Coverage Policy Manual
Policy #: 2000013
Category: Medicine
Initiated: November 1994
Last Review: February 2024
  HDC & Allogeneic Stem &/or Progenitor Cell Support-Myelodysplastic Disease

Description:
High dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose. In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable. HDC results in marrow ablation and thus HDC is accompanied by a reinfusion of stem cells in order to repopulate the bone marrow.
 
Sources of Stem Cells:
 
  • Allogeneic stem cells can be harvested from bone marrow or peripheral circulation of matched, often unrelated, donors. These cells are not contaminated by tumor and offer the possibility of a beneficial graft vs. tumor effect.
  • Blood harvested from the umbilical cord and placenta shortly after delivery of neonates contain stem cells that are antigenically "naive" and thus are associated with a lower incidence of rejection or graft vs. host disease.
 
Allogeneic stem cell support refers to stem cells collected from a genetically dissimilar source.
 
Myelodysplastic syndrome (MDS) refers to a heterogeneous group of clonal hematopoietic disorders with the potential to transform into acute myelocytic leukemia (AML). Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as a curative treatment option for patients with these disorders.
 
Myelodysplastic Syndromes
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 40-60% of patients, frequently involving deletions of chromosome five or seven or as an extra chromosome in trisomy 8. Most MDS diagnoses occur in individuals older than age 55 to 60 years, with an age-adjusted incidence of 62% among individuals older than age 70 years. Patients succumb either to disease progression to 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 Syndrome Classification and Prognosis
The French-American-British system was previously used to classify MDS into 5 subtypes: (1) refractory anemia; (2) refractory anemia with ringed sideroblasts; (3) refractory anemia with excess blasts; (4) refractory anemia with excess blasts in transformation; and (5) chronic myelomonocytic leukemia. The French-American-British system was supplanted by that of the World Health Organization (WHO), which differentiates between MDS defined by genetic abnormalities or by morphologic features (in the form of dysplastic cell lineages), and reduces the threshold maximum blast percentage for the diagnosis of MDS from 30% to 20% (Khoury, 2022).
 
The most commonly used prognostic scoring system for MDS is the International Prognostic Scoring System (IPSS), which groups patients into 1 of 4 prognostic categories based on the number of cytopenias, cytogenetic profile, and the percentage of blasts in the bone marrow. This system underweights the clinical importance of severe, life-threatening neutropenia and thrombocytopenia in therapeutic decisions and does not account for the rate of change in critical parameters (e.g., peripheral blood counts, blast percentage). However, the IPSS has been useful in a comparative analysis of clinical trial results, and its utility confirmed at many institutions. An updated 5-category IPSS has been proposed for prognosis in patients with primary MDS or secondary AML to account for chromosomal abnormalities frequently seen in MDS (Schanz, 2012). This system stratifies patients into 5 categories: very poor, poor, intermediate, good, and very good. There has been an investigation into using the 5-category IPSS to better characterize risk in MDS. A second prognostic scoring system incorporates the WHO subgroup classification that accounts for blast percentage, cytogenetics, and severity of cytopenias as assessed by transfusion requirements. The WHO classification-based Prognostic Scoring System uses a 6-category system, which allows more precise prognostication of overall survival (OS) duration, as well as risk for progression to AML.
 
Myelodysplastic Syndrome Treatment
Treatment of nonprogressing MDS has previously involved best supportive care, including red blood cell and platelet transfusions and antibiotics. Active therapy was given only when MDS progressed to AML or resembled AML with severe cytopenias. An array of therapies are now available to treat MDS, including hematopoietic growth factors (e.g., erythropoietin, darbepoetin, granulocyte colony-stimulating factor), transcriptional-modifying therapy (e.g., U.S. Food and Drug Administration (FDA) approved hypomethylating agents, nonapproved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, mantithymocyte globulin, cyclosporine A), low-dose chemotherapy (e.g., cytarabine), and allogeneic hematopoietic cell transplantation (allo-HCT). Given the spectrum of treatments available, the goal of therapy must be decided upfront whether it is to improve anemia, thrombocytopenia, or neutropenia, to eliminate the need for red blood cell transfusion, to achieve complete remission, or to cure the disease.
 
Allo-HCT is the only approach with curative potential, but its use is governed by patient age, performance status, medical comorbidities, the patient’s preference, risk category, and severity of MDS at presentation.
 
