Advancements in the management of medically less-fit and older adults with newly diagnosed acute myeloid leukemia

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7–30.
   PubMed Web of Science ®Google Scholar
• Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–1152.
   PubMed Web of Science ®Google Scholar
• Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–447.
   PubMed Web of Science ®Google Scholar
• Alibhai SMH, Leach M, Minden MD, et al. Outcomes and quality of care in acute myeloid leukemia over 40 years. Cancer. 2009;115(13):2903–2911.
   PubMed Web of Science ®Google Scholar
• Burnett AK. Treatment of acute myeloid leukemia: are we making progress? Hematology Am Soc Hematol Educ Program. 2012;2012:1–6.
   PubMed Web of Science ®Google Scholar
• Juliusson G, Lazarevic V, Hörstedt AS, et al. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood. 2012;119(17):3890–3899.
   PubMed Web of Science ®Google Scholar
• Juliusson G, Antunovic P, Derolf Å, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish acute leukemia registry. Blood. 2009;113(18):4179–4187.
   PubMed Web of Science ®Google Scholar
• Meyers J, Yu Y, Kaye JA, et al. Medicare fee-for-service enrollees with primary acute myeloid leukemia: an analysis of treatment patterns, survival, and healthcare resource utilization and costs. Appl Health Econ Health Policy. 2013;11(3):275–286.
   PubMedGoogle Scholar
• Oran B, Weisdorf DJ. Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica. 2012;97(12):1916–1924.
   PubMed Web of Science ®Google Scholar
• Medeiros BC, Satram-Hoang S, Hurst D, et al. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015;94(7):1127–1138.
   PubMed Web of Science ®Google Scholar
• Howlader N, Noone AM, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014. Bethesda, MD: National Cancer Institute. 2017. http://seer.cancer.gov/csr/1975_2014/ based on November2016 SEER data submission,posted to the SEER web site, April 2017.
   Google Scholar
• Official Website of the U.S. Social Security Administration: Period Life Table, 2014. Available from: http://www.ssa.gov/oact/STATS/table4c6.html.
   Google Scholar
• Pollyea DA, Kohrt HE, Medeiros BC. Acute myeloid leukaemia in the elderly: a review. Br J Haematol. 2011;152(5):524–542.
   PubMed Web of Science ®Google Scholar
• Yanada M, Naoe T. Acute myeloid leukemia in older adults. Int J Hematol. 2012;96(2):186–193.
   PubMed Web of Science ®Google Scholar
• Prokocimer M, Molchadsky A, Rotter V. Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy. Blood. 2017;130(6):699–712.
   PubMed Web of Science ®Google Scholar
• Sekeres MA, Stone RM, Zahrieh D, et al. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia. 2004;18(4):809–816.
   PubMed Web of Science ®Google Scholar
• Walter RB, Estey EH. Management of older or unfit patients with acute myeloid leukemia. Leukemia. 2015;29(4):770–775.
   PubMed Web of Science ®Google Scholar
• Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML [abstract]. J Clin Oncol. 2016;34(Suppl):7000.
   Web of Science ®Google Scholar
• Sorror M, Storer B, Elsawy M, et al. Relative benefit for intensive versus non-intensive induction therapy for patients with newly diagnosed acute myeloid leukemia (AML) using a composite, age-comorbidity-cytogenetic, model [abstract]. Haematologica. 2016;101(S1):221–222.
   Google Scholar
• Talati C, Kuykendall A, Al Ali N, et al. Outcomes in older adults (age ≥70) with acute myeloid leukemia based on choice of frontline treatment for prolifertive or non-proliferative phenotype [abstract]. Blood. 2017;130(Suppl 1):1412.
   Google Scholar
• 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(3):291–299.
   PubMed Web of Science ®Google Scholar
• Buckley SA, Kirtane K, Walter RB, et al. Patient-reported outcomes in acute myeloid leukemia: where are we now? Blood Rev. 2018;32(1):81–87.
