Br J Haematol - 2022 - Dennis - Management of older patients with frailty and acute myeloid leukaemia

Management of Older Patients with Frailty and Acute Myeloid Leukaemia (British Society for Haematology Good Practice Paper, Br J Haematol 2022;199:205-221) EXECUTIVE SUMMARY • Population addressed: Adults ≥60–65 years (median AML age 70 y) who are frail or otherwise unsuitable for conventional intensive chemotherapy / transplant. • Core message: Good outcomes depend on (1) rapid molecular-cytogenetic diagnosis, (2) structured geriatric and comorbidity assessment, (3) modern low-intensity, mutation-adapted regimens (now centred on venetoclax + azacitidine), and (4) comprehensive supportive, palliative and MDT care. • Key changes since previous UK guidance: – Mandatory early mutation screening (NPM1, FLT3, IDH1/2, TP53). – Geriatric assessment tools (Edmonton Frailty, HCT-CI, ECOG, etc.) formally integrated into fitness decisions. – Venetoclax + azacitidine recognised as new non-intensive standard of care (NICE-approved Dec 2021). – Systematic antimicrobial, antiviral and antifungal prophylaxis for all prolonged-neutropenic regimens. – Clear pathways for targeted agents in relapse (gilteritinib, IDH inhibitors, etc.) and for secondary-AML (CPX-351). KEY TOPICS & MAIN POINTS 1. Methodology – BSH Good Practice Paper developed by AML experts; consensus used where evidence limited. 2. Diagnostics & Risk Stratification – Full morphology, flow, cytogenetics (including FISH), and broad NGS panel at presentation. – 72-h “rapid” testing for NPM1, FLT3-ITD/TKD, IDH1/2, TP53 to guide first-line therapy. – Re-screen at relapse, at minimum for FLT3 (mutation status can change). 3. Assessing Fitness for Therapy – Chronological age alone insufficient. – Combine comorbidity indices (CCI, HCT-CI), performance scores (ECOG, KPS), and geriatric assessment domains (physical, cognitive, nutrition, polypharmacy, social). – High-risk thresholds: Edmonton Frailty >10, HCT-CI >3, ECOG >2. 4. Supportive Care • Universal leucodepleted, CMV-unselected blood components. • Prophylaxis for prolonged neutropenia: quinolone antibiotic + mould-active azole (e.g. posaconazole) + aciclovir. • Annual influenza vaccination; screen/cover HBV/HCV/HIV. • Early palliative-care input; MDT including dietetics, physiotherapy, psychology. 5. Disease-modifying Options (Unfit / Frail) a. Historic standards – Low-dose cytarabine (LDAC): CR 18 %; 2-y OS ≈9 %. – Azacitidine (5-2-2 schedule): CR ≈28 %; OS 12.1 vs 6.9 mo vs conventional care. b. Venetoclax combinations (new standard) – VEN + AZA (VIALE-A): CR/CRi 66 %, median OS 14.7 vs 9.6 mo. – VEN + LDAC (VIALE-C): CR/CRi 48 %; post-hoc OS benefit in combination arm. – Deep durable responses in NPM1- or IDH-mutated AML; reduced activity in TP53 or FLT3. – Typical cycle: AZA 75 mg/m² D1-7 (5-2-2), VEN 400 mg OD (adjust for azoles) 28 days, with dose/length modifications for cytopenias; G-CSF after marrow blast clearance. 6. Secondary / Therapy-related AML – 25–30 % of cases; adverse biology. – CPX-351 (liposomal ara-C/daunorubicin) improves OS vs 7+3 but still intensive; attenuated schedules under study. 7. Targeted Agents & Emerging Therapies – FLT3: Midostaurin (front-line fit), gilteritinib (R/R). – IDH: Ivosidenib (IDH1) & Enasidenib (IDH2) – FDA-approved, trials ongoing in EU/UK. – CD33: Gemtuzumab (add to 3+7 in non-adverse karyotype). – Hedgehog: Glasdegib + LDAC (FDA). – Novel antibodies: magrolimab (CD47) & cusatuzumab (CD70) in phase 2. – MCL-1 inhibitors in early studies. 8. Relapse Management – Median survival only months; reassess mutations, consider gilteritinib, IDH inhibitors, clinical trials. – Palliative and supportive care predominant. 9. Special Situations • COVID-19: minimise inpatient time, follow NICE NG164; use ambulatory regimens where safe. • Acute promyelocytic leukaemia (rare in elderly): start ATRA immediately; ATRA + ATO standard; dose-reduced idarubicin for high-risk (>10 × 10⁹ WBC). • Extramedullary disease: image (CT/PET-CT/MRI); treat with systemic therapy or palliative radiotherapy. 