Description
Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) refer to a heterogeneous group of clonal hematopoietic disorders with the potential to transform into acute myelocytic leukemia. Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as a curative treatment option for patients with these disorders

Background
Myelodtysplastic 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 five 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 (unilineagevs 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 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 (e.g., 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 five 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 (e.g., erythropoietin, darbepoetin, granulocyte colony-stimulating factor), transcriptional-modifying therapy (e.g., Food and Drug Administration‒approved hypomethylating agents, nonapproved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, antithymocyte globulin, cyclosporine A), low-dose chemotherapy (e.g., 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 8,400 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 four classic disorders: chronic myeloid leukemia, polycythemia vera, essential thrombocytopenia, and primary myelofibrosis. The WHO classification also includes chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, mast cell disease, and MPN unclassifiable.

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 Food and Drug Administration (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 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
Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allo-HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naive” and thus are associated with a lower incidence of rejection or graft-versus-host disease. Cord blood is discussed in greater detail in evidence review 7.01.50.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. However, immunologic compatibility between donor and patient is critical for achieving a good outcome of allo-HCT. Compatibility is established by typing of human leukocyte antigen (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA-A, -B, and -DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.

Conventional Preparative Conditioning for HCT
The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect of this procedure is due to a combination of initial eradication of malignant cells and a subsequent graft-versus-malignancy effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower graft-versus-malignancy 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 events that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allo-HCT, immune suppressant drugs are required to minimize graft rejection and graft-versus-host disease, which also increases the susceptibility of the patient to opportunistic infections.

Reduced-Intensity Conditioning for Allo-HCT
RIC refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden and to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of nonrelapse mortality 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, and intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For this evidence review, RIC will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

Regulatory Status
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Related Policies
70150 Placental and Umbilical Cord Blood as a Source of Stem Cells
80126 Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia
80130 Hematopoietic Stem-Cell Transplantation for Chronic Myelogenous Leukemia

Policy
Myeloablative allogeneic hematopoietic cell transplantation (allo-HCT) may be considered MEDICALLY NECESSARY as a treatment of

• Myelodysplastic syndromes (see Policy Guidelines section).
• Myeloproliferative neoplasms (see Policy Guidelines section).

Reduced-intensity conditioning allo-HCT may be considered MEDICALLY NECESSARYas a treatment of 

• Myelodysplastic syndromes.
• Myeloproliferative neoplasms. 

in patients who are at high risk of intolerance of a myeloablative conditioning regimen (see Policy Guidelines section).

Myeloablative allo-HCT or reduced-intensity conditioning allo-HCT for myelodysplastic syndromes and myeloproliferative neoplasms that does not meet the criteria in the Policy Guidelines section is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines 
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).

2022 WHO Classification Scheme for Myeloid Neoplasm and Histiocytic/Dendritic Neoplasms

Clonal hematopoiesis (CH)

• CH of indeterminate potential (CHIP)

• Clonal cytopenia of undetermined significance (CCUS)

Myeloproliferative neoplasms (MPN)

• Chronic myeloid leukemia (CML), BCR-ABL1⁺

• Chronic neutrophilic leukemia (CNL)

• Polycythemia vera

• Primary myelofibrosis (PMF)

• Essential thrombocythemia

• Chronic eosinophilic leukemia

• MPN, not otherwise specified

• Juvenile myelomonocytic leukemia

Mastocytosis

• Cutaneous mastocytosis

• Systemic mastocytosis

• Mast cell sarcoma

Childhood MDS

• Childhood MDS with low blasts

  • Hypocellular

  • Not otherwise specified

• Childhood MDS with increased blasts

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK)

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)

• Chronic myelomonocytic leukemia (CMML)

• MDS/MPN with neutrophilia

• MDS/MPN with SF3B1 mutation and thrombocytosis

• MDS/MPN, not otherwise specified

Myelodysplastic neoplasms (MDS)

• MDS with defining genetic abnormalities

  • MDS with low blasts and isolated 5q deletion (MDS-5q)

  • MDS with low blasts and SF3B1 mutation (MDS-SF3B1), or MDS with low blasts and ring sideroblasts

  • MDS with biallelic TP53 inactivation (MDS-biTP53)

• MDS, morphologically defined

  • MDS with low blasts (MDS-LB)

  • MDS, hypoplastic (MDS-h)

  • MDs with increased blasts (MDS-IB)

    • MDS-IB1

    • MDS-IB2

    • MDS with fibrosis (MDS-f)

