABLE CODES The codes listed in this policy are for reference purposes only. Listing of a service or device code in this policy does not imply that the service described by this code is a covered or non-covered health service. Coverage is determined by the benefit document. This list of codes may not be all inclusive. CPT Code 36511 36512 36513 36514 36515 36516 36522 HCPCS Code S2120 ICD-9 Code 272.0 273.2 273.3 275.01 275.02 275.03 275.09 277.1 279.50 279.51 279.52 279.53 282.60 Description Therapeutic apheresis; for white blood cells Therapeutic apheresis; for red blood cells Therapeutic apheresis; for platelets Therapeutic apheresis; for plasma pheresis Therapeutic apheresis; with extracorporeal immunoadsorption and plasma reinfusion Therapeutic apheresis; with extracorporeal selective adsorption or selective filtration and plasma reinfusion Photopheresis, extracorporeal Description Low density lipoprotein (ldl) apheresis using heparin-induced extracorporeal ldl precipitation Description Pure hypercholesterolemia Other paraproteinemias Macroglobulinemia Hereditary hemochromatosis Hemochromatosis due to repeated red blood cell transfusions Other hemochromatosis Other disorders of iron metabolism Disorders of porphyrin metabolism Graft-versus-host disease, unspecified Acute graft-versus-host disease Chronic graft-versus-host disease Acute on chronic graft-versus-host disease Sickle-cell disease, unspecified

CPT is a registered trademark of the American Medical Association.

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ICD-9 Code 283.11 287.41 287.49 288.60 289.6 356.3 357.0 357.4 357.81 358.00 358.01 358.1 443.0 446.21 446.6 694.4 694.5 695.4 710.0 710.1 714.0 977.9 ICD-9 Procedure Code 99.71 99.72 99.73 99.74 99.79

Description Hemolytic-uremic syndrome Posttransfusion purpura Other secondary thrombocytopenia Leukocytosis, unspecified Familial polycythemia Refsum's disease Acute infective polyneuritis Polyneuropathy in other diseases classified elsewhere Chronic inflammatory demyelinating polyneuritis Myasthenia gravis without (acute) exacerbation Myasthenia gravis with (acute) exacerbation Myasthenic syndromes in diseases classified elsewhere Raynaud's syndrome Goodpasture's syndrome Thrombotic microangiopathy Pemphigus Pemphigoid Lupus erythematosus Systemic lupus erythematosus Systemic sclerosis Rheumatoid arthritis Poisoning by unspecified drug or medicinal substance Description Therapeutic plasmapheresis Therapeutic leukopheresis Therapeutic erythrocytapheresis Therapeutic plateletpheresis Other therapeutic apheresis

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ECRI Institute. Hotline Response. Applications of extracorporeal photopheresis. May 2009. ECRI Institute. Windows on Medical Technology. Plasmapheresis for multiple sclerosis. September 10, 2007. Evans AV, Wood BP, Scarisbrick JJ, et al. Extracorporeal photopheresis in Ssyndrome: hematologic parameters as predictors of response. Blood. 2001;98(5):1298-1301. Faucher C, Albert C, Beaufils H, et al. Remission of a refractory nephrotic syndrome after lowdensity lipoprotein apheresis based on dextrane sulphate adsorption. Nephrol Dial Transplant. 1997;12:10371039. Felson D, LaValley M, Bladassare A, et al. The Prosorba column for treatment of refractory rheumatoid arthritis: a randomized, double-blind, sham-controlled trial. Arth Rheum. 1999(Oct.);42(10): 2153-2159. Flowers ME, Apperley JF, van Besien K, et al. A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease. Blood. 2008 Oct 1;112(7):2667-74. Gandhi GY, Murad MH, Flynn DN, et al. Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials. Clin Endocrinol (Oxf). 2008 Jan 10. Goodin DS, Frohman EM, Garmany GP Jr, et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002;58(2):169-178. Guillaume JC, Roujeau JC, Morel P, et al. Controlled study of plasma exchange in pemphigus. Arch Dermatol. 1988;124(11):1659-1663. Guillaume JC, Vaillant L, Bernard P, et al. Controlled trial of azathioprine and plasma exchange in addition to prednisolone in the treatment of bullous pemphigoid. Arch Dermatol. 1993;129(1):49-53. Hayes, Inc. Medical Technology Directory. Extracorporeal Apheresis for Gastroenterological Indications. Lansdale, PA: Hayes, Inc. March 27, 2007. Last updated April 2009. Hayes, Inc. Medical Technology Directory. Extracorporeal Apheresis for Conditions Affecting the Circulatory System and Blood. Lansdale, PA: Hayes, Inc. December 28, 2007. Last update search December 2008. Hayes, Inc. Medical Technology Directory. Extracorporeal Apheresis for Autoimmune and Connective Tissue Disorders. Lansdale, PA: Hayes, Inc. July 12, 2007. Last updated June 2009. Hayes, Inc. Hayes Medical Technology Directory. Plasma Exchange for Multiple Sclerosis. Lansdale, PA: Hayes, Inc. April 19, 2006. Last updated May 2009.

