Pending Policies - Surgery


Hematopoietic Stem-Cell Transplantation for Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN)

Number:SUR703.032

Effective Date:05-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Allogeneic hematopoietic stem-cell transplantation (allo-HSCT; HSCT) may be considered medically necessary to treat myelodysplastic syndromes (MDS) in patients when meeting the following criteria (Refer to the Description section for MDS categorization and risk for progression to leukemia):

Increasing numbers of blasts, signaling a possible transformation to acute myeloid leukemia (AML). The following subtypes falling into this category are:

o Refractory anemia with excess blasts;

o Refractory anemia with excess blasts in transformation; or

o Chronic myelomonocytic leukemia (CMML);

Refractory anemia with or without ringed sideroblasts when chromosomal abnormalities are present or the disorder is associated with the development of significant cytopenias (e.g., neutrophils <500/mm3, platelets <20,000/mm3); OR

Any of the following indications:

o International Prognostic Scoring System (IPSS) of intermediate-2 or high risk (see NOTE 1 for the IPSS variables and outcome tables);

o Red blood cell transfusion dependence;

o Neutropenia;

o Thrombocytopenia;

o High-risk cytogenetics; or

o Increasing blast percentage.

NOTE 1:

IPSS: MDS 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: MDS Clinical Outcomes

Risk Group

Total Score

Median Survival, years

Time for 25% to Progress to acute myeloid leukemia, years

Low

0

5.7

9.4

Intermediate-1

0.5-1.0

3.5

3.3

Intermediate-2

1.5-2.0

1.2

1.12

High

2.5 or more

0.4

0.2

Scoring system: A score from zero to two is determined for each of the three variables; the three values are added obtain the IPSS score. Thus, a patient with 12 percent bone marrow blasts (score 1.5), complex chromosomal changes (poor karyotype score 1), neutrophil count of 1000/microL, and platelet count of 50,000/microL (two cytopenias, score 0.5) would have an IPSS score of 3 (i.e., high risk).

Karytope definitions:

Cytopenia definitions:

Good: Normal; -Y; del (5q); del (20q).

Poor: Complex (≥3 abnormalities); abnormal chromosome 7.

Intermediate: All others.

Red blood cells: Hemoglobin <10 g/dL (100 g/L).

White blood cells: Absolute neutrophil count <1800/microL.

Platelets: Platelet count <100,000/microL.

Allo-HSCT may be considered medically necessary to treat myeloproliferative neoplasms (MPN) for patients when meeting the following criteria (Refer to the Description section for MPN categorization and risk for progression to leukemia):

Progression to myelofibrosis;

Evolution toward acute leukemia;

Essential thrombocythemia (ET) with an associated thrombotic or hemorrhagic disorder; OR

Any of the following indications:

o Cytopenias;

o Transfusion dependence;

o Increasing blast percentage over 5%; or

o Age 60 to 65 years.

NOTE 2: All patients with intermediate-2 or high risk MDS, as calculated by the IPSS (NOTE 1), should be offered the opportunity to discuss allo-HSCT with a transplantation physician. The final decision on transplant eligibility should be made based on a risk-benefit assessment, and the needs and wishes of the patient.

Allo-HSCT is considered experimental, investigational and/or unproven for MDS or MPN that does not meet the criteria listed above.

Autologous HSCT (auto-HSCT) is considered experimental, investigational and/or unproven as a treatment of either MDS or MPN under any circumstance.

NOTE 3: See Medical Policy SUR703.002 Hematopoietic Stem-Cell Transplantation (HSCT) or Additional Infusion Following Preparative Regimens (General Donor and Recipient Information) for detailed, descriptive information on HSCT related services.

Description:

Hematopoietic Stem-Cell Transplantation (HSCT)

HSCT refers to a procedure in which hematopoietic stem-cells are infused to restore bone marrow function in patients who receive bone-marrow-toxic doses of cytotoxic drugs with or without whole body radiation therapy. Hematopoietic stem-cells may be obtained from the transplant recipient (autologous HSCT; auto-HSCT) or from a donor (allogeneic HSCT; allo-HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem-cells in it are antigenically “naive” and thus, are associated with a lower incidence of rejection or graft-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic stem-cells and the recipient is not an issue in auto-HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allo-HSCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the class I and class II loci on chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Background

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. Allo-HSCT has been proposed as a curative treatment option for patients with these disorders.

