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MP 8.01.38 Nonmyeloablative Allogeneic Transplants of Hematopoietic Stem Cells for Treatment of Malignancy

Medical Policy
Section
Therapy
Original Policy Date
8/15/01
Last Review Status/Date
Reviewed with literature search/5:2008
Issue
5:2008
Return to Medical Policy Index

Disclaimer

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.


Description

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.

Recently, 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 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. Nonmyeloablative chemotherapy is now commonly referred to as reduced-intensity conditioning (RIC), with patients also receiving allogeneic stem-cell support. This procedure has been called "mini-transplant."

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 allotransplants 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.

Note: Donor leukocyte infusions may be administered as part of the above therapy. However, donor leukocyte infusions used as a salvage regimen at relapse following a conventional myeloablative allogeneic stem-cell transplant are considered separately in policy No. 2.03.03.


Policy

Nonmyeloablative allogeneic stem-cell transplantation may be considered medically necessary in patients who would otherwise meet patient selection criteria for high-dose chemotherapy and allogeneic stem-cell transplantation. These criteria are addressed in the following policies:

8.01.20: Non-Hodgkin’s lymphoma

8.01.21: Myelodysplastic diseases

8.01.26 Acute myelogenous leukemia

8.01.29 Hodgkin’s disease

8.01.30 Chronic myelogenous leukemia

8.01.32 Acute lymphocytic leukemia

Other applications of nonmyeloablative allogeneic stem-cell transplantation are considered investigational, including its use in patients who do not meet criteria for high-dose chemotherapy and allogeneic stem-cell transplantation due to either age or comorbidities, or as a treatment of other malignancies, including, but not limited to, multiple myeloma, renal cell carcinoma, other solid tumors, or autoimmune disease.


Policy Guidelines

Steps in nonmyeloablative stem-cell transplant include: collection of donor stem cells, infusion of stem cells into the recipient, collection of donor leukocytes, and infusion of donor leukocytes. The recipient will also undergo preceding nonmyeloablative chemotherapy. The regimens have varied from center to center.

In 2003, CPT established a specific code for one component of this procedure:

38242: Bone marrow or blood-derived peripheral stem-cell transplantation; allogeneic donor lymphocyte infusions.


Benefit Application

BlueCard/National Account Issues

Plans may want to consider whether or not case rates for allogeneic stem-cell transplants would apply to nonmyeloablative stem-cell transplantation, particularly since the morbidity, length of hospital stay (if any), and duration of procedure are likely to be different than for conventional myeloablative stem-cell transplant.


Rationale

The following discussion is based on a 2001 TEC Assessment (1) and August 2003 review of evidence from studies published subsequent to the 2001 Assessment.

The 2001 TEC 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. (1) 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 TEC Assessment (1) reported the following observations and conclusions regarding nonmyeloablative stem-cell transplants:

With respect to patients with chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), Hodgkin's disease (HD), or non-Hodgkin's lymphoma (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 (MM), chronic lymphocytic leukemia (CLL), or myelodysplastic syndrome (MDS):

  • 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.

 

A 2003 systematic review by Djulbegovic et al. (2) summarized data reported by studies included in the 2001 TEC 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 allotransplants.

An August 2003 literature search identified more than 150 articles on nonmyeloablative allogeneic stem cell transplants not referenced in the 2001 Assessment (1) or the review by Djulbegovic et al. (2). The following discussion focuses on the articles identified in the literature search that:

(a) used a nonmyeloablative regimen as stated by the authors or as recognized by one working definition (see Djulbegovic et al. [2]);

(b) included only patients who were ineligible for treatment with a myeloablative regimen by clear statement or description; and

(c) 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 [3]), first chronic phase CML (n=24 [4]), advanced CLL (n=50 [5, 6]), and multiple myeloma (n=31 [7]). 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 is not possible to compare these outcomes with those of established alternatives. Furthermore, 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. (4, 7)

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. (8, 9) 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. (10) 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. (11) 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. (12, 13) Results were mixed relative to acute GVHD (significantly less after nonmyeloablative regimens in 1 study [13]), 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. (14)

