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Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Policy Number: MP-360

Latest Review Date: February 2019

Category:  Surgery                                                                 

Policy Grade:  A

Description of Procedure or Service:

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 HCT (allo-HCT) has been proposed as a curative treatment option for patients with these disorders.

Myelodysplastic Syndromes

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. The vast majority of 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 AML or to complications of pancytopenia. Patients with higher blast counts or complex cytogenetic abnormalities have a greater likelihood of progressing to AML than do other patients.

Myelodysplastic Classification and Prognosis

The French-American-British (FAB) system was used to classify MDS into 5 subtypes as follows: 1) refractory anemia (RA); 2) refractory anemia with ringed sideroblasts (RARS); 3) refractory anemia with excess blasts (RAEB); 4) refractory anemia with excess blasts in transformation (RAEBT); and, 5) chronic myelomonocytic leukemia (CMML). The FAB system has been 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%.

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 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. 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.1 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. 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 WPSS uses a 6-category system which allows more precise prognostication of overall survival duration as well as risk for progression to AML. This system, however, is not yet in widespread use in clinical trials.

Myelodysplastic Treatment

Treatment of smoldering or non-progressing MDS has in the past 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 [FDA] -approved hypomethylating agents, non-approved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, antithymocyte globulin, cyclosporine A), low-dose chemotherapy (e.g., cytarabine), and allogeneic HCT. 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 RBC transfusion; achieve complete remission (CR); or, cure the disease.

Allogeneic HCT 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 (MPNs) are clonal bone marrow stem cell disorders which, as a group, about 8,400 MPNs 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. They 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 MPNs is effective clonal myeloproliferation resulting in peripheral granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, granulocytic dysplasia, or monocytosis.

Myeloproliferative Neoplasm Classification

In 2008, a new WHO classification scheme replaced the term chronic myeloproliferative disorder (CMPD) with the term myeloproliferative neoplasms (MPN). These are a subdivision of myeloid neoplasms that includes the four classic disorders chronic myeloid leukemia (CML), polycythemia vera (PCV), essential thrombocytopenia (ET), and primary myelofibrosis (PMF); the WHO classification also includes chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), mast cell disease (MCD), and MPNs unclassifiable.

Myeloproliferative Neoplasm Treatment

In indolent, non-progressing 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 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 with best available therapy, including antineoplastic agents, most commonly hydroxyurea, glucocorticoids, and no therapy, for myelofibrosis, Harrison et al demonstrated improvements in spleen size and quality of life, but not OS.

Myeloablative allogeneic HCT 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 HCT has extended the potential benefits of this procedure to selected individuals with these disorders.

Hematopoietic Cell Transplantation

Hematopoietic cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic 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 medical policy # 439, Placental/Umbilical Cord Blood as a Source of Stem Cells.

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 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.

Conventional Preparative Conditioning for HCT

The conventional (“classical”) practice of allogeneic 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 allogeneic 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 Allogeneic 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 allogeneic 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 nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

Risk Stratification of MDS

Risk stratification for MDS is performed using the IPSS (see Table 1). This system was developed after pooling data from seven 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.

Table 1. International Prognostic Scoring System: Myelodysplastic Syndrome Prognostic Variables

Variable

0

0.5

1.0

1.5

2.0

Marrow blasts, %

<5%

5%-10%

11%-20%

21%-30%

Karyotype

Good

Intermediate

Poor

Cytopenias

0/1

2/3

Table 2. International Prognostic Scoring System: Myelodysplastic Syndrome Clinical Outcomes

Risk Group

Total Score

Median Survival, y

Time for 25% to Progress to AML, y

Low

0

5.7

9.4

Intermediate-1

0.5-1.0

3.5

3.3

Intermediate-2

1.5-2.0

1.2

1.12

High

³2.5

0.4

0.2

AML: acute myelocytic leukemia, IPSS: International Prognostic Scoring System.

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 MDS, allogeneic HCT 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 HCT when chromosomal abnormalities are present or the disorder is associated with the development of significant cytopenias (e.g., neutrophils less 500/mm3, platelets less than 20,000/mm3).

Patients with MPNs may be considered candidates for allogeneic HCT when there is progression to myelofibrosis, or when there is evolution toward acute leukemia. In addition, allogeneic HCT may be considered in patients with essential thrombocythemia with an associated thrombotic or hemorrhagic disorder. The use of allogeneic HCT should be based on cytopenias, transfusion dependence, increasing blast percentage over 5%, and age.

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for RIC allogeneic HCT. 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 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 three of the six major histocompatibility antigens. The majority of 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.