Myelodysplastic Syndromes (MDS)

Overview

MDS can occur as a primary (idiopathic) disease or can be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. 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 approximately 62% among individuals older than age 70 years. Patients either succumb to disease progression to 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

For the past 20 years, the French-American-British (FAB) system has been used to classify MDS into 5 subtypes as follows:

1) Refractory anemia (RA);

2) Refractory anemia with ringed sideroblasts (RARS);

3) Refractory anemia with excess blasts (RAEB);

4) Refractory anemia with excess blasts in transformation (RAEBT); and

5) Chronic myelomonocytic leukemia (CMML).

The FAB system has been supplanted by that of the World Health Organization (WHO), which records the number of lineages in which dysplasia is seen (unilineage versus multilineage), separates the 5q-syndrome, and reduces the threshold maximum blast percentage for the diagnosis of MDS from 30% to 20%. The myeloid neoplasms are categorized according to criteria developed by the WHO. They are risk-stratified according to the International Prognostic Scoring System (IPSS).

Refer to the following for the Myeloid Neoplasm Categorization:

The 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 (CML),

3.2 Polycythemia vera (PV),

3.3 Essential thrombocythemia (ET),

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 (CMML),

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 MPS).

The 2008 WHO Classification of Myelodysplastic Syndromes

1. Refractory anemia (RA),

2. RA with ring sideroblasts (RARS),

3. Refractory cytopenia with multilineage dysplasia (RCMD),

4. RCMD with ring sideroblasts,

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

6. del 5q syndrome,

7. Unclassified MDS.

The most commonly used prognostic scoring system for MDS is the 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. The IPSS underweights the clinical importance of severe, life-threatening neutropenia and thrombocytopenia in therapeutic decisions and does not account for the rate of change in critical parameters, such as peripheral blood counts or blast percentage. However, IPSS has been useful in comparative analysis of clinical trial results and its utility confirmed at many institutions. A second prognostic scoring system incorporates the WHO subgroup classification that accounts for blast percentage, cytogenetics, and severity of cytopenias as assessed by transfusion requirements. The WHO classification-based Prognostic Scoring System (WPSS) uses a 6-category system, which allows more precise prognostication of overall survival (OS) duration, as well as risk for progression to AML. This system, however, is not yet in widespread use in clinical trials.

Risk Stratification of MDS

Risk stratification for MDS is performed using the IPSS (Refer to Table 1 below). 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 built based on blast count, degree of cytopenia, and blast percentage. Risk scores were weighted relative to their statistical power. This system is widely used to divide patients into 2 categories: 1) low-risk and 2) high-risk groups (Refer to Table 2 below). The low-risk group includes low-risk and Int-1 IPSS groups; the goals in low-risk MDS patients are to improve quality of life and achieve transfusion independence. In the high-risk group - which includes intermediate-2 and high-risk IPSS groups--the goals are slowing the progression of disease 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 becomes worse by 1 category change.

Table 1: IPSS: MDS Prognostic Variables

Variable

0

0.5

1.0

1.5

2.0

Marrow blasts

<5

5-10

-

11-20

21-30

Karyotype

Good

Intermediate

Poor

-

-

Cytopenias

0/1

2/3

-

-

-

Table 2: IPSS: MDS Clinical Outcomes

Risk Group

Total Score

Median Survival, years

Time for 25% to Progress to acute myeloid leukemia, years

Low

0

5.7

9.4

Intermediate-1

0.5-1.0

3.5

3.3

Intermediate-2

1.5-2.0

1.2

1.12

High

2.5 or more

0.4

0.2

An updated 5-category IPSS has been proposed for prognosis in patients with primary MDS or secondary AML to account for chromosomal abnormalities frequently seen in MDS. (1) This system stratifies patients into 5 categories: very poor, poor, intermediate, good, and very good. There has been investigation into using the 5-category IPSS to better characterize risk in MDS.

