Acute Myeloid Leukemia in Older Patients: From New Biological Insights to Targeted Therapies
Abstract
:1. Introduction
2. Search Strategy and Selection Criteria
3. AML Profiling for Diagnosis and Prognosis
3.1. Nucleic Acids
3.2. Proteomic Profiling
3.3. Metabolic Profiling
3.4. Ambience Profiling
3.5. Extensive Data Analysis, Machine Learning, and AI Tools
3.5.1. Diagnostic and Classification Challenges
3.5.2. Older Patients: New Approaches in Risk Assessment and Monitoring of AML
3.5.3. A Comprehensive Approach in Older AML Patients
4. Clinical Management of AML in Older Patients in the Current Era
4.1. The AZA/VEN “Revolution”
4.2. Hedgehog Pathway Inhibition
4.3. IDH1/2 Inhibition
4.4. FLT3 Inhibition
4.5. More Therapies for Elder AML Patients
4.6. Intensive Chemotherapy and Allogeneic SCT
4.7. The Holistic Approach to Managing AML in Older Patients: Prioritizing Toxicities Management Alongside Quality of Life and Early Palliative
5. Summary
6. Key Points
7. Conclusions
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Blast Threshold | WHO-5 | ICC | Blast Threshold |
---|---|---|---|
No cut-off | AMLs with DGA | APL with t (15; 17) (q24.1; q21.2)/PML: RARA. APL with others RARA rearrangement | 10% |
APL with PML: RARA fusion gene. | |||
AML with RUNX1: RUNX1T1 fusion gene. | AML with t (8/21) (q22; q22.1)/RUNX1: RUNX1T1 fusion gene. | ||
AML with CBFB: MYH11 fusion gene. | AML with inv (16) (p13.1; q22) or t (16; 16) (p13.1; q22)/CBFB: MYH11. | ||
AML with KMT2A rearrangements. | AML with t (9; 11) (p21.3; q23.3)/MLLT3: KTM2A or other KMT2A rearrangements. | ||
AML with DEK: NUP214 fusion gene. | AML with t (6; 9) (p22.3; q34.1)/DEK: NUP214. | ||
AML with MECOM rearrangements | AML with inv (3) (q21.3q; 26.2) or t (3; 3) (q21.3; q26.2)/GATA: MECOM (EV1) or other MECOM rearrangements | ||
AML with other rare translocations (NUP98; RBM15; MRTF1, DEK: NUP214) | |||
20% | AML with BCR: ABL1 fusion gene | AML with t (9; 22) (q34.1; q11.2)/BCR: ABL1 | 20% |
No cut-off. | AML with NPM1 mutation. | 10% | |
20% | AML with CEBPA mutation. | AML with bZIP CEBPA in-frame mutation. | 20% |
Not classified. | AML with TP53 mutation. | 20% | |
20% | AML with MDS-related genetic abnormalities. | AML with MDS-related genetic abnormalities (ASXL1; BCOR, EZH2; RUNX1; SF3B1; SRSF2; STAG2; U2AF1, ZRSR2). AML with MDS-related cytogenetic alterations. | 20% |
20% | AMLs defined by differentiation (Table 2). | AML NOS. | 20% |
10% | MDS-IB2. | MDS/AML. | 10–19% |
Myeloid sarcoma |
AML Subtype | Diagnostic Criteria |
---|---|
AML with minimal differentiation. | Cytochemistry: MPO and SBB negative blasts (<3%). |
MFC: expression of myeloid antigens (two or more), such as CD13, CD33, and CD117. | |
AML without maturation. | Morphology: <10% maturing myeloid progenitors of the BM nucleated cells. |
Cytochemistry: ≥3% blasts positive for MPO or SBB and negative for NSE. | |
MFC: expression of myeloid antigens (two or more), such as MPO, CD13, CD33, and CD117. | |
AML with maturation. | Morphology: >10% maturing myeloid progenitors and <20% of the monocytic lineage cells of the BM nucleated cells. |
Cytochemistry: ≥3% blasts positive for MPO or SBB. | |
MFC: expression of myeloid antigens (two or more), such as MPO, CD13, CD33, and CD117. | |
Acute basophilic leukemia. | Morphology: blasts and mature/immature basophils. |
Cytochemistry. Basophils: metachromasia on toluidine blue staining. Blasts: negative for MPO, SBB, and NSA. | |
MFC: negative CD117 (to exclude mast cell leukemia). | |
Acute myelomonocytic leukemia. | Morphology: ≥20% monocytes or their precursors and ≥20% maturing granulocytic cells. |
Cytochemistry and/or MFC: ≥3% of MPO-positive blasts. | |
Acute monocytic leukemia. | Morphology: ≥80% of monocytes and/or their precursors (monoblasts and/or promonocytes); ≤20% of maturing granulocytic cells. |
MFC/cytochemistry: expression of monocytic antigens (two or more), such as CD11c, CD14, CD36, and CD64, on blasts and promonocytes or their NSE positivity. | |