Clinical input suggests RIC allogeneic HCT may be considered for patients as follows:

MDS

  • IPSS intermediate-2 or high risk

  • RBC transfusion dependence

  • Neutropenia

  • Thrombocytopenia

  • High risk cytogenetics

  • Increasing blast percentage

MPN

  • Cytopenias

  • Transfusion dependence

  • Increasing blast percentage over 5%

  • Age 60-65 years

Policy:

Myeloablative allogeneic HCT may be considered medically necessary as a treatment of:

  • Myelodysplastic syndromes (see Additional Policy Guidelines); or

  • Myeloproliferative neoplasms (see Additional Policy Guidelines).

Reduced-intensity conditioning allogeneic HCT may be considered medically necessary as a treatment of myelodysplastic syndromes or myeloproliferative neoplasms in patients who for medical reasons would be unable to tolerate a myeloablative conditioning regimen.

Additional Policy Guidelines

Myeloid Neoplasms

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

  2. Myelodysplastic syndromes (MDS)

  3. Myeloproliferative neoplasms (MPN)

3.1 Chronic myelogenous leukemia

3.2 Polycythemia vera

3.3 Essential thrombocythemia

3.4 Primary myelofibrosis

3.5 Chronic neutrophilic leukemia

3.6 Chronic eosinophilic leukemia, not otherwise categorized

3.7 Hypereosinophilic leukemia

3.8 Mast cell disease

3.9 MPNs, unclassifiable

4. MDS/MPN

4.1 Chronic myelomonocytic leukemia

4.2 Juvenile myelomonocytic leukemia

4.3 Atypical chronic myeloid leukemia

4.4 MDS/MPN, unclassifiable

5. Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1

5.1 Myeloid neoplasms associate with PDGFRA rearrangement

5.2 Myeloid neoplasms associate with PDGFRB rearrangement

5.3 Myeloid neoplasms associate with FGFR1 rearrangement (8p11 myeloproliferative syndrome)

2008 WHO Classification of Myelodysplastic Syndromes

  1. Refractory anemia (RA)

  2. RA with ring sideroblasts (RARS)

  3. Refractory cytopenia with multilineage dysplasia (RCMD)

  4. RCMD with ring sideroblasts

  5. RA with excess blasts 1 and 2 (RAEB 1 and 2)

  6. del 5q syndrome

  7. unclassified MDS

Key Points:

This policy was originally created in December 1999 and updated periodically with literature reviews, most recently through October 30, 2018. Following is the summary of the key literature to date.

The clinical evidence to determine whether the use of technology improves the net health outcome is assessed by evidence reviews. Health outcomes are assessed by the length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Outcome measures are validated to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

The net health outcome of technology is assessed by whether the evidence is sufficient enough to draw conclusions, while examining two domains: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. In various conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence is determined by study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is favored to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Myelodysplastic Syndromes (MDS)

Clinical Context and Therapy Purpose

The purpose of myeloablative (MAC) or reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplant (allo-HCT) in patients who have myelodysplastic syndromes (MDS) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: In patients with MDS, does MAC and RIC allo-HCT improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients

The patient population of interest are patients with MDS.

Interventions

The therapy being considered is MAC and RIC allo-HCT.

Comparators

Standard of care is currently being used.

Outcomes

The outcomes of interest are mortality and morbidity.

Beneficial outcomes are an improvement in overall survival (OS) and disease-specific survival (DSS).

Harmful outcomes are treatment-related morbidity and mortality.

Timing

Follow-up over years is necessary to monitor relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient setting.

Myeloablative Conditioning: Allogeneic Hematopoietic Cell Transplantation

Despite the successes seen with new drugs now available to treat MDS (e.g., decitabine, azacitidine, lenalidomide), allogeneic HCT is the only treatment capable of complete and permanent eradication of the MDS clone.

A 2009 review of HCT for MDS evaluated the evidence for allogeneic HCT with myeloablative conditioning for MDS. The authors included 24 studies (prospective and retrospective) published between 2000 and 2008 that included a total 1,378 cases with age range of 32–59 years. A majority of patients (n = 885) received MRD allogeneic HCT, with other donor types including syngeneic, MUD, mismatched URD, and umbilical cord blood. Most studies included de novo and secondary MDS, chronic myelomonocytic leukemia, MPNs, de novo and secondary AML and transformed AML. Peripheral blood and bone marrow stem-cell grafts were allowed in most studies. The most commonly used conditioning regimens were busulfan plus cyclophosphamide (BU/CY) and CY plus total body irradiation (CY/TBI), with cyclosporine A (CYA) used for GVHD prophylaxis. Length of follow-up ranged from 5 months to about 8 years. Grades II-IV acute GVHD varied from 18% to 100%. Relapse risk ranged from a low of 24% at one year to 36% at 5 years. Overall survival ranged from 25% at two years to 52% at 4 years, with NRM ranging from 19% at day 100 to 61% at 5 years.