MDS Treatment

Treatment of smoldering or non-progressing MDS has involved best supportive care, including red blood cell (RBC) and platelet transfusions and antibiotics. Active therapy was given only when MDS progressed to AML or resembled AML with severe cytopenias. Diverse arrays of therapies are now available to treat MDS, including hematopoietic growth factors (e.g., erythropoietin, darbepoetin, and granulocyte colony-stimulating factor), transcriptional-modifying therapy (e.g., U.S. Food and Drug Administration [FDA]-approved hypomethylating agents, non-approved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, antithymocyte globulin, cyclosporine A), low-dose chemotherapy (e.g., cytarabine), and allogeneic HSCT. Given the spectrum of treatments available, the goal of therapy must be decided upfront whether it is to improve anemia; thrombocytopenia; or neutropenia, eliminate the need for RBC transfusion, achieve complete remission, or cure the disease.

Chronic Myeloproliferative Neoplasms (MPN)

Overview

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

MPNs are characterized by the slow but relentless expansion of a clone of cells with the potential evolution into a blast crisis similar to AML. MPN share a common stem-cell-derived clonal heritage, with phenotypic diversity attributed to abnormal variations in signal transduction as the result of a spectrum of mutations that affect protein tyrosine kinases or related molecules. The unifying characteristic common to all MPN is effective clonal myeloproliferation resulting in peripheral granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, granulocytic dysplasia, or monocytosis.

MPN Classification

In 2008, the WHO classification scheme replaced the term chronic myeloproliferative disorder with the term MPN. MPNs are a subdivision of myeloid neoplasms that includes 4 classic disorders: chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocytopenia (ET), and primary myelofibrosis (PMF). The WHO classification also includes chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, mast cell disease, and MPN unclassifiable.

MPN Treatment

In indolent, non-progressing cases, therapeutic approaches are based on relief of symptoms. Supportive therapy may include prevention of thromboembolic events. Hydroxyurea may be used in cases of high-risk ET and PV, and intermediate- and high-risk PMF.

In November 2011, the FDA approved the orally administered selective Janus kinase 1 and 2 inhibitor ruxolitinib for the treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib has been associated with improved OS, spleen size, and symptoms of myelofibrosis when compared with placebo. (2) The COMFORT-II trial compared ruxolitinib to best available therapy in patients with intermediate- and high-risk myelofibrosis, and demonstrated improvements in spleen volume and OS. (3) In a randomized trial comparing ruxolitinib to best available therapy, including antineoplastic agents, most commonly hydroxyurea, glucocorticoids, and no therapy, for myelofibrosis, Harrison et al. demonstrated improvements in spleen size and quality of life, but not OS. (4)

NOTE 4: Refer to medical policy SUR703.041 for the coverage position of Hematopoietic Stem-Cell Transplant Chronic Myeloid Leukemia (CML).

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research (CBER), under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. (52) Hematopoietic stem-cells are included in these regulations.

Rationale:

This policy was originally created in 1990, moved to this policy in 2010. The policy has been updated with reviews of the MedLine database. The most recent literature review was performed through March 2018. While the coverage of this policy does not address myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) prior to hematopoietic stem-cell transplantation (HSCT), discussion of HSCT outcomes may be influenced by the type of preparative conditioning completed prior to the transplantation. The following is a summary of the key literature to date for preparative conditioning and allogeneic HSCT (allo-HSCT).

Literature reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are 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 a technology, 2 domains are examined: the relevance and the 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. The randomized controlled trial (RCT) 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.

Myelodysplastic Syndromes (MDS)

Myeloablative Preparative Conditioning HSCT for MDS

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

A 2009 review of HSCT for MDS evaluated the evidence for allo-HSCT 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-HSCT, 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 (CMML), 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 (BU) plus cyclophosphamide (CY) and CY plus total body irradiation (TBI), with cyclosporine A (CYA) 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. Overall survival (OS) rates ranged from 25% at 2 years to 52% at 4 years, with non-relapse 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 (ASBMT) evaluated the evidence related to HSCT in the therapy of MDS, with associated treatment recommendations. (7) Reviewers concluded that outcomes improved with early HSCT 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 HSCT 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 (ESBMT) 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.

