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Review

Non-intensive acute myeloid leukemia therapies for older patients

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Pages 171-180 | Received 05 Nov 2022, Accepted 21 Feb 2023, Published online: 02 Mar 2023

References

  • Wei AH, Döhner H, Pocock C, et al. Oral Azacitidine maintenance therapy for acute myeloid leukemia in first remission. NEJM. 2020;383(26):2526–2537.
  • Babakhanlou R, Ravandi-Kashani F. SOHO state of the art updates and next questions - the role of maintenance therapy in acute myeloid leukemia Clinical Lymphoma. Myeloma and Leukemia. 2022;23(1):1–7.
  • Pollyea DA, Kohrt HE, Medeiros BC. Acute myeloid leukaemia in the elderly: a review. Br J Haematol. 2011;152:524–542.
  • Palmieri R, Paterno G, De Bellis E, et al. Therapeutic choice in older patients with acute myeloid leukemia: a matter of fitness. Cancers (Basel). 2020;12(20):1–19.
  • National Cancer Institute. https://seer.cancer.gov/statfacts/html/amyl.html Cited 2022 Sept 19
  • Sanford D, Ravandi R. Management of newly diagnosed acute myeloid leukemia in the elderly: current strategies and future directions. Drugs Ageing. 2015;32:983–997.
  • Krug U, Buechner T, Berdel WE, et al. The treatment of elderly patients with acute myeloid leukemia. Deutsches Aerzteblatt. 2011;108(51–52):863–870.
  • Ossenkoppele G, Loewenberg B. How I treat the older patient with acute myeloid leukemia. Blood. 2015;125(5):767–774.
  • Webster JA, Pratz KW. Acute myeloid leukemia in the elderly: therapeutic options and choice. Leuk Lymphoma. 2018;59(2):274–287.
  • Thomas X, Le Jeune C. Treatment of elderly patients with acute myeloid leukemia. Curr Treat Options Oncol. 2017;18(2):1–16.
  • Abdallah M, Xie Z, Ready A, et al. Management of acute myeloid leukemia (AML) in older patients. Curr Oncol Rep. 2020;22(103):1–14.
  • Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–3485.
  • Loh KP, Klepin HD. Geriatric assessment in older patients with acute myeloid leukemia. Cancers (Basel). 2018;10(225):1–11.
  • Wheatley K, Brookes CL, Howman AJ, et al. Prognostic factor analysis of the survival of elderly patients with AML in the MRC AML11 and LRF AML14 trials. Br J Haematol. 2009;145:598–605.
  • Kantarjian H, O’Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer. 2006;106:1090–1098.
  • Rollig C, Thiede C, Gramatzki M, et al. A novel prognostic model in elderly patients with acute myeloid leukemia – results of 909 patients entered into the prospective AML96 trial. Blood. 2010;116:971–978.
  • Tsimberidou AML, Kantarjian HM, Wen S, et al. The prognostic significance of serum beta2 microglobulin levels in acute myeloid leukemia and prognostic score predicting survival: analysis of 1180 patients. Clin Cancer Res. 2008;14:721–730.
  • Wahlin A, Markevarn B, Golovleva I, et al. Prognostic significance of risk group stratification in elderly patients with acute myeloid leukemia. Br J Haematol. 2001;115:25–33.
  • Gupta V, Chun K, Yi QL, et al. Disease biology rather than age is the most important determinant of survival in patients > or = 60 years with acute myeloid leukemia treated with uniform intensive therapy. Cancer. 2005;103:2082–2090.
  • Latagliata R, Bongarzoni V, Carmosino I, et al. Acute myelogenous leukemia in elderly patients not eligible for intensive chemotherapy: the dark side of the moon. Ann Oncol. 2006;17:281–285.
  • Mohile SG, Dale W, Somerfield MR, et al. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology. J clin oncol. 2018;36:2326–2347.
  • Hamaker ME, Prins MC, Stauder R, et al. The relevance of geriatric assessment for elderly patients with a haematological malignancy – a systematic review. Leuk Res. 2014;38:275–283.
  • Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J clin oncol. 2012;30:1829–1834.
  • Giles FJ, Borthakur G, Ravandi F, et al. The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia. Br J Haematol. 2007;136:624–627.
  • Nabhan C, Kamat S, Kish JK. Acute myeloid leukemia in the elderly: what constitutes treatment value? Leuk Lymphoma. 2019;60(5):1164–1170.
  • Lancet JE, Giralt S. Therapy for older AML patients: the role of novel agents and allogeneic stem cell transplant. J National the Comprehensive Can Net. 2008;6:1017–1025.
  • Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J clin oncol. 1989;7(9):1268–1274.
  • Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from Swedish Acute Leukemia Registry. Blood. 2009;113:4179–4187.
  • Burnett AK, Russel NH, Hills RK, et al. A randomized comparison of daunorubicin 90 mg/m2 vs. 60 mg/m2 in AML induction: results from the UK NCRI AML 17 trial in 1206 patients. Blood. 2015;125(25):3878–3885.
  • Lowenberg N, Ossenkoppele GJ, van Putten W, et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009;361(13):1235–1248.
  • Assi R, Kantarjian H, Ravandi F, et al. Immune therapies in acute myeloid leukemia. Curr Opin Hematol. 2018;25:136–145.
  • Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukemia (ALFA-0701): a randomized, open label, phase 3 study. Lancet. 2012;379(9825):1508–1516.
  • Amadori S, Suciu S, Selleslag D, et al. Gemzutumab Ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J clin oncol. 2016;34:972–979.
  • Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomized controlled trials. Lancet Oncol. 2014;15(9):986–996.
  • Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicine vs. cytarabine/daunorubicine in older adults with untreated AML. Blood. 2014;123(21):3239–3246.
  • Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J clin oncol. 2018;36:2684–2692.
  • Kantarjian H, Kadia T, DiNardo C, et al. Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 2021;11:41.
  • Devine SM, Owzar K, Blum W, et al. Phase II study of allogeneic transplantation for older patients with acute myeloid leukemia in first complete remission using a reduced-intensity conditioning regimen: results from Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J clin oncol. 2015;33(35):4167–4175.
  • Solomon SR, Solh M, Jackson KC, et al. Real-world outcomes of unselected elderly acute myeloid leukemia patients referred to a leukemia/hematopoietic cell transplant program. Bone Marrow Transplant. 2020;55(1):189–198.
  • Modi D, Deol A, Kim S, et al. Age does not adversely influence outcomes among patients older than 60 years who undergo allogeneic hematopoietic stem cell transplant for AML and myelodysplastic syndrome. Bone Marrow Transplant. 2017;52(11):1530–1536.
  • Rashidi A, Ebadi M, Colditz GA, et al. Outcomes of allogeneic stem cell transplantation in elderly patients with acute myeloid leukemia: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2016;22(4):651–657.
  • Vey N. Low-intensity regimens versus standard-intensity induction strategies in acute myeloid leukemia. Ther Adv Hematol. 2020;11:2040620720913010.
  • Bryant JC, Jabbour E. Management of relapsed/refractory acute myeloid leukemia in the elderly: current strategies and developments. Drugs Aging. 2015;32:623–637.
  • Burnet AK, Milligan D, Prentice AG, et al. Comparison of low dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer. 2007;109:1114–1124.
  • Kantarjian HM, Thomas XG, Dmoszynska A, et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J clin oncol. 2012;30(21):2670–2677.
  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in higher-risk myelodysplastic syndromes: a randomized, open-label, phase 3 study. Lancet Oncol. 2009;10:223–232.
  • Mamdani H, Dos Santos C, Konig H. Treatment of acute myeloid leukemia in elderly patients – a therapeutic dilemma. JAMDA. 2016;17:581–587.
  • Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J clin oncol. 2002;20:2429–2440.
  • Al-Ali KH, Jaekel N, Junghanss C, et al. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma. 2012;53:110–117.
