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Hematopoietic Stem Cell Transplantation
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 radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (i.e., autologous HSCT) or from a donor (i.e., 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 vs. host disease. 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 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 class I and class II loci on 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 Hematopoietic Stem-Cell Transplantation
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.
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 nonself 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, 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 Allogeneic Hematopoietic Stem-Cell Transplantation
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 traditional 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 nonrelapse 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 (traditional) regimens.
Non-Hodgkin’s Lymphomas (NHL)
A heterogeneous group of lymphoproliferative malignancies, NHL usually originates in lymphoid tissue. Historically, uniform treatment of patients with NHL was hampered by the lack of a uniform classification system. In 1982, the Working Formulation (WF) was developed to unify different classification systems into one. The WF divided NHL into low-, intermediate-, and high-grade, with subgroups based on histologic cell type. Since our understanding of NHL has improved, the diagnosis has become more sophisticated and includes the incorporation of new immunophenotyping and genetic techniques. As a result, the WF has become outdated.
European and American pathologists proposed a new classification, the Revised European American Lymphoma (REAL) Classification, and an updated version of the REAL system, the new World Health Organization (WHO) classification. The WHO/REAL classification recognizes 3 major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma. Hodgkin lymphoma and SCT is addressed in the Hematopoietic Stem Cell Transplantation for Hodgkin Lymphoma policy.
Updated WHO Classification
Mature B-cell neoplasms
Mature T-cell and NK-cell neoplasms
*These represent provisional entities or provisional subtypes of other neoplasms.
In the United States, B-cell lymphomas represent 80–85% of cases of NHL and T-cell lymphomas 15–20%. NK lymphomas are relatively rare.
The International Lymphoma Classification Project identified the most common NHL subtypes as follows: diffuse large B-cell lymphoma (DLBCL) 31%, follicular lymphoma (FL) 22%, small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) 6%, mantle cell lymphoma (MCL) 6%, peripheral T-cell lymphoma (PTCL) 6%, and marginal zone B-cell lymphoma/mucosa-associated lymphoid tissue (MALT) lymphoma 5%. All other subtypes each represent less than 2% of cases of NHL.
In general, the NHL can be divided into two prognostic groups, indolent and aggressive. Indolent NHL has a relatively good prognosis, with a median survival of 10 years; however, they it is not curable in advanced clinical stages. Early stage indolent NHL (stage 1 or 2) may be effectively treated with radiation alone. Although indolent NHL is responsive to radiation and chemotherapy, a continuous rate of relapse is seen in advanced stages. These patients can often be retreated if their disease remains of the indolent type. Indolent NHL may transform into a more aggressive form, which is generally treated with regimens that are used for aggressive, recurrent NHL. Histologic transformation to higher grade lymphoma occurs in up to 70% of patients with low-grade lymphomas, and median survival with conventional chemotherapy is 1 year or less.
FL is the most common indolent NHL (70–80% of cases), and often the terms indolent lymphoma and FL are used synonymously. Also included in the indolent NHL are SLL/CLL, lymphoplasmacytoid lymphoma, marginal zone lymphomas, and cutaneous T-cell lymphomas.
Aggressive NHL has a shorter natural history; however, 30–60% of these patients can be cured with intensive combination chemotherapy regimens. Aggressive lymphomas include DLBCL, MCL, PTCL, anaplastic large cell lymphoma, and Burkitt’s lymphoma.
Oncologists developed a clinical tool to aid in predicting the prognosis of patients with aggressive NHL (specifically DLBCL), referred to as the International Prognostic Index (IPI). Prior to the development of IPI in 1993, prognosis was predominantly based upon disease stage.
Based on the number of risk factors present and adjusted for patient age, the IPI defines 4 risk groups: low, low intermediate, high intermediate, and high risk, based upon 5 significant risk factors prognostic of overall survivial (OS):
Risk groups are stratified according to the number of adverse factors as follows: 0 or 1 is low risk, 2 is low intermediate, 3 is high intermediate, and 4 or 5 are high risk.
Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. Age-adjusted IPI and stage-adjusted modifications of this IPI are used for younger patients with localized disease.
Adverse risk factors for age-adjusted IPI include stage III or IV disease, elevated LDH and ECOG performance status >2, and can be calculated as follows: 0 is low risk, 1 is low intermediate, 2 is high intermediate, and 3 is high risk.
With the success of the IPI, a separate prognostic index was developed for FL, which has multiple independent risk factors for relapse after a first complete remission. The proposed and validated Follicular Lymphoma International Prognostic Index (FLIPI) contains 5 adverse prognostic factors:
These 5 factors are used to stratify patients into 3 categories of risk: low (0-1 risk factor), intermediate (2 risk factors), or poor (more than 3 risk factors).
