Transplant Eligible and Ineligible Elderly Patients with AML—A Genomic Approach and Next Generation Questions
Abstract
:1. Introduction
2. The Biology of Aging, Leukemia, and Bone Marrow Transplantation
3. European Leukemia Network-2022 Stratification Refinement
3.1. Case 1 Overview, Favorable Risk ELN-2022
3.2. Recent Advances
Where Are We with Hypomethylating Agents Plus IDH1 or IDH2 Combinations?
3.3. Case 2 Overview (Intermediate Risk ELN-2022)
3.4. Recent Advances
What Are the New FLT3 Inhibitor Alternatives?
3.5. Triple Therapy for FLT3-ITD in Elderly Patients with AML
3.6. Case 3 Overview (Adverse Risk ELN-2022)
What Is the Role of Pre-Transplant Flow Cytometry Measurable Residual Disease (MRD)?
3.7. Recent Advances
Menin Inhibitors
4. Transplant Considerations
4.1. Transplant Eligible Elderly Patients with AML
4.2. Definition of Transplant Eligible
- Has a suitable donor available;
- Can tolerate the indicated conditioning chemotherapy regimen;
- Can tolerate the planned GVHD prophylaxis regimen and GVHD manifestation(s);
- Will safely tolerate being in an immunosuppressive state and recover from it.
4.3. Patient’s Risk Stratification and Assessment of Health Status
4.4. Modifiable Factors
4.5. Non-Modifiable Factors
4.6. Conditioning Regimen Selection
4.7. Donor Selection
- MRDs are considered the best option for allo-HCT as HLA matching and shared non-HLA genetic polymorphisms reduce alloimmune reactions and contribute to optimal outcomes due to fast immunological reconstitution and lower incidence of acute GVHD [109,110]. Although the outcomes with MRD and MUD are comparable [111], MRDs are favored because of their faster and more cost-effective workup. However, when a related donor is likely to carry the same genetic mutation as the patient or may be significantly older than unrelated donors, unrelated donors may be preferred;
- Younger donor age (≤40 years old) has been shown to be a predictor for improved survival in older patients with AML and MDS and receiving PTCy-haplo-HCT [112]. One aspect related to the selection of donor(s) for a haplo-HCT is the importance of the presence of donor-specific antibodies (DSA) in the recipient. They mediate graft rejection in HLA-mismatched allo-HCT [113]. Recipients planning to undergo a haplo-HCT should be screened for DSA, and the donor who carries HLA alleles targeted by these DSA should be avoided. A test for DSA is considered positive when mean fluorescence intensity (MFI) is above 1000, and graft failure risk increases significantly when DSA levels are >5000 MFI at transplant [114]. A thorough review can be found in Timofeeva OA et al. [115].
4.8. Post-Allo-HCT Maintenance Therapy Considerations
- a.
- Hypomethylating Agents
- b.
- IDH mutated AML
- c.
- FLT3-mutated AML
- d.
- Donor lymphocytes infusion
4.9. Case 4 Overview
4.10. Recent Advances
4.11. Role of Maintenance Therapy in Transplant-Ineligible Elderly Patients with AML
5. Future Directions and Discussion
5.1. Where Are We with Oral Agent Inductions?
5.2. What Are the Most Promising Oral Agents Recently Approved and in Development for AML?
5.2.1. Newer IDH Inhibitors
5.2.2. Newer Oral HMA+ Cedazuridine
5.3. Where Are We with Potentially Stopping HMA Plus Venetoclax in Responder Subgroups?
5.4. How to Improve Outcomes in Elderly AML Patients Receiving Allo-HCT
- The optimal approach to performing haplo-HCT and PTCy;
- Impact of early incorporation of multidisciplinary care, including attention to physical therapy, nutrition, and psychosocial health that may improve a patient’s fitness to undergo and tolerate allo-HCT in general;
- How to best improve GVHD prophylaxis and treatments available.