   PubMed Web of Science ®Google Scholar
• Löwenberg 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.
   PubMed Web of Science ®Google Scholar
• Kahn SB, Begg CB, Mazza JJ, et al. Full dose versus attenuated dose daunorubicin, cytosine arabinoside, and 6-thioguanine in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol. 1984;2(8):865–870.
   PubMed Web of Science ®Google Scholar
• Tilly H, Castaigne S, Bordessoule D, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol. 1990;8(2):272–279.
   PubMed Web of Science ®Google Scholar
• Appelbaum FR, Gundacker H, Head DR, et al. Age and acute myeloid leukemia. Blood. 2006;107(9):3481–3485.
   PubMed Web of Science ®Google Scholar
• Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol. 2013;31(27):3360–3368.
   PubMed Web of Science ®Google Scholar
• Kayser S, Zucknick M, Döhner K, et al. Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies. Blood. 2012;119(2):551–558.
   PubMed Web of Science ®Google Scholar
• Burnett AK, Milligan D, Prentice AG, et al. A 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(6):1114–1124.
   PubMed Web of Science ®Google Scholar
• El-Jawahri A, Abel GA, Greer J, et al. Perceptions of prognosis and treatment risk in older patients with acute myeloid leukemia [abstract]. Blood. 2017;130(Suppl 1):349.
   Google Scholar
• Walter RB, Othus M, Borthakur G, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol. 2011;29(33):4417–4423.
   PubMed Web of Science ®Google Scholar
• TRM score, online calculator. Available from: https://cstaging.fhcrc-research.org/TRM/.
   Google Scholar
• Röllig 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(6):971–978.
   PubMed Web of Science ®Google Scholar
• 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(5):598–605.
   PubMed Web of Science ®Google Scholar
• Krug U, Röllig C, Koschmieder A, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet. 2010;376(9757):2000–2008.
   PubMed Web of Science ®Google Scholar
• Pastore F, Dufour A, Benthaus T, et al. Combined molecular and clinical prognostic index for relapse and survival in cytogenetically normal acute myeloid leukemia. J Clin Oncol. 2014;32(15):1586–1594.
   PubMed Web of Science ®Google Scholar
• Walter RB, Othus M, Burnett AK, et al. Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/ SAKK,SWOG and MD anderson cancer center. Leukemia. 2015;29(2):312–320.
   PubMed Web of Science ®Google Scholar
• Walter RB, Othus M, Paietta EM, et al. Effect of genetic profiling on prediction of therapeutic resistance and survival in adult acute myeloid leukemia. Leukemia. 2015;29(10):2104–2107.
   PubMed Web of Science ®Google Scholar
• Othus M, Wood BL, Stirewalt DL, et al. Effect of measurable (‘minimal’) residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia. Leukemia. 2016;30(10):2080–2083.
   PubMed Web of Science ®Google Scholar
• Sorror ML, Storer BE, Fathi AT, et al. Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality. JAMA Oncol. 2017;3(12):1675–1682.
   PubMed Web of Science ®Google Scholar
• Othus M, Kantarjian H, Petersdorf S, et al. Declining rates of treatment-related mortality in patients with newly diagnosed AML given ‘intense’ induction regimens: a report from SWOG and MD Anderson. Leukemia. 2014;28(2):289–292.
   PubMed Web of Science ®Google Scholar
• Percival ME, Tao L, Medeiros BC, et al. Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: a SEER database analysis. Cancer. 2015;121(12):2004–2012.
   PubMed Web of Science ®Google Scholar
• Halpern AB, Culakova E, Walter RB, et al. Association of risk Factors, mortality, and care costs of adults with acute myeloid leukemia with admission to the intensive care unit. JAMA Oncol. 2017;3(3):374–381.
