Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS)

CMS NCA document | source_status=Closed | review_type=1st Recon | public_comment_open=False | document_id=CAG-00415R

Summary of Final National Coverage Determination (NCD): CMS has reconsidered one aspect of the national coverage determination established at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03. The Centers for Medicare and Medicaid Services (CMS) is finalizing the proposed NCD for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) using bone marrow or peripheral blood stem cell products and is adding coverage to the final NCD to include the use of umbilical cord blood stem cell products. Also, in addition to finalizing patients with MDS designated as high-risk or very high-risk with a score of ≥ 4.5 according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R), CMS is finalizing coverage of additional risk designations and scoring systems. The final NCD includes patients with MDS designated as Intermediate-2 or high-risk with a score of ≥ 1.5 according to criteria specified by the International Prognostic Scoring System (IPSS) and patients with MDS designated as high-risk or very high-risk with a score of ≥ 0.5 according to criteria specified by the Molecular International Prognostic Scoring System (IPSS-M). Final Decision: We are expanding Medicare coverage for allogeneic hematopoietic stem cell transplant using bone marrow, peripheral blood or umbilical cord blood stem cell products for Medicare patients with myelodysplastic syndromes who have prognostic risk scores of: ≥ 1.5 (Intermediate-2 or high) using the International Prognostic Scoring System (IPSS), or ≥ 4.5 (high or very high) using the International Prognostic Scoring System - Revised (IPSS-R), or ≥ 0.5 (high or very high) using the Molecular International Prognostic Scoring System (IPSS-M). For these patients, the evidence demonstrates that the treatment is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act. In addition, coverage of all other indications for stem cell transplantation not otherwise specified will be made by local Medicare Administrative Contractors under section 1862(a)(1)(A) of the Act. See Appendix B for the NCD manual language, specifically Section B.1.c for the expanded nationally covered indications and Section D recognizing that the Medicare Administrative Contractors may determine coverage under section 1862(a)(1)(A) for other beneficiaries with myelodysplastic syndromes.

Decision Memo: TO: Administrative File: CAG-00415R SUBJECT: Reconsideration- Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) National Coverage Determination DATE: March 6, 2024 I. Decision Summary of Final National Coverage Determination (NCD): CMS has reconsidered one aspect of the national coverage determination established at section 110.23 of the Medicare National Coverage Determinations Manual Pub. 100-03. The Centers for Medicare and Medicaid Services (CMS) is finalizing the proposed NCD for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) using bone marrow or peripheral blood stem cell products and is adding coverage to the final NCD to include the use of umbilical cord blood stem cell products. Also, in addition to finalizing patients with MDS designated as high-risk or very high-risk with a score of ≥ 4.5 according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R), CMS is finalizing coverage of additional risk designations and scoring systems. The final NCD includes patients with MDS designated as Intermediate-2 or high-risk with a score of ≥ 1.5 according to criteria specified by the International Prognostic Scoring System (IPSS) and patients with MDS designated as high-risk or very high-risk with a score of ≥ 0.5 according to criteria specified by the Molecular International Prognostic Scoring System (IPSS-M). Final Decision: We are expanding Medicare coverage for allogeneic hematopoietic stem cell transplant using bone marrow, peripheral blood or umbilical cord blood stem cell products for Medicare patients with myelodysplastic syndromes who have prognostic risk scores of: ≥ 1.5 (Intermediate-2 or high) using the International Prognostic Scoring System (IPSS), or ≥ 4.5 (high or very high) using the International Prognostic Scoring System - Revised (IPSS-R), or ≥ 0.5 (high or very high) using the Molecular International Prognostic Scoring System (IPSS-M). For these patients, the evidence demonstrates that the treatment is reasonable and necessary under section 1862(a)(1)(A) of the Social Security Act. In addition, coverage of all other indications for stem cell transplantation not otherwise specified will be made by local Medicare Administrative Contractors under section 1862(a)(1)(A) of the Act. See Appendix B for the NCD manual language, specifically Section B.1.c for the expanded nationally covered indications and Section D recognizing that the Medicare Administrative Contractors may determine coverage under section 1862(a)(1)(A) for other beneficiaries with myelodysplastic syndromes. II. Background Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations. Please find below a list of these acronyms and corresponding full terminology: AEs-Adverse Events aGVHD-acute Graft Versus Host Disease AHRQ-Agency for Healthcare Research and Quality AHSCT-Allogeneic Hematopoietic Stem Cell Transplantation AlloHSCT-Allogeneic Hematopoietic Stem Cell Transplantation AML-Acute Myelogenous Leukemia ANC- Absolute Neutrophil Count ASXL1- ASXL Transcriptional Regulator 1mutation ATG-Antithymocyte Globulin AuSCT-Autologous Stem Cell Transplantation BBM-Bone Marrow Blast BMT-Bone Marrow Transplantation CED-Coverage with Evidence Development CFR-Code of Federal Regulations cGVHD-chronic Graft Versus Host Disease CI-Confidence Interval CIBMTR-Center for International Blood and Marrow Transplant Research CMML-Chronic myelomonocytic leukemia CMS-Centers for Medicare & Medicaid Services CR-Complete Remission DFS-Disease-free Survival DIPSS-Dynamic International Prognostic Scoring System EBMT-European (Society for) Blood and Marrow Transplantation EFS-Event-free Survival EPO/ESA- Epoetin alfa/Erythropoiesis-Stimulating Agents EZH2- Enhancer of zeste homolog 2 mutation FAB-French-American-British classification system FDA-Food and Drug Administration GvHD/GVHD-Graft