Clinical UM Guideline


Subject:  Pharmacotherapy for Gaucher Disease
Guideline #:  CG-DRUG-08Current Effective Date:  07/15/2014
Status:RevisedLast Review Date:  05/15/2014

Description

Gaucher disease is a genetic disorder resulting in the malfunction or absence of an enzyme critical for metabolism of lipids in certain organs. Treatment focuses on either replacement of the missing or ineffective enzyme, or reduction of the substrate upon which it acts.

This document addresses the treatment of Gaucher disease with enzyme replacement therapy (ERT) using imiglucerase (Cerezyme® Genzyme, Cambridge, MA), taliglucerase alfa (ELELYSO™ Pfizer Labs, New York, NY), velaglucerase alfa (VPRIV Shire Human Genetic Therapies, Inc., Cambridge, MA), or substrate reduction therapy (SRT) with miglustat (Zavesca® Actelion Pharmaceuticals US, Inc., South San Francisco, CA).

Clinical Indications

Note: Please refer to Appendix A, "Initial Testing and Monitoring Recommendations for Gaucher Disease" for recommendations on testing and monitoring.

Medically Necessary: 

  1. Imiglucerase, taliglucerase alfa or velaglucerase alfa are considered medically necessary for the treatment of Adults (greater than or equal to 18 years of age) with type 1 Gaucher disease when the criteria below are met:
    1. The drug is used as monotherapy; AND
    2. Type 1 Gaucher disease is confirmed by either of the following:
      1. Glucocerebrosidase activity in the white blood cells or skin fibroblasts less than or equal to 30% of normal activity; or
      2. Genotype testing indicates mutation of two alleles of the glucocerebrosidase genome
        AND
    3. There are clinically significant manifestations of Gaucher disease, including any of the following:
      1. Skeletal disease as demonstrated by any of the following:
        1. Avascular necrosis; or
        2. Erlenmeyer flask deformity (failure of bone remodeling); or
        3. Lytic disease; or
        4. Marrow infiltration; or
        5. Osteopenia; or
        6. Osteosclerosis; or
        7. Pathological fracture; or
        8. Radiological evidence of joint deterioration
          or
      2. Presents with at least two of the following:
        1. Clinically significant hepatomegaly;
        2. Clinically significant splenomegaly;
        3. Hemoglobin less than or equal to 11.5 g/dL for females and less than 12.5 g/dL for males, or 1.0 g/dL below lower limit for normal for age and sex;
        4. Platelet count less than or equal to 120,000 mm3
  2. Imiglucerase or velaglucerase alfa are considered medically necessary for the treatment of Children (less than 18 years of age) with type 1 Gaucher disease when the following criteria are met:
    1. The drug is used as monotherapy;
      AND
    2. Type 1 Gaucher disease is confirmed by either of the following:
      1. Glucocerebrosidase activity in the white blood cells or skin fibroblasts less than or equal to 30% of normal activity; or
      2. Genotype testing indicates mutation of two alleles of the glucocerebrosidase genome
        AND
    3. There are clinically significant manifestations of Gaucher disease including any of the following:
      1. Abdominal or bone pain; or
      2. Hepatosplenomegaly; or
      3. Documented growth failure not associated with other conditions; or
      4. Cachexia; or
      5. Exertional limitations; or
      6. Fatigue; or
      7. Evidence of skeletal involvement, including, but not limited to, Erlenmeyer flask deformity (failure of bone remodeling); or
      8. Anemia with hemoglobin less than 2.0 g/dL below lower limit of normal for age and sex; or
      9. Platelet count less than 60,000 mm3 or documented abnormal bleeding episode(s).
  3. Imiglucerase, taliglucerase alfa, or velaglucerase alfa are considered medically necessary for the treatment of Adults (greater than or equal to 18 years of age) with type 3 Gaucher disease when the criteria below are met:
    1. The drug is used as monotherapy;
      AND
    2. Type 3 Gaucher disease is confirmed by genotype testing indicating the presence of two homozygous alleles for neuropathic Gaucher disease
      AND
    3. There are clinically significant manifestations of Gaucher disease, including any of the following:
      1. Skeletal disease as demonstrated by any of the following:
        1. Avascular necrosis; or
        2. Erlenmeyer flask deformity (failure of bone remodeling); or
        3. Lytic disease; or
        4. Marrow infiltration; or
        5. Osteopenia; or
        6. Osteosclerosis; or
        7. Pathological fracture; or
        8. Radiological evidence of joint deterioration
          or
      2. Presents with at least two of the following:
        1. Clinically significant hepatomegaly;
        2. Clinically significant splenomegaly;
        3. Hemoglobin less 1.0 g/dL below lower limit for normal for age and sex;
        4. Platelet count less than or equal to 120,000mm3.
          AND
    4. There are neurological findings consistent with type 3 Gaucher disease based on evaluation which includes all of the following tests:
      1. Neurological examination by a neurologist; and
      2. Eye movement examination by an ophthalmologist; and
      3. Neuro-ophthalmological investigation with direct ophthalmoloscopy; and
      4. Measurement of peripheral hearing (electro-acoustical emission in small children, pure tone audiometry in older individuals); and
      5. Brain Imaging, preferably by magnetic resonance imaging (MRI), or if MRI is unavailable, by computed tomography; and
      6. Electroencephalography (EEG); and
      7. Diagnostic brain stem evoked responses (BSER); and
      8. Intelligence quotient (IQ) testing, when appropriate and reasonable.
  4. Imiglucerase or velaglucerase alfa are considered medically necessary for the treatment of Children (less than 18 years of age) with type 3 Gaucher disease when the following criteria are met:
    1. The drug is used as monotherapy;
      AND
    2. Type 3 Gaucher disease is confirmed by genotype testing indicating the presence of two homozygous alleles for neuropathic Gaucher disease
      AND
    3. There are clinically significant manifestations of type 3 Gaucher disease including any of the following:
      1. Abdominal or bone pain; or
      2. Hepatosplenomegaly; or
      3. Documented growth failure not associated with other conditions; or
      4. Cachexia; or
      5. Exertional limitations; or
      6. Fatigue; or
      7. Evidence of skeletal involvement, including, but not limited to, Erlenmeyer flask deformity (failure of bone remodeling); or
      8. Hemoglobin less than 2.0 g/dL below lower limit of normal for age and sex; or
      9. Platelet count less than 60,000 mm3 or documented abnormal bleeding episode(s).
        AND
    4. There are neurological findings consistent with type 3 Gaucher disease based on evaluation which includes all of the following tests:
      1. Neurological examination by a neurologist; and
      2. Eye movement examination by an ophthalmologist; and
      3. Neuro-ophthalmological investigation with direct ophthalmoloscopy; and
      4. Measurement of peripheral hearing (electro-acoustical emission in small children, pure tone audiometry in older individuals); and
      5. Brain Imaging, preferably by magnetic resonance imaging (MRI), or if MRI is unavailable, by computed tomography; and
      6. Electroencephalography (EEG); and
      7. Diagnostic brain stem evoked responses (BSER); and
      8. Intelligence quotient (IQ) testing, when appropriate and reasonable.
  5. Miglustat is considered medically necessary for the treatment of Adults (greater than or equal to 18 years of age) with type 1 Gaucher disease when the following criteria are met:
    1. The drug is used as monotherapy,
      AND
    2. Type 1 Gaucher disease is confirmed by either of the following:
      1. Glucocerebrosidase activity in the white blood cells or skin fibroblasts less than or equal to 30% of normal activity; or
      2. Genotype testing indicates mutation of two alleles of the glucocerebrosidase genome
        AND
    3. There are clinically significant manifestations of Type 1 Gaucher disease, including any of the following:
      1. Skeletal disease as demonstrated by any of the following:
        1. Avascular necrosis; or
        2. Erlenmeyer flask deformity (failure of bone remodeling); or
        3. Lytic disease; or
        4. Marrow infiltration; or
        5. Osteopenia; or
        6. Osteosclerosis; or
        7. Pathological fracture; or
        8. Radiological evidence of joint deterioration
          or
      2. Presents with at least two of the following:
        1. Clinically significant hepatomegaly;
        2. Clinically significant splenomegaly;
        3. Hemoglobin less than or equal to 11.5 g/dL for females and less than 12.5 g/dL for males, or 1.0 g/dL below lower limit for normal for age and sex;
        4. Platelet count less than or equal to 120,000mm3
          AND
    4. Enzyme replacement therapy with imiglucerase, taliglucerase alfa or velaglucerase alfa is contraindicated due to intolerability, allergy to components of these drugs, or poor venous access.