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Muso E, Yashiro M, Matsushima M, et al. Does LDL-apheresis in steroid-resistant nephritic syndrome affect prognosis? Nephrol Dial Transplant. 1994;9:257-264. Nakae H, Asanuma Y, Tajimi K. Cytokine removal by plasma exchange with continuous hemodiafiltration in critically ill patients. Ther Apheresis. 2002;6(6):419-424. Naguma S, Agishi T, and Ota K. LDL apheresis in atherosclerotic disease with hyperlipidemia. ASAIO J. 1992;38: M436-M439. National Institutes of Health (NIH) Consensus Statement. The utility of therapeutic plasmapheresis for neurological disorders. June 1986. Updated February 14, 2002. Website: http://consensus.nih.gov/1986/1986Plasmapheresis056html.htm. Accessed July 2009. Palcoux JB, Atassi-Dumont M, Lefevre P, et al. Low-density lipoprotein apheresis in children with familial hypercholesterolemia: follow-up to 21 years. Ther Apher Dial. 2008 Jun;12(3):195-201. Park J, Merz M, and Braun P. Effect of H.E.L.P.-LDL-apheresis on outcomes in patients with advanced coronary atherosclerosis and severe hypercholesterolemia. Atherosclerosis. 1998(Aug.);139(2): 401-409. Quaglino P, Fierro MT, Rossotto GL, et al. Treatment of advanced mycosis fungoides/Ssyndrome with fludarabine and potential adjunctive benefit to subsequent extracorporeal photochemotherapy. Br J Dermatol. 2004;150(2):327-336. Richardson SK, Lin JH, Vittorio CC, et al. High clinical response rate with multimodality immunomodulatory therapy for Sazary syndrome. Clin Lymphoma Myeloma. 2006 Nov;7(3):226-32. Richter W, Donner M, and Schwandt P. Three low density lipoprotein apheresis techniques in treatment of patients with familial hypercholesterolemia: a long-term evaluation. Ther Apheresis. 1999;3(3): 203-208. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. N Engl J Med. 1991;325(6):393-397. Rook AH, Freundlich B, Jegasothy BV, et al. Treatment of systemic sclerosis with extracorporeal photochemotherapy: results of a multicenter trial. Arch Dermatol. 1992 Mar;128(3):337-46. Rostami AM, Sater RA, Bird SJ, et al. A double-blind, placebo-controlled trial of extracorporeal photopheresis in chronic progressive multiple sclerosis. Mult Scler. 1999 Jun;5(3):198-203. Roth S. Effects of Prosorba column apheresis in patients with chronic refractory rheumatoid arthritis. J Rheumatol. 2004 Nov;31(11):2131-5. Roujeau JC, Guillaume JC, Morel P, et al. Plasma exchange in bullous pemphigoid. Lancet. 1984;2(8201):486-488.

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Yokoyama K, Sakai S, Sigematsu T, et al. LDL adsorption improves the response of focal glomerulosclerosis to corticosteroid therapy. Clin Nephrol. 1998;50:1-7.

PROTOCOL HISTORY/REVISION INFORMATION Date 10/01/2010 10/28/2010 06/24/2010 06/26/2009 Action/Description Medical Technology Assessment Committee Corporate Medical Affairs Committee

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