   PubMed Web of Science ®Google Scholar
• VanderWalde N, Jagsi R, Dotan E, et al. NCCN guidelines insights: older adult oncology, version 2.2016. J Natl Compr Canc Netw. 2016;14(11):1357–1370.
   PubMed Web of Science ®Google Scholar
• O’Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, version 1.2018, NCCN clinical practice guidelines in oncology. Available from: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf.
   Google Scholar
• Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457–3465.
   PubMed Web of Science ®Google Scholar
• Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer. 2012;118(13):3377–3386.
   PubMed Web of Science ®Google Scholar
• Soubeyran P, Fonck M, Blanc-Bisson C, et al. Predictors of early death risk in older patients treated with first-line chemotherapy for cancer. J Clin Oncol. 2012;30(15):1829–1834.
   PubMed Web of Science ®Google Scholar
• Hamaker ME, Prins MC, Stauder R. The relevance of a geriatric assessment for elderly patients with a haematological malignancy–a systematic review. Leuk Res. 2014;38(3):275–283.
   PubMed Web of Science ®Google Scholar
• Klepin HD, Geiger AM, Tooze JA, et al. The feasibility of inpatient geriatric assessment for older adults receiving induction chemotherapy for acute myelogenous leukemia. J Am Geriatr Soc. 2011;59(10):1837–1846.
   PubMed Web of Science ®Google Scholar
• Deschler B, Ihorst G, Platzbecker U, et al. Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome. Haematologica. 2013;98(2):208–216.
   PubMed Web of Science ®Google Scholar
• Klepin HD, Re K, Sanford BL, et al. Feasibility of geriatric assessement for older adults with acute myeloid leukemia (AML) recieving intensive chemotherapy on a cooperative group trail: CALGB 361006 (Alliance) [abstract]. J Clin Oncol. 2014;32(15 Suppl):7102.
   Web of Science ®Google Scholar
• Klepin HD, Geiger AM, Tooze JA, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood. 2013;121(21):4287–4294.
   PubMed Web of Science ®Google Scholar
• Sherman AE, Motyckova G, Fega KR, et al. Geriatric assessment in older patients with acute myeloid leukemia: a retrospective study of associated treatment and outcomes. Leuk Res. 2013;37(9):998–1003.
   PubMed Web of Science ®Google Scholar
• Guralnik JM, Simonsick EM, Ferrucci L, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission. J Gerontol. 1994;49(2):M85M94.
   Google Scholar
• Guralnik JM, Ferrucci L, Simonsick EM, et al. Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability. N Engl J Med. 1995;332(9):556–561.
   PubMed Web of Science ®Google Scholar
• Guralnik JM, Ferrucci L, Pieper CF, et al. Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery. J Gerontol A Biol Sci Med Sci. 2000;55(4):M221–m231.
   PubMed Web of Science ®Google Scholar
• Ostir GV, Volpato S, Fried LP, et al. Reliability and sensitivity to change assessed for a summary measure of lower body function: results from the women’s health and aging study. J Clin Epidemiol. 2002;55(9):916–921.
   PubMed Web of Science ®Google Scholar
• Studenski S, Perera S, Wallace D, et al. Physical performance measures in the clinical setting. J Am Geriatr Soc. 2003;51(3):314–322.
   PubMed Web of Science ®Google Scholar
• Volpato S, Cavalieri M, Sioulis F, et al. Predictive value of the short physical performance battery following hospitalization in older patients. J Gerontol A Biol Sci Med Sci. 2011;66(1):89–96.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency. Reflection paper on physical frailty: instruments for baseline characterisation of older populations in clinical trials.[cited 2018 Mar 29]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2018/02/WC500244285.pdf
   Google Scholar
• Teng EL, Chui HC. The Modified Mini-Mental State (3MS) examination. J Clin Psychiatry. 1987;48(8):314–318.
   PubMed Web of Science ®Google Scholar
• Studenski S, Perera S, Patel K, et al. Gait speed and survival in older adults. Jama. 2011;305(1):50–58.
