Medical Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Waldenström Macroglobulinemia

Number:SUR703.050

Effective Date:07-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Autologous hematopoietic stem-cell transplantation (HSCT) may be considered medically necessary as salvage therapy of chemosensitive Waldenström macroglobulinemia (WM).

Allogeneic HSCT is considered experimental, investigational and/or unproven to treat WM.

NOTE: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplantation (HSCT) refers to a procedure in which hematopoietic stem-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 stem-cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). 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).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Waldenström Macroglobulinemia (WM)

WM is a clonal disorder of B-lymphocyte cell that accounts for 1% to 2% of hematologic malignancies, with an estimated 1500 new cases annually in the U.S. 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 ß2-microglobulin level as predictors of outcome.

The Revised European American Lymphoma (REAL) and World Health Organization (WHO) classification and a consensus group formed at the Second International Workshop on WM 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.

Treatment

The 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 less than 10 g/dL; platelet count less than 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 HSCT often combine rituximab with other agents (e.g., 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.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (1) Hematopoietic stem-cells are included in these regulations.

Rationale:

This policy was originally created in 1990, moved to this policy in 2010. This policy has been updated periodically with reviews of the MedLine database. The most recent literature review was performed through June 2018. While the coverage of this policy does not address myeloablative (MA) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes may be influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function--including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Few published data are available and there is a lack of studies comparing HSCT with other treatments (e.g., chemotherapy) in patients who have Waldenström macroglobulinemia (WM). Several retrospective series have been published.

Autologous HSCT

Kyriakou et al. (2010) evaluated 158 adults with WM reported to the European Group for Blood and Marrow Transplantation between 1991 and 2005. (2) Median time from diagnosis to autologous HSCT was 1.7 years (range, 0.3-20.3 years); 32% of the patients experienced treatment failure with at least 3 lines of therapy; and 93% had sensitive disease at the time of HSCT. Median follow-up for surviving patients was 4.2 years (range, 0.5-14.8 years). Nonrelapse mortality was 3.8% at 1 year. Relapse rate was 52.1% at 5 years. Progression-free survival and overall survival (OS) were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemo-refractoriness at HSCT. Authors concluded that autologous HSCT is a feasible procedure in young patients with advanced WM but that it should not be offered to patients with chemoresistant disease or to those who have received more than 3 lines of therapy.

Allogeneic HSCT

Data from the Center for International Blood and Marrow Transplant Research registry have been published periodically, most recently in 2017. Cornell et al. (2017) reported retrospectively on 144 adults with WM entered in the registry between 2001 and 2013 who underwent allogeneic HSCT. (3) Patients had relapsed after receiving at least 1 line of prior therapy. Hematopoietic cells were obtained from human leukocyte antigen (HLA)-matched or -mismatched donors; cord blood stem-cells were excluded. Sixty-seven patients received MA conditioning (MAC) and 67 received RIC. Over half of patients (n=82 [57%]) had chemosensitive disease. Median follow-up after transplant was 70 months. OS rates were 74% at 1 year and 52% at 5 years. Patients with chemosensitive disease had significantly better 1- and 5-year OS rates compared with patients who had chemoresistant disease. Conditioning intensity (MAC versus RIC) did not impact treatment-related mortality, relapse-free survival (RFS), or progression-free survival (PFS) rates. Sixty-five deaths were reported, with the most common causes being GVHD (28%) and primary disease (23%).

Kyriakou et al. (2010) retrospectively analyzed data on 86 patients who had allogeneic HSCT for WM. (4) Patients underwent MAC (n=37) or RIC (n=49) regimens. Median age was 49 years (range, 23-64 years); 47 patients had received 3 or more previous lines of therapy; and 8 patients had experienced failure on a prior autologous HSCT. Fifty-nine (68.6%) patients had chemosensitive disease at the time of allogeneic HSCT. Median follow-up of the surviving patients was 50 months. The overall response rate was 75.6%. Relapse rates at 3 years were 11% for MAC and 25% for RIC. The OS rate at 5 years was 62% for MAC and 64% for RIC. Thirty deaths were reported; causes of death included GVHD (23%) and primary disease (23%). The occurrence of chronic GVHD was associated with a lower relapse rate.

Section Summary: Autologous and Allogeneic HSCT

Several retrospective series have evaluated HSCT for WM. Analyses of registry data have reported 5-year OS rates of 52% after allogeneic HSCT and 68.5% after autologous HSCT. The total number of patients studied was small and there is a lack of published controlled studies.

Ongoing and Unpublished Clinical Trials

Currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT01251575

Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients with Blood Cancer Undergoing Peripheral Blood Stem Cell Transplant

80

Nov 2018

NCT02844361

Comparison of ASCT and Conventional Chemotherapy in High Risk Waldenström Macroglobulinemia (BDH-WM03)

70

May 2020

Table Key:

NCT: national clinical trial.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

In 2011, the Blue Cross Blue Shield Association requested and received clinical input from various physician specialty societies and academic medical centers.

In particular, the reviewers were specifically asked to address the issue of the use of HSCT in the treatment of WM. The input indicated that autologous HSCT may be considered medically necessary as salvage therapy in WM that is chemosensitive. The input was mixed for use of allogeneic HSCT, with comments about this being performed as part of a clinical trial.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

The NCCN guidelines on WM and lymphoplasmacytic lymphoma (v.1.2018) indicate that, for patients with previously treated WM, stem-cell transplantation may be appropriate in selected cases with either: high-dose therapy with autologous stem-cell rescue or allogeneic stem-cell transplant (myeloablative or nonmyeloablative). (5) The NCCN noted that allogeneic HSCT “should ideally be undertaken in the context of a clinical trial.” For potential autologous HSCT candidates, the guidelines also provide suggested treatment regimens considered non-stem-cell toxic and possibly stem-cell toxic.