Acute erythroid leukemia. | Morphology: erythroid predominance in the BM (>80% of BM cellularity); >30% of immature erythroid (proerythroblasts). |
Acute megakaryoblastic leukemia. | MFC: expression of one or more platelet GPs: CD41(GP IIb), CD61 (GP IIIa), or CD42b (GP Ib). |
ELN 2022 and ICC 2022 | WHO-5 | |
---|---|---|
MDS/AML (without AML defining genetic alterations). | 10–19% blasts | Designated as MDS-IB2 (10–19% BM or 5–19% PB or Auer Roads). |
AML with antecedent MDS, MDS/MPM, or prior exposure to therapy. | MDS was added as a diagnostic qualifier. | Included as a separate entity, “AML-MR”. |
AML with NPM1 mutations, KMT2A rearrangement, MECOM rearrangement, and NUP98 rearrangement. | Requires ≥ 10% blasts in BM or PB. | It can be diagnosed irrespective of blast count. |
AML with CEPA mutation. | Requires ≥ blasts in BM or PB. | Requires ≥ 20% blasts in BM or PB. Includes bi-allelic and bzip mutations. |
TP53 mutation. | Included separately in the hierarchical classification. | Not included in a separate entity for AML. |
Therapy-related. | Added as a diagnostic qualifier. | Included as a separate entity, “AML pCT”. |
Risk category | Favorable | Genetic abnormalities |
t (8; 21) (q22; q22.1)/RUNX1: RUNX1T1 °*. | ||
inv (16) (p13.1q22) or t (16; 16) (p13.1; q22)/CBFB: MYH11 °*. | ||
Mutated NPM1 °, ^ without FLT3-ITD. | ||
bZIP in-frame mutated CEBPA °°. | ||
Intermediate | Mutated NPM1 °, * with FLT3-ITD. | |
Wild-type NPM1 with FLT3-ITD (without ARG). | ||
t (9; 11) (p21.3; q23.3)/MLLT3: KMT2A ° | ||
Cytogenetic and/or molecular abnormalities not classified as favorable or adverse. | ||
Adverse | t (6; 9) (p23.3; q34.1)/DEK: NUP214. | |
t (v; 11q23.3)/KMT2A-rearranged °°°. | ||
t (9; 22) (q34.1; q11.2)/BCR: ABL1. | ||
t (8; 16) (p11.2; p13.3)/KAT6A: CREBBP. | ||
inv (3) (q21.3q26.2) or t (3; 3) (q21.3; q26.2)/GATA2, MECOM(EVI1). | ||
t (3q26.2; v)/MECOM(EVI1)-rearranged. | ||
Monosomy 5 or del(5q); −7; −17/abn(17p). | ||
Complex karyotype ^^ monosomic karyotype ^^. | ||
Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2 ^^^. | ||
Mutated TP53 ***. |
Risk Category | Genetic Marker | Median OS (Months) |
---|---|---|
Favorable | Mutated NPM1 (FLT3-ITD neg, NRAS wt, KRAS wt, TP53 wt) | 39 |
Mutated IDH2 (FLT3-ITD neg, NRAS wt, KRAS wt, TP53 wt) | 37 | |
Mutated IDH1 (TP53 wt) | 29 | |
Mutated DDX41 | >24 | |
AML with MDS-related gene mutations (FLT3-ITD neg, NRAS wt, KRA Swt, TP53 wt) | 23 | |
Intermediate | AML with MDS-related gene mutations (FLT3-ITD pos and/or NRAS mut and/or KRAS mut; TP53 wt) | 13 |
Other cytogenetic and molecular abnormalities (FLT3-ITD pos and/or NRAS mut and/or KRAS mut; TP53 wt) | 12 | |
Adverse | Mutated TP53 | 5–8 |
Therapeutic Mechanisms and Biological Targets | Therapeutic Agent | Indications | |
---|---|---|---|
Antiapoptotic by inhibition of BCL2 overexpression | Venetoclax | ND AML in patients > 75 years old or with comorbidities in combination with HMA or LODAC | |
FLT3 | FLT-3 ITD FLT-3 TKD | Midostaurin, Quizartinib | Frontline, in combination with ICT |
Gilteritinib | R/R setting | ||
Sorafenib | Maintenance following consolidation | ||
IDH1 | IDH1 | Ivosidenib | ND AML in patients > 75 years old or with comorbidities; R/R setting |
Olutasidenib | R/R setting | ||
IDH2 | IDH2 | Enasidenib | R/R setting |
Inhibition of Hedgehog pathway | Glasdegib | Adults older than 75 years who have comorbidities. | |
ICT with liposomal compounds in s-AML and t-AML | CPX-351 | As induction ICT for ND s-AML and t-AML | |
Anti-CD33 monoclonal antibodies | GO | During induction, ICT for CD33-positive AML or as a single agent in the R/R setting. | |
Targeting CD123 membrane receptor, cell death via disruption of intracellular protein synthesis by CD123 binding and internalization of the drug | Tagraxofusp (anti-CD123 conjugate with toxin) | Treatment of BPDCN |
Clinical Study | ClinicalTrials.Gov Identifier |
---|---|