Acute myeloid leukemia (AML)

• AML with defining genetic abnormalities

• AML, defined by differentiation

Secondary myeloid neoplasms

• Myeloid neoplasms post cytotoxic therapy

• Myeloid neoplasms associated with germline predisposition

Dendritic cell and histiocytic neoplasms

• Plasmacytoid dendritic cell neoplasms

• Langerhans cell and other dendritic cell neoplasms

• Histiocytic neoplasms

Acute leukemias of ambiguous lineage (ALAL)

• ALAL with defining genetic abnormalities

• ALAL, immunophenotypically defined

Genetic tumor syndromes with predisposition to myeloid neoplasia

Risk stratification for MDS is performed using the IPSS (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 individuals into either low-risk or high-risk groups (Table PG2). The low-risk group includes low-risk and intermediate-1 IPSS groups; treatment goals in low-risk MDS individuals 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.

Variable	0	0.5	1.0	1.5	2.0
Marrow blasts, %	< 5	5 to 10	NA	11 to 20	21 to 30
Karyotype	Good	Intermediate	Poor	NA	NA
Cytopenias	0/1	2/3	NA	NA	NA

Table PG2. International Prognostic Scoring System: 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 to 1.0	3.5	3.3 years
Intermediate-2	1.5 to 2.0	1.2	1.12 years
High	≥ 2.5	0.4	0.2 years

An updated 5-category IPSS has been proposed for prognosis in individuals with primary MDS or secondary AML to account for chromosomal abnormalities frequently seen in MDS (see 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 individuals 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 CMML.

Individuals 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 (e.g., neutrophils < 500/mm³, platelets < 20,000/mm³).

Individuals with myeloproliferative neoplasms 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 individuals 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 individuals for whom a conventional myeloablative allo-HCT could be curative may be candidates for reduced-intensity conditioning (RIC) allo-HCT. These include individuals whose age (typically > 60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude the use of a standard myeloablative conditioning (MAC) 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 individual , who usually share only 3 of the 6 major histocompatibility antigens. Most individuals will have such a donor; however, the risk of graft-versus-host disease (GVHD) and overall morbidity of the procedure may be severe, and experience with these donors is not as GVHD extensive as that with matched donors.

Evidence and clinical guidelines suggest RIC allo-HCT may be considered as a risk-adapted strategy for high-risk individuals of MAC-intolerance as follows:

MDS

• Older age

• IPSS intermediate-2 or high risk

• Multiple comorbidities (e.g., hematopoietic cell transplantation -comorbidity index (HCT-CI) score higher than 2)

• Red blood cell transfusion dependence

• Neutropenia

• Thrombocytopenia

• High-risk cytogenetics

• Increasing blast percentage

Myeloproliferative neoplasm

• Cytopenias

• Transfusion dependence

• Increasing blast percentage over 5%

• Age 60 to 65 years

Coding
See the Codes Table for details

Benefit Application
BlueCard/National Account Issues
Some plans may have contract or benefit exclusions for genetic testing.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are 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 to managing the course of that condition. Validated outcome measures are necessary 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.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and the quality and credibility. To be relevant, studies must represent 1 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. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Myelodysplastic Syndromes
Clinical Context and Therapy Purpose
The purpose of myeloablative or reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplant (allo-HCT) in patients who have myelodysplastic syndrome (MDS) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations
The relevant population of interest is individuals with MDS.

Interventions
The therapies being considered are myeloablative or RIC allo-HCT.

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

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Myeloablative Conditioning Allogeneic Hematopoietic Cell Transplantation
Despite the successes seen with drugs now available to treat MDS (e.g., decitabine, azacitidine, lenalidomide), allo-HCT is the only treatment capable of complete and permanent eradication of the MDS clone.⁷