   PubMed Web of Science ®Google Scholar
• Goede V, Bahlo J, Chataline V, et al. Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: results of the CLL9 trial of the German CLL study group. Leuk Lymphoma. 2016;57(4):789–796.
   PubMed Web of Science ®Google Scholar
• Ferrat E, Paillaud E, Laurent M, et al. Predictors of 1-year mortality in a prospective cohort of elderly patients with cancer. J Gerontol A Biol Sci Med Sci. 2015;70(9):1148–1155.
   PubMed Web of Science ®Google Scholar
• Hshieh TT, Jung WF, Grande LJ, et al. Prevalence of cognitive impairment and association with survival among older patients with hematologic cancers. JAMA Oncol. 2018; in press.
   PubMed Web of Science ®Google Scholar
• Grishina O, Schmoor C, Döhner K, et al. DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy. BMC Cancer. 2015;15:430.
   PubMed Web of Science ®Google Scholar
• Abel GA, Klepin HD. Frailty and the management of hematologic malignancies. Blood. 2018;131(5):515–524.
   PubMed Web of Science ®Google Scholar
• Gardin C, Turlure P, Fagot T, et al. Postremission treatment of elderly patients with acute myeloid leukemia in first complete remission after intensive induction chemotherapy: results of the multicenter randomized Acute Leukemia French Association (ALFA) 9803 trial. Blood. 2007;109(12):5129–5135.
   PubMed Web of Science ®Google Scholar
• Alibhai SM, Breunis H, Timilshina N, et al. Quality of life and physical function in adults treated with intensive chemotherapy for acute myeloid leukemia improve over time independent of age. J Geriatr Oncol. 2015;6(4):262–271.
   PubMed Web of Science ®Google Scholar
• Pautas C, Merabet F, Thomas X, et al. Randomized study of intensified anthracycline doses for induction and recombinant interleukin-2 for maintenance in patients with acute myeloid leukemia age 50 to 70 years: results of the ALFA-9801 study. J Clin Oncol. 2010;28(5):808–814.
   PubMed Web of Science ®Google Scholar
• Löwenberg B, 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.
   PubMed Web of Science ®Google Scholar
• Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30(32):3924–3931.
   PubMed Web of Science ®Google Scholar
• Godwin CD, Gale RP, Walter RB. Gemtuzumab ozogamicin in acute myeloid leukemia. Leukemia. 2017;31(9):1855–1868.
   PubMed Web of Science ®Google Scholar
• Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–1496.
   PubMed Web of Science ®Google Scholar
• Petersdorf SH, Kopecky KJ, Slovak M, et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013;121(24):4854–4860.
   PubMed Web of Science ®Google Scholar
• 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 randomised controlled trials. Lancet Oncol. 2014;15(9):986–996.
   PubMed Web of Science ®Google Scholar
• Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369–377.
   PubMed Web of Science ®Google Scholar
• Burnett A, Cavenagh J, Russell N, et al. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial. Haematologica. 2016;101(6):724–731.
   PubMed Web of Science ®Google Scholar
• Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012;379(9825):1508–1516.
   PubMed Web of Science ®Google Scholar
• Amadori S, Suciu S, Stasi R, et al. Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol. 2013;31(35):4424–4430.
   PubMed Web of Science ®Google Scholar
• Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added to daunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid leukemia: a multicenter, randomized phase III study. J Clin Oncol. 2012;30(20):2441–2448.
   PubMed Web of Science ®Google Scholar
• Pluta A, Robak T, Wrzesien-Kus A, et al. Addition of cladribine to the standard induction treatment improves outcomes in a subset of elderly acute myeloid leukemia patients. Results of a randomized Polish Adult Leukemia Group (PALG) phase II trial. Am J Hematol. 2017;92(4):359–366.
