Age alone should not be barrier to hematopoietic stem cell transplantation consult
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A patient aged 72 years with high-risk myelodysplastic syndrome presents at a community hematology/oncology clinic.
Another hematologist/oncologist is treating a patient aged 69 years with acute myeloid leukemia.
Are the patients candidates for allogeneic hematopoietic stem cell transplantation? At one point, the answer likely was “No.”
However, reduced-intensity conditioning regimens and other advances in transplant procedures make it possible for older patients with myelodysplastic syndrome (MDS) and AML to undergo allogeneic HSCT.
This commentary explores research studies that demonstrate HSCT for older patients with MDS and AML is feasible and should be considered as a standard-of-care treatment option with no upper age limit. Additionally, the article will share insights for clinicians who treat older patients with a condition for which HSCT is indicated.
What the research showed
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducted a multicenter, prospective biologic assignment trial of 384 patients aged 50 to 75 years who had higher-risk de novo MDS — International Prognostic Scoring System intermediate-2 or high — who were candidates for reduced-intensity conditioning allogeneic HSCT.
Researchers assigned patients either to a donor group (n = 260) or no donor group (n = 124) based on the availability of a related or unrelated 8/8 HLA-matched family member or unrelated donor.
The results — published last year in Journal of Clinical Oncology — showed a significant 3-year OS advantage for those in the donor group (47.9% vs. 26.6%; P = .0001), as well as improved 3-year leukemia-free survival (35.8% vs. 20.6%; P = 0.003).
Investigators observed the benefits across all subgroups, including individuals older than or younger than 65 years.
In addition, researchers explored quality of life as a secondary outcome. They analyzed patient-reported outcomes measured at the time of enrollment and at 6, 12, 18, 24 and 36 months.
Those in the donor group who underwent HSCT did not experience worse quality-of-life outcomes than those in the no donor group. At 18 months follow up, differences for bodily pain and general health favored the donor group.
Researchers concluded HSCT should be offered to patients aged 50 to 75 years who have a suitable donor.
Initial results of an observational study published in JAMA Oncology also demonstrated patients with MDS aged 65 years and older derived similar benefits from allogeneic HSCT as those aged 55 to 64 years.
This ongoing study (NCT01166009) is being conducted by CIBMTR (Center for International Blood and Marrow Transplant Research), a research collaboration of the National Marrow Donor Program (NMDP)/Be The Match and Medical College of Wisconsin.
A retrospective observational study conducted by CIBMTR — results of which were published this year in Bone Marrow Transplantation — also indicated that age should not be a barrier to adults undergoing HSCT for AML in first complete remission.
Researchers reviewed data from 1,321 patients with AML aged 60 or older who received allogeneic HSCT in first complete remission from 2007 through 2017. The study examined how age, comorbidities and disease factors affected the optimal approach to allogeneic HSCT. Researchers reported 3-year OS of 40% to 50% among all age groups evaluated (60 to 64 years, 65 to 69 years, and 70 years or older).
Although age appeared associated with a small decrease in OS after HSCT, age as a risk factor was substantially less than the impact on survival tied to other disease-related risk factors, such as poor cytogenetics and measurable residual disease (MRD). In fact, poor cytogenetics or MRD prior to HSCT accounted for most of the adverse impact on OS and DFS.
Researchers concluded that age alone should not exclude patients from allogeneic HSCT.
Implications for clinical practice
Allogeneic HSCT is the only potentially curative therapy for patients with MDS, and it is the most common curative therapy for AML — a disease for which median age at diagnosis is 67 years. However, HSCT has not been used extensively in this patient population due to barriers such as perceptions about age criteria and insurance coverage concerns.
At one time, age alone could exclude a patient from HSCT; however, that is no longer true. Transplant centers use a comprehensive assessment of the patient’s functional performance status and comorbidities when making decisions about the appropriateness of transplant.
Many patients aged older than 65 years — or even 70 years — are good candidates for HSCT. In fact, CIBMTR data show the proportion of adults aged 65 years or older who receive allogeneic HSCT increased steadily from 2005 through 2020.
