Myelodysplastic Syndromes

MDS can occur as a primary (idiopathic) disease or can be secondary to cytotoxic therapy, ionizing radiation, or other environmental insults. Chromosomal abnormalities are seen in 40% to 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 older than age 55 to 60 years, with an age-adjusted incidence of 62% among individuals older than age 70 years. Patients succumb either 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 system was used to classify MDS into 5 subtypes: (1) refractory anemia; (2) refractory anemia with ringed sideroblasts; (3) refractory anemia with excess blasts; (4) refractory anemia with excess blasts in transformation; and (5) chronic myelomonocytic leukemia. The French-American-British system was supplanted by that of the World Health Organization (WHO), which records the number of lineages in which dysplasia is seen (unilineage vs. 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 1 of 4 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 (eg, peripheral blood counts, blast percentage). However, the IPSS has been useful in a 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 an 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 WHO classification-based Prognostic Scoring System 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 is not yet in widespread use in clinical trials.

MDS Treatment

Treatment of nonprogressing MDS has involved best supportive care, including red blood cell and platelet transfusions and antibiotics. Active therapy was given only when MDS progressed to AML or resembled AML with severe cytopenias. An array of therapies are now available to treat MDS, including hematopoietic growth factors (eg, erythropoietin, darbepoetin, granulocyte colony-stimulating factor), transcriptional-modifying therapy (eg, FDA‒approved hypomethylating agents, nonapproved histone deacetylase inhibitors), immunomodulators (eg, lenalidomide, thalidomide, antithymocyte globulin, cyclosporine A), low-dose chemotherapy (eg, cytarabine), and allogeneic hematopoietic cell transplantation (allo-HCT). Given the spectrum of treatments available, the goal of therapy must be decided upfront whether it is to improve anemia, thrombocytopenia, or neutropenia, to eliminate the need for red blood cell transfusion, to achieve complete remission, or to cure the disease.

Allo-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. Allo-HCT is discussed in more detail in a subsequent section.

Chronic Myeloproliferative Neoplasms

Chronic MPN are clonal bone marrow stem cell disorders; as a group, approximately 8400 MPN are diagnosed annually in the United States. Like MDS, MPN primarily occurs in older individuals, with approximately 67% reported in patients aged 60 years and older.

MPN are characterized by the slow but progressive 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 variants that affects 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.

MPN Classification

The WHO (2008) classification scheme replaced the term chronic myeloproliferative disorder with the term myeloproliferative neoplasm. MPN are a subdivision of myeloid neoplasms that includes 4 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.

MPN Treatment

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.

The FDA (2011) 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 compared with placebo.^2, The Randomized Study of Ruxolitinib Tablets Compared to Best Available Therapy in Subjects WithPrimary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis(COMFORT-II trial [2013]) compared ruxolitinib with best available therapy in patients who had intermediate- and high-risk myelofibrosis, and demonstrated improvements in spleen volume and OS.^3, In a randomized trial comparing ruxolitinib with best available therapy (including antineoplastic agents, most commonly hydroxyurea, glucocorticoids) with no therapy for treatment of myelofibrosis, Harrison et al (2012) reported improvements in spleen size and quality of life, but not OS.^4,

Myeloablative allo-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 events of this procedure. However, the use of reduced-intensity conditioning (RIC) of conditioning regimens for allo-HCT has extended the potential benefits of this procedure to selected individuals with these disorders. Allo-HCT is discussed in more detail in the next section.

Hematopoietic Cell Transplantation

HCT is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allo-HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in 'Placental and Umbilical Cord Blood as a Source of Stem Cells' (Policy #012 in the Surgery Section).

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (eg, cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not graft-versus-host disease.

Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation

RIC refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total 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. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

Regulatory Status

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Related Policies

• Placental and Umbilical Cord Blood as a Source of Stem Cells (Policy #012 in the Surgery Section)
• Hematopoietic Cell Transplantation for Acute Myeloid Leukemia (Policy #037 in the Treatment Section)
• Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia (Policy #035 in the Treatment Section)

1. Clinical history of the member including results of diagnostic procedures performed (i.e., laboratory, pathology, radiology), and previous modes of therapy with results;
2. Treatment protocol of the facility where the procedure is being performed.

• myelodysplastic syndromes (see Policy Guidelines section) or
• myeloproliferative neoplasms (see Policy Guidelines section).

• myelodysplastic syndromes, or
• myeloproliferative neoplasms
in members who are at high-risk of intolerance of a myeloablative conditioning regimen. (see Policy Guidelines section)

FIDE SNP: For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

Myeloid Neoplasms

Myeloid neoplasms are categorized according to criteria developed by the World Health Organization (WHO). Neoplasms are risk-stratified using the International Prognostic Scoring System (IPSS).

2008 WHO Classification Scheme for Myeloid Neoplasms

1. Acute myeloid leukemia (AML)
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)

1. Refractory anemia (RA)
2. RA with ring sideroblasts
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

Risk stratification for MDS is performed using the IPSS (see Table PG1). This system was developed after pooling data from 7 studies that used independent, risk-based prognostic factors. The prognostic model and the scoring system were 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 group patients into either low-risk and high-risk groups (see Table PG2). The low-risk group includes low-risk and intermediate-1 IPSS groups; treatment goals in low-risk MDS patients are to improve quality of life and achieve transfusion independence. In the high-risk group, which includes intermediate-2 and high-risk IPSS groups, treatment goals are slowing disease progression to AML and improving survival. IPSS is usually calculated on diagnosis. The role of lactate dehydrogenase, marrow fibrosis, and β₂-microglobulin also should be considered after establishing IPSS. If elevated, the prognostic category worsens by 1 category change.

Table PG1. IPSS: 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	‒	‒	‒

IPSS: International Prognostic Scoring System.

Table PG2. IPSS: Myelodysplastic Syndrome Clinical Outcomes

Risk Group	Total Score	Median Survival, y	Time for 25% of patients to Progress to AML
Low	0	5.7	9.4 years
Intermediate-1	0.5-1.0	3.5	3.3 years
Intermediate-2	1.5-2.0	1.2	1.12 years
High	³2.5	0.4	0.2 years

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 (Schanz et al, 2012). This system stratifies patients into 5 categories: very poor, poor, intermediate, good, and very good. There has also been an investigation into using the 5-category IPSS to better characterize risk in MDS.

Given the long natural history of MDS, allogeneic hematopoietic cell transplantation (allo-HCT) is typically considered in patients with increasing numbers of blasts, signaling a possible transformation to AML. 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 allo-HCT when chromosomal abnormalities are present, or when the disorder is associated with the development of significant cytopenias (eg, neutrophils <500/mm³, platelets <20,000/mm³).

Patients with MPN may be considered candidates for allo-HCT when there is a progression to myelofibrosis or toward acute leukemia. In addition, allo-HCT may be considered in patients with essential thrombocythemia with an associated thrombotic or hemorrhagic disorder. Use of allo-HCT should be based on the following criteria: cytopenias, transfusion dependence, increasing blast percentage over 5%, and age.

Some patients for whom a conventional myeloablative allo-HCT could be curative may be candidates for reduced-intensity conditioning allo-HCT. They include patients whose age (typically >60 years) or comorbidities (eg, liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude the 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 (6/6). Related donors mismatched at 1 locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, who usually share only 3 of the 6 major histocompatibility antigens. Most patients will have such a donor; however, the risk of graft-versus-host disease 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.