A review from the American Society for Blood and Marrow Transplantation (ASBMT) in 2009 assembled and evaluated the evidence related to HCT in the therapy of MDS, with associated treatment recommendations. The authors conclude that outcomes are improved with early HCT for patients with an International Prognostic Scoring System (IPSS) score of intermediate-2 or high-risk at diagnosis, who have a suitable donor, and meet the transplant center’s eligibility criteria, and for selected patients with a low or intermediate-1 risk IPSS score at diagnosis who have a poor prognostic feature not included in the IPSS (i.e., older age, refractory cytopenias, etc.). Koenecke et al (2015) evaluated the impact on the revised 5-category IPSS score (IPSS-5) on outcomes after HCT in patients with MDS or secondary acute myeloid leukemia (evolved from MDS). In a cohort of 903 patients retrospectively identified from the European Society for Blood and Marrow Transplantation database, those with poor and very poor risk had shorter relapse-free survival (RFS) and OS than those with very good, good, or intermediate risk. However, the ways that transplant management strategies should change based on cytogenetic abnormalities are not currently well-defined.

Reduced Intensity Conditioning HCT for MDS

Evidence from a number of largely heterogeneous uncontrolled studies of RIC with allogeneic HCT shows long-term remissions (i.e., longer than 4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with MDS/AML who otherwise would not be candidates for myeloablative conditioning regimens. These prospective and retrospective studies included cohorts of 16–215 patients similar to those in the myeloablative allogeneic HCT studies. The most common conditioning regimens used were fludarabine based, with CYA and tacrolimus used for GVHD prophylaxis. The reported incidence of grades II–IV GVHD was 9-63%, with relapse risk of 6–61%. The OS rates ranged between 44% at 1 year to 46% at 5 years, with a median follow-up range of 14 months to over 4 years.

The American Society for Blood and Marrow Transplantation’s 2009 systematic review (previously described) assessed the evidence supporting RIC and MAC regimens and drew the following conclusions: “There are insufficient data to make a recommendation for an optimal conditioning regimen intensity. A range of dose intensities is currently being investigated, and the optimal approach will likely depend on disease and patient characteristics, such as age and comorbidities.” Other reviews (2010-2012) have also drawn conclusions similar to those of the American Society for Blood and Marrow Transplantation. Given the absence of curative therapies for these patients, however, RIC allo-HCT may be considered a treatment for patients with MDS who could benefit from allo-HCT but who for medical reasons would not tolerate a MAC regimen.

In 2012, Kim et al published a randomized Phase III trial (N=83 patients) to compare the toxicities of two different conditioning regimens (reduced cyclophosphamide [Cy], fludarabine, and anti-thymocyte globulin [ATG]; standard Cy-ATG). Four (of 83) patients had MDS, and the remaining study patients had severe aplastic anemia. Overall, the incidence of toxicities were reported to be lower in patients receiving the reduced-conditioning regimen (23% vs. 55%; p=0.003). Subgroup analyses showed no differences in the overall results based on differential diagnosis.

Zeng et al (2014) conducted a systematic review and meta-analysis comparing outcomes for patients with MDS or AML treated with HCT with either RIC or MA conditioning. The review included 8 studies (2 prospective, 8 retrospective), with a total of 6464 AML/MDS patients. A total of 171 received RIC and 4893 received MA conditioning. Overall, RIC-treated patients were older and more likely to have multiple comorbidities. In pooled analysis, OS, RFS, and NRM did not differ significantly between patients receiving RIC and MA conditioning. Relapse incidence was significantly lower in the MA conditioning arm (odds ratio for RIC vs MA conditioning, 1.41; 95% confidence interval [CI], 1.24 to 1.59; p<0.001).

Aoki et al (2015) compared RIC with MA conditioning in a retrospective cohort of 448 patients aged 50 to 69 years with advanced MDS (refractory anemia with excess blasts or refractory anemia in transformation). Of the total, 197 (44%) and 251 (56%) received MA conditioning or RIC, respectively. The groups differed at baseline: patients who received RIC were significantly more likely to be 60 to 69 years old (vs 50-59 years; 47% for RIC vs 47% for MA; p=0.001), and less likely to receive an unrelated donor transplant (54% vs 70%; p=0.001). Three-year OS did not differ between groups (44.1% for RIC vs 42.7% for MA; p=0.330). Although patients treated with RIC had a significantly lower 3-year cumulative incidence of NRM (25.6% vs 37.9%; p=0.002), but they had significantly higher 3-year incidence of relapse than patients treated with MA conditioning (29.9% vs 22.8%; p=0.029).

In general, these RIC trials showed a low rate of engraftment failure and low NRM, but at the cost of a higher relapse rate than with myeloablative allogeneic HCT. However, in the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative and RIC regimens with allogeneic HCT. Furthermore, no randomized trials have been published in which RIC with allogeneic HCT has been compared with conventional chemotherapy alone, which has been the standard of care in patients with MDS/AML for whom myeloablative chemotherapy and allogeneic HCT are contraindicated.  Nonetheless, given the absence of curative therapies for these patients, coupled with clinical input (see below) RIC allogeneic HCT may be considered medically necessary for patients with MDS who could benefit from allogeneic HCT but who for medical reasons (see Policy Guidelines) would be unable to tolerate a myeloablative conditioning regimen.

