Prognostic Relevance of NPM1 and FLT3 Mutations in Acute Myeloid Leukaemia, Longterm Follow-Up-A Single Center Experience

Erika Borlenghi, Chiara Cattaneo, Diego Bertoli, Elisa Cerqui, Silvana Archetti, Angela Passi, Margherita Oberti, Tatiana Zollner, Carlotta Giupponi, Chiara Pagani, Nicola Bianchetti, Chiara Bottelli, Samuele Bagnasco, Margherita Sciumè, Alessandra Tucci, Giuseppe Rossi, Erika Borlenghi, Chiara Cattaneo, Diego Bertoli, Elisa Cerqui, Silvana Archetti, Angela Passi, Margherita Oberti, Tatiana Zollner, Carlotta Giupponi, Chiara Pagani, Nicola Bianchetti, Chiara Bottelli, Samuele Bagnasco, Margherita Sciumè, Alessandra Tucci, Giuseppe Rossi

Abstract

The prognosis of acute myeloid leukemia depends on genetic aberrations, particularly NPM1 and FLT3-ITD mutations. The targeted drugs’ availability has renewed interest in FLT3 mutations, but the impact of these genetic alterations using these treatments is yet to be confirmed. Our objective was to evaluate the results obtained with the intensified NILG-AML 01/00 protocol (ClinicalTrials.gov Identifier: NCT 00400673) in 171 unselected patients (median age, 54.5 years, range 15−74) carrying the FLT3 (ITD or TKD) and/or NPM1 mutations. The CR rate and 5-y survival were 88.3% and 58% +/− 4, respectively, significantly higher in the NPM1-mutated (CR 93.9%, p: 0.0001; survival 71% +/− 6, p: 0.0017, respectively). In isolated ITD patients, the CR was lower (66.7%, p: 0.0009), and the 3 years-relapse-free survival worse (24%, p: <0.0002). The presence of ITD, irrespective of the allelic ratio, or TKD mutation, did not significantly affect the survival or relapse-free survival among the NPM1-co-mutated patients. Our data indicate that a high dose of ARAC plus idarubicin consolidation exerts a strong anti-leukemic effect in NPM1-mutated patients both with the FLT3 wild-type and mutated AML, while in the NPM1 wild-type and FLT3-mutated, the therapeutic effect remains unsatisfactory. New strategies incorporating target therapy with second-generation inhibitors will improve these results and their addition to this aggressive chemotherapeutic program merits testing.

Trial registration: ClinicalTrials.gov NCT00400673.

Keywords: FLT3 mutation; NPM1 mutation; acute myeloid leukaemia; high dose cytarabine (HD-ARAC); idarubicin.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Study Cohort.
Figure 2
Figure 2
Relapse-Free Survival (RFS): (a) in the whole study cohort and according to age. (b) According to molecular data (NPM1/FLT3-ITD): NPM1m/ITDwt vs. NPM1wt/ITDm, vs. NPM1m/ITDm.
Figure 3
Figure 3
Overall Survival (OS): (a) in the whole study cohort; (b) According to molecular data: NPM1/FLT3-ITD status.

