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

Umbilical cord blood (UCB) has been used as a graft source for a hematopoietic stem cell transplants (HSCT) in over 45,000 transplants worldwide, and thus is a well-established graft source for this procedure. UCB has several advantages over other sources of hematopoietic stem cells, including a non-invasive collection process, immediate availability, less stringent HLA matching requirements, and lower incidence of chronic graft-versus-host disease.¹

The proposed language by CMS related to HSCT for patients with myelodysplastic syndromes specifies that allogenic HSCT will only include bone marrow or peripheral blood stem cell products. The current language excludes UCB as a graft source in this setting. HSCT using UCB for myelodysplastic syndromes has been well-documented in the literature. A comparative retrospective review of trials which included UCB as a graft source for HSCT for hematologic malignancies, including myelodysplastic syndromes, was described by Kindwall-Keller and Ballen². The data indicates that UCB has comparable outcomes for hematologic malignancies as compared to bone marrow or peripheral blood stem cells from a matched unrelated or a mismatched unrelated donor, suggesting that UCB is an excellent alternative graft source.

By excluding UCB as a graft source for HSCT, this will likely limit treatment access for patients with myelodysplastic syndromes where an adequately matched bone marrow or peripheral blood donor is not available.

1. Zhu X, Tang B, Sun Z. Umbilical cord blood transplantation: Still growing and improving. Stem Cells Transl Med. 2021;10 Suppl 2(Suppl 2):S62-S74. doi:10.1002/sctm.20-0495
2. Kindwall-Keller TL, Ballen KK. Alternative Donor Graft Sources for Adults with Hematologic Malignancies: A Donor for All Patients in 2017!. Oncologist. 2017;22(9):1125-1134. doi:10.1634/theoncologist.2017-0009

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City of Hope
1500 East Duarte Road Duarte, CA 91010-3000
Phone 800-826-HOPE
Fax 800-555-5555
CityofHope.org

January 7, 2024

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) CAG-00415R

Dear Ms. Syrek Jensen:

On behalf of City of Hope, we thank you for the opportunity to submit comments regarding the Proposed Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) CAG-00415R. City of Hope is the only freestanding National Cancer Institute(NCI)–designated Comprehensive Cancer Center in California that is not affiliated with a university, and one of the 11 prospective payment system (PPS)-exempt specialty cancer centers. City of Hope has the largest allogeneic HSCT (alloHSCT) programs in the nation, having performed more than 19,000 blood and marrow transplants since our program was founded more than 40 years ago and has delivered alloHSCT to patients with a consistent record of high performance in the Stem Cell Therapeutic Outcomes Database (SCTOD) annual center-specific survival analyses. We are dedicated to delivering the highest quality care to our patients while advancing both laboratory and clinical research on innovative treatments and cures for cancer and other life-threatening diseases.

We commend the Center for Medicare & Medicaid Services (CMS) for their continued efforts to improve patient access to high quality lifesaving care. We believe that the agency’s proposal to remove the designation of “coverage under evidence development” for Medicare beneficiaries with MDS is an important first step in improving equitable access to potentially lifesaving alloHSCT. We believe, however, that some important revisions are needed to the proposed decision memo, however, to allow CMS beneficiaries full and equitable access to alloHSCT, which is the only known curative treatment for patients with MDS. We believe that there are three missed opportunities within the proposed coverage determination:

1. Under the CMS proposed coverage determination, transplantation for beneficiaries with MDS who do not meet high-risk criteria would be left to the separate and independent discretion of the 12 Medicare Administrative Contractors (MACs) across the United States.

2. This coverage determination would limit the stem cell sources only to related and unrelated blood and/or marrow grafts. CMS beneficiaries would be ineligible to receive transplantation using cord blood grafts. The population most adversely impacted by the decision to not include cord grafts will be patients who are from underrepresented minorities or bi-racial, because often the only appropriately matched cell product for them is a cord blood product. Based upon our review of the literature and our extensive experience in delivering transplant services to this patient population, we recommend that the agency carefully re-examine these exclusions and consider revisions to the coverage determination that would provide CMS beneficiaries with coverage that reflects the clinical outcomes data more fully.

3. Risk stratification systems for MDS have been rapidly evolving with the advance in our understanding of the molecular profiles and their prognostic impact upon patients affected by these diseases. Therefore, the use of a specific risk model (International Prognostic Scoring System – Revised) can easily become outdated over time. We believe that the coverage should be based upon any of the current, validated scoring systems recognized by the authoritative organizations, such as the National Comprehensive Cancer Networks (NCCN) and/or expert panels in the academic societies such as the American Society for Hematology (ASH)/American Society for Transplantation and Cellular Therapies (ASTCT).

We would like to expand our comments regarding the following concerns:

Exclusion of Intermediate Risk MDS Patients
Both the NCCN Clinical Practice Guidelines and the ASTCT consensus statement on indications for transplantation include alloHSCT as one of the standards of care for patients with MDS.^1,2 In alignment with the proposed coverage determination, each of these independently produced guidelines recognizes transplantation for patients with myelodysplastic syndromes designated as high-risk or very high-risk with a score of = 4.5 points according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R) as a standard of care treatment.^1.2 Yet this set of transplant eligibility criteria are incomplete. In its extensive review of the prospective and retrospective literature, the agency notes:

For those studies that did a comparative analysis based on treatment, they all showed that patients who received alloHSCT had superior outcomes compared to patients who received alternative therapy...

In those studies that evaluated Disease-free survival/Leukemia-free survival/Event-free survival/Progression-free survival as an outcome, patients that received alloHSCT had better outcomes (longer disease-free intervals) than patients who received alternative treatments...

In summary, the use of alloHSCT in patients with MDS provides a benefit of improved survival as well as prolonged disease-free intervals, with no decrease in quality of life compared to alternative treatments. AlloHSCT provides other favorable outcomes to patients with MDS. The studies also revealed that age is not a contributing factor in these outcomes. In conclusion, based on the analysis of all the above studies Medicare-aged patient with MDS had improved health outcomes after alloHSCT.³

We concur with this analysis. Where we disagree with the agency’s analysis is in what we believe is an undervaluing by the agency of the positive impact and improved outcomes achieved by patients with intermediate risk MDS. In the agency’s analysis, one of the key papers cited in this determination is the trial led by Dr. Nakamura of City of Hope.⁴ While we agree with the agency’s interpretation of these data, we are concerned that the Agency has incorrectly undervalued the beneficial impact of alloHSCT upon patients with a risk score <4.5, despite the Agency having noted that, "The survival benefit was seen across all subgroups of MDS."³

We respectfully request that the agency reexamine these outcomes data because we believe that the benefit to lower risk patients is very clear from these data and justify the inclusion of this intermediate-risk group of patients under the coverage determination. Here are data representing the overall study outcomes with accompanying forest plots showing the clear benefit of alloHSCT for lower risk patients than those included under this proposed coverage determination.

In addition, we have retrospectively reviewed the outcomes for 363 patients with MDS who underwent alloHSCT at City of Hope between 2014 and 2022. Among the 363 MDS patients, 130 patients had IPSS-R scores < 4.5 and 233 patients had IPSS-R scores = 4.5. The IPSS-R score used was the higher of the two scores determined at diagnosis and at transplant. The median follow-up time from HCT to last contact or death is approximately 24 months. The 2-year point estimates of Overall Survival (OS), Progression-Free Survival (PFS), Cumulative Incidence of Relapse or Progression (RP), and Non-Relapse Mortality (NRM) are summarized in the following table. Once again, these data validate the significant benefit for alloHSCT for patients with both intermediate- and high-risk MDS.

Survival Outcome Summary for MDS patients with AlloHSCTs between 2014 and 2022 (N=363)

Post-alloHSCT Follow-Up / Endpoints
Median (Range)
N (%)
Points of Estimate (95% CI)
Time from Transplant to Last Contact or death (months)
All, N=363
      Alive (n=213)
      Dead (n=150)
22.0 (0.3 – 99.7)
35.6 (5.5 – 99.7)
8.0 (0.3 – 77.8)
IPSS-R Score
      < 4.5
     > 4.5
130 (36%)
233 (64%)
Time from Transplant to Last Contact or death (months)
      IPSS-R score < 4.5 (n=130)
      IPSS-R score > 4.5 (n=233)
24.0 (0.3 – 99.7)
19.1 (0.4 – 97.8)
Overall Survival at 2 years
     IPSS-R score < 4.5 (n=130)
      IPSS-R score > 4.5 (n=233)
72 (95% CI: 63 – 80)
59 (95% CI: 52 – 66)
Progression-Free Survival at 2 years
     IPSS-R score < 4.5 (n=130)
     IPSS-R score > 4.5 (n=233)
65 (95% CI: 56 – 73)
56 (95% CI: 49 – 63)
Relapse/Progression at 2 years
     IPSS-R score < 4.5 (n=130)
     IPSS-R score > 4.5 (n=233)
10 (95% CI: 6 – 18)
19 (95% CI: 15 – 25)
Non-Relapse Mortality at 2 years
      IPSS-R score < 4.5 (n=130)
     IPSS-R score > 4.5 (n=233)
24 (95% CI: 18 – 34)
25 (95% CI: 20 – 31)

Outcomes by Age at HSCT

Factor, Post-HSCT Follow-Up and Endpoints
Median (Range)
N (%)
Points of Estimate (95% CI)
Number of Patients, by Age at HSCT (N=363)
< 65 years old
> 65 years old 64 (7 – 78)
186 (51%)
177 (49%)
Time from Transplant to Last Contact or death (months)
      Age < 65
      Age >= 65
24.3 (1.0 – 99.7)
22.7 (0.3 – 96.6)
Overall Survival at 2 years
      Age < 65
      Age >= 65
68 (95% CI: 62 – 75)
59 (95% CI: 52 – 67)
Progression-Free Survival at 2 years
      Age < 65
     Age >= 65
64 (95% CI: 57 – 71)
54 (95% CI: 46 – 62)
Relapse/Progression at 2 years
     Age < 65
     Age >= 65
13 (95% CI: 9 – 19)
19 (95% CI: 14 – 27)
Non-Relapse Mortality at 2 years
     Age < 65
     Age >= 65
23 (95% CI: 17 – 30)
26 (95% CI: 20 – 34)

Outcomes by IPSS-R Score and Age at HSCT

Factors and Endpoints N (%) or
Points of Estimate (95% CI)
Number of Patients, by IPSS-R score and Age at HSCT (N=363)
     Score < 4.5 and Age < 65
     Score < 4.5 and Age >= 65
     Score >= 4.5 and Age < 65
     Score >= 4.5 and Age >= 65
72 (20%)
58 (16%)
114 (31%)
119 (33%)
Time from Transplant to Last Contact or death (months)
     Score < 4.5 and Age < 65
     Score < 4.5 and Age >= 65
     Score >= 4.5 and Age < 65
     Score >= 4.5 and Age >= 65
24.3 (1.0 – 99.7)
22.7 (0.3 – 96.6)
24.0 (0.5 – 97.8)
12.7 (0.4 – 96.9)
Overall Survival at 2 years
     Score < 4.5 and Age < 65
     Score < 4.5 and Age >= 65
     Score >= 4.5 and Age < 65
     Score >= 4.5 and Age >= 65
75 (95% CI: 62 – 83)
69 (95% CI: 55 – 80)
64 (95% CI: 54 – 73)
55 (95% CI: 44 – 63)
Progression-Free Survival at 2 years
      Score < 4.5 and Age < 65
     Score < 4.5 and Age >= 65
     Score >= 4.5 and Age < 65
     Score >= 4.5 and Age >= 65
70 (95% CI: 57 – 79)
59 (95% CI: 44 – 72)
61 (95% CI: 51 – 70)
52 (95% CI: 42 – 61)
Relapse/Progression at 2 years
     Score < 4.5 and Age < 65
     Score < 4.5 and Age >= 65
     Score >= 4.5 and Age < 65
     Score >= 4.5 and Age >= 65
9 (95% CI: 4 – 20)
12 (95% CI: 6 – 26)
15 (95% CI: 10 – 23)
23 (95% CI: 16 – 32)

Factors and Endpoints
Points of Estimate (95% CI)
Non-Relapse Mortality at 2 years
     Score < 4.5 and Age < 65
     Score < 4.5 and Age >= 65
     Score >= 4.5 and Age < 65
     Score >= 4.5 and Age >= 65
21 (95% CI: 13 – 34)
29 (95% CI: 18 – 44)
24 (95% CI: 17 – 33)
25 (95% CI: 18 – 35)

Once again, these data validate the significant benefit for alloHSCT for patients with both intermediate- and high-risk MDS. Based upon these data, as well as the additional data sets that led the agency to conclude that, “The survival benefit was seen across all subgroups of MDS,” we respectfully request that CMS extend the coverage determination to include alloHSCT coverage for patients with intermediate-risk MDS as well as high-risk and very high risk MDS.

