Noncontact ultrasound treatment for wounds is considered investigational.

Electrical stimulation for the treatment of wounds, including but not limited to low-intensity direct current, high-voltage pulsed current, alternating current, and transcutaneous electrical nerve stimulation, is considered investigational.

Electrical stimulation performed by the patient in the home setting for the treatment of wounds is considered investigational.

Electromagnetic therapy for the treatment of wounds is considered investigational.

Nonpharmacologic treatment of rosacea, including but not limited to laser and light therapy, dermabrasion, chemical peels, surgical debulking, and electrosurgery, is considered investigational.

A trial of transcutaneous electrical nerve stimulation (TENS) of at least 30 days may be considered medically necessary to establish efficacy for the management of refractory chronic pain (eg, chronic musculoskeletal pain or neuropathic pain) that causes significant disruption of function when the following conditions have been met:

The pain is unresponsive to at least 3 months of conservative medical therapy; and

The trial is monitored by a physician.

Continued use of TENS may be considered medically necessary for treatment of refractory chronic pain (eg, chronic musculoskeletal or neuropathic pain) that causes significant disruption of function when the following conditions have been met:

Efficacy has been demonstrated in an initial therapeutic trial (see Policy Guidelines section); and

Compliance has been demonstrated in the therapeutic trial with the device used on a regular basis (eg, daily or near daily use) throughout the trial period.

TENS is considered investigational for the management of acute pain (eg, postoperative or during labor and delivery).

TENS is considered investigational for the prevention or treatment of migraine headache.

TENS is considered investigational for the management of essential tremor.

TENS is considered investigational for the management of attention deficit hyperactivity disorder.

The use of TENS for any other condition, including but not limited to the treatment of dementia is considered investigational.

Devices using bioimpedance (bioelectrical impedance spectroscopy) are considered investigational for use in the diagnosis, surveillance, or treatment of patients with lymphedema, including use in subclinical secondary lymphedema.

Autologous and allogeneic hematopoietic cell transplantation are considered investigational to treat advanced stage epithelial ovarian cancer.

Psoralen plus ultraviolet A for the treatment of vitiligo that is not responsive to other forms of conservative therapy (eg, topical corticosteroids, coal/tar preparations, ultraviolet light) may be considered medically necessary.

Targeted phototherapy is considered investigational for the treatment of vitiligo.

Photodynamic therapy may be considered medically necessary as a treatment of:

Nonhyperkeratotic actinic keratoses of the face and scalp (see policy guidelines).

Nonhyperkeratotic actinic keratoses of the upper extremities (see policy guidelines).

Low-risk (eg, superficial and nodular) basal cell skin cancer only when surgery and radiation are contraindicated.

Cutaneous squamous cell carcinoma in situ (Bowen disease) only when surgery and radiation are contraindicated.

Photodynamic therapy is considered investigational for other dermatologic applications, including, but not limited to, acne vulgaris, high-risk basal cell carcinomas, hidradenitis suppurativa, and mycoses.

Photodynamic therapy as a technique of skin rejuvenation, hair removal, or other cosmetic indications is considered investigational.

Laser treatment of onychomycosis is considered investigational.

Single autologous hematopoietic cell transplantation (HCT) may be considered medically necessary as salvage therapy for germ cell tumors:

in individuals with favorable prognostic factors that have failed a previous course of conventional-dose salvage chemotherapy; or

in individuals with unfavorable prognostic factors as initial treatment of first relapse (ie, without a course of conventional-dose salvage chemotherapy) and in individuals with platinum-refractory disease. (See Policy Guidelines section for prognostic factors.)

Tandem autologous HCT or transplant with sequential high-dose chemotherapy may be considered medically necessary for the treatment of testicular tumors either as salvage therapy or with platinum-refractory disease.

Autologous HCT is considered investigational as a component of first-line treatment for germ cell tumors.

Allogeneic HCT is considered investigational to treat germ cell tumors, including, but not limited, to its use as therapy after a prior failed autologous HCT.

Autologous or allogeneic hematopoietic cell transplant is considered investigational for the following malignancies in adults:

•         Lung cancer, any histology

•         Colon cancer

•         Rectal cancer

•         Pancreatic cancer

•         Stomach cancer

•         Esophageal cancer

•         Gall bladder cancer

•         Cancer of the bile duct

•         Renal cell cancer

•         Cervical cancer

•         Uterine cancer

•         Cancer of the fallopian tubes

•         Prostate cancer

•         Nasopharyngeal cancer

•         Paranasal sinus cancer

•         Neuroendocrine tumors

•         Soft tissue sarcomas

•         Thyroid tumors

•         Tumors of the thymus

•         Tumors of unknown primary origin

•         Malignant melanoma.

Autologous hematopoietic cell transplantation may be considered medically necessary for:

initial treatment of high-risk neuroblastoma,

recurrent or refractory neuroblastoma,

initial treatment of high-risk Ewing sarcoma,

recurrent or refractory Ewing sarcoma, and

metastatic retinoblastoma.

Tandem autologous hematopoietic cell transplantation may be considered medically necessary for high-risk neuroblastoma.

Autologous hematopoietic cell transplantation is considered investigational as initial treatment of low- or intermediate-risk neuroblastoma, initial treatment of low- or intermediate-risk Ewing sarcoma, and for other solid tumors of childhood including, but not limited, to the following:

rhabdomyosarcoma,

Wilms tumor,

osteosarcoma, and

retinoblastoma without metastasis.

Tandem autologous hematopoietic cell transplantation is considered investigational for the treatment of all other types of pediatric solid tumors except high-risk neuroblastoma, as noted above.

Allogeneic (myeloablative or nonmyeloablative) hematopoietic cell transplantation is considered investigational for treatment of pediatric solid tumors.

Salvage allogeneic hematopoietic cell transplantation for pediatric solid tumors that relapse after autologous transplant or fail to respond is considered investigational.

Myeloablative allogeneic hematopoietic cell transplantation (allo-HCT) may be considered medically necessary as a treatment of

myelodysplastic syndromes (see Policy Guidelines section) or

myeloproliferative neoplasms (see Policy Guidelines section).

Reduced-intensity conditioning (RIC) allo-HCT may be considered medically necessary as a risk-adapted treatment of

myelodysplastic syndromes or

myeloproliferative neoplasms

in individuals who are at high risk of intolerance of a myeloablative conditioning regimen (see Policy Guidelines section).

Myeloablative allo-HCT or RIC allo-HCT for myelodysplastic syndromes and myeloproliferative neoplasms that do not meet the criteria in the Policy Guidelines section is considered investigational.

Embryonal Tumors of the Central Nervous System

Autologous Hematopoietic Cell Transplantation

Autologous hematopoietic cell transplantation may be considered medically necessary as consolidation therapy for previously untreated embryonal tumors of the central nervous system (CNS) that show partial or complete response to induction chemotherapy, or stable disease after induction therapy (see Policy Guidelines section).

Autologous hematopoietic cell transplantation may be considered medically necessary to treat recurrent embryonal tumors of the CNS.

Tandem autologous hematopoietic cell transplantation is investigational to treat embryonal tumors of the CNS.

Allogeneic Hematopoietic Cell Transplantation

Allogeneic hematopoietic cell transplantation is investigational to treat embryonal tumors of the CNS.

Ependymoma

Autologous, tandem autologous, and allogeneic hematopoietic cell transplantation are investigational to treat ependymoma.

A single unattended (unsupervised) home sleep apnea test with a minimum of 3 recording channels with the following sensors: nasal pressure, chest and abdominal respiratory inductance plethysmography, and oximetry; or alternatively peripheral arterial tone (PAT), oximetry, and actigraphy may be considered medically necessary in adults who are at high-risk for obstructive sleep apnea (OSA) and have no evidence of a health condition that might alter ventilation or require alternative treatment (ie, central sleep apnea, heart failure, chronic pulmonary disease, obesity hypoventilation syndrome, neuromuscular disorders with sleep-related symptoms, injurious or potentially injurious parasomnias, or narcolepsy). The Policy Guidelines section defines high pretest probability.

A single unattended (unsupervised) home sleep apnea test with a minimum of recording channels as described above, may be considered medically necessary as a screening tool in individuals who are scheduled for bariatric surgery and have no evidence of a health condition that might alter ventilation or require alternative treatment (see Policy Guidelines section).

Unattended home sleep studies are considered investigational in children (<18 years of age). Repeated unattended (unsupervised) home sleep apnea test with a minimum of 3 recording channels with the following sensors: nasal pressure, chest and abdominal respiratory inductance plethysmography, and oximetry; or alternatively PAT, oximetry, and actigraphy, may be considered medically necessary in adults under the following circumstances: To assess efficacy of surgery or oral appliances or devices; OR To reevaluate the diagnosis of OSA and need for continuous positive airway pressure (CPAP) (eg, if there is a significant change in weight or change in symptoms suggesting that CPAP should be retitrated or possibly discontinued). Supervised polysomnography (PSG) performed in a sleep laboratory may be considered medically necessary in individuals with a moderate or high pretest probability of OSA in the following situations: Pediatric individuals (ie, <18 years of age); OR When individuals do not meet criteria for an unattended home sleep apnea test as described above; OR A previous home study failed to establish the diagnosis of OSA in an individual with a high pretest probability of OSA; OR A previous home study was technically inadequate; OR Failure of resolution of symptoms or recurrence of symptoms during treatment; OR When testing is done to rule out other sleep disorders such as central sleep apnea, injurious or potentially injurious parasomnias, or narcolepsy (see evidence review 2.01.99); OR Presence of a comorbidity that might alter ventilation or decrease the accuracy of a home sleep apnea test, including, but not limited to heart failure, neuromuscular disease, chronic pulmonary disease, or obesity hypoventilation syndrome. A repeated, supervised PSG performed in a sleep laboratory may be considered medically necessary in individuals who meet the criteria above for an in-laboratory PSG under the following circumstances: To initiate and titrate CPAP in adults who have: An Apnea/Hypopnea Index (AHI) or Respiratory Disturbance Index (RDI) of at least 15 events per hour, OR An AHI or RDI of at least 5 events per hour in an individual with 1 or more signs or symptoms associated with OSA (eg, excessive daytime sleepiness, hypertension, cardiovascular heart disease, or stroke); Note: A split-night study, in which moderate-to-severe OSA is documented during the first portion of the study using PSG, followed by CPAP during the second portion of the study, can eliminate the need for a second study to titrate CPAP (see Policy Guidelines section for criteria to perform a split-night study). To initiate and titrate CPAP in children: In pediatric individuals, an AHI or RDI of ≥5; OR An AHI or RDI ≥1.5 in an individual with excessive daytime sleepiness, behavioral problems, or hyperactivity. To assess efficacy of surgery (including adenotonsillectomy) or oral appliances/devices. Supervised or unattended home sleep apnea tests that do not meet the above criteria are considered investigational. Multiple sleep latency testing is considered investigational in the diagnosis of OSA.

Eculizumab and Ravulizumab-cwvz – Initial Treatment

Eculizumab and ravulizumab-cwvz may be considered medically necessary for individuals with generalized myasthenia gravis (gMG) if they meet criteria 1 through 6:

18 years of age or older.

Diagnosis of gMG with a class II to IV disease per the Myasthenia Gravis Foundation of America (MGFA) classification system (see Policy Guidelines).

Anti-acetylcholine receptor (AChR) antibody positive.

Impaired activities of daily living defined as a MG-Activities of Daily Living (MG-ADL) total score of ≥ 6.

Inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) and at least ONE immunosuppressive therapy (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) either in combination or as monotherapy.

Not receiving dual therapy with another C5 complement inhibitor for gMG.

Vaccination against Neisseria meningitidis at least 2 weeks prior to initiation of therapy [unless treatment cannot be delayed].

Prescribing physician is enrolled in the appropriate Risk Evaluation and Mitigation Strategies (REMS) program.

Initial authorization period is for 6 months.

Eculizumab and Ravulizumab-cwvz – Continuation of Treatment

Incremental reauthorization for eculizumab and ravulizumab-cwvz may be considered medically necessary for individuals with gMG if they meet criteria 1 through 2:

Continues to meet the initial treatment criteria cited above.

Decrease of 2 points in MG-ADL total score from pre-treatment baseline value.

Reauthorization period is for 12 months.

Eculizumab and ravulizumab-cwvz are considered investigational for generalized myasthenia gravis when the above criteria are not met.

Efgartigimod alfa-fcab (intravenous) and efgartigimod alfa and hyaluronidase-gvfc (subcutaneous) – Initial Treatment

Efgartigimod alfa-fcab and efgartigimod alfa and hyaluronidase-gvfc may be considered medically necessary for individuals with gMG if they meet criteria 1 through 6:

18 years of age or older.

Diagnosis of gMG with class II to IV disease per the MGFA classification system (see Policy Guidelines).

Anti-AChR antibody positive.

Impaired activities of daily living defined as a MG-ADL total score of ≥ 5.

Inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) and at least ONE immunosuppressive therapy (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) either in combination or as monotherapy.

IgG levels ≥ 6 g/L.

Initial authorization period is for 6 months.

Efgartigimod alfa-fcab (intravenous) and efgartigimod alfa and hyaluronidase-gvfc (subcutaneous) – Continuation of Treatment

Incremental reauthorization for efgartigimod alfa-fcab and efgartigimod alfa and hyaluronidase-gvfc (subcutaneous) may be considered medically necessary for individuals with gMG if they meet criteria 1 through 2:

Continues to meet the initial treatment criteria cited above.

Decrease of 2 points in MG-ADL total score from pre-treatment baseline value.

Reauthorization period is for 12 months.

Efgartigimod alfa-fcab is considered investigational when the above criteria are not met.

Rozanolixizumab-noli – Initial Treatment

Rozanolixizumab-noli may be considered medically necessary for individuals with gMG if they meet criteria 1 through 6:

18 years of a or older.

