Latest Review Date: January 2024

Category: Surgery                                                                 

POLICY:

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.

DESCRIPTION OF PROCEDURE OR SERVICE:

Primary Systemic 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 exhibit a pathognomonic red-green birefringences when stained with Congo red dye and examined under polarized light. These diseases are classified based on the type of amyloidogenic protein involved, as well as 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 protein is produced at the site of deposition. Light-chain amyloidosis (AL), the most common type of systemic amyloidosis, has an incidence of approximately 9 to 14 cases per million persons per year with approximately 4000 new cases in the US each year. The typical age at diagnosis is approximately about 50 to 65. The amyloidogenic protein in AL amyloidosis is an immunoglobulin (Ig) light chain or light-chain fragment that is produced by a clonal population of plasma cells in the bone marrow. While the plasma cell burden in AL 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 AL amyloidogenic proteins causes organ dysfunction, most frequently in the kidneys, heart, and liver, although the central nervous system and brain may be affected.

Treatment

Historically, primary systemic amyloidosis 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 (e.g., 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 a 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.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) refers to a procedure in which hematopoietic cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole-body radiation therapy. Hematopoietic cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. 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 (GVHD). The use of cord blood is discussed in Medical Policy #439: Placental/Umbilical Cord Blood as a Source of Stem Cells.

Autologous HCT

Immunologic 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 remission. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Allogeneic HCT

Immunologic 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. HLA 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 (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM 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 effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and GVHD, 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 non-relapse mortality and relapse due to residual disease. RIC 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 evidence review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be non-myeloablative, as opposed to fully myeloablative (conventional) regimens.

KEY POINTS:

The most recent literature review was performed through November 13, 2023. The following is a summary of key literature to date.

Summary of Evidence

For individuals with primary amyloidosis who receive autologous HCT, the evidence includes a network meta-analysis, RCT, non-randomized comparative studies, and large case series. Relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, and treatment-related morbidity and mortality. Use of autologous HCT for primary amyloidosis rapidly eradicates the amyloid light chain produced by the clonal plasma cell populations, which is the proximal cause of pathology and subsequent death. This procedure has extended survival rates to a reported 77% at 5 years and 56% at 10 years in patients who respond to treatment. Complete response to treatment has been reported in 34% to 69.6% of patients, while transplant-related mortality rates have declined significantly in studies that are more recent. Therefore, autologous HCT is an important treatment option for patients who are deemed eligible. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with primary amyloidosis who receive allogeneic HCT, the evidence includes case reports. Relevant outcomes are overall survival , disease-specific survival, change in disease status, and treatment-related morbidity and mortality. Evidence on the use of allogeneic HCT is sparse and has shown high treatment-related mortality. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Practice Guidelines and Position Statements

American Society for Transplantation and Cellular Therapy

In 2020, the American Society for Transplantation and Cellular Therapy (ASTCT) issued guidelines on indications for hematopoietic cell transplantation (HCT) and immune effector therapy. ASTCT gave the rating of N (not generally recommended; neither evidence nor clinical practice supports the routine use) for the use of allogeneic HCT in the treatment of primary amyloidosis in adults. ASTCT gave a rating of S (standard of care) for the use of autologous HCT in the treatment of primary amyloidosis in adults.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network guidelines on systemic light chain amyloidosis (v.1.2024) recommend assessing organ involvement based on amyloidosis consensus criteria in newly diagnosed disease. Next, patients should be evaluated for stem cell transplant candidacy. The current guidelines prefer the regimen of daratumumab and hyaluronidase-fihj/bortezomib/cyclophosphamide/dexamethasone as initial systemic therapy in most individuals. 

U.S. Preventive Services and Task Force Recommendations

Not applicable.