RIC HSCT for MDS

Evidence from a number of largely heterogeneous, uncontrolled studies of RIC with allo-HSCT 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. (6, 9-19) These prospective and retrospective studies included cohorts of 16 to 215 patients similar to those in the MAC allo-HSCT studies. The most common conditioning regimens used were fludarabine-based, with CYA and tacrolimus used for GVHD prophylaxis. The reported incidence of grades II to IV GVHD was 9% to 63%, with 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).

Zeng et al. (2014) conducted a systematic review and meta-analysis comparing outcomes for patients who had MDS or AML treated with HSCT plus RIC or MAC. (20) 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 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 versus 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). (21) 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 (versus 50-59 years; 47% for RIC versus 47% for MAC; p=0.001), and less likely to receive an unrelated donor transplant (54% versus 70%; p=0.001). Three-year OS rates did not differ between groups (44.1% for RIC versus 42.7% for MAC; p=0.330). Although patients treated with RIC had a significantly lower 3-year cumulative incidence of NRM (25.6% versus 37.9%; p=0.002), they had significantly higher 3-year incidence of relapse than patients treated with MAC (29.9% versus 22.8%; p=0.029).

In 2012, Kim et al. published a phase 3 randomized trial (N=83 patients) comparing toxicity rates for 2 conditioning regimens (reduced CY, fludarabine, and antithymocyte globulin [ATG]; standard CY-ATG). (22) 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% versus 55%; p=0.003). Subgroup analyses showed no differences in the overall results based on differential diagnosis.

In general, these RIC trials showed a low rate of engraftment failure and low NRM, but a higher relapse rate than with MAC allo-HSCT. However, in the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with MAC and RIC regimens with allo-HSCT. Furthermore, no published randomized trials have compared RIC plus allo-HSCT with conventional chemotherapy alone, which has been the standard of care in patients with MDS and AML for whom MAC chemotherapy and allo-HSCT are contraindicated.

The ASBMT’s 2009 systematic review (previously described) assessed the evidence supporting RIC and MAC regimens and drew the following conclusions: “There are insufficient data to make a recommendation for an optimal conditioning regimen intensity. A range of dose intensities is currently being investigated, and the optimal approach will likely depend on disease and patient characteristics, such as age and comorbidities.” (7) Other reviews (2010-2012) have also drawn conclusions similar to those of the ASBMT. (23-28) Given the absence of curative therapies for these patients, however, RIC allo-HSCT may be considered a treatment for patients with MDS who could benefit from allo-HSCT but who for medical reasons would not tolerate a MAC regimen.

Outcomes after HSCT-Allo in Mixed MDS Populations

A number of studies, primarily retrospective, continue to report outcomes from allo-HSCT 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 3.

Table 3: Case Series of HSCT Treatment for MDS

Study

Patient Population

Type of HSCT

Summary of Outcomes

Basquiera et al. (2015) (29)

52 pediatric patients with MDS

• Allo-HSCT

• 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) (30)

60 adults with MDS or secondary AML

• Allo-HSCT

• MA conditioning in 36 patients; RIC conditioning in 24

10-y OS: 46%

Damaj et al.

(2014) (31)

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

RIC allo-HSCT

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

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

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

Di Stasi et al. (2014) (32)

227 patients with MDS or AML

• Allo-HSCT

Donor source:

o Matched-related donor, 38%

o Matched-unrelated donor, 48%

o Haploidentical, 14%

3-y PFS for patients in remission:

• 57% for matched-related donor

• 45% for matched-unrelated donor

• 41% for haploidentical (p=0.417)

Onida et al.

(2014) (33)

• 523 patients with MDS treated with HSCT

IPSS cytogenic risk group:

o Good risk: 53.5%

o Intermediate risk: 24.5%

o Poor risk: 22%

• Allo-HSCT

• RIC conditioning in 12%

5-y OS based on IPSS cytogenic risk group:

• Good risk: 48%

• Intermediate risk: 45%

• Poor risk: 30%

Oran et al.

