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Hematopoietic stem-cell transplantation (SCT) 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 (i.e., autologous SCT) or from a donor (i.e., allogeneic SCT). 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-versus-host disease (GVHD). Cord blood is discussed in greater detail in the Placental Umbilical Cord Blood as a Source of Stem cells policy.

Immunologic compatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. 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 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.

Conventional Preparative Conditioning for Hematopoietic SCT

The conventional (“classical”) practice of allogeneic SCT 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 SCT, 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 SCT 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 SCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous SCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic SCT

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 non-myeloablative, as opposed to fully myeloablative (conventional) regimens.

Acute Lymphocytic Leukemia

Childhood ALL 
ALL is the most common cancer diagnosed in children and represents almost 25% of cancers in children younger than 15 years. (1) Complete remission of disease is now typically achieved with pediatric chemotherapy regimens in approximately 95% of children with ALL, with up to 85% long-term survival rates. Survival rates have improved with the identification of effective drugs and combination chemotherapy through large, randomized trials, integration of presymptomatic central nervous system prophylaxis, and intensification and risk-based stratification of treatment.
ALL is a heterogeneous disease with different genetic alterations resulting in distinct biologic subtypes. Patients are stratified according to certain clinical and genetic risk factors that predict outcome, with risk-adapted therapy tailoring treatment based on the predicted risk of relapse.  Two of the most important factors predictive of risk are patient age and white blood cell count (WBC) at diagnosis. Certain genetic characteristics of the leukemic cells strongly influence prognosis. Clinical and biologic factors predicting clinical outcome can be summarized as follows:

Adult ALL
ALL accounts for approximately 20% of acute leukemias in adults. Approximately 60%–80% of adults with ALL can be expected to achieve complete remission after induction chemotherapy; however, only 35%–40% can be expected to survive 2 years.  Differences in the frequency of genetic abnormalities that characterize adult ALL versus childhood ALL help, in part, to explain the outcome differences between the two groups. For example, the “good prognosis” genetic abnormalities like hyperdiploidy and t(12;21) are seen much less commonly in adult ALL, whereas they are some of the most common in childhood ALL. Conversely, “poor prognosis” genetic abnormalities like the Philadelphia chromosome (t[9;22]) are seen in 25%–30% of adult ALL but infrequently in childhood ALL. Other adverse prognostic factors in adult ALL include age greater than 35 years, poor performance status, male sex, and leukocytosis at presentation of >30,000/µL (B-cell lineage) and >100,000/µL (T-cell lineage).

Note: The use of killer (LAK) cells in the treatment of malignancies is addressed in a separate policy, Adoptive Immunotherapy.

Children
Allogeneic or autologous hematopoietic stem-cell transplantation (SCT) may be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high risk of relapse. (For definition of high-risk factors, see Policy Guidelines).

Autologous or allogeneic hematopoietic SCT may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL.

Allogeneic hematopoietic SCT is considered investigational to treat relapsing ALL after a prior autologous SCT.

Adults

Autologous hematopoietic SCT may be considered medically necessary to treat adult ALL in first complete remission but at high risk of relapse (For definition of high-risk factors, see Policy Guidelines).

Allogeneic hematopoietic SCT may be considered medically necessary to treat adult ALL in first complete remission for any risk level (For definition of risk factors, see Policy Guidelines)

Allogeneic hematopoietic SCT may be considered medically necessary to treat adult ALL in second or greater remissions, or in patients with relapsed or refractory ALL.

Reduced-intensity conditioning (RIC) allogeneic hematopoietic SCT  may be considered medically necessary as a treatment of ALL in patients who are in complete marrow and extramedullary first or second remission, and who, for medical reasons (see Policy Guidelines), would be unable to tolerate a standard myeloablative conditioning regimen. 

Autologous hematopoietic SCT is investigational to treat adult ALL in second or greater remission or those with refractory disease.

Allogeneic hematopoietic SCT is investigational to treat relapsing ALL after a prior autologous SCT.

NOTE: The use of donor leukocyte infusions to treat relapse after allogeneic SCT for either children or adults is considered separately in the Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allogeneic Stem-Cell Transplant policy.

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.

Adult ALL
Risk factors for relapse are less well defined in adults, but a patient with any of the following may be considered at high risk for relapse: age greater than 35 years, leukocytosis at presentation of >30,000/µL (B-cell lineage) and >100,000/µL (T-cell lineage),“poor prognosis” genetic abnormalities like the Philadelphia chromosome (t(9;22)), extramedullary disease, and time to attain complete remission longer than 4 weeks (American Society of Hematology Education Program Handbook, 2007).

Reduced-Intensity Conditioning 
Some patients for whom a conventional myeloablative allogeneic hematopoietic stem-cell transplantation (HSCT) could be curative may be considered candidates for reduced-intensity conditioning (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.

Note: Unless otherwise specified in the text of this Policy, it is assumed that the term “allogeneic SCT” refers to the use of a myeloablative pretransplant conditioning regimen.

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 graft-versus-host-disease and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.

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

6/25/2004: Code Reference section completed

11/18/2004: Reviewed by MPAC, the following changed from investigational to medically necessary; "High-dose chemotherapy and allogeneic stem cell support may be medically necessary to treat relapsing ALL after a prior course of high-dose chemotherapy and autologous stem cell support."

10/21/2005: Code reference section updated, codes 38230, g0355 - G0364 added, J9000 - J9999 deleted, ICD9 procedure codes 41.01, 41.02, 41.03, 41.09 added, statement under HCPCS title added, description revised for ICD9 procedure code 99.79, policy revised

3/22/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy

5/21/2007: Policy reviewed, no changes

9/18/2007: Policy reviewed, no changes

12/20/2007:  Coding updated per 2008 CPT/HCPCS revisions

7/22/2008: Policy updated; terminology modified but materially unchanged. High dose chemotherapy terminology removed from title and policy statement and replaced with stem cell transplantation (SCT). Policy statement added; reduced-intensity conditioning (RIC) allogeneic SCT is considered investigational as treatment of ALL in those who do not qualify for a myeloablative allogeneic SCT.

9/11/2008: Annual ICD-9 updates effective 10-1-2008 applied

1/6/2009: Policy reviewed, "prior authorization before evaluation" deleted

9/30/2009: Code reference section updated. New ICD9 procedure code 17.70 added to covered table. HCPC codes G0265, G0266 and G0267 deleted from covered table due to codes were deleted as of 12-31-2007.

04/27/2010:  The term “Lymphocytic” was changed to “Lymphoblastic” in the policy title and throughout the policy. Policy description and guidelines updated regarding prevalence of disease and treatment approaches.  Policy statement updated to indicate when RIC allogeneic hematopoietic SCT would be considered medically necessary as a treatment of ALL in adults. Policy statement regarding treatment of adult ALL in first complete remission but at high risk of relapse split to address allogeneic and autologous transplant separately. FEP and State and School Employees verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826 and HCPCS code S2140 and S2142.

04/19/2011: Policy reviewed; no changes.

03/02/2012: 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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