Mayo Clinic Cancer Center

In 2017, the Mayo Clinic Cancer Center updated its guidelines on the diagnosis and management of WM. (6) The guidelines noted that patients who are potentially eligible for autologous HSCT (<70 years of age and with chemosensitive disease), should consider harvesting stem-cells during first remission after a low tumor burden has been achieved. The guidelines recommended: “Autologous HSCT should be considered for first or second relapse in transplant-eligible patients with chemosensitive disease, especially if the first remission duration is short (<2 years). Patients with refractory WM should not be offered [autologous HSCT] (level 3, grade B).”

Eighth International Workshop on Waldenström’s Macroglobulinemia

In 2016, consensus recommendations from the Eighth International Workshop on Waldenström’s Macroglobulinemia were published. (7) The panel concluded that autologous HSCT is a treatment option for high-risk WM patients who are eligible for transplant. It further stated that autologous HSCT should be offered at early relapses and is not as beneficial once patients have been exposed to more than 3 lines of therapy or in those with chemotherapy-refractory disease. Regarding allogeneic HSCT, it stated that this treatment, “when appropriate, should preferably be considered in the context of clinical trials.”

Myeloma Foundation of Australian

In 2017, the Myeloma Foundation of Australia published practice guidelines on the treatment of patients with WM. (8) The guidelines provided the following treatment recommendation for HSCT: “Younger patients with good physical fitness should be considered for autologous and allogeneic stem-cell transplantation at first or second relapse and should avoid stem-cell-toxic therapies such as fludarabine (Level III, grade C).”

Summary of Evidence

For individuals who have Waldenström macroglobulinemia (WM) who receive hematopoietic stem-cell transplantation (HSCT), the evidence includes case series. Relevant outcomes are overall survival (OS), change in disease status, quality of life, and treatment-related mortality and morbidity. Several retrospective series have evaluated HSCT for WM. Analyses of registry data have found 5-year OS rates of 52% after allogeneic HSCT and 68.5% after autologous HSCT. The total number of patients studied is small and there is a lack of published controlled studies. However, based on clinical input, autologous HSCT being used as a salvage therapy for chemosensitive WM, the evidence is sufficient to determine the effects of the technology on health outcomes. For allogeneic HSCT to treat WM, the evidence is insufficient to determine the effects of the technology on health outcomes.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. FDA – Tissue and Tissue Products (Parts 1270 and 1271) (February 23, 2016). Food and Drug Administration – Center for Biologics Evaluation and Research. Available at <http://www.fda.gov> (accessed on 2018 June 16).

2. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and autologous stem-cell transplantation in Waldenström macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. May 1 2010; 28(13):2227-32. PMID 20958570

3. Cornell RF, Bachanova V, D'Souza A, et al. Allogeneic transplantation for relapsed Waldenstrom macroglobulinemia and lymphoplasmacytic lymphoma. Biol Blood Marrow Transplant. Jan 2017; 23(1):60-6. PMID 27789362

4. Kyriakou C, Canals C, Cornelissen JJ, et al. Allogeneic stem-cell transplantation in patients with Waldenström macroglobulinemia: report from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. Nov 20 2010; 28(33):4926-34. PMID 20956626

5. NCCN – Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. V.1.2018; Available at <http://www.nccn.org> (accessed 2018 June 16).

6. Kapoor P, Ansell SM, Fonseca R, et al. Diagnosis and management of Waldenstrom macroglobulinemia: Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol. Sep 1 2017; 3(9):1257-65. PMID 28056114

7. Leblond V, Kastritis E, Advani R, et al. Treatment recommendations from the Eighth International Workshop on Waldenstrom's Macroglobulinemia. Blood. Sep 8 2016; 128(10):1321-8. PMID 27432877

8. Talaulikar D, Tam CS, Joshua D, et al. Treatment of patients with Waldenstrom macroglobulinaemia: clinical practice guidelines from the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Intern Med J. Jan 2017; 47(1):35-49. PMID 28076910

9. Hematopoietic Stem-Cell Transplantation for Waldenström’s Macroglobulinemia. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 February) Therapy 8.01.54.

Policy History:

DateReason
7/15/2018 Document updated with literature review. Coverage unchanged. Rationale reorganized. References 1,3, 6-8 were added; numerous references removed.
4/15/2017 Reviewed. No changes.
7/1/2016 Document updated with literature review. Coverage unchanged.
2/1/2015 Document updated with literature review. Coverage language modified, without change to coverage position. CPT/HCPCS code(s) updated. Title changed from: Stem-Cell Transplant for Waldenstrom Macroglobulinemia.
10/15/2013 New medical document originating from: SUR703.046, Stem-Cell Transplant for Primary Amyloidosis and Waldenström’s Macroglobulinemia (WM). Allogeneic stem-cell support (AlloSCS), autologous stem-cell support (AutoSCS), tandem or triple stem-cell transplant, donor leukocyte infusion (DLI), and hematopoietic progenitor cell boost are considered experimental, investigational and unproven. Any related services for the treatment of WM, such as short tandem repeat (STR) markers, are considered experimental, investigational and unproven. Previously the coverage information originated from SUR703.046, Stem-Cell Transplant for Primary Amyloidosis and Waldenström’s Macroglobulinemia (as a combined policy document) and from: SUR703.017, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies. Stem cell transplant continues to be medically necessary when stated criteria are met. NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem Cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem Cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem Cell Support for Malignancies.

Archived Document(s):

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