(2014) (34)

• 256 patients with MDS

Pretreatment:

o No cytoreductive Chemotherapy: 30.5%

o Chemotherapy: 15.6%

o HMA: 47.7%

o Chemotherapy + HMA: 6.2%

• Allo-HSCT

• RIC conditioning in 36.7%

3-y EFS based on cytoreductive therapy:

• No cytoreductive chemotherapy: 44.2%

• Chemotherapy: 30.6%

• HMA: 34.2%

• Chemo + HMA: 32.8% (p=0.50)

Yoshimi et al. (2014) (35)

17 children with secondary MDS/AML after childhood aplastic anemia

Allo-HSCT

5-y OS and EFS: 41%

Basquiera et al. (2015) (36)

84 adults with MDS treated with HSCT

Cytogenic risk group:

o Standard risk: 65.5%

o Adverse risk: 12.6%

o Unknown: 21.9%

Allo-HSCT

RIC conditioning in 31.1%

Overall Survival:

Median: 23.5-month (95% CI, 1.7- to 45.3- month)

1-y: 61% (95% CI, 50% to 70%)

4/y: 38% (95% CI, 27% to 49%)

Progression Free Survival:

Median: 19.9-month (95% CI, 9- to 31-month)

1-y: 57% (95% CI, 46% to 67%)

4-y: 37% (95% CI, 26% to 48%)

Symeonidis et al.

(2015) (37)

513 adults with CMML treated with HSCT

Pretreatment:

o No prior DMT: 28%

o DMT: 72%

Allo-HSCT

RIC conditioning in 41.6%

Non-Relapse Mortality:

1-y: 31%

4-y: 41%

4-y RFS: 27%

4-y OS: 33%

Pohlen et al. (2016) (38)

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

Allo-HSCT

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) (39)

313 adults with MDS and secondary AML, age ≥ 70 Cytogenic risk group:

o Good: 51%

o Intermediate: 22%

o Poor/very poor: 11%

Allo-HSCT

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%

Table Key:

AML: acute myelogenous leukemia;

AZA: azacitidine;

BSC: best supportive care;

CMML: chronic myelomonocytic leukemia;

DFS: disease-free survival;

DMT: disease-modifying therapy;

HMA: hypomethylating agents;

HSCT: hematopoietic stem-cell transplantation;

IPSS: International Prognostic Scoring System;

MA: myeloablative;

MDS: myelodysplastic syndrome;

NRM: non-relapse mortality;

OS: overall survival;

PFS: progression-free survival;

RIC: reduced-intensity conditioning;

RFS: relapse-free survival;

y: year.

Section Summary: MDS

Primarily uncontrolled, observational studies of HSCT 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. Direct comparisons between RIC and MAC prior to HSCT with randomly selected populations are not available. Evidence from nonrandomized comparisons has suggested that RIC may be used in patients who are older and with more comorbidities without significantly worsening OS. RIC appears to be associated with lower rates of NRM but higher cancer relapse than MAC HSCT.

Myeloproliferative Neoplasms (MPN)

Data on therapy for MPN are sparse. (16, 40, 41) As outlined in this medical policy, with the exception of MAC chemotherapy and allo-HSCT, no therapy has yet proven to be curative or to prolong survival of patients with MPN.

The largest study identified evaluating allo-HSCT 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 (CIBMTR). (42) 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-HSCT 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. reported better DFS rates in a 2014 analysis of 233 patients with primary myelofibrosis who underwent RIC HSCT from 1997 to 2010. (43) 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-HSCT (n=190) or conventional therapies (n=248) at diagnosis. (44) In the HSCT group, 91 and 97 subjects received RIC and MAC, respectively. Patients at low-risk based on the Dynamic IPSS model treated with HSCT 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 HSCT 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 HSCT 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 HSCT for primary myelofibrosis.

The significant toxicity of MAC plus allo-HSCT in MPN has led to study of RIC regimens for these diseases. Data from direct, prospective comparison of outcomes of MAC and allo-HSCT versus RIC and allo-HSCT in MPN are not available, but single-arm series and nonrandomized comparative studies have reported outcomes after RIC allo-HSCT. One 2008 series included 27 patients (mean age, 59 years) with MPN who underwent allo-HSCT using an RIC regimen of low-dose (2 Gy) total body irradiation alone with or without fludarabine. (14) 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 (ET) and polycythemia vera (PV) myelofibrosis were included in a prospective, multicenter, phase 2 trial to determine the efficacy of a BU plus fludarabine-based RIC regimen followed by allo-HSCT from related (n=33) or unrelated (n=70) donors. (45) 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-HSCT in patients with myelofibrosis. (46) 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%] versus 43% [range, 35%-76%], respectively; p=0.11); there was a similar trend in the 3-year OS rate (68% [range, 45%-84%] versus 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-HSCT in this population.

