December 11, 2008 (San Francisco, California) — Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes should not be prevented from proceeding to allogeneic hematopoietic cell transplantation (HCT) on the basis of age alone. Study results, presented here at the American Society of Hematology 50th Annual Meeting and Exposition, showed that outcomes for older patients undergoing allogeneic HCT were not significantly different from those of younger patients, even after adjustment for multiple comorbidities.
"The main impetus for the introduction of reduced-intensity conditioning was to allow for allogeneic transplants in older patients," said senior author Sergio A. Giralt, MD, professor in the Department of Stem Cell Transplantation and Cellular Therapy at the University of Texas MD Anderson Cancer Center, in Houston.
Dr. Giralt and colleagues at MD Anderson pioneered the use of reduced-intensity conditioning, and nonmyeloablative preparation has allowed patients who were not previously considered to be suitable candidates to receive transplants.
Up until that time, older patients were not considered to be candidates for transplantation because the of high doses of radiation and chemotherapy that were needed for engraftment, Dr. Giralt explained. Today, about 30% to 40% of all stem-cell transplants are performed using a low-intensity regimen.
Both AML and myelodysplastic syndromes primarily affect older adults, and although myelodysplastic syndromes are not malignancies themselves, about 30% of the time the syndromes are a precursor to leukemias, such as AML and chrome myelomonocytic leukemia. Transplantation is the best-established curative therapy, but it is usually not made available to older patients because of concerns about toxicity and poor outcomes. Reduced-intensity-conditioning regimens have been developed to allow allografting in older patients, but there are limited data to support their use in patients older than 65 years.
"It is important to recognize that one of the impetuses to do this study [was the fact that] currently in the United States, the Centers for Medicaid and Medicare Services do not consider myelodysplastic syndromes a 'covered' benefit," said Dr. Giralt. "So for many of these patients, an allogeneic transplant is not being covered."
Age Not a Factor for Survival
Dr. Giralt and colleagues retrospectively analyzed data reported to the Center for International Blood and Marrow Transplant Research on 565 patients with AML and 551 patients with myelodysplastic syndromes for transplant-related mortality, engraftment, incidence of acute and chronic graft-vs-host disease, leukemia-free survival, and overall survival. The patients included in the analysis all received reduced-intensity HCT and achieved a first complete remission. The goal was to evaluate the influence of age as a predictor of outcome after allogeneic HCT.
Using multivariate analysis, the researchers did not find statistically significant differences in transplant-related mortality across age groups for either AML or myelodysplastic syndromes patients, and no overall difference in the occurrence of acute graft-vs-host disease (31% to 35% at 100 days) or chronic graft-vs-host disease (36% to 53% at 2 years). Rates of relapse at 3 years were 29% to 30%, and were similar across all age groups. There was also no statistically significant impact of age on transplant-related mortality, leukemia-free survival, or overall survival.
Survival and Relapse Rates for Acute Myeloid Leukemia Patients
| 40–54 years, n=220 (range) | 55–60 years, n=150 (range) | 60–65 years, n=132 (range) | ≥65 years, n=63 (range) | |
| Transplant-related mortality | ||||
| - 100 days, % | 11 (7 - 16) | 6 (3 - 10) | 13 (8 - 20) | 10 (4 - 18) |
| - 1 year, % | 20 (15 - 26) | 18 (12 - 24) | 24 (17 - 33) | 30 (19 - 42) |
| Relapse | ||||
| - 1 year, % | 27 (21 - 33) | 34 (26 - 42) | 31 (23 - 40) | 22 (12 - 33) |
| - 3 years, % | 32 (26 - 39) | 35 (27 - 43) | 39 (30 - 49) | 33 (21 - 46) |
| Leukemia-free survival | ||||
| - 1 year, % | 53 (46 - 60) | 49 (41 - 58) | 44 (35 - 53) | 48 (36 - 61) |
| - 3 years, % | 43 (36 - 51) | 41 (32 - 50) | 27 (19 - 37) | 34 (22 - 47) |
| Overall survival | ||||
| - 100 days, % | 84 (78 - 88) | 92 (87 - 96) | 83 (76 - 89) | 89 (80 - 95) |
| - 1 year, % | 59 (52 - 65) | 60 (52 - 68) | 51 (42 - 60) | 51 (39 - 64) |
| - 3 years, % | 45 (40 - 54) | 47 (42 - 59) | 30 (25 - 43) | 36(24 - 49) |
| Follow-up (months) | 37 (2 - 110) | 25 (1 - 87) | 36 (3 - 96) | 29 (3 - 59) |
Only disease stage and status at transplantation were significant risk factors for overall survival and leukemia-free survival at 1 year and influenced transplant-related mortality at 2 years.
Clinical characteristics were well matched across all age cohorts, but most AML patients presented with de novo disease and received their allograft from a matched related donor. Half (51%) of patients 65 years and older had a matched related donor. Conversely, myelodysplastic syndromes patients more often had unrelated donors, and this was particularly prevalent in the older cohorts (73% for ≥65 years); but donor type was not significantly different between groups. Most of the patients in the entire cohort received peripheral blood allografts (76% to 97%), fludarabine-containing regimens for conditioning, and cyclosporine-containing regimens for graft-vs-host disease prophylaxis.
"These results allow us to conclude that, for older patients, an allogeneic transplant with a reduced-intensity regimen will result in long-term disease control and should be considered a valid therapeutic strategy, and age should no longer be considered a contraindication," Dr. Giralt said. "Our data should further support the coverage of allogeneic transplant for patients with myelodysplastic syndromes."
Physicians Still Hesitant
In countries where coverage is not an issue, noted Armand Keating, MD, director of the Division of Hematology and professor of medicine at the University of Toronto, in Ontario, physician hesitancy may still limit the use of allogeneic HCT in older patients.
"If you set aside resource availability and payment issues, the reluctance is based on physician acceptance," said Dr. Keating, who was not involved in the study. "One of the reasons that study is important is that it dispels the idea that older patients aren't suitable."
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