KEY WORDS:

Amyloidosis, High-Dose Chemotherapy, Primary Amyloidosis, Systemic Amyloidosis, Hematopoietic Cell Transplant, HCT, Light-chain amyloidosis, AL

APPROVED BY GOVERNING BODIES:

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.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  

CURRENT CODING: 

CPT Codes:  

HCPCS:

REFERENCES:

1. Cai Y, Xu S, Li N, et al. Efficacy of Chemotherapies and Stem Cell Transplantation for Systemic AL Amyloidosis: A Network MetaAnalysis. Front Pharmacol. 2019; 10: 1601.
2. Cibeira MT, Sanchorawala V, Seldin DC et al. Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation; long-term results in a series of 421 patients. Blood Oct 20 2011; 118(16):4346-4352.
3. Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood 2002; 99(12):4276-4282.
4. Comenzo RL, Vosburgh E, Falk RH et al. Dose-intensive melphalan with blood stem-cell support for the treatment of AL amyloidosis: survival and responses in 25 patients. Blood 1998; 91(10):3662-3670.
5. Dispenzieri A, Lacy MQ, Kyle RA et al. Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival. J Clin Oncol 2001; 19(14):3350-3356.
6. Dispenzieri A, Kyle RA, Lacy MQ et al. Superior survival in primary systemic amyloidosis patients undergoing peripheral blood stem cell transplantation: a case-control study. Blood 2004; 103(10):3960-3963.
7. Dispenzieri A, Seenithamby K, Lacy MQ et al. Patients with immunoglobulin light chain amyloidosis undergoing autologous stem cell transplantation have superior outcomes compared with patients with multiple myeloma: a retrospective review from a tertiary referral center. Bone Marrow Transplant Oct 2013; 48(10):1302-1307.
8. D'Souza A, Dispenzieri A, Wirk B, et al. Improved outcomes after autologous hematopoietic cell transplantation for light chain amyloidosis: a Center for International Blood and Marrow Transplant Research study. J Clin Oncol. Nov 10 2015; 33(32):3741-3749.
9. Gertz MA, Lacy MQ, Dispenzieri A. Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant Mar 2000; 25(5):465-470.
10. Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, prognosis, and conventional therapy. In: Hematology May 1999; 74(5):490-494.
11. Girnius S, Seldin DC, Meier-Ewert HK et al. Safety and efficacy of high-dose melphalan and auto- SCT in patients with AL amyloidosis and cardiac involvement. Bone Marrow Transplant. Mar 2014; 49(3):434-439.
12. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
13. Jaccard A, Moreau P, Leblond V et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med Sept 13 2007; 357(11):1083-1093.
14. Jimenez-Zepeda VH, Franke N, Reece DE et al. Autologous stem cell transplant is an effective therapy for carefully selected patients with AL amyloidosis: experience of a single institution. Br J Haematol. Mar 2014; 164(5):722-728.
15. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247- 1256.
16. Kim SJ, Lee GY, Jang HR et al. Autologous stem cell transplantation in light-chain amyloidosis patients: a single-center experience in Korea. Amyloid Dec 2013; 20(4):204-211.
17. Madan S, Kumar SK, Dispenzieri A et al. High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement. Blood Feb 02 2012; 119(5):1117-1122.
18. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-1869.
19. Moreau P, Leblond V, Bourquelot P et al. Prognostic factors of survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol Jun1998; 101(4):766-769.
20. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Systemic Light Chain Amyloidosis. Version 1.2024. www.nccn.org/professionals/physician_gls/pdf/amyloidosis.pdf. 
21. National Organization for Rare Disorders (NORD). Amyloidosis rarediseases.org/rare-diseases/amyloidosis/#:~:text=While%20the%20incidence%20is%20thought,at%20about%20age%2050%2D65. Update 2018. 
22. Parmar S, Kongtim P, Champlin R, et al. Auto-SCT improves survival in systemic light chain amyloidosis: a retrospective analysis with 14-year follow-up. Bone Marrow Transplant. Aug 2014; 49(8):1036-1041.
23. Saba N, Sutton D, Ross H et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant Oct 1999; 24(8):853-855.
24. Sanchorawala V, Hoering A, Seldin DC et al. Modified high-dose melphalan and autologous SCT for AL amyloidosis or high-risk myeloma: analysis of SWOG trial S0115. Bone Marrow Transplant Nov 2013; 48(12):1537-1542.
25. Sanchorawala V, Skinner M, Quillen K et al. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood Nov 2007; 110(10):3561-3563.
26. Sharpley FA, Manwani R, Petrie A, et al. Autologous stem cell transplantation vs bortezomib based chemotherapy for the first-line treatment of systemic light chain amyloidosis in the UK. Eur J Haematol. Apr 2021; 106(4): 537-545.
27. Sharpley FA, Petrie A, Mahmood S, et al. A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom. Br J Haematol. Dec 2019; 187(5): 642-652.
28. Skinner M, Sanchorawala V, Seldin DC et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med Jan 20 2004; 140(2):85-93.
29. Vesole DH, Perez WS, Akasheh M et al. High-dose therapy and autologous hematopoietic stem cell transplantation for patients with primary systemic amyloidosis: a Center for International Blood and Marrow Transplant research study. Mayo Clin Proc Jul 2006; 81(7):880-888.
30. Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment of AL amyloidosis. Br J Haematol. Feb 2008; 140(4): 365-77.

