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Risk stratification of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) guides therapy decisions, which may include hematopoietic cell transplantation for those with poor risk features.
Conventional Preparative Conditioning for Hematopoietic Cell Transplantation
Hematopoietic cell transplantation (HCT) 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. Hematopoetic stem cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic hematopoietic cell transplantation [allo- HCT]). 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 HCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allo-HCT. 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.
The conventional 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. The slower GVM effect is considered 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, immunosuppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.
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. Patients who undergo autologous HCT are susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.
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, 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 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.
Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are neoplasms of hematopoietic origin characterized by the accumulation of lymphocytes with a mature, generally well-differentiated morphology. In CLL, these cells accumulate in blood, bone marrow, lymph nodes, and spleen, in SLL they are generally confined to lymph nodes. The Revised European-American/WHO Classification of Lymphoid Neoplasms considers B-cell CLL and SLL a single disease entity.
CLL and SLL share many common features and are often referred to as blood and tissue counterparts of each other, respectively. Both tend to present as asymptomatic enlargement of the lymph nodes, tend to be indolent in nature, but can undergo transformation to a more aggressive form of disease (e.g., Richter transformation). The median age at diagnosis of CLL is approximately 72 years, but it may present in younger individuals, often as poor-risk disease with significantly reduced life expectancy.
Treatment regimens used for CLL are generally the same as those used for SLL, and outcomes of treatment are comparable for both diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses with median survivals of 6 to 10 years; however, the median survival of high-risk CLL or SLL may be only 2 years. Although typically responsive to initial therapy, CLL and SLL are rarely cured by conventional therapy, and nearly all patients ultimately die of their disease. This natural history prompted investigation of hematopoietic cell transplantation as a possible curative regimen.
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 cells are included in these regulations.
No benefits will be provided for a covered transplant procedure or a transplant evaluation unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.
Allogeneic hematopoietic cell transplantation may be considered medically necessary to treat chronic lymphocytic leukemia or small lymphocytic lymphoma in patients with markers of poor-risk disease (see Policy Guidelines). Use of a myeloablative or reduced-intensity pretransplant conditioning regimen should be individualized based on factors that include patient age, the presence of comorbidities, and disease burden.
Allogeneic hematopoietic cell transplantation is considered investigational to treat chronic lymphocytic leukemia or small lymphocytic lymphoma except as noted above.
Autologous hematopoietic cell transplantation is considered investigational to treat chronic lymphocytic leukemia and small lymphocytic lymphoma.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Staging and Prognosis of Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)
Two scoring systems are used to determine stage and prognosis of patients with CLL/SLL. As outlined in Table 1, the Rai and Binet staging systems classify patients into 3 risk groups with different prognoses, and are used to make therapeutic decisions.
Table 1. Rai and Binet Classification for CLL/SLL
Because prognoses of patients vary within the different Rai and Binet classifications, other prognostic markers are used in conjunction with staging to determine clinical management. These are summarized in Table 2, according to availability in clinical centers.
Table 2. Markers of Poor Prognosis in CLL/SLL
Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation
The ideal allogeneic donors are human leukocyte antigen (HLA)-identical siblings, matched at the HLA-A, B, and DR loci (6/6). 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, haploidentical donors--typically a parent or a child of the patient--with whom usually there is sharing of only 3 of the 6 major histocompatibility antigens, have been under investigation as a stem cell source. 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.
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 # 8.01.15 per approval by Medical Policy Advisory Committee (MPAC)
7/14/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC: The phrase "either autologous or allogeneic" removed from the following statement: "High-dose chemotherapy with autologous stem cell support is considered investigational as a treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma." The following statement was added: "High-dose chemotherapy with allogeneic stem cell support is considered medically necessary for patients with T-cell disease." Code Reference section updated; Non-Covered table was split into two tables -- Covered and Non-Covered.
10/27/2005: Code Reference section updated: Covered table -- CPT-4 code 38230 added; ICD-9 Procedure codes 41.02, 41.03, HCPCS G0355, G0356, G0357, G0358, G0359, G0360, G0361, G0362, G0363, G0364 added, J9000-J9999 deleted; Non-Covered table -- ICD-9 Procedure codes 41.01, 41.09
3/22/2006: Coding policy updated. CPT4/HCPCS revisions added to policy.
12/20/2007: Coding updated per 2008 CPT/HCPCS revisions
9/29/2008: Description updated; terminology modified but materially unchanged. High dose chemotherapy terminology removed from title and policy statement and replaced with stem cell transplantation (SCT).
04/26/2010: Policy title revised to change “Stem-Cell Support” to “Stem-Cell Transplantation.” Policy description updated regarding treatment approaches. Policy statement changed to indicate that allogeneic hematopoietic stem-cell transplantation may be considered medically necessary to treat chronic lymphocytic leukemia or small lymphocytic lymphoma in patients with markers of poor-risk disease. 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. Also added HCPCS S2140 and S2142 to the covered table. Deleted HCPCS G0265, G0266, and G0267 from the code section as these codes were deleted on 12/31/2007.
04/19/2011: Policy reviewed; no changes.
03/02/2012: Policy reviewed; no changes.
04/04/2013: Policy reviewed; no changes.
03/12/2014: Policy reviewed; no changes.
02/20/2015: Policy description updated regarding median age at diagnosis of CLL. Policy statements unchanged. Policy guidelines updated.
08/26/2015: Code Reference section updated to add ICD-10 codes, updated the code descriptions for 38240, 38241, and 38242; removed deleted HCPCS code G0363, and removed deleted code CPT 96445 and replaced with CPT code 96446.
07/15/2016: "Hematopoietic stem cell transplantation (HSCT)" was replaced with "Hematopoietic cell transplantation (HCT)" throughout the policy. Policy description updated regarding FDA regulations. Policy statements unchanged. Table 2 of Policy Guidelines updated to change "loss of P53" to "mutation TP53." Policy Guidelines also updated regarding haploidentical donors.
09/30/2016: Code Reference section updated to add the following new ICD-10 procedure codes: 30230G2, 30233G2, 30240G2, 30243G2, 30230G3, 30233G3, 30240G3, 30243G3, 30230G4, 30233G4, 30240G4, 30243G4, 30230Y2, 30233Y2, 30240Y2, 30243Y2, 30230Y3, 30233Y3, 30240Y3, 30243Y3, 30230Y4, 30233Y4, 30240Y4, and 30243Y4.
Blue Cross Blue Shield Association policy # 8.01.15
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.