Coverage Policy Manual
Policy #: 2000031
Category: Medicine
Initiated: August 2000
Last Review: October 2018
  Non-Myeloablative Allogeneic Stem Cell Transplantation

Transplantation of allogeneic hematopoietic stem cells derived from bone marrow or peripheral blood, in conjunction with myeloablative chemotherapy, is an established therapy for various malignancies, including acute and chronic leukemias, Hodgkin’s disease, and non-Hodgkin’s lymphomas. The treatment effect results from chemotherapeutic ablation of malignant cells, as well as an associated immune-mediated graft versus malignancy effect. The conventional practice of allogeneic stem-cell transplants (allo-SCT) involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at high enough doses to cause bone marrow failure in most patients. While such treatment may eradicate the malignant cells, patients are as likely to die from opportunistic infections, graft-versus-host disease, and organ failure as from the underlying malignancy.
Regimens have been developed that seek to reduce treatment-related adverse effects while retaining beneficial (i.e., graft versus malignancy) effects. So-called nonmyeloablative regimens (or reduced intensity conditioning)  have been tentatively defined as those that do not eradicate the patient’s hematopoietic ability, allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) without a transplant. Examples of such regimens include fludarabine-cyclophosphamide and fludarabine-idarubicin-cytarabine combinations. On engraftment, patients treated with nonmyeloablative regimens will demonstrate mixed chimerism initially. Most will subsequently convert to full-donor chimerism and may be supplemented with donor lymphocyte infusions to further eradicate malignant cells. The following coverage includes both nonmyeloablative and reduced intensity regimens.
Two general categories of patients have been considered candidates for nonmyeloablative allotransplants: those who would otherwise be considered candidates for a conventional myeloablative allotransplant, and those who would not. In the former category, nonmyeloablative allotransplant could be considered as a variant of a standard chemotherapy conditioning regimen. In the latter category, nonmyeloablative transplants would be considered a novel approach, either for patients whose comorbidities preclude a standard myeloablative conditioning regimen, or in those with malignancies that have not been shown to be effectively treated with conventional myeloablative allogeneic transplants.

Nonmyeloablative allogeneic stem-cell transplantation or reduced intensity conditioning meets member benefit certificate Primary Coverage Criteria for the following conditions:
    • Aplastic anemia (2000) for patients who fail treatment with immunosuppressive regimens and who do not have a sustained response to growth factor therapy;
    • Non-Hodgkin’s lymphoma (2004);
    • Hodgkin’s disease (2004);
    • Chronic myelogenous leukemia (2004):
    • Acute myelogenous leukemia (2004);
    • Myelodysplastic and myeloproliferative disease (2004);
    • Acute lymphocytic leukemia in patients who are in complete marrow and extramedullary first or second remission, and who, for medical reasons would be unable to tolerate a standard myeloablative conditioning regimen. (2004);
    • Multiple myeloma when used in tandem following high dose chemotherapy and autologous stem cell transplant (2008).
The use of nonmyeloablative chemotherapy and allogeneic stem cell transplantation or reduced intensity conditioning for treatment of other malignancies including, but not limited to, multiple myeloma as single treatment, other solid tumors or autoimmune disease, chronic lymphocytic leukemia, or small lymphocytic cell lymphoma is not covered based on benefit certificate Primary Coverage Criteria for effectiveness.   
For contracts without Primary Coverage Criteria, supplies or drugs associated with nonmyeloablative allogeneic stem cell transplantation or reduced intensity conditioning and related procedures are considered investigational when used for any indication not listed with a bullet in the first paragraph.  Investigational services are an exclusion in the member benefit certificate of coverage.  