Evidence and clinical guidelines suggest reduced-intensity conditioning allo-HCT may be considered as a risk-adapted strategy for high-risk patients of MAC-intolerance as follows:

MDS

• Older age
• IPSS intermediate-2 or high risk
• Multiple comorbidities (e.g., HSCT-comorbidity index (HCT-CI) score higher than 2)
• Red blood cell transfusion dependence
• Neutropenia
• Thrombocytopenia
• High-risk cytogenetics
• Increasing blast percentage

• Cytopenias
• Transfusion dependence
• Increasing blast percentage over 5%
• Age 60 to 65 years.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: 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. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. TheRCT is preferred 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. The following is a summary of the key literature to date.

Myelodysplastic Syndromes

Clinical Context and Therapy Purpose

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

The question addressed in this policy is: Does MAC or RIC allo-HCT improve the net health outcome in patients with MDS?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is patients with MDS.

Interventions

The therapies being considered are MAC or RIC allo-HCT. Patients are actively managed by hematologists/oncologists in an inpatient and outpatient setting.

Comparators

The following therapies are currently being used: standard of care.

Outcomes

The general 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. Follow-up over months to years is of interest for relevant outcomes.

Myeloablative Conditioning Allo-HCT

Despite the successes seen with drugs now available to treat MDS (eg, decitabine, azacitidine, lenalidomide), allo-HCT is the only treatment capable of complete and permanent eradication of the MDS clone.^5,

A 2009 review of HCT for MDS evaluated the evidence for allo-HCT with MAC for MDS.^6, Reviewers selected 24 studies (prospective and retrospective) published between 2000 and 2008 that included a total 1378 cases (age range, 32-59 years). Most patients (n=885) received matched-related donor allo-HCT, with other donor types including syngeneic, matched, unrelated donor, mismatched unrelated donor, and umbilical cord blood. Most studies included de novo and secondary MDS, chronic myelomonocytic leukemia, myeloproliferative neoplasms (MPN), de novo and secondary acute myeloid leukemia (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 (CY) and CY plus total body irradiation, with cyclosporine A used for graft-versus-host disease (GVHD) prophylaxis. Length of follow-up ranged from 5 months to approximately 8 years. Acute GVHD (grades II-IV) varied from 18% to 100%. Relapse risk ranged from 24% at 1 year to 36% at 5 years. The OS rates ranged from 25% at 2 years to 52% at 4 years, with nonrelapse mortality (NRM) ranging from 19% at day 100 to 61% at 5 years.

A 2009 review from the American Society for Blood and Marrow Transplantation evaluated the evidence related to HCT in the therapy of MDS, with associated treatment recommendations.^7, Reviewers concluded that outcomes improved with early HCT for patients with an International Prognostic Scoring System (IPSS) score of intermediate-2 or high-risk at diagnosis who had a suitable donor and met the transplant center’s eligibility criteria, and for selected patients with a low or intermediate-1 risk IPSS score at diagnosis who had a poor prognostic feature not included in the IPSS (ie, older age, refractory cytopenias). 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 AML (evolved from MDS).^8, 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 Allo-HCT for MDS

No published randomized trials have compared RIC plus allo-HCT with conventional chemotherapy alone in patients with MDS and AML for whom MAC chemotherapy and allo-HCT are contraindicated.

Three RCTs have compared RIC and MAC regimens before allo-HCT in patients with MDS.^9,10,11,The RCTs are heterogeneous in patient characteristics and conditioning regimens and their findings vary based on these differences. In patients who were considered eligible for standard MAC (eg, median age 50-55; HCT Comorbidity Index ≤ 4), results were mixed between 2 studies that compared RIC to standard MAC regimens. In the European Society of Blood and Marrow Transplantation RCT by Kroger et al (2017) of 129 patients from 18 centers primarily with MDS (median age=50 years; HCT Comorbidity Index NR), RIC and MAC had similar rates of 2-year relapse (17% vs. 15%; p=0.6), relapse-free survival 62% vs. 58%; p=0.58) and OS (76% vs. 63%, p=0.08).^11, In contrast, in the Blood and Marrow Transplant Clinical Trials Network RCT by Scott et al (2017), enrollment was stopped early after 272 patients (median age=55 years; 67% had HCT Comorbidity Index of 0-3; 80% AML) because of a significantly greater risk of relapse at 18 months with RIC (48.3% vs. 13.5%; p<0.001). ^10,At that time, OS was similar for MAC versus RIC (77.5% vs. 67.7%; difference=9.8%; 95% CI, -0.8 to 20.3%). These findings suggest use of RIC allo-HCT may put MAC-eligible patients at a disadvantage in some circumstances.