Chronic Myeloproliferative Neoplasms
Chronic myeloproliferative neoplasms are clonal bone marrow stem cell disorders; as a group, approximately 8,400 myeloproliferative neoplasms are diagnosed annually in the United States. Like MDS, myeloproliferative neoplasms primarily occur in older individuals, with approximately 67% reported in patients aged 60 years and older.
 
Myeloproliferative neoplasms are characterized by the slow but progressive expansion of a clone of cells with the potential evolution into a blast crisis similar to AML. Myeloproliferative neoplasms share a common stem cell-derived clonal heritage, with phenotypic diversity attributed to abnormal variations in signal transduction as the result of a spectrum of variants that affects protein tyrosine kinases or related molecules. The unifying characteristic common to all myeloproliferative neoplasms is effective clonal myeloproliferation resulting in peripheral granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, granulocytic dysplasia, or monocytosis.
 
Myeloproliferative Neoplasm Classification
Myeloproliferative neoplasms are a subdivision of myeloid neoplasms that includes 4 classic disorders: chronic myeloid leukemia, polycythemia vera, essential thrombocytopenia, and primary myelofibrosis. The WHO classification also includes chronic neutrophilic leukemia, chronic eosinophilic leukemia not otherwise specified, and myeloproliferative neoplasm unclassifiable. In the 2016 classification, mastocytosis is no longer considered a subgroup of the myeloproliferative neoplasms due to its unique clinical and pathologic features.
 
Myeloproliferative Neoplasm Treatment
In indolent, nonprogressing cases, therapeutic approaches are based on relief of symptoms. Supportive therapy may include prevention of thromboembolic events. Hydroxyurea may be used in cases of high-risk essential thrombocytosis and polycythemia vera, and intermediate- and high-risk primary myelofibrosis.
 
The FDA approved the orally administered selective Janus kinase 1 and 2 inhibitor ruxolitinib for the treatment of intermediate- or high-risk myelofibrosis. Ruxolitinib has been associated with improved OS, spleen size, and symptoms of myelofibrosis compared with placebo (Verstovsek, 2012). The Randomized Study of Ruxolitinib Tablets Compared to Best Available Therapy in Subjects With Primary Myelofibrosis, Post-Polycythemia Vera-Myelofibrosis or Post-Essential Thrombocythemia Myelofibrosis (COMFORT-II trial [2013]) compared ruxolitinib with best available therapy in patients who had intermediate- and high-risk myelofibrosis, and demonstrated improvements in spleen volume and OS (Cervantes, 2013). In a randomized trial comparing ruxolitinib with best available therapy (including antineoplastic agents, most commonly hydroxyurea, glucocorticoids) with no therapy for treatment of myelofibrosis, Harrison et al reported improvements in spleen size and quality of life, but not OS (Harrison, 2012). In 2019, the FDA also approved fedratinib (Inrebic®) for adults with intermediate-2 or high-risk primary or secondary myelofibrosis based on results from a double-blind, randomized, placebo-controlled trial that found improvement in spleen volume and myelofibrosis-related symptoms (FDA, 2019).
 
Myeloablative allo-HCT has been considered the only potentially curative therapy, but because most patients are of advanced age with attendant comorbidities, its use is limited to those who can tolerate the often-severe treatment-related adverse events of this procedure. However, the use of reduced-intensity conditioning (RIC) for allo-HCT has extended the potential benefits of this procedure to selected individuals with these disorders.
 
Hematopoietic Cell Transplantation
Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allo-HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates.
 
Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. Human leukocyte antigen refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome 6. An acceptable donor will match the patient at all or most of the HLA loci.
 
Conditioning for Hematopoietic Cell Transplantation
Conventional Conditioning
The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections.
 
The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVHD.
 
Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation
RIC refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose MAC treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term RIC will refer to all conditioning regimens intended to be nonmyeloablative.
 
Regulatory Status
The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR)Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.
 
Reimbursement for high dose chemotherapy (HDC) with stem and/or progenitor cell transplant that has been pre-authorized is made as a global fee limited to the lesser of billed charges or the average allowable charge authorized by the Blue Quality Centers for Transplant in the geographic region where the transplant is performed. This global payment includes all related transplant services including institutional, professional, ancillary, and organ procurement. The global period begins one day prior to the date of the transplant and continues for 48 days after the transplant. This covers the inpatient/outpatient stay and provides a per diem outlier payment if necessary. This global fee also includes the cost of complications arising from the original procedure when services are rendered within the global postoperative period for the particular transplant.