Versus Host Disease HLA-Human Leukocyte Antigen HMA-Hypomethylating Agents HPC-Hematopoietic stem/progenitor cells HR-Hazard Ratio HSCT-Hematopoietic Stem Cell Transplantation IDH2- Isocitrate dehydrogenase 1 mutation IPSS-International Prognostic Scoring System IPSS-M—Molecular-International Prognostic Scoring System IPSS-R-International Prognostic Scoring System Revised IRIC-Intensive Remission Induction Chemotherapy ISS-International Staging System MAC-Myeloablative Conditioning MDS-Myelodysplastic Syndromes MDS-del(5q)- Myelodysplastic Syndromes with isolated del(5q) MDS-EB1- Myelodysplastic Syndromes with excess blast, subgroup 1 MDS-EB2- Myelodysplastic Syndromes with excess blast, subgroup 2 MDS-MLD-Myelodysplastic Syndromes with Multilineage Dysplasia MDS-SLD- Myelodysplastic Syndromes with Single lineage Dysplasia MDS-RS-MLD- Myelodysplastic Syndromes with Ring Sideroblast, Multilineage Dysplasia MDS-RS-SLD- Myelodysplastic Syndromes with Ring Sideroblast, Singl NCA-National Coverage Analysis NCD-National Coverage Determination NIH-National Institutes of Health NMA-Non-Myeloablative Conditioning NMDP-National Marrow Donor Program NRM-Non-relapsing Mortality OS-Overall Survival PFS-Progression-free Survival QALE-Quality-Adjusted Life Expectancy QoL-Quality of Life RA-Refractory Anemia RAEB-RA with Excess Blasts RAEB-T-RAEB in transition to AML RARS-RA with Ringed Sideroblasts RBC-Red Blood Cell RCUD-Refractory Cytopenias with Unilineage Dysplasia RCMD-Refractory Cytopenia with Multilineage Dysplasia RCMD/RS-RCMD with Ringed Sideroblasts RFS-Relapse Free Survival RIC-Reduced-intensity Conditioning RUNX1- Runt-related transcription factor 1 mutation SCT-Stem Cell Transplantation SF3B1-SF3B1 mutation TP53- Tumor protein P53 mutation TRM-Transplantation-related Mortality UCB-umbilical cord blood WHO-World Health Organization WPSS-WHO Prognostic Scoring System Myelodysplastic Syndromes Myelodysplastic Syndromes (MDS) are a heterogeneous group of hematologic disorders characterized by (1) cytopenia (decreased number of red blood cells, white blood cells and platelets) due to bone marrow failure and (2) the potential development of acute myeloid leukemia (AML). In MDS, groups of clonal stem cell disorders are observed, characterized by low blood cell counts, abnormal blood cell development, genetic markers, hypercellular bone marrow, cytopenias, and dysplastic cells. Anemia, often with thrombocytopenia and neutropenia, occurs with dysmorphic (abnormal appearing) hematologic cells and usually abnormal cellular bone marrow, which results in ineffective blood cell production. Because of bone marrow failure, MDS patients are at risk for symptomatic anemia, infection, and bleeding. For treatment purposes, patients with MDS are often stratified into risk groups based on the potential development of AML, which varies widely across MDS subtypes. Most patients with MDS have “low-risk” status, and bone marrow failure is part of their clinical course. Other patients designated as “high-risk” are more likely to have leukemic progression. In this “high-risk” group, patients often present with myeloblasts at the time of diagnosis, as well as chromosomal abnormalities and genetic mutations. MDS shares clinical and pathologic features with AML, but MDS has a lower percentage of blasts in peripheral blood and bone marrow (by definition, < 20 percent). MDS often results in fatality due, most often, to complications of cytopenia, or to progression to leukemia, but a large proportion of MDS patients will die of concurrent disease, and the comorbidities typical in an elderly population. MDS are a disease of the elderly; the mean age at onset is older than 70 years (Harrison’s Principles of Medicine, 20 th edition, Jameson, Fauci, Kasper et al. 2018). Approximately 6% of cases of MDS are diagnosed in people under 50 years of age (Ma 2012). MDS is a relatively common form of bone marrow failure, with reported incidence rates of 35 to > 100 per million persons in the general population and 120 to > 500 per million in older adults. Estimates of incidence in the United States range from 30,000 to 40,000 new cases annually and a prevalence of 60,000-120,000 in the population. MDS is rare in children, in whom it often has an identifiable genetic basis (Kuendgen, et al. 2006). Secondary or therapy-related MDS is not age related. Rates of MDS have increased over time due to better recognition of the syndrome by physicians, and an aging population. MDS has been associated with long-term exposure to certain environmental chemicals, including benzene and chemicals used in the rubber and petroleum industry. It also has been found in patients who have received radiation, radiomimetic alkylating agents, as well as other forms of treatment for cancer. Genomics plays a major role in this disease, and the types and number of cytogenetic mutations strongly correlate with the probability of leukemic transformation and survival. Over 100 genes, including some recurrent somatic mutations have been associated with MDS. Many of these same genes are also mutated in AML without MDS, whereas others are distinctive in subtypes of MDS. Some mutations correlate with prognosis (e.g., spliceosome defects are associated with favorable outcomes), while mutations in EZH2, TP53, RUNX1 , and ASXL1 are associated with poor outcomes. Classification of MDS As noted above, MDS is a heterogeneous group of hematologic disorders. The disease course varies greatly from patient to patient. Because of the various clinical and biological presentations, an accurate means of making a definitive diagnosis is needed. Proper diagnosis is crucial so that patients receive the most-effective treatment for MDS. A high-quality morphologic analysis, which includes a review of a peripheral blood smear, a representative bone marrow aspirate, and an adequate bone marrow biopsy is required in making the diagnosis and staging of the disease. Diagnosis is established by the presence of unexplained cytopenia and dysplasia. Bone marrow karyotype, peripheral blood counts and relevant molecular genetic testing may also be required. A number of diagnostic classification systems, which primarily look at morphology and percentage of blasts, have been developed over the years. The