The NCCN Practice Guidelines for the treatment of MDS on the use of alloHSCT note that

Patients with IPSS Intermediate-1, IPSS-R Intermediate, and WPSS Intermediate Risk MDS with severe cytopenias would also be considered candidates for HCT. Matched sibling, unrelated donor, or alternative (haploidentical or cord blood when appropriate) donor, including standard and reduced-intensity preparative approaches, may be considered.

We believe that this articulation of the standard of care for this population of patients would be a better and more inclusive standard for coverage that fully reflects the published literature to date, including data from Nakamura et al⁴, Atallah et al⁵, Kroger et al⁶, and McClune et al⁷. In their analysis, Atallah et al found that, “On multivariable analysis after adjusting for excess risk of mortality in the older group, age had no significant association with OS (HR, 1.09; 95% CI, 0.94-1.27; P?=?.23) or NRM (HR, 1.19; 95% CI, 0.93-1.52; P?=?.16).”

The preponderance of clinical evidence demonstrates that alloHSCT is effective for patients with intermediate risk MDS. Based upon this, alloHSCT is included as a standard of care recommendation for lower risk MDS under both the NCCN and ASTCT Practice Guidelines and Transplant Indications, respectively^1.2

In addition to the recommendation to expand coverage eligibility to Medicare beneficiaries with intermediate risk MDS, we additionally recommend the inclusion of patients with secondary or treatment related MDS under the coverage determination. This biologically distinct subset of MDS patients have a very poor prognosis with non-transplant treatments. AlloHSCT is the sole curative option for this group of patients.⁸ This should be reflected in the coverage decision.

Exclusion of Cord Blood as a Hematopoietic Stem Cell Source
In its proposed coverage determination, the agency notes:

In this national coverage analysis, the sources of stem cells included bone marrow as well as peripheral blood. As mentioned in the background section, other sources of stem cells may include the placenta, amniotic fluid, as well as cord blood. None of the included studies used these other sources for stem cells. There is no study evidence that other sources for stem cell transplantation in Medicare patients with MDS have similar benefits and harms treatment profiles. Therefore, we propose that national coverage will be restricted to the sources of stem cells used in the studies reviewed as part of this analysis (bone marrow and peripheral blood).

The rationale for the exclusion of cord blood grafts from this coverage determination is unclear. The study published by Atallah et al⁴ included 61 patients who received either single or double units of cord blood as their hematopoietic stem cell grafts. We believe that the coverage determination should be revised to provide transplant physicians with the clinical discretion to make use of the hematopoietic allogeneic stem cell source that is most appropriate. We recommend that all clinically established donor sources should be allowed, including bone marrow, peripheral blood stem cells, and (single or double) cord blood units to support greater care access and to improve care equity for underserved patients for whom blood or marrow stem cell grafts may not be available. The use of cord blood stem cell grafts is included as one of the standards of care for MDS patients (with category 2A evidence) under the NCCN practice guidelines.¹

Conclusion
We appreciate the opportunity to provide feedback to the Agency on this proposed coverage determination. We offer our insights based on our extensive experience in caring for older patients with MDS at one of the nation’s leading alloHSCT centers. We urge CMS to consider our recommendations and revise the coverage determination to provide its beneficiaries with care access that is equitably aligned with that available to patients with other types of health care coverage. We are concerned that the current version of the coverage determination, without revisions, would create a two-tiered system of access that could potentially worsen care access disparities. The relegation of alloHSCT coverage discretion for a large portion of transplant-eligible Medicare beneficiaries to the MACs would create confusion amongst referring physicians as to which patients are transplant eligible and could exacerbate existing referral barriers.

City of Hope remains committed to working alongside CMS and other stakeholder groups to support revision of the proposed coverage determination in ways that would improve beneficiary access to lifesaving care and would enhance alignment between referring physicians and transplant centers across the country.

Thank you once again for your consideration of our comments and for your efforts in shaping a healthcare system that fosters excellence and compassion. We look forward to continued collaboration in creating a brighter future for greater healthcare equity in our nation.

Sincerely,

Harlan Levine, MD
President, Health Innovation and Policy

Joseph Alvarnas, MD
Vice President of Government Affairs
Professor, Department of Hematology & Hematopoietic Cell Transplantation

Ryo Nakamura, MD
Jan & Mace Siegel Professor in Hematology & Hematopoietic Cell Transplantation, Division of Leukemia, Department of Hematology & Hematopoietic Cell Transplantation
Director, Center for Stem Cell Transplantation

Eileen P. Smith, MD
Professor; Francis & Kathleen McNamara Distinguished Chair in Hematology and Hematopoietic Cell Transplantation

F. Marc Stewart, MD
Chief Medical Officer
Professor, Department of Hematology & Hematopoietic Cell Transplantation

Guido Marcucci, MD
Chief, Division of Leukemia
Director, Gehr Family Center for Leukemia Research
Chair, Department of Hematologic Malignancies Translational Science
Professor, Department of Hematology & Hematopoietic Cell Transplantation
Director, Hematopoietic Tissue Biorepository (HTB)

Stephen J. Forman, MD
Director, Hematologic Malignancies Research Institute
Professor, Department of Hematology & Hematopoietic Cell Transplantation

References
1. Greenberg PL, Stone RL, Al-Kali A, et al. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes Version 1.2023. National Comprehensive Cancer Network, Inc. 2023. All rights reserved. www.nccn.org. Accessed January 2, 2024.
2. Kanate AS, Majhail NS, Savani BN, Bredeson C, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. 26 (2020): 1247-1256.
3. Centers for Medicare and Medicaid Services. Allogeneic hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). https://www.cms.gov/medicare-coverage-database/view/ncacal-decision-memo.aspx?proposed=Y&NCAId=312
4. Nakamura R, Saber W, Martens MJ, et al. Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age with Advanced Myelodysplastic Syndrome. J Clin Onc 2021.
5. Atallah E, Logan B, Chen M, et al. Comparison of patient age groups in transplantation for myelodysplastic syndrome: the Medicare Coverage with Evidence Development study. JAMA Oncol. 2020 ;6(4) :486-493.
6. Kröger N. Allogeneic stem cell transplantation for elderly patients with myelodysplastic syndrome. Blood. 2012; 119:5632.
7. McClune B, Weisdorf D, Pedersen T, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010 Apr 10;28(11):1878-87. doi: 10.1200/JCO.2009.25.4821.
8. Methey L, Callander NS, Hall AC, Zhang MJ, et al. Allogeneic Transplantation to Treat Therapy-Related Myelodysplastic Syndrome and Acute Myelogenous Leukemia in Adults. Transplant Cell Ther. 2021 Nov;27(11):923.e1-923.e12. doi: 10.1016/j.jtct.2021.08.010.

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The Aplastic Anemia and MDS International Foundation (AAMDSIF) welcomes the opportunity to comment on the proposed decision memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS). As a patient advocacy organization, we appreciate the proposed removal of coverage with evidence development (CED) criteria for HSCT patients with MDS. We are writing to express our agreement with ASH, ASTCT, NMDP, and CIBMTR for the following modifications to support appropriate medical indications and equitable access to care:

- Remove the exclusion of cord blood as a donor source – this exclusion potentially limits equitable access to transplantation for some Medicare patients, particularly those from certain racial and ethnic populations for whom cord blood may be the only HSCT option if a matched allogenic adult donor cannot be identified. Cord blood is also an important option for patients who need treatment urgently, regardless of their racial or ethnic status, due to its rapid availability. Cord blood has been an accepted graft source for transplantation for many years and individual physicians are in the best position to judge which graft source best fits the needs of their patients.

- Allow use of the most current validated scoring system as recognized by the World Health Organization and the NCCN - the IPSS-R is currently being replaced as the clinical standard by the IPSS-M as the clinical standard because it incorporates important molecular mutations in the prognostic model as well as changes in patients over time and across treatments. As scoring systems evolve and new prognostic factors are incorporated, patients’ classification and risk level may change significantly so flexibility in the CMS coverage is needed so physicians can provide the most appropriate treatment options based on the most current approach to assessing risk.

- Inclusion of intermediate risk MDS – the benefit of allogeneic HSCT for patients with intermediate risk MDS compared to currently available conventional therapy is supported by extensive clinical evidence, particularly the BMT CTN 1102 study which demonstrated a survival advantage in these patients as well as high risk patients. Also, the above noted evolution of risk level scoring systems may re-categorize MDS patients into a higher-risk prognosis.

- Inclusion of secondary MDS – patients with secondary MDS, which develops as a consequence of prior chemoradiotherapy, are typically considered to have very high-risk disease and allogeneic HSCT is the only accepted therapy for secondary MDS. We support CMS coverage of allogeneic HSCT for all Medicare beneficiaries with secondary MDS.

On behalf of the MDS patients whom we serve, AAMDSIF encourages your consideration of these modifications to CMS coverage of allogeneic HSCT based on medical evidence to benefit as many Medicare beneficiaries as possible.

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I disagree with any decision to restrict the physician's ability to make the best choice of care for their patients with MDS. I believe that creating rigid restrictions would preclude the use of a potentially life saving transplant for patients who may not meet formal criteria (for a variety of reasons) but who clearly require a transplant. I also worry about restrictions regarding the donor stem cell source as there are many issues related to access for patients and these new rules could create increased inequity in who would be eligible for transplant (certain minority groups have a lower likelihood of having an unrelated bone marrow match in public banks).

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An IPSS-R cutoff of 4.5 is not an appropriate threshold for determining eligibility for hematopoietic cell transplantation (HCT). Specifically, this cutoff would exclude patients who have life-threatening cytopenias but no increase in blasts. In this scenario, some patients with MDS become transfusion dependent and/or at risk of severe infections due to prolonged neutropenia. Although they may not have excess blasts or high-risk cytogenetics, they have functional marrow failure. These individuals are still at risk of substantial morbidity/mortality and would benefit from prompt allogeneic HCT; delay increases the risk of ineligibility due to alloimmunization, iron overload affecting organ function, and uncontrolled infections due to prolonged neutropenia. In the era of PTCy with marked improvement in overall HCT safety, patients with MDS should not have to wait until their IPSS-R reaches 4.5 to become eligible for a potentially life-saving allogeneic HCT, especially when this arbitrary threshold fails to capture the marrow failure phenotype of MDS.