Policy/
Coverage:
Effective February 2020
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
High dose chemotherapy with allogeneic stem cell support for MYELODISPLASTIC SYNDROME (including primary [e.g. idiopathic] and acquired [e.g. secondary to drug or toxin exposure] meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  This includes:
 
    • patients with myelodysplastic syndrome and refractory anemia;
    • patients with myelodysplastic syndrome and refractory anemia with ringed sideroblasts;
    • patients with myelodysplastic syndrome with excess blasts;
    • patients with myelodysplastic syndrome with excess blasts in transformation;
    • patients with chronic myelomonocytic leukemia.
 
High dose chemotherapy with allogeneic stem cell support for MYELODYSPLASTIC DISORDERS meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  This includes:
 
    • Patients with polycythemia vera
    • Patients with essential thrombocythemia
    • Patients with myelofibrosis
    • Patients with agnogenic myeloid metaplasia with myelofibrosis
 
Non-myeloablative chemotherapy with allogeneic transplant (aka “mini” allogeneic transplant or reduced-intensity conditioning allogeneic stem cell transplant) as a risk-adapted treatment of any of these forms of Myelodysplastic Syndrome in patients who are at high-risk of intolerance of a myeloablative conditioning regimen meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Myeloablative allogeneic stem cell transplant or Non-myeloablative chemotherapy with allogeneic transplant for myelodysplastic syndromes or disorders that do not meet the criteria listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, myeloablative allogeneic stem cell transplant or Non-myeloablative chemotherapy with allogeneic transplant for myelodysplastic syndromes or disorders that do not meet the criteria listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to February 2020
 
High dose chemotherapy with allogeneic stem cell support for MYELODYSPLASTIC SYNDROME (including primary [e.g. idiopathic] and acquired [e.g. secondary to drug or toxin exposure] meets primary coverage criteria for effectiveness and is covered.  This includes
    • patients with myelodysplastic syndrome and refractory anemia;
    • patients with myelodysplastic syndrome and refractory anemia with ringed sideroblasts;
    • patients with myelodysplastic syndrome with excess blasts;
    • patients with myelodysplastic syndrome with excess blasts in transformation;
    • patients with chronic myelomonocytic leukemia.
 
Non-myeloablative chemotherapy with allogeneic transplant (aka “mini” allogeneic transplant) as primary treatment of any of these forms of Myelodysplastic Syndrome meets primary coverage criteria for effectiveness and is also covered.
 
High dose chemotherapy with allogeneic stem cell support for MYELODYSPLASTIC DISORDERS (including patients with polycythemia vera; patients with essential thrombocythemia; patients with myelofibrosis; and patients with agnogenic myeloid metaplasia with myelofibrosis) meets primary coverage criteria for effectiveness and is covered.
 

Rationale:
This policy is based in part on a 1992 Blue Cross Blue Shield Association Technology Evaluation Center Assessment that focused on high dose chemotherapy and allogeneic stem cell support as a treatment of myelodysplastic syndrome.  The following conclusions were offered:
    • High dose chemotherapy appears to improve health outcome of selected patients with MDS.  The largest study showed an overall survival of 45% at three years.
    • Compared to conventional therapy, consisting of supportive therapy, survival after high dose therapy can be considered at least as good.
 
The following summarizes the recent literature regarding high dose chemotherapy for myeloproliferative disorders.
 
Myeloproliferative Disorders
Due to the prolonged natural history of both polycythemia vera or essential thrombocythemia disorders and older average age of onset (60 years), high dose chemotherapy with allogeneic stem cell support has not been extensively studied in these patients. A 1998 review reported only 9 patients with PV had been treated with high dose chemotherapy.  However, considering that PV represents an emerging malignant clone of cells, and the success of high dose chemotherapy in other hematopoietic disorders, it seems reasonable to extrapolate the results of high dose chemotherapy for myelodysplastic syndrome to PV. There has been more research in agnogenic myeloid metaplasia (AMM, also called myelofibrosis) since this disorder may also occur in children. In addition, the short median survival of AMM compared to other myeloproliferative disorders has prompted earlier consideration of high dose chemotherapy. Of the total 29 patients reported in the literature, 16 patients were alive without evidence of relapsed disease between 7 months and 15 years after transplant.
 