Diagnosis of gMG with class II to IVa disease per the MGFA classification system (see Policy Guidelines).

Anti-AChR antibody positive or anti-muscle-specific tyrosine kinase (MuSK) antibody positive.

Impaired activities of daily living defined as a MG-DLS total score of ≥ 3 and at least 3 points from non-ocular symptom(s).

Inadequate treatment response, intolerance, or contraindication to an acetylcholinesterase inhibitor (e.g., pyridostigmine, neostigmine) and at least ONE immunosuppressive therapy (e.g., azathioprine, cyclosporine, mycophenolate mofetil, tacrolimus, methotrexate, cyclophosphamide) either in combination or as monotherapy.

IgG levels ≥ 5.5 g/L.

Initial authorization period is for 6 months.

Rozanolixizumab-noli – Continuation of Treatment

Incremental reauthorization of rozanolixizumab-noli may be considered medically necessary for individuals with gMG if they meet criteria 1 through 2:

Individual continues to meet the initial treatment criteria cited above.

Decrease of 2 points in MG-ADL total score from pre-treatment baseline value.

Reauthorization period is for 12 months.

Rozanolixizumab-noli is considered investigational when the above criteria are not met.

Subcutaneously administered Food and Drug Administration (FDA)-approved monoclonal antibodies for calcitonin gene-related peptide may be considered medically necessary for the preventive treatment of episodic or chronic migraine under the following conditions:

The individual is ≥ 18 years of age; AND

Has ≥ 4 migraine headache days per month; AND

Has failed a trial (eg, not effective or not tolerated) from ≥ 3 classes of prophylactic pharmacologic therapies (eg, anti-depressants, anticonvulsants, and beta-blockers, if not contraindicated) AND;

Has not received botulinum toxin headache prophylaxis in the past 4 months.

Intravenously administered FDA-approved monoclonal antibody for calcitonin gene-related peptide may be considered medically necessary for the preventive treatment of episodic or chronic migraine under the following conditions:

The individual is ≥ 18 years of age; AND

Has ≥ 4 migraine headache days per month; AND

Has failed a trial (eg, not effective or not tolerated) from ≥ 3 classes of prophylactic pharmacologic therapies (eg, anti-depressants, anticonvulsants, and beta-blockers, if not contraindicated) AND;

Has not received botulinum toxin headache prophylaxis in the past 4 months.

Galcanezumab may be considered medically necessary for the treatment of episodic cluster headaches under the following conditions:

The individual is ≥ 18 years of age; AND

Individual has been diagnosed with episodic cluster headaches as defined as having at least 2 cluster periods lasting from 7 days to 1 year, separated by pain-free remission periods lasting at least 1 month;

Individua has been unable to achieve a reduction in weekly cluster headache attack frequency with preventative medication(s).

Treatment with monoclonal antibodies for calcitonin gene-related peptide is considered investigational in all other situations including treatment of acute migraine.

Initial Treatment – Hereditary Transthyretin-Mediated Amyloidosis Polyneuropathy

Patisiran, inotersen, and vutrisiran are considered medically necessary for individuals if they meet criteria 1 through 5:

18 years of age or older.

Confirmatory diagnosis of hATTR by a genetic test OR tissue biopsy showing amyloid deposition.

Presence of clinical signs and symptoms of polyneuropathy characterized by any one of the following:

Baseline polyneuropathy disability (PND) IIIb or lower (see Table 1 in background section)

Baseline familial amyloid polyneuropathy (FAP) Stage 1 or 2 (see Table 1 in background section).

Does not have ANY of the following:

New York Heart Association (NYHA) class III or IV heart failure

Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.)

Prior liver transplantation.

Does not have any U.S. Food and Drug Administration (FDA) labeled contraindications to the requested agent and is intended to be used consistently with the FDA approved label (see policy guidelines).

Initial authorization period is for 12 months.

Continuation of Treatment – Hereditary Transthyretin-Mediated Amyloidosis Polyneuropathy

Incremental reauthorization of patisiran, inotersen, and vutrisiranare considered medically necessary for individuals if they meet criteria 1 through 2:

Continues to meet the initial treatment criteria cited above.

Documentation of stabilization OR improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or 5 EQ-5D.

Reauthorization period is for 12 months.

Patisiran, inotersen, and vutrisiran are considered investigational when the above criteria are not met.

Initial Treatment – Hereditary Transthyretin-Mediated Amyloidosis Cardiomyopathy

Tafamidis and tafamidis meglumine are considered medically necessary for individuals if they meet criteria 1 through 5:

18 years of age or older.

Confirmatory diagnosis of hereditary or wild-type transthyretin-mediated amyloidosis by a genetic test OR tissue biopsy showing amyloid deposition.

Presence of clinical signs and symptoms of cardiac involvement by all of the following:

End-diastolic interventricular septal wall thickness exceeding 12 mm on echocardiography.

History of heart failure, with at least one prior hospitalization for heart failure or clinical evidence of heart failure (without hospitalization) manifested in signs or symptoms of volume overload or elevated intracardiac pressures requiring treatment with a diuretic for improvement.

Baseline NT-proBNP ≥ 600 pg/mL.

Does not have any of the following:

NYHA class IV heart failure.

Presence of light-chain amyloidosis.

History of liver or heart transplantation.

Implanted cardiac device.

Does not have any U.S. FDA labeled contraindications to the requested agent and is intended to be used consistently with the FDA approved label (see policy guidelines).

Initial authorization period is for 12 months.

Continuation of Treatment – Hereditary Transthyretin-mediated Amyloidosis Cardiomyopathy

Incremental reauthorization for tafamidis and tafamidis meglumine are considered medically necessary for individuals if they meet criteria 1 through 2:

Continues to meet the initial treatment criteria cited above.

Documentation of stabilization OR improvement via use of objective measurements, such as number of hospitalizations, 6-MWT, or KCCQ-OS.

Reauthorization period is for 12 months.

Tafamidis and tafamidis meglumine are considered investigational when the above criteria are not met.

Recombinant platelet-derived growth factor (ie, becaplermin) may be considered medically necessary when used as an adjunct to standard wound management for the following indications (for further information on patient selection criteria, see Policy Guidelines next):

Neuropathic diabetic ulcers extending into the subcutaneous tissue

Pressure ulcers extending into the subcutaneous tissue.

Other applications of recombinant platelet-derived growth factor (ie, becaplermin) are considered investigational, including, but not limited to, ischemic ulcers, venous stasis ulcers, and ulcers not extending through the dermis into the subcutaneous tissue.

Use of platelet-rich plasma (ie, autologous blood-derived preparations) is considered investigational for the treatment of acute or chronic wounds, including surgical wounds and nonhealing ulcers.

Auto-adjusting positive airway pressure (APAP) may be considered medically necessary for the titration of pressure in individuals with clinically significant obstructive sleep apnea (OSA) defined as those who have:

An Apnea/Hypopnea Index (AHI), Respiratory Disturbance Index (RDI), or Respiratory Event Index (REI) of at least 15 events per hour, OR

An AHI, RDI, or REI of at least 5 events per hour in an individual with 1 or more signs or symptoms associated with OSA (eg, excessive daytime sleepiness, hypertension, cardiovascular heart disease, or stroke); OR

If there is a significant change in weight or change in symptoms suggesting that continuous positive airway pressure (CPAP) should be retitrated or possibly discontinued.

CPAP may be considered medically necessary in adult or pediatric individuals with clinically significant OSA.

Clinically significant OSA in adults is:

An AHI, RDI, or REI ≥15, OR

An AHI, RDI, or REI ≥5 in an individual with 1 or more signs or symptoms associated with OSA (e.g., excessive daytime sleepiness, hypertension, cardiovascular heart disease, or stroke).

Clinically significant OSA in pediatric individuals is:

An AHI or RDI ≥5 OR

An AHI or RDI ≥1.5 in an individual with excessive daytime sleepiness, behavioral problems or hyperactivity.

Bilevel positive airway pressure (PAP) or APAP may be considered medically necessary in individuals with clinically significant OSA who have failed a prior trial of CPAP or for whom bilevel PAP is found to be more effective in the sleep lab.

Intraoral appliances (tongue-retaining devices or mandibular advancing/positioning devices) may be considered medically necessary in adults with clinically significant OSA under the following conditions:

OSA, defined by an AHI, RDI, or REI of at least 15 events per hour or an AHI, RDI, or REI of at least 5 events per hour in an individual with 1 or more signs or symptoms associated with OSA (e.g., excessive daytime sleepiness, hypertension, cardiovascular heart disease, or stroke), AND

A trial with CPAP has failed or is contraindicated, AND

The device is prescribed by a treating physician, AND

The device is custom-fitted by qualified dental personnel, AND

There is absence of temporomandibular dysfunction or periodontal disease.

Note: CPAP has been shown to have greater effectiveness than oral appliances in general. This difference in efficacy is more pronounced for individuals with severe OSA, because oral appliances have been shown to be less efficacious in individuals with severe OSA than in individuals with mild-to-moderate OSA. Therefore, it is particularly important that individuals with severe OSA have an initial trial of CPAP and that all reasonable attempts are made to continue treatment with CPAP, prior to the decision to switch to an oral appliance.

The use of CPAP, bi-level PAP, APAP, and intraoral appliances that do not meet the above criteria is considered investigational for the treatment of OSA.

The use of an abbreviated daytime sleep session for acclimation to CPAP (PAP-NAP) is considered investigational.

The use of a sleep positioning trainer with vibration is considered investigational for the treatment of positional OSA.

The use of daytime electrical stimulation of the tongue is considered investigational for the treatment of OSA.

Palate and mandible expansion devices are considered investigational for the treatment of OSA.

Nasal expiratory positive airway pressure (EPAP) and oral pressure therapy devices are considered investigational.

Skin biopsy with epidermal nerve fiber density measurement for the diagnosis of small fiber neuropathy may be considered medically necessary when all of the following conditions are met:

Individual presents with symptoms of painful sensory neuropathy; AND

There is no history of a disorder known to predispose to painful neuropathy (eg, diabetic neuropathy, toxic neuropathy, HIV neuropathy, celiac neuropathy, inherited neuropathy); AND

Physical examination shows no evidence of findings consistent with large-fiber neuropathy, such as reduced or absent muscle-stretch reflexes or reduced proprioception and vibration sensation; AND

Electromyography and nerve conduction studies are normal and show no evidence of large-fiber neuropathy.

Skin biopsy with epidermal nerve fiber density measurement is investigational for all other conditions, including, but not limited to, the monitoring of disease progression or response to treatment.

Measurement of sweat gland nerve fiber density is investigational.

Transoral incisionless fundoplication (ie, EsophyX) is considered investigational as a treatment of gastroesophageal reflux disease.

Transesophageal radiofrequency to create submucosal thermal lesions of the gastroesophageal junction (ie, Stretta procedure) is considered investigational as a treatment of gastroesophageal reflux disease.

Endoscopic submucosal implantation of a prosthesis or injection of a bulking agent (eg, polymethylmethacrylate beads, zirconium oxide spheres) is considered investigational as a treatment of gastroesophageal reflux disease.

Wireless capsule endoscopy of the small bowel may be considered medically necessary for the following indications:

Suspected small bowel bleeding, as evidenced by prior inconclusive upper and lower gastrointestinal (GI) endoscopic studies performed during the current episode of illness.

Initial diagnosis in patients with suspected Crohn disease without evidence of disease on conventional diagnostic tests such as small bowel follow-through and upper and lower endoscopy.

In patients with an established diagnosis of Crohn disease, when there are unexpected change(s) in the course of disease or response to treatment, suggesting the initial diagnosis may be incorrect and reexamination may be indicated.

For surveillance of the small bowel in patients with hereditary GI polyposis syndromes, including familial adenomatous polyposis and Peutz-Jeghers syndrome.

Other indications for wireless capsule endoscopy are considered investigational, including but not limited to:

Evaluation of the extent of involvement of known Crohn disease or ulcerative colitis.

Evaluation of the esophagus, in patients with gastroesophageal reflux or other esophageal pathologies.

Evaluation of other GI diseases and conditions not presenting with GI bleeding, including but not limited to, celiac sprue, irritable bowel syndrome, Lynch syndrome (risk for hereditary nonpolyposis colorectal cancer), portal hypertensive enteropathy, small bowel neoplasm, and unexplained chronic abdominal pain.

Evaluation of the colon, including but not limited to, detection of colonic polyps or colon cancer.

Initial evaluation of patients with acute upper GI bleeding.
Evaluation of patients with evidence of lower GI bleeding and major risks for colonoscopy or moderate sedation.

Evaluation of patients following incomplete colonoscopy.
The patency capsule is considered investigational, including use to evaluate patency of the GI tract before wireless capsule endoscopy.

Magnetic capsule endoscopy is considered investigational for the evaluation of patients with unexplained upper abdominal complaints and all other indications.

Vagus nerve stimulation may be considered medically necessary as a treatment of medically refractory seizures.

Vagus nerve stimulation is considered investigational as a treatment of other conditions, including but not limited to depression, heart failure, upper-limb impairment due to stroke, essential tremor, headaches, fibromyalgia, tinnitus, and traumatic brain injury.

Transcutaneous (nonimplantable) vagus nerve stimulation devices are considered investigational for all indications.

Dermal chemical peels used to treat individuals with numerous (>10) actinic keratoses or other premalignant skin lesions, such that treatment of the individual lesions becomes impractical, may be considered medically necessary.

Epidermal chemical peels used to treat individuals with active acne that has failed a trial of topical and/or oral antibiotic acne therapy are considered medically necessary. In this setting, superficial chemical peels with 40% to 70% alpha hydroxy acids are used as a comedolytic therapy. (Alpha-hydroxy acids can also be used in lower concentrations [8%] without the supervision of a physician.).