10. Clinical Trials & Research – Innovative “pick-a-winner” adaptive designs encouraged; quality-of-life endpoints important. – International collaboration needed for genetic sub-sets. IMPORTANT DETAILS & KEY DATA • Early death with intensive induction in ≥65 y: ~30 % by week 8. • LDAC median time to first CR: 95 d (≈3 cycles). • Azacitidine platelet recovery can predict response; avoid >6-week intervals between cycles. • VEN combinations: – Time to initial marrow response: 1 mo; to best response: 2 mo. – MRD-negativity by flow (>3-log) achieved in 25 % after cycle 1 and correlated with prolonged remission. • CPX-351 phase III (age 60–75, secondary AML): median OS 9.56 vs 5.95 mo (HR 0.69). • Gilteritinib (ADMIRAL): median OS 9.3 mo vs 5.6 mo with salvage chemo (HR 0.64) in ≥65 y subset. • Glasdegib + LDAC: OS 8.8 vs 4.9 mo; CR 17 % vs 2 %. • APL trials (ATRA + ATO): >90 % long-term survival in standard-risk; early death still 10-18 %. CONCLUSIONS Older, frail AML patients now have evidence-based options that meaningfully extend survival and improve remission rates, primarily the venetoclax-azacitidine regimen. Optimal care demands: 1. Rapid molecular diagnostics to allocate targeted or combination therapies. 2. Structured geriatric assessment to balance efficacy with tolerability. 3. Rigorous supportive care (infection prophylaxis, transfusion strategy, early palliative input). 4. Access to clinical trials and innovative designs to further improve outcomes. COMPREHENSIVE LIST OF RECOMMENDATIONS (paraphrased for clarity) DIAGNOSTICS & WORK-UP 1. Perform morphology, flow cytometry, cytogenetics and molecular testing on every new AML presentation. 2. Re-test for FLT3 mutations at relapse; broader mutation panel as clinically indicated. 3. Use peripheral blood instead of marrow if circulating blasts are present. 4. Discuss all cases at a local/regional haemato-oncology MDT. ASSESSING FITNESS 5. Evaluate every patient’s ability to tolerate intensive chemotherapy using geriatric assessment tools focused on performance status, physical function and comorbidities. Thresholds indicating high risk: Edmonton Frailty >10, HCT-CI >3, ECOG >2. 6. When needed, obtain specialist input (e.g., cardiology, respiratory) and objective tests (ECHO, PFTs) to refine decisions; implement or adapt a local GA tool. 7. Patients deemed fit after GA should have therapy tailored to their AML biological risk. SUPPORTIVE CARE 8. Adopt transfusion and antimicrobial support as standard even though evidence is mainly extrapolated. 9. For regimens causing prolonged neutropenia, prescribe primary prophylaxis with a quinolone antibiotic, a mould-active azole, and aciclovir per local policy. 10. Prioritise quality of life by involving palliative and community services early. THERAPEUTIC STRATEGY 11. Use venetoclax + azacitidine as the first-line standard for older/unfit AML patients. 12. For NPM1-mutated patients unsuitable for AZA, venetoclax + LDAC is an acceptable alternative. RELAPSE MANAGEMENT 13. At relapse reassess disease morphology; add immunophenotype, cytogenetics and molecular studies when appropriate. 14. Consider re-using prior therapy if it previously produced a good response. 15. Offer investigational or targeted therapies to patients with actionable mutations who have adequate performance status and minimal comorbidity. 16. Recognise that survival after relapse is brief; palliative care is appropriate for many. CLINICAL TRIALS 17. Offer clinical-trial participation to all older AML patients at diagnosis and relapse. 18. Future research should explore reserve capacity, resilience, QoL and non-oncological interventions. 19. Employ innovative trial designs suited to this heterogeneous, often rare, population. SPECIAL SCENARIOS 20. In APL, start ATRA immediately with full supportive measures; combine ATRA + ATO for most, and consider dose-reduced idarubicin in high-risk cases. These 20 recommendations capture every explicit guidance statement in the paper while maintaining original intent.