In the third RCT by Beelan et al (2019), patients who were considered ineligible for standard MAC based on age (≥50 years), an HCT comorbidity index of more than 2, or both, a ‘reduced toxicity’ MAC regimen (treosulfan plus fludarabine) was compared to RIC.^9, Findings in the overall population (N=476; 64% acute myeloid leukemia; 36% MDS) suggest a superior 2-year event-free survival with the reduced-toxicity MAC regimen (hazard ratio [HR] O.65; 95% CI, 0.47, 0.90; p<0.001 for noninferiority and p<0.0051 for superiority) and a similar relapse or progression (HR 0.87; 95% CI, 0.59, 1.30). However, in the MDS subgroup (n=167), differences between the reduced-toxicity MAC regimen and the RIC regimen were not statistically significant for event-free survival (HR 0.70; 95% CI, 0.36 to 1.36) or relapse or progression (HR 0.92; 95% CI, 0.58 to 1.48). The incidence of 2-year OS in both groups (approximately 48% to 68%) appears numerically greater than those described above from an earlier 2009 review of MAC for MDS (25%), suggesting that RIC or reduced toxicity MAC may be a reasonable strategy for those who may be MAC-intolerant.^6, These findings also appear consistent with the American Society for Blood and Marrow Transplantation’s (2009) systematic review (previously described), which 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.”^7, Other reviews (2010-2012) have also drawn conclusions similar to those of the American Society for Blood and Marrow Transplantation.^{12,13,14,15,16,17,} Given the absence of curative therapies for these patients, RIC allo-HCT may be considered as a risk-adapted treatment strategy for patients with MDS who could benefit from allo-HCT but who are at high-risk of MAC regimen intolerance.

Additional nonrandomized evidence includes uncontrolled studies and prospective and retrospective cohort studies. Evidence from a number of largely heterogeneous, uncontrolled studies of RIC with allo-HCT has shown long-term remission (ie, >4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with MDS or AML who otherwise would not be candidates for MAC regimens.^{6,18,19,20,21,22,23,24,25,26,27,28,} These prospective and retrospective studies included cohorts of 16 to 215 patients similar to those in the MAC allo-HCT studies. The most common conditioning regimens used were fludarabine-based, with cyclosporine A and tacrolimus used for GVHD prophylaxis. The reported incidence of grades II to IV GVHD was 9% to 63%, with a relapse risk of 6% to 61%. OS rates ranged between 44% at 1 year and 46% at 5 years (median follow-up range, 14 months to >4 years).

In general, nonrandomized studies of RIC compared to MAC showed a low rate of engraftment failure and low non-relapse mortality with RIC, but a higher relapse rate than with MAC allo-HCT. Zeng et al (2014) conducted a systematic review and meta-analysis comparing outcomes for patients who had MDS or AML treated with HCT plus RIC or MAC.^29, Reviewers included 8 studies (2 prospective, 8 retrospective), with a total of 6464 AML or MDS patients. Of these, 171 received RIC and 4893 received MAC. Overall, RIC-treated patients were older and more likely to have multiple comorbidities. In the pooled analysis, OS, RFS, and NRM did not differ significantly between patients receiving RIC and MAC. Relapse incidence was significantly lower in the MAC arm (odds ratio for RIC vs. MAC, 1.41; 95% confidence interval [CI], 1.24 to 1.59; p<0.001).