Not Medically Necessary:

Miglustat is considered not medically necessary for the treatment of pregnant women and for women who may become, or are considering becoming pregnant while taking this drug.

Imiglucerase, taliglucerase alfa, or velaglucerase alfa is considered not medically necessary for the treatment of individuals with type 2 Gaucher disease.

Imiglucerase, taliglucerase alfa or velaglucerase alfa in conjunction with each other, or with miglustat is considered not medically necessary under all circumstances.

Imiglucerase, taliglucerase alfa or velaglucerase alfa for the treatment of Adults and Children with type 1 or type 3 Gaucher disease is considered not medically necessary for all other uses, including when the criteria above have not been met.

The use of glucosylceramide synthetase inhibitor miglustat is considered not medically necessary in all other circumstances, including when the criteria above are not met.

Coding

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

HCPCS 
J1786Injection, imiglucerase, 10 units [Cerezyme]
J3060Injection, taliglucerase alfa, 10 units [ELELYSO]
J3385Injection, velaglucerase alfa, 100 units [VPRIV]
J8499Prescription drug, oral, non chemotherapeutic, NOS [when specified as miglustat (Zavesca)]
S9357Home infusion therapy, enzyme replacement intravenous therapy (e.g. Imiglucerase); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2015]
272.7Lipidoses (Gaucher disease)
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2015]
E75.22Gaucher disease
  
Discussion/General Information

Gaucher disease is a rare, inherited, and potentially fatal genetic disorder that affects approximately 20,000 people in the United States. It most frequently occurs in individuals of Northern, Central and Eastern European Jewish descent (Ashkenazi Jews), with a frequency of 1 in approximately 500 to 1,000 births. In non-Ashkenazi populations, the frequency is approximately 1 in 60,000 births (National Gaucher Foundation, 2007).

Gaucher disease is an autosomal recessive disease, requiring the inheritance of a defective gene from each parent in order for an individual to have this condition. Individuals with Gaucher disease have impaired ability to produce a key enzyme called glucocerebrosidase, which is vital to the breakdown of a substance called glucosylceramide, a significant byproduct of the breakdown of old or damaged red and white blood cells. Impairment of glucocerebrosidase results in the collection of glucosylceramide in cells in the spleen, liver, bones, and bone marrow, resulting in dysfunction of those organs. In some forms of Gaucher disease, the collection of glucosylceramide in the brain is seen, resulting in neurologic impairment and dysfunction. The main characteristics of Gaucher disease include enlarged spleen and liver (visceral involvement), abnormally decreased or increased bone mineral density and bone marrow function leading to easily broken and/or pain in the bones (bone disease), poor clotting and decreased red blood cell concentrations leading to fatigue (hematologic involvement). Some forms of Gaucher disease result in neurological dysfunction, including seizures, eye movement and vision problems, progressive brain damage, and poor coordination. Diagnosis of this disease involves clinical examination; radiological imaging of the bones, spleen and liver; and laboratory testing to detect defective enzyme function and platelets and red blood cell counts.

