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Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with different genetic alterations resulting in distinct biologic subtypes. Patients are stratified to risk-adapted therapy according to certain clinical and genetic risk factors that predict outcome. Therapy may include hematopoietic cell transplantation (HCT).
Immunologic compatibility between infused hematopoietic cells and the recipient is not an issue in autologous hematopoietic cell transplantation (HCT). However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome with allogeneic HCT (allo-HCT). 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).
Conventional Preparative Conditioning for HCT
The success of autologous HCT 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 before undergoing bone marrow ablation. As a consequence, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission (CR). Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not graft-versus-host disease (GVHD).
The conventional (“classical”) practice of allo-HCT 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 allo-HCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.
Reduced-Intensity Conditioning for Allo-HCT
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 and to minimize as much as possible associated treatment-related morbidity and non-relapse mortality (NRM) when 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 allo-HCT 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 Lymphoblastic Leukemia
Childhood Acute Lymphoblastic Leukemia
ALL is a heterogeneous disease with different genetic alterations resulting in distinct biologic subtypes. Patients are stratified by 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 at diagnosis. Certain genetic characteristics of the leukemic cells strongly influence prognosis. Clinical and biologic factors predicting clinical outcomes and relapse risk are summarized in the Policy Guidelines section.
Adult Acute Lymphoblastic Leukemia
Note: The use of killer cells in the treatment of malignancies is addressed in a separate policy, Adoptive Immunotherapy.
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 the Code of Federal Regulation 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.
Autologous or allogeneic HCT may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL.
Allogeneic HCT is considered medically necessary to treat relapsing ALL after a prior autologous HCT.
Autologous HCT 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 HCT 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 HCT may be considered medically necessary to treat adult ALL in second or greater remission, or in patients with relapsed or refractory ALL.
Reduced-intensity conditioning (RIC) allogeneic HCT 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 HCT is investigational to treat adult ALL in second or greater remission or those with refractory disease.
Allogeneic HCT is medically necessary to treat relapsing ALL after a prior autologous HCT.
NOTE: The use of donor leukocyte infusions to treat relapse after allogeneic HCT for either children or adults is considered separately in the Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allogeneic Stem-Cell Transplant policy.
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.
Relapse Risk Prognostic Factors
The ideal allogeneic donors are human leukocyte antigen (HLA)-identical siblings, matched at the HLA-A, -B, and DR (antigen-D related) loci on each arm of chromosome 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. Most 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.
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 # 8.01.32 per approval by Medical Policy Advisory Committee (MPAC)
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.
10/17/2013: Added the following policy statement under the Children coverage criteria: Reduced-intensity conditioning allogeneic HSCT 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.
07/15/2014: Policy reviewed; description updated regarding childhood ALL. Policy statement revised to change "Children" and "Adults" to "Childhood ALL" and "Adult ALL." Policy statements on allogeneic HSCT to treat relapsing ALL after a prior autologous SCT changed from "investigational" to "medically necessary." Policy statement revised to remove the statement on reduced-intensity conditioning from the Childhood ALL section. Policy guidelines updated to add "Relapse Risk Prognostic Factors" as a heading. Added "including autologous or allogeneic HSCT" to the paragraph on reduced-intensity conditioning in the policy guidelines.
08/21/2015: Code Reference section update to add ICD-10 codes. Revise the descriptions for CPT codes 38240 and 38242; removed deleted HCPCS code G0363; remove deleted code CPT 96445 and replaced with CPT code 96446.
10/01/2015: Policy description updated to remove table regarding prognostic factors for childhood ALL; information in Policy Guidelines. Policy statements unchanged. Policy Guidelines updated to add medically necessary and investigative definitions.
04/20/2016: "Hematopoietic stem cell transplantation (HSCT)" changed to "hematopoietic cell transplantation (HCT)" in the policy title and throughout the policy. Policy description updated regarding FDA regulations. Policy statements unchanged. Policy guidelines updated regarding ideal allogeneic donors.
05/26/2016: Policy number added.
SOURCE(S)Blue Cross Blue Shield Association Policy # 8.01.32
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.