The recent decision by the Centers for Medicare and Medicaid Services (CMS) to cover allogeneic hematopoietic cell transplantation (alloHCT) for eligible patients with sickle cell disease (SCD), myelofibrosis, and multiple myeloma (MM) is a boon for hematology. But, as is often the case with good news, this National Coverage Determination (NCD) needs to be taken with quite a few grains of salt. In this case, the specific criteria needed to be met that govern exactly how and when CMS will cover eligible patients are causing many transplanters to slightly curb their enthusiasm.
"This decision is a very significant milestone that reflects our advances in the art and science of stem cell transplantation," said Krishna Komanduri, MD, director of the Adult Stem Cell Transplant Program at the University of Miami Health System's Sylvester Comprehensive Cancer Center in Miami, Florida. "Beyond that, there are some caveats, including that, within each disease state, there are some eligibility restrictions for patients based on their risk level and the severity of disease."
The NCD requires the establishment of clinical trials to assess and validate alloHCT in Medicare patients with SCD, myelofibrosis, and MM, and those will take some time to develop and start enrolling patients, added Dr. Komanduri, who is also president-elect of the American Society for Blood and Marrow Transplantation (ASBMT). (For a timeline of the NCD see the Sidebar.)
Laura Michaelis, MD, associate professor of medicine at the Medical College of Wisconsin in Milwaukee, Wisconsin, agreed that this decision is a clear "win" for clinicians and patients, but that "there are still aspects [of the NCD] that need to be finalized."
"I don't think these criteria are meant to be restrictive," Dr. Michaelis said. "I think CMS wants to expand coverage, and that's great, but they also want to gather information to ensure that this course of action is appropriate. We need to make sure that we work with CMS to achieve that goal."
Mary Horowitz, MD, chief of the Division of Hematology and Oncology at the Medical College of Wisconsin, called the NCD "a way forward that removes the financial barrier to transplant for a growing population of patients who can benefit from it." She also cautioned that the transplant community and CMS still have to agree on what constitutes acceptable clinical data to support coverage.
Drs. Kumanduri, Michaelis, and Horowitz, as well as other members of the transplant community spoke with ASH Clinical News about the details of this NCD and what it means for hematologists, transplant specialists, and patients – both now and in the near future.
The Big Picture and the Finer Points
With NCDs such as these, CMS can mandate or prohibit coverage for specific procedures in specific indications. Prior to the recent NCD, CMS was "silent" on the use of alloHCT for the treatment of SCD and myelofibrosis. That meant coverage decisions were up to local Medicare Administrative Contractors, so patients and transplant centers were put in a position of potentially taking on the full financial burden of the procedure if coverage was denied, explained Stephanie Farnia, MPH, director of payer policy at the National Marrow Donor Program (NMDP)/Be The Match. Beyond that, CMS outright prohibited coverage of alloHCT for MM.
Enter the new NCD, with coverage of alloHCT in these three disease states and the caveat that reimbursement would be provided only if the patient is enrolled in a CMS-approved clinical trial designed to evaluate the benefit of alloHCT in a Medicare population.
Called a Coverage with Evidence Development (CED), this requirement mandates that eligible beneficiaries meet the following criteria to receive coverage:
- Symptomatic, stage II or III MM
- Intermediate-2 or High Dynamic International Prognostic Scoring System myelofibrosis, plus score in primary or secondary disease
- Severely symptomatic SCD
Additionally, the CED trial requirements for alloHCT in these conditions state that patients must be participating in an approved prospective clinical study that meet the following criteria:
"There must be appropriate statistical techniques in the analysis to control for selection bias and potential confounding by age, duration of diagnosis, disease classification, International Myeloma Working Group classification, International Staging System score, Durie Salmon staging, comorbid conditions, type of preparative/conditioning regimen, graft-versus-host disease (GVHD) prophylaxis, donor type, and cell source."1
The principal objective, according to the CED, is to test whether alloHCT therapy improves health outcomes, to compare survival outcomes between alloHCT and non-alloHCT therapies, and address acute and chronic GVHD and transplant-related adverse events. Analysis of quality-of-life among those receiving alloHCT is an optional component to these studies, according to CMS.
This isn't the transplant community's first go-round with a CED – in 2010, CMS required one for coverage of myelodysplastic syndromes (MDS), although the CED in that setting was much less demanding, asking that trials:
- Prospectively compare MDS Medicare beneficiaries who receive alloHCT therapy and determine if they have better outcomes than those who do not get alloHCT treatment.
- Examine how International Prognostic Scoring System score, age, cytopenias, and comorbidities predict outcomes among these patients.
- Assess what treatment facility characteristic predicts meaningful clinical improvement in outcomes.