Systematic Review
A 2009 review of HCT for MDS evaluated the evidence for allo-HCT with myeloablative conditioning (MAC) for MDS.⁸ Reviewers selected 24 studies (prospective and retrospective) published between 2000 and 2008 that included a total 1378 cases (age range, 32 to 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, 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 to 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 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.⁹ 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 (i.e., 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).¹⁰ 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 Allogeneic Hematopoietic Cell Transplantation
Systematic Reviews
Song et al. (2021) evaluated the efficacy of RIC followed by allo-HCT in patients with AML and MDS via a meta-analysis of 6 RCTs (N = 1413).¹¹ The 6 RCTs compared RIC to MAC before first allo-HCT in patients with AML in complete remission or MDS, had a median follow-up of > 1 year, and displayed a low risk of bias. The primary endpoint was OS. Results revealed that OS was not significantly different between RIC and MAC (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.64 to 1.4; p = .80), with combined long-term follow-up data also showing no difference in OS between the 2 conditioning approaches (HR, 0.86; 95% CI, 0.53 to 1.41; p = .56). The cumulative incidence of relapse was also similar between the groups (HR, 1.18; 95% CI, 0.88 to 1.49; p = .28). Nonrelapse mortality was significantly improved with RIC as compared to total body irradiation/busulfan-based MAC (HR, 0.53; 95% CI, 0.36 to 0.8; p = .002); however, treosulfan-based MAC significantly reduced nonrelapse mortality as compared to RIC (HR, 1.67; 95% CI, 1.02 to 2.72; p = .04). RIC was associated with a trend of increasing graft failure (p = .06); however, graft failure in both arms was rare. The median duration of follow-up among the studies ranged from 12 to 119 months. The authors concluded that RIC is recommended as an adequate option of preparative treatment before allo-HCT for patients with AML in complete remission or MDS. Limitations of the meta-analysis included the small number of included clinical trials, significant heterogeneity between included studies for some outcomes, and lack of blinding in some studies.

Randomized Controlled Trials
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, all of which are included in the systematic review by Song et al. (2021),¹¹ have compared RIC and myeloablative regimens before allo-HCT in patients with MDS.^12,13,14 The RCTs are heterogeneous in patient characteristics and conditioning regimens and their findings vary based on these differences. In a long-term follow-up of one of the RCTs¹³ Scott et al. (2021) found that, at 4 years, transplant-related mortality was significantly increased with MAC as compared to RIC (25.1% vs. 9.9%; p < .001) and those who received RIC had a significantly increased relapse risk (HR, 4.06; 95% CI, 2.59 to 6.35; p < .001).¹⁵ Among those who relapsed after HCT, postrelapse survival was similar between groups at 3 years (24% for MAC vs. 26% for RIC). Patients administered MAC had superior OS (HR, 1.54; 95% CI, 1.07 to 2.2; p = .03).

Overall, findings from these RCTs appear consistent with the American Society for Blood and Marrow Transplantation’s (2009) systematic review (previously described), which assessed the evidence supporting reduced-intensity and myeloablative conditioning 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.”⁹ Other reviews (2010 to 2012) have also drawn conclusions similar to those of the American Society for Blood and Marrow Transplantation.^{16,17,18,19,20,21} 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.

Noncomparative and Observational Studies
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 (i.e., > 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.^{8,22,23,24,25,26,27,28,29,30,31,32} 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%. Rates of OS 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 reduced-intensity or myeloablative conditioning.³³ 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, r RIC treated patients were older and more likely to have multiple comorbidities. In the pooled analysis, OS, RFS, and nonrelapse mortality did not differ significantly between patients receiving reduced-intensity and myeloablative conditioning. Relapse incidence was significantly lower in the MAC arm (odds ratio [OR] for RIC vs. MAC, 1.41; 95% CI, 1.24 to 1.59; p < .001).

Aoki et al. (2015) compared RIC with MAC in a retrospective cohort of 448 patients (age range, 50 to 69 years) with advanced MDS (refractory anemia with excess blasts or refractory anemia in transformation).³⁴ Of the total, 197 (44%) and 251 (56%) received myeloablative or r RIC, respectively. The groups differed at baseline: patients who received r RIC were significantly more likely to be 60 to 69 years old (vs. 50 to 59 years; 47% for RICvs. 47% for MAC; p = .001), and less likely to receive an unrelated donor transplant (54% vs. 70%; p = .001). Three-year OS rates did not differ between groups (44.1% for RIC vs. 42.7% for MAC; p = .330). Although patients treated with RIC had a significantly lower 3-year cumulative incidence of nonrelapse mortality (25.6% vs. 37.9%; p = .002), they had a significantly higher 3-year incidence of relapse than patients treated with MAC (29.9% vs. 22.8%; p = .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).³⁵ 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 = .003). Subgroup analyses showed no differences in the overall results based on differential diagnosis.