Aoki et al (2015) compared RIC with MAC in a retrospective cohort of 448 patients (age range, 50-69 years) with advanced MDS (refractory anemia with excess blasts or refractory anemia in transformation).^30, Of the total, 197 (44%) and 251 (56%) received MAC 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 MAC; p=0.001), and less likely to receive an unrelated donor transplant (54% vs. 70%; p=0.001). Three-year OS rates did not differ between groups (44.1% for RIC vs. 42.7% for MAC; 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), they had a significantly higher 3-year incidence of relapse than patients treated with MAC (29.9% vs. 22.8%; p=0.029).

Kim et al (2012) published a phase 3 randomized trial (n=83 patients) comparing toxicity rates for 2 conditioning regimens (reduced CY, fludarabine, and anti-thymocyte globulin; standard CY anti-thymocyte globulin ).^31, Four patients had MDS, and the remaining patients had severe aplastic anemia. Overall, the incidence of reported toxicities was lower in patients receiving the RIC regimen (23% vs. 55%; p=0.003). Subgroup analyses showed no differences in the overall results based on differential diagnosis.

Outcomes After Allo-HCT in Mixed MDS Populations

A number of studies, primarily retrospective, continue to report outcomes from allo-HCT for MDS in a variety of patient populations and to evaluate the impact of specific patient, conditioning, and donor characteristics on outcomes; representative studies are summarized in Table 1.

Table 1. Case Series of HCT Treatment for MDS

Study	Patient Population	Type of HCT	Summary of Outcomes
Basquiera et al (2015)32,	52 pediatric patients with MDS	·Allo-HCT (59% with related donors) ·Stem cell source: o Bone marrow, 63% o Peripheral blood, 26% o Umbilical cord blood, 11%	·5-y DFS=50% ·5-y OS=55%
Boehm et al (2014)33,	60 adults with MDS or secondary AML	·Allo-HCT ·MAC in 36 patients; RIC in 24 patients	10-y OS=46%
Damaj et al (2014)34,	128 adults with MDS: 40 received AZA before HCT and 88 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)35,	227 patients with MDS or AML	·Allo-HCT ·Donor source: o Matched-related, 38% o Matched-unrelated, 48% o 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)36,	·523 patients with MDS ·IPSS cytogenic risk group: o Good risk: 53.5% o Intermediate risk: 24.5% o 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)37,	·256 patients with MDS ·Pretreatment: o No cytoreductive chemo: 30.5% o Chemo: 15.6% o HMA: 47.7% o 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)38,	17 children with secondary MDS or AML after childhood aplastic anemia	·Allo-HCT	5-y OS and EFS=41%
Basquiera et al (2016)39,	·84 adults with MDS Cytogenic risk group: o Standard: 65.5% o Adverse: 12.6% oUnknown: 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)40,	·513 adults with CMML ·Pretreatment: o No prior disease-modifying therapy: 28% o Disease-modifying therapy: 72%	·Allo-HCT ·RIC in 41.6%	·1-y NRM=31% ·4-y NRM=41% ·4-y RFS=27% ·4-y OS=33%
Pohlen et al (2016)41,	·187 patients with refractory AML (87%) or high-risk MDS (13%)	·Allo-HCT ·RIC in 52% ·Unrelated donors in 73% ·Stem cell source: o Bone marrow, 6% o Peripheral blood, 94%	3-y RFS=32% (95% CI, 25% to 39%) 3-y OS=35% (95% CI, 27% to 42%)
Heidenreich et al (2017)42,	·313 adults with MDS and secondary AML, age ≥ 70 Cytogenic risk group: o Good: 51% o Intermediate: 22% o Poor/very poor: 11%	·Allo-HCT ·RIC or non-MAC in 83% ·Unrelated donors in 75% ·Stem cell source: o Bone marrow, 6% o Peripheral blood, 94%	1-y NRM: 32% 3-y relapse: 28% 3-y OS: 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; EFS: event-free survival; HMA: hypomethylating agents; HCT: hematopoietic cell transplantation; IPSS: International Prognostic Scoring System; MAC: myeloablative conditioning; MDS: myelodysplastic syndromes; NRM: nonrelapse mortality; OS: overall survival; PFS: progression-free survival; RFS: relapse-free survival; RIC: reduced-intensity conditioning.