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January 5, 2024

Tamara Syrek Jensen, JD
Director, Coverage & Analysis Group
Centers for Medicare & Medicaid Services
7500 Security Boulevard
Baltimore, MD 21244

Re: Proposed Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) CAG-00415R

Dear Ms. Syrek Jensen:

On behalf of the American Society of Hematology (ASH), the American Society for Transplantation and Cellular Therapy (ASTCT), the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), the Center for International Blood and Marrow Transplantation (CIBMTR), and the National Marrow Donor Program (NMDP), thank you for this opportunity to comment on the proposed decision memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS). We are pleased that the Centers for Medicare & Medicaid Services (CMS) has proposed to remove the coverage with evidence development (CED) criteria for HSCT for patients with Myelodysplastic Syndromes (MDS), but note that important modifications are needed to the proposed decision memo to support appropriate medical indications and equitable access to care.

Allogeneic HSCT is the only curative therapy for patients with MDS, a group of blood disorders in which the bone marrow does not produce enough healthy, functioning blood cells. MDS primarily impacts older adults. The median age at diagnosis is 70 years, making Medicare coverage for HSCT essential for most patients to have access to this life-saving treatment.

The patients we care for have greatly benefited from the CED policy established more than 10 years ago. The availability of HSCT through the CIBMTR and BMT CTN CED studies dramatically increased access among Medicare beneficiaries to levels that reflect the clinically appropriate need in the patient population, as demonstrated by the growth in annual volume from fewer than one hundred patients per year before 2010 and to more than seven hundred per year in 2022. We appreciate the Agency’s work on this issue and appreciate the commitment to appropriate patient care.

The proposed decision memo requests comments on the nationally covered indications for allogenic HSCT under section 110.23 – Stem Cell Transplantation (Formerly 110.81) of the Medicare National Coverage Determinations Manual. The proposed modifications to the nationally covered indications are as follows: c) Effective for services performed on or after xx/xx/xx, allogeneic HSCT using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes (MDS) designated as high-risk or very high-risk with a score of = 4.5 points according to criteria specified by the International Prognostic Scoring System-Revised (IPSS-R).

We respectfully submit the following proposed changes, as follows:

c) Effective for services performed on or after xx/xx/xx, allogeneic HSCT hematopoietic stem cell sources for Medicare patients with myelodysplastic syndromes (MDS) designated as intermediate or high-risk according to criteria specified by a current validated scoring system, as recognized by authoritative clinical bodies such as the World Health Organization or National Comprehensive Cancer Network (NCCN).

The following comments support our requested changes to the text.

Exclusion of Cord Blood as a Donor Source:

The specific exclusion of cord blood as a graft source will limit the availability of curative transplantations for some Medicare patients, particularly those from certain racial and ethnic populations. Many Medicare beneficiaries, particularly those who are not of Caucasian descent, will have difficulty identifying a suitably matched allogenic adult donor and cord blood may be the only HSCT option. Cord blood provides an additional option for any patient, no matter their racial or ethnic status, and has been shown to be an effective hematopoietic stem cell source in numerous studies over the past twenty years. It has the advantage of being rapidly available, an asset for patients with very high-risk disease. We believe that the physician must be able to choose the best available graft source for their patients, based on the patient’s unique disease characteristics, acuity, and the degree of Human Leukocyte Antigens (HLA) match and availability of the stem cell product. Data from the CIBMTR indicate that cord blood provides access to HSCT for a small, but meaningful number of patients annually. It should be noted that cord blood is included as a stem cell source under the current CIBMTR CED study and accounted for about sixty patients in the 2020 JAMA Oncology paper resulting from that CED (Atallah, E. et.al); in multivariate analyses of HSCT outcomes in that study, results were like other unrelated donor graft sources.

The rationale to exclude cord blood under the proposed NCD is unclear, would be inconsistent with current policy regarding allogeneic HSCT under the CED and for other indications, and would exclude a donor source that may be the best source available to certain populations. Therefore, we strongly encourage CMS to rephrase the covered indications to state hematopoietic stem cell sources as opposed to limiting language to “bone marrow or peripheral blood stem cell products” to allow the physician to have the decision-making power to determine the most appropriate donor source.

In the proposed decision memo, CMS states the following: “In this national coverage analysis, the sources of stem cells included bone marrow as well as peripheral blood. As mentioned in the background section, other sources of stem cells may include the placenta, amniotic fluid, as well as cord blood. None of the included studies used these other sources for stem cells. There is no study evidence that other sources for stem cell transplantation in Medicare patients with MDS have similar benefits and harms treatment profiles. Therefore, we propose that national coverage will be restricted to the sources of stem cells used in the studies reviewed as part of this analysis (bone marrow and peripheral blood).” Placenta and amniotic fluid are not currently validated sources for stem cells capable of hematologic and immunologic reconstitution and should not be compared to peripheral blood stem cells, bone marrow or cord blood, where there is more than 20-year history of comparable results in diverse indications.

CMS’ claims processing manual specifically focuses on the three stem cell sources utilized for HSCT, and as outlined in the Further Consolidated Appropriations Act of 2020:

“90.3 - Stem Cell Transplantation (Rev. 11113; Issued: 11-16-21; Effective: 12-17-21; Implementation: 12-17-21) A. General Stem cell transplantation is a process in which stem cells are harvested from either a patient’s (autologous) or donor’s (allogeneic) bone marrow or peripheral blood for intravenous infusion. Autologous stem cell transplantation (AuSCT) is a technique for restoring stem cells using the patient's own previously stored cells. AuSCT must be used to effect hematopoietic reconstitution following severely myelotoxic doses of chemotherapy (HDCT) and/or radiotherapy used to treat various malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure in which a portion of a healthy donor's stem cell or bone marrow is obtained and prepared for intravenous infusion. Effective for cost reporting periods beginning on or after October 1, 2020, for subsection (d) hospitals (that is, hospitals paid under the IPPS) furnishing an allogeneic hematopoietic stem cell transplant, such transplant is defined, in accordance with Section 108 of the Further Consolidated Appropriations Act, 2020 (Pub. L. 116-94), as the intravenous infusion of hematopoietic cells derived from bone marrow, peripheral blood stem cells, or cord blood, but not including embryonic stem cells, of a donor to an individual that are or may be used to restore hematopoietic function in such individual having an inherited or acquired deficiency or defect.”

Use of the International Prognostic Scoring System-Revised (IPSS-R):

We strongly encourage the agency to not require adherence to a specific scoring system. Instead, we suggest the agency allow use of the most current validated scoring system as recognized by authoritative clinical bodies such as the World Health Organization and the NCCN. Use of a specific scoring system locks the coverage language to a particular point in time, whereas such scoring systems are not static but evolve with scientific advances in diagnosis and prognosis. Risk stratification systems for MDS are rapidly evolving. For example, while the BMT CTN trial was based on the original IPSS, the agency proposed a decision memo based on the IPSS-R. However, currently, IPSS-R is being replaced as the clinical standard by the IPSS-M (Bernard et al, NEJM 2022). This scoring system incorporates important molecular mutations in the prognostic model and is dynamic to account for changes in patients across time and treatments. Importantly, it is not always possible to crosswalk a score from a current scoring system to an outdated system due to new factors implemented as the systems evolve – thus it may not be simple nor practical for a physician to score a patient using whatever the current system is and score the same patient via IPSS-R for purposes of Medicare coverage.

More importantly, as new prognostic factors such as molecular mutations are incorporated into scoring systems, patients’ prognostic classification may substantially change compared to historic systems, with some patients historically classified as lower risk now recognized to be higher risk based on molecular or other criteria. We point this out to note the need for flexibility in CMS’ coverage language so clinicians can treat the most appropriate candidates going forward. The NCCN clinical guidelines, for example, are reviewed annually, are almost universally referenced by payers in the United States and are regularly updated to reflect the most current and validated scoring system.

In addition to the IPSS, there are other risk stratification models including personalized prediction models, and the EuroMDS. These models provide important prognostic information and have improved risk prediction guidance for clinicians, yet under the NCD, would be excluded from use. Prognostic models will continue to evolve alongside our understanding of risk prediction, and we therefore believe the use of a specific risk model, as indicated in the proposed decision memo, does not allow flexibility for providers and patients when choosing treatment options.

Inclusion of Intermediate Risk MDS:

We believe the medical evidence demonstrates the benefits of allogeneic HSCT compared to currently available conventional therapy for patients with intermediate risk MDS and supports its inclusion in the indication. Enrollment criteria for BMT CTN 1102 included patients characterized as Intermediate-2 or High according to the IPSS criteria available when the study was designed. Overall results from the study for all patients show a survival advantage with allogeneic HSCT. We acknowledge mapping from IPSS to IPSS-R is challenging, and a recently published study from the EBMT has shown that retrospective application of the IPSS-R criteria to patients who received HSCT for MDS resulted in up-classification to higher risk in 76% of patients compared to the IPSS criteria (Robin et al). Retrospective application of IPSS-R criteria of high risk or very high risk to the population of patients included in BMT CTN 1102 based on IPSS criteria would eliminate approximately one third of eligible patients demonstrated to benefit from allogeneic HSCT in the BMT CTN study. The authors of that study presented a subgroup analysis that shows overall survival benefit in the donor arm (allogeneic HSCT) for patients with IPSS intermediate risk. The odds ratio for retrospectively applied IPSS-R risk groups also demonstrated overall survivor benefit for the patients who met IPSS-R intermediate risk (including six patients categorized as very low or low) in the donor arm. There was not a statistically significant interaction between risk score and treatment effect, indicating similar benefit in all risk strata included in the study, including the one third of patients with intermediate risk disease.

The French Biologic Assignment trial and Vidazaallo also demonstrate survival benefit of allogeneic HSCT in intermediate risk MDS. We also note NCCN guidelines characterize IPSS-R intermediate as higher risk MDS.

Additionally, the proposed restriction does not address the issue of secondary MDS (MDS that arises because of prior chemoradiotherapy). Patients with secondary MDS have a uniformly worse prognosis than primary MDS, and, while these patients are excluded from all prognostic scoring systems, these patients are universally accepted as very high risk. Allogeneic HSCT is the only accepted therapy for secondary MDS, and we encourage CMS to cover allogeneic HSCT for all Medicare beneficiaries with secondary MDS.

Lastly, we note a minor correction to the decision memo, which states that the CED study BMT CTN 1102 was funded by industry (Helocyte, Miyarisan Pharmaceutical). This study was conducted by the BMT CTN which is an NIH-funded network supported by the National Heart, Lung and Blood Institute and the National Cancer Institute and this study was fully funded by NIH grants U10HL069294 and U24HL138660.

Thank you for your consideration of our comments. If beneficial to the decision-making process, we are available to meet with you and your colleagues to discuss our proposed changes. Should you have any questions or require more information, please contact Suzanne Leous, American Society of Hematology’s Chief Policy Officer, at sleous@hematology.org or 202-292-0258.

Sincerely,

Mohandas Narla, DSc
2024 President, ASH

Robert A. Brodsky, MD
2023 President, ASH

Miguel Perales, MD
President, ASTCT

Corey Cutler, MD
President-Elect, ASTCT, and BMT CTN 1102 Co-Principal Investigator

Mary M. Horowitz, MD, MS, MACP
Principal Investigator, BMT CTN Data and Coordinating Center, Medical College of Wisconsin

J. Douglas Rizzo, MD, MS
Senior Scientific Director and Principal Investigator, Stem Cell Therapeutic Outcomes Database, CIBMTR-Medical College of Wisconsin

Bronwen Shaw, MD, PhD
Chief Scientific Director, CIBMTR-Medical College of Wisconsin

Jeffery J. Auletta, MD
Senior Vice President, NMDP
Chief Scientific Director, CIBMTR-NMDP

Steven Devine, MD
Chief Medical Officer, NMDP/Be the Match

cc: Kimberly Long, Lead Analyst
James Rollins, M.D., Lead Medical Officer

Appendix A: Literature outlining clinical evidence which supports eliminating the CED requirement

Atallah E, Logan B, Chen M, et al. Comparison of patient age groups in transplantation for myelodysplastic syndrome: the Medicare Coverage with Evidence Development study. JAMA Oncol. 2020;6(4) :486-493.