The severity and presentation of Gaucher disease are highly dependent upon the genetic mutations that cause the condition. There are over 150 distinct mutations currently identified to cause the absence or altered function of glucocerebrosidase. Three specific mutations are known to account for most cases of Gaucher disease, and each has been associated with one of the three different types of Gaucher disease, referred to as type 1, type 2 and type 3.

Type 1 is the most common form of Gaucher disease, responsible for approximately 90% of all cases. It is the most common form seen in Ashkenazi Jews. The age of onset for type 1 is highly variable, with some individuals presenting with symptoms in childhood and others not until late adulthood. The average age of onset is approximately 30 years old. Alternatively, some individuals with the genotype for Gaucher disease never have any symptoms at all. Individuals with type 1 Gaucher disease exhibit visceral, bone and hematologic symptoms which progress in severity over time. There is no neurologic involvement with this type. Commonly seen symptoms include fatigue, growth delay in childhood and easy bruising or bleeding. When present in children, symptoms progress fairly rapidly, resulting in an obvious increasing severity over a short period of time. When present in adults, the course is slower and less evident. Current treatment options available for type 1 Gaucher disease are ERT, SRT, and in rare circumstances, bone marrow or hematopoietic stem cell transplantation.

Type 2, also referred to as neuropathic Gaucher syndrome, is the rarest form of this disease. Type 2 is characterized by early age of onset, anywhere between in utero to one year of age. This type includes serious and rapidly progressive neurologic deterioration with less severe visceral involvement than seen in individuals with type 1 Gaucher disease. The neurologic involvement primarily involves the brain, and widespread dysfunction leading to severe seizures, rigidity and other motor dysfunction is common. There is currently no treatment for this type of Gaucher disease which slows the progression and individuals with this condition rarely live past the age of two years. In some rare circumstances, ERT may be used to alleviate somatic symptoms, but such measures are usually palliative in nature.

Type 3 Gaucher disease is a less severe neuropathic form of Gaucher disease, compared to type 2. It is usually more aggressive and progressive in presentation of hematologic, visceral and bone involvement than type 1 disease. The age of onset may occur anywhere from early childhood to late adulthood and the course of the disease is much more variable than type 1 Gaucher disease. This form of Gaucher disease also involves neurologic dysfunction, including poor coordination, paralysis of the eye muscles, and dementia. However, the severity of these conditions is much less severe than with type 2 Gaucher disease. There are three subtypes of type 3 Gaucher disease. Type 3a, also known as Norbottnian Gaucher, is characterized by progressive dementia, loss of coordination, and muscle spasms. Type 3b involves extensive visceral and bone involvement with neurologic involvement limited to paralysis of the eye muscles. Finally, type 3c, the rarest type 3 form and occasionally referred to as type 4 Gaucher disease, is characterized by limited visceral involvement, paralysis of the eye muscles, clouding of the cornea of the eye, and extensive heart and aorta calcification. Individuals with type 3 usually live into adulthood, but with a shortened life span usually limited to the third or fourth decade. The currently available treatment options for type 3 disease include ERT, and in rare circumstances, the use of bone marrow or hematopoietic stem cell transplantation is being studied under clinical trials.

The diagnosis and management of Gaucher disease can be very complex due to its impact on a wide variety of physiologic functions. The International Collaborative Gaucher Group (ICGG), a well-respected group of physicians specializing in the treatment of Gaucher disease has published comprehensive recommendations for the initial assessment and monitoring of individuals with type 1 and type 3 Gaucher disease (refer to Appendix A). These recommendations take into consideration the multiple variables that need to be addressed, including the hematologic, visceral, bone, and neurological aspects of the disease. Additionally, these recommendations provide guidance for the timing of the various tests required.

Kaplan and colleagues (2013) published updated recommendations for the management of children with Gaucher disease. According to the Gaucher Registry, children treated with alglucerase or imiglucerase showed most of the hematologic benefits and approximately half of the organomegaly benefits during the first year of treatment, with continued or sustained improvement in all parameters for greater than or equal to eight years of treatment. Enzyme replacement therapy was recommended for all symptomatic children with type 1 and 3 Gaucher disease, which prevents debilitating and often irreversible disease progression and allows those with non-neuropathic disease to lead normal healthy lives.

The current treatment option of choice for type 1 Gaucher disease is ERT with glucocerebrosidase analogs  imiglucerase, approved by the U.S. Food and Drug Administration (FDA) for long-term treatment of type 1 Gaucher disease in adults or children when specific visceral, bone or hematologic symptoms are present. In February of 2010 a new ERT, velaglucerase alfa received approval by the FDA for the treatment of type 1 Gaucher disease. Regulatory approval was based on a priority review of data from three pivotal trials of 82 subjects aged 4 years and older, some of which switched to velaglucerase alfa after being treated with imiglucerase. The FDA determined there was sufficient evidence of safety and efficacy for the use of velaglucerase alfa in type 1 Gaucher disease based on these three phase III trials. Velaglucerase alfa is an alternative for those individuals currently receiving treatment for type 1 Gaucher disease with the current ERT imiglucerase. According to the FDA's Office of Drug Evaluation, "Patients who previously received Cerezyme as an enzyme replacement therapy for their Type 1 Gaucher disease can be safely switched to VPRIV."