Investigating The Prognostic Significance Of Malnutrition And Sarcopenia in Older Adults with Acute Myeloid Leukemia. | NCT05458258 |
A Pilot Randomized Controlled Trial of a Patient-Centered Communication Tool (UR-GOAL) for Older Patients With Acute Myeloid Leukemia, Their Caregivers, and Their Oncologists. | NCT05335369 |
Allogeneic Hematopoietic Cell Transplantation Versus Best Available Standard of Care Therapy in Elderly Patients With Acute Myeloid Leukemia: a Randomized Phase 3 Trial. | NCT04822766 |
A Randomized Phase II Study of Venetoclax and HMA-Based Therapies for the Treatment of Older and Unfit Adults With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia (AML): A myelomatch Treatment Trial. | NCT06317649 |
Phase I/II Clinical Trial Assessing the Combination of Sulfasalazine With Standard of Care Induction Therapy in Newly Diagnosed Acute Myeloid Leukemias (AML) Patients 60 Years or Older- the SALMA Study. | NCT05580861 |
A Phase Ib Trial of Azacitidine, Venetoclax and Allogeneic NK Cells for Acute Myeloid Leukemia (ADVENT-AML). | NCT05834244 |
Relatlimab With Nivolumab and 5-Azacytidine for the Treatment of AML (AARON). | NCT04913922 |
Dual Growth Factor (rhtpo + G-CSF) and Chemotherapy Combination Regimen for Elderly Patients with Acute Myeloid Leukemia: A Phase II Single-Arm Multicenter Study. | NCT05258799 |
Dual Growth Factor (rhtpo + G-CSF) and Chemotherapy Combination Regimen in Acute Myeloid Leukemia: Study Protocol for a Randomized Controlled Trial. | NCT05382390 |
A Prospective, Single-arm, Open-label, Non-interventional, Multi-centre, Post Marketing Surveillance (PMS) Study of Mylotarg®. | NCT05189639 |
Randomized, Sequential, Open-Label Study to Evaluate the Efficacy of IDH Targeted/Non-Targeted Versus Non-targeted/IDH-targeted Approaches in the Treatment of Newly Diagnosed IDH Mutated AML Patients Not Candidates for Intensive Induction Therapy (I-DATA Study). | NCT05401097 |
Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia. | NCT06225128 |
Phase IA/B Combination Study of ADI-PEG 20, Venetoclax and Azacitidine in Patients with Acute Myeloid Leukemia (AML). | NCT05001828 |
The Feasibility of Telehealth-Based Palliative Care Intervention and Digital Symptom Monitoring on Patients With AML Receiving Low-Intensity Induction Therapy. | NCT04885127 |
An Investigator-Sponsored Randomized Phase II Study of Selinexor in Combination With Induction/Consolidation Therapy in Acute Myeloid Leukemia Patients. | NCT02835222 |
A Prospective Non-interventional Study Documenting the Management and Outcomes of Adult Patients With Acute Myeloid Leukemia (AML). | NCT04777916 |
Integrative “Omics” Approaches for Leukemia Target Identification and Matched Therapeutic Intervention. | NCT06626893 |
Maintenance Treatment With Oral Azacitidine for Patients With de Novo AML Including t-AML and AML-MRC in First Remission After CPX-351. | NCT06349239 |
Phase II Study of Maintenance Ruxolitinib After Allogeneic Stem Cell Transplantation for Older Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS) in Complete Remission. | NCT03286530 |
Do Decreased Dietary Fat and Increased Fiber Reduce Recurrence of Clostridioides Difficile Infection in Oncology Patients? | NCT04940468 |
A Telehealth Advance Care Planning Intervention for Older Patients With Myeloid Malignancies: A Pilot Randomized Controlled Trial. | NCT05875805 |
Phase 1a/1b Study of Itacitinib (INCB039110) for Cytokine Release Syndrome Prevention and Minimization of Immunosuppression Following Nonmyeloablative Related Partially HLA-mismatched Peripheral Blood Stem Cell Transplant (PBSCT) With High-dose Posttransplantation Cyclophosphamide in Older Patients (Age 60 Years). | NCT05823571 |
Prospective, Observational Study of the Role of Primary Antifungal Prophylaxis to Prevent Invasive Aspergillosis in Elderly Patients With Acute Myeloid Leukemia Undergoing Consolidation Therapy. | NCT06382922 |
A Master Protocol for Biomarker-Based Treatment of AML (The Beat AML Trial). | NCT03013998 |