Cusatis R, Martens MJ, Nakamura R, et al. Health-Related Quality of Life in Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients Aged 50-75 with Advanced Myelodysplastic Syndrome: BMT CTN 1102. Am J Hematol, 2021.

Nakamura R, Saber W, Martens MJ, et al. Biologic Assignment Trial of Reduced-Intensity Hematopoietic Cell Transplantation Based on Donor Availability in Patients 50-75 Years of Age with Advanced Myelodysplastic Syndrome. J Clin Onc 2021.

DeFillip Z, Ciurea SO, Cutler C et al. Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines. TCT 29; 71-81, 2023.

Greenberg PL, Stone RL, Al-Kali A, et al. NCCN Clinical Practice Guidelines in Oncology for Myelodysplastic Syndromes Version 1.2023. National Comprehensive Cancer Network, Inc. 2023. All rights reserved. www.nccn.org. Accessed June 26, 2023.

Bernard E, Tuechler H, Greenberg PL et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndrome; NEJM Evid 2022.

Nazha A, Komrokji R, Meggendorfer M, et al. Personalized Prediction Model to Risk Stratify Patients with Myelodysplastic Syndromes. J Clin Oncology 2021; 39:3737.

Bersanelli M, Travaglino E, Meggendorfer M, et al. Classification and Personalized Prognostic Assessment on the Basis of Clinical and Genomic Features in Myelodysplastic Syndromes. J Clin Oncol 2021; 39:1223.

Auletta, J, Kou J, Chen, M et al. Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research. Transplant Cell Ther 2023.

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I applaud the CMS decision to offer coverage for bone marrow transplant for their medicare population with MDS. The current requirements for coverage will be sufficient for the majority of patients with MDS who may benefit from transplantation, but considerable "holes" remain in the plan. The two groups who may be disadvantaged by the proposal are those with transfusion dependance who are not high risk by the proposed criteria, and those with high risk molecular finding such as ASXL1 or TP53. The former group of patients face long-term transfusion dependence, iron overload, the need to expensive and chronic iron chelation therapy, and diminished quality of life. These patients have excellent outcomes with BMT and improved survival. The latter group is identified as high-risk MDS according to the recently validated International Prognostic scoring system - molecular (IPSS-M) and includes the molecular findings from gene testing. Many patients may be initially found to have intermediate or better risk scores according to the IPSS-R, but high-risk scores by the IPSS-M. Providing BMT to these patients early, before disease transformation to a higher risk phenotype, will improve outcomes and reduce morbidity associated with attempts to improve BMT candidacy using aggressive pre-HCT therapy or AML treatment.

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Dear CMS Coverage Analysis Committee,
I am a Professor of Medicine and the Director of the Stem Cell Transplantation and Cellular Therapy Program at the University of Colorado. I am writing to express concern about two specific elements of the proposed Centers for Medicare & Medicaid Services (CMS) coverage decision regarding allogeneic transplantation (HSCT) for myelodyplastic syndromes (MDS). I object to the exclusion of cord blood as a donor source for HSCT. I also have concern about the requirement that MDS patients have a score of = 4.5 points according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R) to be considered eligible for transplant.
The proposed determination notes:

In this national coverage analysis, the sources of stem cells included bone marrow as well as peripheral blood. As mentioned in the background section, other sources of stem cells may include the placenta, amniotic fluid, as well as cord blood. None of the included studies used these other sources for stem cells. There is no study evidence that other sources for stem cell transplantation in Medicare patients with MDS have similar benefits and harms treatment profiles. Therefore, we propose that national coverage will be restricted to the sources of stem cells used in the studies reviewed as part of this analysis (bone marrow and peripheral blood).

For many reasons, I disagree with this assessment. While I am unaware of the use of placenta or amniotic fluid as a stem cell source for HSCT and have no objection to their exclusion, cord blood is a well validated donor source of stem cells. Cord blood has been demonstrated in many studies to result in comparable outcomes across the spectrum of diseases (including MDS) for which HSCT is appropriate. At expert centers, and when comparable patients are compared, cord blood may in fact be associated with better outcomes than other donor sources. ^1-6 The fact that no cited studies in the proposed coverage decision include cord blood data does not mean that cord blood is an inappropriate donor source.
We reviewed our institutional experience of patients undergoing HSCT for MDS since 2014 and compared outcomes among patients undergoing cord blood versus matched related, matched unrelated, and haploidentical transplants. Among Medicare patients, we conducted 22 cord blood transplants and 17 matched related, matched unrelated, and haploidentical transplants. Overall survival is entirely comparable (p=0.70). Curves available upon request.
In a similar analysis of all MDS patients transplanted in that period, we conducted 51 cord blood transplants and 32 matched related, matched unrelated, and haploidentical transplants. Overall survival is also comparable (p=0.49). Curves available upon request.
Additionally, there is robust published data from Japanese groups demonstrating efficacy of cord blood transplant in older patients, and others have demonstrated the feasibility of cord blood as a donor source for older MDS patients.^7-12
Importantly, even for those centers without cord blood transplant expertise, cord blood may be the only viable donor source available for a patient based on the less stringent HLA matching requirements needed for cord blood as compared to adult donors. This issue is most prominent for patients of mixed and minority race and ethnicity who may only have cord blood as a potential donor source. The exclusion of cord blood as a donor source would therefore have directly negative consequences on questions of diversity, equity, and inclusion for healthcare access.
While expert cord centers could pool their data and publish on the issue, there is no question that cord blood is an acceptable donor source for transplants for MDS. I am concerned also that limiting stem cell donor source selection by Medicare would set a dangerous precedent that could lead to further inappropriate administrative restrictions that are not in the best interest of patient care.
With respect to the question of R-IPSS classification for transplant approval, I know others will be commenting clearly on this issue. I would note, however, that the R-IPSS has already been supplanted by many with the molecular-IPSS. Prognostic scoring systems will continue to rapidly evolve. Moreover, the decision to pursue a transplant for MDS in an older patient is a very personal one that requires complex consideration between physician and patient. No studies on the question are sufficiently suitable in my mind to create black and white determinations on the question. I would favor a more broad coverage determination similar to that granted for AML.
Best regards,

Jonathan Gutman

1. Sharma P, Purev E, Haverkos B, et al. Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant. Blood Adv 2020;4:2227-35.
2. Brunstein CG, Gutman JA, Weisdorf DJ, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood 2010;116:4693-9.
3. Gutman JA, Ross K, Smith C, et al. Chronic graft versus host disease burden and late transplant complications are lower following adult double cord blood versus matched unrelated donor peripheral blood transplantation. Bone Marrow Transplant 2016;51:1588-93.
4. Milano F, Gooley T, Wood B, et al. Cord-Blood Transplantation in Patients with Minimal Residual Disease. N Engl J Med 2016;375:944-53.
5. Ponce DM, Zheng J, Gonzales AM, et al. Reduced late mortality risk contributes to similar survival after double-unit cord blood transplantation compared with related and unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011;17:1316-26.
6. Milano F, Gutman JA, Deeg HJ, et al. Treosulfan-based conditioning is feasible and effective for cord blood recipients: a phase 2 multicenter study. Blood Adv 2020;4:3302-10.
7. Konuma T, Itonaga H, Shimomura Y, et al. Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy. Hematol Oncol 2023.
8. Konuma T, Shimomura Y, Ishiyama K, et al. Haploidentical transplantation with post-transplant cyclophosphamide versus single cord blood transplantation for myelodysplastic syndrome: A retrospective study from the Adult Myelodysplastic Syndrome Working Group of the Japanese Society for Transplantation and Cellular Therapy (JSTCT). Am J Hematol 2022;97:E447-E50.
9. Terakura S, Nishida T, Sawa M, et al. Prospective evaluation of alternative donor from unrelated donor and cord blood in adult acute leukemia and myelodysplastic syndrome. Bone Marrow Transplant 2020;55:1399-409.
10. Pourhassan H, DeFor T, Trottier B, et al. MDS disease characteristics, not donor source, predict hematopoietic stem cell transplant outcomes. Bone Marrow Transplant 2017;52:532-8.
11. Konuma T, Tsukada N, Kanda J, et al. Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol 2016;91:E284-92.
12. Sandhu KS, Brunstein C, DeFor T, et al. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged >/=70 Years. Biol Blood Marrow Transplant 2016;22:390-3.

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January 4, 2024
VIA ELECTRONIC SUBMISSION
The Honorable Chiquita Brooks-LaSure
Administrator
Centers for Medicare & Medicaid Services
Department of Health and Human Services
7500 Security Blvd
Baltimore MD 21244

RE: Proposed Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes (MDS) (CAG-00415R)

Dear Administrator Brooks-LaSure:

Gamida Cell appreciates the opportunity to comment on the Proposed Decision Memo on Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes posted on December 7, 2023. Gamida Cell appreciates CMS’s decision to reconsider the existing National Coverage Determination (NCD) for Allogeneic HSCT for MDS and supports CMS’s proposal to remove existing Coverage with Evidence Development (CED) requirements. We are concerned with CMS’s proposal to restrict national Medicare coverage of Allogeneic HSCT for MDS to transplants using only bone marrow or peripheral blood stem cell products.

Background on Gamida Cell and Omisirge®

Gamida Cell is striving to enable patients with blood cancers and serious blood disorders to reach cures through nicotinamide (NAM) modified cell therapies. On April 17, 2023, Gamida Cell received Food and Drug Administration (FDA) approval for its biologic Omisirge® (omidubicel-onlv)¹, which the FDA describes as “a nicotinamide (NAM) modified allogeneic hematopoietic progenitor cell therapy derived from cord blood used as an allogeneic stem cell donor source.”² Omisirge® is a cord blood based donor source for allogeneic hematopoietic stem cell transplant (HSCT) for use in adult and pediatric patients 12 years and older with hematologic malignancies planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection. Omisirge® is a significant development in hematopoietic stem cell transplantation, and may broaden transplant access for eligible patients, including MDS patients, and particularly those from racial and ethnic minorities who are unable to find an optimal match in registries. In the phase 3 clinical trial for Omisirge®, over 40 percent of patients were racially and ethnically diverse.³ This is consistent with CIBMTR data demonstrating that patients from racially and ethnically diverse background are more reliant on cord blood products.⁴

The Proposed Decision Memo would exclude Medicare coverage of Allogeneic HSCTs using umbilical cord blood (UCB) stem cell products. It should be noted that UCB has less stringent matching criteria than other donor sources, increasing the likelihood of finding a donor source for racially and ethnically diverse patients. Since Omisirge® is derived from cord blood it also has a less stringent matching criteria expanding access to more Medicare beneficiaries in need of a transplant, as demonstrated in our phase 3 clinical trial patient enrollment. As explained in more detail below, there is significant evidence demonstrating the efficacy and benefits of Allogeneic HSCTs for MDS patients using UCB products. Furthermore, broad access to Allogeneic HSCTs using UCB stem cell products is essential for ethnically diverse Medicare patients who often lack access to conventional donor sources.

