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Acute myeloid leukemia (AML) refers to leukemias that arise from a myeloid precursor in the bone marrow. There is a high incidence of relapse, which has prompted research into various post-remission strategies using either allogeneic or autologous hematopoietic stem cell transplantation (HSCT). HSCT refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of drugs with or without whole body radiotherapy.
Hematopoietic Stem-Cell Transplantation
Hematopoietic stem-cell transplantation (HSCT) may use stem cells obtained from the transplant recipient (autologous HSCT) or from a related or unrelated donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in the Placental and Umbilical Cord Blood as a Source of Stem Cells policy.
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 of human leukocyte antigen (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA-A, -B, and -DR (antigen-D related) 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 (with the exception of umbilical cord blood).
Complete remissions can be achieved initially using conventional doses of combination chemotherapy in up to 80% of acute myeloid leukemia (AML) patients. However, the high incidence of disease relapse has prompted research into a variety of post-remission (consolidation) strategies, typically using high-dose chemotherapy with autologous HSCT or high-dose or reduced-intensity chemotherapy with allogeneic HSCT. As outlined next, the two treatments--autologous HSCT and allogeneic HSCT--represent two different strategies. The first, autologous HSCT, is a “rescue” but not therapeutic procedure; the second, allogeneic HSCT, is a “rescue” plus a therapeutic procedure.
Conventional Preparative Conditioning for Hematopoietic Stem Cell Transplantation
The conventional (“classical”) practice of allogeneic HSCT involves administration of cytotoxic agents (e.g., 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 mediated by non-self-immunologic effector cells that develop after engraftment of allogeneic stem cells within the patient’s 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, immunosuppressant 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 prior to 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 non-relapse 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.
Acute Myeloid Leukemia (AML)
Acute myeloid leukemia (also called acute nonlymphocytic leukemia) refers to a set of leukemias that arise from a myeloid precursor in the bone marrow. AML is characterized by proliferation of myeloblasts, coupled with low production of mature red blood cells, platelets, and often non-lymphocytic white blood cells (granulocytes, monocytes). Clinical signs and symptoms are associated with neutropenia, thrombocytopenia, and anemia. The incidence of AML increases with age, with a median of 67 years. Approximately 13,000 new cases are diagnosed annually.
The pathogenesis of AML is unclear. It can be subdivided according to resemblance to different subtypes of normal myeloid precursors using the French-American-British (FAB) classification system. This system classifies leukemias from M0–M7, based on morphology and cytochemical staining, with immunophenotypic data in some instances. The World Health Organization (WHO) subsequently incorporated clinical, immunophenotypic, and a wide variety of cytogenetic abnormalities that occur in 50% to 60% of AML cases into a classification system that can be used to guide treatment according to prognostic risk categories.
The WHO system recognizes 5 major subcategories of AML:
AML with recurrent genetic abnormalities includes AML with t(8;21)(q22;q22), inv(16)(p13:q22) or t(16;16)(p13;q22), t(15;17)(q22;q12), or translocations or structural abnormalities involving 11q23. Younger patients may exhibit t(8;21) and inv(16) or t(16;16). AML patients with 11q23 translocations include two subgroups: AML in infants and therapy-related leukemia. Multilineage dysplasia AML must exhibit dysplasia in 50% or more of the cells of two lineages or more, which is associated with cytogenetic findings that include-7/del(7q), -5/del(5q), +8, +9, +11, del(11q), del(12p), -18, +19, del(20q)+21, and other translocations. AML not otherwise categorized includes disease that does not fulfill criteria for the other groups and essentially reflects the morphologic and cytochemical features and maturation level criteria used in the FAB classification, except for the definition of AML as having a minimum 20% (as opposed to 30%) blasts in the marrow. AML of ambiguous lineage is diagnosed when blasts lack sufficient lineage-specific antigen expression to classify as myeloid or lymphoid.
Molecular studies have identified a number of genetic abnormalities that also can be used to guide prognosis and management of AML. Cytogenetically normal AML (CN-AML) is the largest defined subgroup of AML, comprising approximately 45% percent of all AML cases. Despite the absence of cytogenetic abnormalities, these cases often have genetic mutations that affect outcomes, six of which have been identified. The FLT3 gene that encodes FMS-like receptor tyrosine kinase (TK) 3, a growth factor active in hematopoiesis, is mutated in 33% to 49% of CN-AML cases; among those, 28% to 33% consist of internal tandem duplications (ITD), 5% to 14% are missense mutations in exon 20 of the TK activation loop, and the rest are point mutations in the juxtamembrane domain. All FLT3 mutations result in a constitutively activated protein and confer a poor prognosis. Several pharmaceutical agents that inhibit the FLT3 TK are under investigation.
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.
POLICYNo benefits will be provided for a covered transplant procedure unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.
Allogeneic hematopoietic stem-cell transplantation (HSCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:
Allogeneic HSCT using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of AML in patients who are in complete marrow and extramedullary remission (CR1 or beyond), and who for medical reasons would be unable to tolerate a myeloablative conditioning regimen (see Policy Guidelines).