Outcomes After Allogeneic Hematopoietic Cell Transplantation in Mixed Myelodysplastic Syndrome Populations
Noncomparative and Observational Studies
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 Hematopoietic Cell Transplantation Treatment for Myelodysplastic Syndrome

Study	Patient Population	Type of HCT	Summary of Outcomes
Basquiera et al. (2015)36	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)37	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)38	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 = .69) 3-y RFS = 37% in AZA group vs. 42% in BSC group (p = .78) 3-y NRM = 20% in AZA group vs. 23% in BSC group (p = .74)
Di Stasi et al. (2014)39	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 = .417)
Onida et al. (2014)40	523 patients with MDS 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)41	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 = .50)
Yoshimi et al. (2014)42	17 children with secondary MDS or AML after childhood aplastic anemia	Allo-HCT	5-y OS and EFS = 41%
Basquiera et al. (2016)43	84 adults with MDS 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)44	513 adults with CMML Pretreatment: No prior disease-modifying therapy: 28% 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)45	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%	3-y RFS = 32% (95% CI, 25% to 39%) 3-y OS = 35% (95% CI, 27% to 42%)
Heidenreich et al. (2017)46	313 adults with MDS and secondary AML, age ≥ 70 Cytogenic risk group: Good: 51% Intermediate: 22% Poor/very poor: 11%	Allo-HCT RIC or non-MAC in 83% Unrelated donors in 75% Stem cell source: Bone marrow, 6% Peripheral blood, 94%	1-y NRM: 32% 3-y relapse: 28% 3-y OS: 34%
Robin et al. (2022)47	1114 adults with CMML age 18 to 70 years CMML Prognosis Scoring System risk: Low: 20% Intermediate-1: 31% Intermediate-2: 40% High: 9% Underwent allo-HCT: 43% Transformed to AML prior to allo-HCT: 10%	MAC or RIC allo-HCT; details of intensity and donor source not reported	5-y OS: Lower-risk disease: 20% with allo-HCT vs. 42% without allo-HCT (p < .001) Higher-risk disease: 27% with allo-HCT vs. 15% without allo-HCT (p = .13) Multivariate analyses of risk of death within 2 years and after 2 years: Lower-risk disease: Increased risk of death within 2 years with allo-HCT (HR = 3.19); no difference in long-term survival after 2 years (HR = 0.98) Higher-risk disease: Increased risk of death within 2 years with allo-HCT (HR = 1.46); no difference in long-term survival after 2 years (HR = 0.60) Conditioning regimen intensity and donor type were not associated with post-transplant survival (data not reported)

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: Myelodysplastic Syndrome
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 nonrelapse mortality 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 myeloproliferative neoplasms is to provide a treatment option that is an alternative to or an improvement on existing therapies.

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

Populations
The relevant population of interest is individuals who have myeloproliferative neoplasms.

Interventions
The therapies being considered are MAC or RIC allo-HCT.

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

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Data on therapy for myeloproliferative neoplasms are sparse.^29,48,49 As outlined in this evidence review, with the exception of MAC chemotherapy and allo-HCT, no therapy has yet proven to be curative or to prolong survival of patients with myeloproliferative neoplasms.

Systematic Reviews
Bewersdorf et al. (2021) assessed the available evidence on the efficacy and safety of allo-HCT in patients with myelofibrosis in a systematic review involving 43 studies (N = 8739).⁵⁰ The analysis included 38 retrospective, 1 prospective, and 4 phase II clinical trials. Conditioning regimens used were variable with only 3 and 14 studies using exclusively MAC or RIC regimens, respectively. Additionally, donor sources and pre-transplantation treatment histories differed considerably among studies. The co-primary outcome was 1-, 2-, and 5-year OS. Rates of nonrelapse mortality, RFS or progression-free survival (PFS), and safety were also evaluated. Regarding survival, 1-year, 2-year, and 5-year OS rates were 66.7% (95% CI, 63.5% to 69.8%), 64.4% (95% CI, 57.6% to 70.6%), and 55% (95% CI, 51.8% to 58.3%), respectively. Nonrelapse mortality rates for the same time periods were 25.9% (95% CI, 23.3% to 28.7%), 29.7% (95% CI, 24.5% to 35.4%), and 30.5% (95% CI, 25.9% to 35.5%). Rates of 1-, 2- and 5-year RFS were 65.3% (95% CI, 56.5% to 73.1%), 56.2% (95% CI, 41.6% to 69.8%), and 53.6% (95% CI, 39.9% to 66.9%), respectively. PFS rates were 56.9% (95% CI, 41.4% to 71.2%), 50.6% (95% CI, 39.7% to 61.4%), and 43.5% (95% CI, 31.9% to 55.8%) for these same time periods. Acute GVHD was reported in 44% of patients, with chronic GVHD occurring in 46.5% of patients. The combined rate of graft failure was 10.6% (95% CI, 8.9% to 12.5%). Overall, the quality of the evidence was limited by the absence of RCTs and the retrospective design of most studies. Additionally, patient and transplant characteristics were variable among the included studies leading to moderate to substantial heterogeneity in the analyses.