References

    1. Papaemmanuil E., Gerstung M., Bullinger L., Gaidzik V.I., Paschka P., Roberts N.D., Potter N.E., Heuser M., Thol F., Bolli N., et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N. Engl. J. Med. 2016;374:2209–2221. doi: 10.1056/NEJMoa1516192.
    1. Döhner H., Estey E., Grimwade D., Amadori S., Appelbaum F.R., Büchner T., Dombret H., Ebert B.L., Fenaux P., Larson R.A., et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–447. doi: 10.1182/blood-2016-08-733196.
    1. Schlenk R.F., Döhner K., Krauter J., Fröhling S., Corbacioglu A., Bullinger L., Habdank M., Späth D., Morgan M., Benner A., et al. German-Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N. Engl. J. Med. 2008;358:1909–1918. doi: 10.1056/NEJMoa074306.
    1. Kayser S., Schlenk R.F., Londono M.C., Breitenbuecher F., Wittke K., Du J., Groner S., Späth D., Krauter J., Ganser A., et al. German-Austrian AML Study Group (AMLSG). Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood. 2009;114:2386–2392. doi: 10.1182/blood-2009-03-209999.
    1. Patel J.P., Gonen M., Figueroa M.E., Fernandez H., Sun Z., Racevskis J., Van Vlierberghe P., Dolgalev I., Thomas S., Aminova O., et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012;366:1079–1089. doi: 10.1056/NEJMoa1112304.
    1. Scholl S., Theuer C., Scheble V., Kunert C., Heller A., Mügge L.O., Fricke H.J., Höffken K., Wedding U. Clinical impact of nucleophosmin mutations and Flt3 internal tandem duplication in patents older than 60yr with acute myeloid leukemia. Eur. J. Haematol. 2008;80:208–215. doi: 10.1111/j.1600-0609.2007.01019.x.
    1. Thiede C., Koch S., Creutzig E., Steudel C., Illmer T., Schaich M., Ehninger G. Prevalence and prognostic impact of NPM1 mutations in 1485 adult with acute myeloid leukemia (AML) Blood. 2006;107:4011–4020. doi: 10.1182/blood-2005-08-3167.
    1. Schnittger S., Schoch C., Kern W., Mecucci C., Tschulik C., Martelli M.F., Haferlach T., Hiddemann W., Falini B. Nucleophosfomin gene mutations are predictor of favourable prognosis in acute myelogenous leukemia with normal karyotype. Blood. 2005;106:3733–3739. doi: 10.1182/blood-2005-06-2248.
    1. Oran B., Cortes J., Beitinjaneh A., Chen H.C., de Lima M., Patel K., Ravandi F., Wang X., Brandt M., Andersson B.S., et al. Allogeneic transplantation in first remission improves outcomes irrespective of FLT3-ITD allelic ratio in FLT3-ITD positive acute myelogenous leukemia. Biol. Blood Marrow. Transplant. 2016;22:1218–1226. doi: 10.1016/j.bbmt.2016.03.027.
    1. Gale R.E., Hills R., Kottaridis P.D., Srirangan S., Wheatley K., Burnett A.K., Linch D.C. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): An analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. 2005;106:3658–3665. doi: 10.1182/blood-2005-03-1323.
    1. Bornhauser M., Illmer T., Schaich M., Soucek S., Ehninger G., Thiede C. AML SHG 96 study group. Improved outcome after stem-cell transplantation in FLT3/ITDpositive AML. Blood. 2007;109:2264–2265. doi: 10.1182/blood-2006-09-047225.
    1. Brunet S., Labopin M., Esteve J., Cornelissen J., Socié G., Iori A.P., Verdonck L.F., Volin L., Gratwohl A.-, Sierra J., et al. Impact of FLT3 internal tandem duplication on the outcome of related and unrelated hematopoietic transplantation for adult acute myeloid leukemia in first remission: A retrospective analysis. J. Clin. Oncol. 2012;30:735–741. doi: 10.1200/JCO.2011.36.9868.
    1. Gale R.E., Green C., Allen C., Mead A.J., Burnett A.K., Hills R.K., Linch D.C. Medical Research Council Adult Leukaemia Working Party. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood. 2008;111:2776–2784. doi: 10.1182/blood-2007-08-109090.
    1. Schnittger S., Bacher U., Kern W., Alpermann T., Haferlach C., Haferlach T. Prognostic impact of FLT3-ITD load in NPM1 mutated acute myeloid leukemia. Leukemia. 2011;25:1297–1304. doi: 10.1038/leu.2011.97.
    1. Pratcorona M., Brunet S., Nomdedéu J., Ribera J.M., Tormo M., Duarte R., Escoda L., Guàrdia R., de Llano M.P.Q., Salamero O., et al. Grupo Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas Mieloblásticas. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: Relevance to post-remission therapy. Blood. 2013;121:2734–2738.
    1. Bacher U., Haferlach C., Kern W., Haferlach T., Schnittger S. Prognostic relevance of FLT3–TKD mutations in AML: The combination matters-an analysis of 3082 patients. Blood. 2008;111:2527–2537. doi: 10.1182/blood-2007-05-091215.
    1. Thiede C., Steudel C., Mohr B., Schaich M., Schäkel U., Platzbecker U., Wermke M., Bornhäuser M., Ritter M., Neubauer A., et al. Analysis of FLT3- activating mutations in 979 patients with acute myelogenous leukemia: Association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335. doi: 10.1182/blood.V99.12.4326.
    1. Stone R.M., Mandrekar S.J., Sanford B.L., Laumann K., Geyer S., Bloomfield C.D., Thiede C., Prior T.W., Döhner K., Marcucci G., et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N. Engl. J. Med. 2017;377:454–464. doi: 10.1056/NEJMoa1614359.