  • Ivanoff S, Berengere Gruson B, Chantepie SP, et al. 5-azacitidine treatment for relapsed or refractory acute myeloid leukemia after intensive chemotherapy. Am J Hematol. 2013;88:601–605.
  • Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs. conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015;126:291–299.
  • Lubbert M, Ruter BH, Claus R, et al. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica. 2012;97:393–401.
  • Cashen AF, Schiller GJ, O’Donnell MR, et al. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J clin oncol. 2010;28:556–561.
  • Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proceedings of the National Academy of Sciences of the United States of America, 2010; 107: 7473–7478.
  • Zeidan AM, Fenaux P, Gobbi M, et al. Prospective comparison of outcomes with azacitidine and decitabine in patients with AML ineligible for intensive chemotherapy. Blood. 2022;140(3):285–289.
  • Doehner H, Symeonidis A, Deeren D, et al. Adjunctive volasertib in patients with acute myeloid leukemia not eligible for standard induction therapy: a randomized, phase 3 trial. Hemasphere. 2021;5(8):1–10.
  • Dohner H, Lubbert M, Fiedler W, et al. Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood. 2014;124(9):1426–1433.
  • Mehta SV, Shukla SN, Vora HH, et al. Overexpression of BCL-2 protein predicts chemoresistance in acute myeloid leukemia. Its correlation with FLT3. Neoplasma. 2014;60:666–675.
  • Souers AJ, Leverson JD, Boghaert ER. ABT-199, a potent and selective BCL-2 inhibitor, achieved antitumor activity while sparing platelets. Nat Med. 2013;19:202–208.
  • Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase 2 study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–1117.
  • DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.
  • 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.
  • Wei AH, Strickland S, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J clin oncol. 2019;37(15):1277–1284.
  • Pollyea DA, Dinardo CD, Thirman MJ, et al. Results of a phase 1b study of venetoclax plus decitabine or azacitidine in untreated acute myeloid leukemia patients > 65 years ineligible for standard induction therapy. J clin oncol. 2016;128:34.
  • OK CY, Singh RR, Vega F. Aberrant activation of the hedgehog signaling pathway in malignant hematological neoplasms. Am J Pathol. 2012;180:2–11.
  • Armas-Lopez L, Zuniga J, Arrieta O, et al. The Hedgehog/GLI pathway in embryonic development and cancer: Implications for pulmonary oncology therapy. Oncotarget. 2017;8:60684–60703.
  • Aberger F, Hutterer E, Sternberg C, et al. Acute myeloid leumemia – strategies and challenges for targeting oncogenic Hedgehog/GLI signaling. Cell Commun Signaling. 2017;15(1):8.
  • Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia. 2019;33:379–389.
  • Savona MR, Pollyea DA, Stock W, et al. Phase Ib study of Glasdegib, a Hedgehog pathway inhibitor, in combination with standard chemotherapy in patients with AML or high-risk MDS. Clin Cancer Res. 2018;24:2294–2303.
  • Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17(3):225–234.
  • Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J clin oncol. 2010;28(22):3636–3643.
  • Montalban-Bravo G, DiNArdo CD. The role of IDH mutations in acute myeloid leukemia. Future Oncol. 2018;14:979–993.
  • 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;378:2386–2398.
  • Roboz GJ, DiNardo CD, Stein EM, et al. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood. 2020;135(7):463–471.
  • DiNardo CD, Stein AS, Stein EM, et al. Mutant isocitrate dehydrogenase 1 inhibitor ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia. J clin oncol. 2021;39(1):57–65.
  • Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130:722–731.
  • DiNardo C, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukemia (AG221-AML-005): a single-arm, phase 1b and randomized, phase 2 trial. Lancet Oncol. 2021;22:1597–1608.
  • Bonate PL, Artaud L, Cantrell JWR, et al. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat Rev Drug Discov. 2006;5(10):855–863.
