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Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) refer to a heterogeneous group of clonal hematopoietic disorders with the potential to transform into acute myelocytic leukemia. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been proposed as a curative treatment option for patients with these disorders.
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cells may be obtained from the transplant recipient (autologous hematopoietic stem cell transplantation [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. 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 antigen (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 HSCT
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 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 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 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 and 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 nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.
Myelodysplastic syndromes (MDS) can occur as a primary (idiopathic) disease or be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. Chromosomal abnormalities are seen in 40%–60% of patients, frequently involving deletions of chromosome 5 or 7, or an extra chromosome as in trisomy 8. Most MDS diagnoses occur in individuals over the age of 55–60 years, with an age-adjusted incidence of about 62% among individuals over age 70 years. Patients either succumb to disease progression to acute myeloid leukemia (AML) or to complications of pancytopenias. Patients with higher blast counts or complex cytogenetic abnormalities have a greater likelihood of progressing to AML than do other patients.
MDS Classification and Prognosis
The French-American-British (FAB) system was used to classify MDS into five subtypes as follows:
The FAB system was supplanted by that of the World Health Organization (WHO), which records the number of lineages in which dysplasia is seen (unilineage versus multilineage), separates the 5q- syndrome, and reduces the threshold maximum blast percentage for the diagnosis of MDS from 30% to 20% (see Policy Guidelines for WHO classification scheme for myeloid neoplasms).
The most commonly used prognostic scoring system for MDS is the International Prognostic Scoring System (IPSS), which groups patients into one of four prognostic categories based on the number of cytopenias, cytogenetic profile, and the percentage of blasts in the bone marrow. This system underweights the clinical importance of severe, life-threatening neutropenia and thrombocytopenia in therapeutic decisions and does not account for the rate of change in critical parameters, such as peripheral blood counts or blast percentage. However, the IPSS has been useful in comparative analysis of clinical trial results and its utility confirmed at many institutions. A second prognostic scoring system incorporates the WHO subgroup classification that accounts for blast percentage, cytogenetics, and severity of cytopenias as assessed by transfusion requirements. The WHO Classification-based Prognostic Scoring System (WPSS) uses a 6-category system, which allows more precise prognostication of overall survival (OS) duration, as well as risk for progression to AML. This system, however, is not yet in widespread use in clinical trials.
Treatment of smoldering or nonprogressing MDS has involved best supportive care, including red blood cell (RBC) and platelet transfusions and antibiotics. Active therapy was given only when MDS progressed to AML or resembled AML with severe cytopenias. A diverse array of therapies are now available to treat MDS, including hematopoietic growth factors (e.g., erythropoietin, darbepoetin, granulocyte colony-stimulating factor), transcriptional-modifying therapy (e.g., U.S. Food and Drug Administration-approved hypomethylating agents, nonapproved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, antithymocyte globuliln, cyclosporine A), low-dose chemotherapy (e.g., cytarabine), and allogeneic HSCT. Given the spectrum of treatments available, the goal of therapy must be decided upfront, whether it is to improve anemia, thrombocytopenia, or neutropenia, eliminate the need for red blood cell transfusion, achieve complete remission (CR), or cure the disease.
Allogeneic HSCT is the only approach with curative potential, but its use is governed by patient age, performance status, medical comorbidities, the patient’s risk preference, and severity of MDS at presentation.
Chronic Myeloproliferative Neoplasms
Chronic myeloproliferative neoplasms (MPN) are clonal bone marrow stem cell disorders. As a group, about 8,400 MPN are diagnosed annually in the U.S. Like MDS, MPNs occur primarily in older individuals, with about 67% reported in patients aged 60 years and older.
MPNs are characterized by the slow but relentless expansion of a clone of cells with the potential evolution into a blast crisis similar to AML. MPN share a common stem cell-derived clonal heritage, with phenotypic diversity attributed to abnormal variations in signal transduction as the result of a spectrum of mutations that affect protein tyrosine kinases or related molecules. The unifying characteristic common to all MPN is effective clonal myeloproliferation resulting in peripheral granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, granulocytic dysplasia, or monocytosis.