In order to protect access for Medicare patients from all racial and ethnic backgrounds and to further advance the agency’s goals of promoting health equity in the Medicare program, we urge CMS to reconsider this aspect of its proposal, and to clarify in the final NCD that national Medicare coverage of Allogeneic HSCT for MDS patients will be extended to transplants using stem cell products derived from UCB, such as Omisirge®.

Allogeneic HSCT using UCB Stem Cell Products for MDS Patients

The efficacy, benefits, and safety of Allogeneic HSCT using UCB stem cell products for MDS patients is well established in the research literature. Several studies have found that Allogeneic HSCTs using UCB stem cell products can result in long-term, disease-free survival, particularly for MDS patients who lack a matched sibling or unrelated donor.^5,6,7,8,9

For example, one study found that patients with MDS undergoing Allogeneic HSCT with UCB experienced sustained engraftment without excessive graft failures, as well as encouraging rates of overall survival and disease-free survival.¹⁰ Furthermore, another study found that Allogeneic HSCT using UCB for adult hematologic malignancies, including Adult Acute Leukemia and MDS, demonstrated significantly better overall survival than the threshold survival rate, and outcomes that are comparable to historical unrelated donor transplantation in certain adults. The study also noted that “this treatment is now considered a feasible option for patients who cannot obtain an appropriate UD [unrelated donor] in a timely manner.”¹¹

A recent multi-center study including MDS patients found that the 3-year disease free survival and overall survival for Allogeneic HSCT using UCB products aligns with outcomes for allogeneic unrelated and family member donated bone marrow and peripheral blood stem cell products.¹² In another recent study of older MDS patients, chronic GvHD-free, relapse-free survival was better for MDS patients treated with UCB products compared to matched-sibling donors.¹³

We also note that coverage and access to Allogeneic HSCT using UCB stem cell products is a significant health equity issue. Access to Allogeneic HSCT can be severely limited for patients of racial and ethnic minorities without suitable sibling donors.¹⁴ Because UCB stem cells allow for greater donor matching opportunities, they significantly expand access to Allogeneic HSCT for these patients, who otherwise have limited donor source options. Compared to matched related donor and matched unrelated donor HSCTs, more racially and ethnically diverse patients are receiving HSCTs using UCB.¹⁵ Importantly, racially and ethnically “diverse patients are undergoing allogeneic HCTs at higher rates” in part because of the increasing availability of alternative donor platforms using UCB.¹⁶ We also note that a recent report evaluating clinical trials of Allogeneic HSCT using Omisirge® as the UCB stem cell product, including MDS patients, found that 39% of study patients were nonwhite, highlighting a key demographic with more limited donor availability.¹⁷ A cord blood derived product, like Omisirge®, is likely to improve access to potentially life-saving allogeneic HSCT for patients with MDS and other serious, life-threatening hematologic malignancies.

The need for access to all suitable donor sources, including UCB stem cell products that allow for greater opportunity with donor matching, is particularly heightened for MDS patients. As CMS notes in the proposed NCD, “MDS are a disease of the elderly” with a mean age at onset of older than 70 years.¹⁸ Older MDS patients are likely to have older siblings, increasing the likelihood that potential related donors are unsuitable due to comorbid conditions.¹⁹ Thus, older Medicare patients, and particularly older Medicare patients of racial or ethnic minority backgrounds, are even less likely to have a suitable match from other stem cell donor sources, and are in greater need of the donor matching opportunities unique to UCB stem cell products. Restricting national Medicare coverage to only Allogeneic HSCT that use bone marrow and peripheral blood stem cell products, and excluding UCB stem cell products, will have the effect of limiting coverage of potentially lifesaving HSCT for marginalized communities, in direct contradiction of CMS’s stated goal of advancing health equity in the Medicare program.

Lastly, in the proposed NCD, CMS states “[c]urrently, 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).” This statement is inconsistent with the FDA-approved indications for UCB stem cell products, which also encompass patients undergoing Allogeneic HSCT for hematologic malignancies.²⁰ We note that Omisirge® is indicated for use in adults and pediatric patients 12 years and older with hematologic malignancies who are planned for umbilical cord blood transplantation following myeloablative conditioning to reduce the time to neutrophil recovery and the incidence of infection. The indication for Omisirge® is specific to patients undergoing an allogeneic stem cell transplant for hematologic malignancies, inclusive of MDS.

Given the above, we recommend that in the Final Decision Memo, CMS clarifies that national Medicare coverage of Allogeneic HSCT will be extended to include transplants using donor sources from bone marrow, peripheral blood, and UCB stem cell products, such as Omisirge®.

***

Thank you for your consideration. Please contact me with any questions or requests for additional information.

Sincerely,

Rocio Manghani, MPH
Senior Vice President, Market Access
Gamida Cell

References:
1. Please see Full Prescribing Information, including Boxed Warning available at www.fda.gov/media/167202/download.
2. See https://www.fda.gov/media/167202/download.
3. M. E. Horwitz et al., Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study, Blood, 2021 Oct 21;138(16):1429-1440, https://doi.org/10.1182/blood.2021011719.
4. J. J. Auletta et al., Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research, Transplant Cell Ther., 2023 Jun;29(6), https://doi.org/10.1016/j.jtct.2023.03.007.
5. J. Ooi, The efficacy of unrelated cord blood transplantation for adult myelodysplastic syndrome, Leukemia & Lymphoma, Volume 47, 2006 - Issue 4 (July 1, 2009), https://www.tandfonline.com/doi/abs/10.1080/10428190500421013.
6. A. Sato et al., Unrelated cord blood transplantation after myeloablative conditioning in adults with advanced myelodysplastic syndromes, Bone Marrow Transplant 46, 257–261 (2011), https://doi.org/10.1038/bmt.2010.91.
7. A. T. Gerds et al., Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes, Biol Blood Marrow Transplant. 2017 Jun;23(6):971-979, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5474679/pdf/nihms867817.pdf.
8. L. Roberts, Cord Blood Transplantation Is an Effective Treatment Option in Patients with Myelodysplastic and Myeloproliferative Syndromes, Blood 2019; 134 (Supplement_1): 2048, https://doi.org/10.1182/blood-2019-126216.
9. S. Terakura et al., Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome, Biol Blood Marrow Transplant 26 (2020) 139-144, https://doi.org/10.1016/j.bbmt.2019.09.021.
10. L. Roberts, Cord Blood Transplantation Is an Effective Treatment Option in Patients with Myelodysplastic and Myeloproliferative Syndromes, Blood 2019; 134 (Supplement_1).
11. S. Terakura et al., Prospective Phase 2 Study of Umbilical Cord Blood Transplantation in Adult Acute Leukemia and Myelodysplastic Syndrome, Biol Blood Marrow Transplant 26 (2020) 139-144.
12. C. Lin, et al., Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials. Transplant Cell Ther, 2023. 29(5): p. 338 e1-338 e6.
13. T. Konuma, et al., Should a matched sibling donor still be considered the primary option for allogeneic hematopoietic cell transplantation in patients over 50 years of age with myelodysplastic syndrome? Bone Marrow Transplant, 2023. 58(8): p. 893-906.
14. J. N. Baker et al., Availability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities, Biol Blood Marrow Transplant. 2010 November; 16(11): 1541–1548.
15. J. J. Auletta et al., Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research, Transplant Cell Ther., 2023 Jun;29(6).
16. Id.
17. C. Lin et al., Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials. Transplant Cell Ther, 2023. 29(5): p. 338 e1-338 e6.
18. Harrison’s Principles of Medicine, 20th edition, Jameson, Fauci, Kasper et al. 2018.
19. A. T. Gerds et al., Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes, Biol Blood Marrow Transplant. 2017 Jun;23(6):971-979.
20. See, e.g., DUCORD (HPC, Cord Blood), Full Prescribing Information, https://www.fda.gov/media/84567/download?attachment; see also HEMACORD (HPC, Cord Blood), Full Prescribing Information, https://www.fda.gov/media/82016/download?attachment.

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January 3, 2024

RE: CMS Proposed Decision Memo re: HSCT for MDS

To Whom It May Concern:

The Cord Blood Association, CBA, is submitting comments to CMS on the Proposed Decision Memo regarding treatment of myelodysplasia (MDS) with hematopoietic stem cell transplantation (HSCT) released on December 6, 2023. The Cord Blood Association represents the leaders of both the public and family cord blood banking industries around the world. The CBA aligns banks and related industry partners to accelerate the use of cord blood and birthing tissues to benefit patients and advance medicine.
Representing this constituency, the CBA would like to provide comments to CMS regarding the proposed memo.
The draft language in the memo states that “allogeneic HSCT using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes (MDS) designated as high-risk or very risk……” will be covered by Medicare. The CBA is very concerned about two aspects of this memo:
1) The omission of cord blood as a potential donor for HSCT will prevent access to HSCT for some patients who lack a fully matched related or unrelated donor. This is particularly true for patients of non-Caucasian ancestry and potentially limits equity in access to a lifesaving HSCT for these patients. Cord blood has been utilized as a donor for HSCT in patients with MDS successfully for over 20 years and cord blood should be covered by Medicare, if designated by the patient’s medical care team, as the best donor for a given patient.
2) Patients with intermediate MDS should also be covered for HSCT by Medicare and per #1, all donor sources of cells should be allowed.
3) The decision regarding the best donor for a given patient should be made by that patient’s medical care team and should not be restricted by the payor for their HSCT procedure.
The Cord Blood Association deeply values CMS’s commitment to safeguarding public health. Our dedication aligns with theirs, as we collaborate closely to establish policies that prioritize both the safety and quality of medical products and practices. The CBA appreciates the opportunity to respond to the proposed decision memo.
Sincerely,
Joanne Kurtzberg, MD
Jerome Harris Distinguished Professor of Pediatrics and Professor of Pathology
Duke University School of Medicine
Director, Marcus Center for Cellular Cures (MC3)
Director, Carolinas Cord Blood Bank
President, Cord Blood Association

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The proposed rules regarding allogeneic transplantation for MDS are a step forward; but too restrictive and will limit patient access for those needing this life-saving therapy
SCT for patients with MDS should be allowed for patients designated as intermediate or high-risk according not only by the IPSS-R but also by criteria using a scoring system as recognized and/or referenced by the NCCN, WHO or other knowledgable clinical source or evaluation body.
All clinically established donor sources should be allowed, including bone marrow, peripheral blood stem cells and cord blood, to support equity in patient access to transplant. Excluding cord blood as a graft source will limit access, particularly for minority patients or those with mixed ethnic heritage for whom unrelated donor sources may not provide a suitable donor.

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The new Medicare covered indication for an allogeneic transplant for MDS. will only include patients with high-risk disease (IPSS score of 4.5 or higher).
Such a requirement will exclude MDS patients who do not have a high-risk disease but do have intermediate risk 1 or intermediate risk 2 disease and are needing frequent blood product transfusion support. Such patients will also benefit from proceeding to an allogeneic transplant before they develop serious issues with iron overload and blood product sensitization, waiting to become high-risk. Medicare should re consider the coverage indication for MDS to include patients with intermediate 1 or 2 disease who are needing frequent blood transfusion support.