This policy was initially developed following the publication of a technology assessment on the topic in 2001 by the Blue Cross Blue Shield Association Technology Evaluation Center Assessment.  This assessment focused on nonmyeloablative stem-cell transplants in patients who would not otherwise be considered candidates for conventional allogeneic stem-cell transplant due to age or comorbidities.  The Assessment further focused on those malignancies for which conventional allogeneic stem-cell transplant has a proven treatment benefit and those malignancies for which the treatment effectiveness of conventional allogeneic stem-cell transplant is still uncertain. The rationale for this focus was that overlap was apparent in the literature between what some consider myeloablative versus intensity-reduced versus nonmyeloablative conditioning regimens. Therefore, for patients who are candidates for a conventional allogeneic transplant, the intensity of the conditioning regimen is determined primarily by physician preference. However, for those ineligible for a conventional myeloablative transplant, nonmyeloablative transplants represent a unique approach.
The 2001 Blue Cross Blue Shield Association Technology Evaluation Center Assessment reported the following observations and conclusions regarding nonmyeloablative stem cell transplants:
With respect to patients with CML, AML, ALL, HD, or NHL who are not eligible for conventional allogeneic stem-cell transplant:
The available evidence was insufficient to permit scientific conclusions. For each of the above malignancies, the sample size was inadequate even when data were pooled from all studies. In addition, the follow-up duration in all of the studies ranged from 3 months to slightly more than 1 year. This duration is short relative to either the natural history of these malignancies or the reported duration of survival after alternative therapies. No data were reported on results of conventional management of well-matched controls; thus, direct comparison of outcomes was not possible.
The limited evidence suggested that patients with contraindications to conventional allogeneic transplant experienced a high rate of transplant-related mortality after nonmyeloablative transplant.
With respect to patients with multiple myeloma, chronic lymphocytic leukemia, or myelodysplastic syndrome:  
The same limitations were noted as for the above indications.
With respect to patients with renal cell carcinoma or other tumors of solid organs:
Only 1 study of patients with renal cell carcinoma met the study selection criteria. However, the study size was small (n=13) and the follow-up was short (median=13 months). No data were reported by studies that met selection criteria on outcomes of nonmyeloablative transplant for other tumors of solid organs.
2003 Update
A 2003 systematic review by Djulbegovic et al. summarized data reported by studies included in the 2001 Blue Cross Blue Shield Association Technology Evaluation Center Assessment and several subsequent studies. The review again found published data inadequate to permit conclusions with respect to patients or malignancies ineligible for conventional myeloablative aallotransplant
An August 2003 literature search identified more than 150 articles on nonmyeloablative allogeneic stem cell transplants not referenced in the 2001 Assessment or the review by Djulbegovic et al.  The following discussion focuses on the articles identified in the literature search that:
used a nonmyeloablative regimen as stated by the authors or as recognized by one working definition (see Djulbegovic et al.);
included only patients who were ineligible for treatment with a myeloablative regimen by clear statement or description; and
either reported long-term outcomes (survival) for patients with the same malignancy and in the same risk category, or compared treatment-related adverse effects to controls given myeloablative conditioning regimens in populations with various malignancies.
Twelve studies met these selection criteria: 5 reported disease-specific survival; 4 reported data on infectious or other treatment-related complications; and 3 compared frequencies and outcomes of GVHD for nonmyeloablative and myeloablative conditioning regimens.
Disease-specific survival after nonmyeloablative allo-SCT: New data on survival after treatment with nonmyeloablative allo-SCT was reported for patients with high-risk ALL (n=22), first chronic phase CML (n=24), advanced CLL (n=50), and multiple myeloma (n=31). Outcome measures varied widely reflecting the variable prognoses of these disease types: engraftment ranged from 82% to 100%, median survival ranged from 105 days to “not yet reached,“ and overall survival at 2 years ranged from 0% to 90%. Because these studies did not include concurrent control groups it was not possible to compare these outcomes with those of established alternatives. Although patients in each of these clinical series were treated for a single malignancy, they were rather heterogeneous with respect to important baseline characteristics that effect outcomes of treatment (e.g., prior treatment, histotype, disease status at allo-SCT). Adverse events and complications remain a concern with one third to one half of the cohort in some studies dying of treatment-related causes.