In 2008, the WHO classification scheme replaced the term chronic myeloproliferative disorder with the term myeloproliferative neoplasms (MPN). MPNs are a subdivision of myeloid neoplasms that includes four classic disorders: chronic myeloid leukemia, polycythemia vera, essential thrombocytopenia, and primary myelofibrosis. The WHO classification also includes chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, mast cell disease, and MPN unclassifiable (see Policy Guidelines).
In indolent, nonprogressing cases, therapeutic approaches are based on relief of symptoms. Supportive therapy may include prevention of thromboembolic events. Hydroxyurea may be used in cases of high-risk essential thrombocytosis and polycythemia vera and intermediate- and high-risk primary myelofibrosis.
In November 2011, FDA approved the orally administered selective Janus kinase 1 and 2 inhibitor ruxolitinib for the treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib has been associated with improved OS, spleen size, and symptoms of myelofibrosis when compared with placebo. The COMFORT-II trial compared ruxolitinib to best available therapy in patients with intermediate- and high-risk myelofibrosis, and demonstrated improvements in spleen volume and OS. In a randomized trial comparing ruxolitinib to best available therapy, including antineoplastic agents, most commonly hydroxyurea, glucocorticoids, and no therapy, for myelofibrosis, Harrison and colleagues demonstrated improvements in spleen size and quality of life, but not OS.
Myeloablative allogeneic HSCT has been considered the only potentially curative therapy, but because most patients are of advanced age with attendant comorbidities, its use is limited to those who can tolerate the often severe treatment-related adverse effects of this procedure. However, the use RIC of conditioning regimens for allogeneic HSCT has extended the potential benefits of this procedure to selected individuals with these disorders.
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 or a transplant evaluation unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.
Myeloablative allogeneic HSCT may be considered medically necessary as a treatment of:
Reduced-intensity conditioning allogeneic HSCT may be considered medically necessary as a treatment of:
in patients who for medical reasons would be unable to tolerate a myeloablative conditioning regimen. (See Policy Guidelines)
Myeloablative allogeneic HSCT or reduced-intensity conditioning allogeneic HSCT for myelodysplastic syndromes and myeloproliferative neoplasms that does not meet the criteria in the Policy Guidelines section is considered investigational.
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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
The myeloid neoplasms are categorized according to criteria developed by the World Health Organization (WHO). They are risk-stratified according to the International Prognostic Scoring System (IPSS).
2008 WHO Classification Scheme for Myeloid Neoplasms:
1. Acute myeloid leukemia
5. Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
2008 WHO Classification of MDS
Risk Stratification of MDS
Risk stratification for MDS is performed using the IPSS. This system was developed after pooling data from 7 previous studies that used independent, risk-based prognostic factors. The prognostic model and the scoring system were built based on blast count, degree of cytopenia, and blast percentage. Risk scores were weighted relative to their statistical power. This system is widely used to divide patients into two categories: (1) low risk and (2) high-risk groups. The low-risk group includes low risk and Int-1 IPSS groups; the goals in low-risk MDS patients are to improve quality of life and achieve transfusion independence. In the high-risk group — which includes Int-2 and high-risk IPSS groups — the goals are slowing the progression of disease to AML and improving survival. The IPSS is usually calculated on diagnosis. The role of lactate dehydrogenase, marrow fibrosis, and beta 2-microglobulin also should be considered after establishing the IPSS. If elevated, the prognostic category becomes worse by one category change.
An updated 5-category IPSS has been proposed for prognosis in patients with primary MDS or secondary AML to account for chromosomal abnormalities frequently seen in MDS. This system stratifies patients into 5 categories: very poor, poor, intermediate, good, and very good. There has been investigation into using the 5-category IPSS to better characterize risk in MDS.
Given the long natural history of myelodysplastic syndrome, allogeneic HSCT is typically considered in those with increasing numbers of blasts, signaling a possible transformation to acute myeloid leukemia. Subtypes falling into this category include refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.
Patients with refractory anemia with or without ringed sideroblasts may be considered candidates for allogeneic HSCT when chromosomal abnormalities are present or the disorder is associated with the development of significant cytopenias (e.g., neutrophils less than 500/mm³, platelets less than 20,000/mm³).
