Hematopoietic Cell Transplantation for Primary Amyloidosis or Waldenstrom's Macroglobulinemia

POLICY NUMBER

A.8.01.42

DESCRIPTION

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) refers to the infusion of hematopoietic stem cells to restore bone marrow function in individuals with cancer who receive bone-marrow-toxic doses of drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT). These cells can be harvested from bone marrow, peripheral blood, or umbilical cord blood. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease. The use of cord blood is discussed in the Placental and Umbilical Cord Blood as a Source of Stem Cells policy.

Primary Amyloidosis

The primary amyloidoses comprise a group of diseases with an underlying clonal plasma cell dyscrasia. They are characterized by the extracellular deposition of pathologic, insoluble protein fibrils with a beta-pleated sheet configuration that exhibits a pathognomonic red-green birefringence when stained with Congo red dye and examined under polarized light. These diseases are classified by the type of amyloidogenic protein involved and by the distribution of amyloid deposits. In systemic amyloidosis, the unnatural protein is produced at a site that is remote from the site(s) of deposition, whereas, in localized disease, the amyloid light chain protein is produced at the site of deposition. Primary or amyloid light chain amyloidosis, the most common type of systemic amyloidosis, has an incidence of approximately 9 to 14 cases per million person-years with approximately 4,000 new cases in the US each year. The typical age at diagnosis is about 50 to 65 years. The amyloidogenic protein in primary amyloidosis is an immunoglobulin light chain or light chain fragment produced by a clonal population of plasma cells in the bone marrow. While the plasma cell burden in primary amyloidosis is typically low, ranging from 5% to 10%, this disease also may occur in association with multiple myeloma in 10% to 15% of patients. Deposition of primary amyloidogenic proteins causes organ dysfunction, most frequently in the kidneys, heart, and liver, although the central nervous system and brain may be affected.

TreatmentHistorically, this disease has had a poor prognosis, with median survival from diagnosis of approximately 12 months, although outcomes have improved with combination chemotherapy using alkylating agents and autologous hematopoietic cell transplantation (HCT). Emerging approaches include the use of immunomodulating drugs (eg, thalidomide, lenalidomide, pomalidomide) and the proteasome inhibitor bortezomib. The anti-CD38 monoclonal antibody daratumumab/hyaluronidase-fihj received approval in July 2021 for treatment of newly-diagnosed light chain amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone. Regardless of the approach, treatment of primary amyloidosis aims at rapidly reducing the production of amyloidogenic monoclonal light chains by suppressing the underlying plasma cell dyscrasia, with supportive care to decrease symptoms and maintain organ function. The therapeutic index of any chemotherapy regimen is a key consideration in the context of underlying organ dysfunction.

Chemotherapy for the treatment of light chain amyloidosis was introduced in 1972 in the form of melphalan and prednisone. This chemotherapy regimen has yielded higher response and longer survival rates than colchicine or prior therapies. Survival after oral melphalan with prednisone (typically 12 to 18 months) is longer than for untreated patients or those given older therapies (10 to 14 months), but more effective regimens have been sought. Combination therapy with vincristine, doxorubicin, and dexamethasone, a well-established regimen for myeloma, has been investigated. However, because of its toxicity, vincristine, doxorubicin, and dexamethasone therapy is usually limited to patients without peripheral neuropathy or cardiomyopathy, both common complications of amyloidosis.

Because conventional regimens rarely cure systemic amyloidosis and because of the close biologic similarity to multiple myeloma, myeloablative chemotherapy with HCT is being investigated for this disease.

Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia (WM) is a clonal disorder of B lymphocytes that accounts for 1% to 2% of hematologic malignancies, with an estimated 1,500 new cases annually in the United States. Symptoms include weakness, headaches, stroke-like symptoms (confusion, loss of coordination), vision problems, excessive bleeding, unexplained weight loss, and frequent infections. The median age of WM patients is 63 to 68 years, with men comprising 55% to 70% of cases. Median survival of WM ranges from 5 to 10 years, with age, hemoglobin concentration, serum albumin level, and beta-2-microglobulin level as predictors of outcome.