Epidermal chemical peels used to treat photoaged skin, wrinkles, or acne scarring or dermal peels used to treat end-state acne scarring are considered cosmetic and investigational .

Multiple Myeloma

A single or second (salvage) autologous hematopoietic cell transplantation may be considered medically necessary to treat multiple myeloma.

Tandem autologous hematopoietic cell transplantation may be considered medically necessary to treat multiple myeloma in patients who fail to achieve at least a near-complete or very good partial response after the first transplant in the tandem sequence. (For definitions of near-complete response and very good partial response, see Policy Guidelines section.)

Tandem transplantation with an initial round of autologous hematopoietic cell transplantation followed by a non-marrow-ablative conditioning regimen and allogeneic hematopoietic stem cell transplantation (ie, reduced-intensity conditioning transplant) may be considered medically necessary to treat newly diagnosed multiple myeloma patients.

Allogeneic hematopoietic cell transplantation, myeloablative or nonmyeloablative, as upfront therapy of newly diagnosed multiple myeloma or as salvage therapy, is considered investigational.

POEMS Syndrome

Autologous hematopoietic cell transplantation may be considered medically necessary to treat disseminated POEMS syndrome (see Policy Guidelines section).

Allogeneic and tandem hematopoietic cell transplantation are considered investigational to treat POEMS syndrome.

However, not all studies have found a benefit for MLD over standard management for reducing limb volume [38,44].

However, MLD as a component of multimodal therapy in the form of complete decongestive therapy does appear to reliably reduce limb volume [45]. In observational studies, the reduction in limb volume ranged from 33 to 68 percent and was associated with improved pain, cosmoses, and/or function [39,40,46-51]. In a small phase III trial, 53 patients with lymphedema after breast cancer treatment were randomly assigned to complete decongestive therapy (MLD, multilayer compression bandaging, elevation, remedial exercise, and skin care) versus standard physiotherapy (bandages, elevation, head-neck and shoulder exercises, and skin care) [52]. The group receiving complete decongestive therapy had a significantly greater improvement in edema as measured by circumferential and volumetric measurements.

However, another trial suggested that the benefit is minimal for complete decongestive therapy compared with compression therapy as a first-line treatment for lymphedema [53]. In this trial, 95 female breast cancer survivors with lymphedema (defined as an absolute increase in arm volume of at least 10 percent between the affected and unaffected arm) were randomly assigned to complete decongestive therapy or the use of compression garments alone. Compared with compression garment use, complete decongestive therapy resulted in a significantly greater absolute reduction in arm volume (250 versus 142 mL), but the mean reduction in arm volume was not significantly different (29 versus 23 percent). There were no differences in severe adverse events, which consisted of a temporary rash or mild to moderate pain in the affected arm.

The following physical therapy services are not considered for payment:

Services not related to the written treatment plan

Services that do not require the professional skills of a physician or a physical therapist to perform or supervise them.

The use of processed nerve allograft for the repair and closure of peripheral nerve gaps is considered investigational.

The use of synthetic nerve conduits for the repair and closure of peripheral nerve gaps is considered investigational.

Remote electrical neuromodulation for acute migraine is considered investigational.

Carbon dioxide (CO2) fractional laser ablation treatment of hypertrophic scars or keloids for functional improvement is considered investigational.

Therapy for the treatment of dysphagia is considered medically necessary and proceeds for payment when any of the following criteria are met:

• Weight loss or malnutrition due to inability to obtain adequate nutrition orally, or

• History of, or being at high risk of, recurring aspirations or suffocation, or

• The patient is unable to swallow and has a nasogastric tube or gastrostomy for feeding.

Dysphagia therapy does not apply for payment for all other indications, since its effectiveness for indications other than those mentioned above has not been established.

Esophageal dilation proceeds for payment for the treatment of symptomatic obstruction of the esophagus.

Esophageal dilation for the treatment of non-obstructive esophageal dysphagia is not applicable for payment, since its efficacy has not been established.

The placement of a stent may be considered for payment in cases of refractory stenosis (it can not be dilated to an adequate diameter), such as malignant esophageal strictures.

The following interventions, but not limited to these alone, do not proceed for payment for the treatment of dysphagia because their efficacy in these indications has not been established:

• Botulinum toxin

• Electrical stimulation

• Pharyngeal motor cortex stimulation

• Repetitive transcranial magnetic stimulation

Radiofrequency coblation tenotomy is considered investigational as a treatment for musculoskeletal conditions, including but not limited to the following conditions:

plantar fasciitis
lateral epicondylitis
shoulder or rotator cuff tendinopathy
Achilles tendinopathy
patellar tendinopathy
wrist tendinopathy

The use of adipose-derived stem cells in autologous fat grafting to the breast is considered investigational.

Breast reconstructive surgery using allogeneic acellular dermal matrix productsa (including each of the following: AlloDerm®, AlloMend®, Cortiva® [AlloMax™], DermACELL™, DermaMatrix™, FlexHD®, FlexHD® Pliable™, GraftJacket®; see Policy Guidelines) may be considered medically necessary:

when there is insufficient tissue expander or implant coverage by the pectoralis major muscle and additional coverage is required,

when there is viable but compromised or thin postmastectomy skin flaps that are at risk of dehiscence or necrosis, or

the inframammary fold and lateral mammary folds have been undermined during mastectomy and reestablishment of these landmarks is needed.

Treatment of chronic, noninfected, full-thickness diabetic lower-extremity ulcers using the following tissue-engineered skin substitutes may be considered medically necessary:

AlloPatch®a

Apligraf®b

Dermagraft®b

Integra® Omnigraft™ Dermal Regeneration Matrix (also known as Omnigraft™) and Integra Flowable Wound Matrix.

Treatment of chronic, noninfected, partial- or full-thickness lower-extremity skin ulcers due to venous insufficiency, which have not adequately responded following a 1-month period of conventional ulcer therapy, using the following tissue-engineered skin substitutes may be considered medically necessary:

Apligraf®b

Oasis™ Wound Matrixc.

Treatment of dystrophic epidermolysis bullosa using the following tissue-engineered skin substitutes may be considered medically necessary:

OrCel™ (for the treatment of mitten-hand deformity when standard wound therapy has failed and when provided in accordance with the humanitarian device exemption [HDE] specifications of the U.S. Food and Drug Administration [FDA])d.

Treatment of second- and third-degree burns using the following tissue-engineered skin substitutes may be considered medically necessary:

Epicel® (for the treatment of deep dermal or full-thickness burns comprising a total body surface area ≥30% when provided in accordance with the HDE specifications of the FDA)d

Integra® Dermal Regeneration Templateb.

a Banked human tissue.
b FDA premarket approval.
c FDA 510(k) clearance.
d FDA-approved under an HDE.

All other uses of the bioengineered skin and soft tissue substitutes listed above are considered investigational.

All other skin and soft tissue substitutes not listed above are considered investigational, including, but not limited to:

ACell® UBM Hydrated/Lyophilized Wound Dressing

AlloSkin™

AlloSkin™ RT

Aongen™ Collagen Matrix

Architect® ECM, PX, FX

ArthroFlex™ (Flex Graft)

AxoGuard®Nerve Protector (AxoGen)

Biobrane®/Biobrane-L

Bio-ConneKt® Wound Matrix

CollaCare®

CollaCare® Dental

Collagen Wound Dressing (Oasis Research)

CollaGUARD®

CollaMend™

CollaWound™

Coll-e-derm

Collexa®

Collieva®

Conexa™

Coreleader Colla-Pad

CorMatrix®

Cymetra™ (Micronized AlloDerm)™

Cytal™ (previously MatriStem®)

Dermadapt™ Wound Dressing

Derma-gide

DermaPure™

DermaSpan™

DressSkin

Durepair Regeneration Matrix®

Endoform Dermal Template™

ENDURAGen™

Excellagen®

ExpressGraft™

E-Z Derm™

FlowerDerm™

GammaGraft

Geistlich Derma-Gide™

GraftJacket® Xpress, injectable

Helicoll™

hMatrix®

Hyalomatrix®

Hyalomatrix® PA

InnovaMatrix

Integra™ Bilayer Wound Matrix

Integra® Matrix Wound Dressing (previously Avagen)

InteguPly®

Keramatrix®

Kerecis™ Omega3

Keroxx™

MatriDerm®

MatriStem

Matrix HD™

MicroMatrix®

Miroderm®

Mediskin®

MemoDerm™

Microderm® biologic wound matrix

MyOwn skin

Oasis® Burn Matrix

Oasis® Ultra

Ologen™ Collagen Matrix

Omega3 Wound (originally Merigen wound dressing)

Permacol™

PriMatrix™

PriMatrix™ Dermal Repair Scaffold

Progenamatrix

Puracol® and Puracol® Plus Collagen Wound Dressings

PuraPly™ Wound Matrix (previously FortaDerm™)

PuraPly™ AM (Antimicrobial Wound Matrix)

Puros® Dermis

RegenePro™

Repliform®

ReCell®

Repriza™

SkinTE™

StrataGraft®

Strattice™

Suprathel®

SurgiMend®

Talymed®

TenoGlide™

TenSIX™ Acellular Dermal Matrix

TissueMend

TheraForm™ Standard/Sheet

TheraSkin®

TransCyte™

TruSkin™

Veritas® Collagen Matrix

XCM Biologic® Tissue Matrix

XenMatrix™ AB.

Laser interstitial thermal therapy (LITT) is considered investigational for all neurological indications, including but not limited to individuals with primary or metastatic brain tumors, radiation necrosis, and drug-resistant epilepsy.

The use of a temporarily implanted nitinol device (eg, iTind) is considered investigational as a treatment of lower urinary tract symptoms due to benign prostatic hyperplasia.

Allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:

poor- to intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) (see Policy Guidelines section for information on risk stratification); or

AML that is refractory to standard induction chemotherapy but can be brought into CR with intensified induction chemotherapy; or

AML that relapses following chemotherapy-induced CR1 but can be brought into CR2 or beyond with intensified induction chemotherapy; or

AML in individuals who have relapsed following a prior autologous HCT but can be brought into CR with intensified induction chemotherapy and are medically able to tolerate the procedure.

Allogeneic HCT using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of AML in individuals who are in complete marrow and extramedullary remission (CR1 or beyond), and who for medical reasons would be unable to tolerate a myeloablative conditioning regimen (see Policy Guidelines section).

Autologous HCT may be considered medically necessary to treat AML in CR1 or beyond, or relapsed AML, if responsive to intensified induction chemotherapy in individuals who are not candidates for allogeneic HCT.

Allogeneic and autologous HCT are investigational in individuals not meeting any of the above criteria.

Allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen may be considered medically necessary as a treatment of chronic myeloid leukemia.

Allogeneic HCT using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of chronic myeloid leukemia in patients who meet clinical criteria for an allogeneic HCT but who are not considered candidates for a myeloablative conditioning allogeneic HCT.

Autologous HCT is investigational as a treatment of chronic myeloid leukemia.

Autologous hematopoietic cell transplantation (HCT) may be considered medically necessary in patients with primary refractory or relapsed Hodgkin lymphoma.

Allogeneic HCT, using either myeloablative or reduced-intensity conditioning regimens, may be considered medically necessary in patients with primary refractory or relapsed Hodgkin lymphoma.

Second autologous HCT for relapsed lymphoma after a prior autologous HCT is considered investigational.

Tandem autologous HCT is considered investigational in patients with Hodgkin lymphoma.

Other uses of HCT in patients with Hodgkin lymphoma are considered investigational, including, but not limited to, initial therapy for newly diagnosed disease to consolidate a first complete remission.

Mesenchymal stem cell therapy is considered investigational for all orthopedic applications, including use in repair or regeneration of musculoskeletal tissue.

Allograft bone products containing viable stem cells, including but not limited to demineralized bone matrix with stem cells, are considered investigational for all orthopedic applications.

Allograft or synthetic bone graft substitutes that must be combined with autologous blood or bone marrow are considered investigational for all orthopedic applications.

Childhood Acute Lymphoblastic Leukemia

Autologous or allogeneic hematopoietic cell transplantation (HCT) may be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high-risk of relapse (for definition of high-risk factors, see Policy Guidelines section).

Autologous or allogeneic HCT may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL.

Allogeneic HCT is considered medically necessary to treat relapsing ALL after a prior autologous HCT in children.

Adult Acute Lymphoblastic Leukemia

Autologous HCT may be considered medically necessary to treat adult ALL in first complete remission but at high-risk of relapse (for definition of high-risk factors, see Policy Guidelines section).

Allogeneic HCT may be considered medically necessary to treat adult ALL in first complete remission for any risk level (for definition of risk factors, see Policy Guidelines section).

Allogeneic HCT may be considered medically necessary to treat adult ALL in second or greater remission, or in adults with relapsed or refractory ALL.

Autologous HCT is investigational to treat adult ALL in second or greater remission or those with refractory disease.

Allogeneic HCT is considered medically necessary to treat relapsing adult ALL after a prior autologous HCT.

Reduced-intensity conditioning allogeneic HCT may be considered medically necessary as a treatment of ALL in patients who are in complete marrow and extramedullary first or second remission, and who, for medical reasons (see Policy Guidelines section), would be unable to tolerate a standard myeloablative conditioning regimen.

Cranial electrotherapy stimulation (also known as cranial electrostimulation therapy) is investigational in all situations.

Electrical stimulation of auricular acupuncture points is investigational in all situations.

Allogeneic hematopoietic cell transplantation is considered medically necessary to treat chronic lymphocytic leukemia or small lymphocytic lymphoma in individuals with markers of poor-risk disease (see Policy Guidelines and Rationale sections). Use of a myeloablative or reduced-intensity pretransplant conditioning regimen should be individualized based on factors that include age, the presence of comorbidities, and disease burden.

