Page 47 - 2019_08-Haematologica-web

MRD in AML
Hypomethylating agents for measurable residual disease-positive acute myeloid leukemia
Although HSCT has historically been the preferred con- solidation option for patients with high-risk AML, there is also interest in the use of hypomethylating agents for these patients, including those with detectable MRD. Several studies have suggested that treatment with hypomethylating agents (azacitidine or decitabine) may be beneficial for patients with AML and persistent or recurrent MRD.82-85 The RELAZA2 trial was the largest prospective study to assess this issue.84 One hundred and ninety patients with AML or myelodysplastic syndrome who achieved complete remission after chemotherapy or HSCT were monitored for MRD for 24 months with either PCR for mutant NPM1, leukemia-specific gene fusions (DEK-NUP214, RUNX1-RUNX1T1, or CBFB- MYH11) or donor chimerism in flow cytometry-sorted CD34+ cells (for patients who had undergone prior allo- geneic HSCT). Patients who developed detectable MRD received a standard dose of azacitidine for up to 24 cycles. Among the 53 evaluable patients who became MRD-pos- itive and received treatment with azacitidine, 19 (36%) achieved MRD-negativity after 6 months of treatment. Median relapse-free survival and overall survival times for these MRD-positive patients who received azacitidine was 10 months and 31 months, respectively. Importantly, MRD response was associated with improved relapse-free survival (HR, 0.2; 95% CI: 0.1-0.5; P<0.0001) and a trend towards improved overall survival (HR, 0.4; 95% CI: 0.1- 1.3; P=0.112). These data suggest that hypomethylating agents may be a reasonable option for patients with MRD-positive AML, particularly those who are not suit- able candidates for allogeneic HSCT. Other studies have, however, failed to demonstrate a benefit for the routine use of hypomethylating agents in the maintenance setting.86,87 A phase III randomized study of an oral formu- lation of azacitidine as maintenance therapy in patients with AML in remission will likely provide further impor- tant information in this area (NCT01757535).
Conclusions
Despite substantial heterogeneity across studies of MRD in AML (e.g. variations in AML subtype, MRD methodology and target, cutoff, regimen, and timing of assessment), achievement of MRD negativity has been reliably shown to predict risk of relapse and long-term outcomes. More sensitive assays are still needed, howev- er, as up to 50% of patients who are “MRD-negative” according to commonly applied MRD technologies still relapse. Beyond the important prognostic information that MRD provides, the ultimate goal of assessing MRD is to use this information to appropriately guide decisions regarding post-remission therapies. This approach is, however, strongly dependent on the availability of thera- pies that are effective in eradicating small amounts of residual leukemia (as with blinatumomab in acute lym- phoblastic leukemia). While some studies suggest that allogeneic HSCT or hypomethylating agents may provide benefit for some patients with persistent or recurrent MRD, long-term outcomes with these approaches are largely disappointing. Innovative treatments are therefore needed for these patients. There are several ongoing MRD-directed clinical trials that are evaluating novel immune-based strategies (e.g. checkpoint inhibitors, vac- cines, and T-cell-based therapies such as bi-specific T-cell engaging antibodies and chimeric antigen receptor T cells) which may be able to overcome the chemoresistant phe- notype associated with MRD-positive disease. Novel combinations with Bcl-2 inhibitors (e.g. venetoclax) may also be promising in this setting. Ultimately, enrollment of high-risk patients into these trials is imperative in order to advance our understanding of how to use MRD informa- tion to drive clinical decisions and to improve outcomes of patients with AML.
Funding
Supported by an MD Anderson Cancer Center Support Grant (CA016672).
References
1. Short NJ, Rytting ME, Cortes JE. Acute myeloid leukaemia. Lancet. 2018;392 (10147):593-606.
2. Dohner 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.
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. CornelissenJJ,BlaiseD.Hematopoieticstem cell transplantation for patients with AML in first complete remission. Blood. 2016;127 (1):62-70.
5. HouriganCS,KarpJE.Minimalresidualdis- ease in acute myeloid leukaemia. Nat Rev Clin Oncol. 2013;10(8):460-471.
6. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the
European LeukemiaNet MRD Working
Party. Blood. 2018;131(12):1275-1291.
7. Short NJ, Jabbour E, Albitar M, et al. Recommendations for the assessment and management of measurable residual disease in adults with acute lymphoblastic leukemia: a consensus of North American
experts. Am J Hematol. 2019;94(2):257-265.
8. Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal resid- ual disease measurements in the context of risk-based therapy in childhood acute lym- phoblastic leukaemia: a prospective study.
Lancet Oncol. 2015;16(4):465-474.
9. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual dis- ease (UKALL 2003): a randomised controlled
trial. Lancet Oncol. 2013;14(3):199-209.
10. Campana D, Pui CH. Minimal residual dis- ease-guided therapy in childhood acute lym- phoblastic leukemia. Blood. 2017;129(14):
1913-1918.
11. Bruggemann M, Raff T, Kneba M. Has MRD
monitoring superseded other prognostic fac- tors in adult ALL? Blood. 2012;120(23):4470- 4481.
12. Freeman SD, Virgo P, Couzens S, et al. Prognostic relevance of treatment response measured by flow cytometric residual dis- ease detection in older patients with acute myeloid leukemia. J Clin Oncol. 2013;31(32):4123-4131.
13. Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31(31):3889-3897.
14. Balsat M, Renneville A, Thomas X, et al. Postinduction minimal residual disease pre- dicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the Acute Leukemia French Association Group. J Clin Oncol. 2017;35(2):185-193.
15. Ivey A, Hills RK, Simpson MA, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374
haematologica | 2019; 104(8)
1539