In a 2012 retrospective study in 9 Nordic transplant centers, 92 patients with myelofibrosis in chronic phase underwent allo-HSCT. (47) 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 (DLI) 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 HSCT for MPN have reported a range of 3- to 5-year OS rates from 35% to 50% and suggested that HSCT 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.

Ongoing and Unpublished Clinical Trials: MDS and MPN

Some currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT00176930

Allogeneic Transplant for Hematological Malignancy

350

Dec 2017

NCT02581007

Reduced Intensity Conditioning and Transplantation of Partially HLA-Mismatched Peripheral Blood Stem-Cells for Patients with Hematologic Malignancies

30

Feb 2018

NCT00887068

Randomized Controlled Study of Post-transplant Azacitidine for Prevention of Acute Myelogenous Leukemia and Myelodysplastic Syndrome Relapse

246

Apr 2018

NCT00739141

Conditioning Regimen and the Transplantation of Unrelated Donor Umbilical Cord Blood in Patients with Hematologic Malignancies

80

Aug 2018

NCT01366612

PRO#1278: Fludarabine and Busulfan versus. Fludarabine, Busulfan and Total Body Irradiation

54

Aug 2018

NCT01471444a

A Randomized Study of Once Daily Fludarabine-Clofarabine Versus Fludarabine Alone Combined with Intravenous Busulfan Followed by Allogeneic Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

250

Nov 2017

NCT00822393

Clinical Phase III Trial Treosulfan-Based Conditioning Versus Reduced-Intensity Conditioning (RIC) Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with AML or MDS Considered Ineligible to Standard Conditioning Regimens

960

Mar 2019

NCT02626715

Reduced Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC) for HSCT in AML/MDS

16

Sep 2019

NCT01760655

Reduced Intensity Conditioning Before Donor Stem Cell Transplant in Treating Patients with High-Risk Hematologic Malignancies

50

Jan 2020

NCT02757989

Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Myelodysplastic Syndrome Low Risk

105

Apr 2021

Table Key:

NCT: national clinical trial;

a: Denotes industry-sponsored or cosponsored trial.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers: MDS and MPN

In 2009, the Blue Cross Blue Shield Association requested and received clinical input from various physician specialty societies and academic medical centers. There was consensus among reviewers that RIC allo-HSCT was of value in patients with MDS or MPN who would be medically unable to tolerate an MAC HSCT. The clinical input for allo-HSCT to treat MDS or MPN suggests that patients have the following indications:

MDS

IPSS intermediate-2 or high risk,

RBC transfusion dependence,

Neutropenia,

Thrombocytopenia,

High-risk cytogenetics,

Increasing blast percentage.

MPN

Cytopenias,

Transfusion dependence,

Increasing blast percentage over 5%,

Age 60-65 years.

Practice Guidelines and Position Statements: MDS and MPN

National Comprehensive Cancer Network (NCCN) Guidelines

Current NCCN clinical guidelines for MDS (v.2.2018) make the following general recommendation about allo-HSCT (48): “For patients who are transplant candidates, the first choice of a donor has remained an HLA [human leukocyte antigen]-matched sibling, although results with HLA-matched unrelated donors have improved to levels comparable to those obtained with HLA-matched siblings. With the increasing use of cord blood or HLA-haploidentical related donors, HSCT has become a viable option for many patients. High-dose conditioning is typically used for younger patients, whereas RIC [reduced-intensity conditioning] for HSCT is generally the strategy in older individuals.”

Specific NCCN guidelines related to HSCT for MDS are outlined in Table 5.

Table 5: NCCN Guidelines for Allo-HSCT for MDS

Prognostic Category

Recommendations for HSCT

IPSS low/intermediate-1 OR

IPSS-R very low, low, intermediate OR

WPSS very low, low, intermediate.