The National Comprehensive Cancer Network makes the following statement regarding therapy for higher risk patients:
“Therapy for higher risk patients is dependant on whether or not they are felt to be candidates for Intensive therapy (e.g., allogeneic hematopoietic stem cell transplant or intensive chemotherapy.  Clinical features relevant for this determination include the patient’s age, performance status and absence of major comorbid conditions.  In addition, the patient’s personal preference for type of therapy needs particular consideration…  The potential for patients’ receipt of an allogeneic HSCT (in addition to the patient’s clinical characteristics, as above) is also dependent on whether a donor is available and if the patient’s marrow blast count is sufficiently low.  For those patients with an available donor, preference is for a matched sibling donor, although data using matched-unrelated donors is nearly comparable in selected patients.  Standard conditioning is used for relatively younger patients whereas the experimental approach using non-myeloablative transplant conditioning is preferable in older individuals…High-risk <= 60 years old should proceed to transplant at diagnosis, whereas for those Low or INT-1 MDS patients, it would be beneficial to delay transplantation until disease progression.”  (NCCN Practice Guidelines in Oncology – v.4.2006, accessed 2 Aug 06).
 
2004-2007 Update
Recent literature focuses primarily on different RIC regimens and allogeneic SCT for MDS in an attempt to reduce toxicity.  The specific conditioning regimen used is not a focus of this policy, and thus the policy statement is unchanged. Numerous reports of RIC regimens with allogeneic SCT in patients with MDS have also been published.  However, properly designed, specific randomized trials are not yet available in this area.
 
2007 National Comprehensive Cancer Network Guidelines
The 2007 National Comprehensive Cancer Network (NCCN) treatment guidelines (V.1.2007) for MDS suggest allogeneic SCT from an HLA-matched sibling donor is a preferred approach, in particular for those with high-risk disease.  The guidelines also suggest RIC regimens and matched unrelated donor SCTs are becoming options at some centers. However, the NCCN states that comparative clinical trials are needed to determine the role of these approaches.
 
2007 National Cancer Institute (NCI) Clinical Trials Database (PDQ®)
A search of the NCI PDQ database in March 2007 identified the following active trials that involve stem-cell support for patients with MDS:
    • Phase II/III Combination Chemotherapy and Bone Marrow Transplant in Treating Patients With Aplastic Anemia or Hematologic Cancer (RPCI-RP-9815)
    • Phase II/III Stem Cell Transplantation for Hematological Malignancies (0005M52481)
    • Phase II/III Stem Cell Transplant for Bone Marrow Failures (9504M09637)
    • Phase III Filgrastim-Mobilized Peripheral Stem Cell Transplantation Compared With Bone Marrow Transplantation From Unrelated Donors in Treating Patients With Hematologic Malignancies (BMTCTN-0201)
    • Phase III Treatment of Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplasia (AMLO2)
    • Phase III Biology and Treatment Strategy of AML in Its Subgroups: Multicenter Randomized Trial by the German Acute Myeloid Leukemia Cooperative Group (AMLCG) (AMLCG 99)
 
2008 Update
No randomized, clinical trials have been identified subsequent to the last update on the use of myeloablative chemotherapy with allogeneic SCT for MDS/AML. However, a growing body of evidence from largely heterogeneous uncontrolled studies of RIC with allogeneic SCT shows long-term remissions (>4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with MDS/AML who otherwise would not be candidates for myeloablative conditioning regimens.  In the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative and RIC regimens with allogeneic SCT. Furthermore, no randomized trials have been published in which RIC with allogeneic SCT has been compared with conventional chemotherapy alone, which has been the standard of care in patients with MDS/AML for whom myeloablative chemotherapy and allogeneic SCT are contraindicated.
 
Data on therapy for MPD remain sparse. As outlined previously in this policy, with the exception of myeloablative chemotherapy and allogeneic SCT, no therapy has yet been proven to be curative or to prolong survival of patients with MPD.  However, the significant toxicity of myeloablative conditioning and allogeneic SCT in MPD has led to study of the use of RIC regimens for these diseases. A recent series included 27 patients (mean age: 59 years) with MPD who underwent allogeneic SCT using a RIC regimen of low-dose (2 Gy) total body irradiation alone or with the addition of fludarabine.  At a median follow-up of 47 months, the 3-year relapse-free survival was 37% and overall survival was 43%, with a 3-year nonrelapse mortality of 32%. While this approach has promise, data comparing outcomes of potentially curative myeloablative conditioning and allogeneic SCT versus RIC and allogeneic stem-cell support are not available.
 