French, American, British Group system was first developed in 1982, but was later replaced by the WHO diagnostic classification. This schema divides MDS into subtypes depending on the percentage of myeloblasts, the presence or absence of ringed sideroblasts, the number of dysplastic lineages in the bone marrow, and the genetic profile of the bone marrow cells (cytogenetic abnormalities (e.g., the isolated 5q deletion) as well as mutations (e.g., SF3B1)). Another classification system used is the International Consensus Classification (ICC). Both the WHO and ICC classification systems are similar because they recognize the significance of bone marrow blast count, extent of dysplasia, and cytogenetic and molecular abnormalities for categorizing MDS. For diagnostic purposes the WHO system now recognizes 6 types of MDS: MDS with multilineage dysplasia (MDS-MLD) - This is the most common type of MDS and it has a higher occurrence in men. The clinical course is variable and is influenced by karyotype and the degree of cytopenias and dysplasia (Greenberg, et al. 2012; Malcovati, et al. 2005; Della Porta, et al. 2015). There is no definitive evidence that specific mutations influence prognosis within this category of MDS. Median overall survival (OS) was 36 months and evolution to AML was approximately 15 percent at two years and 28 percent at five years according to a database of 1,010 MDS-MLD patients (Reuss-Borst, et al. 1993). Patients with complex karyotypes have outcomes similar to those with MDS with excess blasts (Maassen, et al. 2013). MDS with single lineage dysplasia (MDS-SLD) - This form of MDS is not common and it seldom, if ever, progresses to AML. Patients with this type of MDS can often live a long time, even without treatment. MDS-SLD accounts for 7 to 20 percent of all cases of MDS (Reuss-Borst, et al. 1993). Median overall survival (OS) is approximately 66 months, and the rate of progression to AML at five years is 10 percent (Greenberg, et al. 2012; Germing, et al. 2006). MDS ring sideroblasts (MDS-RS)— This form of MDS is divided into 2 types based on how many of the cell types in the bone marrow are affected by dysplasia: MDS-RS with single lineage dysplasia (MDS-RS-SLD) MDS-RS with multilineage dysplasia (MDS-RS-MLD) MDS-RS accounts for 3 to 11 percent of all cases of MDS, with MDS-RS-MLD the more common subtype (Reuss-Borst, et al. 1993). For MDS-RS-SLD, approximately 1 to 2 percent of cases evolve to AML and the median OS is 69 to 108 months (Germing, et al. 2000). For MDS-RS-MLD, median OS is 28 months and approximately 8 percent progress to AML (Breccia, et al. 2006; Germing, et al. 2000; Ghesquieres, et al. 2015). RUNX1 mutation is associated with shorter survival (Malcovati, et al. 2015). MDS with excess blasts (MDS-EB)—This form of MDS can be further characterized as MDS-EB-1 or MDS-EB-2 based on the percentage of bone marrow and peripheral blood blasts, as well as the absence or presence of Auer rods. MDS-EB2 is characterized as having Auer rods. MDS-EB, accounts for 1 in 4 cases of MDS. Approximately 25 percent of MDS-EB-1 and 33 percent of MDS-EB-2 progress to AML (Reuss-Borst, et al. 1993). The median OS is approximately 16 months for MDS-EB-1, and 9 months for MDS-EB-2. Clonal cytogenetic findings are present in 30 to 50 percent of cases of MDS-EB (Reuss-Borst, et al. 1993). The most common findings are gain of chromosome 8, del(5q) or t(5q), loss of chromosome 7 or del(7q), and del(20q). Also, complex karyotypes may be seen in this form of MDS (Maassen et al. 2013). Mutations, including TP53, IDH1/IDH2 , those involving the RAS pathway, and cohesion complex genes are commonly found in these MDS subgroups (Malcovati et al. 2014). MDS with isolated del(5q) primarily occurs in older women, and the female-to-male ratio is approximately 7:3 (Ingram et al. 2006). Because platelets and white blood cells are reasonably normal, there is a low incidence of bleeding and infection in these patients. Those with this form of MDS tend to have a good prognosis. They usually have a relatively benign course that extends over several years and have a low incidence of transformation into acute leukemia (Vardiman et al. 2008; Boultwood et al. 1994). MDS, unclassifiable (MDS-U)-This type of MDS has no distinguishing morphologic features and occurs infrequently. MDS-U subtypes exist as the following: MDS-U with 1 percent blood blasts MDS-U with SLD and pancytopenia MDS-U based on a defining cytogenetic abnormality For MDS-U patients the median survival and five-year cumulative risk of progression to AML is approximately 35 months and 14 percent, respectively. In addition to the diagnostic classification of MDS, a second classification system was developed for the purpose of treatment and management. Though the WHO also has a system to address/estimate prognosis (WPSS), the IPSS and IPSS-R systems are more commonly used for this purpose. These classifications of MDS will be reviewed in the analysis section of this document. Treatment of MDS Currently, there are a number of medical and surgical treatments in the management of patients with MDS. For patients with low-risk of AML transformation supportive care is available (e.g., transfusion therapy, erythropoietin, immunosuppressants), as well as treatment that is directed toward the specific cause of MDS (e.g., hypomethylating agents (HMA therapy)). Though these treatments may offer some temporary benefit, they do not alter the course of the disease. For patients at high-risk of AML transformation, more aggressive treatments such as chemotherapy that is used in the treatment of AML (intensive remission induction chemotherapy-IRIC), as well as hematopoietic allogeneic stem cell transplants (HSCT) are often part of the treatment regimen. Selection of treatment is influenced by the severity of symptoms and cytopenias, MDS classification, prognostic category, medical fitness, and patient preferences. Goals of therapy are different in patients at lower-risk (e.g., decrease need for transfusions and transformation to higher risk disease or AML) as opposed to patients at higher risk as well as in those with failure along the course of treatment (e.g., improve survival). These treatments not only improve blood counts but also delay onset of leukemia and improve