Autologous hematopoietic cell transplantation is considered investigational to treat chronic lymphocytic leukemia or small lymphocytic lymphoma.

For individuals with non-Hodgkin lymphoma (NHL) B-cell subtypes considered aggressive (except mantle cell lymphoma), either allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen or autologous HCT may be considered medically necessary:

as salvage therapy for individuals who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy;

to achieve or consolidate a CR for those in a chemosensitive first or subsequent relapse; or

to consolidate a first CR in individuals with diffuse large B-cell lymphoma, with an age-adjusted International Prognostic Index score that predicts a high- or high-intermediate risk of relapse.

For individuals with mantle cell lymphoma:

Autologous HCT may be considered medically necessary to consolidate a first remission.

Allogeneic HCT, with myeloablative or reduced-intensity conditioning, may be considered medically necessary as salvage therapy.

Autologous HCT is considered investigational as salvage therapy.

Allogeneic HCT is considered investigational to consolidate a first remission.

For individuals with NHL B-cell subtypes considered indolent, either allogeneic HCT using a myeloablative conditioning regimen or autologous HCT may be considered medically necessary:

as salvage therapy for individuals who do not achieve CR after first-line treatment (induction) with a full course of standard-dose chemotherapy; or

to achieve or consolidate CR for those in a first or subsequent chemosensitive relapse, whether or not their lymphoma has transformed to a higher grade.

Either autologous HCT or allogeneic HCT is considered investigational:

as initial therapy (ie, without a full course of standard-dose induction chemotherapy) for any NHL;

to consolidate a first CR for individuals with diffuse large B-cell lymphoma and an International Prognostic Index score that predicts a low- or low-intermediate risk of relapse;

to consolidate a first CR for those with indolent NHL B-cell subtypes.

For individuals with mature T-cell or natural killer cell (peripheral T-cell) neoplasms:

Autologous HCT may be considered medically necessary to consolidate a first CR in high-risk subtypes (see Policy Guidelines section).

Autologous or allogeneic HCT (with myeloablative or reduced-intensity conditioning) may be considered medically necessary as salvage therapy.

Allogeneic HCT is considered investigational to consolidate a first remission.

For individuals with hepatosplenic T-cell lymphoma:

Allogenic HCT may be considered medically necessary to consolidate a first CR or partial response.

Autologous HCT may be considered medically necessary to consolidate a first response if a suitable donor is not available or for individuals who are ineligible for allogeneic HCT.

Autologous or allogeneic HCT as initial therapy (i.e., without a full course of standard-dose induction chemotherapy) is considered investigational.

Reduced-intensity conditioning with allogeneic HCT may be considered medically necessary as a treatment of NHL in individuals who meet criteria for an allogeneic HCT but who do not qualify for a myeloablative allogeneic HCT (see Policy Guidelines section).

Tandem transplants are considered investigational to treat patients with any stage, grade, or subtype of NHL.

Note: Small lymphocytic lymphoma may be considered a node-based variant of chronic lymphocytic leukemia. Therefore, small lymphocytic lymphoma is considered along with chronic lymphocytic leukemia in evidence review 08.001.047. Lymphoplasmacytic lymphoma/Waldenström macroglobulinemia is considered in evidence review 08.001.054.

Autologous or allogeneic hematopoietic cell transplantation (HCT) is considered investigational as a treatment of autoimmune diseases, including, but not limited to, the following:

multiple sclerosis

systemic lupus erythematosus

juvenile idiopathic or rheumatoid arthritis

chronic inflammatory demyelinating polyneuropathy

type 1 diabetes.

Autologous HCT is considered medically necessary as a treatment of systemic sclerosis (scleroderma) if all of the following conditions are met:

adult individuals <60 years of age; AND maximum duration of condition of 5 years; AND modified Rodnan skin scores>15; AND

internal organ involvement as noted in the Policy Guidelines; AND

history of <6 months treatment with cyclophosphamide; AND no active gastric antral vascular ectasia; AND do not have any exclusion criteria as noted in the Policy Guidelines. Autologous HCT as a treatment of systemic sclerosis/scleroderma not meeting the above criteria is considered investigational.

Autologous hematopoietic cell transplantation may be considered medically necessary to treat primary systemic amyloidosis.

Allogeneic hematopoietic cell transplantation is considered investigational to treat primary systemic amyloidosis.

Tisagenlecleucel for B-cell Acute Lymphoblastic Leukemia

Tisagenlecleucel is considered medically necessary for individuals with B-cell acute lymphoblastic leukemia if they meet criteria 1 through 7 :

Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts).

Meet any one of the following:

Relapsed disease defined as the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant.

Refractory disease defined as failure to obtain complete response with induction therapy (ie, failure to eradicate all detectable leukemia cells [< 5% blasts] from the bone cellularity and normal peripheral blood counts). When Philadelphia chromosome-positive: failure of 2 tyrosine kinase inhibitors. Are up to 25 years of age at the time of infusion Have not received prior CD19-directed chimeric antigen receptor T-cell treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy. Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis. Do not have any of the following: Burkitt lymphoma. Active hepatitis B, C, or any uncontrolled infection. Grade 2 to 4 graft-versus-host disease. Concomitant genetic syndrome associated with bone marrow failure with the exception of Down syndrome. Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to tisagenlecleucel infusion. Active central nervous system acute lymphoblastic leukemia (ie, white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts). Tisagenlecleucel for Non-Hodgkin Lymphoma Tisagenlecleucel is considered medically necessary for individuals with large B-cell lymphoma if they meet criteria 1 through 7 : Histologically confirmed diagnosis of diffuse large B-cell lymphoma not otherwise specified, high grade B-cell lymphoma, or diffuse large B-cell lymphoma arising from follicular lymphoma. Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy including anti-CD20 monoclonal antibody for CD20-positive tumor and anthracycline-containing chemotherapy. When the individual has histological transformation of follicular lymphoma or nodal marginal zone lymphoma to diffuse large B-cell lymphoma: prior chemotherapy for follicular lymphoma and ≥2 chemo-immunotherapy regimens for the transformed disease. At least 18 years of age at the time of infusion. Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist. Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy. Do not have primary central nervous system lymphoma. Tisagenlecleucel is considered investigational for the treatment of relapsed or refractory primary mediastinal large B-cell lymphoma. Tisagenlecleucel for Follicular Lymphoma Tisagenlecleucel is considered medically necessary for individuals with follicular lymphoma if they meet criteria 1 through 6: Histologically confirmed diagnosis of follicular lymphoma. Relapsed or refractory disease as defined as progression after ≥2 lines of systemic therapy for follicular lymphoma. At least 18 years of age at the time of infusion. Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist. Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy. Do not have primary central nervous system lymphoma. Axicabtagene Ciloleucel for Non-Hodgkin Lymphoma Axicabtagene ciloleucel is considered medically necessary for individuals with large B-cell lymphoma if they meet criteria 1 through 5: Meet any one of the following: Histologically confirmed diagnosis of large B-cell lymphoma that is considered relapsed or primary refractory within 12 months following completion of first-line chemo-immunotherapy that included an anti-CD20 monoclonal antibody and anthracycline-containing regimen. Histologically confirmed diagnosis of diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, or diffuse B-cell lymphoma arising from follicular lymphoma, and all of the following: Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy including anti-CD20 monoclonal antibody for CD20-positive tumor and anthracycline-containing chemotherapy. When the individual has histological transformation of follicular lymphoma or nodal marginal zone lymphoma to diffuse large B-cell lymphoma: prior chemotherapy for follicular lymphoma and ≥2 chemo-immunotherapy regimens for the transformed disease. At least 18 years of age at the time of infusion. Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist. Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy. Do not have primary central nervous system lymphoma. Axicabtagene Ciloleucel for Follicular Lymphoma Axicabtagene ciloleucel is considered medically necessary for individuals with follicular lymphoma if they meet criteria 1 through 6: Histologically confirmed diagnosis of follicular lymphoma. Relapsed or refractory disease defined as progression after ≥2 lines of systemic therapy for follicular lymphoma. At least 18 years of age at the time of infusion. Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist. Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy. Do not have primary central nervous system lymphoma. Brexucabtagene Autoleucel for B-cell Acute Lymphoblastic Leukemia Brexucabtagene autoleucel is considered medically necessary for individuals with B-cell acute lymphoblastic leukemia if they meet criteria 1 through 7 : Confirmed diagnosis of CD19-positive B-cell acute lymphoblastic leukemia with morphologic bone marrow tumor involvement (≥5% lymphoblasts). Meet any one of the following: Relapsed disease defined as the reappearance of leukemia cells in the bone marrow or peripheral blood after the attainment of a complete remission with chemotherapy and/or allogeneic cell transplant. Refractory disease defined as failure to obtain complete response with induction therapy (ie, failure to eradicate all detectable leukemia cells [<5% blasts] from the bone marrow and blood with subsequent restoration of normal hematopoiesis [>25% marrow cellularity and normal peripheral blood counts]).

When Philadelphia chromosome-positive: failure of tyrosine kinase inhibitors.

At least 18 years of age at the time of infusion.

Have not received prior CD19-directed chimeric antigen receptor T-cell treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy.

Have adequate organ function with no significant deterioration in organ function expected within 4 weeks after apheresis.

Do not have any of the following:

Burkitt lymphoma.

Active hepatitis B, C, or any uncontrolled infection.

Grade 2 to 4 graft-versus-host disease.

Concomitant genetic syndrome associated with bone marrow failure with the exception of Down syndrome.

Received allogeneic cellular therapy, such as donor lymphocyte infusion, within 6 weeks prior to brexucabtagene autoleucel infusion.

Active central nervous system acute lymphoblastic leukemia (ie, white blood cell count ≥5 cells/μL in cerebrospinal fluid with presence of lymphoblasts).

Brexucabtagene Autoleucel for Mantle Cell Lymphoma

Brexucabtagene autoleucel is considered medically necessary for individuals with mantle cell lymphoma if they meet criteria 1 through 5:

Histologically confirmed diagnosis of relapsed or refractory mantle cell lymphoma.

Received adequate prior therapy including anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody, and a Bruton tyrosine kinase inhibitor (ie, acalabrutinib, ibrutinib, zanubrutinib).

At least 18 years of age at the time of infusion.

Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist.

Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any other gene therapy or are being considered for treatment with any other cell therapy or any gene therapy.

Lisocabtagene Maraleucel for Non-Hodgkin Lymphoma

Lisocabtagene maraleucel is considered medically necessary for individuals with large B-cell lymphoma if they meet criteria 1 through 6:

Histologically confirmed diagnosis of large B-cell lymphoma, including diffuse large B-cell lymphoma not otherwise specified (including diffuse large B-cell lymphoma arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Meets at least one of the following:

Primary refractory or relapsed disease within 12 months of first-line chemo-immunotherapy that included an anti-CD20 monoclonal antibody and anthracycline-containing regimen.

Primary refractory or relapsed disease within 12 months of first-line chemo-immunotherapy that included an anti-CD20 monoclonal antibody and anthracycline-containing regimen and are not eligible for hematopoietic stem cell transplantation due to comorbidities or age.

Relapsed or refractory disease as defined as progression after ≥2 lines of systemic therapy including anti-CD20 monoclonal antibody for CD20-positive tumor and anthracycline-containing chemotherapy.

When the individual has histological transformation of follicular lymphoma or marginal zone lymphoma to diffuse large B-cell lymphoma: prior chemotherapy for follicular lymphoma or marginal zone lymphoma and ≥2 chemo-immunotherapy regimens for the transformed disease.

At least 18 years of age at the time of infusion.

Have adequate organ and bone marrow function as determined by the treating oncologist/hematologist.

Have not received prior CD19-directed chimeric antigen receptor T-cell therapy treatment, any other cell therapy, or any gene therapy or are being considered for treatment with any other cell therapy or any gene therapy.

Do not have primary central nervous system lymphoma.

Tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel are considered investigational when the above criteria are not met.

Tisagenlecleucel, axicabtagene ciloleucel, brexucabtagene autoleucel, and lisocabtagene maraleucel are considered investigational for all other indications.

Multitarget polymerase chain reaction testing for the diagnosis of bacterial vaginosis is considered investigational.

*** In a small subgroup of patients where a clinical diagnosis is unable to be met, either because of atypical presentations, frequent recurrence of the infection, or treatment failures. In this small subgroup of symptomatic patients, PCR testing may be considered medically necessary.

Intracellular micronutrient panel testing is considered investigational.

Nutrient/nutritional panel testing is considered investigational for all indications including but not limited to testing for nutritional deficiencies in patients with mood disorders, fibromyalgia, unexplained fatigue, and healthy individuals.

Measurement of bone turnover markers is considered investigational to determine fracture risk in patients with osteoporosis or with age-related risk factors for osteoporosis.

Measurement of bone turnover markers is considered investigational to determine response to therapy in patients who are being treated for osteoporosis.

Measurement of bone turnover markers is considered investigational in the management of patients with conditions associated with high rates of bone turnover, including but not limited to Paget disease, primary hyperparathyroidism, and renal osteodystrophy.

Fecal analysis of the following components is considered investigational as a diagnostic test for the evaluation of intestinal dysbiosis, irritable bowel syndrome, malabsorption, or small intestinal overgrowth of bacteria:

Triglycerides

Chymotrypsin

Iso-butyrate, iso-valerate, and n-valerate

Meat and vegetable fibers

Long-chain fatty acids

Cholesterol

Total short-chain fatty acids

Levels of Lactobacilli, bifidobacteria, and Escherichiacoli and other “potential pathogens,” including Aeromonas, Bacillus cereus, Campylobacter, Citrobacter, Klebsiella, Proteus, Pseudomonas, Salmonella, Shigella, Staphylococcus aureus, and Vibrio

Identification and quantitation of fecal yeast (including Candida albicans, Candida tropicalis, Rhodotorula, and Geotrichum)

N-butyrate

b-glucuronidase

pH

Short-chain fatty acid distribution (adequate amount and proportions of the different short-chain fatty acids reflect the basic status of intestinal metabolism)

Fecal secretory immunoglobulin A.