Section Summary: MDS

Primarily uncontrolled, observational studies of HCT for MDS have reported a relatively large range of OS and progression-free survival values, which reflect the heterogeneity in patient populations, conditioning regimens, and other factors. Reported estimates for 3- to 5-year OS of 40% to 50% are typical. Evidence from randomized and nonrandomized comparisons has suggested that RIC may be used as a risk-adapted strategy in high-risk patients who are older and with more comorbidities without significantly worsening OS. RIC appears to be associated with lower rates of NRM but higher cancer relapse than MAC HCT.

Myeloproliferative Neoplasms

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 policy is: Does MAC or RIC allo-HCT improve the net health outcome in patients who have MPN?

The following PICO was used to select literature to inform this review.

Patients

The relevant population of interest is patients who have MPN.

Interventions

The therapies being considered are MAC or RIC allo-HCT. Patients are actively managed by hematologists/oncologists in an inpatient and outpatient setting.

Comparators

The following therapies are currently being used: standard of care.

Outcomes

The general outcomes of interest are mortality and morbidity.

Beneficial outcomes are an improvement in OS and DSS.

Harmful outcomes are treatment-related morbidity and mortality. Follow-up over months to years is of interest for relevant outcomes.

Data on therapy for MPN are sparse.^25,43,44, As outlined in this policy, with the exception of MAC chemotherapy and allo-HCT, no therapy has yet proven to be curative or to prolong survival of patients with MPN.

The largest study identified evaluating allo-HCT for primary myelofibrosis comes from a 2010 analysis of the outcomes for 289 patients treated between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research.^45, Median age was 47 years (range, 18-73 years). Donors were human leukocyte antigen (HLA)‒identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and GVHD prophylaxis regimens. Splenectomy was performed in 65 patients before 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. Disease-free survival (DFS) rates were 33%, 27%, and 22%, respectively. DFS for patients receiving RIC allo-HCT 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 RFS in about one-third of patients.

Gupta et al(2014) reported better DFS rates in an analysis of 233 patients with primary myelofibrosis who underwent RIC HCT from 1997 to 2010.^46, The 5-year OS rate 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.^47, In the HCT group, 91 and 97 subjects received RIC and MAC, 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 disease 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 differ significantly 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 MAC plus allo-HCT in MPN has led to study of RIC regimens for these diseases. Data from a direct, prospective comparison of outcomes of MAC and allo-HCTversus RIC and allogeneic stem cell support in MPN are not available, but single-arm series and nonrandomized comparative studies have reported outcomes after RIC allo-HCT. One 2008 series included 27 patients (mean age, 59 years) with MPN who underwent allo-HCT using an RIC regimen of low-dose (2 gray) total body irradiation alone with or without fludarabine.^23, At a median follow-up of 47 months, 3-year RFS was 37%, 3-year OS was 43%, and 3-year NRM was 32%. In a second series (2009), 103 patients (median age, 55 years; range, 32-68 years) with intermediate- to high-risk (86% of total patients) primary myelofibrosis or post-essential thrombocythemia and polycythemia vera myelofibrosis were included in a prospective, multicenter, phase 2 trial to determine the efficacy of a busulfan plus fludarabine-based RIC regimen followed by allo-HCT from related (n=33) or unrelated (n=70) donors.^48, Acute GVHD (grade II-IV) occurred in 27% of patients, and chronic GVHD in 43%. The cumulative incidence of NRM at 1 year in all patients was 16% (95% CI, 9% to 23%), but reached 38% (95% CI, 15% to 61%) among those with a mismatched donor versus 12% (95% CI, 5% to 19%) among cases with a matched donor (p=0.003). The cumulative relapse rates at 3 and 5 years were 22% (95% CI, 13% to 31%) and 29% (95% CI, 16% to 42%), respectively. After a median follow-up of 33 months (range, 12-76 months), the 5-year estimated DFS and OS rates were 51% (95% CI, 38% to 64%) and 67% (95% CI, 55% to 79%), respectively.