Noncomparative and Observational Studies
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.⁵¹ Median age was 47 years (range, 18 to 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. Rates of DFS for patients receiving reduced-intensity conditioning allo-HCT were 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.

The significant toxicity of MAC plus allo-HCT in myeloproliferative neoplasms has led to study of RIC regimens for these diseases. Data from a direct, prospective comparison of outcomes of MAC allo-HCT versus RIC allo-HCT in myeloproliferative neoplasms 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 myeloproliferative neoplasms who underwent allo-HCT using a RIC regimen of low-dose (2 gray) total body irradiation alone with or without fludarabine.²⁷ At a median follow-up of 47 months, 3-year RFS was 37%, 3-year OS was 43%, and 3-year nonrelapse mortality was 32%.

A 2009 retrospective study analyzed the impact of conditioning intensity on outcomes for allo-HCT in patients with myelofibrosis.⁵² 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 to 60 years) underwent MAC and 23 patients (median age, 54 years; range, 38 to 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 to 89 months), there was a trend for a better PFS rate at 3 years in RIC patients than in MAC patients (58% [range, 23% to 62%] vs. 43% [range, 35% to 76%], respectively; p = .11); there was a similar trend in the 3-year OS rate (68% [range, 45% to 84%] vs. 48% [range, 27% to 66%], respectively; p = .08). Nonrelapse mortality rates at 3 years trended higher in MAC cases (48%; range, 31% to 74%) than in r RIC cases (27%; range, 14% to 55%; p = .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.

Section Summary: Myeloproliferative Neoplasms
Observational studies of HCT for myeloproliferative neoplasms 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. Primarily, 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.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in "Supplemental Information" if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
Current National Comprehensive Cancer Network clinical guidelines for myelodysplastic syndromes (v. 1.2023) make the following general recommendation about allogeneic hematopoietic cell transplanatation (allo-HCT):⁵³

“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 2.⁵³

Table 2. Guidelines for Allogeneic Hematopoietic Cell Transplantation 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 select patients who have clinically relevant thrombocytopenia or neutropenia , 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 or lower serum erythropoietin level with inadequate response to erythropoetin stimulating agents and/or lenalidomide, with poor probability of or inadequate response/intolerance to immunosuppressive therapy, and no response or intolerance to azacitidine/decitabine or immunosuppressive therapy Consider allo-HCT for patients who have symptomatic anemia with del(5q), with inadequate response/intolerance to lenalidomide and/or erythropoetin stimulating agents, 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. 3.2022) on the use of allo-HCT for the treatment of myeloproliferative neoplasms.53, 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 Allogeneic Hematopoietic Cell Transplantation for Myeloproliferative Neoplasms

Prognostic Category	Recommendations for Allo-HCT
Lower-risk myelofibrosis MIPSS-70 ≤ 3 MIPSS-70 + Version 2.0 ≤ 3 DIPSS-Plus ≤ 1 DIPSS ≤ 2 MYSEC-PM < 14	In symptomatic patients with disease progression despite treatment with ruxolitinib, peginterferon alfa-2a, and/or hydroxyurea (if cytoreduction would be symptomatically beneficial), consider allo-HCT immediately or bridging therapy 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
Higher-risk myelofibrosis MIPSS-70 ≥ 4 MIPSS-70+ Version 2.0 ≥ 4 DIPSS-Plus > 1 DIPSS > 2 MYSEC-PM ≥ 14	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 all patients
Disease progression to advanced-stage/AML	Induce remission with hypomethylating agents ± JAK inhibitors or intensive induction chemotherapy followed by allo-HCT

allo: allogeneic; AML: acute myeloid leukemia; DIPSS: Dynamic International Prognostic Scoring System; HCT: hematopoietic cell transplantation; MIPSS: Mutation-Enhanced International Prognostic Scoring System; MYSEC-PM: Myelofibrosis Secondary to PV [polycythemia vera] and ET [essential thrombocythemia]-Prognostic Model; JAK: Janus kinase.