Measurement of human epididymis protein 4 is investigational for all indications.

Use of the immune cell function assay to monitor and predict immune function after solid organ transplantation is considered investigational.

Use of the immune cell function assay to monitor and predict immune function after hematopoietic cell transplantation is considered investigational.

Use of the immune cell function assay for all other indications is considered investigational.

The use of urinary tumor markers is considered investigational in the screening, diagnosis of, and monitoring for bladder cancer, or screening for precancerous colonic polyps.

Measurement of plasma levels of homocysteine is considered investigational in the screening, evaluation, and management of individualsfor cardiovascular disease.

Measurement of plasma levels of homocysteine is considered investigational in the screening, evaluation, and management of individuals with venous thromboembolism or risk of venous thromboembolism.

Ultrasonic diathermy devices for the treatment of musculoskeletal pain are considered investigational.

Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, andCEBPA variants may be considered medically necessary in cytogenetically normal acute myeloid leukemia (see Policy Guidelines section).

Genetic testing for FLT3-ITD , NPM1, and CEBPA variants is considered investigational in all other situations.

Genetic testing for FLT3 tyrosine kinase domain variants is considered investigational.

Genetic testing for FLT3, NPM1, and CEBPA variants to detect minimal residual disease is considered investigational.

Genetic testing for the diagnosis of Fanconi anemia may be considered medically necessary when the following criteria are met:

Clinical signs and symptoms of Fanconi anemia are present; AND

A definitive diagnosis of Fanconi anemia cannot be made after standard workup, ie, nondiagnostic results on chromosome breakage analysis.

Genetic testing for the diagnosis of Fanconi anemia is considered investigational when the above criteria are not met.

Genetic testing of asymptomatic individuals to determine future risk of disease may be considered medically necessary when there is a first-degree relative with a documented diagnosis of Fanconi anemia (see Policy Guidelines).

Genetic testing for Fanconi anemia is considered investigational in all other situations.

All uses of the OVA1, Overa, and ROMA tests are investigational, including but not limited to:

preoperative evaluation of adnexal masses to triage for malignancy, OR

screening for ovarian cancer, OR

selecting individuals for surgery for an adnexal mass, OR

evaluation of individuals with clinical or radiologic evidence of malignancy, OR

evaluation of individuals with nonspecific signs or symptoms suggesting possible malignancy, OR

postoperative testing and monitoring to assess surgical outcome and/or to detect recurrent malignant disease following treatment.

Genetic testing classified in one of the categories below may be considered medically necessary when all criteria are met for each category, as outlined in the Rationale section:

1.     Testing of an affected (symptomatic) individual’s germline DNA to benefit the individual (excluding reproductive testing)

a.     Diagnostic

b.     Prognostic

c.     Therapeutic

2.     Testing cancer cells of an affected individual to benefit the individual

a.     Diagnostic

b.     Prognostic

c.     Therapeutic

3.     Testing an asymptomatic individual to determine future risk of disease.

Genetic testing that does not meet the criteria for a specific category is considered investigational or not medically necessary, according to the standard definitions used for these terms (see Policy Guidelines section).

Genetic testing is considered medically necessary when the diagnosis of an inherited peripheral motor or sensory neuropathy is suspected due to signs and/or symptoms, but a definitive diagnosis cannot be made without genetic testing.

Genetic testing for an inherited peripheral neuropathy is considered investigational for all other indications.

Genetic testing for fragile X mental retardation 1 gene (FMR1) variants may be considered medically necessary for the following populations:

Individuals with characteristics of fragile X syndrome (FXS) or a fragile X-associated disorder, including:

Individuals with intellectual disability, developmental delay, or autism spectrum disorder;

Women with primary ovarian insufficiency under the age of 40 in whom fragile X-associated primary ovarian insufficiency is suspected;

Individuals with neurologic symptoms consistent with fragile X-associated tremor or ataxia syndrome.

Individuals who have a personal or family history of FXS who are seeking reproductive counseling, including:

Individuals who have a family history of FXS or a family history of undiagnosed intellectual disability;

Affected individuals or relatives of affected individuals who have had a positive cytogenetic fragile X test result who are seeking information on carrier status;

Prenatal testing of fetuses of known carrier mothers.

Genetic testing for FMR1 variants is investigational for all other uses.

Long QT Syndrome
Genetic testing to confirm a diagnosis of congenital long QT syndrome (LQTS) may be considered medically necessary when signs and/or symptoms of LQTS are present, but a definitive diagnosis cannot be made without genetic testing. This includes:

Individuals who do not meet the clinical criteria for LQTS (ie, those with a Schwartz score <4) but have a moderate-to-high pretest probability (see Policy Guidelines section) based on the Schwartz score and/or other clinical criteria. Genetic testing of asymptomatic individuals to determine future risk of LQTS may be considered medically necessary when at least one of the following criteria is met: A close relative (ie, first-, second-, or third-degree relative) with a known LQTS variant; or A close relative diagnosed with LQTS by clinical means whose genetic status is unavailable. Genetic testing for LQTS for all other situations not meeting the criteria outlined above, including but not limited to determining prognosis and/or directing therapy in individuals with known LQTS, is considered investigational. Brugada Syndrome Genetic testing to confirm a diagnosis of Brugada syndrome (BrS) may be considered medically necessary when signs and/or symptoms consistent with BrS (see Policy Guidelines section) are present, but a definitive diagnosis cannot be made without genetic testing. Genetic testing of asymptomatic individuals to determine future risk of BrS may be considered medically necessary when individuals have a close relative (ie, first-, second-, or third-degree relative) with a known BrS variant. Genetic testing for BrS for all other situations not meeting the criteria outlined above is considered investigational. Catecholaminergic Polymorphic Ventricular Tachycardia Genetic testing to confirm a diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) may be considered medically necessary when signs and/or symptoms of CPVT are present, but a definitive diagnosis cannot be made without genetic testing. Genetic testing of asymptomatic individuals to determine future risk of CPVT may be considered medically necessary when at least one of the following criteria is met: A close relative (ie, first-, second-, or third-degree relative) with a known CPVT variant; or A close relative diagnosed with CPVT by clinical means whose genetic status is unavailable. Genetic testing for CPVT for all other situations not meeting the criteria outlined above is considered investigational. Short QT Syndrome Genetic testing of asymptomatic individuals to determine future risk of short QT syndrome (SQTS) may be considered medically necessary when individuals have a close relative (ie, first-, second-, or third-degree relative) with a known SQTS variant. Genetic testing for SQTS for all other situations not meeting the criteria outlined above is considered investigational.

For testing performed as a panel, see evidence review 11.001.015.

Genetic Counseling
Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding
See the Codes table for details.

Genetic panels that use next-generation sequencing or chromosomal microarray analysis, and are classified in one of the categories below, may be considered medically necessary when all criteria are met for each category, as outlined in the Rationale section:

•         Panels for hereditary or genetic conditions

o    Diagnostic testing of an individual’s germline to benefit the individual

o    Testing of an asymptomatic individual to determine future risk of disease

•         Cancer panels

o    Testing of an asymptomatic individual to determine future risk of cancer

o    Testing cancer cells from an individual to benefit the individual by identifying targeted treatment

•         Reproductive panels

o    Preconception testing – Carrier testing of the parent(s)

o    Prenatal testing

§  Carrier testing of the parent(s)

§  In utero testing of a fetus, including testing for aneuploidy or familial variants

o    Preimplantation genetic testing.

Genetic panels that use next-generation sequencing or chromosomal microarray that do not meet the criteria for a specific category are considered investigational.

Fecal calprotectin testing may be considered medically necessary for the evaluation of individuals when the differential diagnosis is inflammatory bowel disease or noninflammatory bowel disease (including irritable bowel syndrome) for whom endoscopy with biopsy is being considered.

Fecal calprotectin testing is considered investigational in the management of inflammatory bowel disease, including the management of active inflammatory bowel disease and surveillance for relapse of disease in remission.

Testing vitamin D levels in individuals with signs and/or symptoms of vitamin D deficiency or toxicity (see Policy Guidelines section) may be considered medically necessary.

Testing vitamin D levels in asymptomatic individuals may be considered medically necessary in the following populations:

Individuals who have risk factors for vitamin D deficiency (see Policy Guidelines section).

Institutionalized individuals (see Policy Guidelines section).

Testing vitamin D levels in asymptomatic individuals is considered investigational when the above criteria are not met.

Coverage is provided in the following conditions:

• Patient is at least 13 years of age; AND

Universal Criteria

• Must be prescribed by, or in consultation with, a specialist in: allergy, immunology, hematology, pulmonology, or medical genetics; AND

• Patient does not have a history of allergy to rabbits or rabbit-derived products; AND

• Confirmation the patient is avoiding the following possible triggers for HAE attacks:

o Estrogen-containing oral contraceptive agents AND hormone replacement therapy;
AND
o Antihypertensive agents containing ACE inhibitors; AND
o Dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin); AND
o Neprilysin inhibitors (e.g., sacubitril); AND

Treatment of acute abdominal, peripheral, or facial attacks of Hereditary Angioedema (HAE)

Patient has a history of moderate to severe cutaneous attacks (without concomitant hives)OR abdominal attacks OR mild to severe airway swelling attacks of HAE (i.e. debilitating cutaneous/gastrointestinal symptoms OR laryngeal/pharyngeal/tongue swelling); AND
Patient has one of the following clinical presentations consistent with a HAE subtype§,which must be confirmed by repeat blood testing (treatment for acute attack should not bedelayed for confirmatory testing):

HAE I (C1-Inhibitor deficiency)

 Low C1 inhibitor (C1-INH) antigenic level (C1-INH antigenic level below the lower limit of
normal as defined by the laboratory performing the test); AND

 Low C4 level (C4 below the lower limit of normal as defined by the laboratory performing
the test); AND

 Low C1-INH functional level (C1-INH functional level below the lower limit of normal as
defined by the laboratory performing the test); AND

o Patient has a family history of HAE; OR

o Acquired angioedema has been ruled out (i.e., patient onset of symptoms occur prior
to 30 years old, normal C1q levels, patient does not have underlying disease such as
lymphoma or benign monoclonal gammopathy [MGUS], etc.)

HAE II (C1-Inhibitor dysfunction)

Normal to elevated C1-INH antigenic level; AND

• Low C4 level (C4 below the lower limit of normal as defined by the laboratory performing
the test); AND

• Low C1-INH functional level (C1-INH functional level below the lower limit of normal as
defined by the laboratory performing the test)

HAE with normal C1INH (formerly known as HAE III)

 Normal C1-INH antigenic level; AND

 Normal C4 level; AND

 Normal C1-INH functional level; AND

 Repeat blood testing during an attack has confirmed the patient does not have abnormal lab
values indicative of HAE I or HAE II; AND

 Either of the following:

o Patient has a known HAE-causing mutation (e.g., mutation of coagulation factor XII gene [F12 mutation], mutation in the angiopoietin-1 gene, mutation in the plasminogen gene, mutation in the kininogen 1 gene, mutation in the myoferlin gene, mutation in the heparan sulfate 3-O-sulfotransferase 6 gene, etc.); OR

o Patient has a family history of HAE and documented evidence of lack of efficacy of chronic high-dose antihistamine therapy (e.g. cetirizine standard dosing at up to four times daily or an alternative equivalent, given for at least one month or an interval long enough to expect three or more angioedema attacks) AND corticosteroids with or without omalizumab

FDA Approved Indication(s); Ф Orphan Drug

Laser treatment of port wine stains in the presence of functional impairment related to the port wine stains may be considered medically necessary. (See Benefit Application section regarding reconstructive services.) Treatment of port wine stains with lasers in combination with photodynamic therapy or topical angiogenesis inhibitors is considered investigational.

Primary hyperoxalurias are a group of rare genetic diseases. There are 3 subtypes each resulting in the overproduction of oxalate by the liver. Type 1 is the most common type, which accounts for approximately 80% of cases and occurs as a result of a genetic defect in the alanine:glyoxylate aminotransferase (AGXT) gene that encodes the enzyme alanine glyoxylate aminotransferase. Defect in the enzyme results in overproduction of oxalate, which leads to deposition of calcium oxalate crystals in the kidneys and urinary tract. The result is the formation of painful and recurrent nephrolithiasis (renal stones), nephrocalcinosis, and renal failure. Compromised renal function exacerbates the disease as the excess oxalate can no longer be effectively excreted, resulting in subsequent accumulation and crystallization in bones, eyes, skin, and heart, leading to severe illness and death. Lumasiran is a subcutaneously administered RNA interference (RNAi) therapeutic that silences the HAO1 gene, which encodes for a glycolate oxidase enzyme. By silencing the HAO1 gene, levels of glycolate oxidase are depleted, decreasing production of oxalate, the metabolite that directly contributes to the pathophysiology of primary hyperoxaluria type 1.

Patisiran Only
It is given as intravenous infusion based on body weight.

For individuals less than 100 kg: 0.3 mg/kg once every 3 weeks

For individuals weighing 100 kg or more: 30 mg once every 3 weeks.

Treatment requires premedication with intravenous corticosteroid, oral acetaminophen, intravenous H1 blocker, and intravenous H2 blocker prior to its administration to reduce the risk of infusion-related reactions. For premedications not available or not tolerated intravenously, equivalents may be administered orally.

Inotersen Only
It is given as subcutaneous injection 284 mg once weekly.

Contraindicated if platelet count is less than 100 x 109 /L or if the individual has a history of acute glomerulonephritis caused by inotersen or if the individual has a history of a hypersensitivity reaction to inotersen.

Assess platelet count prior to treatment and monitored during treatment as inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening.