Treatment-related infections and other complications: Two reports from a single study provided data on the incidence and outcome of bacterial, fungal, and cytomegalovirus (CMV) infections in 56 consecutive patients with hematologic malignancies treated with nonmyeloablative allo-SCT compared to control groups treated with conventional allo-SCT.  During the 100-day period immediately following treatment, infections and infectious complications occurred significantly less frequently in the nonmyeloablative allo-SCT group; this difference had disappeared by 1 year after transplant. A retrospective analysis of 65 consecutive patients with advanced hematologic malignancies found no difference in rate of infectious complications as a function of donor-patient HLA matching.  Last, significantly fewer platelet and red cell transfusions were required in 40 patients with advanced hematologic malignancies treated with a nonmyeloablative regimen compared to a concurrent control group of 60 patients treated with myeloablative regimens.  The study did not present evidence on whether observed differences in post-transplant transfusion requirements effected long-term outcomes.
Graft-Versus-Host Disease (GVHD). GVHD is a major concern with conventional, myeloablative allogeneic stem-cell transplant and causes a large proportion of treatment-related adverse events. Two recent studies compared the incidence and outcomes of GVHD for patient groups treated with nonmyeloablative versus myeloablative regimens.  Results were mixed relative to acute GVHD (significantly less after nonmyeloablative regimens in one study), but neither study observed a difference in chronic GVHD or survival. The use of alemtuzumab reduced the risk of GVHD in patients treated with nonmyeloablative regimens, but any beneficial effect this might have had on outcome was offset by an increased risk of infection.
2005 Update
A literature review performed for the period of 2003 through December 2004 did not identify any studies that would prompt reconsideration of the policy statement. Studies continue to explore the role of nonmyeloablative allogeneic stem-cell transplant in patients with  chronic lymphocytic leukemia (CLL), renal cell cancer, and other malignancies and conditions that would not routinely be considered for conventional myeloablative stem-cell allotransplant.  However, the underlying premise of this policy is that nonmyeloablative stem-cell transplant is one of many types of conditioning regimens that can be used for malignancies for which the evidence supports that allogeneic stem-cell transplant improves health outcomes. The role of nonmyeloablative transplant in other settings is uncertain and requires direct comparative trials with adequate follow-up to analyze its safety and effectiveness. No such controlled trials were identified.
2008 Update
A literature search performed in March 2008 did not identify any comparative trials of nonmyeloablative allo-SCT versus either myeloablative allogeneic transplant or cytotoxic chemotherapy alone in similar patients. Several review articles compiled results from numerous single-arm series or retrospective studies of nonmyeloablative or reduced-intensity conditioning (RIC) regimens with allogeneic stem-cell support for a number of hematologic and solid malignancies. (Chakrabarti S, 2007; Kato K, 2007; Sandmaier BM, 2007)  Taken together, the available data suggest that RIC regimens with allogeneic stem-cell support are associated with lower rates of treatment-related morbidity and mortality, but at the expense of a greater risk for disease relapse.
RIC regimens with allogeneic stem-cell support are increasingly being used in many centers, and it is clear that they will continue to evolve and will likely supplant myeloablative conditioning regimens for select patients. However, the scientific evidence available to date does not provide direct comparison of health outcomes with sufficiently long follow-up in similar patient groups to draw sound conclusions about the net health benefit of this therapeutic approach. There seems little chance that well-designed trials will directly compare RIC regimens with myeloablative allotransplant in populations clearly eligible for transplant.
2009 Update
Investigation continues on the use of nonmyeloablative allogeneic transplantation or reduced intensity conditioning for other malignancies, but the studies remain ongoing.
2018 Update
A literature search was conducted through September 2018.  There was no new information identified that would prompt a change in the coverage statement.    