Autologous HSCT may be considered medically necessary to treat AML in CR1 or beyond, or relapsed AML if responsive to intensified induction chemotherapy.
POLICY EXCEPTIONSFor Federal Employee Program (FEP) subscribers, the Service Benefit Plan includes specific conditions in which autologous or allogeneic blood or marrow stem cell transplants would be considered eligible for coverage.
For State and School Employee subscribers, all bone marrow/stem cell transplants must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained.
POLICY GUIDELINESPrimary refractory acute myeloid leukemia (AML) is defined as leukemia that does not achieve a complete remission after conventionally dosed (non-marrow ablative) chemotherapy.
In the French-American-British (FAB) criteria, the classification of AML is solely based on morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.
Clinical features that predict poor outcomes of AML therapy include, but are not limited to, the following:
The newer, currently preferred, World Health Organization (WHO) classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers. It attempts to construct a classification that is universally applicable and prognostically valid. The WHO system was adapted by the National Comprehensive Cancer Network (NCCN) to estimate individual patient prognosis to guide management, as shown in the following table:
Risk Status of AML Based on Cytogenetic and Molecular Factors
The relative importance of cytogenetic and molecular abnormalities in determining prognosis and guiding therapy is under investigation.
The ideal allogeneic donors are HLA-identical siblings, matched at the HLA-A, -B, and -DR loci (6 of 6). 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, typically a parent or a child of the patient, for which there usually is sharing of only 3 of the 6 major histocompatibility antigens. Most patients will have such a donor; however, the risk of GVHD and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY3/25/2004: See policy "High-Dose Chemotherapy with Hematopoietic Stem Cell Support for Malignancies" prior to 3/25/2004, separate policy developed and aligned with BCBSA policy # 8.01.26 per approval by Medical Policy Advisory Committee (MPAC)
7/13/2004: Code Reference section completed
7/1/2004: Reviewed by MPAC; The following changed from investigational to medically necessary: "High-dose chemotherapy with allogeneic stem cell support is may be medically necessary to treat AML relapsing after prior therapy with high-dose chemotherapy and autologous stem cell support."
10/27/2005: Code Reference section updated; CPT-4 code 38230 added; ICD-9 Procedure 41.01, 41.02, 41.03, 41.09 added; HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added, J9000-J9999 deleted
3/22/2006: Coding updated. CPT4/HCPCS revisions added to policy
5/18/2007: Policy reviewed, no changes
12/20/2007: Coding updated per 2008 CPT/HCPCS revisions
7/14/2008: Policy updated; terminology modified but materially unchanged. High dose chemotherapy terminology removed from title and policy statement and replaced with stem cell transplantation (SCT). High dose chemotherapy will allogeneic stem cell support changed to investigational for treatment of AML relapsing after prior therapy with HDC and autologous stem cell support
9/11/2008: Annual ICD-9 updates effective 10-1-2008 applied
1/6/2009: Policy reviewed, "prior authorization before evaluation" deleted
8/07/2009: Policy Description Section updated with definitions and descriptions for Conventional Preparative Conditioning for HSCT, Reduced-Intensity Conditioning for Allogeneic HSCT, and AML as well as WHO information and molecular studies information specific to AML, Policy Statement Section revised to add specific medically necessary criteria to the treatment of AML with Allogeneic HSCT using a myeloablative conditioning regimen, Allogeneic HSCT using a reduced-intensity conditioning regimen, and Autologous HSCT, Policy Guidelines updated to add AML with antecedent hematologic disease as a clinical feature that predicts poor outcomes of AML therapy, WHO classification of AML Risk Status table, candidate information, and donor information, Coding Section updated with a Note added to the CPT-4 Covered Codes Table, ICD-9 Procedure Code 41.00 added to Covered Table, HCPCS codes S2140 and S2142 added to covered table, removed deleted HCPCS codes G0265, G0266, G0267, and G0363 from Covered Table
04/26/2010: FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826.
09/28/2011: Policy reviewed; no changes.
09/27/2012: Policy reviewed; no changes.
11/15/2013: Policy reviewed; no changes.
10/10/2014: Policy reviewed; description updated. Policy statement unchanged. Policy guidelines updated to add nonmyeloablative conditioning allogeneic HSCT as a conditioning regimen for some patients for whom a conventional myeloablative allotransplant could be curative.
08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38242; removed deleted code CPT 96445 and replaced with CPT code 96446.
11/18/2015: Policy description updated regarding complete remissions. Policy statements updated to add complete remission information for clarification. Table in policy guidelines section updated to change the following risk status from "Better" to "Favorable."
03/21/2016: Policy description updated regarding FDA regulations. Policy statements unchanged.
05/25/2016: Policy number added.
SOURCE(S)Blue Cross Blue Shield Association Policy # 8.01.26
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.