BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Acute Myelogenous Leukemia
Chapter: Transplant
Current Effective Date: December 27, 2013
Original Effective Date: December 27, 2013
Publish Date: September 27, 2013
Description

Acute myelogenous leukemia (AML), also known as Non-Lymphocytic Leukemia (NLL), results from an acquired (not inherited) genetic damage to the DNA of developing cells in the bone marrow.  The effects of this disease include:

  • the uncontrolled, exaggerated growth and accumulation of cells called "leukemic blasts" which fail to function as normal blood cells,
  • the blockade of the production of normal marrow cells, leading to a deficiency of red cells (anemia), platelets (thrombocytopenia) and normal white cells (especially neutrophils, i.e. neutropenia) in the blood.

Unlike ALL (acute lymphocytic leukemia), AML is relatively rare in childhood, with a median age of onset at 55 years.

High-Dose Chemotherapy (HDC) as a treatment of first CR is typically reserved for patients with high-risk factors, which include, but are not limited to the following characteristics:

  • AML secondary to prior chemotherapy and/or radiotherapy for another malignancy,
  • Presence of circulating blasts at the time of diagnosis,
  • Difficulty in obtaining first CR,
  • Leukemia with monocytoid differentiation (FAB classification M4 or M5),
  • Certain cytogenetic abnormalities, such as abnormalities of chromosome 12, deletions of chromosomes 5 and 7, or trisomy of chromosome 8.
Policy

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan 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 or contract, the benefit plan or contract will govern.

Coverage

Coverage for evaluation of 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 AML (Acute Myelogenous Leukemia) is identified in the grid below.

Allogeneic

May be considered medically necessary in first CR (complete remission or complete response), as a treatment of primary refractory AML or relapsed AML.

Is considered experimental, investigational and unproven for salvage allogeneic transplantation after a prior failed HDC (high-dose chemotherapy) with Autologous SCS (stem-cell support) regimen for treatment of AML.

Autologous

May be considered medically necessary in first CR, as a treatment of primary refractory AML or relapsed AML.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven. 

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven. 

Rationale

High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (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 or bone marrow stem-cells. 

Hematopoietic SCT has been investigated in three general settings: as consolidation therapy after first complete remission, as salvage therapy after first relapse or second complete remission, and to treat primary refractory disease.

Post-Remission Therapy

In patients in first complete remission, allogeneic SCT with myeloablative conditioning has been shown to decrease the leukemic relapse rate, but at the price of increased treatment-related morbidity and mortality.  This finding raises the question of whether allogeneic SCT offers any real benefit as a post-remission strategy in patients in first remission.  Furthermore, it is unclear whether the outcomes associated with myeloablative therapy are better compared to those associated with other non-marrow ablative dose-intensification strategies, such as high-dose cytarabine.  Therefore, at the present time, myeloablative allogeneic stem-cell support is typically reserved for patients with high-risk factors.  These factors include AML secondary to prior chemotherapy and/or radiotherapy for another malignancy, AML preceded by a myelodysplastic syndrome, presence of circulating blasts at the time of diagnosis, difficulty in obtaining first complete remission, or leukemias with monocytoid differentiation (FAB classification M4 or M5).  Certain cytogenetic abnormalities are also associated with a poor prognosis, such as abnormalities of chromosome 12, deletions of chromosomes five and seven, or trisomy of chromosome eight.  In contrast, chromosomal abnormalities with a good prognosis include translocations between chromosomes eight and 12 and 15 and 17, or an internal derangement of chromosome 16.  The use of allogeneic SCS (stem cell support) may be limited by older age range of AML in general and the lack of a suitable donor.

The ideal allogeneic donors are HLA (human leukocyte antigen)-identical siblings, matched at the HLA-A, B, and DR loci.  Related donors mismatched at one locus are also considered suitable donors.  A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered.  Recently, there has been interest in haploidentical donors, i.e., a parent or a child of the patient, where typically there is sharing of only three of the six major histocompatibility antigens.  The majority of patients will have such a donor; however, the risk of GVHD (graft-versus-host disease) and overall morbidity of the procedure may be severe, and experience with these donors is limited.

The overall survival after autologous SCT is similar to that reported after allogeneic SCT from HLA-matched donors.  The decreased treatment-related mortality of autologous transplant is counterbalanced by the increased relapse rate due to the lack of a beneficial graft-versus-leukemia effect.  Similar to allogeneic SCT, it is not clear if autologous SCT results in improved outcomes compared to conventional-dose chemotherapy or high-dose cytarabine.