  • Burnett AK, Russel NH, Hunter AE, et al. Clofarabine doubles the response rate in older patients with acute myeloid leukemia but does not improve survival. Blood. 2013;122(8):1384–1394.
  • Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low dose cytarabine as frontline therapy for patients aged 60 years and older for acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood. 2008;112(5):1638–1645.
  • Kadia T, Cortes JE, Ravandi F, et al. Phase 2 trial of cladribine and low-dose cytarabine alternating with decitabine as frontline therapy for older patients with acute myeloid leukemia. Lancet Hematol. 2018;5(9):e411–e421 .
  • Budziszewska BK, Salomon-Perzynski A, Pruszczyk K, et al. Cladribine combined with low-dose cytarabine as frontline treatment for unfit elderly acute myeloid leukemia patients: results from a prospective multicenter study of Polish Adult Leukemia Group (PALG). Cancers (Basel). 2021;13:4189.
  • Kadia TM, Reville RK, Wang X, et al. Phase II study of venetoclax added to cladribine plus low-dose cytarabine alternating with 5-azacitidine in older patients with newly diagnosed acute myeloid leukemia. J clin oncol. 2022;40(33):3848–3859.
  • Kantarjian HM, Begna KH, Altman JK, et al. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS). Cancer. 2021;127:4421–4431.
  • Bullinger L, Doehner K, Doehner H. Genomics of acute myeloid leukemia diagnosis and pathways. J clin oncol. 2017;35:934–946.
  • Bohl SR, Bullinger L, Ruecker FG. New targeted agents in acute myeloid leukemia: new hope on the rise. Int J Mol Sci. 2019;20:1983.
  • Kiyoi H, Towatari M, Yokota S, et al. Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. Leukemia. 1998;12:1333–1337.
  • Kayser S, Schlenk RF, Londono MC, et al. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114:2386–2392.
  • Schlenk RF, Doehner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. 2008;358:1909–1918.
  • Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin and cytarabine in younger patients with acute myeloid leukemia. J clin oncol. 2010;28:1856–1862.
  • Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3-mutant AML in first relapse. Blood. 2011;117:3294–3301.
  • Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377:454–464.
  • Ohanian M, Garcia-Manero G, Levis M, et al. Sorafenib combined with 5-azacitidine in older patients with untreated FLT3-ITD mutated acute myeloid leukemia. Am J Hematol. 2018;93:1136–1141.
  • Esteve J, Schots R, Bernal Del Castillo T, et al. Multicenter, open-label, 3-arm study of Gilteritinib, Gilteritinib plus Azacitidine, or Azacitidine alone in newly diagnosed FLT3 mutated acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort. Blood. 2018;132:2736.
  • Yilmaz M, Kantarjian H, Short NJ, et al. Hypomethylating agent and venetoclax with FLT3-inhibitor ‘triplet’ therapy in older/unfit patients with FLT3-mutated AML. Blood Cancer J. 2022;12:77.
  • Senapati J, Kadia TM. Which FLT3-Inhibitor for treatment of AML? Curr Treat Options Oncol. 2022;23:359–380.
  • Jaiswal S, Jamieson CHM, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138:271–285.
  • Majeti R, Chao MP, Alizadeh AA, et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138:286–299.
  • Liu J, Wang L, Zhao F, et al. Pre-clinical development of a humanized anti-CD47 antibody with anti-cancer therapeutic potential. PLoS One. 2015;10:e0137345.
  • Feng D, Gip P, McKenna KM, et al. Combination treatment with 5F9 and azacitidine enhances phagocytic elimination of acute myeloid leukemia. Blood. 2018;132:2729.
  • Sallman DA, Malki MA, Asch AS, et al. Tolerability and efficacy of the first-in-class anti-CD47 antibody magrolimab combined with azacitidine in MDS and AML patients: Phase Ib results. J clin oncol. 2020;38:7507.
  • Riether C, Pbast T, Höpner S, et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med. 2020;26:1459–1467.
  • Riether C, Schürch CM, Bührer ED, et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med. 2017;214:359–380.

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