In May 2012, a new ERT, taliglucerase alfa was granted Orphan Drug approval by the FDA for long-term treatment for adults with a confirmed diagnosis of Type 1 Gaucher disease. Taliglucerase alfa is a hydrolytic lysosomal glucocerebroside-specific enzyme infused every other week providing an alternative to other ERT. The regulatory determination for taliglucerase alfa was based on a review of data from two trials of 56 subjects with type 1 Gaucher disease, in one study 25 participants switched from imiglucerase another ERT. Study outcomes reported over a nine month period demonstrated taliglucerase alfa effective in maintaining spleen and liver volumes, blood platelet courts, and hemoglobin levels. Zimran and colleagues (2012) reported on a parallel-dose study, 31 adults who had not previously been treated with ERT, were randomly selected to receive either taliglucerase alfa 30 units per kg or taliglucerase alfa 60 units per kg. Study results demonstrated the effectiveness of treatment with taliglucerase alfa over a nine month period, as evidence by significant reduction in spleen volume from baseline in both doses of ERT, 30 U/kg dose group 26.9% (95% confidence interval [CI], -31.9, -21.8) and 60 U/kg dose group 38.0% (95% CI, -43.4, -32.8). During the study there were no serious adverse events reported for individuals treated with taliglucerase alfa. Currently there is an ongoing trial in which many participants have continued treatment with taliglucerase alfa through a long-term extension study to evaluate the drugs long-term effect. The FDA determined there was sufficient evidence to support the efficacy for use of taliglucerase alfa in the treatment of adults with type 1 Gaucher disease.

Imiglucerase is a "recombinant" drug, produced through the insertion of a genetically engineered version of the human gene for glucocerebrosidase into cells that grow easily in a laboratory, in this case hamster ovary cells. This allows for more controllable and safer production of this drug, providing a more stable source, with greatly reduced risk of infection due to tainted product. The pharmacologic difference between these two substances is negligible, and their clinical use in terms of dosing and timing is identical. Cerezyme has replaced the precedent drug Ceredase for the majority of individuals on ERT.

Scientific studies have shown that ERT effectively ameliorates or reverses many of the symptoms and manifestations of type 1 Gaucher disease, including the visceral, bone and hematologic presentations. Similar benefits have been demonstrated for individuals with type 3 Gaucher disease. Unfortunately, neither alglucerase nor imiglucerase are capable of passing through the blood-brain barrier that protects the brain from harmful substances and diseases. Therefore, the impact of these drugs on neurologic symptoms seen in type 2 and 3 Gaucher disease is minimal to none at the doses customarily used. However, some individuals with type 3 Gaucher disease have had improvement in neurologic function at higher doses. Another consideration is some individuals with type 3 Gaucher disease never develop neurologic symptoms and ERT for these individuals is most beneficial. The National Gaucher Foundation Summary of Gaucher disease (2009) established categorization by disease status, with prioritization for treatment based on those at highest risk with disease progression requiring treatment with ERT.

The administration method for ERT is via intravenous infusion over a period of one to two hours every two weeks for the duration of an individual's life. The ICGG recommends specific initial dosing guidelines for ERT treatment, but indicates long-term treatment should be tailored to the needs of the individual based upon disease severity, symptoms, and rate of progression.

Substrate reduction therapy may be an option for individuals who are unable to tolerate ERT due to excessive side effects or allergies, inadequate access to blood vessels for infusion therapy, as well as those for whom ERT is unsuccessful. Substrate reduction therapy is different from ERT as it does not attempt to replace absent or impaired enzyme function. Instead, SRT interrupts the function of glucosylceramide synthase, an enzyme responsible for the production of glucosylceramide, the substance that accumulates in the body and results in symptoms of Gaucher disease. At this time, the only glucosylceramide synthase drug approved by the FDA is miglustat. It must be noted this drug does not completely halt the production of glucosylceramide, but with appropriate dosing, can significantly decrease its concentrations, allowing any residual glucocerebrosidase activity within the body to be effective.

The administration method for miglustat is via pill taken orally 1 to 3 times per day for the duration of the individual's life. Dosing varies with the severity of an individual's condition. As is the case with ERT, at this time, there are no standardized dosing guidelines and the ICGG has not yet provided any guidance for the use of miglustat.

Imiglucerase has been approved by the FDA for the treatment of type 1 Gaucher disease when visceral, bone or hematologic symptoms are present. Velaglucerase alfa is the most recent ERT to received approval by the FDA for the treatment of Type 1 Gaucher disease. The criteria in this document provides for the accurate confirmation of the presence of the required genotype and corresponding symptoms to avoid confusion of this condition with other diseases, including other lipidoses. Exclusion of demonstrated skeletal disease in diagnoses for children is due to a frequent lack of such symptoms in this population. Several well-conducted case series studies from well-known experts in the treatment of Gaucher disease have shown the use of ERT provides significant relief and even cessation of symptoms of this disorder in a safe and effective manner in the populations identified above. The use of either of these drugs in conjunction with each other, or with SRT with miglustat has not been properly evaluated at this time.