Refractory AML

Twenty percent to 40% of patients with AML will not achieve remission with conventional-dose chemotherapy, connoting refractory AML.  Allogeneic SCT using a matched related or unrelated donor can cure a subset of these patients.  For patients who lack a suitable donor, alternative treatments include salvage chemotherapy with high-dose cytarabine or etoposide-based regimens, monoclonal antibodies (e.g., gemtuzumab ozogamicin), multidrug resistance modulators, and investigational agents.

Relapsed AML

Fifty percent to 70% of patients with AML are expected to have a relapse after attaining a first complete remission.  Conventional chemotherapy is generally not curative once relapse occurs, even if a second complete remission can be achieved.  Allogeneic or autologous SCT is associated with a prolonged disease-free survival in 30–40% of patients in first relapse or second complete remission.  Due to the mortality associated with remission induction, allogeneic SCT may be considered the initial treatment of relapsed disease.  In patients without an allogeneic donor, or those who are not candidates for allogeneic SCS due to age or other factors, autologous SCT may be considered after a second complete remission.  Due to contamination of stem-cell populations by malignant cells, autologous stem cells are typically harvested only when the patient is in remission.  Alternatively, this procedure may be used for initial therapy of relapsed disease if autologous stem cells were stored at the time of first complete remission.

A 2000 Blue Cross Blue Shield Association TEC (technology evaluation center) Assessment focused on allogeneic SCT to treat relapsed or refractory disease after a prior autologous transplant for patients with various malignancies, including AML.  The TEC Assessment found insufficient data to permit conclusions about this treatment strategy.  A small series of pediatric patients (n=23) treated in this fashion has been published since that Assessment.  The study reports nine of 21 AML patients surviving after allogeneic SCT, but also reports an equal proportion of deaths from regimen-related toxicity. 

Additional Review of Literature Through 2008

Literature review updates did not identify clinical trial evidence to suggest a change to the coverage statement or Policy Guidelines listed here.  This policy’s position is reinforced by discussions in four reviews.  Also, in a randomized trial of 120 patients with de novo AML, Tsimberidou and colleagues compared allogeneic SCT, high-dose cytarabine, and autologous SCT as post-remission treatment.  The authors reported comparable survival outcomes, although the proportion of three year failure-free survivors was larger in the allogeneic recipient group. Several other randomized trials have been published; however, these compared outcomes using stem cells with or without growth factors, or compared two or more myeloablative regimens.  The American Society for Blood and Marrow Transplantation (ASBMT) has published a systematic review of peer-reviewed evidence on the role of cytotoxic therapy with SCT in AML in pediatric (defined as younger than 21 years of age) patients.  The findings of the ASBMT expert panel are consistent with the policy statements listed here.  An ASBMT report on adult patients is in preparation.

A search of the National Cancer Institute (NCI) clinical trial database (PDQ®) identified eight active randomized trials in the United States that involve stem-cell support for patients with AML.  Trials include allo- and autografting, using various conditioning regimens.  The role of immunotherapy using gemtuzumab ozogamicin at induction is under investigation in one trial.

The search also identified 15 active randomized trials in the United States that involve stem-cell support for patients with AML Trials include allo- and autografting, using various HDC regimens.

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for acute myeloid leukemia indicate autologous SCT is appropriate for consolidation therapy in patients with good-risk or intermediate-risk cytogenetics or in patients with relapse after a long remission. The NCCN guideline panel had reservations concerning allogeneic SCT to consolidate patients with good-risk cytogenetics because of prohibitive long-term toxicities associated with this procedure.  Allogeneic SCT is appropriate when there is induction failure; for patients in first relapse; and as consolidation therapy in patients with intermediate (matched-sibling donor allogeneic SCS only) or poor-risk cytogenetics, secondary AML, or prior myelodysplasia. Allogeneic SCT without induction chemotherapy may be appropriate in patients with secondary AML or prior myelodysplasia due to the poor probability of attaining remission with induction chemotherapy.  

A growing body of evidence is accruing from clinical studies of RIC (reduced-intensity conditioning) with allogeneic SCT for AML.  Overall, these data suggest long-term remissions (two–four years) can be achieved in patients with AML who because of age or underlying comorbidities would not be candidates for myeloablative conditioning regimens.  No direct comparative studies with sufficiently long follow-up in matched patient groups are available to define the relative net health benefit of allogeneic SCT with RIC versus myeloablative treatments.  Indirect comparison of study results is compromised by heterogeneity among patients, treatments, outcome measures, and insufficient follow-up.  Further, RIC with allogeneic SCT has not been directly compared with conventional chemotherapy alone, which has been the standard of care in patients with AML for whom myeloablative chemotherapy and allogeneic SCT are contraindicated.