Based on these findings, the policy statements are unchanged.
 
2008 National Comprehensive Cancer Network Guidelines
The 2008 National Comprehensive Cancer Network treatment guidelines (V.2.2008) for myelodysplastic syndromes are unchanged from the 2007 version.
 
2008 National Cancer Institute (NCI) Clinical Trials Database (PDQ®)
A search of the NCI PDQ database in April 2008 identified 7 new active phase III trials that involve stem-cell support for patients with MDS/AML or MPD besides those outlined above in the previous update of this policy. At least 12 phase II trials of various treatments for these diseases are actively recruiting patients. Information on these trials can be accessed via the following link (http://www.cancer.gov/search/psrv.aspx?cid=111158&protocolsearchid=4415677).
 
2012 Update
A literature review using the MEDLINE database was conducted through July 2013.  There was no new information identified that would prompt a change in the coverage statement.
 
The 2011 National Comprehensive Cancer Network (NCCN) treatment guidelines (v.2.2011) for the use of allogeneic HSCT indicate this procedure is preferred at diagnosis in patients who are candidates for high-intensity therapy, have a suitable donor, and have de novo MDS classified as IPSS Int-2 and High, or those who have de novo MDS classified as Int-1 with severe cytopenias unresponsive to standard therapies.
 
Reduced-intensity or myeloablative conditioning may be used based on patient age, performance status, comorbid conditions, psychosocial status, patient preference, and availability of caregiver. MRD cells are preferred, but MUD cells are an option at some centers. The role of pretransplant remission induction using intensive chemotherapy has not been established.
 
The recommendations of a systematic review of the role of allogeneic HSCT in patients with MDS prepared by the American Society for Blood and Marrow Transplantation (ASBMT) are congruent with the present policy statements (Oliansky, 2009).
 
2013 Update
A literature review of the MEDLINE database was conducted through July 2012.  There was no new information identified that would prompt a change in the coverage statement.
 
2014 Update
A literature search conducted through October 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A table of Case Series of HSCT Treatment for MDS was identified and broken into paragraph form as follows:
 
  • A study by Basquiera et al (Basquiera, 2014); had a patient population of 52 pediatric patients with MDA. The type of HSCT was Allo-HSCT  59% with related donors, stem cell source: Bone marrow – 63%, peripheral blood – 26%, umbilical cord blood – 11%; there was a summary of outcomes of 5-year disease-free survival (DFS) and 5 –year overall survival (OS).
  • A study by Boehm et al (Boehm, 2014); had a patient population of 60 adults with AML. The type of HSCT was Allo-HSCT myeloablative  (MA) conditioning in 36 patients; reduced intensity conditioning  (RIC) conditioning in 24 patients: summary of outcomes of 10 year OS: 46%
  • A study by Damaj et al (Damaj, 2014); had a patient population of 128 adults with MDS, 40 of whom received AZA before HSCT and 88 who received BSC. The type of HSCT was RIC allo-HSCT; summary of outcomes 3-year OS; 53% for AZA group vs 53% for BSC group (P=0.69), 3-year RFS: 37% for AZA group vs 42% for BSC group (P=0.78), 3-year nonrelapse mortality (NRM): 20% for AZA group vs 23% for BSC group (P=0.74).
  • A study  by Onida et al (Onida, 2014); had a patient population of 523 patients with MDS treated with HSCT. IPSS cytogenic risk group: Good risk 53.5%; Intermediate risk 24.5%; Poor risk 22%:  summary of outcomes 5-year OS based on IPSS cytogenic risk group: Good risk 48%; Intermediate risk 45%; Poor risk 30%.
  • A study by Oran et al (Oran, 2014); had a patient population of 256 patients with MDS. Pretreatment: No cytoreductive chemotherapy 30.5%; chemotherapy 15.6%; HMA 47.7%; Chemo + HMA 6.2%. The type of HSCT was Allo-=HSCT. RIC conditioning in 36.7%; summary of outcomes 3-year disease free survival (DFS) on cytoreductive therapy: no cytoreductive chemotherapy 44.2%; HMA 34.2%; Chemo + HMA 32.8% (P+0.50), 5-year OS and DFS 41%.
   
