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Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Policy Number: MP-360

 

Latest Review Date: March 2020

Category:  Surgery                                                                 

Policy Grade:  A

POLICY:

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

  • Myelodysplastic syndromes (see Policy Guidelines); or

  • Myeloproliferative neoplasms (see Policy Guidelines).

Reduced-intensity conditioning allo-HCT may be considered medically necessary as a risk-adapted treatment of

  • myelodysplastic syndromes or

  • 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 do not meet the criteria in the Policy Guidelines section is considered investigational.

Effective for dates of service on or after March 5, 2020:

For patients with Systemic Mastocytosis (SM):

Allogeneic HCT, myeloablative or reduced-intensity conditioning, may be considered medically necessary:

  • As salvage therapy for patients with advanced SM (e.g., Aggressive systemic mastocytosis (ASM), Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), or Mast cell leukemia) that does not respond adequately to initial medical therapy.

  • For SM patients with an associated hematologic neoplasm (AHN) or mast cell leukemia (MCL)-AHN, in which the SM component manifests a significant response, but the AHN continues to progress characterized by the worsening of clinically significant cytopenias and/or elevated blood counts with dysplasia, monocytosis, eosinophilia, and/or increased peripheral blood and/or bone marrow blasts.

  ●     High-risk molecular and/or karyotypic features  (e.g., monosomy 7, complex karyotype) and/or one or more high-risk non-KIT mutations (e.g., SRSF2, ASXL1, and/or RUNX1)  in a patient whose best response to midostaurin is stable disease or a partial response of either the SM or AHN component.

 

Allogeneic HCT is considered not medically necessary and investigational to treat patients with Indolent systemic mastocytosis (ISM) and smoldering systemic mastocytosis (SSM).

POLICY GUIDELINES:

Myeloid Neoplasms

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

2008 WHO Classification Scheme for Myeloid Neoplasms

  1. Acute myeloid leukemia

  2. Myelodysplastic syndromes (MDS)

  3. Myeloproliferative neoplasms (MPN)

3.1 Chronic myelogenous leukemia

3.2 Polycythemia vera

3.3 Essential thrombocythemia

3.4 Primary myelofibrosis

3.5 Chronic neutrophilic leukemia

3.6 Chronic eosinophilic leukemia, not otherwise categorized

3.7 Hypereosinophilic leukemia

3.8 Mast cell disease

3.9 MPNs, unclassifiable

     4. MDS/MPN

4.1 Chronic myelomonocytic leukemia

4.2 Juvenile myelomonocytic leukemia

4.3 Atypical chronic myeloid leukemia

4.4 MDS/MPN, unclassifiable

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

          PDGFRB, or FGFR1

            5.1 Myeloid neoplasms associate with PDGFRA rearrangement

5.2 Myeloid neoplasms associate with PDGFRB rearrangement

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

2008 WHO Classification of Myelodysplastic Syndromes

  1. Refractory anemia (RA)

  2. RA with ring sideroblasts (RARS)

  3. Refractory cytopenia with multilineage dysplasia (RCMD)

  4. RCMD with ring sideroblasts

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

  6. del 5q syndrome

  7. unclassified MDS

2016 WHO Classification of mastocytosis

1. Cutaneous mastocytosis (CM)

2. Systemic mastocytosis

a. Indolent systemic mastocytosis (ISM)*

b. Smoldering systemic mastocytosis (SSM)*

c. Systemic mastocytosis with an associated hematological neoplasm (SM-AHN)†

d. Aggressive systemic mastocytosis (ASM)*

e. Mast cell leukemia (MCL)

3. Mast cell sarcoma (MCS)

Risk Stratification of MDS

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

Table PG1. IPSS: Myelodysplastic Syndrome Prognostic Variables

Variable

0

0.5

1.0

1.5

2.0

Marrow blasts, %

<5

5-10

‒

11-20

21-30

Karyotype

Good

Intermediate

Poor

Cytopenias

0/1

2/3

‒

‒

‒

IPSS: International Prognostic Scoring System.

Table PG2. IPSS: Myelodysplastic Syndrome Clinical Outcomes

Risk Group

Total Score

Median Survival, y

Time for 25% of patients

to Progress to AML

Low

0

5.7

9.4 years

Intermediate-1

0.5-1.0

3.5

3.3 years

Intermediate-2

1.5-2.0

1.2

1.12 years

High

³2.5

0.4

0.2 years

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

An updated 5-category IPSS has been proposed for prognosis in patients with primary MDS or secondary AML to account for chromosomal abnormalities frequently seen in MDS (Schanz et al, 2012). This system stratifies patients into 5 categories: very poor, poor, intermediate, good, and very good. There has also been an investigation into using the 5-category IPSS to better characterize risk in MDS.