Consider allo-HSCT for selected IPSS-1 patients who have clinically relevant thrombocytopenia or neutropenia or increased marrow blasts, with disease progression after azacitidine/decitabine or immunosuppressive therapy for selected patients or clinical trial.

Consider allo-HSCT for selected IPSS-1 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 for selected patients or clinical trial.

IPSS intermediate-2, high OR

IPSS-R intermediate, high, very high OR

WPSS high, very high.

Recommend allo-HSCT if a high-intensity therapy candidate and transplant candidate and donor available.

Table Key:

HSCT: hematopoietic stem-cell transplantation;

IPSS: International Prognostic Scoring System;

NCCN: National Comprehensive Cancer Network;

WPSS: WHO Classification-based Prognostic Scoring System.

Table 6 summarizes the NCCN recommendations (v.2.2018) on the use of allo-HSCT for the treatment of MPN. (49) The guidelines note that selection of allo-HSCT should be based on age, performance status, major comorbid conditions, psychosocial status, patient preference, and availability of caregiver.

Table 6. Guidelines for Allo-HSCT for MPN

Prognostic Category

Recommendations for HSCT

Intermediate risk – 1 myelofibrosis:

IPSS=1

DIPSS-Plus=1

DIPSS=1 or 2

Consider observation or ruxolitinib if symptomatic or allo-HSCT.

Evaluation for allo-HSCT 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-HSCT immediately or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to transplant.

Evaluation for allo-HSCT 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-HSCT.

Table Key:

HSCT: hematopoietic stem-cell transplantation;

IPSS: International Prognostic Scoring System;

DIPSS: Dynamic International Prognostic Scoring System;

NCCN: National Comprehensive Cancer Network;

WPSS: WHO Classification-based Prognostic Scoring System;

AML: acute myeloid leukemia.

NOTE 5: Use of autologous HSCT was not addressed in the NCCN guidelines.

American Society for Blood and Marrow Transplantation (ASBMT)

In 2015, the ASBMT published guidelines on indications for HSCT, based on the recommendations of a multiple-stakeholder task force. (50) Table 7 summarizes categorizations for allo-HSCT.

Table 7. Recommendations for the Use of HSCT to Treat MDS, Myelofibrosis, and MPN

Indication

Recommendation

Myelodysplastic Syndromes

Low/intermediate-1 risk

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

Intermediate-2/high-risk

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

Myelofibrosis and Myeloproliferative Neoplasms

Primary, low risk

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

Primary, intermediate/high risk

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

Secondary

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

Hypereosinophilic syndromes, refractory

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

European Blood and Marrow Transplantation Group (EBMTG) and European Leukemia-Net (ELN)

In 2015, an expert panel convened by the EBMTG and the ELN published recommendations for the use of allo-HSCT in primary myelofibrosis and for pre- and post-transplant management and donor selection. (51) Recommendations related to the selecting of patients for allo-HSCT include:

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

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

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

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

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

Summary of Evidence: Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN)

For individuals who have MDS or MPN who receive myeloablative conditioning allogeneic hematopoietic stem-cell transplantation (allo-HSCT), the evidence includes case series, which are often heterogeneous in terms of diseases included. Relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. Primarily uncontrolled, observational studies of HSCT 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 HSCT for MPN, data are more limited. At least 1 comparative study of HSCT for myelofibrosis has demonstrated improved survival using HSCT compared with standard therapy. At present, HSCT 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 receive reduced-intensity conditioning (RIC) allo-HSCT, the evidence includes primarily retrospective observational series. Relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. Direct, prospective comparisons of outcomes after HSCT with either myeloablative conditioning or RIC in either MDS or MPN are not available. Evidence from retrospective, nonrandomized comparisons has suggested that RIC may be used in patients who are older and have more comorbidities without significantly worsening OS. RIC appears to be associated with lower rates of non-relapse mortality but higher cancer relapse than myeloablative HSCT. At present, HSCT 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.

