Management of Myelodysplastic Syndrome and Acute Myeloid Leukemia in the Elderly

Educational Objectives

The goal of this program is to improve the management of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in elderly patients. After hearing and assimilating this program, the clinician will be better able to:

1. Improve transfusion independence in erythropoiesis-stimulating agent-naive patients with transfusion-dependent, lower-risk MDS.
2. Treat patients with relapsed or refractory MDS with specific mutations, eg, mutant isocitrate dehydrogenase (IDH)-1.
3. Optimize the treatment of adults with relapsed or refractory AML with specific mutations.

Summary

Management of Myelodysplastic Syndrome (MDS) in the Elderly

General management approach for MDS: International Prognostic Scoring System-Molecular (IPSS-M) calculation is crucial in decision-making; it corporates the complete blood cell count (CBC), marrow findings, cytogenetics, and molecular data (next-generation sequencing panel); one should check for the presence of symptomatic cytopenia; asymptomatic patients with MDS and low IPSS-M score are observed with serial monitoring of their CBC; treatment is initiated with disease progression; the goals of treatment (ie, improving the quality of life, improving overall survival [OS; in patients with comorbidities]) should be considered when determining the therapeutic strategy

Luspatercept (LUS) in MDS: LUS is a fusion protein that neutralizes select transforming growth factor-β (TGF-β) superfamily ligands, thereby reducing aberrantly upregulated small mothers against decapentaplegic 2 and 3 (SMAD2/3) signaling in MDS and enhancing late-stage erythropoiesis

MEDALIST study: in a phase-3 randomized controlled trial, (RCT) Fenaux et al (2020) observed that 38% of patients in the LUS group had transfusion independence for ≥8 wk vs 13% of those in the placebo group; this led to US Food and Drug Administration (FDA) approval of LUS for treatment of anemia in patients with low-risk MDS refractory to erythropoiesis-stimulating agents (ESAs) requiring regular red blood cell (RBC) transfusions with ring sideroblasts (RS), or in patients with MDS-myeloproliferative neoplasms (MPN) with RS and thrombocytosis

COMMANDS study (Della et al [2024]; phase-3 RCT): significantly more patients had RBC transfusion independence for ≥8 wk and hemoglobin level improvement with LUS than with epoetin alfa (60% vs 35%); thus, LUS was approved by the FDA for the treatment of anemia in ESA-naive patients with lower-risk MDS and for patients without MDS characterized by ring sideroblasts

Imetelstat in MDS: imetelstat is a lipid-conjugated oligonucleotide sequence complementary to the RNA template of human telomerase; it acts as a competitive inhibitor of telomerase activity, ie, decreases the capacity of malignant cells to maintain telomere length and leads to progressively shortened telomeres, which results in cell-cycle arrest, apoptosis, or senescence

The IMerge study (Platzbecker et al [2024]; phase-3 RCT): in patients with transfusion-dependent, nondeletion (5q), and lower-risk MDS who have relapsed or are refractory to ESAs, imetelstat resulted in significantly higher RBC-transfusion independence at ≥8 wk (39.8% vs 15%) and ≥24 wk (28% vs 3.3) compared with placebo; in 2024, the FDA approved imetelstat for use in adults with low-to-intermediate-risk MDS with transfusion-dependent anemia (≥4 RBC units over 8 wk) and for those who have not responded to ESAs previously or are ineligible for ESA therapy

Ivosidenib (IVO) in MDS: isocitrate dehydrogenase (IDH)-1 mutations are gain-of-function mutations that increase the production of D-2-hydroxyglutarate (2-HG), which drives multiple oncogenic processes, eg, histone and DNA methylation, impaired cellular differentiation; IVO is a small-molecule inhibitor of mutant IDH1; DiNardo et al (2024) reported a complete remission (CR) rate of 38% and a high rate of RBC and platelet transfusion independence with once-daily IVO in patients with relapsed refractory mutated IDH1 MDS; it was also well tolerated; in 2023, IVO was approved by the FDA for the treatment of adults with relapsed refractory MDS characterized by mutant IDH1

Management of Acute Myeloid Leukemia (AML) in the Elderly

General management approach for AML: the majority of elderly patients are ineligible for standard intensive induction chemotherapy, thus, its alternatives should be considered; the patient’s molecular profile, comorbid conditions, cytogenetics, and social and logistical issues should be considered before determining therapy; alternatives to standard induction chemotherapy — azacitidine (AZA) plus venetoclax (VEN; most common), hypomethylating agents monotherapy, low-dose cytarabine (LDAC) plus VEN, IVO monotherapy, AZA plus IVO (depending on the molecular profile), and LDAC plus glasdegib; consider maintenance strategy or hematopoietic stem cell transplantation for patients with CR; consider supportive care or second-line treatment options for patients with relapsed or refractory disease