Outcomes after Allo-HCT in Mixed MDS Populations

A number of studies, primarily retrospective, continue to report outcomes from HCT for MDS in variety of patient populations and to evaluate the impact of specific patient, conditioning, and donor characteristics on outcomes; representative studies are summarized in Table 3.

Table 3: Case Series of HCT Treatment for MDS

Study

Patient Population

Type of HCT

Summary of Outcomes

Basquiera et al (2015)

52 pediatric patients with MDS

  • Allo-HCT (59% with related donors)

  • Stem cell source:

  • Bone marrow, 63%

  • Peripheral blood, 26%

  • Umbilical cord blood, 11%

  • 5-y DFS: 50%

  • 5-y OS: 55%

Boehm et al (2014)

60 adults with MDS or secondary AML

  • Allo-HCT

  • MA conditioning in 36 patients; RIC in 24 patients

10-y OS: 46%

Damaj et al (2014)

128 adults with MDS, 40 of whom received AZA before HCT and 88 who received BSC

RIC allo-HCT

  • 3-y OS: 53% in AZA group vs 53% in BSC group (p=0.69)

  • 3-y RFS: 37% in AZA group vs 42% in BSC group (p=0.78)

  • 3-y NRM: 20% in AZA group vs 23% in BSC group (p=0.74)

Di Stasi et al (2014)

227 patients with MDS or AML

  • Allo-HCT

  • Donor source:

  • Matched-related, 38%

  • Matched-unrelated, 48%

  • Haploidentical, 14%

3-y PFS for patients in remission:

  • 57% for matched-related

  • 45% for matched-unrelated

  • 41% for haploidentical (p=0.417)

Onida et al (2014)

  • 523 patients with MDS treated with HCT

  • IPSS cytogenic risk group:

  • Good risk: 53.5%

  • Intermediate risk: 24.5%

  • Poor risk: 22%

  • Allo-HCT

  • RIC in 12%

5-y OS based on IPSS cytogenic risk group:

  • Good: 48%

  • Intermediate: 45%

  • Poor: 30%

Oran et al (2014)

  • 256 patients with MDS

  • Pretreatment:

  • No cytoreductive chemo: 30.5%

  • Chemo: 15.6%

  • HMA: 47.7%

  • Chemo + HMA: 6.2%

  • Allo-HCT

  • RIC in 36.7%

3-y EFS based on cytoreductive therapy:

  • No cytoreductive chemo: 44.2%

  • Chemo: 30.6%

  • HMA: 34.2%

  • Chemo + HMA: 32.8% (p=0.50)

Yoshimi et al (2014)

17 children with secondary MDS or AML after childhood aplastic anemia

  • Allo-HCT

5-y OS and EFS: 41%

Basquiera et al (2016)

  • 84 adults with MDS treated with HCT

  • Cytogenic risk group:

  • Standard: 65.5%

  • Adverse: 12.6%

  • Unknown: 21.9%

  • Allo-HCT

  • RIC in 31.1%

OS:

  • Median: 23.5 mo (95% CI, 1.7 to 45.3 mo)

  • 1-y: 61% (95% CI, 50% to 70%)

  • 4-y: 38% (95% CI, 27% to 49%)

PFS:

  • Median: 19.9 mo (95% CI, 9 to 31 mo)

  • 1-y: 57% (95% CI, 46% to 67%)

  • 4-y: 37% (95% CI, 26% to 48%)

Symeonidis et al (2015)

  • 513 adults with CMML treated with HCT

  • Pretreatment:

  • No prior disease-modifying therapy: 28%

  • Disease-modifying therapy: 72%

  • Allo-HCT

  • RIC in 41.6%

NRM:

  • 1-y: 31%

  • 4-y: 41%

  • 4-y RFS: 27%

  • 4-y OS: 33%

Pohlen et al (2016)

  • 187 patients with refractory AML (87%) or high-risk MDS (13%)

  • Allo-HCT

  • RIC in 52%

  • Unrelated donors in 73%

  • Stem cell source:

  • Bone marrow, 6%

  • Peripheral blood, 94%

RFS at 3 y: 32% (95% CI, 25% to 39%)

OS at 3 y: 35% (95%CI, 27% to 42%)

Heidenreich et al (2016)

  • 313 adults with MDS and secondary AML, age ≥ 70 y treated with allo-HCT

  • Cytogenic risk group:

  • Good: 51%

  • Intermediate: 22%

  • Poor/very poor: 11%

  • Allo-HCT

  • RIC or non-MA conditioning in 83%

  • Unrelated donors in 75%

  • Stem cell source:

  • Bone marrow, 6%

  • Peripheral blood, 94%

NRM at 1 y: 32%

Relapse at 3 y: 28%

OS at 3 y: 34%

allo; allogeneic; AML: acute myelogenous leukemia; AZA: azacitidine; BSC: best supportive care; chemo: chemotherapy; CI: confidence interval; CMML: chronic myelomonocytic leukemia; DFS: disease-free survival; HMA: hypomethylating agents; HCT: hematopoietic cell transplantation; IPSS: International Prognostic Scoring System; MA: myeloablative; MDS: myelodysplastic syndrome; NRM: nonrelapse mortality; OS: overall survival; RFS: relapse-free survival; RIC: reduced-intensity conditioning.

Section Summary: Myelodysplastic Syndromes

Primarily uncontrolled, observational studies of HCT for MDS have reported a relatively large range of OS and progression-free survival (PFS) values, which reflects the heterogeneity in patient populations, conditioning regimens, and other factors. Reported estimates for 3- to 5-year OS of approximately 40% to 50% are typical. Direct comparisons between RIC and MAC conditioning prior to HCT with randomly selected populations are not available. Evidence from nonrandomized comparisons has suggested that RIC may be used in patients who are older and with more co-morbidities without significantly worsening OS. RIC appears to be associated with lower rates of NRM but higher cancer relapse than MAC HCT.

Myeloproliferative Neoplasms (MPN)

Clinical Context and Therapy Purpose

The purpose of MAC and RIC allo-HCT in patients who have MPN is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: In patients who have MPN, does MAC and RIC allo-HCT improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients

The patient population of interest are patients who have MPN.

Interventions

The therapy being considered is MAC and RIC allo-HCT.

Comparators

Standard of care is currently being used.

Outcomes

The outcomes of interest are mortality and morbidity.

Beneficial outcomes are an improvement in OS and DSS.

Harmful outcomes are treatment-related morbidity and mortality.

Timing

Follow-up over years is necessary to monitor relevant outcomes.

Setting

Patients are actively managed by hematologists/oncologists in an inpatient and outpatient setting.

Data on therapy for MPN remain sparse. As outlined previously in this review, with the exception of myeloablative chemotherapy and allogeneic HCT, no therapy has yet been proven to be curative or to prolong survival of patients with MPN.

A series by Laport et al (2008) included 27 patients (mean age: 59 years) with MPN who underwent allogeneic HCT using a RIC regimen of low-dose (2 Gy) total body irradiation alone or with the addition of fludarabine. At a median follow-up of 47 months, the three-year relapse-free survival was 37% and overall survival was 43%, with a 3-year non-relapse mortality of 32%. Kroger et al (2009) reported on a second series. In this series, 103 patients (median age 55 years, range 32-68 years) with intermediate to high risk (86% of total patients) primary myelofibrosis (PMF) or post-essential thrombocythemia (PT) and polycythemia vera myelofibrosis (PVM) were included on a prospective multicenter Phase II trial to determine efficacy of a busulfan plus fludarabine-based RIC regimen followed by allogeneic HCT from related (n=33) or unrelated (n=70) donors. Acute Grade II-IV GVHD occurred in 27%, and chronic GVHD in 43% of patients. The cumulative incidence of NRM at one year in all patients was 16% (95% confidence interval [CI], 9-23%) but reached 38% (95% CI, 15-16%) among those with a mismatched donor versus 12% (95% CI, 5-19%) among cases with a matched donor (p=0.003). The cumulative relapse rate at three and five years was 22% (95% CI, 13-31%) and 29% (95% CI, 16-42%), respectively. After a median follow-up of 33 months (range, 12-76 months) five-year estimated disease-free survival (DFA) and OS was 51% (95% CI, 38-64%) and 67% (95% CI, 55-79%), respectively.

A 2009 retrospective study by Gupta et al (2009) analyzed the impact of conditioning intensity on outcomes of allogeneic HCT in patients with myelofibrosis (MF). This multicenter trial included 46 consecutive patients treated at three Canadian and four European transplant centers between 1998 and 2005. Twenty-three patients (median age 47 years, range 31-60 years) underwent myeloablative conditioning, and 23 patients (median age 54 years, range 38-74 years) underwent RIC. The majority in both groups (85%) were deemed intermediate- or high-risk. At a median follow-up of 50 months (range 20-89), there was a trend for better progression-free survival (PFS) at three years in RIC patients compared to myeloablative-conditioned patients (58%, range 23-62 vs. 43%, range 35-76, respectively, p=0.11); there was a similar trend in three-year OS (68%, range 45-84 vs. 48%, range 27-66, respectively, p=0.08). NRM rates at three years trended higher in myeloablative conditioned cases than RIC cases (48%, range 31-74 vs. 27%, range 14-55, respectively, p=0.08). The results of this study suggest that both types of conditioning regimens have curative potential in patients with MF. Despite the RIC patients being significantly older with longer disease duration and poorer performance status than those who received conventional conditioning, the groups had similar outcomes, supporting the use of RIC allogeneic HCT in this population.