"As a result, fewer transplants have been performed in this Medicare population for these disease states," agreed Ms. Farnia. "But that changed over time; the science has come along to support allogeneic transplant in this patient population, and that's taken some time to work through the CMS [NCD] process."
Another obstacle to acquiring data about alloHCT in these diseases is their rarity. For instance, myelofibrosis has an incidence rate ranging from 0.1 per 100,000 per year to 1 per 100,000 per year.2
As Ms. Farnia mentioned, though, the science has advanced, and studies have demonstrated the efficacy of alloHCT for myelofibrosis in older patients, including a retrospective registry analysis of 289 patients (age range = 18-73 years) that found a long-term relapse-free survival in one-third of patients who received a transplant.3,4
Dr. Michaelis was part of a group that facilitated some changes to the NCD when it was still in the planning stages. In an early version of the NCD, there was a requirement that Medicare-eligible patients with myelofibrosis undergoing alloHCT be matched to non-transplant control patients.
"As myelofibrosis specialists, we had some concerns about that. [CMS] wanted a scenario where patients would be transplanted and non-transplanted simultaneously," Dr. Michaelis said. "So, a group of us who specialize in myelofibrosis – 22 in total – sent a letter to the CMS Coverage and Analysis Group asking that they not require concurrent non-transplant controls. We felt that patients seeking transplant were seeking any and all curative options for their illness; it was unlikely that they would be willing to move into a non-transplant control group."
Additionally, people who are ineligible for alloHCT are "inherently poor controls and wouldn't serve as a good comparative group," she said. In the final NCD, controls are still required in the form of data on non-transplant myelofibrosis patients, but the information does not have to be gathered concurrently.
This is one example of how the transplant community and advocacy groups are working with CMS to fine-tune the NCD – and an example of how those groups will continue to collaborate.
"We are very confident that we will be able to work with CMS and address their concerns," said Linda Burns, MD, vice president and medical director of Health Services Research at NMDP/Be The Match.
To that end, the Center for International Blood and Marrow Transplant Research (CIBMTR), on whose executive committee Dr. Burns also serves, has designated a faculty to develop the protocols to "get these trials up and running as soon as possible, certainly in less than a year. We recognize that we need to do this quickly, but also appropriately."
Dr. Horowitz noted that when the MDS study launched in 2010, the expectation was that the study would take time just for patient accrual, but that wasn't the case. Now, more than 1,200 patients have been enrolled.
"Clearly, there was an underserved population for allogenic transplant," she said, suggesting that the same kind of rapid enrollment is possible with the current CED.
The CED Paradigm
However challenging the CED may seem, organizations such as the CIBMTR already prospectively collect data on all alloHCT recipients in the United States, and the existing data collection and analysis protocol meet CMS requirements for study quality, Dr. Horowitz noted.
The U.S. Stem Cell Therapeutic Outcomes Database, a component of the C.W. Bill Young Cell Transplantation Program, is another organization charged with collecting and assessing outcomes data for all U.S. allogeneic transplants. Dr. Horowitz is the research and project director of the database.
In addition, many individual transplant centers often keep their own registries on alloHCT patient outcomes, Ms. Farnia pointed out. She encourages centers to continue that practice. The trials under the NCD CED "are intended to be national studies that can be opened at all transplant centers," she said, "but there are other studies that individual transplant centers can submit to CMS. We don't see a conflict with that right now."
Overall, the doctors who spoke with ASH Clinical News are optimistic that protocols and registries that meet the CED requirements will be in place by the end of 2016.
Despite that even the advocates who worked closely with CMS on this NCD did not necessarily have information beforehand about its specific details.
To further complicate matters, it is not clear how much data and how long of a delivery timeframe will be enough. Ms. Farnia noted that the NCD does not address either of these points.
"We don’t know how long these studies are going to last," she explained. "For instance, the MDS CED is a study that's been open since 2010, and Medicare doesn't give a timeline or minimum number of patients required to satisfy it. Do they want to see data for three years? For 300 patients? We don't know how long the additional data gathering is going to be required."
The stringent criteria laid out in the CED prompted the American Society of Hematology (ASH) to caution, during the NCD review process, that the CED "will yield small numbers of patients and insufficient power to add meaningful clinical questions about prognostic factors for patients, policymakers, and physicians."4
Nonetheless, the CIBMTR has already laid out target dates for submitting trial protocols to CMS, most of which fall before summer 2016. In myelofibrosis, the hope is that an existing CIBMTR study can be adapted to be compliant, while in SCD, the SCURT trial (Evaluating the Safety and Effectiveness of Bone Marrow Transplants in Children With Sickle Cell Disease; BMT CTN 0601) is active.5 Finally, in MM, the hope is to use patients who have received autologous hematopoietic cell transplantations (autoHCT) as controls.
