Hematopoietic Cell Transplantation for Waldenström Macroglobulinemia - CAM 80154HB

Hematopoietic cell transplantation (HCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in 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). 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 "naive" and thus are associated with a lower incidence of rejection or graft-versus-host disease. Cord blood is discussed in greater detail in evidence review 70150.

For individuals who have Waldenström macroglobulinemia who receive HCT, the evidence includes case series. Relevant outcomes are overall survival, change in disease status, quality of life and treatment-related mortality and morbidity. Several retrospective series have evaluated HCT for Waldenström macroglobulinemia. Analyses of registry data have found overall survival rates of 52% at 5 years after allogeneic HCT and 68.5% after autologous HCT. The total number of patients studied is small and there is a lack of published controlled studies. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Clinical input and national and international clinical guidelines support the use of autologous HCT as salvage therapy for chemosensitive Waldenström macroglobulinemia. Allogeneic HCT is recommended in the context of clinical trials. Thus, autologous HCT may be considered medically necessary as salvage therapy for chemosensitive Waldenström macroglobulinemia and allogeneic HCT for Waldenström macroglobulinemia is considered investigational.

Waldenström 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 β2-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 Waldenström’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. 

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/L; 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 (HCT) 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.

Conventional Preparative Conditioning for HCT
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 patients’ bone marrow space. While the slower graft-versus-malignancy effect is considered 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 preengraftment 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 graft-versus-host disease, which also increases susceptibility of the patient to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiotherapy 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 prior to engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning for Allogeneic HCT
Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiotherapy than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of nonrelapse 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 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.

Autologous hematopoietic cell transplantation may be considered MEDICALLY NECESSARY
as salvage therapy of chemosensitive Waldenström macroglobulinemia.

Allogeneic hematopoietic cell transplantation is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY to treat Waldenström macroglobulinemia.

Policy Guidelines
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
The following considerations may supersede this policy:

  • State mandates requiring coverage for autologous bone marrow transplantation offered as part of clinical trials of autologous bone marrow transplantation approved by the National Institutes of Health (NIH).
  • Some plans may participate in voluntary programs offering coverage for patients participating in NIH-approved clinical trials of cancer chemotherapy, including autologous bone marrow transplantation.
  • Some contracts or certificates of coverage (e.g., FEP) may include specific conditions in which autologous bone marrow transplantation would be considered eligible for coverage.

Evidence reviews 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 uses 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 is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials 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.

Hematopoietic Cell Transplantation for Waldenström Macroglobulinemia
Clinical Context and Test Purpose
The purpose of hematopoietic cell transplantation is to provide a treatment option that is an alternative to or an improvement on existing therapies in individuals with Waldenström macroglobulinemia.

The question addressed in this evidence review is: does the use of hematopoietic cell transplantation improve the net health outcomes of individuals with Waldenström macroglobulinemia?

The following PICO was used to select literature to inform this review.

The relevant population of interest are patients with Waldenström macroglobulinemia.

The therapy being considered is hematopoietic cell transplantation.

Comparators of interest include chemotherapy, targeted therapy drugs, ad biologic therapy drugs.

The general outcomes of interest include overall survival, quality of life, treatment-related mortality, and treatment-related morbidity.

Follow-up over months to years is of interest for relevant outcomes.

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient clinical setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:  

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

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

Review of Evidence
Autologous Hematopoietic Cell Transplantation
Kyriakou et al. (2010) evaluated 158 adults with WM reported to the European Group for Blood and Marrow Transplantation between 1991 and 2005.1 Median time from diagnosis to autologous HCT 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 HCT. 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 HCT. Authors concluded that autologous HCT 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 Hematopoietic Cell Transplantation
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 HCT.2 Patients had relapsed after receiving at least 1 line of prior therapy. Hematopoietic cells were obtained from human leukocyte antigen-matched or -mismatched donors; cord blood stem cells were excluded. Sixty-seven patients received myeloablative conditioning (MAC) and 67 received reduced-intensity conditioning (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 vs RIC) did not impact treatment-related mortality, relapse, or progression-free survival rates. Sixty-five deaths were reported, with the most common causes being graft-versus-host disease (28%) and primary disease (23%).

Kyriakou et al. (2010) retrospectively analyzed data on 86 patients who had allogeneic HCT for WM.3 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 HCT. Fifty-nine (68.6%) patients had chemosensitive disease at the time of allogeneic HCT. 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 graft-versus-host disease (23%) and primary disease (23%). The occurrence of chronic graft-versus-host disease was associated with a lower relapse rate.

Section Summary: Hematopoietic Cell Transplantation for Waldenström Macroglobulinemia
Several retrospective series have evaluated HCT for WM. Analyses of registry data have reported 5-year OS rates of 52% after allogeneic HCT and 68.5% after autologous HCT. The total number of patients studied was small and there is a lack of published controlled studies.