A 2009 retrospective study analyzed the impact of conditioning intensity on outcomes for allo-HCT in patients with myelofibrosis.^49, This multicenter trial included 46 consecutive patients treated at 3 Canadian and 4 European transplant centers between 1998 and 2005. Twenty-three patients (median age, 47 years; range, 31-60 years) underwent MAC 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 months), there was a trend for a better progression-free survival rate at 3 years in RIC patients than in MAC patients (58% [range, 23%-62%] vs. 43% [range, 35%-76%], respectively; p=0.11); there was a similar trend in the 3-year OS rate (68% [range, 45%-84%] vs. 48% [range, 27%-66%], respectively; p=0.08). NRM rates at 3 years trended higher in MAC cases (48%; range, 31%-74%) than in RIC cases (27%; range, 14%-55%; p=0.08). The results of this study suggested that both types of conditioning regimens have curative potential in patients with myelofibrosis. 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 allo-HCT in this population.

In a 2012 retrospective study in 9 Nordic transplant centers, 92 patients with myelofibrosis in chronic phase underwent allo-HCT.^50,MAC was given to 40 patients and RIC to 52 patients. Mean age in the 2 groups at transplantation was 46 and 55 years, respectively (p<0.001). When adjustment for age differences was made, 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 10-year survival close to 80%) than for patients older than 60 years. The stem cell source did not significantly affect survival. No significant difference was found in NRM at 100 days between the MAC- and the RIC-treated patients. The probability of survival at 5 years was 49% for the MAC group and 59% in the RIC group (p=0.125). Patients treated with RIC experienced significantly less acute GVHD than in patients treated with MAC (p<0.001). The OS rates at 5 years were 70%, 59% and 41% for patients with Lille scores 0, 1, and 2, respectively (p=0.038, when adjusting for age). Furthermore, 21% of patients in the RIC group were given donor lymphocyte infusion because of incomplete donor chimerism, compared with none of the MAC-treated patients (p<0.002); 9% of patients needed a second transplant because of graft failure, disease progression, or transformation to AML, with no significant differences between groups.

Section Summary: MPN

Observational studies of HCT for MPN have reported a range of 3- to 5-year OS rates from 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 MDS or MPN who receive MAC allo- HCT, the evidence includes case series, which are often heterogeneous in terms of diseases included. Relevant outcomes areOS, DSS, and treatment-related mortality and morbidity. 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 OS 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 using HCT compared with standard therapy. At present, HCT is 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 receiveRIC allo- HCT, the evidence includes RCTs and primarily retrospective observational series. Relevant outcomes are OS, DSS, and treatment-related mortality and morbidity. Direct, prospective comparisons of outcomes after HCT with either MAC or RIC in either MDS or MPN are not available. Evidence from RCTs and retrospective, nonrandomized comparisons have suggested that RIC may be used as a risk-adapted strategy in high-risk patients who are older and have more comorbidities without significantly worsening OS. RIC appears to be associated with lower rates of nonrelapse mortality but higher cancer relapse than MAC HCT. At present, HCT is 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.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

Current National Comprehensive Cancer Network clinical guidelines for myelodysplastic syndromes (v.2.2020) make the following general recommendation about allo-HCT^51,:

“For patients who are transplant candidates, an HLA [human leukocyte antigen]-matched sibling, or HLA-matched unrelated donor can be considered. 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 [reduced-intensity conditioning] for HCT is generally the strategy in older individuals.”