The Revised European American Lymphoma and World Health Organization classification and a consensus group formed at the Second International Workshop on Waldenstrom's Macroglobulinemia recognize WM primarily as a lymphoplasmacytic lymphoma with an associated immunoglobulin M (IgM) monoclonal gammopathy. The definition also requires the presence of a characteristic pattern of bone marrow infiltration with small lymphocytes demonstrating plasmacytic differentiation with variable cell surface antigen expression. The Second International Workshop indicated no minimum serum concentration of IgM is necessary for a diagnosis of WM.

TreatmentThe goal of therapy for patients with WM is to achieve symptomatic relief and reduce organ damage without compromising quality of life. Treatment of WM is indicated only in symptomatic patients and should not be initiated solely on the basis of serum IgM concentration. Clinical and laboratory findings that indicate the need for therapy of diagnosed WM include a hemoglobin concentration <10 g/dL; platelet count <100,000 /µL; significant adenopathy or organomegaly; symptomatic Ig-related hyperviscosity (>50 g/L); severe neuropathy; amyloidosis; cryoglobulinemia; cold-agglutinin disease; or evidence of disease transformation.

Primary chemotherapeutic options in patients that may undergo autologous hematopoietic cell transplantation often combine rituximab with other agents (eg, dexamethasone, cyclophosphamide, bortezomib, bendamustine), but other agents may also be used, including purine analogues (cladribine, fludarabine). Plasma exchange is indicated for acute treatment of symptomatic hyperviscosity.

Autologous Hematopoietic Cell TransplantationImmunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. As a consequence, autologous HCT is typically performed as consolidation therapy when the patient's disease is in complete response. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Allogeneic Hematopoietic Cell TransplantationImmunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HCT. Compatibility is established by typing human leukocyte antigen (HLA) using cellular, serologic, or molecular techniques. Human leukocyte antigen refers to the tissue type expressed at the HLA-A, -B, and -DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

The conventional (“classical”) practice of allogeneic HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower graft-versus-malignancy effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse events that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and graft-versus-host disease, which also increases susceptibility of the patient to opportunistic infections.

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden and to minimize as much as possible treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Although the definition of RIC remains variable with numerous versions employed, all seek to balance the competing effects of nonrelapse mortality and relapse due to residual disease. These regimens can be viewed as a continuum in effects, from nearly totally myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For this policy, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

POLICY

No benefits will be provided for a covered transplant procedure or a transplant evaluation unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.

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.

Autologous hematopoietic cell transplantation may be considered medically necessary as salvage therapy of chemosensitive Waldenstrom macroglobulinemia.

Allogeneic hematopoietic cell transplantation is considered investigational to treat Waldenstrom Macroglobulinemia.

POLICY EXCEPTIONS

For Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage.

For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

1/2004: Interim policy, High-dose chemotherapy with autologous stem-cell support considered investigational to treat primary amyloidosis or Waldenstrom's macroglobulinemia

3/25/2004: Reviewed by MPAC, "High-dose chemotherapy with autologous stem-cell support to treat primary systemic amyloidosis" changed to medically necessary, "High-dose chemotherapy with autologous stem-cell support to treat Waldenstrom’s macroglobulinemia" remains investigational

5/5/2004: Code Reference section completed

8/18/2004: Code Reference section updated, CPT 38215 note added covered codes, CPT chemotherapy administration code range added covered codes, CPT 96520, 96530, 96545 added covered codes, ICD-9 procedure code 41.07, 99.25 added covered codes, HCPCS chemotherapy drug range added covered codes, HCPCS Q0083, Q0084, Q0085 added covered codes, HCPCS S2150 note added covered codes, non-covered table added, CPT 38205, 38240, 38242 added non-covered codes, ICD-9 procedure code 41.05, 41.08, 41.91 added non-covered codes

11/18/2004: Reviewed by MPAC; no changes

10/27/2005: Code Reference sections updated; Covered table:  CPT codes 38230 added; ICD-9 procedure 41.09 added; HCPCS codes G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added; J9000-J9999 deleted; Non-Covered table: CPT-4 code 38204, 86812, 86816, 86817, 86821, 86822 added, ICD-9 Procedure 41.02, 41.03 added

3/21/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy

8/31/2006: Policy reviewed, no changes

9/12/2006: Coding updated. ICD9 2006 revisions added to policy

9/18/2007: Policy reviewed, no changes

12/19/2007: Coding updated per 2008 CPT/HCPCS revisions

9/26/2008: Allogeneic SCT added to policy statements as investigational. Policy description updated. "High Dose Chemotherapy" removed from policy title. Term "stem-cell support" replaced with "stem-cell transplantation"

8/19/2009: Policy reviewed, no changes

4/13/2010: "Support to Treat" was changed to "Transplantation" in the Policy Title. Policy description was updated regarding conventional and reduced-intensity conditioning. FEP and State and School Employee verbiage added to Policy Exceptions section. Added new CPT Codes 86825 and 86826 to the Non-covered table. HCPCS G0265, G0266 and G0267 deleted from Covered table due to codes were deleted as of 12-31-2007. ICD-9 diagnosis code 277.3 deleted from covered table due to code was deleted as of 9-30-2006.