2016 Update
A literature search conducted through April 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A review from the American Society for Blood and Marrow Transplantation (ASBMT) in 2009 assembled and evaluated the evidence related to HSCT in the therapy of MDS, with associated treatment recommendations (Oliansky, 2009) The authors 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 (ie, older age, refractory cytopenias). Koenecke and colleagues evaluated the impact on the revised 5- category IPSS score (IPSS-5) on outcomes after HSCT in patients with MDS or secondary acute myeloid leukemia (evolved from MDS) (Koenecke, 2015).  In a cohort of 903 patients retrospectively identified from the European Society for Blood and Marrow Transplantation database, those with poor and very poor risk had shorter relapse-free survival (RFS) and OS than those with very good, good, or intermediate risk. However, the ways that transplant management strategies should change based on cytogenetic abnormalities are not currently well-defined.
 
Aoki and colleagues compared RIC with MA conditioning in a retrospective cohort of 448 patients aged 50 to 69 years with advanced MDS (refractory anemia with excess blasts or refractory anemia in transformation) (Aoki, 2015). Of the total, 197 (44%) and 251 (56%) received MA conditioning or RIC, respectively. The groups differed at baseline: patients who received RIC were significantly more likely to be 60 to 69 years old (vs 50-59 years; 47% for RIC vs 47% for MA; p=0.001), and less likely to receive an unrelated donor transplant (54% vs 70%; p=0.001). Three-year OS did not differ between groups (44.1% for RIC vs 42.7% for MA; p=0.330). Although patients treated with RIC had a significantly lower 3-year cumulative incidence of NRM (25.6% vs 37.9%; p=0.002), but they had significantly higher 3-year incidence of relapse than patients treated with MA conditioning (29.9% vs 22.8%; p=0.029).
 
Kim and colleagues published a phase 3 randomized trial (N=83 patients) comparing the toxicities of 2 different conditioning regimens (reduced CY, fludarabine, and antithymocyte globulin [ATG]; standard CYATG). Four patients had MDS, and the remaining patients had severe aplastic anemia. Overall, the incidence of reported toxicities were lower in patients receiving the reduced-conditioning regimen (23% vs 55%; p=0.003). Subgroup analyses showed no differences in the overall results based on differential diagnosis (Kim, 2012).
 
The significant toxicity of MA conditioning and allo-HSCT in MPN has led to study of RIC regimens for these diseases. Data from direct, prospective comparison of outcomes of MA conditioning and allo-HSCT versus RIC and allogeneic stem cell support in MPN are not available, but single-arm series and nonrandomized comparative studies report outcomes after RIC allo-HSCT. One 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 or with the addition of fludarabine (Laport, 2008) At a median follow-up of 47 months, the 3-year RFS was 37%, and OS was 43%, with a 3-year NRM of 32%. In a second series, 103 patients (median age, 55 years; range, 32-68 years) with intermediate-to-high risk (86% of total patients) primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis were included in a prospective, multicenter, phase 2 trial to determine efficacy of a busulfan plus fludarabine-based RIC regimen followed by allo-HSCT from related (n=33) or unrelated (n=70) donors (Kroger, 2009). Acute grade II-IV GVHD 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) 5-year estimated DFS and OS were 51% (95% CI, 38% to 64%) and 67% (95% CI, 55% to 79%), respectively.
 
2017 Update
A literature search conducted through June 2017 did not reveal any new information that would prompt a change in the coverage statement.
 
2018 Update
A literature search was conducted through June 2018.  There was no new information identified that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through June 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2019, the FDA also approved fedratinib (Inrebic®) for adults with intermediate-2 or high-risk primary or secondary myelofibrosis based on results from a double-blind, randomized, placebo-controlled trial that found improvement in spleen volume and myelofibrosis-related symptoms (FDA, 2021).
 