survival. This NCD does not address the treatment and management of AML, which is a possible sequela of MDS. It is beyond the scope of this NCD. As mentioned before, treatment and management are often based on MDS classification strata as well as prognostic status. Hematopoietic Stem Cell Transplantation (HSCT) Hematopoietic stem cells are multi-potent cells that give rise to all the blood cell types. Sources of stem cells include bone marrow, umbilical cord, placenta, amniotic fluid, as well as peripheral blood. Stem cell transplantation (SCT) is a process that includes mobilization, harvesting, and transplant of stem cells and the administration of high dose chemotherapy and/or radiotherapy prior to the transplant. This pre-treatment cytoreduction process can take place in the form of Myeloablative Conditioning (MAC), which is generally reserved for patients ≤ 65 years of age, Non-myeloablative Conditioning (NMA), which usually uses much lower and less toxic doses of chemotherapy and radiation than MAC, or Reduced Intensity Conditioning (RIC), a form of NMA conditioning, which is generally preferred for patients > 65 years of age. Hematopoietic Stem Cell Transplantations (HSCT) have been around since the 1970s. During the process, stem cells are harvested from either the patient (autologous) or a donor (allogeneic) and subsequently administered by intravenous infusion to the recipient. For allogeneic transplants, the stem cell source may be a related or unrelated donor. In addition, the transplant can be HLA-identical (matched), unmatched or half-matched (also known as haplo-identical). The degree of matching is important because if the HLA match is not close, the donor’s immune cells, which are transplanted along with the donor’s stem cells, will attack the patient’s tissues; this is called graft versus host disease (GVHD). Allogeneic stem cell transplants (alloHSCT) may be used to restore function in recipients having an inherited condition (such as Sickle Cell Disease) or an acquired condition (such as occurs after severely myelotoxic doses of chemotherapy and/or radiotherapy, which are used to treat various malignancies). AlloHSCT might also be used in conditions or deficiencies or even a defect if they are amiable to transplants. Autologous stem cell transplants (AuSCT) are used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy and/or radiotherapy. Allogeneic Stem Cell Transplants in Patients with MDS Studies have shown that allogeneic hematopoietic stem cell transplantation provides the highest likelihood of long-term survival for patients with high/very high-risk MDS (Chang et al. 2007; Kröger et al. 2012; de Witt et al, 2017; Heidenreich et al. 2017), but participants included in those studies were younger than Medicare-aged patients. The lack of studies involving patients 65 and older is due to the high toxicity associated with myeloablative conditioning, and the inability of older patients with concomitant morbidities to tolerate these pre-transplant chemotherapy-related toxicities (Murillo, et al. 2018). The use of RIC is an attempt to ameliorate symptoms associated with the toxic effect of cytoreduction. Results from selected studies have reported prolonged disease-free survival in about 30 to 50% of patients who receive the transplant (Chang et al. 2007). It is the only approach that offers a substantial possibility of cure (Passweg, et al. 2011), and some believe that the earlier the transplantation is carried out in the disease course, the better are the long-term results. Because of the findings of these studies, some have advocated the use of allogeneic HSCT in patients with high-risk disease, even in patients of Medicare-aged population. Studies done in the past on younger patients (64 years and younger) have revealed that allogeneic HSCT has resulted in 30 to 52 percent overall survival (OS), 16 to 50 percent disease-free survival (DFS), and 10 to 50 percent treatment reduction mortality (TRM) at three years in patients with MDS (Saber et al. 2013; de Witte et al. 2000; Kindwall et al. 2009; Scott et al. 2006). Up until recently, there have been no studies that have demonstrated a clear association between age and clinical outcomes following the use of allogeneic HSCT in patients with high/very high-risk MDS (Lim et al. 2010; Sorror et al. 2011; Kröger et al. 2012; Bokhari et al. 2012; Wallen et al. 2005). Also, there are no randomized clinical trials that have directly compared allogeneic HCT versus intensive remission induction therapy or other intensive approaches for patients with high/very high-risk MDS. Some have also recommended the use of alloSCT in patients with low to intermediate-risk disease, especially if they possess certain mutations as well as cytogenic features (Robin et al. 2017; Platzbecker 2019; Jabbour, et al. 2015), but other studies have shown no benefit of using alloHSCT in patients with low-risk disease (Cutler, et al. 2004; Koreth, et al. 2013). Some believe that the current advances in transplant technology are sufficient to allow the use of alternative donors to be the source of allogeneic stem cell transplants in older patients with MDS (Garcia-Manero et al. 2020; Zhang , et al. 2017; Abel, et al. 2021), though others believe that patients, including those Medicare-aged with less advanced disease (e.g., low-risk) even when perfectly matched should not be exposed to the substantial risk of mortality from this procedure because of the favorable prognosis with standard treatment alone (de Witte, et al. 2017). III. History of Medicare Coverage CMS determined, on August 4, 2010, that the evidence did not demonstrate that the use of allogeneic hematopoietic stem cell transplantation (HSCT) improved health outcomes in Medicare beneficiaries with myelodysplastic syndrome (MDS). Therefore, the agency determined that allogeneic HSCT for MDS was not reasonable and necessary under §1862(a)(1)(A) of the Social Security Act (the Act). However, CMS believed the available evidence shows that allogeneic HSCT for MDS was reasonable and necessary under §1862(a)(1)(E) of the Act and could be covered through Coverage with Evidence Development (CED). Therefore, Allogeneic HSCT for MDS was covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that met specific criteria. Two