Tuesday, May 30, 2023
| Patients | ||
|---|---|---|
| Characteristic | n | % |
| Full cohort, n | 295 | 100 |
| Recipient age, median (range) | 66 (6-76) | |
| Recipient sex | ||
| Female | 117 | 40 |
| Male | 178 | 60 |
| HCT-CI score | ||
| 0 | 83 | 28 |
| 1-2 | 81 | 27 |
| 3+ | 120 | 40 |
| Missing | 11 | 4 |
| Type of AML (clinically defined) | ||
| De novo | 173 | 59 |
| Secondary | 91 | 31 |
| Therapy-related | 31 | 11 |
| Cytogenetics* | ||
| Normal | 136 | 46 |
| Core binding factor | 6 | 2 |
| Complex karyotype | 41 | 14 |
| Other | 112 | 38 |
| 2017 ELN risk group | ||
| Favorable | 53 | 18 |
| Intermediate | 85 | 29 |
| Adverse | 152 | 52 |
| Missing | 5 | 2 |
| Initial therapy | ||
| Intensive induction | 249 | 84 |
| Non-intensive induction | 46 | 16 |
| Reinduction | ||
| Yes | 90 | 31 |
| No | 204 | 69 |
| Missing | 1 | 0.3 |
| Remission quality | ||
| CR with hematologic recovery | 225 | 75 |
| CRi | 67 | 23 |
| Missing | 1 | 0.3 |
| Donor type | ||
| Matched related | 54 | 18 |
| Matched unrelated | 154 | 52 |
| Mismatch related | 7 | 2 |
| Mismatch unrelated | 29 | 10 |
| Haploidentical | 51 | 17 |
| Conditioning regimen | ||
| Myeloablative | 28 | 9 |
| Reduced intensity | 267 | 91 |
| T-cell depletion | 25 | 9 |
| Stem cell source | ||
| Peripheral blood | 216 | 73 |
| Bone marrow | 71 | 24 |
| Umbilical cord blood | 8 | 3 |
Table 1. Cohort characteristics
Shown are the pretransplant characteristics of the 295 patients included in the cohort. HCT-CI: hematopoietic cell transplant comorbidity index score. CRi denotes complete remission with incomplete recovery of at least 1 hematopoietic cell lineage.
ELN, European Leukemia Network.
* Core binding factor: inv(16) or t(8;21); complex karyotype: 3 or more chromosomal abnormalities within a single clone.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
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This activity is intended for hematologists, oncologists, internists, geriatricians, and other clinicians caring for older patients with acute myeloid leukemia (AML).
The goal of this activity is that the learner will be better able to describe factors that drive outcomes of allogeneic hematopoietic cell transplantation (HCT) for AML in older patients, according to a targeted mutational genomic analysis of paired diagnostic and available remission specimens in a multi-institutional cohort of 295 patients with AML aged ≥ 60 years who underwent HCT in first complete morphologic remission (CR1).
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Older patients with acute myeloid leukemia (AML) have high relapse risk and poor survival after allogeneic hematopoietic cell transplantation (HCT). Younger patients may receive myeloablative conditioning to mitigate relapse risk associated with high-risk genetics or measurable residual disease (MRD), but older adults typically receive reduced-intensity conditioning (RIC) to limit toxicity. To identify factors that drive HCT outcomes in older patients, we performed targeted mutational analysis (variant allele fraction ≥2%) on diagnostic samples from 295 patients with AML aged ≥60 years who underwent HCT in first complete remission, 91% of whom received RIC, and targeted duplex sequencing at remission in a subset comprising 192 patients. In a multivariable model for leukemia-free survival (LFS) including baseline genetic and clinical variables, we defined patients with low (3-year LFS, 85%), intermediate (55%), high (35%), and very high (7%) risk. Before HCT, 79.7% of patients had persistent baseline mutations, including 18.3% with only DNMT3A or TET2 (DT) mutations and 61.4% with other mutations (MRD positive). In univariable analysis, MRD positivity was associated with increased relapse and inferior LFS, compared with DT and MRD-negative mutations. However, in a multivariable model accounting for baseline risk, MRD positivity had no independent impact on LFS, most likely because of its significant association with diagnostic genetic characteristics, including MDS-associated gene mutations, TP53 mutations, and high-risk karyotype. In summary, molecular associations with MRD positivity and transplant outcomes in older patients with AML are driven primarily by baseline genetics, not by mutations present in remission. In this group of patients, where high-intensity conditioning carries substantial risk of toxicity, alternative approaches to mitigating MRD-associated relapse risk are needed.
Acute myeloid leukemia (AML) in adults aged ≥60 years is associated with inferior outcomes in comparison with younger patients.[1-3] In older patients, AML frequently evolves from antecedent myelodysplastic syndromes (MDS),[4,5] is enriched for high-risk cytogenetic abnormalities,[6] and is often resistant to conventional chemotherapy.[4,6,7] Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment option for many older patients with AML, but prognosis after transplant in this age group is limited.[8,9]
With current treatment approaches, the inferior outcomes for older patients who undergo transplants for AML are primarily related to a high rate of relapse after transplantation.[8] This is related in part to the use of less intensive conditioning regimens for older adults at increased risk of treatment-related toxicity,[10,11] but may also reflect enrichment of high-risk biological features in older AML populations.[4,12] Genomic assessment of AML cohorts, either at diagnosis or first complete remission (CR1), may identify prognostic subgroups with distinct risks of relapse or nonrelapse mortality (NRM), thereby suggesting specific risk-adapted therapeutic strategies.
Molecular assessment at remission could be particularly meaningful in the older AML population, given recent findings that measurable residual disease (MRD), defined as detectable AML mutations at the time of complete remission (CR), is associated with increased relapse risk among those who undergo reduced intensity conditioning (RIC) regimens.[13] These results, however, were from a randomized trial that excluded patients >65 years of age and required that all patients be eligible for myeloablative conditioning (MAC) and thus may not apply equally to a broad population of real-world older patients with AML. At many centers, transplants are offered to patients into their 70s, and reduced-intensity regimens are employed in more than 85% of cases.[14]
Dedicated studies in older patients with AML may identify those most likely to benefit from transplantation and enable development of strategies tailored to a patient’s specific profile of relapse and toxicity risk, as determined by pretransplant characteristics. In the absence of randomized data in the older AML population, retrospective analysis of real-world older cohorts may be preferable to extrapolation from studies of younger patients. We report a genomic analysis of paired diagnostic and available remission specimens in a multi-institution cohort of older patients with AML who underwent allogeneic transplantation in morphologic CR1.