American Society of Transplantation and Cellular Therapy
In 2020, the American Society of Transplantation and Cellular Therapy (formerly The American Society for Blood and Marrow Transplantation) published updated guidelines on indications for HCT and immune effector cell therapy based on the recommendations of a multiple-stakeholder task force.⁵⁴ Table 4 summarizes categorizations for allo-HCT in adults.

Table 4. Recommendations for the Use of Hematopoietic Cell Transplantation 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 and observational studies 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”)

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing 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
NCT01760655	Reduced Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients with High-Risk Hematologic Malignancies	72	Sep 2022 (last update posted Sep 2021)
NCT02757989	Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome Low Risk	79	Jun 2024
NCT05367583	Cohort Study Assessing the Treatment Strategy for High-Risk Myelodysplastic Syndromes in Patients Under 70 (COMYRE)	107	Oct 2024

NCT: national clinical trial.

References: 

1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. Jul 2022; 36(7): 1703-1719. PMID 35732831
2. Schanz J, Tüchler H, Solé F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. Mar 10 2012; 30(8): 820-9. PMID 22331955
3. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. Mar 01 2012; 366(9): 799-807. PMID 22375971
4. Cervantes F, Vannucchi AM, Kiladjian JJ, et al. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. Dec 12 2013; 122(25): 4047-53. PMID 24174625
5. Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. Mar 01 2012; 366(9): 787-98. PMID 22375970
6. Food and Drug Administration. FDA approves fedratinib for myelofibrosis. August 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis. Accessed November 20, 2022.
7. Kasner MT, Luger SM. Update on the therapy for myelodysplastic syndrome. Am J Hematol. Mar 2009; 84(3): 177-86. PMID 19195035
8. Kindwall-Keller T, Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant. Apr 2009; 43(8): 597-609. PMID 19252532
9. Oliansky DM, Antin JH, Bennett JM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant. Feb 2009; 15(2): 137-72. PMID 19167676
10. Koenecke C, Göhring G, de Wreede LC, et al. Impact of the revised International Prognostic Scoring System, cytogenetics and monosomal karyotype on outcome after allogeneic stem cell transplantation for myelodysplastic syndromes and secondary acute myeloid leukemia evolving from myelodysplastic syndromes: a retrospective multicenter study of the European Society of Blood and Marrow Transplantation. Haematologica. Mar 2015; 100(3): 400-8. PMID 25552702
11. Song Y, Yin Z, Ding J, et al. Reduced Intensity Conditioning Followed by Allogeneic Hematopoietic Stem Cell Transplantation Is a Good Choice for Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Meta-Analysis of Randomized Controlled Trials. Front Oncol. 2021; 11: 708727. PMID 34692485
12. Beelen DW, Trenschel R, Stelljes M, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. Jan 2020; 7(1): e28-e39. PMID 31606445
13. Scott BL, Pasquini MC, Logan BR, et al. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes. J Clin Oncol. Apr 10 2017; 35(11): 1154-1161. PMID 28380315
14. Kröger N, Iacobelli S, Franke GN, et al. Dose-Reduced Versus Standard Conditioning Followed by Allogeneic Stem-Cell Transplantation for Patients With Myelodysplastic Syndrome: A Prospective Randomized Phase III Study of the EBMT (RICMAC Trial). J Clin Oncol. Jul 01 2017; 35(19): 2157-2164. PMID 28463633
15. Scott BL, Pasquini MC, Fei M, et al. Myeloablative versus Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation in Acute Myelogenous Leukemia and Myelodysplastic Syndromes-Long-Term Follow-Up of the BMT CTN 0901 Clinical Trial. Transplant Cell Ther. Jun 2021; 27(6): 483.e1-483.e6. PMID 33775615
16. Akhtari M. When to treat myelodysplastic syndromes. Oncology (Williston Park). May 2011; 25(6): 480-6. PMID 21717901
17. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation?. Blood. Dec 02 2010; 116(23): 4762-70. PMID 20702782
18. Giralt SA, Horowitz M, Weisdorf D, et al. Review of stem-cell transplantation for myelodysplastic syndromes in older patients in the context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome emanating from the Centers for Medicare & Medicaid Services. J Clin Oncol. Feb 10 2011; 29(5): 566-72. PMID 21220586
19. Deeg HJ, Bartenstein M. Allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: current status. Arch Immunol Ther Exp (Warsz). Feb 2012; 60(1): 31-41. PMID 22143157
20. Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol. Jul 2012; 87(7): 692-701. PMID 22696212
21. Kröger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood. Jun 14 2012; 119(24): 5632-9. PMID 22504927
22. Barrett AJ, Savani BN. Allogeneic stem cell transplantation for myelodysplastic syndrome. Semin Hematol. Jan 2008; 45(1): 49-59. PMID 18179969
23. Blaise D, Vey N, Faucher C, et al. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. Apr 2007; 92(4): 533-41. PMID 17488664