The largest study identified of allogeneic HCT for primary myelofibrosis was published by Ballen et al (2010) and comes from analysis of the outcomes of 289 patients treated between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA-identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA non-identical family members in 26 patients. Patients were treated with a variety of conditioning regimens and GVHD prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year OS rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients.

In a 2012 retrospective study in nine Nordic transplant centers, a total of 92 patients with MF in chronic phase underwent allogeneic HCT. MA conditioning was given to 40 patients, and RIC was used in 52 patients. The mean age in the two groups at transplantation was 46±12 and 55±8 years, respectively (p<0.001). When adjustment for age differences was made, the survival of the patients treated with RIC was significantly better (p=0.003). Among the RIC patients, survival was significantly (p=0.003) greater for patients younger than age 60 years (a ten-year survival close to 80%) than for patients older than 60 years. The stem-cell source did not significantly affect the survival. No significant difference was found in NRM at 100 days between the MA- and the RIC-treated patients. The probability of survival at five years was 49% for the MA-treated patients and 59% in the RIC group (p=0.125). Patients treated with RIC experienced significantly less acute GVHD compared with patients treated with MA conditioning (p<0.001). The OS at five years was 70%, 59% and 41% for patients with Lille score 0, 1 and 2, respectively (p=0.038, when age adjustment was made). Twenty-one percent of the patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MA-treated patients (p<0.002). Nine percent of the patients needed a second transplant because of graft failure, progressive disease or transformation to AML, with no significant difference between the groups.

In 2014, Gupta et al reported better disease-free survival rates in a 2014 analysis of 233 patients with primary myelofibrosis who underwent RIC HCT from 1997 to 2010. Five-year OS was 47% (95% CI, 40% to 53%). Conditioning regimen was not significantly associated with OS.

In another relatively large study that included patients with primary myelofibrosis who were under 65 years old at diagnosis, Kroger et al (2015) compared outcomes for patients treated with allo-HCT (n=190) or conventional therapies (n=248) at diagnosis. In the HCT group, 91 and 97 subjects received RIC and MA conditioning, respectively. Patients at low risk based on the Dynamic International Prognostic Scoring System model treated with HCT had a relative risk of death, compared with conventionally treated patients, of 5.6 (95% CI, 1.7 to 19; p=0.005). In contrast, those with intermediate-2 and high risk treated with HCT had a relative risk of death, compared with conventionally treated patients, of 0.55 (95% CI, 0.36 to 0.83; p=0.005) and 0.37 (95% CI, 0.21 to 0.66; p<0.001), respectively. Intermediate-1 patients treated with HCT did not significantly differ in risk of death from those treated with conventional therapies. Although the study design was limited by the potential for bias due to patient selection, these results support using prognosis to guide decisions about HCT for primary myelofibrosis.

The significant toxicity of myeloablative conditioning and allogeneic HCT in MPN has led to study of the use of RIC regimens for these diseases. Data from direct, prospective comparison of outcomes of MA conditioning and allo-HCT versus RIC and allogeneic stem cell support in MPN are not available, but single-arm series and nonrandomized comparative studies report outcomes after RIC allo-HCT.

Section Summary: Myeloproliferative Neoplasms

Observational studies of HCT for MPN have reported a range of 3- to 5-year OS of 35% to 50% and suggested that HCT may be associated with improved survival in patients with intermediate-2 and high-risk disease. Currently, only retrospective studies have compared the RIC and MAC regimens. While these nonrandomized comparisons have suggested that RIC may be used in patients who are older and who have poorer performance status without significantly worsening OS, randomized trials are needed to provide greater certainty in the efficacy of the conditioning regimens.

Summary of Evidence

For individuals who have myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) who receive myeloablative conditioning allogeneic hematopoietic cell transplantation (allo-HCT), the evidence includes case series, which are often heterogeneous in terms of diseases included. Relevant outcomes are overall survival, disease-specific survival, and treatment-related morbidity and mortality. Primarily uncontrolled, observational studies of HCT for MDS have reported a relatively large range of overall and progression-free survival rates, which reflect the heterogeneity in patient populations, conditioning regimens, and other factors. Reported estimates for 3- to 5-year overall survival of 40% to 50% are typical. For HCT for MPN, data are more limited. At least 1 comparative study of HCT for myelofibrosis has demonstrated improved survival with HCT compared with standard therapy. HCT is at present the only potentially curative treatment option for patients with MDS and MPN. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have MDS or MPN who receive reduced-intensity conditioning (RIC) allo-HCT, the evidence includes primarily retrospective observational series. Relevant outcomes are overall survival, disease-specific survival, and treatment-related morbidity and mortality. Direct, prospective comparisons of outcomes after HCT with either myeloablative conditioning or RIC in either MDS or MPN are not available. Evidence from retrospective nonrandomized comparisons has suggested that RIC may be used in patients who are older and have more comorbidities without significantly worsening overall survival. RIC appears to be associated with lower rates of nonrelapse mortality but higher cancer relapse than myeloablative HCT. HCT is at present the only potentially curative treatment option for patients with MDSs and MPN. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for myelodysplastic syndromes (MDS; v.2.2019) make the following recommendation about allogeneic hematopoietic cell transplantation (allo-HCT):