There have been some small case series studies published evaluating the use of ERT with alglucerase and imiglucerase for the treatment of type 3 Gaucher disease. These studies have demonstrated ERT has minimal effect on alleviating or reducing the neurological manifestations of this form of the disease. However, ERT has been shown to provide significant benefits in controlling visceral, bone and hematologic symptoms, similar to when used to treat type 1 Gaucher disease. Confirmation of the presence of type 3 disease must be accurately made, and thorough evaluation of neurological function, in addition to visceral, bone and hematologic systems, is vital. Additionally, identification of specific allele combinations is important in identifying the presence of two alleles coding for neuropathic Gaucher disease. It is well known the mutation for neuropathic Gaucher disease is recessive and the presence of two such genes is required for neuropathic symptoms to be present.

The use of ERT for the treatment of individuals with type 2 Gaucher disease has been described in only a few case series studies due to its relative rarity. As with type 3 Gaucher disease, these studies demonstrated the use of ERT reduces visceral, bone and hematologic symptoms while providing little to no impact on neurological symptoms. In these individuals, the progression of neurological symptoms is very rapid. The use of ERT in these individuals provides little real benefit in clinical outcomes or quality of life with the exception of some very limited circumstances.

The use of imiglucerase for the treatment of other conditions aside from Gaucher disease has not been described in the medical literature at this time. Such use is not supported by any evidence.

The use of miglustat has been approved by the FDA for the treatment of type 1 Gaucher disease in individuals for whom ERT is not feasible or has failed to provide adequate results. Several small trials have demonstrated that this therapy provides significant benefits to such individuals. Use of miglustat by individuals under 18 years of age has not been evaluated. As noted in the FDA labeling, the use of miglustat has been shown in animal models to have harmful effects on the development and survival of a fetus. The use of this drug by pregnant women or those considering pregnancy is considered not medically necessary. Also, the FDA warns that miglustat is known to harm the development of sperm and caution must be taken when used by males. Additionally, the FDA indicates that it is unknown if miglustat is excreted in human milk, therefore nursing while taking this drug should be avoided.

The FDA approved labeling for Zavesca includes the following warnings/precautions:

Zavesca is contraindicated in women who are or may become pregnant. If this drug is administered to a woman with reproductive potential, the patient should be apprised of the potential hazard to a fetus. This information is based upon the results of animal studies. It must be noted that the effect of this drug upon pregnancy outcomes in humans has not been studied.
Male patients should maintain reliable contraceptive methods while taking Zavesca. Studies in the rat have shown that miglustat adversely affects spermatogenesis and sperm parameters, thereby reducing fertility. Until further information is available, it is advised that before seeking to conceive, male patients should cease Zavesca and maintain reliable contraceptive methods for 3 months thereafter.
It is not known whether miglustat is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from miglustat, Zavesca should not be used in nursing mothers unless the potential benefit justifies the risk to the infant. A decision should be made to discontinue nursing or discontinue the drug, taking into the account the importance of the drug to lactating women.
Cases of peripheral neuropathy have been reported in patients treated with Zavesca. All patients undergoing Zavesca treatment should undergo baseline and repeat neurological evaluations at approximately 6-month intervals. Patients who develop symptoms such as numbness and tingling should have a careful re-assessment of the risk/benefit of Zavesca therapy and cessation of treatment may be considered.

There are ongoing clinical trials studying alternate dosing schedules for ERT. De Fost and colleagues (2007) reported on a small series of eleven subjects who were randomized to either weekly or low frequency (every 4 weeks) infusions. Two out of six subjects in the low frequency cohort failed to maintain disease stability. The researchers concluded low frequency maintenance dosing could be achieved in Type 1 adult Gaucher disease, but close monitoring of all subjects was required.

References

Peer Reviewed Publications:

  1. Andersson HC, Charrow J, Kaplan P, et al for the International Collaborative Gaucher Group (ICGG) US Regional Coordinators. Individualization of long term enzyme replacement (ERT) for Gaucher's disease. Genet Med. 2005; 7(2):105-110.
  2. Charrow J, Andersson HC, Kaplan P, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. 2004; 144(1):112-120.
  3. Charrow J, Esplin JA, Gribble TJ, et al. Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med. 1998; 158(16):1754-1760.
  4. Cox TM, Aerts J, Andria G, et al. The role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I (non-neuronopathic) Gaucher disease: A position statement. J Inherit Metab Dis. 2003; (26):513-526.
  5. de Fost M, Aerts JM, Groener JE, et al. Low frequency maintenance therapy with imiglucerase in adult type I Gaucher disease: a prospective randomized controlled trial. Haematologica. 2007; 92(2):215-221.
  6. Elstein Y, Eisenberg V, Granovsky-Grisaru S, et al. Pregnancies in Gaucher disease: a 5-year study. Am J Obstet Gynecol. 2004; 190(2):435-441.
  7. Erikson A, Astrom M, Mansson JE. Enzyme infusion therapy of the Norrbottnian (type 3) Gaucher disease. Neuropediatrics. 1995; 26(4):203-207.
  8. Kaplan P, Baris H, De Meirleir L, et al. Revised recommendations for the management of Gaucher disease in children. Eur J Pediatr. 2013; 172(4):447-458.
  9. Martins AM, Valadares ER, Porta G, et al. Recommendations on diagnosis, treatment, and monitoring for Gaucher disease. J Pediatr. 2009; 155(4):10-18.
  10. McCormack PL, Goa KL. Miglustat. Drugs. 2003; 63(22):2427-2434.
  11. NIH Technology Assessment Panel on Gaucher Disease. Gaucher Disease. Current issues in diagnosis and treatment. NIH technology assessment panel on Gaucher disease. JAMA. 1996; 275(7):548-553.
  12. Ono H, Fujiwara M, Ito K, et al. Neurological features in Gaucher's disease during enzyme replacement therapy. Acta Paediatr. 2001; 90(2):229-231.
  13. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004 Oct; 41(4 Suppl 5):4-14.
  14. Vellodi A, Bembi B, de Villemeur TB, et al. Neuronopathic Gaucher Disease Task Force of the European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis. 2001; 24(3):319-327.
  15. Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: Revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004; 41(4 Suppl 2):15-22.
  16. Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002; 113(2):112-119.
  17. Zimran A, Altarescu G, Philips M, et al. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010; 115(23):4651-4656.
  18. Zimran A, Brill-Almon E, Chertkoff R, et al. Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease. Blood. 2011; 118(22):5767-5773.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Cerezyme, [Product Information]. Cambridge, MA; Genzyme, March 3, 2005. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/20367s066lbl.pdf. Accessed on March 25, 2014.
  2. ELELYSO, [Product information], New York, NY; Pfizer Labs, May 1, 2012. Available at: http://www.elelyso.com/sites/default/files/ELELYSO_Prescribing_Information.pdf. Accessed on March 25, 2014.
  3. Imiglucerase. In: DrugPoints® System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated November 17, 2011. Available at: http://www.micromedexsolutions.com. Accessed on March 25, 2014.
  4. Imiglucerase Monograph. Lexicorp ® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Corp., Inc. Last reviewed January 1, 2005.
  5. International Collaborative Gaucher Group (ICGG). Minimum recommendations for monitoring patients with non-neuronopathic (Type 1) Gaucher disease. Available at: https://www.lsdregistry.net/gaucherregistry/hcp/pdfs/greg_Recommendations_for_Monitoring.pdf. Accessed on March 25, 2014.
  6. Miglustat. In: DrugPoints® System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated November 19, 2013. Available at: http://www.micromedexsolutions.com. Accessed on March 25, 2014.
  7. Miglustat Monograph. Lexicorp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Corp., Inc. Last reviewed January 1, 2005.
  8. National Gaucher Foundation. Summary of Gaucher disease. Patient prioritization for treatment recommendations from the meeting of Gaucher treatment experts. September 9, 2009. Available at: http://www.gaucherdisease.org/shire_patient_prioritization.pdf. Accessed on March 25, 2014.
  9. US ICGG Regional Coordinators. Consensus statement by the ICGG US regional coordinators on individualization of enzyme replacement therapy for type 1 Gaucher disease. Presented at ICGG Regional Coordinators Meeting. Univ of PA, Nov. 9, 1997.
  10. Velaglucerase alfa. Lexicorp® Online, American Hospital Formulary Services® (AHFS®) Online, Hudson, Ohio, Lexi-Corp., Inc. Last reviewed February 15, 2013.
  11. Velaglucerase alfa. In: DrugPoints System (electronic). Truven Health Analytics, Greenwood Village, CO. Updated December 6, 2013. Available at: http://www.micromedexsolutions.com. Accessed on March 25, 2014.
  12. VPRIV, [Product Information] Cambridge, MA, Shire Human Genetic Therapies, Inc., November 21, 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022575s012lbl.pdf. Accessed on March 25, 2014.
  13. Zavesca [Product Information], South San Francisco, CA. Actelion Pharmaceuticals US, Inc., February 10, 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021348s010lbl.pdf. Accessed on March 25, 2014.
Websites for Additional Information
  1. National Gaucher Foundation Website. Available at: http://www.gaucherdisease.org. Accessed on February 26, 2014.
  2. National Tay-Sachs and Allied Diseases Association, Inc. The NTSAD Diseases Family: Gaucher Disease. Available at: http://www.ntsad.org/. Accessed on February 27, 2014.
Index

Enzyme Replacement Therapy
Gaucher Disease
Imiglucerase (Cerezyme)
Miglustat (Zavesca)
Substrate Reduction Therapy
Taliglucerase alfa (ELELYSO)
Velaglucerase alfa (VPRIV)

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Revised05/15/2014Medical Policy & Technology Assessment Committee (MPTAC) review. Revised medically necessary and not medically necessary statements with removal of alglucerase (Ceredase) and all brand names. Updated Description, Coding, Discussion, Index, References, and Websites.
 01/01/2014Updated Coding section with 01/01/2014 HCPCS changes; removed C9294 deleted 12/31/2013.
Revised05/09/2013MPTAC review. Revised medically necessary criteria for ERT in children (less than 18 years of age) with Type 1 & 3 Gaucher disease. Updated Discussion, References and Websites.
 01/01/2013Updated Coding section with 01/01/2013 HCPCS changes.
Revised05/10/2012MPTAC review. Updated medically necessary statements for type 1 and type 3 Gaucher disease to include coverage of new enzyme replacement therapy (ERT). Clarified medically necessary criteria. Updated not medically necessary statement to address coverage limitations of new ERT. Updated Description, Coding, Discussion, Index, References and Websites.
Revised05/19/2011MPTAC review. Removed FDA labeling warning/precaution information from miglustat (Zavesca) not medically necessary statement. Updated Discussion, References and Websites
 01/01/2011Updated Coding section with 01/01/2011 HCPCS changes; removed C9271, J1785 deleted 12/31/2010.
 10/01/2010Updated Coding section with 10/01/2010 HCPCS changes.
Revised05/13/2010MPTAC review. Updated medically necessary statements for type 1 and type 3 Gaucher disease to include coverage of new enzyme replacement therapy (ERT). Updated not medically necessary statement to address new ERT. Discussion, references, and websites updated.
Reviewed05/21/2009MPTAC review. Clarified pediatric age criteria. Removed place of service section. References updated.
Reviewed05/15/2008MPTAC review. Updated references and added Website section.
Reviewed05/17/2007MPTAC review. Updated references and coding.
Reviewed06/08/2006MPTAC annual review. References updated. No change to guideline position.
New07/14/2005MPTAC initial guideline development.