One of the advantages that the transplant community has over other areas of medicine is that it has been engaged in data-tracking on patient outcomes for some time.
"The transplant community is really well organized," Dr. Komanduri said. "There's excellent cooperation between NMDP, ASBMT, and CIBMTR. We have a really cohesive group of organizations in hematology and transplantation that are used to taking on these kinds of [data collection] challenges."
Dr. Horowitz noted that autoHCT is an accepted Medicare-covered standard therapy for many of these disease states. Because of the work CIBMTR and the transplant community as a whole has done for MDS, she is confident that CED-ready studies can be designed and launched fairly quickly for the new NCD.
With clinicians and their patients in a holding pattern as the logistics of the CED are sorted out and implemented, what are the next steps?
Ms. Farnia recommended that clinicians continue to work with their transplant centers and local Medicare contractors on a patient-by-patient basis.
"We would say [to] always refer a patient who might be eligible for transplant to your transplant center," she explained. "Then we are suggesting that transplant centers have conversations with their local Medicare contractors to see if they can find a workaround on a local level. We are continuing to have conversations with Medicare about what we can do in the interim at a national level."
Dr. Burns recommended that clinicians continue to follow various published treatment guidelines – developed by NMDP, ASBMT, and the National Comprehensive Cancer Network – to determine which patients should be referred to transplant centers. "These are based on the best evidence available and regularly updated," she said.
Dr. Komanduri suggested that interested parties continue to check in regularly at the ASBMT and NMDP websites for updates on the situation – and to have some patience. "I've already gotten emails on the local level from physicians saying, â€˜I understand that we can now refer Medicare patients to you for allogenic transplant for SCD.' I have to walk them back, and say, â€˜Yes, that will be possible, but there are some criteria that have to be met first.'"
Dr. Komanduri also emphasized the importance of early referral of patients to experienced hematologists and transplant centers to discuss all available treatment options – alloHCT or otherwise.
"For MM, the primary treatment approach has been autologous transplant, so allogeneic transplant is not typically used as an upfront option. It's generally used in the salvage setting and, even then, in the context of clinical trials," he explained. "For SCD and myelofibrosis, these diseases may have an indolent course, and there are certain subsets of patients who should not be considered for allogeneic transplant. There are multiple treatment options that should be considered."
For Dr. Horowitz, there is still some concern that the NCD will put a stopper on alloHCT for Medicare-eligible patients who were covered during the "silent" era, simply because local Medicare contractors will want to wait to see how the CED requirements play out.
"There are a number of places in the country where patients were being appropriately covered, in my opinion. Those patients are now in limbo; it's uncertain as to how that's going to be handled," she said. "We are in a situation where, in the short term, access to alloHCT may be hindered rather than helped. Of course, there are also many areas where local contractors did not approve allogenic transplantation, so in the long run, this [NCD] will benefit everyone." â€”By Shalmali Pal
- Centers for Medicare & Medicaid Services. Decision Memo for Stem Cell Transplantation (Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease) (CAG-00444R). Accessed March 12, 2016 from https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=280.
- Moulard O, Mehta J,Fryzek J, et al. Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol. 2014;92:289-97.
- Ballen KK, Shrestha S, Sobocinski KA, et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant. 2010;16:358-67.
- "American Society of Hematology's Comments on Proposed National Coverage Determination on Stem Cell Transplantation (letter to the Centers for Medicare & Medicaid Services)." November 27, 2015.
- ClinicalTrials.gov. Evaluating the safety and effectiveness of bone marrow transplants in children with sickle cell disease (BMT CTN 0601) (SCURT). Accessed March 12, 2016 from https://clinicaltrials.gov/ct2/show/NCT00745420?term=00745420&rank=1.
Timeline of the National Coverage Determination for AlloHCT in Multiple Myeloma, Myelofibrosis, and Sickle Cell Disease
The changes to the National Coverage Determination (NCD) for allogeneic hematopoietic cell transplantation (alloHCT) have been a long time coming. Here is a timeline of the actions – from CMS' "silence" on alloHCT for the treatment of sickle cell disease and myelofibrosis to the most recent changes in coverage.
- April 30, 2015: Formal request for coverage determination initiated by Sergio Giralt, MD, president of the American Society for Blood and Marrow Transplantation, and Michael Boo, JD, chief strategy officer of the National Marrow Donor Program (ASH supported the request.)
- April 30, 2015 through May 30, 2015: Public comment period
- October 29, 2015: Proposed NCD memo released
- October 29, 2015 through November 28, 2015: Proposed NCD public comment period (ASH submitted comments on November 27.)
- January 27, 2016: NCD memo released