Summary of Evidence
For individuals who have Waldenström macroglobulinemia who receive HCT, the evidence includes case series. Relevant outcomes are overall survival, change in disease status, quality of life, and treatment-related mortality and morbidity. Several retrospective series have evaluated HCT for Waldenström macroglobulinemia. Analyses of registry data have found 5-year overall survival rates of 52% after allogeneic HCT and 68.5% after autologous HCT. The total number of patients studied is small and there is a lack of published controlled studies. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 5 academic medical centers, including 3 transplant centers, while this policy was under review in 2011. Input indicated that autologous hematopoietic cell transplantation may be considered medically necessary as salvage therapy for Waldenström macroglobulinemia that is chemosensitive. Input was mixed on use of allogeneic hematopoietic cell transplantation, with comments suggesting the procedure be performed as part of a clinical trial.

Practice Guidelines and Position Statements
National Comprehensive Cancer Network
National Comprehensive Cancer Network guidelines on Waldenström macroglobulinemia (WM) and lymphoplasmacyticlymphoma (v.1.2021) 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 cell transplant(myeloablative or nonmyeloablative).4 The Network noted that allogeneic cell transplantation "should ideally be undertaken in the context of a clinical trial." For potential autologous cell transplantation candidates, the guidelines also provide suggested treatment regimens considered non-stem-cell toxic.

Mayo Clinic Cancer Center
In 2017, the Mayo Clinic Cancer Center updated its guidelines on the diagnosis and management of WM.5 The guidelines noted that patients who are potentially eligible for autologous hematopoietic cell transplantation (HCT; < 70years 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 HCT should be considered for first orsecond 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 HCT) (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.The panel concluded that autologous HCT is a treatment option for high-risk WM patients who are eligible for transplant. It further stated that autologous HCT 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 HCT, 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.7 The guidelines provided the following treatment recommendation for HCT: "Younger patients with good physical fitness shouldbe 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)."

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Currently unpublished trials that might influence this review are listed in Table 1.

Table 1. Summary of Key Trials


Trial Name

Planned Enrollment

Completion Date




A Phase II Study to Assess Immunosuppression With Sirolimus Combined With Cyclosporine (CSP) and Mycophenolate Mofetil (MMF) for Prevention of Acute GVHD After Non-Myeloablative HLA Class I or II Mismatched Donor Hematopoietic Cell Transplantation- A Multi-Center Trial



Feb 2019 (completed)




Autologous Stem-cell Transplantation Versus Conventional Chemotherapy for High Risk Waldenström Macroglobulinemia - a Prospective Multicentre    Phase Trial From China



May 2020 (recruitment status unknown as of Jul 2016)


NCT: national clinical trial.  


  1. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and autologous stem-cell transplantation in Waldenstrom macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. JClin Oncol. May 01 2010; 28(13): 2227-32. PMID 20368570
  2. 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): 60-66.PMID 27789362
  3. Kyriakou C, Canals C, Cornelissen JJ, et al. Allogeneic stem-cell transplantation in patients with Waldenstrom 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
  4. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma. Version 1.2021.https://www.nccn.org/professionals/physician_gls/pdf/waldenstroms.pdf. Accessed January 4, 2021.
  5. Kapoor P, Ansell SM, Fonseca R, et al. Diagnosis and Management of Waldenstrom Macroglobulinemia: MayoStratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016. JAMA Oncol. Sep 012017; 3(9): 1257-1265. PMID 28056114
  6. Leblond V, Kastritis E, Advani R, et al. Treatment recommendations from the Eighth International Workshop on Waldenstrom's Macroglobulinemia. Blood. Sep 08 2016; 128(10): 1321-8. PMID 27432877
  7. 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

Coding Section






Management of recipient hematopoietic cell donor search and cell acquisition



Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic



Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous



Transplant preparation of hematopoietic progenitor cells; cryopreservation and storage



 thawing of previously frozen harvest without washing, per donor



 thawing of previously frozen harvest, with washing, per donor



 specific cell depletion with harvest, T-cell depletion



 tumor-cell depletion



 red blood cell removal



 platelet depletion



 plasma (volume) depletion



 cell concentration in plasma, mononuclear, or buffy coat layer



Bone marrow harvesting for transplantation; allogeneic



Bone marrow harvesting for transplantation; autologous



Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor



 autologous transplantation



Chemotherapy administration code range



Chemotherapy drug code range



Cord blood harvesting for transplantation, allogeneic



Cord blood derived stem-cell transplantation, allogeneic




Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of posttransplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)

ICD-10- CM


Waldenstrom macroglobulinemia



ICD-10-PCS codes are only used for inpatient services.




Administration, circulatory, transfusion, central vein, percutaneous, autologous, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list



30243X2, 30243Y2

Administration, circulatory, transfusion, central vein, percutaneous, allogeneic related, code by substance (bone marrow, cord blood or stem cells, hematopoietic) code list



30243X3, 30243Y3

Administration, circulatory, transfusion, central vein, percutaneous, allogeneic unrelated, code by substance (bone marrow, cord blood or stem cells, hematopoietic)




Administration, circulatory, transfusion, central vein, percutaneous, allogeneic unspecified, code by substance (bone marrow, cord blood or stem cells, hematopoietic)










Surgical, lymphatic and hemic systems, extraction, bone marrow, code list

Type of Service



Place of Service



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. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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