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MP 8.01.54 Hematopoietic Stem-Cell Transplantation for Waldenström Macroglobulinemia

Medical Policy    
Original Policy Date
Last Review Status/Date
Reviewed with literature search/2:2015
  Return to Medical Policy Index


Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


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 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.

Conventional Preparative Conditioning for HSCT

The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (eg, 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 patients’ 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 HSCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

The success of autologous HSCT 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 HSCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic HSCT

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 but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM 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 HSCT 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 the purposes of this policy, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

Waldenström Macroglobulinemia

WM is a B-cell malignancy that accounts for 1% to 2% of hematologic malignancies, with an estimated 1500 new cases annually in the United States. The median age of WM patients at presentation is 63 to 68 years, with men comprising 55% to 70% of cases. Median survival of WM ranges from 5 to10 years, with age, hemoglobin concentration, serum albumin level, and β2-microglobulin level as predictors of outcome.

The Revised European American Lymphoma (REAL) and World Health Organization 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 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 hemoglobin concentration less than 100 g/L; platelet count less than 100x109/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 have included alkylating agents (chlorambucil, cyclophosphamide, melphalan), purine analogs (cladribine, fludarabine), and monoclonal antibody agents (rituximab), alone or in various combinations. Plasma exchange is indicated for acute treatment of symptomatic hyperviscosity.



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

Allogeneic hematopoietic stem cell transplantation is considered investigational to treat Waldenström macroglobulinemia.



Policy Guidelines 

In 2003, CPT centralized codes describing allogeneic and autologous HSCT services to the hematology section (38204-38242). Not all codes are applicable for each stem-cell transplant procedure. For example, Plans should determine if cryopreservation is performed. A range of codes describes services associated with cryopreservation, storage, and thawing of cells (38208-38215).

CPT 38208 and 38209 describe thawing and washing of cryopreserved cells

CPT 38210-38214 describe certain cell types being depleted

CPT 38215 describes plasma cell concentration

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.



This policy was created in 2011 and has been updated regularly with searches of the National Library of Medicine PubMed database. The most recent literature review is for the period December 23, 2013, to December 2, 2014. Following is a summary of key literature to date.

A 2002 International Workshop summarized clinical experience (combined n=49) using autologous hematopoietic stem-cell transplantation (HSCT) for Waldenström macroglobulinemia (WM).(1) These were all small feasibility studies that reported response rates but lacked data on survival and other long-term outcomes. A total of 9 (18%) achieved complete response and 39 (80%) achieved partial response, but data on the durability of these responses were unavailable.

A consensus panel from the Second International Workshop on Waldenström’s Macroglobulinemia recommended that autologous HSCT may be considered for selected patients with refractory or relapsing disease, but allogeneic transplants should be used only in the context of a clinical trial.(2) Another recent review agreed that the role of autologous HSCT for WM was not fully defined, although its empirical use might be appropriate for some patients with relapsed or refractory disease.(3) This review also considered allogeneic transplants for WM to be investigational therapy.

In 2004, a consensus panel from the Third International Workshop on Waldenström’s Macroglobulinemia suggested autologous HSCT may be considered for eligible patients with primary refractory or relapsing disease but that allogeneic transplants should be cautiously approached, only in the context of a clinical trial.(4) However, the review article does not cite evidence to support the recommendations. The panelists also concluded that it was not possible to recommend a particular first-line therapeutic approach; rather, the choice should be made on the basis of individual patient considerations. A retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) registry analysis of HSCT (autologous, n=10, allogeneic, n=26) for WM reported 3-year overall survival (OS) rates of 46% (95% confidence interval [CI], 27% to 65%) for allogeneic HSCT recipients and 70% (95% CI, 40% to 93%) for autologous HSCT patients. (5) Although the CIBMTR results appear favorable, it should be noted that patients in this report were heavily pretreated, highly heterogeneous in terms of disease characteristics and risk factors, and received a variety of conditioning regimens, including myeloablative and RIC, between 1986 and 2002. These data, taken together, are insufficient to form conclusions about the potential clinical efficacy of HSCT for WM. Subsequent additional review articles are in general agreement with this position.(6,7)

Kyriakou et al reported on 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation between January 1991 and December 2005.(8) 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 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 (NRM) was 3.8% at 1 year. Relapse rate was 52.1% at 5 years. Progression-free survival and 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. The authors conclude 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 and to those who have received more than 3 lines of therapy.