Song et al evaluated the efficacy of RIC followed by allo-HCT in patients with AML and MDS via a meta-analysis of 6 RCTs (N=1413) (Song, 2021). The 6 RCTs compared RIC to MAC before first allo-HCT in patients with AML in complete remission or MDS, had a median follow-up of >1 year, and displayed a low risk of bias. The primary endpoint was OS. Results revealed that OS was not significantly different between RIC and MAC (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.64 to 1.4; p=.80), with combined long-term follow-up data also showing no difference in OS between the 2 conditioning approaches (HR, 0.86; 95% CI, 0.53 to 1.41; p=.56). The cumulative incidence of relapse was also similar between the groups (HR, 1.18; 95% CI, 0.88 to 1.49; p=.28). Nonrelapse mortality was significantly improved with RIC as compared to total body irradiation/busulfan-based MAC (HR, 0.53; 95% CI, 0.36 to 0.8; p=.002); however, treosulfan-based MAC significantly reduced nonrelapse mortality as compared to RIC (HR, 1.67; 95% CI, 1.02 to 2.72; p=.04). RIC was associated with a trend of increasing graft failure (p=.06); however, graft failure in both arms was rare. The median duration of follow-up among the studies ranged from 12 to 119 months. The authors concluded that RIC is recommended as an adequate option of preparative treatment before allo-HCT for patients with AML in complete remission or MDS. Limitations of the meta-analysis included the small number of included clinical trials, significant heterogeneity between included studies for some outcomes, and lack of blinding in some studies.
 
Scott et al found that, at 4 years, transplant-related mortality was significantly increased with MAC as compared to RIC (25.1% vs. 9.9%; p<.001) and those who received RIC had a significantly increased relapse risk (HR, 4.06; 95% CI, 2.59 to 6.35; p<.001) (Scott, 2021). Among those who relapsed after HCT, postrelapse survival was similar between groups at 3 years (24% for MAC vs. 26% for RIC). Patients administered MAC had superior OS (HR, 1.54; 95% CI, 1.07 to 2.2; p=.03).
 
Bewersdorf et al assessed the available evidence on the efficacy and safety of allo-HCT in patients with myelofibrosis in a systematic review involving 43 studies (N=8739) (Bewersdorf, 2021). The analysis included 38 retrospective, 1 prospective, and 4 phase II clinical trials. Conditioning regimens used were variable with only 3 and 14 studies using exclusively MAC or RIC regimens, respectively. Additionally, donor sources and pre-transplantation treatment histories differed considerably among studies. The co-primary outcome was 1-, 2-, and 5-year OS. Rates of nonrelapse mortality, RFS or progression-free survival (PFS), and safety were also evaluated. Regarding survival, 1-year, 2-year, and 5-year OS rates were 66.7% (95% CI, 63.5% to 69.8%), 64.4% (95% CI, 57.6% to 70.6%), and 55% (95% CI, 51.8% to 58.3%), respectively. Nonrelapse mortality rates for the same time periods were 25.9% (95% CI, 23.3% to 28.7%), 29.7% (95% CI, 24.5% to 35.4%), and 30.5% (95% CI, 25.9% to 35.5%). Rates of 1-, 2- and 5-year RFS were 65.3% (95% CI, 56.5% to 73.1%), 56.2% (95% CI, 41.6% to 69.8%), and 53.6% (95% CI, 39.9% to 66.9%), respectively. PFS rates were 56.9% (95% CI, 41.4% to 71.2%), 50.6% (95% CI, 39.7% to 61.4%), and 43.5% (95% CI, 31.9% to 55.8%) for these same time periods. Acute GVHD was reported in 44% of patients, with chronic GVHD occurring in 46.5% of patients. The combined rate of graft failure was 10.6% (95% CI, 8.9% to 12.5%). Overall, the quality of the evidence was limited by the absence of RCTs and the retrospective design of most studies. Additionally, patient and transplant characteristics were variable among the included studies leading to moderate to substantial heterogeneity in the analyses.
 
In 2020, the American Society of Transplantation and Cellular Therapy (formerly The American Society for Blood and Marrow Transplantation) published updated guidelines on indications for HCT and immune effector cell therapy based on the recommendations of a multiple-stakeholder task force (Kanate, 2020).
 