Given the long natural history of MDS, allogeneic hematopoietic cell transplantation (allo-HCT) is typically considered in patients with increasing numbers of blasts, signaling a possible transformation to AML. Subtypes falling into this category include refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.

Patients with refractory anemia with or without ringed sideroblasts may be considered candidates for allo-HCT when chromosomal abnormalities are present, or when the disorder is associated with the development of significant cytopenias (e.g., neutrophils <500/mm3, platelets <20,000/mm3).

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

Some patients for whom a conventional myeloablative allo-HCT could be curative may be candidates for reduced-intensity conditioning allo-HCT. They include patients whose age (typically >60 years) or comorbidities (eg, liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude the use of a standard myeloablative conditioning regimen. The ideal allogeneic donors are human leukocyte antigen (HLA)-identical siblings, matched at the HLA-A, -B, and -DR loci (6/6). Related donors mismatched at 1 locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, who usually share only 3 of the 6 major histocompatibility antigens. Most patients will have such a donor; however, the risk of graft-versus-host disease and overall morbidity of the procedure may be severe, and experience with these donors is not as graft-versus-host disease extensive as that with matched donors.

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

MDS

  • Older age

  • IPSS intermediate-2 or high risk

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

  • Red blood cell transfusion dependence

  • Neutropenia

  • Thrombocytopenia

  • High-risk cytogenetics

  • Increasing blast percentage

MPN

  • Cytopenias

  • Transfusion dependence

  • Increasing blast percentage over 5%

  • Age 60 to 65 years.

DESCRIPTION OF PROCEDURE OR SERVICE:

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

Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) can occur as a primary (idiopathic) disease, or be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. Chromosomal abnormalities are seen in 40%–60% of patients, frequently involving deletions of chromosome 5 or 7, or an extra chromosome as in trisomy 8. The vast majority of MDS diagnoses occur in individuals over the age of 55–60 years, with an age-adjusted incidence of about 62% among individuals over age 70 years. Patients either succumb to disease progression to AML or to complications of pancytopenia. Patients with higher blast counts or complex cytogenetic abnormalities have a greater likelihood of progressing to AML than do other patients.

Myelodysplastic Classification and Prognosis

The French-American-British (FAB) system was used to classify MDS into 5 subtypes as follows: 1) refractory anemia (RA); 2) refractory anemia with ringed sideroblasts (RARS); 3) refractory anemia with excess blasts (RAEB); 4) refractory anemia with excess blasts in transformation (RAEBT); and, 5) chronic myelomonocytic leukemia (CMML). The FAB system has been supplanted by that of the World Health Organization (WHO), which records the number of lineages in which dysplasia is seen (unilineage versus multilineage), separates the 5q- syndrome, and reduces the threshold maximum blast percentage for the diagnosis of MDS from 30% to 20%.

The most commonly used prognostic scoring system for MDS is the International Prognostic Scoring System (IPSS), which groups patients into one of four prognostic categories based on the number of cytopenias, cytogenetic profile and the percentage blasts in the bone marrow. This system underweights the clinical importance of severe, life-threatening neutropenia and thrombocytopenia in therapeutic decisions and does not account for the rate of change in critical parameters, such as peripheral blood counts or blast percentage. However, the IPSS has been useful in comparative analysis of clinical trial results and its utility confirmed at many institutions. An updated 5-category IPSS has been proposed for prognosis in patients with primary MDS or secondary AML to account for chromosomal abnormalities frequently seen in MDS. This system stratifies patients into 5 categories: very poor, poor, intermediate, good, and very good. There has been investigation into using the 5-category IPSS to better characterize risk in MDS. A second prognostic scoring system incorporates the WHO subgroup classification that accounts for blast percentage, cytogenetics, and severity of cytopenias as assessed by transfusion requirements. The WPSS uses a 6-category system which allows more precise prognostication of overall survival duration as well as risk for progression to AML. This system, however, is not yet in widespread use in clinical trials.

Myelodysplastic Treatment

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

Allogeneic HCT is the only approach with curative potential, but its use is governed by patient age, performance status, medical comorbidities, the patient’s risk preference, and severity of MDS at presentation.

Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative neoplasms (MPNs) are clonal bone marrow stem cell disorders which, as a group, about 8,400 MPNs are diagnosed annually in the U.S.  Like MDS, MPNs occur primarily in older individuals, with about 67% reported in patients aged 60 years and older.

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

Myeloproliferative Neoplasm Classification

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

Myeloproliferative Neoplasm Treatment

In indolent, non-progressing cases, therapeutic approaches are based on relief of symptoms. Supportive therapy may include prevention of thromboembolic events. Hydroxyurea may be used in cases of high-risk essential thrombocytosis and polycythemia vera and intermediate- and high-risk primary myelofibrosis.

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

Myeloablative allogeneic HCT has been considered the only potentially curative therapy, but because most patients are of advanced age with attendant comorbidities, its use is limited to those who can tolerate the often severe treatment-related adverse effects of this procedure.  However, the use RIC of conditioning regimens for allogeneic HCT has extended the potential benefits of this procedure to selected individuals with these disorders.

Myeloid Neoplasms

Systemic Mastocytosis

In 2016, Systemic Mastocytosis was classified by the World Health Organization (WHO) in its own category under myeloid neoplasms after previously being classified as a myeloproliferative neoplasm. Mastocytosis has been defined in medical literature as an abnormal accumulation of mast cells in one or more organ systems. The three major categories of mastocytosis are: cutaneous mastocytosis (CM), systemic mastocytosis (SM) and mast cell sarcoma these diseases occur in both children and adults. This medical policy will specifically discuss advanced categories of systemic mastocytosis: Aggressive systemic mastocytosis (ASM), Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and Mast cell leukemia).

Treatment

In indolent or smoldering cases of systemic mastocytosis, therapeutic approaches are based on relief of symptoms. Specifically, antihistamines, antileukotriene drugs, glucocorticoids, omalizumab, and cytoreductive agents. 

Myeloablative allogeneic HCT has been considered the only potentially curative therapy for advanced systemic mastocytosis. However, the use RIC of conditioning regimens for allogeneic HCT has extended the potential benefits of this procedure to selected individuals with this disorder.

Hematopoietic Cell Transplantation

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

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

Conventional Preparative Conditioning for HCT

The conventional (“classical”) practice of allogeneic HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect in this procedure is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. While the slower GVM effect is considered to be the potentially curative component, it may be overwhelmed by extant disease without the use of pretransplant conditioning. However, intense conditioning regimens are limited to patients who are sufficiently fit medically to tolerate substantial adverse effects that include pre-engraftment opportunistic infections secondary to loss of endogenous bone marrow function and organ damage and failure caused by the cytotoxic drugs. Furthermore, in any allogeneic HCT, immune suppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

Reduced-Intensity Conditioning for Allogeneic HCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden, but also to minimize as much as possible associated treatment-related morbidity and non-relapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allogeneic HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For the purposes of this Policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative (conventional) regimens.

KEY POINTS:

This policy was originally created in December 1999 and updated periodically with literature reviews, most recently through November 24, 2019. Following is the summary of the key literature to date.

Summary of Evidence

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

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

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

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

“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 3.

Table 3. Guidelines for Allo-HCT for Myelodysplastic Syndromes

Prognostic Category

Recommendations for Allo-HCT

IPSS low/intermediate-1 OR

IPSS-R very low, low, intermediate OR

WPSS very low, low, intermediate

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

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

IPSS intermediate-2, high OR

IPSS-R intermediate, high, very high OR

WPSS high, very high

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

allo: allogeneic; HCT: hematopoietic cell transplantation; IPSS: International Prognostic Scoring System; WPSS: WHO Classification-based Prognostic Scoring System.

Table 4 summarizes the National Comprehensive Cancer Network recommendations (v.3.2019) on the use of allo-HCT for the treatment of myeloproliferative neoplasms. 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 4. Guidelines for Allo-HCT for Myeloproliferative Neoplasms

Prognostic Category

Recommendations for Allo-HCT

Intermediate risk - 1 myelofibrosis

IPSS=1

DIPSS-Plus=1

DIPSS=1 or 2

·Consider observation or ruxolitinib if symptomatic or allo-HCT.

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

Intermediate risk - 2 myelofibrosis

IPSS=2

DIPSS-Plus=2 or 3

DIPSS=3 or 4

High-risk myelofibrosis

IPSS>3

DIPSS-Plus=4 to 6

DIPSS=5 or 6

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

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

Disease progression to advanced-stage/AML

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

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

American Society of Transplantation and Cellular Therapy

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

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

Indication

Recommendation

Myelodysplastic syndromes

Low/intermediate-1 risk

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

Intermediate-2/high-risk

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

Myelofibrosis and myeloproliferative neoplasms

Primary, low-risk

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

Primary, intermediate/high-risk

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

Secondary

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

Hypereosinophilic syndromes, refractory

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

HCT: hematopoietic cell transplantation.