Kyriakou et al also reported on a retrospective analysis of a smaller group of patients who had allogeneic HSCT for WM.(9) A total of 86 patients received allogeneic HSCT by using either myeloablative conditioning (MAC; n=37) or reduced-intensity conditioning (RIC; n=49) regimens. The 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. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of allogeneic HSCT. Median follow-up of the surviving patients was 50 months. The overall response rate was 75.6%. The relapse rates at 3 years were 11% for MAC and 25% for RIC. OS at 5 years was 62% for MAC and 64% for RIC, respectively. The occurrence of chronic GVHD was associated with a lower relapse rate. The authors concluded that allogeneic HSCT can induce durable remissions in a selected population of young and heavily pretreated patients who have WM.

Little additional published evidence is available on use of autologous HSCT for WM, as summarized in review articles published in 2011 and 2012.(10-13) No randomized trials have been reported. For the most recent update (February 2014) no clinical trials or other studies have been reported.

Ongoing and Unpublished Clinical Trials

A search of the National Cancer Institute Physician Data Query (PDQ) Database on December 30, 2014, showed no current studies specifically focused on the use of HSCT to treat patients with WM.

Clinical Input Received through 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 no physician specialty societies and 5 academic medical centers, including 3 transplant centers, while this policy was under review in 2011The 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.

Summary of Evidence

Based on the literature and clinical input, autologous hematopoietic stem-cell transplantation (HSCT) may be considered medically necessary as salvage therapy for chemosensitive Waldenström macroglobulinemia (WM). Allogeneic hematopoietic stem-cell transplantation for WM is considered investigational.

Practice Guidelines and Position Statements
The 2014 National Comprehensive Cancer Network guidelines Waldenström Macroglobulinemia/Lymphoplasmacytic Lymphoma (v2.2015) indicate that in selected cases, stem cell transplantation may be appropriate with either: high-dose therapy with autologous stem cell rescue or allogeneic stem cell transplant (myeloablative or nonmyeloablative).(14)

U.S. Preventive Services Task Force Recommendations
Not applicable.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.


  1. Munshi NC, Barlogie B. Role for high-dose therapy with autologous hematopoietic stem cell support in Waldenstrom's macroglobulinemia. Semin Oncol. Apr 2003;30(2):282-285. PMID 12720153
  2. Gertz MA, Anagnostopoulos A, Anderson K, et al. Treatment recommendations in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. Apr 2003;30(2):121-126. PMID 12720120
  3. Ghobrial IM, Gertz MA, Fonseca R. Waldenstrom macroglobulinaemia. Lancet Oncol. Nov 2003;4(11):679-685. PMID 14602248
  4. Treon SP, Gertz MA, Dimopoulos M, et al. Update on treatment recommendations from the Third International Workshop on Waldenstrom's macroglobulinemia. Blood. May 1 2006;107(9):3442-3446. PMID 16410453
  5. Anagnostopoulos A, Hari PN, Perez WS, et al. Autologous or allogeneic stem cell transplantation in patients with Waldenstrom's macroglobulinemia. Biol Blood Marrow Transplant. Aug 2006;12(8):845-854. PMID 16864055
  6. Fonseca R, Hayman S. Waldenstrom macroglobulinaemia. Br J Haematol. Sep 2007;138(6):700-720. PMID 17672883
  7. Vijay A, Gertz MA. Waldenstrom macroglobulinemia. Blood. Jun 15 2007;109(12):5096-5103. PMID 17303694
  8. 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. J Clin Oncol. May 1 2010;28(13):2227-2232. PMID 20368570
  9. 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):4926-4934. PMID 20956626
  10. Usmani S, Sexton R, Crowley J, et al. Autologous stem cell transplantation as a care option in Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma Leuk. Feb 2011;11(1):139-142. PMID 21454216
  11. Bachanova V, Burns LJ. Hematopoietic cell transplantation for Waldenstrom macroglobulinemia. Bone Marrow Transplant. Mar 2012;47(3):330-336. PMID 21572463
  12. Gertz MA, Reeder CB, Kyle RA, et al. Stem cell transplant for Waldenstrom macroglobulinemia: an underutilized technique. Bone Marrow Transplant. Sep 2012;47(9):1147-1153. PMID 21874060
  13. Gertz MA. Waldenstrom macroglobulinemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. May 2012;87(5):503-510. PMID 22508368
  14. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Waldenstrom’s Macroglobulinemia/Lymphoplasmacytic Lymphoma (V.2.2013). Available online at: Last accessed January 2014.




