Page 14 - 2018_10-Haematologica-web

Editorials
study in newly diagnosed patients,11 the AML-19 study in patients with newly diagnosed AML unsuitable for inten- sive chemotherapy,12 and the MyloFrance-1 study in relapsed/refractory AML,13 GO was reapproved by the FDA in 2017 for the treatment of newly-diagnosed CD33+ AML in adults and treatment of relapsed or refractory CD33+ AML in adults and in pediatric patients 2 years and older. In Europe, GO was approved in 2018 for the treat- ment of patients aged 15 years and older with previously untreated, de novo, CD33+ AML. Both approvals (FDA, EMA) for newly-diagnosed CD33+ AML in adults included the addition of GO (3 mg/m2, day 1) to consolidation ther- apy with daunorubicin and cytarabine. However, in two trials assessing GO administered on a randomized basis in post-remission therapy, no significant impact on survival was observed.14,15 In the MRC AML-15 trial a total of 948 patients were randomly assigned to receive or not receive GO as an adjunct to first consolidation therapy.14 Once again, there was no evidence that relapses were prevented (P=0.20) and the overall survival rates of the patients in the two groups were nearly superimposable (hazard ratio, 1.02; 95% confidence interval: 0.82-1.27). In a study of the HOVON group, older patients achieving complete remis- sion after intensive induction therapy were randomized to three cycles of GO (6 mg/m2 every 4 weeks) or no postre- mission therapy.15 The two treatment groups (113 patients receiving GO versus 119 control patients) were comparable with respect to age, performance status, and cytogenetics. There were no significant differences between the groups with regard to overall survival (P=0.52) and disease-free survival (P=0.40).
These examples consistently show that new drugs that are active as an adjunctive therapy to standard induction are not necessarily active in consolidation therapy. But why is this the case and how can we improve the situa- tion? In AML patients with active disease (newly diag- nosed, relapsed or refractory) there is usually a bulk popu- lation of leukemic cells which can be characterized in depth by sophisticated methods and treated with targeted drugs if the target is present, such as activating FLT3 muta- tions, CD33 expression, or probably active AKT signaling. In contrast, the clinical situation of consolidation therapy is currently difficult to model in vitro or in vivo. Therefore, the preclinical evidence available before the initiation of a clinical trial is often limited. For example, the senescence- associated reprogramming of non-stem bulk leukemia cells into self-renewing, leukemia-initiating stem cells,16 which may occur during the course of AML treatment, is currently not assessed within clinical trials. It is, therefore, of the utmost importance that methodologies of stem cell research are adapted to be fit for the purpose of use in clin- ical studies, particularly addressing consolidation research questions.
We also need to improve the sensitivity and specificity of our methods of describing the depth of remission dur- ing the consolidation treatment phase. The term molecular remission has been introduced in current guidelines.1,5 Nevertheless, consolidation therapy still resembles flying blind in that after each cycle complete remission is docu- mented but frequently without taking measurable residual disease (MRD)17 assessment into account. In addition, more than 50% of relapses are not predicted by MRD
assessment and occur in MRD-negative groups.4 The con- sequences of this are low levels of test sensitivity of real- time quantitative polymerase chain reaction-based meth- ods,18,19 whereas flow-cytometry and sequencing-based methods have been characterized by low levels of speci- ficity.20-22 Thus, MRD assessment during the course of AML treatment is essential and may help to improve clin- ical research in consolidation therapy of AML. Nevertheless, its assessment is currently only informative for the evaluation of consolidation treatment strategies if MRD is positive and declining or rising. Negative results are still difficult to interpret.4
References
1. 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.
2. Schlenk RF, Müller-Tidow C, Benner A, Kieser M. Relapsed/refractory acute myeloid leukemia: any progress? Curr Opin Oncol. 2017;29(6):467-473.
3. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 1994;331(14):896-903.
4. Schlenk RF, Jaramillo S, Müller-Tidow C. What’s new in consolidation therapy in AML? Semin Hematol. 2018; In press.
5. NCCN Guidelines https://www.nccn.org/store/login/login.aspx? ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/a ml.pdf
6. Burnett AK, Gupta ED, Knapper S, et al. Addition of the mammalian target of rapamycin inhibitor, everolimus, to consolidation therapy in acute myeloid leukemia: experience from the UK NCRI AML17 trial. Haematologica 2018;103(10):1654-1661.
7. Kaymakcalan MD, Je Y, Sonpavde G, et al. Risk of infections in renal cell carcinoma (RCC) and non-RCC patients treated with mammalian target of rapamycin inhibitors. Br J Cancer. 2013;108(12):2478-2484.
8. HarringtonD,DrazenJM.Learningfromatrialstoppedbyadataand safety monitoring board. N Engl J Med. 2018;378(21):2031-2032.
9. 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.
10. StoneRM,MandrekarSJ,SanfordBL,etal.Theadditionofmidostaurin to standard chemotherapy decreases cumulative incidence of relapse (CIR) in the international prospective randomized, placebo-controlled, double-blind trial (CALGB 10603 / RATIFY [Alliance]) for newly diag- nosed acute myeloid leukemia (AML) patients with FLT3 mutations. Blood. 2017;130(Suppl 1):2580.
11. Castaigne S, Pautas C, Terré C, et al. Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a ran- domised, open-label, phase 3 study. Lancet. 2012;379(9825):1508-1516.
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13. TaksinAL,LegrandO,RaffouxE,etal.Highefficacyandsafetyprofile of fractionated doses of Mylotarg as induction therapy in patients with relapsed acute myeloblastic leukemia: a prospective study of the ALFA group. Leukemia. 2007;21(1):66-71.
14. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gem- tuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011;29(4):369-377.
15. Löwenberg B, Beck J, Graux C, et al. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood. 2010;115(13):2586-2591.
16. Milanovic M, Fan DNY, Belenki D, et al. Senescence-associated repro- gramming promotes cancer stemness. Nature. 2018;553 (7686):96-100. 17. SchuurhuisGJ,HeuserM,FreemanS,etal.Minimal/measurableresid- ual disease in AML: a consensus document from the European
LeukemiaNet MRD Working Party. Blood. 2018;131(12):1275-1291. 18. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual
disease in standard-risk AML. N Engl J Med. 2016;374(5):422-433.
19. KrönkeJ,SchlenkRF,JensenKO,etal.Monitoringofminimalresidual
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