2007 Update

A literature review performed through March 2007 did not identify any studies that would prompt reconsideration of the policy statement. Work continues to explore the role of nonmyeloablative allogeneic stem-cell transplant in patients with multiple myeloma, chronic lymphocytic leukemia (CLL), renal cell cancer, and other malignancies and conditions that would not routinely be considered for conventional myeloablative stem-cell allotransplant. (15-19) One review article examines means to optimize allogeneic transplant conditioning, primarily focusing on older patients and those who for other reasons would not be eligible for conventional myeloablative conditioning regimens. (20) Issues of importance include patient characteristics; the disease under treatment; pretransplantation induction chemotherapy; stem-cell source; and, post-transplant management. The authors conclude that while important insights have been gained over the past decade regarding differences between high-dose and nonmyeloablative conditioning regimens, more disease-specific trials, dose-optimization studies, and well-designed prospective trials are needed to determine the relative role of specific conditioning approaches. A second review summarizes clinical results from 39 published studies of nonmyeloablative allogeneic stem cell transplantation for hematologic malignancies. (21) The median age at transplant ranged from 31 to 59 years, but is over 50 years in most protocols. Inclusion of younger patients in some studies implies they had other comorbidities, often including prior autologous stem-cell transplantation, which dictated this type of therapy. However, outcomes often were not reported separately for patients with significant comorbidities or age older than 50.

Taken together, the available evidence suggests that nonmyeloablative allogeneic stem-cell transplantation may achieve favorable outcomes in some patients who would not normally be considered for stem-cell transplantation. However, these regimens suffer from many of the same limitations as standard-intensity transplants—relapse, GVHD (particularly chronic GVHD), and mortality from treatment-related causes other than myelotoxicity. 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. It also seems unlikely that properly designed and powered trials will be conducted to compare standard stem-cell transplantation with nonmyeloablative transplantation in populations clearly eligible for transplant, largely because the two methods are applied to different patient populations.

2008 Update

A literature search performed in March 2008 did not identify any comparative trials of nonmyeloablative allogeneic stem-cell transplantation 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. (22-24) 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. Limitations to conclusive interpretation of available date, and additional caveats, remain the same as those outlined in the 2007 update of this Policy.
RIC regimens with allogeneic stem-cell support are increasingly being used in many centers, and it is clear 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. For the same reasons noted in 2007, there seems little chance that well-designed trials will directly compare RIC regimens with myeloablative allotransplants in populations clearly eligible for transplant.
Based on the discussion above, the current Policy statements are unchanged.

 

References:

  1. TEC Assessments 2001. Tab 3.
  2. Djulbegovic B, Seidenfeld J, Bonnell C et al. Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: a systematic review. Cancer Control 2003; 10(1):17-41.
  3. ArnoldR, Massenkeil G, Bornhäuser M et al. 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.
  4. Or R, Shapira MY, Resnick I et al. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003; 101(2):441-5.
  5. Khouri IF, Saliba RM, Giralt SA et al. 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.
  6. Schetelig J, Thiede C, Bornhauser M et al. 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.
  7. Badros A, Barlogie B, Siegel E et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20(5):1295-303.
  8. Junghanss C, Marr KA, Carter RA et al. 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.
  9. Junghanns C, Boeckh M, Carter RA et al. 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.
  10. Daly A, McAfee S, Dey B et al. Nonmyeloablative bone marrow transplantation: infectious complications in 65 recipients of HLA-identical and mismatched transplants. Biol Blood Marrow Transplant 2003; 9(6):373-82.
  11. Weissinger F, Sandmaier BM, Maloney DG et al. 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.
  12. Mineishi S, Kanda Y, Saito T et al. 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.
  13. Mielcarek M, Martin PJ, Leisenring W et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102(2):756-62.
  14. Perez-Simon JA, Kottaridis PD, Martino R et al. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood 2002; 100(9):3121-7.
  15. Takahashi Y, Childs RW. Nonmyeloablative transplantation: an allogeneic-based immunotherapy for renal cell carcinoma. Clin Cancer Res 2004; 10(18 pt 2):6353S-9S.
  16. Anagnastopoulos A, Aleman A, Giralt S. Nonmyeloablative reduced-intensity transplantation in multiple myeloma. Semin Oncol 2004; 31(1):33-6.
  17. Burt RK, Oyama Y, Verda L et al. Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed chimerism. Arthritis Rheum 2004; 50(8):2466-70.
  18. Khouri IF, Lee MS, Saliba RM et al. Nonablative allogeneic stem cell transplantation for chronic lymphocytic leukemia: impact of rituximab on immunomodulation and survival. Exp Hematol 2004; 32(1):28-35.
  19. Maloney DG, Molina AJ, Sahebi F et al. Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003; 102(9):3447-54.
  20. Deeg HJ, Maris MB, Scott BL et al. Optimization of allogeneic transplant conditioning: not the time for dogma. Leukemia 2006; 20(10):1701-5.
  21. Barrett AJ, Savani BN. Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents. Leukemia 2006; 20(10):1661-72.
  22. Chakrabarti S, Buyck HC. Reduced-intensity transplantation in the treatment of haematological malignancies: current status and future prospects. Curr Stem Cell Res Ther 2007; 2(2):163-88.
  23. Kato K, Khaled Y, Mineishi S. Reduced-intensity stem cell transplantation for haematological malignancies: current status and the future. Curr Stem Cell Res Ther 2007; 2(2):149-62.
  24. Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioning for allogeneic hematopoietic cell transplantation: current perspectives. Biol Blood Marrow Transplant 2007; 13(1 Suppl 1):87-97.

 

Codes

Number

Description

CPT  See policy guidelines
ICD-9 Procedure  41.02  Allogeneic bone marrow transplant with purging 
  41.03  Allogeneic bone marrow transplant without purging 
  41.05  Allogeneic hematopoietic stem-cell transplant without purging 
  41.08  Allogeneic hematopoietic stem-cell transplant with purging 
ICD-9 Diagnosis  200.00-200.88  Lymphoma code range 
  201.00-201.98 Hodgkin’s disease code range 
  204.00-204.91 Lymphoid leukemia code range 
  205.00-205.91 Myeloid leukemia code range 
  238.71-238.79 Myelofibrosis or myelodysplastic syndrome code range
HCPCS  Q0083, Q0084, Q0085  Chemotherapy administration code range 
  J9000, J9001, J9010, J9015, J9017, J9020, J9025, J9027, J9031, J9035, J9040, J9041, J9045, J9050, J9055, J9060, J9062, J9065, J9070, J9080, J9090, J9091, J9092, J9093, J9094, J9095, J9096, J9097, J9098, J9100, J9110, J9120, J9130, J9140, J9150, J9151, J9160, J9165, J9170, J9175, J9178, J9181, J9182, J9185, J9190, J9200, J9201, J9202, J9206, J9208, J9209, J9211, J9212, J9213, J9214, J9215, J9216, J9217, J9218, J9219, J9225, J9226, J9230, J9245, J9250, J9260, J9261, J9263, J9264, J9265, J9266, J9268, J9270, J9280, J9290, J9291, J9293, J9300, J9303, J9305, J9310, J9320, J9340, J9350, J9355, J9357, J9360, J9370, J9375, J9380, J9395, J9600, J9999  Chemotherapy drugs code range 
Type of Service  Therapy 
Place of Service  Outpatient 


Index

Mini-Transplant
Nonmyeloablative Allogeneic Transplant

Reduced-Intensity Conditioning
Transplant Lite


Policy History

Date Action Reason
08/15/01 Add to Therapy section New policy
12/18/02 Replace policy Update CPT code only
10/9/03 Replace policy Policy updated; policy statement remains unchanged
04/1/05 Replace policy Policy updated with literature review; no change in policy statement
03/7/06 Replace policy Policy updated with literature review; no change in policy statement
04/17/07 Replace policy Policy updated with literature review; references 20 and 21 added. No change to policy statement.
05/08/08 Replace policy  Policy updated with literature review; reference numbers 22-24 added. No change to policy statement


 

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