Although RIC/allogeneic SCT may have many of the same limitations as standard-intensity conditioning SCT — relapse, GVHD (particularly chronic GVHD), and mortality from treatment-related causes other than myelotoxicity, this approach is increasingly being used in many centers, comprising an estimated 34% of all allogeneic transplantations in 2005.  RIC procedures will continue to evolve and will likely supplant myeloablative conditioning regimens for large numbers of patients.  It is therefore unlikely that properly designed and powered trials will be conducted to compare myeloablative allogeneic SCT with RIC allogeneic SCT in populations otherwise eligible for transplant, largely because the two methods have been typically applied to different patient populations.  Nonetheless, the underlying premise of this policy is that allogeneic SCT with RIC is one of many therapeutic approaches that can be used for which some evidence exists for improved health outcomes in patients who are otherwise eligible for myeloablative allogeneic SCT.

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

Coding

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, 205.00, 205.01

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, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
References
  1. Scheinberg, D.A., Maslak, P., et al.  Acute leukemias. In: DeVita VT, Hellman S, Rosenberg SA (eds.). Cancer. Principles and Practice of Oncology. Philadelphia, Lippincott-Raven, (1997).
  2. High-Dose Chemotherapy with Hematopoietic Stem Cell Support for Malignancies. Chicago, Illinois: Blue Cross Blue Shield Association – Medical Policy Reference Manual (1999 May 7) Therapy: 8.01.15.
  3. Edenfield, W.J., Gore, S.D. Stage-specific application of allogeneic and autologous marrow transplantation in the management of acute myeloid leukemia. Seminars in Oncology (1999) 26(1):21-4.
  4. High-Dose Chemotherapy with Hematopoietic Stem Cell Support for Acute Myelogenous Leukemia. Chicago, Illinois: Blue Cross Blue Shield Association – Medical Policy Reference Manual (2000 January 30) Therapy: 8.01.26.
  5. Nonmyeloablative Allogeneic Stem-Cell Transplantation for Malignancy.  Chicago, Illinois: Blue Cross Blue Shield Technology Evaluation Center Assessment Program (2001 May) 16(3).
  6. Hale, G.A., Tong, X., et al. Allogeneic bone marrow transplantation in children failing prior autologous bone marrow transplantation. Bone Marrow Transplant (2001) 27(2):155-62.
  7. Estey, E.H. Therapeutic options for acute myelogenous leukemia. Cancer (2001) 92(5):1059-73.
  8. Tallman, M.S., Mocharnuk, R.S. Acute myelogenous leukemia: review of current treatment strategies. Medscape (accessed 25 Oct. 2002 at www.medscape.com .
  9. Stanisic, S., Kalaycio, M. Treatment of refractory and relapsed acute myelogenous leukemia. Expert Rev Anticancer Therapy (2002) 2(3):287-95.
  10. Tsimberidou, A.M., Stavroyianni, N., et al. Comparison of allogeneic stem cell transplantation, high-dose cytarabine, and autologous peripheral stem cell transplantation as postremission treatment in patients with de novo acute myelogenous leukemia. Cancer (2003) 97(7):1721-31.
  11. Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allogeneic Stem Cell Transplant. BCBSA Medical Policy Reference Manual (2005 September) Medicine: 2.03.03.
  12. Deschler, B., de Witte, T., et al. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica (2006) 91(11):1513-22.
  13. Acute Myeloid Leukemia. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. (2006) www.nccn.org .  (accessed – 2008 October 3).
  14. Oliansky, D.M., Rizzo, J.D., et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biology of Blood Marrow Transplantation (2007) 13(1):1-25.
  15. Valcarcel, D., Martino, R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Current Opinion in Oncology (2007) 19(6):660-6.
  16. Gratwohl, A., Baldomero, H., et al. Results of the EBMT activity survey 2005 on haematopoietic stem cell transplantation: focus on increasing use of unrelated donors. Bone Marrow Transplant (2007) 39(2):71-87.
  17. Blaise, D., Vey, N., et al. Current status of reduced intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica (2007) 92(4):533-41.
  18. Huisman, C., Meijer, E., et al. Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biology of Blood Marrow Transplantation (2008) 14(2):181-6.
  19. Valcarcel, D., Martino, R., et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. Journal of Clinical Oncology (2008) 26(4):577-84.
  20. Oliansky, D.M., Appelbaum, F., et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in adults: an evidence-based review. Biology of Blood Marrow Transplantation (2008) 14(2):137-80.
  21. Hematopoietic Stem-Cell Transplantation for Acute Myelogenous Leukemia. Chicago, Illinois.  Blue Cross Blue Shield Association Medical Policy Reference Manual (2008 June) Therapy 8.01.26.
History
September 2013  New 2013 BCBSMT medical policy.
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Stem-Cell Transplant for Acute Myelogenous Leukemia