U.S. Preventive Services Task Force Recommendations

Not applicable

KEY WORDS:

Allogeneic Cell Support, Bone Marrow Transplantation, Myeloablation, Myeloproliferative Disorders, Reduced-Intensity Conditioning, Myeloproliferative Syndrome, Myelodysplastic Syndrome, High-Dose Chemotherapy, Myelofibrosis, Cell Transplant, Myelodysplastic Diseases, Hematopoietic Cell Transplant (HCT), Myeloproliferative Neoplasm (MPN), Systemic Mastocytosis, Aggressive systemic mastocytosis (ASM), Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and Mast cell leukemia (MCL), Mast cell sarcoma (MCS)

APPROVED BY GOVERNING BODIES:

Not applicable

BENEFIT APPLICATION:

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

ITS: Home Policy provisions apply

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

CURRENT CODING:

CPT Codes:

38204

Management of recipient hematopoietic cell donor search and cell acquisition

38205

Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic

38208

;thawing of previously frozen harvest, without washing,

per donor

38209

; thawing of previously frozen harvest with washing per donor

38210

; specific cell depletion with harvest, T cell depletion

38211

; tumor cell depletion

38212

; red blood cell removal

38213

; platelet depletion

38214

; plasma (volume) depletion

38215

; cell concentration in plasma, mononuclear, or buffy coat layer

38230

Bone marrow harvesting for transplantation: allogeneic

38232

Bone marrow harvesting for transplantation: autologous

38240

Bone marrow or blood-derived peripheral stem-cell transplantation: allogeneic

86812-86821

Histocompatibility studies code range (e.g., for allogeneic transplant) (82822 deleted effective 12/31/17)

HCPCS:

S2150

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

REFERENCES:

  1. Abelsson J, Merup M, Birgegard G et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012; 47(3):380-386.

  2. Akhtari M. When to treat myelodysplastic syndromes. Oncology (Williston Park) 2011; 25(6):480-486.

  3. 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):463-466.

  4. Arber D, Orazi A, Hasserjan R, Thiele J, Borowitz M, Beau M, Bloomfield C, Cazzola M, Vardiman J. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391-2405.

  5. Ballen KK, Shrestha S, Sobocinski KA et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010; 16(3):358-367.

  6. Barrett AJ and Savani BN. Allogeneic stem cell transplantation for myelodysplastic syndrome.  Semin Hematol 2008; 45(1):49-59.

  7. 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):153-157

  8. 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. Jul 6 2015.

  9. Blaise D, Vey N, Faucher C, et al. Current status of reduced intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2007; 92(4):533-541.

  10. 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):23-29.

  11. 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):4047-4053.

  12. 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 Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Biol Blood Marrow Transplant. Sep 2014; 20(9):1349-1355.

  13. Deeg HJ, Bartenstein M. Allogeneic hematopoietic cell transplantation for myelodysplastic syndrome: current status. Arch Immunol Ther Exp (Warsz). Feb 2012; 60(1):31-41.

  14. Deeg HJ, Sandmaier BM. Who is fit for allogeneic transplantation? Blood 2010; 116(23):4762-4770.

  15. 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 2006; 91(11):1513-1522.

  16. Di Stasi A, Milton DR, Poon LM, et al. Similar transplant outcomes for AML/MDS patients with haploidentical versus 10/10 HLA matched unrelated and related donors. Biol Blood Marrow Transplant. Dec 2014; 20(12):1975-1981.

  17. Garcia-Manero G. Myelodysplastic syndromes: 2012 update on diagnosis, risk-stratification, and management. Am J Hematol. Jul 2012; 87(7):692-701.

  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 and Medicaid Services. J Clin Oncol 2011; 29(5):566-572.

  19.   Gotlib J, Larson, R, Rosmarin, A, & Feldweg, A (2020). Advanced systemic mastocytosis: Management and prognosis, UpToDate. Available from   

  www.uptodate.com/contents/advanced-systemic-mastocytosis-management-and- prognosis search=systemic%20mastocytosis%20treatment&source=search_result&selectedtitle=1~102&usage_type=default&display_rank=1

  1. Gupta V, Kroger 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 2009; 44(5):317-320.

  2. Gupta V, Malone AK, Hari PN, et al. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. Jan 2014; 20(1):89-97.

  3. Harrison C, Kiladjian J-J, Al-Ali HK, et al. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. N Engl J Med. 2012; 366(9):787-798.