24. Deschler B, de Witte T, Mertelsmann R, et al. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica. Nov 2006; 91(11): 1513-22. PMID 17082009
25. Huisman C, Meijer E, Petersen EJ, et al. Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biol Blood Marrow Transplant. Feb 2008; 14(2): 181-6. PMID 18215778
26. Kröger N, Bornhäuser M, Ehninger G, et al. Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol. Jun 2003; 82(6): 336-42. PMID 12728337
27. Laport GG, Sandmaier BM, Storer BE, et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant. Feb 2008; 14(2): 246-55. PMID 18215785
28. Martino R, Caballero MD, Pérez-Simón JA, et al. Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood. Sep 15 2002; 100(6): 2243-5. PMID 12200391
29. Mesa RA. Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. Hematology Am Soc Hematol Educ Program. 2007: 355-62. PMID 18024651
30. Tauro S, Craddock C, Peggs K, et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol. Dec 20 2005; 23(36): 9387-93. PMID 16314618
31. Valcárcel D, Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Curr Opin Oncol. Nov 2007; 19(6): 660-6. PMID 17906468
32. Valcárcel 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. Feb 01 2008; 26(4): 577-84. PMID 18086801
33. 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): 4357-68. PMID 25550955
34. Aoki K, Ishikawa T, Ishiyama K, et al. Allogeneic haematopoietic cell transplantation with reduced-intensity conditioning for elderly patients with advanced myelodysplastic syndromes: a nationwide study. Br J Haematol. Feb 2015; 168(3): 463-6. PMID 25228239
35. Kim H, Lee JH, Joo YD, et al. A randomized comparison of cyclophosphamide vs. reduced dose cyclophosphamide plus fludarabine for allogeneic hematopoietic cell transplantation in patients with aplastic anemia and hypoplastic myelodysplastic syndrome. Ann Hematol. Sep 2012; 91(9): 1459-69. PMID 22526363
36. Basquiera AL, Pizzi S, Correas AG, et al. Allogeneic hematopoietic stem cell transplantation in pediatric myelodysplastic syndromes: a multicenter experience from Argentina. Pediatr Blood Cancer. Jan 2015; 62(1): 153-7. PMID 25264233
37. Boehm A, Sperr WR, Kalhs P, et al. Long-term follow-up after allogeneic stem cell transplantation in patients with myelodysplastic syndromes or secondary acute myeloid leukemia: a single center experience. Wien Klin Wochenschr. Jan 2014; 126(1-2): 23-9. PMID 24249320
38. Damaj G, Mohty M, Robin M, et al. Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire. Biol Blood Marrow Transplant. Sep 2014; 20(9): 1349-55. PMID 24838178
39. Di Stasi A, Milton DR, Poon LM, et al. Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant. Dec 2014; 20(12): 1975-81. PMID 25263628
40. 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 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): 1582-90. PMID 25085359
41. 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): 1618-25. PMID 24953017
42. 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): 425-9. PMID 24316460
43. Basquiera AL, Rivas MM, Remaggi G, et al. Allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndrome: Experience of the Argentinean Group of Bone Marrow Transplantation (GATMO). Hematology. Apr 2016; 21(3): 162-9. PMID 26147089
44. 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. Oct 2015; 171(2): 239-246. PMID 26212516
45. Pohlen M, Groth C, Sauer T, et al. Outcome of allogeneic stem cell transplantation for AML and myelodysplastic syndrome in elderly patients (⩾60 years). Bone Marrow Transplant. Nov 2016; 51(11): 1441-1448. PMID 27295269
46. Heidenreich S, Ziagkos D, de Wreede LC, et al. Allogeneic Stem Cell Transplantation for Patients Age ≥ 70 Years with Myelodysplastic Syndrome: A Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party of the EBMT. Biol Blood Marrow Transplant. Jan 2017; 23(1): 44-52. PMID 27720995
47. Robin M, de Wreede LC, Padron E, et al. Role of allogeneic transplantation in chronic myelomonocytic leukemia: an international collaborative analysis. Blood. Sep 22 2022; 140(12): 1408-1418. PMID 35667047
48. Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol. Feb 10 2011; 29(5): 573-82. PMID 21220604
49. McLornan DP, Mead AJ, Jackson G, et al. Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol. May 2012; 157(4): 413-25. PMID 22463701
50. Bewersdorf JP, Sheth AH, Vetsa S, et al. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis-A Systematic Review and Meta-Analysis. Transplant Cell Ther. Oct 2021; 27(10): 873.e1-873.e13. PMID 34052505
51. Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. Mar 2010; 16(3): 358-67. PMID 19879949
52. Gupta V, Kröger N, Aschan J, et al. A retrospective comparison of conventional intensity conditioning and reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in myelofibrosis. Bone Marrow Transplant. Sep 2009; 44(5): 317-20. PMID 19234505
53. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms, Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf. Accessed November 21, 2022.
54. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247-1256. PMID 32165328
55. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for Stem Cell Transplantation Formerly 110.8.1 (110.23). 2016; https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=366 Accessed November 20, 2022.

