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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 anticancer drugs with or without whole-body radiotherapy. Hematopoietic 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 shortly after delivery of neonates.
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 (autologous HCT) or from a 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 antigens (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 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 non-myeloablative, as opposed to fully myeloablative (traditional) regimens.
Hodgkin lymphoma is a relatively uncommon B-cell lymphoma. In 2011, the estimated number of cases in the United States was approximately 8,830 new diagnoses and 1,300 deaths. The disease has a bimodal distribution, with most patients diagnosed between the ages of 15 and 30 years, with a second peak in adults aged 55 and older.
The World Health Organization (WHO) classification divides Hodgkin lymphoma into 2 main types:
In Western countries, CHL accounts for 95% of cases of Hodgkin lymphoma, and for NLPHL, only 5%. Classic Hodgkin lymphoma is characterized by the presence of neoplastic Reed-Sternberg cells in a background of numerous non-neoplastic inflammatory cells. NLPHL lacks Reed-Sternberg cells, but is characterized by the presence of lymphocytic and histiocytic cells termed “popcorn cells.”
The following staging system for Hodgkin lymphoma recognizes the fact that the disease is thought to typically arise in a single lymph node and spread to contiguous lymph nodes with eventual involvement of extranodal sites. The staging system attempts to distinguish patients with localized Hodgkin lymphoma who can be treated with extended field radiation from those who require systemic chemotherapy.
Staging for Hodgkin Lymphoma
Staging for Hodgkin lymphoma is based on the Ann Arbor staging system. Each stage is subdivided into A and B categories. “A” indicates no systemic symptoms are present and “B” indicates the presence of systemic symptoms, including unexplained weight loss of more than 10% of body weight, unexplained fevers, or drenching night sweats.
Involvement of a single lymph node region (I) or localized involvement 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 a single associated extralymphatic organ or site and its regional lymph node(s) with or without involvement of other lymph node regions on the same side of the diaphragm (IIE). The number of lymph node regions involved should be indicated by a subscript (e.g., II2).
Involvement of lymph node regions or structures on both sides of the diaphragm. These patients are further subdivided as follows:
III-1: disease limited to spleen or upper abdomen
Disseminated (multifocal) involvement of one or more extralymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement.
Patients with Hodgkin lymphoma are generally classified into 3 groups: early-stage favorable (stage I–II with no B symptoms or large mediastinal lymphadenopathy), early-stage unfavorable (stage I–II with large mediastinal mass, with or without B symptoms; stage IB–IIB with bulky disease), and advanced-stage disease (stage III–IV).
Patients with nonbulky stage IA or IIA disease are considered to have clinical early stage disease. These patients are candidates for chemotherapy, combined modality therapy, or radiotherapy alone. Patients with obvious stage III or IV disease, bulky disease (defined as a 10-cm mass or mediastinal disease with a transverse diameter exceeding 33% of the transthoracic diameter), or the presence of B symptoms will require combination chemotherapy with or without additional radiotherapy.
Hodgkin lymphoma is highly responsive to conventional chemotherapy, and up to 80% of newly diagnosed patients can be cured with combination chemotherapy and/or radiotherapy. Patients who prove refractory or who relapse after first-line therapy have a significantly worse prognosis. Primary refractory Hodgkin lymphoma is defined as disease regression of less than 50% after 4–6 cycles of anthracycline-containing chemotherapy, disease progression during induction therapy, or progression within 90 days after the completion of first-line treatment.
In patients with relapse, the results of salvage therapy vary depending on a number of prognostic factors, as follows: the length of the initial remission, stage at recurrence, and the severity of anemia at the time of relapse. Early and late relapse are defined as less or more than 12 months from the time of remission, respectively. Approximately 70% of patients with late first relapse can be salvaged by autologous HSCT, but not more than 40% with early first relapse.
Only approximately 25%-35% of patients with primary progressive or poor-risk recurrent Hodgkin lymphoma achieve durable remission after autologous HSCT, with most failures being due to disease progression after transplant. Most relapses after transplant occur within 1–2 years, and once relapse occurs post-transplant, median survival is less than 12 months.
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.
Autologous or myeoablative allogeneic hematopoietic stem-cell transplantation may be considered medically necessary in patients with primary refractory or relapsed Hodgkin lymphoma.
Tandem autologous HSCT may be considered medically necessary:
Reduced-intensity allogeneic HSCT may be considered medically necessary to treat Hodgkin lymphoma in patients:
A second autologous hematopoietic stem-cell transplantation for relapsed lymphoma after a prior autologous HSCT is considered investigational.
Other uses of hematopoietic stem-cell transplantation in patients with Hodgkin lymphoma are considered investigational, including, but not limited to, initial therapy for newly diagnosed disease to consolidate a first complete remission.
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 from the Plan’s Utilization Review Vendor.
POLICY GUIDELINESIn the Morschhauser study of risk-adapted salvage treatment with single or tandem autologous hematopoietic stem-cell transplantation (HSCT) for first relapse or refractory Hodgkin lymphoma, poor-risk relapsed Hodgkin lymphoma was defined as 2 or more of the following risk factors at first relapse: time to relapse less than 12 months, stage III or IV at relapse, and relapse within previously irradiated sites. Primary refractory disease was defined as disease regression less than 50% after 4 to 6 cycles of doxorubicin-containing chemotherapy or disease progression during induction or within 90 days after the end of first-line treatment.
Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for reduced-intensity conditioning (RIC) allogeneic HSCT. These include those with malignancies that are effectively treated with myeloablative allogeneic transplantation, but whose age (typically older than 55 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.
The ideal allogeneic donors are human leukocyte antigen-identical matched siblings. 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 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 # 8.01.29 per approval by Medical Policy Advisory Committee (MPAC)
7/14/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC, no changes
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
10/26/2005: Code Reference section updated, ICD-9 procedure codes 41.01, 41.02, 41.03, 41.09 added
3/14/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy
5/21/2007: Policy reviewed, no changes
12/19/2007: 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).
1/6/2009: Policy reviewed, "prior authorization before evaluation" deleted.
04/26/2010: Policy description updated regarding conventional and reduced-intensity conditioning. Policy statement changed to indicate that tandem autologous SCT and reduced-intensity conditioning allogeneic SCT may be considered medically necessary in specific situations. Policy statement also updated to indicate that a second autologous stem-cell transplantation for relapsed lymphoma after a prior autologous hematopoietic stem-cell transplant is considered investigational. Supporting explanations added to the policy guidelines. FEP and State and School Employee verbiage added to the Policy Exceptions section. Added new CPT codes 86825 and 86826. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007.
12/28/2010: Added policy statement regarding when tandem autologous HSCT may be considered medically necessary.
01/17/2012: Policy reviewed; no changes.
03/13/2013: Policy reviewed; no changes.
03/10/2014: Policy reviewed; no changes.
01/29/2015: Policy description updated regarding the estimated number of cases for Hodgkin Lymphoma and to change "radiation therapy" to "radiotherapy." Investigational policy statements updated to change "stem-cell transplantation" to "hematopoietic stem-cell transplantation."
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.
03/23/2016: Policy description updated regarding FDA regulations. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigative definitions.
05/26/2016: Policy number added.
SOURCE(S)Blue Cross Blue Shield Association Policy # 8.01.29
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 accordoing to the "Policy" section of this document.