Phase 1 Trial for Patients With Advanced Hematologic Malignancies Undergoing Reduced Intensity Allogeneic HCT With a T-cell Depleted Graft With Infusion of Conventional T-cells and Regulatory T-cells. | NCT05088356 |
A Phase II Trial of HSCT for the Treatment of Patients With Fanconi Anemia Lacking a Genotypically Identical Donor, Using a Risk-Adjusted Chemotherapy Only Cytoreduction With Busulfan, Cyclophosphamide and Fludarabine. | NCT02143830 |
A Single Arm Phase II Trial to Assess Cobicistat Boosted Venetoclax in Combination With Azacitidine (sc) in Adult Patients With Newly Diagnosed Acute Myeloid Leukaemia (AML) Who Are Not Considered Candidates for Intensive Treatment Regimens. | NCT06014489 |
Carolina Senior: UNC Registry for Older Cancer Patients. | NCT01137825 |
Combined Haploidentical Reduced Intensity Bone Marrow and Kidney Transplantation for Patients With Chronic Kidney Disease and Advanced Hematological Disorders. | NCT01758042 |
Collection of Blood, Bone Marrow, Skin, Saliva, and Stool Samples From Healthy Volunteers Used for Comparative Analysis of Myeloid Malignancies. | NCT05588154 |
A Phase I/II Trial of Eltanexor (KPT-8602) With Inqovi (Decitabine-Cedazuridine) in High-Risk Myelodysplastic Syndromes. | NCT05918055 |
Phase I/II Trial to Determine the Lowest Effective Dose of Post-Transplantation Cyclophosphamide in Combination With Sirolimus and Mycophenolate Mofetil as Graft-Versus-Host Disease Prophylaxis After Reduced Intensity Conditioning and Peripheral Blood Stem Cell Transplantation. | NCT05436418 |
Source: https://clinicaltrials.gov/ (accessed on 16 October 2024) |
Therapeutic Agent | Most Common Toxicities and Comments | |
---|---|---|
Venetoclax (ND AML in patients > 75 years old or with comorbidities in combination with HMA or LODAC) | Myelosuppression, notably prolonged neutropenia, could be managed by prolonging treatment intervals and using antimicrobial prophylaxis. G-CSF will be allowed in patients with AML in remission. | |
FLT-3 ITD FLT-3 TKD | Midostaurin, Quizartinib (Frontline, in combination with ICT) | GI side effects. The survival benefit of quizartinib was limited to patients younger than 60. There is a high risk of early mortality in older patients. |
Gilteritinib (R/R setting) | Differentiation syndrome, long QT syndrome, and posterior reversible encephalopathy. | |
IDH1 | Ivosidenib (ND and R/R AML) | Differentiation syndrome, long QT syndrome. |
Olutasidenib (R/R setting) | Differentiation syndrome, hepatotoxicity. | |
IDH2 | Enasidenib (R/R setting) | Differentiation syndrome, hyperbilirubinemia. |
Glasdegib (adults older than 75 years who have comorbidities). | Black, tarry stools, bleeding gums, chest pain, chills, confusion, and cough. | |
CPX-351 (as induction ICT for ND s-AML and t-AML). | Myelosuppression, prolonged neutropenia. | |
Tagraxofusp (anti-CD123 conjugate with toxin). Treatment of BPDCN. | CLS, nausea, tiredness (fatigue), fever, swelling in your legs or feet, and weight gain. |
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Niscola, P.; Gianfelici, V.; Catalano, G.; Giovannini, M.; Mazzone, C.; Noguera, N.I.; de Fabritiis, P. Acute Myeloid Leukemia in Older Patients: From New Biological Insights to Targeted Therapies. Curr. Oncol. 2024, 31, 6632-6658. https://doi.org/10.3390/curroncol31110490
Niscola P, Gianfelici V, Catalano G, Giovannini M, Mazzone C, Noguera NI, de Fabritiis P. Acute Myeloid Leukemia in Older Patients: From New Biological Insights to Targeted Therapies. Current Oncology. 2024; 31(11):6632-6658. https://doi.org/10.3390/curroncol31110490
Chicago/Turabian StyleNiscola, Pasquale, Valentina Gianfelici, Gianfranco Catalano, Marco Giovannini, Carla Mazzone, Nelida Ines Noguera, and Paolo de Fabritiis. 2024. "Acute Myeloid Leukemia in Older Patients: From New Biological Insights to Targeted Therapies" Current Oncology 31, no. 11: 6632-6658. https://doi.org/10.3390/curroncol31110490