“For patients who are transplant candidates, the first choice of a donor has remained an HLA-matched sibling, although results with HLA-matched unrelated donors have improved to levels comparable to those obtained with HLA-matched siblings. With the increasing use of cord blood or HLA-haploidentical related donors, HCT has become a viable option for many patients. High-dose conditioning is typically used for younger patients, whereas RIC for HCT is generally the strategy in older individuals.”

Specific NCCN recommendations for HCT for treatment of MDS are outlined in Table 3.

Table 3: NCCN Guidelines for Allo-HCT for Myelodysplastic Syndromes

Prognostic Category

Recommendations for HCT

IPSS low/intermediate-1 OR

IPSS-R very low, low, intermediate OR

WPSS very low, low, intermediate OR

  • Consider allo-HCT for patients who have clinically relevant thrombocytopenia or neutropenia or increased marrow blasts, with disease progression or no response after azacitidine/decitabine or immunosuppressive therapy

  • Consider allo-HCT for patients who have symptomatic anemia with no 5q deletion, with serum erythropoietin level >500 mU/mL, with poor probability of response to immunosuppressive therapy, and no response or intolerance to azacitidine/decitabine or immunosuppressive therapy

IPSS intermediate-2, high OR

IPSS-R intermediate, high, very high OR

WPSS high, very high

  • Recommend allo-HCT if a high-intensity therapy candidate and transplant candidate and donor stem cell source is available

allo: allogeneic; HCT: hematopoietic cell transplantation; IPSS: International Prognostic Scoring System; NCCN: National Comprehensive Cancer Network; WPSS: WHO Classification-based Prognostic Scoring System.

NCCN developed new guidelines for myeloproliferative neoplasms (MPN) in v.2.2018. Table 4 summarizes the NCCN recommendations for the use of allogeneic HCT (allo-HCT) for the treatment of MPN. The guideline notes that selection of allo-HCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver.

Table 4: NCCN Guidelines for Allo-HCT for Myeloproliferative Neoplasms

Prognostic Category

Recommendations for Allo-HCT

Intermediate risk – 1 myelofibrosis

IPSS=1

DIPSS-Plus=1

DIPSS=1 or 2

Consider observation or ruxolitinib if symptomatic or allo-HCT

Intermediate risk – 2 myelofibrosis

IPSS=2

DIPSS-Plus=2 or 3

DIPSS=3 or 4

High-risk myelofibrosis

IPSS>3

DIPSS-Plus=4 to 6

DIPSS=5 or 6

Consider allo-HCT immediately or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to transplant

Disease progression to advanced stage/AML

Induce remission with hypomethylating agents or intensive induction chemotherapy followed by allo-HCT

allo: allogeneic; AML: acute myeloid leukemia; DIPSS: Dynamic International Prognostic Scoring System; HCT: hematopoietic cell transplantation; IPSS: International Prognostic Scoring System; NCCN: National Comprehensive Cancer Network.

American Society for Blood and Marrow Transplantation

In 2015, the American Society for Blood and Marrow Transplantation (ASBMT) published guidelines on indications for HCT, based on the recommendations of a multiple-stakeholder task force. Table 5 summarizes categorizations for allo-HCT.

Table 5. Recommendations for the Use of HCT to Treat Myelodysplastic Syndromes, Myelofibrosis, and Myeloproliferative Neoplasms

Indication

Recommendation

Myelodysplastic syndromes

Low/intermediate-1 risk

Standard of care, clinical evidence available (large clinical trials are not available; however, sufficiently large cohort studies have shown efficacy with “acceptable risk of morbidity and mortality”)

Intermediate-2/high risk

Standard of care (“well defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies”)

Myelofibrosis and myeloproliferative neoplasms

Primary, low risk

Standard of care (“well defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies”)

Primary, intermediate/high risk

Standard of care (“well defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies”)

Secondary

Standard of care (“well defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies”)

Hypereosinophilic syndromes, refractory

Standard of care, rare indication (clinical trials and observational studies are not feasible due to low incidence; small cohorts have shown efficacy with “acceptable risk of morbidity and mortality”)

European Blood and Marrow Transplantation Group and European LeukemiaNet

In 2015, the European Blood and Marrow Transplantation and European LeukemiaNet Group published recommendations for the use of allo-HCT in primary myelofibrosis and for pre- and posttransplant management and donor selection. Recommendations related to the selection of patients for allo-HCT included:

  • “All patients with intermediate-2 or high-risk disease according to IPSS, DIPSS [Dynamic International Prognostic Scoring System], or DIPSS+, and age < 70 years, should be considered potential candidates for allo-SCT [stem cell transplant].”