 

Appendix A 

Initial Testing And Monitoring Recommendations for Gaucher Disease by the U.S Regional Coordinators of the International Collaborative Gaucher Group

Table I *

Initial Assessment Recommendations for Patients with Gaucher Disease

A complete history of patient and family, preferably including a pedigree
A comprehensive physical examination (annual)
Quality of life (annual): Patient-reported functional health and well-being (SF-36 Health Survey)

Blood Tests:

  • Hemoglobin
  • Platelet count

Biochemical markers (one or more of these biochemical markers should be consistently monitored in conjunction with other clinical assessments of disease activity; chitotriosidase, when available as a validated procedure, may be the most sensitive indicator of changing disease activity, and is therefore preferred)

  • Chitotriosidase
  • ACE (angiotensin-converting enzyme)
  • TRAP (Tartrate-resistant acid phosphatase)

Additional blood tests (to be evaluated selectively based upon each patient's age and clinical status)

  • WBC, PT, and PTT
  • Iron, iron binding capacity, ferritin, vitamin B12
  • AST and/or ALT; alkaline phosphatase; calcium, phosphorous, albumin, total protein, total and direct bilirubin
  • Serum immunoelectrophoresis
  • Hepatitis profile
Beta-glucosidase and mutation analysis
Antibody sample**

Visceral (contiguous transaxial 10-mm thick sections for sum of region of interest)

  • Spleen volume (volumetric MRI or CT)
  • Liver volume (volumetric MRI or CT)

Skeletal

  • MRI (Coronal, T1- and T2-weighted) of the entire femora
  • X-ray (AP view of the entire femora) and lateral view of the spine
  • DXA lumbar spine and femoral neck
Pulmonary (recommended every 12-24 months for patients with borderline or above normal pulmonary pressures at baseline)
ECG, chest x-ray
Doppler echocardiogram (right ventricular systolic pressure) for patients over 18 years of age

* Adopted from: Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: Revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004; 41(4 Suppl 2):15-22.
** A baseline sample to be kept in storage; an optional subsequent sample at 6 months after starting ERT. The samples will only be tested if clinically indicated such as for a suspected immune-mediated adverse event, or for suspected loss or ERT effectiveness.
† Optimally from hips to below knees.

Table II **

Recommendations for Monitoring of Children with Gaucher Disease

 

All patients

Patients not receiving enzyme therapy

Patients receiving enzyme therapy

Assessment Modality or Test

Baseline

Every 12 months

Every 12-24 months

Every 3 months*

Every 12 months*

At time of dosing change

Hematologic      

Hemoglobin

X

X

 

X

 

X

Platelet count

X

X

 

X

 

X

Acid phosphate (total, non-prostatic), angiotensin converting enzyme, chitotriosidase

X

X

 

X

 

X

Visceral§

 

 

 

 

 

 

Spleen volume (volumetric MRI or CT)

X

 

X

 

X

X

Liver volume (volumetric MRI or CT)

X

 

X

 

X

X

Skeletal ***

 

 

 

 

 

 

MRI (coronal; T1 and T2-weighted) of entire femora

X

 

X

 

X

X

Radiograph: AP view of entire femora and lateral view of spine

X

 

X

 

X

X

DEXA: Spine and hips

X

 

X

 

Every 12-24 months

 

Quality of life* *

 

 

 

 

 

 

Patient reported functional health and well-being

X

X

 

 

X

 

** Adapted from:  Charrow J, Andersson HC, Kaplan P, et al.   Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. 2004; 144(1):112-20.
*  For patients who have reached clinical goals and for whom there has been no change in dose, the frequency of monitoring can be decreased to every 12 to 24 months.
† See Table II for additional studies that should be obtained at baseline and followed appropriately is abnormal.  Physicians should determine the appropriateness of these additional laboratory results based on each patient's age and clinical status.
‡ One or more of these markers should be consistently monitored (at least every 12 months) in conjunction with other clinical assessments of disease activity and response to treatment.  Of the three currently recommended biochemical markers, chitotriosidase activity, when available as a validated procedure from an experienced laboratory, may be the most sensitive indicator of changing disease activity, and is therefore preferred.
§ Obtain continuous transaxial 10-mm thick sections for the sum of region of interest.
*** Additional skeletal assessments that are optional include bone age for patients ≤ 14 years old. Follow-up is recommended if baseline is abnormal.
¶ Optimally, obtain hips to below knees. As an alternative, obtain hips to distal femur.
** Ideally, quality of life should be addressed every six months using a standard and valid instrument.