Recommendations for the Use of Hematopoietic Cell Transplantation to Treat Myelodysplastic Syndromes, Myelofibrosis, and Myeloproliferative Neoplasms
    • Myelodysplastic syndromes
      • Low/intermediate-1 risk : Standard of care, clinical evidence available (large clinical trials and observational studies are not available; however, sufficiently large cohort studies have shown efficacy with “acceptable risk of morbidity and mortality”)
      • Intermediate-2/high-risk: Standard of care (“well defined and generally supported by evidence in the form of high-quality clinical trials and/or observational studies”)
    • Myelofibrosis and myeloproliferative neoplasms
      • Primary, low-risk: Standard of care (“well defined and generally supported by evidence in the form of high-quality clinical trials and/or observational studies”)
      • Primary, intermediate/high-risk: Standard of care (“well defined and generally supported by evidence in the form of high-quality clinical trials and/or observational studies”)
      • Secondary: Standard of care (“well defined and generally supported by evidence in the form of high-quality clinical trials and/or observational studies”)
      • Hypereosinophilic syndromes, refractory: Standard of care, rare indication (clinical trials and observational studies are not feasible due to low incidence; small cohorts have shown efficacy with “acceptable risk of morbidity and mortality”)
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through June 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Robin et al reported on a study that consisted of 1114 adults with CMML between the ages of 18 to 70 years (Robin, 2022). CMML Prognosis Scoring System risk: Low 20%; Intermediate-1 31%; Intermediate-2 40%; High 9%. 43% of participants underwent allo-HCT. 10% transformed to AML prior to allo-HCT. Type of HCT included myeloablative conditioning or reduced-intensity conditioning allo-HCT. 5-year Overall Survival: Lower-risk disease 20% with allo-HCT vs. 42% without allo-HCT (p<.001); Higher-risk disease: 27% with allo-HCT vs. 15% without allo-HCT (p=.13). Multivariate analyses of risk of death within 2 years and after 2 years: Lower-risk disease Increased risk of death within 2 years with allo-HCT (HR=3.19) and  no difference in long-term survival after 2 years (HR=0.98); Higher-risk disease Increased risk of death within 2 years with allo-HCT (HR=1.46); no difference in long-term survival after 2 years (HR=0.60).
 
Current National Comprehensive Cancer Network clinical guidelines for myelodysplastic syndromes (v. 1.2023) make the following general recommendation about allogeneic hematopoietic cell transplantation (allo-HCT) (NCCN, 2022):
 
“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 below (NCCN, 2022).,
 
Guidelines for Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes
 
    • Prognostic category: IPSS low/intermediate-1 OR IPSS-R very low, low, intermediate OR WPSS very low, low, intermediate
      • Consider allo-HCT for select patients who have clinically relevant thrombocytopenia or neutropenia, with disease progression or no response after azacitidine/decitabine or immunosuppressive therapy
      • Consider allo-HCT for patients who have symptomatic anemia with no 5q deletion, with serum erythropoietin level >500 mU/mL or lower serum erythropoietin level with inadequate response to erythropoietin stimulating agents and/or lenalidomide, with poor probability of or inadequate response/intolerance to immunosuppressive therapy, and no response or intolerance to azacitidine/decitabine or immunosuppressive therapy
      • Consider allo-HCT for patients who have symptomatic anemia with del(5q), with inadequate response/intolerance to lenalidomide and/or erythropoietin stimulating agents, and no response or intolerance to azacitidine/decitabine or immunosuppressive therapy
    • Prognostic Category: 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
 
Below is a summary of the National Comprehensive Cancer Network recommendations (v. 3.2022) on the use of allo-HCT for the treatment of myeloproliferative neoplasms (NCCN, 2022). 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.
 
Guidelines for Allogeneic Hematopoietic Cell Transplantation for Myeloproliferative Neoplasms
 
    • Prognostic Category: Lower-risk myelofibrosis (MIPSS-703, MIPSS-70+ Version 2.0 3, DIPSS-Plus 1, DIPSS 2, MYSEC-PM <14)
      • In symptomatic patients with disease progression despite treatment with ruxolitinib, peginterferon alfa-2a, and/or hydroxyurea (if cytoreduction would be symptomatically beneficial), consider allo-HCT immediately or bridging therapy to decrease marrow blasts to an acceptable level prior to transplant
      • Evaluation for allo-HCT is recommended for patients with low platelet counts or complex cytogenetics
    • Prognostic Category: Higher-risk myelofibrosis (MIPSS-70 4, MIPSS-70+ Version 2.0 4, DIPSS-Plus >1, DIPSS >2, MYSEC-PM 14)
      • Consider allo-HCT immediately or bridging therapy can be used to decrease marrow blasts to an acceptable level prior to transplant
      • Evaluation for allo-HCT is recommended for all patients
    • Prognostic Category: Disease progression to advanced-stage/AML
      • Induce remission with hypomethylating agents ± JAK inhibitors or intensive induction chemotherapy followed by allo-HCT
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement

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