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Risk Stratification Model | Variable(s) | Stratification | Comments | |
---|---|---|---|---|
Patient-related | Charlson Comorbidity Index (CCI) [5] | Number of comorbid conditions | Scores = 1-year OS 0 = 12% 1–2 = 26% 3–4 = 52% 5 or >5 = 85% | Primarily developed for patients admitted to general medical ward; lacks prior infections and psychiatric disturbances that have a bearing on HCT outcomes. Excellent inter-rater reliability, predicts long-term mortality in different clinical population. Specific ICD coding needed for proper allocation of scoring. |
Karnofsky Performance Status [77] | Daily activity level, ability to perform ordinary tasks | Scores range from 0 to 100, where higher score means that patient is better able to carry out activities. | Global health status, reliable predictor of NRM and OS after transplant. Extremely easy to perform but is subjective; supplement by frailty measure. | |
Fried’s Frailty Phenotype (FFP) [78] | (a) gait speed (b) grip strength (c) activity level (d) exhaustion (e) weight loss | ≥3 criteria = frail 1–2 criteria = pre-frail 0 criterion = fit | Age and FFP associated with restricted mean survival time. Trials for pre-HCT interventions to reverse frailty and incorporation of AML therapy type are needed. Requires objective assessments for accurate phenotype capture. | |
Geriatric Assessment (GA) [79] | (a) Functional status, evaluated by ECOG performance (b) Frailty, by Fried frailty index (FI) (c) Comorbidity, by HCT-CI (d) Mental health * (e) Nutritional status, Alb < 3.5, self-reported weight loss (f) Degree of inflammation, determined by serum CRP >10 mg/L | Scores = 2-year OS 0 = 62% 1 = 44% 2 = 13% | 203 patients ≥50 years, median 58 (range 50–73) Limitations in instrumental ADLs, slow walk speed, high HCT-CI, low mental health, and elevated CRP were significantly associated with inferior OS. May support creation of transplant supportive care package targeting GA-defined limitations. However, study also includes younger patients (50 to 65 year old) and does not discriminate based on prior treatment modalities. | |
Transplant-related | Hematopoietic Cell Transplantation Specific Comorbidity Index (HCT-CI) [19] | (a) Refined comorbidity definitions (b) Evaluate increased severity of comorbidities in correlation with toxicity risk and mortality | 3 risk groups: low risk (score 0) vs. intermediate (score 1–2) vs. high (score ≥ 3) score 0: 2y-OS 71%, 2y-NRM 14%; score 1–2: 2y-OS 60%, 2y-NRM 34%; score ≥3: 2y-OS 34%, 2y-NRM 41% | Refinement in comorbidities definition, introduction of lab and functional testing criteria allowing accurate assessment and replicability across independent observers. Only model prospectively validated in two large studies: higher level of evidence. Online tool: http://www.hctci.org/ (accessed on 15 March 2024). |
Age-adjusted HCT-CI [80] | Age is integrated | Age ≥ 40 years is assigned a weight of 1 Added to the HCT-CI to constitute a composite comorbidity/age index | Age is a poor prognostic factor, less applicable to elderly patients with AML as all of them are >40 years | |
Disease-related | European Leukemia Network (ELN) 2022 [9] | Favorable Core binding factor (CBF): t (8;21); inv16 or t (16;16); bZIP CEBPA NPM1 without FLT3-ITD | Transplant in CR2 or if persistent MRD | Includes the following: revised genetic risk classification, revised response criteria, and treatment recommendations. |
Intermediate Wild type NPM1 with FLT3 ITD Mutated NPM1 with FLT3 ITD t (9;11) (p21.3; q23.3)/MLLT3::KM2TA Cytogenetic aberrations not considered favorable or adverse | Transplant in CR2 or if persistent MRD | Includes management of special situations (hyperleukocytosis, leukostasis), DIC, TLS, DS, and supportive care (anti-infectious prophylaxis and transfusions). | ||
Unfavorable U2AF1, SF3B1, SRSF2, STAG2, RUNX1, ASXL1, P53, and complex karyotype | Transplant in CR1 | |||
Disease Risk Index (DRI) [81] | Disease type (AML vs. ALL vs. CML vs. MDS vs. MPN vs. DLBCL vs. T-cell lymphoma) Remission status CR1 or CR2 vs. PR vs. induction failure vs. active disease) | 4 groups: low vs. intermediate vs. high vs. very high | Stratification by disease and disease status at HCT Not restricted to AML Applicable across different cytogenetics grouping Similar outcomes for MAC and RIC groups are noted | |
Refined DRI [82] | Includes additional entities: (a) ALL Philadelphia+ and Philadelphia− (b) MDS classified based on blast%, cytogenetic, and response to therapy (c) Burkit lymphoma (BL) (d) Mantle cell lymphoma (MCL) | 4 groups: low vs. intermediate vs. high vs. very high 2-year OS ranging from 64% to 24% | Cohort of >13,000 patients Conditioning intensity–independent index Does not include molecular information | |
Combined | European Group for BMT Risk Score [83] | Risk factors: (a) Age (b) Disease stage (c) Time interval and diagnosis to transplant (mo) (d) Donor type (e) Donor–recipient sex combination | Seven groups are defined, with different related TRM and OS Age: <20, 20–40, >40 Disease stage: early, intermediate, and late Time interval: <12 mo and >12 mo Donor: HLA-identical sibling vs. unrelated donor Donor–recipient sex combination: all other vs. D:F, R:M | Incorporates time interval from diagnosis and in AML Can have discordant impact—longer time from CR1 is associated with decreased relapse. |
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Sackstein, P.; Williams, A.; Zemel, R.; Marks, J.A.; Renteria, A.S.; Rivero, G. Transplant Eligible and Ineligible Elderly Patients with AML—A Genomic Approach and Next Generation Questions. Biomedicines 2024, 12, 975. https://doi.org/10.3390/biomedicines12050975
Sackstein P, Williams A, Zemel R, Marks JA, Renteria AS, Rivero G. Transplant Eligible and Ineligible Elderly Patients with AML—A Genomic Approach and Next Generation Questions. Biomedicines. 2024; 12(5):975. https://doi.org/10.3390/biomedicines12050975
Chicago/Turabian StyleSackstein, Paul, Alexis Williams, Rachel Zemel, Jennifer A. Marks, Anne S. Renteria, and Gustavo Rivero. 2024. "Transplant Eligible and Ineligible Elderly Patients with AML—A Genomic Approach and Next Generation Questions" Biomedicines 12, no. 5: 975. https://doi.org/10.3390/biomedicines12050975