Monitor alanine amino transferase, aspartate aminotransferase, and total bilirubin every 4 months during treatment and in case of symptoms of hepatic dysfunction.

Assess serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and a urinalysis prior to starting treatment as inotersen can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis dependent renal failure. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every 2 weeks. Inotersen should not be given to patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m 2, pending further evaluation of the cause.

Inotersen is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program, because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis. Important requirements of REMS program include:

Prescribers must be certified within the program by enrolling and completing training.

Individuals must enroll in the program and comply with ongoing monitoring requirements.

Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive inotersen.

Vutrisiran Only
It is given as subcutaneous injection.

25 mg once every 3 months (Quarterly)

Injection should be administered by a healthcare professional.

Patisiran, Inotersen, and Vutrisiran
Treatment leads to a decrease in serum vitamin A levels and therefore vitamin A supplementation at the recommended daily allowance is advised. Individuals should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Tafamidis and Tafamidis Meglumine
The recommended dose for tafamidis meglumine (brand name Vyndaqel) is 80 mg orally once daily as four 20 mg capsules. The recommended dose tafamidis (brand name Vyndamax) is 61 mg orally once daily as a single 61 mg capsule. Tafamidis and tafamidis meglumine are not substitutable on a per milligram basis.

Genetic testing to confirm a diagnosis of familial hypercholesterolemia (FH) may be considered medically necessary when a definitive diagnosis is required as an eligibility criterion for specialty medications (see Policy Guidelines) and when the following criteria are met:

Genetic testing is targeted to individuals who are in an uncertain category according to clinical criteria (personal and family history, physical exam, lipid levels) (see Policy Guidelines); AND

Alternative treatment considerations are in place for individuals who have an uncertain diagnosis of FH and a negative genetic test.

Genetic testing to confirm a diagnosis of FH is considered investigational in all other situations.

Genetic testing of adults who are close relatives of individuals with FH to determine future risk of disease is considered investigational (see Policy Guidelines).

Genetic testing of children of individuals with FH to determine future risk of disease may be considered medically necessary when the following criteria are met (see Policy Guidelines):

A pathogenic variant is present in a parent; AND

General lipid screening is not recommended based on age or other factors.

Next-generation sequencing (eg clonoSEQ) to detect measurable residual disease (MRD) at a threshold of 10-4 as an alternative test in individuals with acute lymphoblastic leukemia may be considered medically necessary.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of less than 10-4 in individuals with acute lymphoblastic leukemia is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-4 as an alternative test in individuals with chronic lymphocytic leukemia may be considered medically necessary.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of less than 10-4 in individuals with chronic lymphocytic leukemia is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-5 as an alternative test in individuals with multiple myeloma may be considered medically necessary.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of less than 10-5 in individuals with multiple myeloma is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-4 in individuals with diffuse large B-cell lymphoma is considered investigational.

Next-generation sequencing (eg clonoSEQ) to detect MRD at a threshold of 10-4 in individuals with mantle cell lymphoma is considered investigational.

Next-generation sequencing to detect MRD is considered investigational in all other situations.

Adeno-associated virus vector-based gene therapy via subretinal injection with voretigene neparvovec is considered medically necessary for individuals with vision loss due to biallelic RPE65 variant-associated retinal dystrophy if they meet all of the following criteria:

Are adults (age <65 years) or children (age ≥3 years) Documentation of the following: Genetic testing confirming presence of biallelic RPE65 pathogenic variant(s) or likely pathogenic variants (see Policy Guidelines for additional details) Single RPE65 pathogenic variant or likely pathogenic variant found in the homozygous state Two RPE65 pathogenic variants or likely pathogenic variants found in the trans configuration (compound heterozygous state) by segregation analysis Presence of viable retinal cells as determined by treating physicians as assessed by optical coherence tomography imaging and/or ophthalmoscopy: An area of retina within the posterior pole of >100 μm thickness shown on optical coherence tomography, OR

≥3 disc areas of retina without atrophy or pigmentary degeneration within the posterior pole, OR

Remaining visual field within 30° of fixation as measured by III4e isopter or equivalent.

Do not have any of the following:

Pregnancy in females.

Breastfeeding.

Use of retinoid compounds or precursors that could potentially interact with the biochemical activity of the RPE65 enzyme; individuals who discontinue use of these compounds for 18 months may become eligible.

Prior intraocular surgery within 6 months.

Preexisting eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of the study. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (eg, radiotherapy of the orbit; leukemia with central nervous system/optic nerve involvement). Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced retinopathy (eg, macular edema, proliferative changes). Also excluded would be subjects with immunodeficiency (acquired or congenital) because they could be susceptible to opportunistic infection (eg, cytomegalovirus retinitis).

Other applications of voretigene neparvovec are considered investigational.

Genetic testing for neurofibromatosis type 1 (NF1) or neurofibromatosis type 2 (NF2) pathogenic variants may be considered medically necessary when a diagnosis of neurofibromatosis is clinically suspected due to signs of disease, but a definitive diagnosis cannot be made without genetic testing.

Genetic testing for NF1 or NF2 pathogenic variants in at-risk relatives, with no signs of disease, may be considered medically necessary when a definitive diagnosis cannot be made without genetic testing AND at least one of the following criteria is met:

A close relative (ie, first-, second-, or third-degree relative) has a known NF1 or NF2 variant; or

A close relative has been diagnosed with neurofibromatosis but whose genetic status is unavailable.

Genetic testing for neurofibromatosis for all other situations not meeting the criteria outlined above is considered investigational.

Genetic testing for alpha1-antitrypsin deficiency may be considered medically necessary when either of the following conditions are met:

Individual is suspected of having alpha1-antitrypsin deficiency because of clinical factors and/or because the individual may be at high risk of having alpha1-antitrypsin deficiency due to a first-degree relative with alpha1-antitrypsin deficiency (see Policy Guidelines section); OR

Individual has a serum alpha1-antitrypsin level in the range of severe deficiency (see Policy Guidelines section).

Genetic testing for alpha1-antitrypsin deficiency is considered investigational in all other situations.

Immune globulin (also referred to as gamma globulin or immunoglobulin) is a therapeutic compound prepared from pools of plasma obtained from several thousand healthy blood donors that contains antibodies to a wide spectrum of antigens. Immune globulin has been utilized for immune deficiencies identified in individuals with inherited or acquired immunodeficiencies and is used for its capacity in combating infection as a replacement therapy and for its anti-inflammatory and immunomodulating effects. The appropriate use of immune globulin can decrease morbidity and mortality and improve quality of life.1,2

Coverage is provided in the following conditions:
• Patient is at least 13 years of age; AND
Universal Criteria

• Must be prescribed by, or in consultation with, a specialist in: allergy, immunology, hematology, pulmonology, or medical genetics; AND

• Patient does not have a history of allergy to rabbits or rabbit-derived products; AND

• Confirmation the patient is avoiding the following possible triggers for HAE attacks:
o Estrogen-containing oral contraceptive agents AND hormone replacement therapy; AND
o Antihypertensive agents containing ACE inhibitors; AND
o Dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin); AND
o Neprilysin inhibitors (e.g., sacubitril); AND

Treatment of acute abdominal, peripheral, or facial attacks of Hereditary Angioedema (HAE)
Patient has a history of moderate to severe cutaneous attacks (without concomitant hives)OR abdominal attacks OR mild to severe airway swelling attacks of HAE (i.e. debilitating cutaneous/gastrointestinal symptoms OR laryngeal/pharyngeal/tongue swelling); AND

Patient has one of the following clinical presentations consistent with a HAE subtype§,which must be confirmed by repeat blood testing (treatment for acute attack should not bedelayed for confirmatory testing):

BRCA1 and BRCA2 Testing

Genetic testing for BRCA1 or BRCA2 germline variants may be considered medically necessary to predict treatment response to PARP inhibitors (eg, olaparib [Lynparza] and talazoparib [Talzenna]) for human epidermal receptor 2 (HER2)-negative metastatic and early stage, high-risk breast cancer (see Policy Guidelines).

Genetic testing of BRCA1 or BRCA2 germline or somatic variants in individuals with breast cancer for guiding therapy is considered investigational in all other situations.

PIK3CA Testing

PIK3CA testing may be considered medically necessary to predict treatment response to alpelisib (Piqray) in individuals with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen (see Policy Guidelines).

When tumor tissue is available, use of tissue for testing is preferred but is not required (see Circulating Tumor DNA Testing below).

PIK3CA testing of tissue in individuals with breast cancer is considered investigational in all other situations.

Ki-67 Testing

Ki-67 testing to predict treatment response to abemaciclib (Verzenio) in individuals with breast cancer is considered investigational.

RET Testing

RET testing to predict treatment response to selpercatinib (Retevmo) in individuals with breast cancer is considered investigational.

BRAF Testing

BRAF testing to predict treatment response to dabrafenib (Tafinlar) plus trametinib (Mekinist) in individuals with breast cancer is considered investigational.

Circulating Tumor DNA Testing (Liquid Biopsy)

PIK3CA testing using FoundationOne Liquid CDx may be considered medically necessary to predict treatment response to alpelisib (Piqray) in individuals with hormone receptor-positive, HER2 negative advanced or metastatic breast cancer who have progressed on or after an endocrine-based regimen (see Policy Guidelines).

When tumor tissue is available, use of tissue for testing is preferred but is not required.

ESR1 testing using Guardant360 CDx may be considered medically necessary to predict treatment response to elacestrant (Orserdu) in individuals with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy (see Policy Guidelines).

Circulating tumor DNA testing in individuals with breast cancer is considered investigational in all other situations.

Circulating Tumor Cell Testing

Analysis of circulating tumor cells to select treatment in individuals with breast cancer is considered investigational.

Other

Testing for other variants may become available between policy updates.

A microprocessor-controlled knee may be considered medically necessary in individuals with transfemoral amputation who meet the following requirements:

demonstrated need for long distance ambulation at variable rates (use of the limb in the home or for basic community ambulation is not sufficient to justify provision of the computerized limb over standard limb applications) OR demonstrated patient need for regular ambulation on uneven terrain or for regular use on stairs (use of the limb for limited stair climbing in the home or employment environment is not sufficient evidence for prescription of this device over standard prosthetic application); AND

physical ability, including adequate cardiovascular and pulmonary reserve, for ambulation at faster than normal walking speed; AND

adequate cognitive ability to master use and care requirements for the technology.

A microprocessor-controlled knee is considered investigational in individuals who do not meet these criteria.

A powered knee is considered investigational.

A microprocessor-controlled or powered ankle-foot is considered investigational.

Triple-S shall evaluate readmissions, either at the claims level or during the readmission. Payment for readmissions will be adjusted according to the outcome.

Coverage eligibility for Sirolimus protein-bound particles (Fyarro) will be considered when the following criteria are met:

Fyarro may be considered medically necessary in adult for Malignant perivascular epithelioid cell tumor, locally advanced unresectable or metastatic

Coverage is provided in the following conditions:

• Patient is at least 18 years of age; AND

• Patient is up to date with all vaccinations, in accordance with current immunization guidelines, prior to initiating therapy; AND

• Physician has assessed baseline disease severity utilizing an objective measure/tool; AND

Universal Criteria

• Must be prescribed by, or in consultation with, a specialist in gastroenterology; AND

• Patient does not have an active infection, including clinically important localized infections; AND

• Patient has been evaluated and screened for the presence of latent tuberculosis (TB) infection prior to initiating treatment and will receive ongoing monitoring for presence of TB during treatment; AND

• Patient is not on concurrent treatment with another TNF-inhibitor, biologic response modifier or other non-biologic agent (i.e., apremilast, tofacitinib, baricitinib, upadacitinib, etc.); AND

Crohn’s Disease

• Documented moderate to severe active disease; AND

• Documented failure, contraindication, or ineffective response at maximum tolerated doses to a minimum (3) month trial of corticosteroids or immunomodulators (e.g., azathioprine, 6- mercaptopurine, or methotrexate, etc.); OR

• Documented failure, contraindication, or ineffective response at maximum tolerated doses to a minimum (3) month trial on previous therapy with a TNF modifier such as adalimumab, certolizumab, or infliximab.