To improve patient outcomes, there must be a shift toward earlier and more frequent referral of older patients with AML or MDS to transplant centers for an initial conversation about the appropriateness of transplantation.
Early referral by a community hematologist/oncologist to a transplant center ensures appropriate patients receive HSCT at an optimal time by enabling:
• assessment of candidacy for transplantation and other cellular therapy options;
• timely identification of a suitable donor (this can take time, especially if a patient has an HLA type not commonly found on donor registries);
• evaluation of alternative options if a fully matched donor is not available (these options could include a donor with a lower degree of HLA match or a haploidentical donor); and
• identification and resolution of nonmedical barriers to HSCT, such as issues with insurance or caregiver support.
The clinical benefit of early referral and transplantation for AML in first complete remission is evident in research published in JCO Oncology Practice.
Investigators from the SWOG-led intergroup study S1203 (NCT01802333) used an organized, disciplined process for early HLA typing and cytogenetic testing, rapid donor identification and early referral for HSCT for patients with high-risk AML.
This, in turn, led to a 65% HSCT rate in first complete remission and a 37% increase in 2-year OS compared with patients who did not undergo HSCT (48% vs. 35%; P = .031).
Solutions exist despite challenges
Although there are clear benefits to HSCT for older patients, challenges exist.
For example, a fully matched donor is not available for every patient. In addition, insurance issues for older patients cannot be discounted.
However, there are solutions.
Advances in graft-versus-host disease treatments have the potential to safely expand patient access to HSCT for those who do not have a fully matched donor.
For example, a CIBMTR study published in Journal of Clinical Oncology showed patients who received mismatched unrelated donor HSCT with post-transplant cyclophosphamide experienced reduced rates of GVHD and improved outcomes.
Three-year outcomes reported at this year’s European Group for Blood and Marrow Transplantation Annual Meeting showed outcomes remained very good. This study was a precursor to the ACCESS clinical trial (NCT04904588), for which enrollment is underway.
Progress also is being made in insurance coverage for older adults who need HSCT for MDS.
In the past, many older adults with MDS did not receive HSCT because the benefits had not been sufficiently proven for CMS to provide payment coverage.
CMS does not cover allogeneic HSCT for adults aged 65 years or older unless the patient is enrolled in a qualified Coverage with Evidence Development study, such as the ongoing CIBMTR observational study.
The CIBMTR, NMDP/Be The Match, American Society for Transplantation and Cellular Therapy and ASH are providing the CMS with data from the BMT CTN study and the CIBMTR observational study for its use in making coverage policy decisions.
With continued advancements being made in HSCT, the most important step hematologists/oncologists can take is considering this curative option early. This will help to ensure appropriate patients receive HSCT at the optimal time in their disease course for the best outcomes.
References:
- Atallah E, et al. JAMA Oncol. 2020;doi:10.1001/jamaoncol.2019.5140.
- Auletta JJ, et al. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2021. Available at: www.cibmtr.org/ReferenceCenter/SlidesReports/SummarySlides/pages/index.aspx.
- Cusatis R, et al. Blood. 2021;doi:10.1182/blood-2021-147514.
- Maakaron J, et al. Bone Marrow Transplant. 2022;doi:10.1038/s41409-022-01650-5.
- Nakamura R, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03380.
- National Marrow Donor Program/Be The Match. 3-year outcomes remain very good in mismatched unrelated donor HCT patients, highlighting potential to expand access. Available at: bethematchclinical.org/research-and-news/browse-research/3-year-outcomes-remain-very-good-in-mismatched-unrelated-donor-hct-patients,-highlighting-potential-to-expand-access. Accessed Aug. 11, 2022.
- Pagel JM, et al. JCO Oncol Pract. 2020; doi:10.1200/JOP.19.00133.
- Shaw BE, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03502.
For more information:
Stephen Spellman, MBS, is vice president of research and senior scientific director of CIBMTR (Center for International Blood and Marrow Transplant Research) at the National Marrow Donor Program/Be The Match. He can be reached at sspellma@nmdp.org.
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