BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Waldenstrom Macroglobulinemia
Chapter: Surgery: Procedures
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013

Waldenstrom macroglobulinemia (WM) (also known as lymphoplasmacytic lymphoma [LPL]) is a rare disease of elderly patients, with a peak incidence in the sixth and seventh decades. The median age of WM patients, at presentation, is 63 to 68 years, with men comprising 55–70% of cases. It is a B cell malignancy that accounts for 1–2% of hematologic malignancies, with an estimated 1,500 new cases annually in the U.S. Median survival of WM ranges from 5 to10 years, with age, hemoglobin concentration, serum albumin level, and beta-2 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 LPL 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 100 x 109/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 analogues (cladribine, fludarabine), and monoclonal antibody agents (rituximab), alone or in various combinations. Plasma exchange is indicated for acute treatment of symptomatic hyperviscosity.


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.


Coverage of, evaluation for, and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of Waldenstrom macroglobulinemia (WM) is identified in the grid below.

NOTE: SCT may be known by different terminology and used interchangeably. Hereinafter, SCT will be known as stem-cell support (SCS) throughout the balance of this medical policy.  


Is considered experimental, investigational and unproven to treat Waldenstrom macroglobulinemia (WM).


May be considered medically necessary as salvage therapy of chemosensitive WM.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven to treat WM.

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven to treat WM.

Hematopoietic Progenitor Cell Boost (Stem-Cell Boost)

Is considered experimental, investigational and unproven for WM.

Any use of short tandem repeat (STR) markers for the treatment of Waldenstrom macroglobulinemia is considered experimental, investigational and unproven.


High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) transplant is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, umbilical cord blood, or bone marrow stem-cells.

A 2002 International Workshop summarized clinical experience (combined n=49) using autologous stem-cell support (AutoSCS) for Waldenstrom 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 (CR) and 39 (80%) achieved partial response (PR), but data on the durability of these responses were unavailable.

A consensus panel from the Second International Workshop on WM recommended that AutoSCS may be considered for selected patients with refractory or relapsing disease, but allogeneic stem-cell support (AlloSCS) should be used only in the context of a clinical trial. (2) Another recent review agreed that the role of AutoSCS 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 AlloSCS for WM to be investigational therapy.

In 2004, a consensus panel from the Third International Workshop on WM suggested AutoSCS may be considered for eligible patients with primary refractory or relapsing disease but that AlloSCS 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 SCS (autologous, n=10, allogeneic, n=26) for WM reported 3-year overall survival (OS) rates of 46% (95% confidence interval [CI]: 27–65%) for AlloSCS recipients and 70% (95% CI: 40–93%) for AutoSCS 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 conditioning (MAC) and reduced-intensity conditioning (RIC), between 1986 and 2002. These data, taken together, are insufficient to form conclusions about the potential clinical efficacy of SCS 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 (EBMT) between January 1991 and December 2005. (8) Median time from diagnosis to AutoSCS was 1.7 years (range, 0.3 to 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 SCS. Median follow-up for surviving patients was 4.2 years (range: 0.5 to 14.8 years). Nonrelapse mortality (NRM) was 3.8% at 1 year. Relapse rate was 52.1% at 5 years. Progression-free survival (PFS) 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 SCS. The authors conclude that AutoSCS 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 received more than 3 lines of therapy.

Kyriakou and colleagues also reported on a retrospective analysis of a smaller group of patients who had AlloSCS for WM. (9) A total of 86 patients received AlloSCS by using either MAC (n=37) or RIC (n=49) regimens. The median age was 49 years (range: 23 to 64 years); 47 patients had received 3 or more previous lines of therapy, and 8 patients had experienced failure on a prior AutoSCS. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of AlloSCS. 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. Overall survival at 5 years was 62% for MAC and 64% for RIC, respectively. The occurrence of chronic graft-versus-host disease (GVHD) was associated with a lower relapse rate. The authors concluded that AlloSCS 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 AutoSCS for WM, as summarized in 2 recent review articles.(10, 11) No randomized trials have been reported.

Clinical Guidelines and Trials for WM:

National Comprehensive Cancer Network Guidelines:

The 2013 National Comprehensive Cancer Network (NCCN) guidelines indicate that selected cases of WM may be treated with AutoSCS or AlloSCS, but the latter only in a clinical trial. (12)

National Cancer Institute (NCI) Clinical Trial Database (PDQ®):

No current study is specifically focused on SCS for WM. Five Phase III studies are active that may involve patients with WM

Additional Infusion Treatments for NHL

Tandem or triple stem-cell transplant and donor leukocyte infusion (DLI) for WM are considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

As with DLI, hematopoietic progenitor cell (HPC) boost has a positive response rate for relapse following AlloSCS. (16) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (13, 14, 15, 16)

Short Tandem Repeat (STR) Markers

Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (17, 18) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of WM, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (17, 18, 19, 20, 21, 22)


Based on the literature and clinical input, AutoSCS may be considered medically necessary as salvage therapy for chemosensitive WM. AlloSCS for WM is considered experimental, investigational and unproven.

Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of WM are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.


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. 

ICD-9 Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79, 273.3

ICD-10 Codes

C88.0, 30230G0, 30230G1, 30233G0, 30233G1, 30240G0, 30240G1, 30243G0, 30243G1, 30250G0, 30250G0, 30250G1, 30253G0, 30253G1, 30260G0, 30260G1, 30263G0, 30263G1, 3E03005, 3E03305, 3E04005, 3E04305, 3E05005, 3E05305, 3E06005, 3E06305, 6A550Z2, 6A551Z2, 6A550ZT, 6A550ZV, 6A551ZT, 6A551ZV

Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 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, S2140, S2142, S2150
  1. Munshi, N.C., Barlogie, B. Role for high-dose therapy with autologous hematopoietic stem cell support in Waldenström’s macroglobulinemia. Seminars in Oncology (2003) 30(2):282-5.
  2. Gertz, M.A., Anagnostopoulos, A., et al. Treatment recommendations in Waldenström’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenström’s Macroglobulinemia. Seminars in Oncology (2003) 30(2):121-6.
  3. Ghobrial, I.M., Gertz, M.A., et al. Waldenstrom macroglobulinemia. The Lancet Oncology (2003) 4(11):679-85.
  4. Treon, S.P., Gertz, M.A., et al. Update on treatment recommendations from the Third International Workshop on Waldenström’s macroglobulinemia. Blood (2006) 107(9): 3442-6.
  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 2006; 12(8):845-54.
  6. Fonseca R, Hayman S. Waldenstrom macroglobulinaemia. Br J Haematol 2007; 138(6):700-20.
  7. Vijay A, Gertz MA. Waldenstrom macroglobulinemia. Blood 2007; 109(12):5096-103.
  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 2010; 28(13):2227-32.
  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 2010; 28(33):4926-34.
  10. Gertz MA, Reeder CB, Kyle RA et al. Stem cell transplant for Waldenstrom macroglobulinemia: an underutilized technique. Bone Marrow Transplant 2011 [Epub ahead of print].
  11. Usmani S, Sexton R, Crowley J et al. Autologous stem cell transplantation as a care option in Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma Leuk 2011; 11(1):139-42.
  12. NCCN – Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. v.2.2013; Available online at . Accessed 29 January 2013.
  13. ACS – Stem Cell Transplant (Peripheral Blood, Bone Marrow, and Cord Blood Transplants) (2013). American Cancer Society. Available at (accessed – 2013 April 15).
  14. Slatter, M.A., Bhattacharya, A., et al. Outcome of boost hematopoietic stem cell transplant for decreased donor chimerism or grapft dysfunction in primary immunodeficiency. Bone Marrow Transplantation (2005) 35:683-9.
  15. Larocca, A., Piaggio, G., et al. A boost of CD35+-selected peripheral blood cells without further conditioning in patients with poor graft function following allogeneic stem cell transplantation. The Hematology Journal (2006) 91(7):935-40.
  16. NIH – Marrsson, J., Ringden, O., et al. Graft failure after allogeneic hematopoietic cell transplantation. Biology and Blood Marrow Transplant (2008 January) 14(Supplement 1):165-70. National Institutes of Health Public Access. Available at (accessed – 2013 April 15).
  17. Borrill, V., Schlaphoff, T., et al. The use of short tandem repeat polymorphisms for monitoring chimerism follow bone marrow transplantation: a short report. Hematology (2008 August) 13(4):210-4.
  18. Crow, J., Youens, K., et al. Donor cell leukemia in umbilical cord blood transplant patients: a case study and literature review highlighting the importance of molecular engraftment analysis. Journal of Molecular Diagnostics (2010 July) 12(4):530-7.
  19. Park, M., Koh, K.N., et al. Clinical implications of chimerism after allogeneic hematopoietic stem-cell transplantation in children with non-malignant diseases. Korean Journal of Hematology (2011 December) 46(4):258-64.
  20. Odriozola, A., Riancho, J.A., et al. Evaluation of the sensitivity of two recently developed STR multiplexes for the analysis of chimerism after hematopoietic stem-cell transplantation. International Journal of Immunogenetics (2013 April) 40(2):88-92.
  21. Lawler, M., Crampe, M., et al. The EuroChimerism concept for standardized approach to chimerism analysis after allogeneic stem-cell transplantation. Leukemia (2012 August) 26(8):1821-8.
  22. Tilanus, M.G. Short tandem repeat markers in diagnostics: what’s in a repeat? Leukemia (2006 August) 20(8):1353-55. Available at (accessed – 2013 April 22).
  23. Hematopoietic Stem-Cell Transplantation for Waldenström’s Macroglobulinemia. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 February) Therapy 8.01.54.
  24. Donor Leukocyte Infusion for Malignancies Treated with an Allogeneic Stem-Cell Transplant. Chicago, Illinois. Blue Cross Blue Shield Association Medical Policy Reference Manual (2012 May) Medicine: 2.03.03.
September 2013  New 2013 BCBSMT medical policy.
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Stem-Cell Transplant for Waldenstrom Macroglobulinemia