Transplantation for Older Adults with AML and MDS
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, Univesity of Chicago Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: AML and MDS are primarily diseases of older adults with poor long-term outcomes. McClune and colleagues evaluated data from the Centers for International Marrow and Stem Cell Transplantation Registry (CIBMTR) to assess outcomes of adults 40 years or older undergoing HCT for AML in CR1 or MDS after reduced intensity or non-myeloablative regimens. They found 1,080 patients with AML or MDS. The two-year survival rate was over 30%. Older age did not influence overall survival, disease-free survival, non-relapse mortality, or the incidence of acute graft-versus-host disease. Only 10%-12% were 65 years and older. Age alone should not represent a contraindication to considering allogeneic hematopoietic cell transplantation for AML and MDS patients 40 to 70 years of age.
Source: McClune B, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older adults with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28:1878-1887.
Allogeneic hematopoietic cell transplantation (HCT) has generally been recommended for younger adults with high-risk acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS), and possibly for intermediate risk AML.2,3 The significant treatment-related morbidity and mortality using high doses of chemotherapy and/or radiation historically limited HCT to younger and fit adults. AML and MDS predominantly occur in older adults, and the outcomes for adults 60 years and older with AML are dismal using standard chemotherapy alone. As a consequence, many investigators have explored HCT to abrogate these poor outcomes.
The chemotherapy and/or radiotherapy administered before hematopoietic cell infusion, known as the conditioning regimen, provides both an anti-leukemic effect and immunosuppression to facilitate donor cell engraftment. Over the past 10–15 years, the introduction of less intensive conditioning regimens has promoted expansion of HCT to older adults.
In this report, McClune and colleagues report data from the Centers of International Marrow and Stem Cell Transplantation Registry (CIMBTR). Patients aged 40 years or older undergoing Reduced Intensity (RIC) or Non-myeloablative (NMA) conditioning regimens were eligible. NMA regimens are based on the assumption that the conditioning regimen will lead to transient myelosuppression, defined as expected hematopoietic recovery without transplantation within 28 days. Donors were either related or unrelated, thus excluding cord blood units. Of the 1,080 patients, 545 had AML and 535 had MDS among 148 centers. For AML patients, 36% were 60 years and older, whereas 34% of the MDS patients were 60 years or older. Peripheral blood stem cells (PBSC) were much more common than bone marrow as a donor source. Neutrophil recovery was the same or better with advancing recipient age. The following transplant outcomes studied did not differ by age: acute graft-versus-host disease (aGVHD), chronic GVHD, non-relapse mortality, overall survival, and disease free-survival. NMA conditioning was associated with higher relapse rate. Disease-free survival was associated with older donor age.
Karnofsky performance status less than 80% (observed in approximately 16% of all recipients), HLA mismatched unrelated donor, and unfavorable karyotype impaired the two-year survival in multi-variable analysis.
Commentary
In adults younger than 40 years of age, transplant is considered for those not falling in the good-risk cytogenetic categories of t(8;21), inversion(16), and t(15;17). The incidence of acute myeloid leukemia and myelodysplastic syndromes are highly linked to advancing age. Advances in HCT, such as reduced intensity/non-myeloablative conditioning, more tolerable immunosuppression, and better supportive care have extended HCT to older adults. Still, the decision about whether older AML or MDS patients might benefit from allogeneic hematopoietic cell transplantation (HCT) has often been based on personal experience as most data derived from single-institutional feasibility studies with relatively short follow-up.
This report summarizes registry transplant data. These data are less influenced by selection bias related to a specific protocol, institution, or publication, and reflect actual practice and outcomes of reduced intensity and non-myeloablative conditioning for HCT for adults 40 years and older. Overall survival exceeded 30% at two years, which fares quite favorable to chemotherapy-alone approaches in these high-risk patients. Rates of graft-vs.-host disease, death from transplant, relapse, and overall survival did not differ markedly by age. These data provide reassurance, if not encouragement, that select older adults can achieve reasonable long-term outcomes with RIC/NMA transplantation.
Prior results show even at an institution with access to an HCT center, the uptake of HCT for older adults with AML in CR1 is very low. These data confirm low utilization, particularly among adults 65 years and older. Such patients reflect only 10%–12% of HCT in this series but well over 50% of cases of AML and MDS in adults 65 years and older. HCT outcomes in these older adults appear promising compared to the outcomes after standard chemotherapy on cooperative group clinical trials. One must recognize such patients are not directly comparable as patients receiving HCT primarily had controlled disease and likely excellent health enabling HCT to be offered. Confirming to what extent if any HCT benefits older patients will require further investigation. Nevertheless, these data support discussing HCT with older adults, particularly those with a performance status of 80% or greater. There appear to be limited numbers of patients 70 years and older limiting inferences about this age group.
More relapse occurred in the less intensive NMA conditioning approach compared to RIC. These data affirm a general HCT concept that more intensive conditioning reduces relapse at the expense of non-relapse mortality. Others have reported similar long-term survival among adults 60 years and older who underwent ablative conditioning. The optimal conditioning regimen for older adults remains unknown, and the authors correctly call for prospective studies.
Another major issue, as one considers older patients for HCT, relates to whether older siblings should serve as donors. This series shows a tendency for reduced use of related donors compared to unrelated donors with older recipient age. Presumably, health issues or age alone dissuaded transplant physicians from collecting older sibling donors, possibly contributing to the low rate of HCT in the oldest population. The age or health conditions of older sibling donors that increase complications from collection, or worsen recipient outcomes, is unknown.
Adults 40 years and older receiving reduced intensity or non-myeloablative conditioning for AML in CR1 or MDS have reasonable long-term overall survival. Among these patients, older age did not significantly influence acute graft-vs.-host disease, relapse, non-relapse mortality, or overall survival. Hematopoietic transplant should not be restricted based on age alone for MDS or AML in CR1, at least for those between 40 and 70 years. Further study will be needed to determine the risks and benefits of HCT compared to other approaches in older adults.
References
1. Grimwade D, et al. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood. 1998;92:2322-2333.
2. Yanada M, et al. Efficacy of allogeneic hematopoietic stem cell transplantation depends on cytogenetic risk for acute myeloid leukemia in first disease remission: a metaanalysis. Cancer. 2005;103:1652-1658.
3. Cornelissen JJ, et al. Results of a HOVON/SAKK donor versus no-donor analysis of myeloablative HLA-identical sibling stem cell transplantation in first remission acute myeloid leukemia in young and middle-aged adults: benefits for whom? Blood. 2007;109:3658-3666.
4. Dohner K, et al. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood. 2005;106:3740-3746.
5. Yanada M, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia. 2005;19:1345-1349.
6. Schlenk RF, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909-1918.
AML and MDS are primarily diseases of older adults with poor long-term outcomes.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content