  4. 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.

  5. 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 2008; 14(2):181-186.

  6. Kasner MT and Luger SM. Update on therapy for myelodysplastic syndrome. Am J Hematol 2008; 84(3):177-186.

  7. 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 2012; 91(9):1459- 1469.

  8. Kindwall-Keller T and Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant 2009; 43(8):597-609.

  9. Koenecke C, Gohring 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):400-408.

  10. Kroger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood. Jun 14 2012; 119(24):5632-5639.

  11. Kroger N, Bornhauser M, Ehninger G, et al. Allogeneic stem cell transplantation after a fludarabine/busulfan based reduced intensity conditioning inpatients with myelodysplastic syndromes or secondary acute myeloid leukemia. Ann Hematol 2003; 82(6):336-342.

  12. Kroger NM, Deeg JH, Olavarria E, et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia. Nov 2015; 29(11):2126-2133.

  13. Kroger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. May 21 2015; 125(21):3347-3350; quiz 3364.

  14. Kroger N, Holler E, Kobbe G et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114(26):5264-5270.

  15. 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 2008; 14(2):246-255.

  16. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-1869.

  17. Martino R, Caballero R, Simon 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 2002; 100(6):2243-2245.

  18. McLornan DP, Mead AJ, Jackson G, et al. Allogeneic stem cell transplantation for myelofibrosis in 2012. Br J Haematol. May 2012; 157(4):413-425.

  19. Mesa RA. Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. Hematology (Am Soc Hematol Educ Program) 2007; 2007:355-362.

  20. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology, v.1.2009. Myelodysplastic Syndromes. www.nccn.org/professionals/physician_gls/PDF/mds.pdf.

  21. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology 2016. Myelodysplastic Syndromes v1.2016. www.nccn.org/professionals/physician_gls/pdf/mds.pdf.

  22. National Comprehensive Cancer Network. Myelodysplastic Syndromes v1.2015. 2014; www.nccn.org/professionals/physician_gls/pdf/mds.pdf.

  23. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms, Version 2.2018. www.nccn.org/professionals/physician_gls/pdf/mpn.pdf.

  24. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes, Version 1.2018. www.nccn.org/professionals/physician_gls/pdf/mds.pdf.

  25. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myelodysplastic Syndromes, Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf. Accessed December 19, 2018.

  26. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms, Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf. Accessed December 19, 2018.

  27. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Myeloproliferative Neoplasms, Version 2.2019. www.nccn.org/professionals/physician_gls/pdf/mastocytosis.pdf. Accessed February 27, 2020.

  28. 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 2009; 15(2):137-172.

  29. 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):1582-1590.

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

  31. 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.

  32. Schanz J, Tuchler H, Sole 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):820-829.

  33. 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.

  34. 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 2005; 23(36):9387-9393.

  35. Tefferi A, Vainchenker W. Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol 2011; 29(5):573-582.

  36. The Mastocytosis Society (TMS): Mast Cell Diseases. www.tmsforacure.org/overview/. Accessed March, 4, 2020.

  37. Valcarcel D and Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Current Opin Oncol 2007; 19(6):660-666.

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

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

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

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

POLICY HISTORY:

Medical Policy Panel, June 2009

Medical Policy Group, June 2009 (2)

Medical Policy Administration Committee, July 2009

Available for comment July 1-August 14, 2009

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

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

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

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

Medical Policy Panel, November 2013

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

Medical Policy Panel, November 2014

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

Medical Policy Panel, January 2016

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

Medical Policy Panel, January 2017

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

Medical Policy Panel, January 2018

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

Medical Policy Panel, January 2019

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

Medical Policy Panel, January 2020

Medical Policy Group, March 2020 (3): 2020 Updates to Description, Key Points, Practice Guidelines and Position Statements, References and Key Words: added: Systemic Mastocytosis, Aggressive systemic mastocytosis (ASM), Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), Mast cell sarcoma (MCS) and Mast cell leukemia (MCL). Added Systemic Mastocytosis as a covered diagnosis for allogeneic stem cell transplant with critieria for coverage. Available for comment: March 5, 2020 through April 18, 2020. No other changes to policy statement or intent.

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

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

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

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

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

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

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

3. The technology must improve the net health outcome;

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

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

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

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

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

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

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