Medical policy: Hematopoietic Cell Transplantation for Primary Amyloidosis

Policy number: MP 9.045

Effective date: 5/1/2026

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. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Cross-references

• MP 9.001 Placental/Umbilical Cord Blood as a Source of Stem Cells

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO – Refer to FEP Medical Policy Manual .

Description/background

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 4000 new cases in the United States 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.

Treatment

Historically, this disease has had a poor prognosis, with a median survival from diagnosis of approximately 12 months, although outcomes have improved with combination chemotherapy using alkylating agents and autologous hematopoietic stem cell transplantation (HCT).

Emerging approaches include the use of immunomodulatory drugs (e.g., thalidomide, lenalidomide, pomalidomide) and the proteasome inhibitor, bortezomib. The anti-CD38 monoclonal antibody daratumumab/hyaluronidase 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 and 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/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 refers to the infusion of hematopoietic stem cells to restore bone marrow function in cancer patients 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 (GVHD). Cord blood is discussed in greater detail in MP 9.001.

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 response. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.

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 effect mediated by non-self-immunologic effector cells that develop 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 effects 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 suppressive drugs are required to minimize graft rejection and GVHD, which also increase susceptibility 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. 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 evidence review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

Regulatory status

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 (CFR) title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Rationale

Summary of evidence

For individuals with primary amyloidosis who receive autologous HCT, the evidence includes a network meta-analysis, randomized controlled trials (RCTs), nonrandomized 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.

For individuals with primary amyloidosis who receive autologous HCT, the evidence includes a network meta-analysis, randomized controlled trials (RCTs), nonrandomized 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 more recent studies. 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 a meaningful improvement in the net health outcome.

For individuals with primary amyloidosis who receive allogeneic HCT, the evidence includes case reports. Relevant outcomes are OS, 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.

Definitions

N/A

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the members’ benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Investigational; therefore, not covered

Allogeneic hematopoietic cell transplantation to treat primary systemic amyloidosis.

Covered when medically necessary

Autologous hematopoietic cell transplantation to treat primary systemic amyloidosis.

References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Systemic Light Chain Amyloidosis. Version 1.2025. Accessed December 2, 2024.
2. National Organization for Rare Disorders (NORD). Amyloidosis. Updated December 2024. Accessed December 2, 2024.
3. Gertz MA, Lacy MQ, Dispenzieri A. Amyloidosis: recognition, confirmation, prognosis, and therapy. Mayo Clin Proc. May 1999; 74(5): 490-4. PMID 10319082
4. Comenzo RL, Gertz MA. Autologous stem cell transplantation for primary systemic amyloidosis. Blood. Jun 15 2002; 99(12): 4276-82. PMID 12036853
5. Moreau P, Leblond V, Bourquelot P, et al. Prognostic factors for survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol. Jun 1998; 101(4): 766-9. PMID 9674753
6. 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. Jul 15 2001; 19(14): 3350-6. PMID 11454882
7. Comenzo RL, Vosburgh E, Falk RH, et al. Dose-intensive melphalan with blood stem cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients. Blood. May 15 1998; 91(10): 3662-70. PMID 9573002
8. 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. May 15 2004; 103(10): 3960-3. PMID 14739213
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): 465-70. PMID 10713619
10. 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): 853-5. PMID 10516696
11. Cai Y, Xu S, Li N, et al. Efficacy of Chemotherapies and Stem Cell Transplantation for Systemic AL Amyloidosis: A Network Meta‑Analysis. Front Pharmacol. 2019; 10: 1601. PMID 32063846
12. Jaccard A, Moreau P, Leblond V, et al. High-dose melphalan versus melphalan plus dexamethasone for AL amyloidosis. N Engl J Med. Sep 13 2007; 357(11): 1083-93. PMID 17855669
13. 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): 1036-41. PMID 24887378
14. 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. PMID 33460466
15. 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. PMID 14734330
16. Vesole DH, Pérez 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): 880-8. PMID 16835967
17. 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 15 2007; 110(10): 3561-3. PMID 17673601
18. 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): 4346-52. PMID 21828140
19. Madan S, Kumar SK, Lacy MQ, et al. High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement. Blood. Feb 02 2012; 119(5): 1111-22. PMID 22214893
20. Dispenzieri A, White JA, Wik 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): 3741-9. PMID 26371138
21. 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. PMID 31410841
22. 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): 1302-7. PMID 23604071
23. Girnius S, Seldin DC, Meyer-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): 434-9. PMID 24317129
24. 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): 722-8. PMID 24266428
25. Kim SJ, Lee KY, Jang HR, et al. Autologous stem cell transplantation in light-chain amyloidosis patients: a single-center experience in Korea. Amyloid. Dec 2013; 20(4): 204-11. PMID 23914780
26. Sanchorawala V, Horen P, Seldin DC, et al. Modified high-dose melphalan and autologous SCT for AL amyloidosis of high-risk myeloma: analysis of SWOG trial S0115. Bone Marrow Transplant. Nov 2013; 48(12): 1537-42. PMID 23852321
27. Wechalekar AD, Hawkins PN, Gillmore JD. Perspectives in treatment of AL amyloidosis. Br J Haematol. Feb 2008; 140(4): 365-77. PMID 18162121
28. 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. PMID 32165328
29. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Stem Cell Transplantation (Formerly 110.8.1) (110.23). 2024.