I am enclosing the publication from the American Society for transplantation and Cellular therapy Committee on Practice Guidelines: https://www.astctjournal.org/article/S2666-6367(22)01782-1/pdf

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To the Committee,
I am a stem cell transplant physician and board certified geriatrician who focuses on the treatment of older adults (over the age of 65) with MDS and AML. I have three important comments to make regarding your proposal.
First, I would like to point out an important group of patients who were not considered in your review of stem cell transplant for MDS-patients who fail to respond to hypomethylating agents for treatment of their MDS. This group of patients, which may be as high as a third of all patients with MDS (representing all IPSS-R risk score), have a much poorer prognosis than would be expected based purely on their risk stratification. Even those categorized with lower-risk MDS have significantly lower survival and a markedly increased risk of transformation to AML compared to those who respond to hypomethylating agents. This population is under rigorous study, both to identify treatments that may be of benefit, as well as to understand the unique biology of their disease. Over my time as a transplant physician, nearing 20 years, I have successfully transplanted a number of these patients who would not have otherwise met your proposed criteria for transplant. This unique, but very important patient population, would not have access to life-saving therapy under your proposal. Establishing limited rules, which do not account for the individual patients' disease qualities, can be a major disservice to both patients and the transplant community that wants to provide them the best treatments possible.
Two recent citations studying this population are as follows: Urrutia S, et al. Performance of IPSS-M in patients with myelodysplastic syndrome after hypomethylating agent failure. Am J Hematol. 2023 Oct;98(10):E281-E284. doi: 10.1002/ajh.27043. Epub 2023 Jul 29. PMID: 37515433 and Jabbour EJ, et al. Outcome of patients with low-risk and intermediate-1-risk myelodysplastic syndrome after hypomethylating agent failure: a report on behalf of the MDS Clinical Research Consortium. Cancer. 2015 Mar 15;121(6):876-82. doi: 10.1002/cncr.29145. Epub 2014 Nov 19. PMID: 25410759; PMCID: PMC4378905.
Second, your proposal limits the classification system utilized to IPSS-R. Given the unique features in many cases of MDS (like neutropenia as the significant cytopenia, which portends a poor prognosis), I believe stem cell transplant for patients with MDS should be allowed for patients classified as intermediate or high-risk according to criteria by any of the validated scoring systems.
Finally, your proposal limits coverage to stem cell transplant utilizing bone marrow or peripheral blood stem cell products only. I have cared for a number of patients, typically from minoritized populations, who's only stem cell source for transplant was cord blood. I view limitations in stem cell product as jeopardizing the equal care and access to transplant for all those who need it. Populations who benefit from the use of cord blood should not be excluded from accessing a potentially life-saving treatment.
I appreciate your consideration of my comments.
With Best Regards,
Gabrielle Meyers, MD

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SCT for patients with MDS should be allowed for patients designated as intermediate or high-risk according to criteria by a validated scoring system as recognized and/or reference by the NCCN, WHO or other authoritative clinical source. This proposed ruling will limit transplant to only patients with the highest risk disease- patients with adverse mutations who are transfusion dependent but with low blast counts would not qualify. Often by the time these patients progress to higher blast counts they have received so many transfusions and are so iron overloaded that transplant risks rise tremendously. All legitimate and clinically established donor sources should be allowed, including bone marrow, peripheral blood stem cells and cord blood, to support equity in patient access to transplant. Limiting donor sources worsens race and ethnicity related disparities that already exist in medicine. Transplant outcomes are now reaching equivalence with all donor sources and hla match grades.

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On behalf of The University of Texas MD Anderson Cancer Center (MD Anderson), we thank you for reconsidering coverage of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) patients and are pleased to provide additional comments. We fully support the request by 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) to remove the Coverage with Evidence Development (CED) requirement currently in place for Medicare Beneficiaries suffering from MDS. Along with many other cancer treatment centers, the treatment of MDS patients using Allogeneic HSCT has become standard of care at MD Anderson.

By way of background, MD Anderson Cancer Center in Houston is one of the world's most respected centers focused on cancer patient care, research, education and prevention. It is one of the nation's original three comprehensive cancer centers designated by the National Cancer Institute. Since 1944, more than 1.9 million people have turned to MD Anderson for cancer care. The institution pioneered a multidisciplinary approach to research-driven care. In Fiscal Year 2022, MD Anderson invested more than $1.1 billion in research.

Allogeneic HSCT in Intermediate and High-Risk Patients

Currently, Allogeneic HSCT is the only treatment with curative potential for MDS patients. The average age at diagnosis is 70 years; therefore, Medicare coverage of this life-saving treatment is essential for this population. The proposed decision would only provide coverage for patients designated as high-risk or very high-risk with a score of ≥ 4.5 points according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R).

The Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines recommends that patients with MDS who are designated as intermediate or high-risk according to criteria by a validated scoring system as recognized and/or reference by the NCCN, WHO or other authoritative clinical source should have coverage for Allogeneic HSCT as well (see reference 1). Studies have demonstrated that patients with more advanced MDS (IPSS intermediate-2 [int-2] and high risk) who received an Allogeneic HSCT maximized life expectancy compared with nontransplantation approaches (see reference 2).

Therefore, we support coverage of Allogeneic HSCT for Medicare patients with both intermediate and high-risk MDS.

Umbilical Cord Blood Transplantation

The proposed decision would also limit coverage to bone marrow or peripheral blood stem cell products only. Umbilical cord blood would be excluded from coverage which could prevent a viable transplant option in the Medicare population.

A study comparing umbilical cord blood transplantation with unrelated bone marrow transplantation in patients older than fifty years concluded that umbilical cord blood is a reasonable alternative donor/stem cell source for elderly patients with similar outcomes compared with unrelated bone marrow transplantation.

Additionally, for some patients in need of allogeneic transplantation, cord blood may be the only suitable graft source. In addition to challenges with unrelated donor availability (see reference 3), patients may lack suitable haploidentical donors (see reference 4), and the presence of donor-specific anti-human leukocyte antigen antibodies may limit transplantation of haploidentical grafts, especially among multiparous women (see reference 5).

The exclusion of cord blood from coverage also has health equity implications, as transplant candidates from underserved racial/ ethnic/ ancestral populations (and especially African and non-Black Hispanic ancestry patients) are more likely to lack a fully matched unrelated donor and face disparities in access to optimal, timely grafts. Specifically, recent data has shown that patients from non-European ancestral groups face marked disparities in unrelated donor availability (see reference 8) and, for those who are transplanted with adult donors, their transplantations are delayed (see reference 6) and their donors are older (see reference 7), both of which are associated with poorer post-transplant survival. These issues are also compounded by the fact that non-European ancestry patients are also more likely to have lower socioeconomic status which can further limit access to care. (see reference 8). Umbilical cord blood grafts are transplanted the fastest (see reference 6), regardless of patient ancestry, and their use can help overcome disparities in access to optimal, timely grafts.

For these reasons, we support the addition of umbilical cord blood as a covered donor source.

We appreciate your time and consideration. If you require any additional information, please feel free to contact us or Stephanie Walters at sjwalter@mdanderson.org.

Sincerely,

Elizabeth Shpall, M.D.
Chair Ad Interim
Stem Cell Transplantation

Warren Fingrut
Assistant Professor
Stem Cell Transplantation

References:

1. DeFillip Z, Ciurea SO, Cutler C et al. Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines. TCT 29; 71-81, 2023
2. Tanaka M, Miyamura K, Terakura S, et al: Comparison of cord blood transplantation with unrelated bone marrow transplantation in patients older than fifty years. Biol Blood Marrow Transplant: 21(3):517-25.
3. Fingrut W, Davis E, Archer A, Brown S, Devlin S, Nhaissi M, Rapoport C, Chinapen S, Kelly A, Wells D, Scaradavou A, Gyurkocza B, Papadopoulos E, Politikos I, Shaffer B, Barker J. Analysis of 3,843 unrelated donors (URD) for 455 allograft candidates reveals low URD availability with marked racial/ ethnic disparities: major implications for transplant center and registry operations. Blood 2023. 142 (Suppl 1): 5144.
4. Kosuri S, Wolff T, Devlin SM, et al. Prospective Evaluation of Unrelated Donor Cord Blood and Haploidentical Donor Access Reveals Graft Availability Varies by Patient Ancestry: Practical Implications for Donor Selection. Biol Blood Marrow Transplant. 2017. 23(6):965-970.
5. Fingrut W, Davis E, Archer A, Brown S, Devlin S, Chinapen S, Scaradavou A, Politikos I, Blouin A, Shaffer B, Barker
J. Gender disparities in allograft access due to HLA-sensitization in multiparous women: implications for evaluation of female patients for alternative donor transplantation. Blood Advances 2023. In press.
6. Fingrut W, Gyurkocza B, Davis E, Scaradavou A, Chinapen S, Naputo K, Quach S, Cho C, Giralt S, Papadopoulos E, Perales M, Shaffer B, Politikos I, Barker J. Analysis of Disparities in Time to Allogeneic Transplantation in Adults with Acute Myelogenous Leukemia. Blood Advances 2023. 7(15):3824-3833.
7. Fingrut W, Gyurkocza B, Davis E, Flynn J, Chinapen S, Naputo K, Quach S, Cho C, Giralt S, Jakubowski A, Lin R, Papadopoulos E, Perales M, Ponce D, Shaffer B, Sauter C, Tamari R, Young J, Scaradavou A, Politikos I, Barker J. Racial Disparities Persist in the Era of “Donors for All”. Blood Advances 2022. 6(20):5625-5629.
8. Fingrut W, Chinapen S, Katrichis A, Davis E, Shaffer B, Shah G, Barker J. Associations between non-European ancestry, low socioeconomic status, and receipt of HLA-disparate allografts in adult BMT recipients. Blood Advances 2023. 7(15):3834-3837.

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As background, I am a physician who focuses on the care of adult patients with hematologic malignancies undergoing hematopoietic cell transplantation, including MDS. Hence, I am very familiar with the background and data behind CMS's NCA on "Allogeneic HSCT for MDS". I am pleased that CMS is planning to expand Medicare coverage for HSCT for MDS and congratulate the agency for taking this positive step towards facilitating care for Medicare beneficiaries. However, I have concerns about restricting coverage to a subset of patients, which is not in line with current routine clinical practice for patients who receive HSCT for MDS and are otherwise similar to MDS beneficiaries (e.g., older than 65 years in age).

CMS is proposing to restrict allogeneic HSCT for MDS to patients with high-risk or very-high risk IPSS-R scores. Prognostic scoring systems for MDS are evolving and are incorporating risk factors that are not considered in the IPSS-R staging system. One example is the increasing use of molecular mutations in determining prognosis and risk of transformation to acute leukemia, and information on molecular mutations is now routinely used in clinical practice to determine timing and candidacy for allogeneic HSCT and has been incorporated in more contemporary prognostic scoring systems such as Molecular-IPSS (M-IPSS). I request CMS to consider broadening language to allow allogeneic HSCT for MDS to patients designated as intermediate or high-risk according to criteria established by a validated scoring system as recognized and/or referenced by the NCCN, WHO or other authoritative clinical source.

CMS is proposing to restrict allogeneic HSCT for MDS to only bone marrow or peripheral blood stem cell products. Umbilical cord blood (UCB) is a well established donor source for adult patients with MDS. UCB as a donor source is especially relevant for increasing access to HSCT for patients from minority racial/ethnic populations, who typically have a lower likelihood of finding other suitable related or unrelated donor options. To be consistent with routine clinical practice, I request CMS consider broadening language to allow any clinically established donor or graft source for allogeneic HSCT for MDS in its guidance.

I sincerely appreciate this opportunity to provide comments on this very important issue for Medicare patients with MDS.

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The Blood and Marrow Transplant and Cellular Therapies Program at the University of Kansas Cancer Center is grateful for the chance to comment on the National Coverage Analysis Proposed Decision Memo: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS). We are pleased that CMS is proposing coverage absent a CED requirement.