Coding Request  

Codes	Number	Description
CPT	38204	Management of recipient hematopoietic cell donor search and cell acquisition
	38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
	38208	Transplant preparation of hematopoietic progenitor cells; 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
	38240	Bone marrow or blood-derived peripheral stem-cell transplantation: allogeneic
	86812-86822	Histocompatibility studies code range (eg, for allogeneic transplant)
ICD-9 Procedure	41.02	Allogeneic bone marrow transplant with purging
	41.03	Allogeneic bone marrow transplant without purging
	41.05	Allogeneic hematopoietic stem-cell transplant without purging
	41.08	Allogeneic hematopoietic stem-cell transplant with purging
	41.91	Aspiration of bone marrow from donor for transplant
	99.79	Other therapeutic apheresis (includes harvest of stem cells)
ICD-9 Diagnosis	238.72-238.79	Myelofibrosis or myelodysplastic syndrome, code range (myeloproliferative syndrome is included in 238.79)
HCPCS	S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, highdose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services)
ICD-10-CM (effective 10/01/15)	C92.10-C92.12	Chronic myeloid leukemia, BCR/ABL-positive code range
	C92.20-C92.22	Atypical chronic myeloid leukemia, BCR/ABL-negative code range
	C94.6	Myelodysplastic disease, not classified/Myeloproliferative disease, not classified
	D45	Polycythemia vera
	D46.0-D46.9	Myelodysplastic syndromes code range
	D47.0-D47.9	Other neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue code range
ICD-10-PCS (effective 10/01/15)		ICD-10-PCS codes are only used for inpatient services.
	30243G1, 30243X1, 30243Y1	Percutaneous transfusion, central vein, bone marrow or stem cells, nonautologous, code list
	07DQ0ZZ, 07DQ3ZZ, 07DR0ZZ, 07DR3ZZ, 07DS0ZZ, 07DS3ZZ	Surgical, lymphatic and hemic systems, extraction, bone marrow, code list
Type of Service	Therapy
Place of Service	Inpatient/Outpatient

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

07/01/2023	Annual review, no change to policy intent Updating guidelines with 2022 WHO classification schema. Also updating rational and references
07/07/2022	Annual review, no change to policy intent. Updating rationale and references.
07/15/2021	Annual review, no change to policy intent. Updating rationale and references.
07/23/2020	Annual review, no change to policy intent. Policy updated for clarity. Updating guidelines, rationale and references.
07/01/2019	Annual review, no change to policy intent. Updating background, rationale and references.
07/18/2018	Annual review, no change to policy intent. Updating description, background, rationale and references.
08/01/2017	Annual review, no change to policy intent. Updating title, background, description, rationale and references. Policy and guidelines being updated to utilize NCCN terminology, hematopoietic stem cell transplantation changed to hematopoietic cell transplantation.
07/19/2016	Annual review, no change to policy intent. Updating background, description, rationale and references. Adding benefit application and regulatory status.
08/03/2015	Annual review, no change to policy intent, however, for clarity, the following was added to the policy veribiage "Myeloablative allogeneic HSCT or reduced-intensity conditioning allogeneic-HSCT for myelodysplastic syndromes and myeloproliferative neoplasms that does not meet the criteria in the Policy Guidelines section is considered INVESTIGATIONAL.". Updated background, description, rationale and references. Added related policies and coding.
07/09/2014	Annual review. Updated description/background, rationale and references. No change to policy intent.