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) comprises approximately 65-68% of NHL and has been recognized within the past 15 years as a unique lymphoma subtype with a particularly aggressive course. MCL is characterized by a chromosomal translocation t(11;14) and the term “mantle cell lymphoma” was proposed in 1992 by Banks et al. The number of therapeutic trials are not as numerous as for other NHL as it was not widely recognized until the REAL classification. MCL shows a strong predilection for elderly males, and the majority of cases (70%) present with disseminated (stage 4) disease and extranodal involvement is common. Localized MCL is quite rare. MCL has a median survival of approximately 2 - 4 years, and although most patients achieve remission with first line therapy, relapse inevitably occurs, often within 12-18 months. MCL is rarely, if ever, cured with conventional therapy, and no standardized therapeutic approach to MCL is used.
There had been no generally established prognostic index for patients with MCL. Application of the IPI or FLIPI system to patients with MCL showed serious limitations, which included no separation of some important risk groups. In addition, some of the individual IPI and FLIPI risk factors, including number of extranodal sites and number of involved nodal areas showed no prognostic relevance, and hemoglobin showed no independent prognostic relevance in patients with MCL. Therefore, a new prognostic index for patients with MCL was developed, and should prove useful in comparing clinical trial results for MCL.
MCL international prognostic index (MIPI):
MIPI allows separation of 3 groups with significantly different prognoses:
Peripheral T-cell Lymphomas (PTCL)
The majority of peripheral T-cell lymphomas are aggressive and fall into the category of PTCL, unspecified (PTCL-u) or not otherwise specified (PTCL-NOS), angioimmunoblastic or anaplastic large cell which, combined make up approximately 60–70% of T-cell lymphomas. PTCLs are less responsive to standard chemotherapy than DLBCLs and carry a worse prognosis than aggressive B-cell counterparts. Survival rates at 5 years with standard chemotherapy regimens range from 20–35%. The poor results with conventional chemotherapy have prompted exploration of the role of HSCT as therapy.
The Ann Arbor staging classification is commonly used for the staging of lymphomas and is the scheme defined in the AJCC Manual for Staging Cancer. Originally developed for Hodgkin's disease, this staging scheme was later expanded to include non-Hodgkin's lymphoma.
Ann Arbor Classification
Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)
Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE).
Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE) .
Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement.
Note: Small lymphocytic lymphoma may be considered a node-based variant of chronic lymphocytic leukemia (CLL). Therefore, SLL is considered along with CLL in the Hematopoietic Stem-Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma policy.
No 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.
For patients with non-Hodgkin lymphoma (NHL) B-cell subtypes considered aggressive (except mantle cell lymphoma), either allogeneic hematopoietic stem cell transplantation (HSCT) using a myeloablative conditioning regimen or autologous HSCT may be considered medically necessary:
For patients with mantle cell lymphoma:
For patients with NHL B-cell subtypes considered indolent, either allogeneic HSCT using a myeloablative conditioning regimen or autologous HSCT may be considered medically necessary:
Reduced-intensity conditioning allogeneic HSCT may be considered medically necessary as a treatment of NHL in patients who meet criteria above for an allogeneic HSCT but who do not qualify for a myeloablative allogeneic HSCT.
Either autologous HSCT or allogeneic HSCT is considered investigational:
Tandem transplants are considered investigational to treat patients with any stage, grade, or subtype of NHL.
For patients with mature T-cell or NK-cell (peripheral T-cell) neoplasms:
Note: Small lymphocytic lymphoma may be considered a node-based variant of chronic lymphocytic leukemia (CLL). Therefore, SLL is considered along with CLL in the Hematopoietic Stem-Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma policy. Lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia is considered in the Hematopoietic Stem-Cell Transplantation for Primary Amyloidosis or Waldenstrom's Macroglobulinemia policy.
For 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.
Reduced-intensity conditioning (RIC) would be considered an option in patients who meet criteria for an allogeneic hematopoietic stem-cell transplant (SCT) but whose age (typically older than 55 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy) preclude use of a standard conditioning regimen.
In patients who qualify for a myeloablative allogeneic hematopoietic SCT on the basis of overall health and disease status, allogeneic HSCT using either myeloablative or RIC may be considered. However, a myeloablative conditioning regimen with allogeneic HSCT may benefit younger patients with good performance status and minimal comorbidities more than allogeneic HSCT with RIC.
A chemosensitive relapse is defined as relapsed NHL that does not progress during or immediately after standard-dose induction chemotherapy (i.e., achieves stable disease or a partial response).
Transformation describes a lymphoma whose histologic pattern has evolved to a higher-grade lymphoma. Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern.
Tandem transplants usually are defined as the planned administration of two (2) successive cycles of high-dose myeloablative chemotherapy, each followed by infusion of autologous hematopoietic stem cells, whether or not there is evidence of persistent disease following the first treatment cycle. Sometimes, the second cycle may use non-myeloablative immunosuppressive conditioning followed by infusion of allogeneic stem cells.