However, we are concerned that the proposed criteria in the memo do not reflect current standards of care which will limit access to this medically necessary service for Medicare beneficiaries.

We concur with other noted experts such as the National Comprehensive Cancer Network and American Society for Transplantation and Cellular Therapy that the following changes should be made:

Patients with MDS designated as intermediate or high-risk according to criteria by a validated scoring system as recognized and/or referenced by the NCCN, WHO or other authoritative clinical source should be eligible for HSCT. Limiting the language in the memo to the IPSS-R scoring system will place future beneficiaries at risk of being measured against outdated criteria as new methods evolve.

All legitimate and clinically established donor sources should be allowed, including bone marrow, peripheral blood stem cells and cord blood, to support equity in patient access to transplant.

Thank you for considering these changes. We are hopeful the criteria in the proposed memo will be updated to reflect current medical standards and the restrictive language around IPSS-R will be broadened to allow other scoring systems as they evolve and are adapted into practice.

Dr. Joseph P. McGuirk
Schutte-Speas Professor of Hematology-Oncology
Division Director, Hematologic Malignancies and Cellular Therapeutics
Medical Director, Blood and Marrow Transplant
The University of Kansas Cancer Center

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December 20, 2023

Tamara Syrek-Jensen, JD
Director, Coverage and Analysis Group
Centers for Medicare and Medicaid Services
7500 Security Boulevard
Baltimore, MD

RE: National Coverage Analysis Proposed Decision Memo: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) (CAG 00415R)

Dear Ms. Syrek-Jensen:

The National Comprehensive Cancer Network® (NCCN®) appreciates the opportunity to comment on the Centers for Medicare and Medicaid Services (CMS) National Coverage Analysis Proposed Decision Memo: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS). NCCN’s mission is to improve and facilitate quality, effective, equitable, and accessible cancer care so all patients can live better lives. NCCN thanks CMS for proceeding with a proposal to cover HSCT for MDS without evidence development. However, NCCN has significant concern that the proposal as outlined would exclude coverage for Medicare beneficiaries that may benefit from access to this intervention. NCCN is pleased to provide information, recommendations, and resources as CMS considers its coverage of HSCT for MDS.

NCCN Background

As an alliance of 33 leading academic cancer centers in the United States that treat hundreds of thousands of patients with cancer annually, NCCN® is a developer of authoritative information regarding cancer prevention, screening, diagnosis, treatment, and supportive care that is widely used by clinical professionals and payers alike. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a comprehensive set of guidelines detailing the sequential management decisions and interventions that currently apply to 97 percent of cancers affecting patients in the United States.

NCCN Guidelines® and Library of Compendia products help ensure access to appropriate care, clinical decision-making, and assessment of quality improvement initiatives. NCCN was recognized by CMS in 2016 and renewed in 2021 as a qualified Provider Led Entity (PLE) for the Medicare Appropriate Use Criteria (AUC) Program for the development of AUC and the establishment of policy and decision-making for diagnostic imaging in patients with cancer. NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) include information designed to support clinical decision-making around the use of imaging in patients with cancer and are based directly on the NCCN Guidelines®. NCCN Imaging AUC™ include recommendations pertaining to cancer screening, diagnosis, staging, treatment response assessment, follow-up, and surveillance. The NCCN Drugs & Biologics Compendium (NCCN Compendium®) has been recognized by CMS and clinical professionals in the commercial payer setting since 2008 as an evidence-based reference for establishment of coverage policy and coverage decisions regarding off-label use of anticancer and cancer-related medications. The NCCN Biomarkers Compendium® has been referenced as a coverage mechanism and source of evidence by local Medicare Administrative Contractors and serves as a resource for payers, providers, and health care entities navigating the rapidly changing evidence-base for medically necessary biomarker testing in oncology. The NCCN Biomarkers Compendium® contains information derived directly from the NCCN Guidelines to support decision-making around the use of biomarker testing in patients with cancer. The NCCN Biomarkers Compendium is updated continuously in conjunction with the NCCN guidelines to stay evergreen.

NCCN imposes strict policies to shield the guidelines development processes from external influences. The “firewall” surrounding the NCCN Guidelines processes includes the following: financial support policies; panel participation and communication policies; guidelines disclosure policies; and policies regarding relationships to NCCN’s other business development activities. The guidelines development is supported exclusively by the Member Institutions’ dues and does not accept any form of industry or other external financial support for the guidelines development program. The NCCN Guidelines are updated at least annually in an evidence-based process integrated with the expert judgment of multidisciplinary panels of expert physicians from NCCN Member Institutions. The NCCN Guidelines are transparent, continuously updated, available free of charge online for non-commercial use, and are available through a multitude of health information technology (HIT) vendors.

NCCN Recommendations Regarding HCT for MDS

CMS received a request to reconsider the National Coverage Determination regarding HSCT for MDS, specifically coverage of allogeneic HSCT for beneficiaries with MDS. CMS has responded by opening a National Coverage Analysis (NCA) and notes the scope is only for coverage of allogeneic HSCT for beneficiaries with MDS absent a CED requirement. CMS has since released a proposed decision memo of coverage without evidence development of HSCT for MDS with certain parameters. While NCCN applauds CMS for reconsidering this service for coverage without evidence development, NCCN is concerned that the proposed decision memo does not align with nationally recognized clinical practice guidelines or other payer policy around this service. As NCCN content is used as an evidence-based standard for high-quality cancer care, including use by CMS, NCCN is pleased to provide information on NCCN Guideline recommendations related to the use of HCT for MDS. You can also find the most recent version of the NCCN Guidelines for Myelodysplastic Syndromes® on www.NCCN.org.

Consideration of allogeneic HCT is included as a Category 2A recommendation for select patients with lower-risk disease after disease progression or after no response or intolerance to other recommended therapy. Patients with International Prognostic Scoring System (IPSS) Intermediate-1, International Prognostic Scoring System-Revised (IPSS-R) Intermediate, and WHO-Based Prognostic Scoring System (WPSS) Intermediate risk MDS with severe cytopenias would also be considered candidates for HCT. NCCN Guidelines note that matched sibling, unrelated donor, or alternative (haploidentical or cord blood when appropriate) donor, including standard and reduced-intensity preparative approaches, may be considered. Unfortunately, CMS’ proposed decision memo specifically excludes all patients except those that are high-risk or very high-risk with a score of = 4.5 points according to criteria specified by the International Prognostic Scoring System-Revised (IPSS-R). NCCN is concerned that this stringent criteria excludes patients that may benefit from the intervention. Given re-evaluation of the data upon which the IPSS-R was based, the Intermediate prognostic risk category of the IPSS-R was divided into lower and higher risk strata by the International Working Group of Prognosis of MDS (IWG-PM), based upon whether the patient’s IPSS-R score was =3.5 or >3.5, respectively. Considering these data, the NCCN MDS Guidelines Panel recommended Intermediate patients with an IPSS-R score >3.5 as being within the higher risk category and to be treated as such. These recommendations are indicated in MDS 2.2023, footnote p, MDS-6, 6A. Therefore we request that CMS’ proposed decision would include MDS patients with IPSS-R score >3.5 for coverage for HSCT.

NCCN is also concerned that CMS proposes to cover HSCT using only bone marrow or peripheral blood stem cell products. This proposal would exclude the use of cord blood which is also an evidence-based intervention recommended by NCCN Guidelines. For patients who have a higher-risk of disease progression and are eligible for transplant, allogeneic HCT from the most suitable stem cell donor (HLA-matched sibling or unrelated donor, HLA-haploidentical family member or cord blood) is included as a Category 2A recommendation.

NCCN guidelines also emphasize that early referral for transplant evaluation is recommended to allow moving to transplant efficiently. Pre-transplant debulking therapy to reduce marrow blasts to <5% with the goal of reducing post-transplant relapse is recommended, although the optimum strategy (azacitidine, decitabine, induction-type chemotherapy) has not been determined. NCCN Guidelines note that reducing the disease burden pre-transplant is particularly important in patients who will receive a reduced-intensity conditioning regimen. At some centers, failure to achieve <5% blasts with cytoreduction should not preclude from proceeding to transplant, as these patients appeared to derive survival benefit from transplant. , Strategies for patients with specific mutations are under investigation. Patients with TP53 mutations, particularly biallelic, have a poor prognosis even with transplantation. These cases should be discussed with a physician who has expertise in HCT and patients should be enrolled in a clinical trial whenever possible.

For patients who experience a disease relapse after initial HCT or whose disease did not respond to treatment, NCCN Guidelines include as Category 2A consideration of a second allogeneic HCT. NCCN Guidelines specifically note that physicians should consider a second transplant or donor lymphocyte infusion immuno-based therapy for appropriate patients who had a prolonged remission after first transplant.

NCCN also feels it’s important to note that age alone should not be an exclusionary factor for allogenic HCT. In a prospective allogeneic transplant trial using nonmyeloablative conditioning, 372 patients between ages 60 and 75 years with hematologic malignancies (AML, MDS, chronic lymphocytic leukemia, lymphoma, and multiple myeloma) were shown to have no association between age and non-relapse mortality, overall survival, and progression free survival. The study supports the use of comorbidities and disease status, rather than age alone, as criteria for determining the eligibility of patients for allogeneic HCT. Further information can be found in the NCCN Guidelines for Myelodysplastic Syndromes® which are included as an appendix. Additionally, these guidelines are continuously updated and the most up to date version can always be found online at www.nccn.org.

In sum, NCCN thanks CMS for reconsidering coverage of this critical intervention and encouraging CMS to consider expanding coverage to align with nationally recognized clinical practice guidelines and broader payer policy within the United States landscape. NCCN supports coverage of HSCT for MDS without evidence development as outlined within nationally recognized clinical practice guidelines and supported by the literature. NCCN appreciates the opportunity to comment on the CMS National Coverage Analysis and Proposed Decision Memo: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS) (CAG 00415R). NCCN is happy to serve as a resource and looks forward to working together to advance access to equitable, high-quality cancer care.

Sincerely,

Peter L. Greenberg, MD
Panel Chair
NCCN Guidelines for Myelodysplastic Syndromes®

Crystal S. Denlinger, MD, FACP
Chief Executive Officer
National Comprehensive Cancer Network®

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Cleveland Cord Blood Center is providing comment herein in reference to the recent CMS proposed decision to expand coverage for allogeneic hematopoietic stem cell transplant (alloHSCT) using only bone marrow (BM) or peripheral blood stem cell (PBSC) products for Medicare patients with myelodysplastic syndromes (MDS) designated as high-risk or very high-risk per IPSS-R.