05/09/2011: Policy statement revised to state that autologous hematopoietic stem-cell transplantation may be considered medically necessary as salvage therapy of chemosensitive Waldenstrom macroglobulinemia.  Allogeneic hematopoietic stem-cell transplantation remains  investigational to treat Waldenstrom macroglobulinemia.

05/08/2012: Policy reviewed; no changes.

04/16/2013: Policy reviewed; no changes.

03/17/2014: Policy reviewed; no changes.

03/30/2015: Policy description updated. Policy statements regarding primary systemic amyloidosis updated to change "stem-cell transplantation" to "hematopoietic stem-cell transplantation." Policy guidelines updated to add medically necessary and investigative definitions. Sources section updated.

08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38241; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.

05/26/2016: Policy number A.8.01.42 added.

09/30/2016: Code Reference section updated to add the following new ICD-10 diagnoses: 30230G2, 30233G2, 30240G2, 30243G2, 30230G3, 30233G3, 30240G3, 30243G3, 30230G4, 30233G4, 30240G4, 30243G4, 30230Y2, 30233Y2, 30240Y2, 30243Y2, 30230Y3, 30233Y3, 30240Y3, 30243Y3, 30230Y4, 30233Y4, 30240Y4, and 30243Y4.

03/08/2017: Policy title and policy statements updated to change "hematopoietic stem-cell transplantation" to "hematopoietic cell transplantation." Policy description updated regarding primary chemotherapeutic options and FDA regulations.

12/21/2017: Code Reference section updated to add new 2018 CPT code 38222. Revised descriptions for CPT codes 38220 and 38221. Removed deleted ICD-10 procedure codes 30230G1, 30233G1, 30240G1, 30243G1, 30230Y1, 30233Y1, 30240Y1, 30243Y1 and ICD-9 procedure codes 41.02, 41.03, 41.05, and 41.08.

01/22/2018: Policy description updated. Policy statements unchanged.

03/12/2018: Policy description updated regarding Waldenstrom Macroglobulinemia. Policy statements unchanged.

03/18/2019: Policy reviewed; no changes. Code Reference section updated to remove deleted HCPCS code G0364 and CPT code 86822.

09/24/2019: Code Reference section updated to add new ICD-10 procedure codes 30230U2, 30233U2, 30240U2, 30243U2, 30230U3, 30233U3, 30240U3, 30243U3, 30230U4, 30233U4, 30240U4, and 30243U4, effective 10/01/2019.

02/26/2020: Policy description updated regarding conventional conditioning for hematopoietic cell transplantation. Policy statements unchanged.

03/29/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/22/2021: Code Reference section updated to make note of deleted ICD-10 procedure codes.

02/21/2022: Policy description updated regarding treatment of primary amyloidosis. Policy statements unchanged.

11/17/2022: Code Reference section updated to remove deleted ICD-10 procedure codes 30230G0, 30240G0, 30230Y0, 30240Y0, 30230G2, 30240G2, 30230G3, 30240G3, 30230G4, 30240G4, 30230U2, 30240U2, 30230U3, 30240U3, 30230U4, 30240U4, 30230Y2, 30240Y2, 30230Y3, 30240Y3, 30230Y4, and 30240Y4.

03/13/2023: Policy description updated regarding primary amyloidosis. Policy statements unchanged.

12/21/2023: Code Reference section updated to revise the code description for CPT code 96446, effective 01/01/2024.

02/27/2024: Policy reviewed; no changes.

04/08/2025: Policy description updated. Policy statements unchanged.

SOURCE(S)

1. Blue Cross Blue Shield Association policy # 8.01.42

2. Blue Cross Blue Shield Association policy # 8.01.54

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Investigational Codes

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