The term salvage therapy describes therapy given to patients with refractory or relapsed disease. For patients with PTCL, salvage therapy includes patients who do not achieve a CR (eg, achieve only a partial response (PR), have no response, or have progressive disease) with first-line induction chemotherapy (refractory disease) or who relapse after achieving a CR with first-line induction chemotherapy. For mantle cell lymphoma, salvage therapy includes patients with progressive disease with first-line induction chemotherapy (refractory disease) or in patients who relapse after a CR or PR after initial induction chemotherapy, or patients who fail a previous autologous HSCT.
High-risk (aggressive) T-cell and natural killer (NK)‒cell neoplasms: the T-cell and NK-cell neoplasms are a clinically heterogeneous group of rare disorders, most of which have an aggressive clinical course and poor prognosis. The exception includes the following subtypes, which typically have a relatively indolent and protracted course: T-cell large granulocyte leukemia (T-LGL), chronic lymphoproliferative disorder of NK cells, early-stage mycosis fungoides, primary cutaneous anaplastic large-cell lymphoma (ALCL), and ALK+ ALCL.
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.
3/25/2004: 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 # 8.01.20 per approval by Medical Policy Advisory Committee (MPAC)
7/19/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC, “High-dose chemotherapy with allogeneic stem-cell support is considered investigational to treat NHL that progresses or relapses relatively soon after a prior course of high-dose chemotherapy with autologous stem-cell support.” changed to “High-dose chemotherapy with allogeneic stem-cell support may be considered medically necessary to treat NHL that progresses or relapses relatively soon after a prior course of high-dose chemotherapy with autologous stem-cell support.”
7/14/2005: Code Reference section updated, CPT code 38230 added covered codes, HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added covered codes, HCPCS J9000-J9999 statement added to HCPCS and all separately listed codes deleted
10/20/2005: Code Reference section updated, ICD9 procedure codes 41.01, 41.02, 41.03, 41.09 added
3/16/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy
5/17/2007: Policy reviewed, description updated. Added marginal zone lymphoma with indolent behavior or lymphoma or lymphoplasmacytoid lymphoma medically necessary for patients with NHL subtypes IWF classified as indolent
9/13/2007: Code reference section updated per the annual ICD-9 code updates. ICD-9 codes 200.00-200.28 and 200.80-200.88 added
12/19/2007: Coding updated per 2008 CPT/HCPCS revisions
7/11/2008: Policy description and statements updated. Peripheral T-cell lymphoma added as investigational for either autologous or allogeneic stem-cell support. Allogeneic stem-cell support to treat NHL that progresses or relapses soon after a course of HDC with autologous stem-cell support changed to investigational. Title changed to "Stem-Cell Transplantation" and the terminology "High Dose Chemotherapy" removed
1/6/2009: Policy reviewed, "prior authorization before evaluation" deleted
6/04/2010: Policy description updated to include risk groups and adverse risk factors. Policy statement updated to include medically necessary indications for allogeneic SCT and/or autologous SCT and medically necessary indications for reduced intensity conditioning allogeneic SCT. FEP and State and School Employee verbiage added to Policy Exceptions section. Added new CPT Codes 86825 and 86826 to Covered Codes Table. HCPCS Codes G0265, G0266 and G0267 were removed from covered table due to these codes were deleted as of 12-31-2007.
04/20/2011: Policy description updated regarding disease classification, prevalence, and treatment approaches. Policy statement revised to break out mantle cell lymphoma; investigational statements added for autologous as salvage therapy and allogeneic to consolidate a first remission and medically necessary statement added for allogeneic as salvage therapy. Also revised the policy statement to break out peripheral T-cell lymphoma; added statements as medically necessary for autologous to consolidate first remission in specific situations and autologous and allogeneic as salvage therapy, and as investigational regarding allogeneic HSCT to consolidate a first complete remission. Policy guidelines updated regarding high-risk peripheral T-cell lymphoma.
05/08/2012: Policy statement regarding peripheral T-cell lymphomas revised to clarify that this includes mature T-cell and NK-cell neoplasms.
04/16/2013: Policy reviewed; no changes.
04/01/2014: Policy reviewed; description updated regarding Mature T-cell and NK-cell neoplasms and Mantle Cell Lymphoma.
03/13/2015: Policy reviewed; description updated. "Stem-cell transplantation" changed to "hematopoietic stem-cell transplantation" throughout policy. Investigational statement criteria for autologous and allogeneic HSCT updated to change "NHL subtypes" to "NHL B-cell subtypes." In first medically necessary statement for patients with mature T-cell or NK-cell (peripheral T-cell) neoplasms, "high-risk peripheral T-cell lymphoma" changed to "high-risk subtypes." Policy guidelines updated to add information regarding salvage therapy and high-risk (aggressive) T-cell and natural killer cell neoplasms.
08/27/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240 and 38241; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.
05/25/2016: Policy number added. Policy Guidelines updated to add medically necessary and investigative definitions.
Blue Cross Blue Shield Association Policy # 8.01.20
This 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.