The use of alternative allogeneic donor products including haploidentical, mismatched unrelated adult donor (MMUD), and umbilical cord blood (UCB) together provide greater opportunities for ethnically diverse patients to receive alloHSCT. Compared to HLA-matched related allogeneic donor and MUD alloHSCT, more ethnically diverse patients received MMUD, haploidentical donor and UCB alloHSCT during the period 2015-2020, with 3,116 patients treated with UCB products.[1]

Currently there are 136 clinical trials listed in ClinicalTrials.gov that have ongoing enrollment or have completed enrollment and provided alloHSCT outcome data for MDS patients treated in the US and rest of world with UCB products. These studies and published literature provide full clinical data summaries of UCB transplant outcomes for advanced age and MDS patients treated with reduced intensity conditioning that are readily available for CMS review.[2-11]

Initial studies prior to 2013 focused on early events occurring prior to day 100 after alloHSCT with alternative donor products that were unfavorable to UCB products related to rates and kinetics of engraftment. However, over time with improved donor selection, supportive care, and longer follow up data - including as one example a recent UCB alloHSCT multi-center study including MDS patients,[12] UCB product 3-year disease free survival (DFS) is 56.4% (95% CI, 45.9-65.6%) and overall survival (OS) 62.7% (95% CI, 52.1-71.6%) - that aligns with DFS/OS outcomes of allogeneic unrelated and family member donated BM and PBSC products. A second recent registry[4] study in MDS patients over age 50 years reveals that alloHSCT donor products, including matched sibling, MUD, MMUD, and UCB, did not determine OS, DFS or GvHD-free, relapse-free survival; however, chronic GvHD-free, relapse-free survival was better for the n=677 patients treated with UCB products.[11]

Moreover, US health care burden from the time of transplant through year 5 comparing alloHSCT BM/PBSC products and UCB reveals that from day 101 to 365, recipients of UCB products have approximately half the number of face-to-face visits, half as many laboratory studies, and the lowest relative value units (RVU) billed of all alloHSCT product sources (P<0.01 for each component).[13] There was no significant difference in 5-year OS, 5-year DFS, 5-year relapse, and 180-day grade III-IV acute GvHD comparing BM, PBSC, and UCB products. UCB recipients required the longest number of days in hospital prior to day 100. However, in years 1 to 5, UCB recipients had the lowest number of hospital days and readmissions per 100 days of survival. When considering the posttransplant recovery period out to 5 years, the long-term health care burden is lowest overall in recipients of UCB products.[13] This is highly relevant to patient outcomes, as many patients want to know what ‘normal’ life looks like after alloHSCT.

FDA has fully evaluated the benefit: risk ratio of UCB products for patients with hematopoietic malignancies including MDS. Currently there are 9 FDA-approved UCB products for alloHSCT including the recently approved UCB product Omidubicel (Omisirge; Gamida Cell Ltd). UCB shortens the required time for an unrelated donor search and thus increases the chance of proceeding with alloHSCT. UCB also expands the availability of FDA approved products for alloHSCT to more MDS patients. A recent report of UCB alloHSCT noted that 39% of the study patients were nonwhite, highlighting a key demographic with more limited donor availability.[12] This is of particular importance for racial minorities patients who are underrepresented in the US BM/PBSC national registry, and for whom a higher frequency of graft vs. host disease (GvHD) as cause of death for Black/African American patients following MUD alloHSCT has been noted.[1]

The introduction of family member donated HLA matched and mismatched BM/PBSC also provides a rapid route to alloHSCT for MDS patients including underrepresented racial minorities. Mismatched family members’ donated BM/PBSC products including haplo-identical alloHSCT is early in development compared to MUD BM/PBSC and UCB products, and relies on posttransplant cyclophosphamide dosing to overcome severe GvHD in the HLA mismatch setting. A better understanding of haplo-identical family donated BM/PBSC grafts with posttransplant cyclophosphamide-based GvHD prophylaxis as to optimal donor selection, engraftment, impact on malignancy relapse, and incidence of early and late infections,[14-17] is anticipated in the next several years, when longer term transplant outcomes and sufficient sample sizes are available for evaluation and comparison.

Taken together, based on the extensive reported clinical trial data to date and benefit for patients, it is advised that the current CMS proposed decision to limit expansion of coverage for alloHSCT using only BM or PBSC products for Medicare patients with MDS should be updated to include UCB products.

REFERENCES

1. Auletta, J.J., et al., Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research. Transplant Cell Ther, 2023. 29(6): p. 346 e1-346 e10.
2. Konuma, T., et al., Comparison of transplant outcomes from matched sibling bone marrow or peripheral blood stem cell and unrelated cord blood in patients 50 years or older. Am J Hematol, 2016. 91(5): p. E284-92.
3. Tsai, S.B., et al., Reduced-Intensity Allogeneic Transplant for Acute Myeloid Leukemia and Myelodysplastic Syndrome Using Combined CD34-Selected Haploidentical Graft and a Single Umbilical Cord Unit Compared with Matched Unrelated Donor Stem Cells in Older Adults. Biol Blood Marrow Transplant, 2018. 24(5): p. 997-1004.
4. Peffault de Latour, R., et al., Similar overall survival using sibling, unrelated donor, and cord blood grafts after reduced-intensity conditioning for older patients with acute myelogenous leukemia. Biol Blood Marrow Transplant, 2013. 19(9): p. 1355-60.
5. Sharma, P., et al., Adult cord blood transplant results in comparable overall survival and improved GRFS vs matched related transplant. Blood Adv, 2020. 4(10): p. 2227-2235.
6. Cohen, S., et al., Improved outcomes of UM171-expanded cord blood transplantation compared with other graft sources: real-world evidence. Blood Adv, 2023. 7(19): p. 5717-5726.
7. Childs, R.W., et al., Combined haploidentical and cord blood transplantation for refractory severe aplastic anaemia and hypoplastic myelodysplastic syndrome. Br J Haematol, 2021. 193(5): p. 951-960.
8. Milano, F., et al., Infusion of Non-HLA-Matched Off-the-Shelf Ex Vivo Expanded Cord Blood Progenitors in Patients Undergoing Cord Blood Transplantation: Result of a Phase II Clinical Trial. Front Cell Dev Biol, 2022. 10: p. 835793.
9. Sandhu, K.S., et al., Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged >/=70 Years. Biol Blood Marrow Transplant, 2016. 22(2): p. 390-393.
10. Horwitz, M.E., et al., Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. Blood, 2021. 138(16): p. 1429-1440.
11. Konuma, T., et al., Should a matched sibling donor still be considered the primary option for allogeneic hematopoietic cell transplantation in patients over 50 years of age with myelodysplastic syndrome? Bone Marrow Transplant, 2023. 58(8): p. 893-906.
12. Lin, C., et al., Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials. Transplant Cell Ther, 2023. 29(5): p. 338 e1-338 e6.
13. Garcia, J.G., et al., Low 5-year health care burden after umbilical cord blood transplantation. Blood Adv, 2021. 5(3): p. 853-860.
14. Ustun, C., et al., Post-transplantation cyclophosphamide is associated with increased bacterial infections. Bone Marrow Transplant, 2023.
15. Goldsmith, S.R., et al., Posttransplant cyclophosphamide is associated with increased cytomegalovirus infection: a CIBMTR analysis. Blood, 2021. 137(23): p. 3291-3305.
16. Rieger, M.J., et al., Haploidentical transplant with posttransplant cyclophosphamide vs matched related and unrelated donor transplant in acute myeloid leukemia and myelodysplastic neoplasm. Bone Marrow Transplant, 2023. 58(10): p. 1121-1129.
17. Papanicolaou, G.A., et al., Incidence and Impact of Fungal Infections in Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis and Haploidentical Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis. Transplant Cell Ther, 2023.

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I fully support expanding Medicare coverage for allogeneic hematopoietic stem cell transplant using only bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes designated as high-risk or very high-risk with a score of = 4.5 points according to criteria specified by the International Prognostic Scoring System - Revised (IPSS-R). For these particular patients the evidence supports a national coverage determination under section 1862(a)(1)(A) of the Social Security Act.

I support in addition, CMS that coverage of allogeneic hematopoietic stem cell transplant using bone marrow or peripheral blood stem cell products for Medicare patients with myelodysplastic syndromes who are not specified above will be determined by Medicare Administrative Contractors under section 1862(a)(1)(A) of the Act.

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To Whom It May Concern:

I understand that Centers for Medicaid and Medicare Services is updating allogeneic transplant recommendations for management of patients with intermediate- and high-risk myelodysplasia to only include bone marrow and peripheral blood sources of hematopoiesis. I have utilized expanded cord blodd in the setting of allogeneic transplantation for MDS and find that this source of hematopoiesis provides for safer, and more rapid hematopoietic recovery, and should not be left unavailable to patients for whom other donor sources do not exist.

Thank you for taking my comments. I look forward to your consideration.

-Gary Schiller, M.D.

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The agency should reconsider restricting coverage for allogeneic transplantation using stem cells from either bone marrow or peripheral blood stem sources. Coverage should also be extended to those receiving stem cells from umbilical cord blood. Without a cord blood option, this life saving treatment option may not be available to minority populations who do not have an available matched donor or mismatched family alternative donor. Extended follow-up of BMT-CTN 1101 failed to demonstrate a statistically significant difference in progression-free or overall survival among recipients or reduced intensity cord blood or haploidentical transplantation. Real-world data suggests superiority of haploidentical peripheral blood stem cells. Thus it is clear that this source should be prioritized when available (O'Donnell P, Brunstein C et al Trans Cell Therapy 28 (2022) 109. However, umbilical cord blood transplantation also provided a life-saving option for many patients and without question is superior to a non-transplant option.

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The source of stem cells should not be a coverage decision. Physicians will always choose the best donor source for the patient. If no peripheral blood or bone marrow option is available to the patient, cord blood should be an option. There are multiple minorities not well represented in the donor registry who have limited donor options.
Similarly, the IPSS-R is already outdated. There are multiple models that incorporate genomic factor that are more predictive than IPSS-R.
No physician or patient would choose an allogeneic stem cell transplant if they had another option to control the MDS. It's too toxic.
Please use language that is vague enough for the physicians and patients to make the best decision for the patient using the most up to date evidence.

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Response to CMS Coverage consultation on Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndromes (MDS)
Drafted by Professor Paula Williamson, Lead for the COMET Initiative, 9th December 2023

COMET, https://www.comet-initiative.org/, wholeheartedly support the CMS approach to producing national coverage determinations, which involves the evaluation of ‘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.’

Relevant clinical evidence must include relevant health outcomes. COMET supports the CMS in its reference to ‘key health outcomes’ in Appendix A, where it is stated that ‘CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.’ However, there is no information about how outcomes were determined to be key and COMET believes it good practice to (i) identify whether a relevant core outcome set (COS) exists and consider whether the core outcomes should inform the O in the PICO statement for a research evidence review, and (ii) transparently report how outcomes are chosen.

Table 1 shows the O in the PICO statement to be:

1. Overall Survival
2. Progression-free Survival
3. Improved Quality of Life
4. Reduction in recurrence of disease (relapse)
5. Reduction in progression to AML
6. Relapse-free survival
7. Graft versus Host disease (GVHD)
8. Infection
9. Grade =3AEs

A search of the COMET database for myelodysplastic syndrome identifies the following entry: https://www.comet-initiative.org/Studies/Details/1571. The published COS therein, https://onlinelibrary.wiley.com/doi/10.1111/bjh.16654, contains the following core outcomes:

• Health-related quality of life
• Treatment-related mortality
• Overall survival
• Performance status
• Safety
• Haematological improvement

There is clear but not complete overlap. Although patients were not involved in the development of this COS, COMET advises that an otherwise well-developed COS be considered during an evidence review, potentially supplemented through additional consideration of patients’ views.

Since research to determine core outcomes is evidence, we recommend that reference to this COS be made and reported in the CMS evidence review, with decisions regarding how this and other information is used to inform the choice of key outcomes for the review.

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Your proposal allows for MAC discretion on coverage additional diagnoses. First, you and the OIG know that MACs are wildly inconsistent in their determinations. That a diagnosis would be covered in one MAC jurisdiction but be denied in another makes no sense at all. Second, for such costly and risky care, CMS should require the MACs to establish an informal but binding "prior authorization" process that allows a provider to discuss an individual case with a MAC and get assurance of coverage prior to the transplantation base don the spacific circumstances of the case. Without this, hospitals may be forced to provide HINN 1s to patients and subject them to psychological harm and financial risks.

Thanks to CMS staff for all the hard work on a complex topic. I support the covered indications.

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