   PubMed Web of Science ®Google Scholar
• Jaglal MV, Duong VH, Bello CM, et al. Cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) compared to standard induction in acute myeloid leukemia from myelodysplastic syndrome after azanucleoside failure. Leuk Res. 2014;38(4):443–446.
   PubMed Web of Science ®Google Scholar
• Seiter K, Ahmed N, Shaikh A, et al. CLAG-based induction therapy in previously untreated high risk acute myeloid leukemia patients. Leuk Res. 2016;46:74–78.
   PubMed Web of Science ®Google Scholar
• Halpern AB, Othus M, Huebner EM, et al. Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. Leukemia. 2018; in press.
   Google Scholar
• Foran JM, Sun Z, Claxton DF, et al. North American leukemia, intergroup phase 3 randomized trial of single agent clofarabine as induction and post-remission therapy, and decitabine as maintenance therapy in newly-diagnosed acute myeloid leukemia in older adults (age ≥60 years): a trial of the ECOG-ACRIN Cancer Research Group (E2906) [abstract]. Blood. 2015;126(23):217.
   Web of Science ®Google Scholar
• Tvedt TH, Nepstad I, Bruserud Ø. Antileukemic effects of midostaurin in acute myeloid leukemia - the possible importance of multikinase inhibition in leukemic as well as nonleukemic stromal cells. Expert Opin Investig Drugs. 2017;26(3):343–355.
   PubMed Web of Science ®Google Scholar
• 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(5):454–464.
   PubMed Web of Science ®Google Scholar
• Röllig C, Serve H, Hüttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16(16):1691–1699.
   PubMed Web of Science ®Google Scholar
• Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31(25):3110–3118.
   PubMed Web of Science ®Google Scholar
• Champlin R. Reduced intensity allogeneic hematopoietic transplantation is an established standard of care for treatment of older patients with acute myeloid leukemia. Best Pract Res Clin Haematol. 2013;26(3):297–300.
   PubMed Web of Science ®Google Scholar
• Reshef R, Porter DL. Reduced-intensity conditioned allogeneic SCT in adults with AML. Bone Marrow Transplant. 2015;50(6):759–769.
   PubMed Web of Science ®Google Scholar
• Sorror ML, Estey E. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in older adults. Hematology Am Soc Hematol Educ Program. 2014;2014(1):21–33.
   PubMed Web of Science ®Google Scholar
• Sorror ML. Comorbidities and hematopoietic cell transplantation outcomes. Hematology Am Soc Hematol Educ Program. 2010;2010:237–247.
   PubMed Web of Science ®Google Scholar
• Lim Z, Brand R, Martino R, et al. Allogeneic hematopoietic stem-cell transplantation for patients 50 years or older with myelodysplastic syndromes or secondary acute myeloid leukemia. J Clin Oncol. 2010;28(3):405–411.
   PubMed Web of Science ®Google Scholar
• McClune BL, Weisdorf DJ, Pedersen TL, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010;28(11):1878–1887.
   PubMed Web of Science ®Google Scholar
• Farag S, Maharry K, Perez WS, et al. Allogeneic hematopoietic stem cell transplantation (HCT) compared to chemotherapy only in acute myeloid leukemia (AML) patients 60 years and older: a Center for International Blood and Marrow Transplantation Research (CIBMTR)/Cancer and Leukemia Group B (CALGB) study [abstract]. Blood. 2009;114(21):657.
   Google Scholar
• Kurosawa S, Yamaguchi T, Miyawaki S, et al. A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission. Blood. 2011;117(7):2113–2120.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–2036.
   PubMed Web of Science ®Google Scholar
• Short NJ, Kantarjian HM, Garcia-Manero G, et al. A randomized phase II trial of 5-day versus 10-day schedules of decitabine for older patients with previously untreated acute myeloid leukemia [abstract]. Blood. 2017;130(Suppl 1):2577.