Specific National Comprehensive Cancer Network recommendations for HCT for treatment of myelodysplastic syndromes are outlined in Table 2.^51,

Table 2. Guidelines for Allo-HCT for Myelodysplastic Syndromes

Prognostic Category	Recommendations for Allo-HCT
IPSS low/intermediate-1 OR IPSS-R very low, low, intermediate OR WPSS very low, low, intermediate	·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; WPSS: WHO Classification-based Prognostic Scoring System.

Table 3 summarizes the National Comprehensive Cancer Network recommendations (v.3.2019) on the use of allo-HCT for the treatment of myeloproliferative neoplasms.^52, The guidelines note that selection of allo-HCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver.

Table 3. 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. ·Evaluation for allo-HCT is recommended for patients with low platelet counts or complex cytogenetics
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. ·Evaluation for allo-HCT is recommended for patients with low platelet counts or complex cytogenetics
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.

American Society of Transplantation and Cellular Therapy

The American Society of Transplantation and Cellular Therapy (formerly The American Society for Blood and Marrow Transplantation) (2015) published guidelines on indications for HCT, based on the recommendations of a multiple-stakeholder task force.^53, Table 4 summarizes categorizations for allo-HCT.

Table 4. 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”)

HCT: hematopoietic cell transplantation.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT00176930	Allogeneic Transplant for Hematological Malignancy	350	Dec 2019
NCT00739141	Conditioning Regimen and the Transplantation of Unrelated Donor Umbilical Cord Blood in Patients with Hematologic Malignancies	80	Aug 2020
NCT01760655	Reduced Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients with High-Risk Hematologic Malignancies	50	Apr 2021
NCT02757989	Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome Low Risk	105	Apr 2021

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms
Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms
Agnogenic Myeloid Metaplasia, High Dose Chemotherapy
Allogeneic Bone Marrow Transplant, Myelodysplastic Diseases
Anemia, Refractory, High Dose Chemotherapy
Bone Marrow Transplant, Myelodysplastic Diseases
Essential Thrombocythemia, High Dose Chemotherapy
High Dose Chemotherapy with Allogeneic Stem Cell Support for Myelodysplastic Diseases
Myelodysplastic Syndrome, High Dose Chemotherapy
Myelofibrosis, High Dose Chemotherapy
Myeloid Metaplasia, High Dose Chemotherapy
Myeloproliferative Neoplasms, High Dose Chemotherapy
Polycythemia Vera, High Dose Chemotherapy
Primary Myelofibrosis, High Dose Chemotherapy
Refractory Anemia, High Dose Chemotherapy
Stem Cell Transplant, Myelodysplastic Diseases
Thrombocythemia, Essential, High Dose Chemotherapy
Transplantation, Bone Marrow/Stem Cell for Myelodysplastic Diseases

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36. Onida F, Brand R, van Biezen A, et al. Impact of the International Prognostic Scoring System cytogenetic risk groups on the outcome of patients with primary myelodysplastic syndromes undergoing allogeneic stem cell Neoplasms transplantation from human leukocyte antigen-identical siblings: a retrospective analysis of the European Society for Blood and Marrow Transplantation-Chronic Malignancies Working Party. Haematologica. Oct 2014;99(10):1582-1590. PMID 25085359

37. Oran B, Kongtim P, Popat U, et al. Cytogenetics, donor type, and use of hypomethylating agents in myelodysplastic syndrome with allogeneic stem cell transplantation. Biol Blood Marrow Transplant. Oct 2014;20(10):1618-1625. PMID 24953017

38. 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. PMID 24316460

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40. Symeonidis A, van Biezen A, de Wreede L, et al. Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Br J Haematol. Jul 26 2015;171(2):239-246. PMID 26212516

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

38204
38205
38207
38208
38209
38210
38211
38212
38213
38214
38215
38220
38221
38230
38232
38240
38242

S2140
S2142
S2150