38240Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38242Allogeneic lymphocyte infusions

References: 2001 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Tab 3.

Anagnastopoulos A, Aleman A, Giralt S.(2004) Nonmyeloablative reduced-intensity transplantation in multiple myeloma. Semin Oncol 2004; 31(1):33-6.

Arnold R, Massenkeil G, Bornhäuser M et al.(2002) Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not advanced disease. Leukemia 2002; 16(12):2423-8.

Bacigalupo A, Oneto R, Bruno B, et al.(2000) Current results of BMT in pts with acquired severe aplastic anemia. Rpt of the European Group for Blood & Marrow Transplant. On behalf of the Working Party on Severe Aplastic Anemia of the European Group for Blood & Marrow Transplant. Acta Heamatol 2000; 103:19-25.

Badros A, Barlogie B, Siegel E et al.(2002) Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20(5):1295-303.

Burroughs LM, O'Donnell PV, et al.(2008) Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical relate hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant, 2008; 14(11):1279-87.

Burt RK, Oyama Y, Verda L et al.(2004) Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed chimerism. Arthritis Rheum 2004; 50(8):2466-70.

Chakrabarti S, Buyck HC.(2007) Reduced-intensity transplantation in the treatment of haematological malignancies: current status and future prospects. Curr Stem Cell Res Ther, 2007; 2(2):163-88.

Childs R, Chernoff A, Contentin N, et al.(2000) Regression of metastatic renal-cell carcinoma after non-myeloablative allogeneic peripheral-blood stem cell transplantation. NEJM 2000; 343:750-758.

Daly A, McAfee S, Dey B, et al.(2003) Nonmyeloablative bone marrow transplantation: infectious complications in 65 recipients of HLA-identical and mismatched transplants. Biol Blood Marrow Transplant 2003; 9(6):373-82.

Deeg HJ, Seidel K, Casper J, et al.(1999) Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy. Biol BMT 1999; 5:243-52.

Djulbegovic B, Seidenfeld J, Bonnell C et al.(2003) Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: a systematic review. Cancer Control 2003; 10(1):17-41.

Horowitz MM.(2000) Current status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol 2000; 37:30-42.

Junghanns C, Boeckh M, Carter RA, et al.(2002) Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002; 99(6):1978-85.

Junghanss C, Marr KA, Carter RA, et al.(2002) Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002; 8(9):512-20.

Kato K, Khaled Y, Mineishi S.(2007) Reduced-intensity stem cell transplantation for hematological malignancies: current status and the future. Curr Stem Cell Res Ther, 2007; 2(2):149-62.

Khouri IF, Lee MS, Saliba RM, et al.(2004) Nonablative allogeneic stem cell transplantation for chronic lymphocytic leukemia: impact of rituximab on immunomodulation and survival. Exp Hematol 2004; 32(1):28-35.

Khouri IF, Saliba RM, Giralt SA, et al.(2001) Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001; 98(13):3595-9.

Laport GG, Sandmaier BM, et al.(2008) Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant, 2008; 14(2):246-55.

Maloney DG, Molina AJ, et al.(2003) Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood, 2993; 102(9):3447-54.

Maloney DG, Molina AJ, Sahebi F, et al.(2003) Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102(9):3447-54.

Mielcarek M, Martin PJ, Leisenring W, et al.(2003) Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102(2):756-62.

Mineishi S, Kanda Y, Saito T, et al.(2003) Impact of graft-versus-host disease in reduced-intensity stem cell transplantation (RIST) for patients with hematological malignancies. Br J Haematol 2003; 121(2):296-303.

Or R, Shapira MY, Resnick I, et al.(2003) Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003; 101(2):441-5.

Perez-Simon JA, Kottaridis PD, Martino R et al.(2002) Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 2002; 100(9):3121-7.

Rezvani AR, Storer B, et al.(2008) Nonmyeloablative allogeneic hematopoietic cell transplantation in relapsed, refractory, and transformed indolent non-Hodgkin's lymphoma. J Clin Oncol, 2008; 26(2):211-7.

Rotta M, Storer BE, et al.(2009) Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative allografting. Blood, 2009; 113(14):3383-91.

Schetelig J, Thiede C, Bornhauser M, et al.(2003) Evidence of graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21(14):2747-53.

Takahashi Y, Childs RW.(2004) Nonmyeloablative transplantation: an allogeneic-based immunotherapy for renal cell carcinoma. Clin Cancer Res 2004; 10(18 pt 2):6353S-9S.

Weissinger F, Sandmaier BM, Maloney DG, et al.(2001) Decreased transfusion requirements for patients receiving nonmyeloablative compared to conventional peripheral blood stem cell transplants from HLA-identical siblings. Blood 2001; 98(13):3584-8.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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