CPT  38204  Management of recipient hematopoietic cell donor search and cell acquisition 
  38205 Blood-derived hematopoietic progenitor cell harvesting for transpantation, per collection, allogeneic
   38206  Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous 
   38208  Transplant preparation of hematopoietic progenitor cell; thawing of previously frozen harvest without washing
   38209  ;thawing of perviously frozen harvest, with washing
   38210  Specific cell depletion with harvest, T-cell depletion 
   38211  Tumor-cell depletion 
   38212  Red blood cell removal 
    38213  Platelet depletion 
   38214  Plasma (volume) depletion 
   38215  Cell concentration in plasma, mononuclear, or buffy coat layer 
   38220  Bone marrow, aspiration only 
   38221  Biopsy, needle or trocar 
  38230 Bone marrow harvesting for transplantation; allogeneic
    38232 Bone marrow harvesting for transplantation; autologous
  38240  Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic
   38241  Bone marrow or blood-derived peripheral stem-cell transplantation; autologous 
  38242  ;allogeneic donor lymphocyte infusions
ICD-9 273.3 Macroglobulinemia
ICD-9 Procedure  41.01  Autologous bone marrow transplant without purging 
  41.02 Allogeneic bone marrow transplant with purging
  41.03 Allogeneic bone marrow transplant without purging
    41.04  Autologous hematopoietic stem-cell transplant without purging
  41.05 Allogeneic hematopoietic stem-cell transplant without purging
  41.06 Cord blood stem cell transplant
    41.07 Autologous hematopoietic stem-cell transplant with purging
  41.08 Allogeneic hematopoietic stem cell transplant with purging
  41.09 Autologous bone marrow transplant with purging
    41.91  Aspiration of bone marrow from donor for transplant 
   99.79  Other therapeutic apheresis (includes harvest of stem cells) 
ICD-9 Diagnosis 273.3 Macroglobulinemia
HCPCS    Q0083 - Q0085  Chemotherapy administration code range 
   J9000 - J9999  Chemotherapy drug code range 
  S2140 Cord blood harvesting for transplantation; allogeneic
  S2142 Cord blood derived stem-cell transplantation; allogeneic
    S2150  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 post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services) 
ICD-10-CM (effective 10/1/15) C88.0 Waldenstrom macroglobulinemia
ICD-10-PCS (effective 10/1/15)   ICD-10-PCS codes are only used for inpatient services.
  30243G0, 30243X0,
Percutaneous transfusion, central vein, bone marrow or stem cells, autologous, code list
  07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ Surgical, lymphatic and hemic systems, extraction, bone marrow, code list
Type of Service  Therapy 
Place of Service  Inpatient/Outpatient 



High-Dose Chemotherapy, Waldenstrom Macroglobulinemia
Waldenstrom Macroglobulinemia, High-Dose Chemotherapy

Policy History


Date Action Reason
02/10/11 Add to Therapy section New policy created (Waldenstrom macroglobulinemia removed from original policy No. 8.01.42 [previously combined amyloidosis and Waldenstrom policy]). Policy updated with literature search; reference numbers 8 and 9 added; reference 10 updated. Clinical input reviewed. Policy statement changed to indicate autologous SCT may be considered medically necessary as salvage therapy for chemosensitive Waldenstrom macroglobulinemia
2/09/12 Replace policy Policy updated with literature search through mid-January 2012. References 10 and 11 added; reference 12 updated. Policy statements unchanged.
02/14/13 Replace policy Policy updated with literature search through mid-January 2013. References 10-13 added; reference 14 updated. Policy statements unchanged.
2/13/14 Replace policy Policy updated with literature search through December 23, 2013. No references added; reference 14 updated. Policy statements unchanged.
2/12/15 replace policy Policy updated with literature review through December 2, 2014. No
references added; reference 14 updated. Policy statements unchanged.


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