Page 125 - 2019_09-HaematologicaMondo-web

Sequential therapy patients with refractory AML
Our study has several limitations. First, as opposed to our definition of primary refractory disease, the recently published European LeukemiaNet (ELN) guidelines rec- ommend considering primary refractory disease after only two induction cycles, irrespective of the schedule used in the second cycle.11 Nevertheless, when comparing previ- ously published literature to our results, these recommen- dations do not reflect what others have considered to be standard clinical practice. Thus, although a portion of our cohort received only one cycle of induction chemotherapy and may represent a “better prognosis” group, results are still better when compared to other salvage protocols. Second, identifying patients for upfront sequential thera- py may be associated with a selection bias for fitter patients. However, the median age of patients in our
cohort was 54 years, which represents a ‘typical’ trans- planted leukemia patient. Third, creating and operating a system that can quickly identify donors is challenging and requires substantial resources, which are not always avail- able in all centers.
In summary, sequential therapy for patients with pri- mary refractory AML is associated with a substantial anti- leukemic effect, relatively low toxicity, and 61% 3-year OS. Future protocols should focus on better prevention and control of GvHD, predicting and decreasing relapse incidence in high-risk patients using minimal residual dis- ease tests and post-allogeneic maintenance therapy (i.e. tyrosine kinase inhibitors in patients with FLT3-ITD AML), and prospectively validate these results in a larger cohort of patients.
References
1. Buchner T, Schlenk RF, Schaich M, et al. Acute Myeloid Leukemia (AML): different treatment strategies versus a common stan- dard arm--combined prospective analysis by the German AML Intergroup. J Clin Oncol. 2012;30(29):3604-3610.
2. 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.
3. Wattad M, Weber D, Dohner K, et al. Impact of salvage regimens on response and overall survival in acute myeloid leukemia with induction failure. Leukemia. 2017;31(6): 1306-1313.
4. Lowenberg 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.
5. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361(13):1249-1259.
6. Lee JH, Joo YD, Kim H, et al. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood. 2011;118 (14):3832-3841.
7. Schlenk RF, Frohling S, Hartmann F, et al. Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia. 2004;18(11):1798-1803.
8. 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 ran- domised controlled trials. Lancet Oncol. 2014;15(9):986-996.
9. Craddock C, Labopin M, Pillai S, et al. Factors predicting outcome after unrelated donor stem cell transplantation in primary refractory acute myeloid leukaemia. Leukemia. 2011;25(5):808-813.
10. Schlenk RF, Dohner K, Mack S, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelat- ed donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol. 2010;28 (30):4642-4648.
11. 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.
12. Thol F, Schlenk RF, Heuser M, et al. How I treat refractory and early relapsed acute myeloid leukemia. Blood. 2015;126(3):319- 327.
13. Schmid C, Schleuning M, Ledderose G, et al. Sequential regimen of chemotherapy, reduced-intensity conditioning for allogene- ic stem-cell transplantation, and prophylac- tic donor lymphocyte transfusion in high- risk acute myeloid leukemia and myelodys- plastic syndrome. J Clin Oncol. 2005; 23(24):5675-5687.
14. Chemnitz JM, von Lilienfeld-Toal M, Holtick U, et al. Intermediate intensity con- ditioning regimen containing FLAMSA, treo- sulfan, cyclophosphamide, and ATG for allogeneic stem cell transplantation in elder-
ly patients with relapsed or high-risk acute myeloid leukemia. Ann Hematol. 2012; 91(1):47-55.
15. Holtick U, Herling M, Pflug N, et al. Similar outcome after allogeneic stem cell transplan- tation with a modified FLAMSA condition- ing protocol substituting 4 Gy TBI with tre- osulfan in an elderly population with high- risk AML. Ann Hematol. 2017;96(3):479- 487.
16. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induc- tion failure. J Clin Oncol 2010;28(23):3730- 3738.
17. Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophy- laxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trial. Lancet Oncol. 2009;10(9):855-864.
18. Kroger N, Solano C, Wolschke C, et al. Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med. 2016;374(1):43-53.
19. Salem G, Ruppert AS, Elder P, et al. Lower dose of antithymocyte globulin does not increase graft-versus-host disease in patients undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell trans- plant. Leuk Lymphoma. 2015;56(4):1058- 1065.
20. Megias-Vericat JE, Martinez-Cuadron D, Sanz MA, et al. Salvage regimens using con- ventional chemotherapy agents for relapsed/refractory adult AML patients: a systematic literature review. Ann Hematol. 2018;97(7):1115-1153.
haematologica | 2019; 104(9)
1803