A search of peer reviewed literature identified no additional published studies, clinical trials or practice guidelines for the use of autologous HSCT to treat MDS and MPN that would prompt reconsideration of the experimental, investigational and/or unproven coverage statement, which remains unchanged.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage versus. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38222, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86828, 86829, 86830, 86831, 86832, 86833, 86834, 86835, 86849, 86950, 86985, 88240, 88241

HCPCS Codes

S2140, S2142, S2150

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

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37. 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. PMID 26212516

38. 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):1441-8. PMID 27295269

39. 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

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Policy History:

Date Reason
5/15/2018 Document updated with literature review. Coverage unchanged. References 38-39 and 49-50, 52 added.
6/1/2017 Reviewed. No changes.
10/15/2016 Document updated with literature review. The following was added to the allogeneic hematopoietic stem-cell transplantation medically necessary criteria for increasing number of blasts: “Refractory anemia with excess blasts; Refractory anemia with excess blasts in transformation; or Chronic myelomonocytic leukemia (CMML). The following NOTEs and Tables were added to coverage: 1) International Prognostic Scoring System (IPSS) Variables and Outcome information for myelodysplastic syndromes (MDS); 2) Karotype definitions; and 3) Cytopenia definitions.
7/15/2015 Document updated with literature review. The following was added to the medically necessary criteria for myelodysplastic syndromes: “In patients with any of the following indications: International Prognostic Scoring System of intermediate-2 or high risk; Red blood cell transfusion dependence, neutropenia; Neutropenia; Thrombocytopenia; High-risk cytogenetics; or Increasing blast percentage.” The following was added to the medically necessary criteria for myeloproliferative neoplasms: “When there are any of the following indications: Cytopenias; Transfusion dependence; Increasing blast percentage over 5%; or Age 30 to 65 years.” The following coverage statement was added: “Allogeneic HSCT is considered experimental, investigational and/or unproven for myelodysplastic syndrome or for myeloproliferative neoplasm that does not meet the criteria listed above.” Title changed from Stem-Cell Transplant for Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN).
6/1/2014 Document updated with literature review. The following was changed: 1) Expanded coverage to consider a) donor leukocyte infusion (DLI) and hematopoietic progenitor cell (HPC) boost as medically necessary for myelodysplastic syndromes and myeloproliferative neoplasms that has relapsed, to prevent relapse in the setting of a high-risk relapse, or to convert a patient from mixed to full donor chimerism; b) DLI and HPC boost are considered experimental, investigational and/or unproven following an AlloSCS treatment for MDS/MPN that was originally considered experimental, investigational and/or unproven for the treatment of MDS/MPN OR as a treatment prior to AlloSCS; and, 2) Expanded coverage to consider a) short tandem repeat (STR) markers medically necessary when used in pre- or post-stem-cell support testing of the donor and recipient DNA profiles as a way to assess the status of donor cell engraftment following AlloSCS for MDS/MPN; b) all other uses of STR markers MDS and MPN experimental, investigational and/or unproven, if not listed in the coverage section . Description and Rationale were significantly changed, including the 2008 World Health Organization Classification and International Prognostic Scoring System. Title changed from Stem-Cell Transplant for Myelodysplastic Syndromes and Myeloproliferative Diseases.
4/1/2009 New medical document originating from: SUR703.017, Peripheral/Bone Marrow Stem-Cell Transplantation (PSCT/BMT) for Non-Malignancies; SUR703.018, Peripheral/Bone Marrow Stem-Cell Transplantation (PSCT/BMT) for Malignancies; SUR703.022, Cord Blood as a Source of Stem-Cells (CBSC); SUR703.023, Donor Leukocyte Infusion (DLI); and SUR703.024, Tandem/Triple High-Dose Chemoradiotherapy with Stem-Cell Support for Malignancies. Stem-Cell transplant continues to be medically necessary when stated criteria are met. [NOTE: A link to the medical policies with the following titles can be found at the end of the medical policy SUR703.002, Stem-Cell Reinfusion or Transplantation Following Chemotherapy (General Donor and Recipient Information): Peripheral/Bone Marrow Stem-Cell Transplantation (PSCT/BMT) for Non-Malignancies; Peripheral/Bone Marrow Stem-Cell Transplantation (PSCT/BMT) for Malignancies; Cord Blood as a Source of Stem-Cells; Donor Leukocyte Infusion (DLI); and Tandem/Triple High-Dose Chemoradiotherapy with Stem-Cell Support for Malignancies.

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