Table III **

Additional Baseline Laboratory Studies for Children with Gaucher Disease*

 

ASTTotal and direct bilirubin
ALTAlbumin
Angiotensin converting enzymeTotal protein
Alkaline phosphataseFerritin
CalciumSerum iron and iron binding capacity
PhosphorousVitamin B12 level
Prothrombin timeSample to be stored for antibodies
Partial thromboplastin timeChest radiograph

** Adapted from:  Charrow J, Andersson HC, Kaplan P, et al.   Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: consensus recommendations. J Pediatr. 2004; 144(1):112-20.
*  Based upon consideration of the patient's age and clinical status. If abnormal, these should be repeated periodically, as clinically indicated.
†  A sample for antibody testing should be drawn at baseline and 6 months after beginning ERT.  If the 6-month sample is positive, the baseline sample should be analyzed, and repeat samples should be analyzed every 6 months until tolerization occurs

Table IV *

Recommendations for Ongoing Monitoring of Adults with Gaucher Disease

 

Patients not receiving enzyme therapy

Patients receiving enzyme therapy

Assessment Modality or Test

Follow-up every 12 months

Follow-up every 12-24 months

Not achieved therapeutic goals

Follow-up every 12 months

Obtain at time of dosage change or significant complication

Every 3 months

Every 12 months

Every 12-24 months

Comprehensive physical exam**

X

 

 

X

X (annual)

 

SF-36 (QOL) survey

X

 

 

X

X (annual)

X

Blood tests

Hemoglobin

X

 

X

 

X

X

Platelet count

X

 

X

 

X

X

Biochemical markers

X

 

X

 

X

X

Chitotriosidase
ACE
TRAP

 

 

 

 

 

 

Additional Blood testsTo be followed appropriately if abnormal, based on each patient's age and clinical status
Visceral (Contiguous transaxial 10mm thick sections for sum of region of interest) 

 

 

 

 

 

Spleen volume (volumetric MRI or CT)

 

X

 

X

X

X

Liver volume (volumetric MRI or CT)

 

X

 

X

X

X

Skeletal

MRI of the entire femora (coronal; T1 and T2-weighted)

 

X

 

X

X

X

X-ray §¶

 

X

 

X

X

X

DXA

 

X

 

X

X

X

Pulmonary

Recommended every 12-24 months for patients with borderline or above normal pulmonary pressures at baseline

*  Adopted from: Weinreb NJ, Aggio MC, Andersson HC, et al. Gaucher disease type 1: Revised recommendations on evaluations and monitoring for adult patients. Semin Hematol. 2004; 41(4 Suppl 2):15-22.
** A comprehensive physical examination should be performed at least annually
†   One or more of these biochemical markers should be consistently monitored every 12 months and in conjunction with other clinical assessments of disease activity and response to treatment; Chitotriosidase, when available as a validated procedure may be the most sensitive indicator of changing disease activity, and it therefore preferred.
‡    Anatomical sites not included here should be evaluated if symptoms develop in such locations.
§   AP view of the entire femora (optimally from hips to below knees), and lateral view of the spine.
¶   Optimal in absence of new symptoms or evidence of disease progression.

Table V **

Additional Baseline Laboratory Studies for Adults with Gaucher Disease*

Tests

Rationale

Serum Iron, total binding capacity, ferritinSuspect co-existing iron deficiency or iron overload.
Prothrombin time, activated partial thromboplastin timeDetect clotting defects associate with liver disease, with Gaucher disease itself (factors IX and X) of factor XI deficiency that may congregate with Gaucher disease among Ashkenazi Jewish populations.
Alkaline phosphatase, serum calcium, phosphorous, 24-hour urinary calciumMarkers of bone involvement and defects in calcium absorption and metabolism.
Total and direct bilirubin, total protein, albuminMonitor liver function, abnormalities of which may arise from Gaucher disease involvement.
Serum protein electrophoresis, serum immunoelectrophoresisDetect monoclonal gammopathies that may be more common in adult patients with Gaucher disease than in the general population.

** Adapted from: 2. Charrow J, Esplin JA, Gribble TJ, et al. Gaucher disease: recommendations on diagnosis, evaluation, and monitoring. Arch Intern Med. 1998; 158(16):1754-60.
*   Depending on each patient's age and clinical status, these tests may be performed at the time of diagnosis and, if results are abnormal, as needed for follow-up.

Table VI*

Minimal Clinical Protocols for Initial Assessment of Neurological Involvement in Gaucher Disease*

1.  Clinical Examination

  • Neurological examination every 3 months during year 1, every 6 months thereafter
  • Eye movement examination every 6 months
  • Additional neuro-ophthalmological investigation every 12 months
  • Peripheral hearing every 12 months; results should be evaluated in terms of 2-3 year trends

2.  Brain Imaging

  • Only if indicated

3.  Neurophysiology

  • Electroencephalography (EEG) only if indicated; e.g. by presence of seizures
  • Diagnostic brain stem evoked  responses (BSER) every 12 months

4.  Neuropsychometry

  • Every 12 months.

* Adapted from: Vellodi A, Bembi B, de Villemeur TB, et al. Neuronopathic Gaucher Disease Task Force of the European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis. 2001; 24(3):319-27.

Table VII *

Minimal Clinical Protocols for Follow-up of Neurological Involvement in Gaucher Disease*

1.  Clinical Examination

  • Neurological examination every 3 months during year 1, every 6 months thereafter
  • Eye movement examination every 6 months
  • Additional neuro-ophthalmological investigation every 12 months
  • Peripheral hearing every 12 months; results should be evaluated in terms of 2-3 year trends

2.  Brain Imaging

  • Only if indicated

3.  Neurophysiology

  • Electroencephalography (EEG) only if indicated; e.g. by presence of seizures
  • Diagnostic brain stem evoked  responses (BSER) every 12 months

4.  Neuropsychometry

  • Every 12 months.

* Adapted from: Vellodi A, Bembi B, de Villemeur TB, et al. Neuronopathic Gaucher Disease Task Force of the European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis. 2001; 24(3):319-27.