POLICY HISTORY:

Medical Policy Group, August 2009 (2)

Medical Policy Administration Committee, September 2009

Available for comment September 4-October 19, 2009

Medical Policy Panel, September 2010

Medical Policy Group, February 2011 (2)

Medical Policy Panel, February 2011

Medical Policy Group, June 2011 (2): Policy revised to address only primary amyloidosis

Medical Policy Administration Committee, July 2011

Available for comment July 6 through August 22, 2011

Medical Policy Group, December 2011(3): 2012 Code Updates-added 38230 & 38232 and updated codes 38209 & 38209

Medical Policy Group, September 2012 (3): 2012 Updates to Key Points and References

Medical Policy Panel, February 2013

Medical Policy Group, March 2013 (3): 2013 Updates to Key Points and References; no change in policy statement

Medical Policy Group, January 2014 (1): 2014 Coding Update: added current codes Q2049 and Q2050 to coding section; new codes are included in the chemotherapy drug code range

Medical Policy Panel, February 2014

Medical Policy Group, February 2014 (3): 2014 Updates to Key Points & References; no change in policy statement.

Medical Policy Panel, February 2015

Medical Policy Group, February 2015 (2): 2015 Updates to Key Points, Coding, and References, no change to policy statement.

Medical Policy Panel, December 2016

Medical Policy Group, December 2016 (7): 2016 Updates to Title- removed “stem,” Key Points and References. Clarification to Policy Statement- removed “stem” from policy statement. No change in intent.

Medical Policy Group, December 2017. Annual Coding Update 2018. Added new CPT code 38222 effective 1/1/18 to the Current Coding section. Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Panel, December 2017

Medical Policy Group, December 2017 (7): 2017 Updates to Key Points and References. Policy Statement- removed statement from 2011. No change in intent.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3):2019 Updates to Key Points, Practice Guidelines and Position Statements and Key Words: added: Hematopoietic Cell Transplant, HCT, Light-chain amyloidosis, and AL. No changes to policy statement or intent.

Medical Policy Panel, January 2020

Medical Policy Group, February 2020 (3): 2020 Updates to Key Points and References. No changes to policy statement or intent.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements and References. Policy statement updated to remove “not medically necessary,” no changes to policy statement or intent.

Medical Policy Panel, January 2022

Medical Policy group, January 2022 (3): 2022 Updates to Key Points, Practice Guidelines and Position Statements and References. No other changes to policy statement or intent.

Medical Policy Panel, January 2023

Medical Policy Group, January 2023 (3): 2023 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

Medical Policy Panel, January 2024

Medical Policy Group, January 2024 (3): Updates to Description, Key Points, Approved by Governing Bodies, Benefit Application and References. Removed Policy Guidelines due to Policy #478 is archived. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.