Management of Immune Checkpoint Inhibitor-Related Diarrhea/Colitis

• Patient has been receiving therapy with an immune checkpoint inhibitor (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, etc.); AND

• Patient has moderate (grade 2) to severe (grade 3-4) diarrhea or colitis related to their immunotherapy

Coverage is provided in the following conditions:

Universal Criteria

 Must not be used in combination with another anti-IgE, anti-IL4, or anti-IL5 monoclonal antibody (e.g., omalizumab, mepolizumab, reslizumab, dupilumab, etc.); AND

 Must NOT be used for either of the following:

o Treatment of other eosinophilic conditions (e.g., allergic bronchopulmonary aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome, etc.)

o Relief of acute bronchospasm or status asthmaticus; AND

Somatuline® Depot; Lanreotide may be considered medically necessary in patients 18 years of age or older and patient has not received a long-acting somatostatin analogue (e.g., Octreotide LAR depot, Lanreotide SR, Lanreotide auto-gel, pasireotide LAR depot, etc.) within the last 4 weeks; AND

Universal Criteria

Patient has not received a long-acting somatostatin analogue (e.g., Octreotide LAR depot, Lanreotide SR, Lanreotide auto-gel, pasireotide LAR depot, etc.) within the last 4 weeks; AND

Acromegaly1,2,5,6

Patient’s diagnosis is confirmed by elevated (age-adjusted) or equivocal serum IGF-1 as well as inadequate suppression of growth hormone (GH) after a glucose load; AND
Patient has documented inadequate response to surgery and/or radiotherapy or it is not an option for the patient; AND
Patient’s tumor has been visualized on imaging studies (i.e., MRI or CT-scan); AND
Baseline GH and IGF-1 blood levels (renewal will require reporting of current levels); AND
Will not be used in combination with oral octreotide

Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) 1,2

Patient has unresectable, locally advanced or metastatic disease; AND
Patient has non-functioning tumors without hormone-related symptoms; AND
Patient has well or moderately differentiated disease

Carcinoid Syndrome1,2,3

Patient has documented neuroendocrine tumors with a history of carcinoid syndrome
(flushing and/or diarrhea); AND

Used to reduce the frequency of short-acting somatostatin analog rescue therapy; OR
Used for treatment and/or control of symptoms

Neuroendocrine and Adrenal Tumors (e.g., GI Tract, Lung, Thymus, Pancreas, and Pheochromocytoma/Paraganglioma) 1,2,3,8

Used as primary treatment for unresected primary gastrinoma; OR
Used for locoregional unresectable bronchopulmonary or thymic disease as primary therapy or as subsequent therapy if progression on first-line therapy (including disease progression on prior treatment with lanreotide in patients with functional tumors); AND

Used for management of hormone symptoms and/or somatostatin receptor positivedisease determined by imaging (i.e., 68Ga-dotatate imaging PET/CT or PET/MRI or somatostatin receptor scintigraphy); OR

Patient has distant metastatic bronchopulmonary or thymic disease; AND

Used for somatostatin receptor positive disease and/or symptomatic hormonal disease if clinically significant tumor burden and low grade (typical) histology OR evidence of progression OR intermediate grade (atypical histology); AND

Used as primary therapy or as subsequent therapy if progression on first-line therapy (including disease progression on prior treatment with lanreotide in patients with functional tumors); OR

Used for somatostatin receptor positive disease and/or hormonal symptoms if asymptomatic with low tumor burden and low grade (typical) histology; OR
Used for somatostatin receptor positive disease and/or chronic cough/dyspnea that is notresponsive to inhalers with multiple lung nodules or tumorlets and evidence of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH); OR

Used for the management of locoregional advanced or distant metastatic disease of the gastrointestinal tract; AND

Patient is asymptomatic with a low tumor burden; OR
Patient with a clinically significant tumor burden; OR
Patient has disease progression and is not already receiving lanreotide; OR
Patient has disease progression with functional tumors and will be continuing treatment with lanreotide; OR

Used to manage symptoms related to hormone hypersecretion of locoregional neuroendocrine tumors of the pancreas (well differentiated grade 1/2); AND

Patient has gastrinoma, glucagonoma, or VIPoma; OR

Used for tumor control of locoregional advanced and/or distant metastatic neuroendocrine tumors of the pancreas (well differentiated grade 1/2 – Gastrinoma, Glucagonoma, Insulinoma, VIPoma ) [***NOTE: for insulinoma ONLY, patient must have somatostatin-receptor positive disease]; AND

Patient is asymptomatic with a low tumor burden and stable disease; OR
Patient is symptomatic; OR
Patient has a clinically significant tumor burden; OR
Patient has clinically significant progression and is not already receiving lanreotide; OR

Patient has unresectable locally advanced or metastatic neuroendocrine tumors (well differentiated grade 3); AND

Patient has favorable biology (e.g., relatively low Ki-67 [<55%], somatostatin receptorpositive disease); OR Patient has pheochromocytoma or paraganglioma; AND Patient has symptomatic locally unresectable somatostatin receptor-positive disease; OR Patient has distant metastatic disease

Coverage is provided in the following conditions:

Universal Criteria

 Must not be used in combination with another anti-IgE, anti-IL4, or anti-IL5 monoclonal antibody (e.g., benralizumab, omalizumab, reslizumab, dupilumab, etc.); AND

Severe Asthma

 Patient is at least 6 years of age; AND

 Patient must have severe* disease; AND

 Patient must have asthma with an eosinophilic phenotype defined as blood eosinophils ≥300 cells/µL within previous 12 months or ≥150 cells/µL within 6 weeks of dosing; AND

 Must be used for add-on maintenance treatment in patients regularly receiving BOTH of the following:

o Medium to high-dose inhaled corticosteroids; AND

o An additional controller medication (e.g., long-acting beta agonist, leukotriene modifiers, etc.); AND

 Will not be used for treatment of acute bronchospasm or status asthmaticus; AND

 Patient must have two or more exacerbations in the previous year requiring daily oral corticosteroids for at least 3 days (in addition to the regular maintenance therapy defined above); AND

 Baseline measurement of at least one of the following for assessment of clinical status:

o Use of systemic corticosteroids

o Use of inhaled corticosteroids

o Number of hospitalizations, ER visits, or unscheduled visits to healthcare provider due to condition

o Forced expiratory volume in 1 second (FEV1)

Eosinophilic Granulomatosis with Polyangiitis (EGPA)/Churg-Strauss Syndrome

 Patient is at least 18 years of age; AND

 Patient has a confirmed diagnosis of EGPA§ (aka Churg-Strauss Syndrome); AND

 Patient must have blood eosinophils ≥150 cells/µL within 6 weeks of dosing; AND

 Patient has been on stable doses of concomitant oral corticosteroid therapy for at least 4 weeks (i.e., prednisone or prednisolone at a dose of 7.5 mg/day); AND

 Physician has assessed baseline disease severity utilizing an objective measure/tool (e.g., Birmingham Vasculitis Activity Score [BVAS], history of asthma symptoms and/or exacerbations, duration of remission, or rate of relapses, etc.)

Hypereosinophilic Syndrome (HES)

 Patient is at least 12 years of age; AND

 Patient has been diagnosed with HES for at least 6 months prior to starting treatment; AND

 Patient does NOT have non-hematologic secondary HES (e.g., drug hypersensitivity, parasitic helminth infection, HIV infection, non-hematologic malignancy) or FIP1L1- PDGFRα kinase-positive HES; AND

 Patient has a history of 2 or more HES flares within the previous 12 months (e.g., documented HES-related worsening of clinical symptoms or blood eosinophil counts requiring an escalation in therapy); AND

 Patient must have blood eosinophils ≥1000 cells/µL within 4 weeks of dosing; AND

 Used in combination with stable doses of at least one other HES therapy (e.g., oral corticosteroids, immunosuppressive agents, cytotoxic therapy, etc.)

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

 Patient is at least 18 years of age; AND

 Patient has bilateral symptomatic sino-nasal polyposis with symptoms lasting at least 8 weeks; AND

 Patient has failed on at least 8 weeks of intranasal corticosteroid therapy; AND

 Patient has at least four (4) of the following indicators for biologic treatment [Note: Patients with a history of sino-nasal surgery are only required to have at least three (3) of the indicators]:

o Patient has evidence of type 2 inflammation (i.e., biological biomarkers indicating immune dysregulation and epithelial barrier dysfunction)

o Patient has required two or more short courses of systemic corticosteroids within the previous year o Disease significantly impairs the patient’s quality of life o Patient has experienced significant loss of smell o Patient has a comorbid diagnosis of asthma; AND

 Patient does not have any of the following:

o Antrochoanal polyps o Nasal septal deviation that would occlude at least one nostril

o Disease with lack of signs of type 2 inflammation o Cystic fibrosis o Mucoceles; AND

 Other causes of nasal congestion/obstruction have been ruled out (e.g., acute sinusitis, nasal infection or upper respiratory infection, rhinitis medicamentosa, tumors, infections, granulomatosis, etc.); AND

 Physician has assessed baseline disease severity utilizing an objective measure/tool; AND

 Therapy will be used in combination with intranasal corticosteroids unless not able to tolerate or is contraindicated

Coverage is provided in the following conditions:

 Patient is 18 years or older (unless otherwise specified); AND

 Patient has been screened for the presence of Hepatitis B virus (HBV) prior to initiating treatment AND does not have active disease (i.e., positive HBsAg and anti-HBV tests); AND

 Patient has baseline serum immunoglobulins assessed; AND

Universal Criteria

 Patient will not receive live vaccines concurrently with ocrelizumab; AND

 Patient does not have an active infection; AND

Multiple Sclerosis

 Patient must have a confirmed diagnosis* of multiple sclerosis (MS) as documented by laboratory report (i.e., MRI); AND

 Must be used as single agent therapy; AND

o Patient has a diagnosis of a relapsing form of MS [i.e., relapsing-remitting MS (RRMS)*, active secondary progressive disease (SPMS)**, or clinically isolated syndrome (CIS)***]; OR

o Patient has a diagnosis**** of primary progressive MS (PPMS); AND

 Patient is less than 65 years; AND

 Patient has an expanded disability status scale (EDSS) score of ≤ 6.5 † FDA Approved Indication(s)

Coverage is provided in the following conditions:

Patient is at least 18 years of age, unless otherwise specified; AND

Universal Criteria 1

Patient has been evaluated and screened for the presence of latent tuberculosis (TB) infection prior to initiating treatment and will receive ongoing monitoring for presence of TB during treatment; AND
Patient does not have an active infection, including clinically important localized infections; AND
Patient will not receive live vaccines during therapy; AND
Patient is not on concurrent treatment with another TNF inhibitor, biologic response modifier or other non-biologic agent (i.e., apremilast, tofacitinib, baricitinib); AND

Rheumatoid Arthritis (RA) 1-4,9-11,17

Must be prescribed by, or in consultation with, a specialist in rheumatology; AND
Documented moderate to severe active disease; AND
Patient has had at least a 3 month trial and failed of previous therapy with ONE oral disease modifying anti-rheumatic agent (DMARD) such as methotrexate, azathioprine, auranofin, hydroxychloroquine, penicillamine, sulfasalazine, leflunomide, etc.; AND
Prescribed in combination with methotrexate unless contraindicated

Psoriatic Arthritis (PsA) 5,6,8,18

Patient is at least 2 years of age; AND
Must be prescribed by, or in consultation with, a specialist in dermatology or rheumatology; AND
Documented moderate to severe active disease; AND

For patients with predominantly axial disease OR active enthesitis, a trial and failure of at least a 4 week trial of ONE non-steroidal anti-inflammatory agents (NSAIDs), unless use is contraindicated; OR
For patients with peripheral arthritis or dactylitis, a trial and failure of at least a 3 month trial of ONE oral disease-modifying anti-rheumatic agent (DMARD) such as methotrexate, azathioprine, sulfasalazine, or hydroxychloroquine

Ankylosing Spondylitis (AS) 7,12,19

Must be prescribed by, or in consultation with, a specialist in rheumatology; AND
Documented active disease; AND
Patient had an adequate trial and failure of at least TWO (2) non-steroidal anti-inflammatory agents (NSAIDs) over 4 weeks (in total), unless use is contraindicated

Polyarticular Juvenile Idiopathic Arthritis (pJIA) 14

Patient is at least 2 years of age; AND
Documented moderate to severe active polyarticular disease; AND
May be used alone or in combination with methotrexate; AND
Patient has had at least a 1-month trial and failure (unless contraindicated or intolerant) of previous therapy with either oral non-steroidal anti-inflammatory drugs (NSAIDs) OR an oral disease-modifying anti-rheumatic agent (DMARD) (e.g., methotrexate, leflunomide, sulfasalazine, etc.)

Stelara® (ustekinumab) may be considered medically necessary if the following conditions are met:

Patient is at least 18 years of age (unless otherwise specified); AND
Physician has assessed baseline disease severity utilizing an objective measure/tool; AND
Patient is up to date with all age-appropriate vaccinations, in accordance with current vaccination guidelines, prior to initiating therapy; AND
Patient has been evaluated and screened for the presence of latent tuberculosis (TB) infection prior to initiating treatment and will receive ongoing monitoring for presence of TB during treatment; AND
Patient does not have an active infection, including clinically important localized infections; AND
Patient will not receive live vaccines during therapy; AND
Patient is not on concurrent treatment with a TNF-inhibitor, biologic response modifier or other non-biologic agent (i.e., apremilast, tofacitinib, baricitinib, upadacitinib, etc.); AND

Universal Criteria

• Patient has been evaluated and screened for the presence of latent tuberculosis (TB) infection prior to initiating treatment and will receive ongoing monitoring for presence of TB during treatment; AND

• Patient does not have an active infection, including clinically important localized infections; AND

• Patient will not receive live vaccines during therapy; AND

• Patient is not on concurrent treatment with a TNF-inhibitor, biologic response modifier or other non-biologic agent (i.e., apremilast, tofacitinib, baricitinib, upadacitinib, etc.); AND

Adult Plaque Psoriasis (PsO) 1,30,45-48

Documented moderate to severe plaque psoriasis for at least 6 months with at least one of the following:

Involvement of at least 3% of body surface area (BSA); OR
Psoriasis Area and Severity Index (PASI) score of 10 or greater; OR
Incapacitation or serious emotional consequences due to plaque location (i.e., hands, feet, head and neck, genitalia, etc.) or with intractable pruritis; AND

Patient did not respond adequately (or is not a candidate) to a 4 week minimum trial of topical agents (i.e., anthralin, coal tar preparations, corticosteroids, emollients, immunosuppressives, keratolytics, retinoic acid derivatives, and/or vitamin D analogues); AND
Patient did not respond adequately (or is not a candidate) to a 3 month minimum trial of at least one non-biologic systemic agent (i.e., immunosuppressives, retinoic acid derivatives, and/or methotrexate); AND
Patient did not respond adequately (or is not a candidate*) to a 3 month minimum trial of phototherapy (i.e., psoralens with UVA light [PUVA] or UVB with coal tar or dithranol)

Pediatric Plaque Psoriasis (PsO) 1,30,45-49

Patient is at least 6 years of age; AND
Documented moderate to severe plaque psoriasis for at least 6 months with at least one of the following:

Involvement of at least 3% of body surface area (BSA); OR
Psoriasis Area and Severity Index (PASI) score of 10 or greater; OR
Incapacitation or serious emotional consequences due to plaque location (i.e., hands, feet, head and neck, genitalia, etc.) or with intractable pruritis; AND

Patient did not respond adequately (or is not a candidate) to a 4 week minimum trial of topical agents (i.e., anthralin, coal tar preparations, corticosteroids, emollients, immunosuppressives, keratolytics, retinoic acid derivatives, and/or vitamin D analogues); AND
Patient did not respond adequately (or is not a candidate) to a 3 month minimum trial of at least one non-biologic systemic agent (i.e., immunosuppressives, retinoic acid derivatives, and/or methotrexate); AND
Patient did not respond adequately (or is not a candidate*) to a 3 month minimum trial of phototherapy (i.e., psoralens with UVA light [PUVA] or UVB with coal tar or dithranol

Adult Psoriatic Arthritis (PsA) 1,9,33,50

Documented moderate to severe active disease; AND

For patients with predominantly axial disease OR active enthesitis, a trial and failure of at least a 4 week trial of ONE (1) non-steroidal anti-inflammatory agent (NSAID), unless use is contraindicated; OR
For patients with peripheral arthritis or dactylitis, a trial and failure of at least a 3 month trial of ONE (1) oral disease-modifying anti-rheumatic agent (DMARD) such as methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, etc.