CED studies were conducted and are included in the evidence review. See Appendix C for the complete NCD 110.23. A. Current Request CMS received a complete, formal joint request to reconsider NCD 110.23 from the American Society of Hematology (ASH), the American Society for Transplantation and Cellular Therapy (ASTCT), the National Marrow Donor Program (NMDP), and the Center for International Blood and Marrow Transplant Research (CIBMTR). The request seeks full coverage of allogeneic hematopoietic stem cell transplantation (HSCT) for individuals with myelodysplastic syndromes (MDS) and the removal of the Coverage with Evidence Development (CED) requirement currently tied to coverage for HSCT for Medicare beneficiaries with MDS. B. Benefit Category Medicare is a defined benefit program. For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act. CMS has determined that autologous and allogeneic stem cell transplantation fall within the benefit categories of inpatient hospital services under Part A and physicians’ services under Part B. §1861(b) (inpatient hospital services); §1861(s) (2) (incident to physician’s services). Please Note: This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service. IV. Timeline of Recent Activities Date Actions Taken June 6, 2023 CMS initiates this national coverage analysis. A 30-day public comment period begins. July 7, 2023 Initial 30-day public comment period ends. CMS receives 10 timely comments. December 7, 2023 Proposed decision memorandum posted. The second 30-day public comment period begins. January 6, 2024 Second 30-day public comment period ends. CMS receives 30 timely comments. March 6, 2024 CMS posts final decision memorandum. V. Food and Drug Administration (FDA) Status Hematopoietic stem/progenitor cells (HPC) for transplantation are considered human cells, tissues, and cellular- and tissue-based products (HCT/Ps) under 21 CFR 1271.3(d) defines human cells, tissues, or cellular or tissue-based products (HCT/Ps) as "articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient. Examples of HCT/Ps include, but are not limited to, bone, ligament, skin, dura mater, heart valve, cornea, hematopoietic stem/progenitor cells derived from peripheral and cord blood, manipulated autologous chondrocytes, epithelial cells on a synthetic matrix, and semen or other reproductive tissue…" FDA has a tiered, risk-based approach to the regulation of HCT/Ps. HCT/Ps that meet all of the criteria set forth in 21 CFR §1271.10(a) are regulated solely under section 361 of the Public Health Service Act (PHS Act) and the regulations in 21 CFR § 1271, and FDA’s premarket review and approval are not required. To satisfy these criteria, an HCT/P must: be minimally manipulated; be intended for homologous use only; not be combined with another article (with some limited exceptions); and, not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or if it does, it must be intended for autologous use or allogeneic use in a first- or second-degree blood relative. HCT/Ps that do not meet all of these criteria are regulated as drugs, devices, and/or biological products, and require FDA’s premarket review and approval. 21 CFR § 1271.3(a) defines the term autologous use as "the implantation, transportation, infusion, or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered." 1271.3(c) defines the term homologous use as "the repair, reconstruction, replacement or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor." Per 21 CFR §1271.3(d) and (d)(4), “minimally manipulated bone marrow for homologous use and not combined with another article (except for water, crystalloids, or a sterilizing, preserving, or storage agent, if the addition of the agent does not raise new clinical safety concerns with respect to the bone marrow)”, is not considered an HCT/P. Currently, the only stem cell products that are FDA-approved for use in the United States consist of blood-forming stem cells (also known as hematopoietic progenitor cells) that are derived from umbilical cord blood. These products are approved for limited use in patients with disorders that affect the body system that is involved in the production of blood (called the “hematopoietic” system). These FDA-approved stem cell products are listed on the following FDA website: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products . VI. General Methodological Principles When making NCDs, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member. The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary. A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A. Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will be redacted or will not be made available to the public on the CMS website. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination. VII. Evidence A. Introduction This section provides a summary of the evidence we considered during our review. The evidence reviewed to date includes the published medical literature on pertinent clinical trials of the use of allogeneic hematopoietic stem cell transplant in patients with MDS. Our assessment focuses on the three key evidence questions below in B.1. The focus of this National Coverage Analysis (NCA) is to determine if there is sufficient evidence to support the use of allogeneic hematopoietic stem cell transplant in Medicare beneficiaries 65 and older with MDS. B. Discussion of Evidence 1. Evidence Question(s) Question 1: Prospectively, compared to Medicare beneficiaries with MDS who do not receive allogeneic hematopoietic stem cell transplantation, do Medicare beneficiaries with MDS who receive allogeneic hematopoietic stem cell transplantation have improved outcomes as indicated by: relapse free mortality, progression free survival, relapse, and overall survival? Question 2: Prospectively, in Medicare beneficiaries with MDS who receive allogeneic hematopoietic stem cell transplantation, how do International Prognostic Scoring System (IPSS) score, patient age, cytopenias and comorbidities predict the following outcomes: relapse free mortality, progression free survival, relapse, and overall survival? Question 3: Prospectively, in Medicare beneficiaries with MDS who receive allogeneic hematopoietic stem cell transplantation, what treatment facility characteristics predict meaningful clinical improvement in the following outcomes: relapse free mortality, progression free survival, relapse, and overall survival? 