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Hematopoietic stem-cell transplantation (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 cytotoxic drugs with or without whole body radiation therapy. Bone-marrow stem cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta 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 vs. host disease (GVHD). Cord blood is discussed in greater detail in the Placental and Umbilical Cord Blood as a Soure of Stem Cells policy.

Immunologic incompatibility between infused 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 antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each leg of chromosome 6.  Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

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 that develops 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, immune suppressant 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 (sometimes called “acute nonlymphocytic leukemia” [ANLL]) 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. About 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. 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 (see Policy Guidelines).

The WHO system recognizes 5 major subcategories of AML:

1. AML with recurrent genetic abnormalities
2. AML with multilineage dysplasia
3. therapy-related AML and myelodysplasia
4. AML not otherwise categorized
5. acute leukemia of ambiguous lineage

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;aq12), 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 percent or more of the cells of two lineages or more. It 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 percent (as opposed to 30 percent) 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 about 45 percent of all AML cases. Despite the absence of cytogenetic abnormalities, these cases often have genetic mutations that affect outcomes, of which six 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 percent–49 percent of CN-AML cases; among those, 28 percent–33 percent consist of internal tandem duplications (ITD), 5 percent–14 percent 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.

Complete remissions can be achieved initially using combination chemotherapy in up to 80% of AML patients. However, the high incidence of relapse has prompted research into a variety of post-remission strategies using either allogeneic or autologous HSCT.

Allogeneic hematopoietic stem-cell transplantation (HSCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:

• poor- to intermediate-risk AML in remission (see Policy Guidelines for information on risk stratification), or
• AML that is refractory to, or relapses following, standard induction chemotherapy, or
• AML in patients who have relapsed following a prior autologous HSCT and are medically able to tolerate the procedure.

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, 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 first or second remission or relapsed AML if responsive to intensified induction chemotherapy.

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, CareAllies. No benefits will be provided for any transplant procedure unless prior approval for the transplant is obtained from CareAllies.

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:

• Treatment-related AML (secondary to prior chemotherapy and/or radiotherapy for another malignancy)
• AML with antecedent hematologic disease (e.g., myelodysplasia)
• Presence of circulating blasts at the time of diagnosis
• Difficulty in obtaining first complete remission with standard chemotherapy
• Leukemias with monocytoid differentiation (FAB classification M4 or M5)

The newer, currently preferred, World Health Organization (WHO) classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt 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.

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for RIC allogeneic HSCT. These include those whose age (typically older than 60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen. A patient whose disease relapses following a conventional myeloablative allogeneic HSCT could undergo a second myeloablative procedure if a suitable donor is available and his or her medical status would permit it. However, this type of patient would likely undergo RIC prior to a second allogeneic HSCT if a complete remission could be re-induced with chemotherapy.

Autologous HSCT is used for consolidation treatment of intermediate- to poor-risk disease in complete remission, among patients for whom a suitable donor is not available. Better-risk AML often responds well to chemotherapy with prolonged remission if not cure.

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, where usually there is sharing of only 3 of the 6 major histocompatibility antigens. The majority of 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.

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

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.

The code(s) listed below are ONLY covered if the procedure is performed according to the "Policy" section of this document.  

Covered Codes

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