Juvenile Psoriatic Arthritis (PsA) 1,51,52

Patient is at least 6 years of age; AND
Documented moderate to severe active polyarticular disease; AND
May be used as a single agent or in combination with methotrexate; AND
Patient has had at least a 1-month trial and failure (unless contraindicated or intolerant) of previous therapy with either oral non-steroidal anti-inflammatory drugs (NSAIDs) OR an oral disease-modifying anti-rheumatic agent (DMARD) (e.g., methotrexate, leflunomide, sulfasalazine, etc.)

Crohn’s Disease 1,10-12,14,18,24

Documented moderate to severely active disease; AND
Documented failure, contraindication, or ineffective response at maximum tolerated doses to a minimum (3) month trial of corticosteroids or immunomodulators (e.g., azathioprine, 6-mercaptopurine, or methotrexate)

Ulcerative Colitis 1,13,19-23,29

Documented moderate to severe active disease; AND

Documented failure, contraindication, or ineffective response at maximum tolerated doses to a minimum (3) month trial of corticosteroids or immunomodulators (e.g., azathioprine, 6-mercaptopurine, or methotrexate)

Management of Immune Checkpoint Inhibitor-Related Diarrhea/Colitis 35,36

Patient has been receiving therapy with an immune checkpoint inhibitor (e.g., nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, etc.); AND

Patient has mild (grade 1) diarrhea or colitis with persistent or progressive symptoms and is lactoferrin/calprotectin positive; OR
Patient has moderate (grade 2) to severe (grade 3-4) diarrhea or colitis related to their immunotherapy and is refractory to infliximab and/or vedolizumab

Initial Approval Criteria

• Patient is at least 18 years of age; AND Universal Criteria 1,13

• Prescriber and patient must be enrolled in and meet the conditions of the TOUCH program; AND

• Not used in combination with antineoplastic, immunosuppressant, or immunomodulating agents; AND

• Patient must not have a systemic medical condition resulting in significantly compromised immune system function; AND

Multiple Sclerosis

• Patient has been diagnosed with a relapsing form of multiple sclerosis [i.e. relapsingremitting disease (RRMS)*, active secondary progressive disease (SPMS)**, or clinically isolated syndrome (CIS)***]; AND

• Confirmed diagnosis of MS as documented by laboratory report (i.e. MRI); AND • Used as single agent therapy Crohn’s Disease † 1,13

• Patient has moderate to severe active disease; AND

• Physician has assessed baseline disease severity utilizing an objective measure/tool; AND

• Documented trial and failure on ONE oral immunosuppressive therapy for at least 3 months, unless use is contraindicated, such as corticosteroids, methotrexate, azathioprine, and/or 6-mercaptopurine; AND

• Documented trial and failure on ONE TNF-Inhibitor therapy for at least 3 months, unless contraindicated, such as infliximab, certolizumab, or adalimumab; AND

• Used as single agent therapy [Not used concurrently with another biologic drug or immunosuppressant (e.g., 6-mercaptopurine, azathioprine, cyclosporine, methotrexate, etc.) used for Crohn’s Disease] † FDA Approved Indication(s)

Coverage is provided in the following conditions:
• Patient is at least 18 years of age (unless otherwise specified); AND

Universal Criteria Universal Criteria

• Must not be used in combination with another anti-IL4 or anti-IL5 monoclonal antibody
(e.g., benralizumab mepolizumab, reslizumab, dupilumab, etc.); AND

Moderate-to-severe persistent al severe persistent al severe persistent allergic asthma

• Patient is at least 6 years of age; AND

• Will not be used for treatment of acute bronchospasm, status asthmaticus, or allergic conditions (other than indicated);AND

• Patient has a positive skin test or in vitro reactivity to a perennial aero-allergen; AND

• Patient must weigh between 20 kg (44 lbs.) and 150 kg (330 lbs.); AND

• Patient has a serum total IgE level, measured before the start of treatment, of either: o ≥ 30 IU/mL and ≤ 700 IU/mL in patients age ≥ 12 years; OR o ≥ 30 IU/mL and ≤ 1300 IU/mL in patients age 6 to <12 years; AND • Patient has documented ongoing symptoms of moderate-to-severe asthma* with a minimum (3) month trial on previous combination therapy including medium- or high-dose inhaled corticosteroids PLUS another controller medication (e.g., long-acting beta-2 agonist, leukotriene receptor antagonist, theophylline, etc.); AND • Baseline measurement of at least one of the following for assessment of clinical status: o Use of inhaled rescue medication o Use of inhaled or systemic corticosteroids o Reported disease severity symptoms (e.g., number of hospitalizations, ER visits, unscheduled visits to healthcare provider due to condition, asthma attacks, chest tightness or heaviness, coughing or clearing throat, difficulty taking deep breath or difficulty breathing out, shortness of breath, sleep disturbance, night wakening, or symptoms upon awakening, tiredness, wheezing/heavy breathing/fighting for air, etc.) o Forced expiratory volume in 1 second (FEV1) Chronic idiopathic urticaria (CIU) • Patient is at least 12 years of age; AND • The underlying cause of the patient’s condition is NOT considered to be any other allergic condition(s) or other form(s) of urticaria; AND • Patient is avoiding triggers (e.g., NSAIDs, etc.); AND • Documented baseline score from an objective clinical evaluation tool, such as: urticaria activity score (UAS7), angioedema activity score (AAS), Dermatology Life Quality Index (DLQI), Angioedema Quality of Life (AE-QoL), or Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL); AND • Patient had an inadequate response to a one or more month trial on previous therapy with scheduled dosing of a second-generation H1-antihistamine product**; AND • Patient had an inadequate response to a one or more month trial on previous therapy with scheduled dosing of at least one of the following: o Up-dosing/dose advancement (up to 4-fold) of a second generation H1-antihistamine** o Add-on therapy with a leukotriene antagonist (e.g., montelukast, zafirlukast, etc.) o Add-on therapy with another H1-antihistamine o Add-on therapy with a H2-antagonist (e.g. ranitidine, etc.) o Add-on therapy with cyclosporine Note: renewal will require submission of a current (within 30 days) score from an objective clinical evaluation tool (i.e., UAS7, AAS, DLQI, AE-QoL or CU-Q2oL). Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) • Patient has bilateral symptomatic sino-nasal polyposis with symptoms lasting at least 8 weeks; AND • Patient has failed at least 8 weeks of daily intranasal corticosteroid therapy; AND • Patient has at least four (4) of the following indicators for biologic treatment [Note: Patients with a history of sino-nasal surgery are only required to have at least three (3) of the indicators]: o Patient has evidence of type 2 inflammation (i.e., biological biomarkers indicating immune dysregulation and epithelial barrier dysfunction) o Patient has required two or more short courses of systemic corticosteroids within the previous year o Disease significantly impairs the patient’s quality of life o Patient has experienced significant loss of smell o Patient has a comorbid diagnosis of asthma; AND • Patient does not have any of the following: o Antrochoanal polyps o Nasal septal deviation that would occlude at least one nostril o Disease with lack of signs of type 2 inflammation o Cystic fibrosis o Mucoceles; AND • Other causes of nasal congestion/obstruction have been ruled out (e.g., acute sinusitis, nasal infection or upper respiratory infection, rhinitis medicamentosa, tumors, infections, granulomatosis, etc.); AND • Physician has assessed baseline disease severity utilizing an objective measure/tool; AND • Therapy will be used in combination with intranasal corticosteroids unless not able to tolerate or is contraindicated Management of Immune Checkpoint Inhibitor-Related Toxicity • Patient has been receiving therapy with an immune checkpoint inhibitor (e.g. nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, ipilimumab, etc.); AND • Patient has refractory and severe (i.e., grade 3: intense or widespread, constant, limiting self-care activities of daily living or sleep) pruritis; AND • Patient has an increased serum IgE level above the upper limit of normal of the laboratory reference value Systemic Mastocytosis Systemic Mastocytosis • Used for the prevention of one of the following: o Chronic mast cell mediator-related cardiovascular (e.g., pre-syncope, tachycardia, etc.) or pulmonary (e.g., wheezing, throat-swelling, etc.) symptoms insufficiently controlled by conventional therapy (e.g., H1 or H2 blockers or corticosteroids); OR o Unprovoked anaphylaxis; OR o Hymenoptera or food-induced anaphylaxis in patients with a negative test for specific IgE antibodies or a negative skin test; OR • Used to improve tolerance while on immunotherapy (i.e., venom immunotherapy [VIT])

I.            Dose rounding for infused drug products to the nearest lowest vial size if within +/- 10% of the original prescribed dose («the Recommended Dose») will be required unless the following medical necessity criteria are met:

a.       Provider indicates Recommended Dose may result in a suboptimal outcome due to one of the following:

i.      Member’s age is less than 18 years of age

ii.     Member previously demonstrated a suboptimal response to a lower rounded down dose

iii.     Member is clinically unstable and at high risk for hospitalization if the requested medication produces a suboptimal response

iv.     Member’s laboratory values indicate that a dose reduction resulted in a suboptimal response

v.      Patients with relevant enzyme deficiencies, or genetic polymorphisms may not be good candidates for dose rounding

b. All other reasons not mentioned in this policy are not considered medically necessary.

Background

The Hematology/Oncology Pharmacy Association (HOPA) establishes that rounding of biologic and cytotoxic agents within 10% of the ordered dose is designated as acceptable for routine clinical care1. Dose changes ≤ 10% are not expected to reduce the safety or effectiveness of therapy1. The rounding amount 10% is rational in the context of standard dose adjustments for patient tolerance and tumor response, and the influence of interpatient pharmacokinetic variability1. HOPA supports the use of the same threshold for dose rounding of anticancer drugs as that used for palliative and curative therapy1. HOPA recommends each institution to develop its own policy that addresses biologic and cytotoxic agents’ dose rounding1.

Dosage Rounding Calculation

If a drug is available as a 500mg vial size, and the recommended dose is 20mg/kg for an 80kg member, this is equal to a 1,600mg dose. For this member, the dose is rounded to 1,500mg (three 500mg vials), which is equivalent to only a 6% dose reduction. This dose rounding is in accordance with the statement provided in this policy.

References

1.       Fahrenbruch R, Kintzel P, Bott AM, Gilmore S, Markham R. Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association. Journal of oncology practice. 2018;14(3):e130-e136. doi:10.1200/JOP.2017.025411

2.       Horizon Healthcare of New Jersey, Inc. Drug Wastage Program. September 2022.

Policy History

Date
Action
Description

5/11/2023
Policy Crated
New Policy

Initial Approval Criteria
A. Prostate Cancer (must meet all):

1. Diagnosis of prostate cancer;

2. Request is for leuprolide acetate injection, Eligard, or Lupron Depot (7.5 mg, 22.5mg, 30 mg, 45 mg);

3. Prescribed by or in consultation with an oncologist or urologist;

4. Age ≥ 18 years;

5. Request meets one of the following (a, b, or c):*

a. Leuprolide acetate injection (SC): Dose does not exceed 1 mg per day;

b. Eligard (SC)/Lupron Depot (IM): Dose does not exceed 7.5 mg per month, 22.5mg per 3 months, 30 mg per 4 months, 45 mg per 6 months;

c. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).

*Prescribed regimen must be FDA-approved or recommended by NCCN

DOSAGE/ADMINISTRATION

Advanced Prostate Cancer

Lupron: 7.5 mg IM monthly, 22.5 mg IM every 3 months, 30 mg IM every 4 months, or 45 mg IM every 6 months

Eligard: 7.5 mg SC monthly, 22.5 mg SC every 3 months, 30 mg SC every 4 months, 45 mg SC every 6 months

Lutrate Depot: 22.5 mg SC every 3 months

Leuprolide acetate: 1 mg/0.2 mL/day SC

Camcevi: 42 mg SC every 6 months

Adakveo may be considered medically necessary in patients 16 years of age or older with vasoocclusive crises associated with sickle cell disease (SCD) and if the conditions indicated below are met. Adakveo is considered investigational in patients less than 16 years of age and for all other indications.

BEOVU is covered under the Medical Benefit when used within the following guidelines. Use outside of these guidelines may result in non-payment unless approved under an exception process.

Adakveo may be considered medically necessary in patients 16 years of age or older with vasoocclusive crises associated with sickle cell disease (SCD) and if the conditions indicated below are met. Adakveo is considered investigational in patients less than 16 years of age and for all other indications.

Initiation of Danyelza meets the definition of medical necessity when used to treat the following indication and the specific criteria below are met.

Jemperli may be considered medically necessary  if the conditions below are met.

Vascular endothelial growth factor has been implicated in the pathogenesis of a variety of ocular vascular conditions characterized by choroidal neovascularization (CNV) and macular edema.