2. External Technology Assessments CMS did not request an external technology assessment (TA) on this issue. 3. Internal Technology Assessment We searched PubMed/MEDLINE, Embase, and Web of Science for studies published between 2010 and 2023, using a combination of key words along with their synonyms, and Boolean operations to combine search terms. The following search criteria were used: “Myelodysplastic Syndromes” [MeSH] OR “MDS” AND “Hematopoietic Stem Cell Transplantation” [MeSH] AND “Allogeneic stem cell transplantation” [MeSH] “Aged” [MeSH] AND “Humans” [MeSH] AND “Clinical Trial” [MeSH] AND “Meta-Analysis” [MeSH] AND “Retrospective Analysis” [MeSH] AND “Randomized Controlled Trial” [MeSH] AND “English.” To ensure that we captured all the relevant articles, a search was conducted independently by the contractor International Consulting Associates (ICA), and the CMS Coverage and Analysis Group (CAG). Nine full text articles, including two Coverage with Evidence (CED) studies by Atallah et al. and Nakamura et al., met the inclusion criteria and were included in the NCD analysis. Table 1 contains the inclusion and exclusion criteria. Table 1 PICOTS Inclusion Criteria Exclusion Criteria Population All elderly patients (65+ years) with a diagnosis of MDS, no matter the classification or staging of the disease (based on International Prognostic Score System (IPSS-R) or WHO MDS classification). Based on classification, patients may be placed in groups based on potential for developing AML (very low, low, intermediate, high, very high). WHO classification is based on the number of bone marrow blasts and on the degree of atypias of hematopoietic lineages. These include: MDS with single-lineage dysplasia (MDS-SLD) MDS with multiple-lineage dysplasia (MDS-MLD) MDS with Ring Sideroblast (MDS-RS) MDS with isolated Del(5q) MDS with excess blast IPSS-R is based on the percentage of blasts in the bone marrow. Classification includes: Very low-risk low-risk Intermediate risk high-risk Very high-risk Patients with hematological disorders other than MDS Intervention Allogeneic Hematopoietic stem cell transplants Comparators Hypomethylating agents: (e.g., Azacitidine, Decitabine, Inqovi) Standard Chemo drugs: (e.g., Cytarabine (ara-C), Idarubicin, Daurnorubicin) Immunomodulating drugs: (e.g., Lenalidomide) Immune system suppression agents: (e.g., Anti-thymocyte globulin (ATG), Cyclosporin) Guideline-directed medical therapy Comparators other than those listed Outcomes Overall Survival Progression-free Survival Improved Quality of Life Reduction in recurrence of disease (relapse) Reduction in progression to AML Relapse-free survival Graft versus Host disease (GVHD) Infection Grade ≥ 3AEs Outcomes other than those listed Timing Study duration of follow-up: minimum of ≥ 1 year Follow up less than 1 year Setting All transplant centers No exclusion Study design Randomized controlled trials (RCTs), prospective observational, retrospective observational Required sample size (n =30) Existing systematic reviews or meta-analyses Post-protocol implementation and following discussion with CMS, non-comparative or single-arm studies that assess predictors of outcomes of interest among patients with MDS who all received AHSCT as well as those studies that evaluate HSCT in younger (< 65) versus older (=65) years were included via target searching to address relevant aspects of KQ2 and KQ3 Studies that do not meet the required study design, sample size, or publication type Publications Peer-reviewed, English-language publications Publication year: 2010-present Non-English language publications, abstracts, conference proceedings, gray literature, studies published before 2010 4. Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) A MEDCAC meeting was not convened on this issue. Below are four Evidence Tables. Table 2 contains characteristics of included studies. Table 3 contains study outcomes. Table 4 contains study outcomes according to IPSS or IPSS-R Classifications. Table 5 contains study outcomes relevant to Evidence Question 3. The full citation for the publications can be found in the bibliography of this decision memorandum which will allow anyone to find the information reviewed by CMS. Table 2. Characteristics of Included Studies Author, Year, Study, Study Design, Study Sites, Location, Funding Source, (Overall Study Quality) Total N, Intervention (n), Comparators (n), Follow up period (months) Age, median (range), Gender, Female N(%) Histology, Arm 1 vs Arm 2, n(%) Special Population Outcomes Assessed 1 Abel, 2021, NR, Prospective Observational Study, 2 centers (DFCI, MassGen), USA, Leukemia and Lymphoma Society Research Scholar Grant (GAA), (Good) Total: 290 Arm 1: AHSCT: 113(39) Arm 2: Non-AHSCT: 177(61) Follow up: 39.5 months (range: NR) Age: 69(60-75) Arm 1: 67(59-74) Female: 100(34) Arm 1: 40(36) Histology: NR IPSS Low: 43(15) Int-1: 120(41) Int-2: 107(37) High: 20(7) OS, PFS, NRM, Relapse 2 Kroger, 2021, VidazaAllo Study, Prospective nonrandomized controlled trial, Multicenter, NR; Neovii, Novartis, Celgene, Riemser; (Good) Total: 108 Arm 1: AHSCT (RIC): 81 Arm 2: Continuous 5-azacitidine: 27 Follow up: 36 months Age: Overall: NR Arm 1: 63(55-70)° Arm 2: 65(55-72) Female: Arm 1: 27(33) Arm 2: 16(59) Histology: MDS: 66 vs 18 RAEB ½: 60 vs 15 AML < 30% blasts: 14 vs 5 CMML: 1 vs 4 Blasts, median count (range) : 8 (0-28) vs 5 (0-18) IPSS Arm 1: Intermediate-1: 4, Intermediate-2: 40, High-risk: 36 Arm 2: Itermediate-1: 1, Intermediate-2: 16, High-risk: 10 TRM, Relapse, EFS, OS, aGvHD, cGVHD, AEs 10 Nakamura, 2021, CED study, Open-label multicenter non-randomized clinical trial, BMT CTN 1102, 34 transplantation centers, NIH Grants U10HL069294 and U24HL138660, (Good) Total: 384 Arm 1: RIC AHSCT (donor): 260 Arm 2: Non-AHSCT (no-donor): 124 Follow up: RIC AHSCT: 34.2 months (range: 2.3-38 months) Non-AHSCT: 26.9 months (2.4-37.2 months) Age, mean(SD) (years): 65.7(5.7) RIC AHSCT (donor): 65.6 (5.6) Non-AHSCT (no-donor): 66.0 (5.9) 65 years or older, n(%): Total: 235 (61.2) RIC AHSCT (donor): 155 (59.6) Non-AHSCT (no-donor): 80 (64.5) Female: 143 (37.2) RIC AHSCT (donor): 95 (36.5) Non-AHSCT (no-donor): 48 (38.7) Histology: NR IPSS-R, n(%) Arm 1 - RIC AHSCT (donor): Very low: 4 (1.5) Low: 2 (0.8) Int-1: 79 (30.4) Int-2: 82 (31.5) High: 93 (35.8) Arm 2 - Non-AHSCT (no-donor): Very low: 0 Low: 0 Int-1: 34 (27.4) Int-2: 51 (41.1) High: 39 (31.5) WHO, n(%) RCUD: Arm 1: 5 (1.9), Arm 2: 1 (0.8) RARS: Arm 1: 5 (1.9), Arm 2: 2 (1.6) RAEB-1: Arm 1: 61 (23.5), Arm 2: 31 (25) RAEB-2: Arm 1: 132 (50.8), Arm 2: 63 (50.8) RCMD: Arm 1: 36 (13.8), Arm 2: 14 (11.3) Isolated del(5q): Arm 1: 6 (2.3), Arm 2: 7 (5.6) Unclassifiable: Arm 1: 15 (5.8), Arm 2: 6 (4.8) OS, LFS, DFS, QOL 3 Platzbecker, 2012, NR, Retrospective Analysis, Multicenter, Germany and USA, NIH, (Good) Total: 178 Arm 1: AHSCT (103) RIC: 61(59) Conventional: 45(41) Arm 2: Azacitidine (75) Follow up: Arm 1: median, months (range): 39(7-154) Arm 2: median, months (range): 13(1-52) Age: Overall: NR Arm 1: 64 (60-70)° Arm 2: 66 (60-70) Female: Arm 1: 27(26) Arm 2: 20(27) Histology : Blasts , median % (range): 10 (0-80) vs 17 (6-59) FAB, n(%) RAEB: Arm 1: 41 (40) Arm 2: 45 (60) RAEB-T: Arm 1: 10 (10), Arm 2: 21 (28) AML: Arm 1: 43 (42), Arm 2: 7 (9) CMML: Arm 1: 9 (9), Arm 2: 2 (3) WHO, n(%) RAEB-1/CMML-1: Arm 1: 15 (15), Arm 2: 16 (21) RAEB-2/CMML-2: Arm 1: 28 (27), Arm 2: 31 (41) AML: Arm 1: 51 (50), Arm 2: 28 (37) Unknown: Arm 1: 9 (9), Arm 2: 0 (0) IPSS, n(%) INT-1: Arm 1: 9(9), Arm 2: 4(5) INT-2: Arm 1: 23(22), Arm 2: 29(39) HIGH: Arm 1: 19(18), Arm 2: 37(49) AML: Arm 1: 43(42), Arm 2: 0(0) Unknown: Arm 1: 9(9), Arm 2: 5(7) OS, EFS, Relapse rate/ progression, NRM 4 McClune, 2010, Retrospective Analysis, CIBMTR Registry, 28 centers, USA, NR, (Fair) AHSCT, Total: 55 Conditioning Regimen: RIC: 36(65) NMA: 19(35) Follow up: 36 (3-85) Age: ≥ 65 years: 67 (65-78) Female: 16(29) Histology: NR Disease status at transplantation, n(%) Early: 22(43) Advanced*: 29(57) OS, RFS, NRM, aGVHD, cGVHD 5 Atallah, 2019, CED study, Retrospective Analysis, CIBMTR Registry, 420 centers, USA, NR, (Fair) AHSCT-RIC Total: 688 TBI based Myeloablative: 13(2) Fludarabine+Busulfan +/-others Myeloablative: 167(24) Busulfan+Cyclo Myeloablative: 13(2) Fludarabine +Busulfan RIC: 167(24) Fludarabine+Melphalan RIC: 125(18) Fludarabine +TBI+Cytoxan RIC: 57(8) Other TBI based RIC: 98(14) Other Myeloablative: 4(< 1) Other RIC: 44(6) Follow up: 47 (13-73) Age: 67 (65-78) Female: 16(29) Histology: Blasts in BM prior to preparative regimen, % < 5: 443(64) 5-10: 134(19) 11-20: 75(11) Missing: 36(5) IPSS-R Very low: 48(7) Low: 68(10) Intermediate: 161(23) High: 101(15) Very high: 75(11) Missing: 188(27) WHO MDS, not otherwise specified: 121(18) RA: 31(5) CMML: 66(10) RARS: 38(6) RAEB-1: 140(20) RAEB-2: 147(21) RCMD: 124(18) RCMD/RS: 13(2) 5q-syndrome: 3(< 1) FAB RA/RARS: 209(30) RAEB: 287(42) CMML: 66(10) Others: 124(18) Missing: 2 (< 1) OS, Relapse, NRM, RFS, aGVHD, cGVHD 6 Heidenreich, 2016, NR, Retrospective Analysis, Multicenter, Europe, NR, (Fair) AHSCT-RIC Total: 313 MDS: 221(71) AML: 92(29) Conditioning Regimen: NMA: 54(17) RIC: 207(66)M MAC: 52(17) Follow up: 29.8 (26.4-37.1) Age (as used in univariate analysis), n(%) 70-71: 178(57) 72-73: 96(31) 74-78: 39(12) Female: 87(28) Histology: At transplantation, n=236 RA/RARS/del5q/RCMD-RS: 34(14) RAEB/RAEB-1/RAEB-2: 84(36) RAEB-t/transformed to AML: 30(13) Secondary AML from diagnosis onward: 88(37) IPSS-R (n = 72) Very good: 0 Good: 37(51) Intermediate: 16(22) Very poor: 8(11) “Abnormal” (not specified): 4(6) TRM, Relapse, EFS, OS, aGvHD, cGVHD, AEs 7 Yucel, 2017, NR, Retrospective Analysis, MD Anderson Cancer Center, Texas (USA), (Fair) AHSCT Total: 88 IPSS-R at HSCT, n (%) Total: 77(87.5) HMA alone 64(72) HMA and chemotherapy: 12(14) Chemotherapy alone: 1(1) Untreated: 11(12) Follow up: Median, months (range): 32 (6-98) Age: 65 (60-77) Female: NR Histology: At diagnosis, n=88 RA or RARS: 4(4.5) RCMD or RCMD-RA: 11(12.5) RAEB-1 or RAEB-2: 33(37.5) CMML-1 or CMML-2: 14(15.9) 5q syndrome: 1(1.1) MDS unclassified: 25(28.4) IPSS-R IPSS-R at HSCT, n (%) Low/very low: 22 (25) Intermediate: 20 (22.7) High/very high: 40 (45.5) Cumulative incidence of disease progression, TRM, OS, aGVHD, cGVHD Cusatis, 2021, Open label, multicenter, biologic assignment trial; The Blood and Marrow Transplant Clinical Trials Network study 1102 (BMT CTN 1102, NCT02016781) 34 transplantation centers, NIH Grants U10HL069294 and U24HL138660, (Good) Total: 384 Arm 1: RIC AHSCT (donor): 260 Arm 2: Non-AHSCT (no-donor): 124 Total: 384 Arm1 Arm2 Follow-up: 36 months Age- median age 66.7 Range 50.1 to 75.3 Gender-Donor Group Female 95 (36.4%) 166 (Male 63.6%) No Donor Group Female 48 (39%) Male 75 (61%) Histology-NR Highest IPSS Donor No Donor Intermediate-2 174 (66.7%) 80 (65%) high-risk 87 (33.3%) 43 (35%) Highest IPSS-R score Very Low 4 (15%) 0 Low 2 (.8%) 0 Intermediate 79 (30.3%) 34 (27%) High 82 (31.4%) 51 (41.5%) Very High 94 (36%) 38 (30.9) QoL °The eligibility criteria for median age was modified in retrospect to identify studies close to the Medicare population of 65 years and older, due to few studies meeting the PICOTs criteria. *Advanced MDS defined as refractory anemia excess blasts (in transformation), chronic myelomonocytic leukemia, or marrow blasts ≥ 5% Abbreviations: AEs = adverse events, aGVHD = acute GVHD, AHSCT = allogeneic hematopoietic stem cell transplant, AML = acute myeloid leukemia, BM = bone marrow, cGVHD = chronic CVHD, CIBMTR = Center for International Blood and Marrow Transplant Research, CMML = chronic myelomonocytic leukemia, DFCI = Dana-Farber Cancer Institute, EFS = event free survival, FAB = French-American-British classification system, GVHD = graft versus host disease, HMA = hypomethylating agent, IPSS = International Prognostic Scoring System, IPSS-R = Revised IPSS, MAC = myeloablative conditioning, MassGen = Massachusetts General Hospital, MDS = myelodysplastic syndrome, NIH = National Institutes of Health, NMA = non-myeloablative conditioning, NR = not reported, NRM = non-relapse mortality, OS = overall survival, RA = refractory anemia, RAEB = RA with excess blasts, RAEB-T = RAEB in transition to AML, RARS = RA with ringed sideroblasts, RCMD = refractory cytopenia with multilineage dysplasia, RCMD/RS = RCMD with ringed sideroblasts, RFS = relapse free survival, RIC = reduced intensity conditioning, TBI = total body