   Google Scholar
• Harel S, Cherait A, Berthon C, et al. Outcome of patients with high risk Myelodysplastic Syndrome (MDS) and advanced Chronic Myelomonocytic Leukemia (CMML) treated with decitabine after azacitidine failure. Leuk Res. 2015;39(5):501–504.
   PubMed Web of Science ®Google Scholar
• Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab 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(9):972–979.
   PubMed Web of Science ®Google Scholar
• Burnett AK, Hills RK, Hunter AE, et al. The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia. 2013;27(1):75–81.
   PubMed Web of Science ®Google Scholar
• Boddu P, Borthakur G. Therapeutic targeting of isocitrate dehydrogenase mutant AML. Expert Opin Investig Drugs. 2017;26(5):525–530.
   PubMed Web of Science ®Google Scholar
• Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722–731.
   PubMed Web of Science ®Google Scholar
• Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732–741.
   PubMed Web of Science ®Google Scholar
• Pollyea DA, Tallman MS, De Botton S, et al. Enasidenib monotherapy is effective and well-tolerated in patients with previously untreated mutant-IDH2 (mIDH2) acute myeloid leukemia (AML) [abstract]. Blood. 2017;130(Suppl 1):638.
   Google Scholar
• DiNardo CD, De Botton S, Stein EM, et al. Ivosidenib (AG-120) in mutant IDH1 AML and advanced hematologic malignancies: results of a phase 1 dose escalation and expansion study [abstract]. Blood. 2017;130(Suppl 1):725.
   Google Scholar
• Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–1117.
   PubMed Web of Science ®Google Scholar
• Wei A, Strickland SA, Roboz GJ, et al. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naive, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes [outcome]. Blood. 2017;130(Suppl 1):890.
   Google Scholar
• DiNardo CD, Pollyea DA, Jonas BA, et al. Updated safety and efficacy of venetoclax with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia [abstract]. Blood. 2017;130(Suppl 1):2628.
   Google Scholar
• DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216–228.
   PubMed Web of Science ®Google Scholar
• Sd G, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66(12):6361–6369.
   PubMed Web of Science ®Google Scholar
• Kirschbaum M, Gojo I, Goldberg SL, et al. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br J Haematol. 2014;167(2):185–193.
   PubMed Web of Science ®Google Scholar
• Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2ʹ-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108(10):3271–3279.
   PubMed Web of Science ®Google Scholar
• Morabito F, Voso MT, Hohaus S, et al. Panobinostat for the treatment of acute myelogenous leukemia. Expert Opin Investig Drugs. 2016;25(9):1117–1131.
   PubMed Web of Science ®Google Scholar
• Kung Sutherland MS, Walter RB, Jeffrey SC, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013;122(8):1455–1463.
   PubMed Web of Science ®Google Scholar
• Stein EM, Walter RB, Erba HP, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131(4):387–396.
   PubMed Web of Science ®Google Scholar
• Walter RB, Appelbaum FR, Tallman MS, et al. Shortcomings in the clinical evaluation of new drugs: acute myeloid leukemia as paradigm. Blood. 2010;116(14):2420–2428.
   PubMed Web of Science ®Google Scholar
• Mengis C, Aebi S, Tobler A, et al. Assessment of differences in patient populations selected for excluded from participation in clinical phase III acute myelogenous leukemia trials. J Clin Oncol. 2003;21(21):3933–3939.
   PubMed Web of Science ®Google Scholar
• Mandrekar SJ, Dahlberg SE, Simon R. Improving clinical trial efficiency: thinking outside the box. Am Soc Clin Oncol Educ Book. 2015;e141–e147.
   PubMedGoogle Scholar
• Berry DA. Emerging innovations in clinical trial design. Clin Pharmacol Ther. 2016;99(1):82–91.
   PubMed Web of Science ®Google Scholar
• Walter RB, Michaelis LC, Othus M, et al. Intergroup LEAP trial (S1612): A randomized phase 2/3 platform trial to test novel therapeutics in medically less fit older adults with acute myeloid leukemia. Am J Hematol. 2018;93(2):E49–E52.