AZA-VEN in AML: AZA is a DNA-hypomethylating agent that inhibits DNA methyltransferases leading to the reactivation of tumor suppressor genes; VEN binds to B-cell lymphoma 2 (BCL-2; an antiapoptotic protein) and frees the proapoptotic proteins leading to apoptosis; VIALE-A study (DiNardo et al [2020]) — phase 3 RCT showed that, in previously untreated patients with AML who were ineligible for standard induction chemotherapy, OS was longer (14.7 mo vs 9.6 mo) and incidence of CR was higher among patients who received AZA-VEN vs AZA alone

Key points: in 2020, the FDA approved VEN in combination with AZA, decitabine, or LDAC for newly diagnosed AML in adults ≥75 yr of age, or those with comorbidities precluding intensive induction chemotherapy; retrospective studies indicate that the outcomes with shorter durations of VEN (a 7-day or 14-day regimen instead of 28-day regimen) are comparable with the VIALE-A study outcomes

IVO and olutasidenib in AML: mutant IDH1 increases 2-HG which blocks the cellular differentiation of malignant cells with the mutation; IVO (mutant IDH1 inhibitor) was approved in 2018 for adults with relapsed or refractory AML with a susceptible IDH1 mutation; DiNardo et al (2018) — found that the median OS in the primary efficacy population (having IDH1-mutated relapsed or refractory AML) was 8.8 mo with IVO therapy; CR and any response to IVO correlated with OS

Olutasidenib: acts as an inhibitor of mutant IDH1; approved in 2022 for adult patients with IDH1-mutated relapsed or refractory AML; de Botton et al (2023) — found that olutasidenib monotherapy for IDH1-mutated relapsed or refractory AML resulted in an OS of 11.6 mo; improved disease response correlated with improved OS

Enasidenib in AML: IDH2 is a mitochondrial enzyme that catalyzes the production of α-ketoglutarate; IDH2 mutations lead to the build-up of 2-HG which blocks cellular differentiation in the affected neoplastic cells and oncogenesis; in 2017, the FDA approved enasidenib (small molecule mutant IDH2 inhibitor) for adults with relapsed and refractory AML characterized by an IDH2 mutation; Stein et al (2017) — found a median OS of 9.3 mo with enasidenib for relapsed or refractory AML; improved disease response correlated with improved OS; enasidenib is well-tolerated and improves hematologic responses

Gilteritinib (GIL) in AML: FMS-like tyrosine kinase 3 (FLT3) is expressed on the cell surface of hematopoietic progenitors; internal tandem duplication (ITD) of base pairs within the juxtamembrane domain portion or point mutations in the tyrosine kinase domain (TKD) can result in constitutive action of the gene in patients with AML; GIL is a second-generation tyrosine kinase inhibitor that inhibits several kinases, including FLT3; GIL targets ITD and TKD mutations

ADMIRAL study (Perl et al [2019]; phase-3 RCT): GIL was associated with significantly longer survival (9.3 mo vs 5.6 mo) and higher percentages of patients with remission (combined CR and CR with partial hematological recovery; 34% vs 15%) than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML; in 2018, GIL was approved for the treatment of adults with relapsed or refractory AML with FLT3 mutation

Readings

de Botton S, Fenaux P, Yee K, et al. Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML. Blood Adv. 2023;7(13):3117-3127. doi:10.1182/bloodadvances.2022009411; Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): Primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5; DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971; DiNardo CD, Roboz GJ, Watts JM, et al. Final phase 1 substudy results of ivosidenib for patients with mutant IDH1 relapsed/refractory myelodysplastic syndrome. Blood Adv. 2024;8(15):4209-4220. doi:10.1182/bloodadvances.2023012302; DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984; Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892; Othman TA, Tenold ME, Moskoff BN, et al. An evaluation of venetoclax in combination with azacitidine, decitabine, or low-dose cytarabine as therapy for acute myeloid leukemia. Expert Rev Hematol. 2021;14(5):407-417. doi:10.1080/17474086.2021.1938533; Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or chemotherapy for relapsed or refractory FLT3-mutated AML [published correction appears in N Engl J Med. 2022 May 12;386(19):1868. doi: 10.1056/NEJMx220003]. N Engl J Med. 2019;381(18):1728-1740. doi:10.1056/NEJMoa1902688; Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): A multinational, randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2024 Jan 20;403(10423):248. doi: 10.1016/S0140-6736(24)00057-6]. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5; Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Balderman was recorded at the Cleveland Clinic Cancer Conference: Innovations in Multidisciplinary Care, held November 1-3, 2024, in Hollywood, FL, and presented by Cleveland Clinic. For information on upcoming CME activities from this presenter, please visit clevelandclinicmeded.com. Audio Digest thanks the speakers and Cleveland Clinic for their cooperation in the production of this program.

CME/CE INFO

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Lecture ID:

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