Patients with MPN may be considered candidates for allogeneic HSCT when there is progression to myelofibrosis, or when there is evolution toward acute leukemia. In addition, allogeneic HSCT may be considered in patients with essential thrombocythemia with an associated thrombotic or hemorrhagic disorder. The use of allogeneic HSCT should be based on cytopenias, transfusion dependence, increasing blast percentage over 5%, and age.
Some patients for whom a conventional myeloablative allogeneic-HSCT could be curative may be candidates for reduced-intensity conditioning (RIC) allogeneic HSCT. These include those patients 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. The ideal allogeneic donors are human leukocyte antigen (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 (MUD) 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 graft-versus-host disease extensive as that with matched donors.
Clinical input suggests RIC allogeneic HSCT may be considered for patients as follows:
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.
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 # 8.01.21 per approval by Medical Policy Advisory Committee (MPAC)
8/19/2004: Code Reference section completed
11/18/2004: Reviewed by MPAC, no changes
10/19/2005: Code Reference section updated, codes 38204, 38205, 38207-38215, 38242, G0355-G0364 added. J9000-J9999 deleted; ICD9 procedure codes 41.02, 41.03, 41.08 added. Description of ICD9 procedure code 99.25 revised. HCPCS statement added for J9000-J9999 codes
03/10/2006: Coding updated. CPT4/HCPCS 2006 revisions added to policy
09/12/2006: Coding updated. ICD9 2006 revisions added to policy
5/18/2007: Policy reviewed, description updated. Myeloablative or nonmyeloablative added to policy statement as medically necessary as a treatment of myelodysplastic syndrome
12/20/2007: Coding updated per 2008 CPT/HCPCS revisions
5/21/2008: Policy reviewed, no changes
7/14/2008: Policy updated. High dose chemotherapy terminology replaced with allogeneic SCT. Policy statements intent remain unchanged. "Myeloproliferative" diseases added to policy title "High Dose Chemotherapy" removed from title
8/7/2009: Policy Description Section updated to include specific definitions and descriptions for Conventional Preparative Conditioning for HSCT, Reduced-Intensity Conditioning for Allogeneic HSCT, Myelodysplastic Syndromes, and Chronic Myeloproliferative Neoplasms, Policy Statement Section updated to add Reduced -intensity conditioning allogeneic HSCT as medically necessary for the treatment of myelodysplastic syndromes or myeloproliferative neoplasms, Policy Guidelines Section updated with 2008 WHO information for Myeloid Neoplasms, risk stratification information, clinical suggestions for RIC allogeneic HSCT, Updated Coding Section with CPT-4 code 38230 added to Covered Table, Removed deleted ICD-9 diagnosis code 238.7 from Covered Table, Removed deleted HCPCS codes G0265, G0266, G0267, and G0363 from Covered Table
6/04/2010: Title changed from "Allogeneic Stem-Cell Transplantation for Myelodysplastic and Myeloproliferative Diseases" to "Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms." FEP and State and School Employee verbiage added to Policy Exceptions section. New CPT codes 86825 and 86826 added to covered table.
12/28/2010: Policy reviewed; no changes.
01/17/2012: Policy reviewed; no changes.
03/13/2013: Policy reviewed; no changes.
03/11/2014: Policy reviewed; no changes.
12/19/2014: Policy title changed from "Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms" to "Allogeneic Hematopoietic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms." Policy description updated regarding MPN Treatment. Added "Myeloablative" to the first medically necessary policy statement. Added the following investigational statement: Myeloablative allogeneic HSCT or reduced-intensity conditioning allogeneic HSCT for myelodysplastic syndromes and myeloproliferative neoplasms that does not meet the criteria in the Policy Guidelines section is considered investigational.
08/21/2015: Code Reference section update to add ICD-10 codes. Revised the descriptions for CPT codes 38240 and 38242; removed deleted code CPT 96445 and replaced with CPT code 96446.
04/04/2016: Policy description updated regarding myelodysplastic syndromes, myeloproliferative neoplasms, and FDA regulations. Policy statements unchanged. Policy guidelines updated regarding risk stratification of MDS and to add medically necessary and investigative definitions.
05/25/2016: Policy number A.8.01.21 added.
09/30/2016: Code Reference section updated to add new ICD-10 diagnosis code D47.Z2.
SOURCE(S)Blue Cross Blue Shield Association Policy # 8.01.21
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.