irradiation, TRM = treatment related mortality, WHO = World Health Organization classification system Table 3. Study Outcomes Author, Year, Study, Study Design, Study Sites, Location, Funding Source, (Overall Quality) Intervention and Comparators Outcomes Survival Disease Progression Well-Being Adverse Events 1 Abel, 2021, NR, Prospective Observational Study, 2 centers (DFCI, MassGen), USA, Leukemia and Lymphoma Society Research Scholar Grant (GAA), (Good) Total: 290 Arm 1: AHSCT: 113(31) Arm 2: Non-AHSCT: 177(69) MDS Adverse risk: Yes: 175(60) No: 115(40) IPSS: Low/Int-1: 163(56) Int-2/High: 127(44) OS (at 36 months): 46% (95% CI, 40 to 52) OS (Arm 1 vs Arm 2), HR (95% CI), univariable analysis: 0.84 (0.61 to 1.17) RFS PFS (36 months): 53% LFS: NR EFS: NR Survivor follow up, median (range): 39.5 months (7-96) CIR: 39% AML Progression Risk: NR DoR: NR QoL: NR FS: NR LE: NR QALE: NR NRM (36 months): 9.3% Post-transplant median follow-up: NR aGVHD: NR cGVHD: NR TRM: NR AEs: NR 2 Kroger, 2021, VidazaAllo Study, Prospective nonrandomized controlled trial, Multicenter, NR; Neovii, Novartis, Celgene, Riemser, (Good) Arm 1: AHSCT (RIC): 81 Arm 2: Continuous 5-azacitidine (HLA matched): 27 OS (3 years): Arm 1: 50% (39 to 61) Arm 2: 32% (14 to 52) EFS (3 years): Arm 1: 34% (22 to 71) Arm 2: 0% Survivor median follow-up: NR RFS: NR PFS: NR LFS: NR AML Progression Risk: NR DoR: NR QoL: NR FS: NR LE: NR QALE: NR NRM: NR Post-transplant Median follow-up: NR aGVHD: Arm 1: II-IV = 33(41); III or IV = 12(15) Arm 2: NR cGVHD: Arm 1: 45(57) Arm 2: NR TRM (1 year): Arm 1: 19% (11 to 28) Arm 2: 0% AEs: Arm 1: 68 (84) Arm 2: 20(74) 10 Nakamura, 2021, Open-label multicenter non-randomized clinical trial, BMT CTN 1102, 34 transplantation centers, NIH Grants U10HL069294 and U24HL138660, (Good) Total: 384M Arm 1: RIC AHSCT (donor): 260 Arm 2: Non-AHSCT (no-donor): 124 OS (3 years): As-treated analysis: Arm 1 vs Arm 2: 47.4% v 16.4%, P < .0001 Treatment stratified Cox regression model (65+ years): 235, HR: 0.951, 95% CI (0.712, 1.270), P=0.7336 Treatment stratified Cox regression model (IPSS): INT-2 (1.5-2.0): 254, HR: 1, CI: n/a high-risk (> =2.5): 130, HR: 1.754, 95% CI (1.324 to 2.324), P< 0.0001 OS, Cox Models: 65+ years - Univariate analysis: (n=127), HR: 0.949, 95% CI (0.624 to 1.442), P=0.8056 IPSS - Multivariate analysis: INT-2 (1.5-2.0): 150, HR: 1, CI: n/a high-risk (> =2.5): 66, HR: 1.852, 95% CI (1.213 to 2.828), P< 0.0043 LFS As-treated analysis: Arm 1 vs Arm 2: 39.3% v 10.9%, P< 0.0001 Treatment stratified Cox regression model (65+ years): 235, HR: 0.942, 95% CI (0.726 to 1.220), P=0.6494 Treatment stratified Cox regression model (IPSS): INT-2 (1.5-2.0): 254, HR: 1, CI: n/a high-risk (> =2.5): 130, HR: 1.541, 95% CI (1.189 to 1.997), p< 0.0011 DFS (Cox models) IPSS - Multivariate analysis: INT-2 (1.5-2.0): 150, HR: 1, CI: n/a high-risk (> =2.5): 66, HR: 2.167, 95% CI (1.469 to 3.198), P< 0.0001 65+ years - Univariate analysis: (n=127), HR: 0.967, 95% CI (0.656 to 1.425), P=0.8657 AML Progression Risk: NR DoR: NR QOL (at 36 months), Mean (SE), Median (Range) FACT-G Total Score: Arm 1 (n=58): 90.3(2.0), 95.0 (41.0 to 108.0) Arm 2 (n=11): 79.7 (5.9), 81.0 (42.3 to 108.0) MOS Short Form-36 Physical Component Score: Arm 1 (n=59): 44.0 (1.3), 45.6 (12.6 to 58.4) Arm 2 (n=11): 39.3 (3.9), 38.3 (12.4 to 58.6) MOS Short Form-36 Mental Component Score: Arm 1 (n=59): 54.0 (1.1), 56.3 (28.7 to 67.1) Arm 2 (n=11): 53.6 (4.4), 60.0 (16.5 to 65.2) EQ-5D Utility Score: Arm 1 (n=59): 0.835 (0.024), 0.843 (-0.019 to 1.000) Arm 2 (n=11): 0.789 (0.061), 0.843 (0.335 to 1.000) aGVHD: NR cGVHD: NR TRM: NR AEs: NR 3 Platzbecker, 2012, NR, Retrospective Analysis, Multicenter, Germany and USA, NIH, (Good) Total: 178 Arm 1: AHSCT (103) RIC: 61(59) Conventional: 45(41) Arm 2: Azacitidine (75) OS (2 years): Arm 1: 39% (30-50) Arm 2: 23% (14-40) OS (5 years): Arm 1: 35% (26-47) Arm 2: NR EFS (2 years): Arm 1: 37% (28-48) Arm 2: 14% (7-27) EFS (5 years): Arm 1: 36% (27-47) Arm 2: NR Arm 1 vs Arm 2 (at 1 year): OS, HR (95% CI): 1.3 (0.8-2.3), p=0.30 EFS, HR (95% CI): 0.9 (0.5-1.4), p=0.60 Arm 1 vs Arm 2 (after 1 year): OS, HR (95% CI): 0.3 (0.1-0.7), p=0.007 EFS, HR (95% CI): 0.4 (0.2-0.97), p=0.04 Survivor median (range) follow-up: Arm 1: 39 months (7-154) Arm 2: 13 months (1-52) AML Progression Risk: NR DoR: NR QoL: NR FS: NR LE: NR QALE: NR NRM: Arm 1: 33% (23-42) Arm 2: 34% (22-45) Post-transplant Median follow-up: NR aGVHD: NR cGVHD: NR TRM: NR AEs: NR Cusatis, 2021, Open label, multicenter, biologic assignment trial; The Blood and Marrow Transplant Clinical Trials Network study 1102 (BMT CTN 1102, NCT02016781) 34 transplantation centers, NIH Grants U10HL069294 and U24HL138660, (Good) Total: 384 Arm 1: RIC AHSCT (donor): 260 Arm 2: Non-AHSCT (no-donor): 124 Total: 384 Arm1 Arm2 OS (3 years): As-treated analysis: Arm 1 vs Arm 2: 47.4% v 16.4%, P < .0001 LFS As-treated analysis: Arm 1 vs Arm 2: 39.3% v 10.9%, P < 0.0001 AML Progression Risk: NR DoR: NR QoL at enrollment, every 6 months until 24 months, and 36 months. Functional Assessment of Cancer Therapy—General (FACT-G), SF-36 (which included Physical component score (PCS) and Mental component score (MCS)), and EQ-5D were used to assess QoL and their association with outcomes. Baseline FACT-G < 70 (hazard ratio [HR] = 1.61, p < .01), PCS scores < 40 (HR = 1.82, p < 0.001), and EQ-5D < 0.8 (HR = 1.51, p < .05) were significantly associated with overall survival and leukemia-free survival. Also, IPW-IEE models predicting 12 through 36-month QOL found baseline and 6-month scores significantly predict future QOL for FACT-G (baseline MC = 0.168, p < .01; 6-month MC = 0.529, p < .0001), PCS (baseline MC = 0.224, p < .01; 6-month MC = 0.453, p < .0001), and MCS (baseline MC = 0.183, p < .01; 6-month MC = 0.496, p < .0001) after controlling for treatment effect, age, race, ethnicity, disease duration, performance score, IPSS, and response to prior hypomethylation. aGVHD: NR cGVHD: NR TRM: NR AEs: NR Abbreviations: AEs = adverse events, aGVHD = acute GVHD, AHSCT = allogeneic hematopoietic stem cell transplant, AML = acute myeloid leukemia, cGVHD = chronic CVHD, CIBMTR = Center for International Blood and Marrow Transplant Research, CIR = cumulative incidence of relapse, DFCI = Dana-Farber Cancer Institute,