Page 19 - 2018_11-Haematologica-web
P. 19
Editorials
gene mutations (FLT3, TP53, CEBPA, NPM1) and overall survival are related to the mutations’ differential impact on relapse risk.13 In fact, there are limited data available regard- ing the potential association between disease genetics and induction mortality. Notably, ten out of 13 patients with IDH1 mutations experienced early death during induction, while just two had refractory disease. This detail is central to the interpretation of the results and to contemplating clinical actionability. Do IDH1 mutations drive specific chemoresistance in older patients, thereby suggesting aug- mentation of induction with IDH1-directed therapy? Are IDH1 mutations causally or non-causally associated with clinical features that have been linked to increased trans- plant-related mortality?14 A combination of the two? In younger adults the prognostic impact of IDH mutations is unclear. One study suggested that those with both NPM1 and IDH mutations enjoyed a high event-free survival rate when treated with aggressive chemotherapy,15 while others showed a neutral or negative impact.16,17 The simplest expla- nation for the disparate literature regarding IDH1 mutations is that related to the random noise in small samples. Alternatively, the clinical impact of IDH mutations may be ‘context-dependent’, and different depending on its place in the clonal hierarchy (progression mutation in some cases and a founder or ‘early’ mutation in others), the co-occur- ring gene mutations, or undefined clinical characteristics. Does this group of patients in their 70’s and 80’s have IDH1 mutations that reflect a distinct group with particularly chemoresistant disease? If so, one could speculate that such individuals might have fared better with an IDH inhibitor than with chemotherapy. Indeed the single-agent studies with these drugs,18,19 mainly conducted in patients with advanced disease, include some previously untreated patients with comparable outcomes.
In summary, the German Austrian AML Study Group research is important because it confirms the commonality of secondary or stem cell type mutations in adults aged over 74 with AML. It further reminds us that prognostic charac- teristics cannot necessarily be applied with abandon across the age spectrum. However, we remain in the same conun- drum about the utility of aggressive versus less intensive therapy in this age group.
References
1. 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.
2. Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid leukemia in the
elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood. 1997;89(9):3323-3329.
3. Lindsley RC, Mar BG, Mazzola E, et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood. 2015;125(9):1367-1376.
4. Ferrara F, Barosi G, Venditti A, et al. Consensus-based definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO group on a new tool for therapy decision making. Leukemia. 2013;27(5):997-999.
5. Juliusson G, Antunovic P, Derolf A, 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.
6. Ossenkoppele G, Lowenberg B. How I treat the older patient with acute myeloid leukemia. Blood. 2015;125(5):767-774.
7. Prassek VV, Rothenberg-Thurley M, Sauerland MC, et al. Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older. Haematologica. 2018;103(11):1853-1861.
8. BuchnerT,BerdelWE,HaferlachC,etal.Long-termresultsinpatients with acute myeloid leukemia (AML): the influence of high-dose AraC, G-CSF priming, autologous transplantation, prolonged maintenance, age, history, cytogenetics, and mutation status. Data of the AMLCG 1999 trial. Blood. 2009;114(22):485.
9. DöhnerH,EsteyE,GrimwadeD,etal.Diagnosisandmanagementof AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447.
10. GrimwadeD,HillsRK,MoormanAV,etal.Refinementofcytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354-365.
11. PapaemmanuilE,GerstungM,BullingerL,etal.Genomicclassification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209-2221.
12. Metzeler KH, Herold T, Rothenberg-Thurley M, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686-698.
13. Marcucci G, Haferlach T, Döhner H. Molecular genetics of adult acute myeloid leukemia: prognostic and therapeutic implications. J Clin Oncol. 2011;29(5):475-486.
14. WalterRB,OthusM,BorthakurG,etal.Predictionofearlydeathafter 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.
15. PatelJP,GönenM,FigueroaME,etal.Prognosticrelevanceofintegrat- ed genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089.
16. Green CL, Evans CM, Zhao L, et al. The prognostic significance of IDH2 mutations in AML depends on the location of the mutation. Blood. 2011;118(2):409-412.
17. Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol. 2010;28(22):3636-3643.
18. SteinEM,DiNardoCD,PollyeaDA,etal.EnasidenibinmutantIDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722- 731.
19. 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.
haematologica | 2018; 103(11)
1759