   PubMed Web of Science ®Google Scholar
• Appelbaum FR, Rosenblum D, Arceci RJ, et al. End points to establish the efficacy of new agents in the treatment of acute leukemia. Blood. 2007;109(5):1810–1816.
   PubMed Web of Science ®Google Scholar
• Redaelli A, Botteman MF, Stephens JM, et al. Economic burden of acute myeloid leukemia: a literature review. Cancer Treat Rev. 2004;30(3):237–247.
   PubMed Web of Science ®Google Scholar
• Efficace F, Kemmler G, Vignetti M, et al. Health-related quality of life assessment and reported outcomes in leukaemia randomised controlled trials - a systematic review to evaluate the added value in supporting clinical decision making. Eur J Cancer. 2008;44(11):1497–1506.
   PubMed Web of Science ®Google Scholar
• Tvedt THA, Reikvam H, Aasebø E, et al. How should quality of life assessment be integrated in the evaluation of patients with acute myeloid leukemia? Expert Rev Qual Life Cancer Care. 2016;1(5):373–387.
   Google Scholar
• Buckley SA, Jimenez-Sahagun D, Othus M, et al. Quality of life from the perspective of the patient with acute myeloid leukemia. Cancer. 2018;124(1):145–152.
   PubMed Web of Science ®Google Scholar
• Pollyea DA. The case for abandoning induction chemotherapy. The Hematologist. 2017;14(3):1, 13.
   Google Scholar
• Ostronoff F, Othus M, Lazenby M, et al. Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. J Clin Oncol. 2015;33(10):1157–1164.
   PubMed Web of Science ®Google Scholar
• Etienne A, Esterni B, Charbonnier A, et al. Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia. Cancer. 2007;109(7):1376–1383.
   PubMed Web of Science ®Google Scholar
• 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(4):624–627.
   PubMed Web of Science ®Google Scholar
• Holmes HM, Des Bordes JK, Kebriaei P, et al. Optimal screening for geriatric assessment in older allogeneic hematopoietic cell transplantation candidates. J Geriatr Oncol. 2014;5(4):422–430.
   PubMed Web of Science ®Google Scholar
• Saliba D, Elliott M, Rubenstein LZ, et al. The Vulnerable Elders Survey: a tool for identifying vulnerable older people in the community. J Am Geriatr Soc. 2001;49(12):1691–1699.
   PubMed Web of Science ®Google Scholar
• Luciani A, Ascione G, Bertuzzi C, et al. Detecting disabilities in older patients with cancer: comparison between comprehensive geriatric assessment and vulnerable elders survey-13. J Clin Oncol. 2010;28(12):2046–2050.
   PubMed Web of Science ®Google Scholar
• Umit EG, Baysal M, Demir AM. Frailty in patients with acute myeloid leukaemia, conceptual misapprehension of chronological age. Eur J Cancer Care (Engl). 2018;27(2):e12810.
   PubMed Web of Science ®Google Scholar
• Hamaker ME, Mitrovic M, Stauder R. The G8 screening tool detects relevant geriatric impairments and predicts survival in elderly patients with a haematological malignancy. Ann Hematol. 2014;93(6):1031–1040.
   PubMed Web of Science ®Google Scholar
• Cruz-Jentoft AJ, Gonzalez B, de La Rubia J, et al. Further psychometric validation of the GAH scale: responsiveness and effect size. J Geriatr Oncol. 2017;8(3):211–215.
   PubMed Web of Science ®Google Scholar
• Aaldriks AA, Giltay EJ, Nortier JW, et al. Prognostic significance of geriatric assessment in combination with laboratory parameters in elderly patients with aggressive non-Hodgkin lymphoma. Leuk Lymphoma. 2015;56(4):927–935.
   PubMed Web of Science ®Google Scholar