  • “Patients with intermediate-1-risk disease and age <65 years should be considered candidates for allo-SCT [stem cell transplant] if they present with either refractory, transfusion-dependent anemia or a percentage of blasts in PB [peripheral blood] >2%, or adverse cytogenetics (as defined by the DIPSS+ classification).”

  • “Patients with low-risk disease should not undergo allo-SCT. They should be monitored and evaluated for transplantation when disease progression occurs.”

  • “Patients in blast transformation (blasts in PB or in BM [bone marrow] or both equal to or >20%) are not good candidates for allo-SCT. They should receive debulking therapy and be reconsidered for transplant after achieving a partial or complete remission of leukemia.”

  • “Although the use of molecular risk classification for the identification of candidates for allo-SCT among intermediate-1- risk patients deserves further clinical validation, patients in this risk category who are triple negative (that is, JAKV617F, CALR, and MPL negative) or ASXL1 positive, or both, should be considered for allo-SCT.”

U.S. Preventive Services Task Force Recommendations

Not applicable

Key Words:

Allogeneic Cell Support, Bone Marrow Transplantation, Myeloablation, Myeloproliferative Disorders, Reduced-Intensity Conditioning, Myeloproliferative Syndrome, Myelodysplastic Syndrome, High-Dose Chemotherapy, Myelofibrosis, Cell Transplant, Myelodysplastic Diseases, Hematopoietic Cell Transplant (HCT), Myeloproliferative Neoplasm (MPN)

Approved by Governing Bodies:

Not applicable

Benefit Application:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: Special benefit consideration may apply.  Refer to member’s benefit plan.

Current Coding:

CPT Codes:

38204   Management of recipient hematopoietic cell donor search and cell acquisition
38205 Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
38208  

  ; thawing of previously frozen harvest without washing per donor

38209 thawing of previously frozen harvest with washing per donor
38210 ; specific cell depletion with harvest, T cell depletion
38211  ; tumor cell depletion
38212    ; red blood cell removal
38213 ; platelet depletion
38214  ; plasma (volume) depletion
38215   ; cell concentration in plasma, mononuclear, or buffy coat layer
38230 Bone marrow harvesting for transplantation: allogeneic
38232    ; autologous
38240 Bone marrow or blood-derived peripheral stem-cell transplantation: allogeneic
86812-86821 Histocompatibility studies code range (e.g., for allogeneic transplant) (82822 deleted effective 12/31/17)

         

            HCPCS:

S2150              Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs;

                         hospitalization; medical surgical, diagnostic and emergency services)

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  53. Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26(4):577-584.

  54. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. Mar 1 2012; 366(9):799-807.

  55. Yoshimi A, Strahm B, Baumann I, et al. Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia. Biol Blood Marrow Transplant. Mar 2014; 20(3):425-429.

  56. Zeng W, Huang L, Meng F, et al. Reduced-intensity and myeloablative conditioning allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome: a meta-analysis and systematic review. Int J Clin Exp Med. 2014; 7(11):4357-4368.

Policy History:

Medical Policy Panel, June 2009

Medical Policy Group, June 2009 (2)

Medical Policy Administration Committee, July 2009

Available for comment July 1-August 14, 2009

Medical Policy Group, December 2011 (3): 2012 Code verbiage changes for 38208, 38209, 38230 & added new code 38232

Medical Policy Group, February 2012 (2): Updated Key Points, References

Medical Policy Group, November 2012 (4): Title Change, added the word

“Hematopoietic”, Updated Key Points, References.  Policy statement remained unchanged.

Medical Policy Panel, November 2013

Medical Policy Group, November 2013 (3): Updated description, key points and references; no change in policy statement

Medical Policy Panel, November 2014

Medical Policy Group, November 2014 (3): Updates to Description, Key Points, and References. No change in policy statement.

Medical Policy Panel, January 2016

Medical Policy Group, April 2016 (2): Updates to Description, Key Points, Key Words, and References, removed codes 86812-86822 from Current Coding; added myeloablative to allogeneic HSCT in policy; no change in intent of coverage.

Medical Policy Panel, January 2017

Medical Policy Group, March 2017 (7): 2017 Updates to Title, Description, Key Points, Key Words, and References. No change in policy statement.

Medical Policy Panel, January 2018

Medical Policy Group, (7): Updates to Description, Key Points, Coding and References.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): 2019 Updates to Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.