    1. Voso M.T., Larson R.A., Jones D., Marcucci G., Prior T., Krauter J., Heuser M., Lavorgna S., Nomdede J., Geyer S.M., et al. Midostaurin in patients with acute myelod leukemia and FLT3-TKD mutations: A sub analysis from the Ratify trial. Blood Adv. 2020;13:4945–4954. doi: 10.1182/bloodadvances.2020002904.
    1. Doöhner K., Thiede C., Jahn N., Panina E., Gambietz A., Larson R.A., Prior T.W., Marcucci G.-, Jones D., Krauter J., et al. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia. Blood. 2020;135:371–380. doi: 10.1182/blood.2019002697.
    1. International System for Cytogenetic Nomenclature . Guidelines for Cancer Cytogenetics. Supplement to: An International System for Human Cytogenetic Nomenclature. Felix Mitelmann; Memphis, TN, USA: 1995.
    1. Grimwade D., Hills R.K., Moorman A.V., Walker H., Chatters S., Goldstone A.H., Wheatley K., Harrison C.J., Burnett A.K. National Cancer Research Institute Adult Leukaemia Working Group. Refinement of cytogenetic 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;116:354–365.
    1. Gorello P., Cazzaniga G., Alberti F., Dell’Oro M.G., Gottardi E., Specchia G., Roti G., Rosati R., Martelli M.F., Diverio D., et al. Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying Nucleophosmin (NPM1) gene mutations. Leukemia. 2006;20:1103–1108. doi: 10.1038/sj.leu.2404149.
    1. Nakao M., Yokota S., Iwai T., Kaneko H., Horiike S., Kashima K., Sonoda Y., Fujimoto T., Misawa S. Internal tandem duplication of the flt3 gene found in acute myeloid leukemia. Leukemia. 1996;10:1911–1918.
    1. Schuurhuis J.G., Heuser M., Freeman S., Béné M.C., Buccisano F., Cloos J., Grimwade D., Haferlach T., Hills R.K., Hourigan C.S., et al. Minimal/measurable residual disease in AML: A consensus document from the European LeukemiaNet MRD Working Party. Blood. 2018;131:1275–1291. doi: 10.1182/blood-2017-09-801498.
    1. Bassan R., Intermesoli T., Masciulli A., Pavoni C., Boschini C., Gianfaldoni G., Marmont F., Cavattoni I., Mattei D., Terruzzi E., et al. Randomized trial comparing standard vs sequential high-dose chemotherapy for inducing early CR in adult AML. Blood Adv. 2019;3:1103–1117. doi: 10.1182/bloodadvances.2018026625.
    1. Mandelli F., Vignetti M., Suciu S., Stasi R., Petti M.C., Meloni G., Muus P., Marmont F., Marie J.P., Labar B., et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: The EORTC and GIMEMA Groups Study AML-10. J. Clin. Oncol. 2009;27:5397–5403. doi: 10.1200/JCO.2008.20.6490.
    1. The AML Collaborative Group A systematic collaborative overview of randomized trials comparing idarubicin with daunorubicin (or other anthracyclines) as induction therapy for acute myeloid leukaemia. Br. J. Haematol. 1998;103:100–109. doi: 10.1046/j.1365-2141.1998.00948.x.
    1. Aurelius J., Möllgård L., Kiffin R., Sander E.F., Nilsson S., Thorén F.B., Hellstrand K., Martner A. Anthracycline-based consolidation may determine outcome of post-consolidation immunotherapy in AML. Leuk. Lymphoma. 2019;60:2771–2778. doi: 10.1080/10428194.2019.1599110.
    1. Minetto P., Candoni A., Guolo F., Clavio M., Zannier M.E., Miglino M., Dubbini M.V., Carminati E., Sicuranza A., Ciofini S., et al. Fludarabine, High-Dose Cytarabine and Idarubicin-Based Induction May Overcome the Negative Prognostic Impact of FLT3-ITD in NPM1 Mutated AML, Irrespectively of FLT3-ITD Allelic Burden. Cancers. 2020;24:34. doi: 10.3390/cancers13010034.
    1. Castaigne S., Pautas C., Terré C., Raffoux E., Bordessoule D., Bastie J.-N., Legrand O., Thomas X., Turlure P., Reman O., et al. Acute Leukemia French Association. 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;379:1508–1516. doi: 10.1016/S0140-6736(12)60485-1.
    1. Ivey A., Hills R.K., Simpson M.A., Grech G.A., Patel G.Y., Bhudia N., Farah H., Mason J., Wall K., Akiki S., et al. UK National Cancer Research Institute AML Working Group. Assessment of minimal residual disease in standard-risk AML. N. Engl. J. Med. 2016;374:422–433. doi: 10.1056/NEJMoa1507471.
    1. Balsat M., Renneville A., Thomas X., de Botton S., Caillot D., Marceau A., Lemasle E., Marolleau J.P., Nibourel O., Berthon C., et al. Postinduction minimal residual disease predicts 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;35:185–193. doi: 10.1200/JCO.2016.67.1875.
    1. Chua C., Grigg A., Singh J., Droogleever M.P., Zhang L., Lim A., Fong C.Y., Ting S.B., Schwarer A., Tiong I.S., et al. Treatment practice and outcome in FLT3-mutant acute myeloid leukemia in the re-midostaurin era: A real world experience from Australian tertiary hospitals. Leuk. Lymphoma. 2020;61:848–854. doi: 10.1080/10428194.2019.1691192.
    1. Döhner H., Wei A.H., Appelbaum F.R., Craddock C., DiNardo C.D., Dombret H., Ebert B.L., Fenaux P., Godley L.A., Hasserjian R.P., et al. Diagnosis and Management of AML in Adults: 2022 ELN Recommendations from an International Expert Panel. Blood. :2022. doi: 10.1182/blood.2022016867. online ahead of print .
    1. Erba H., Montesinos P., Vrhovac R., Patkowska E., Kim H.J., Zak P., Wang P.N., Mitov T., Hanyok J., Liu L., et al. Quizartinib prolunged survival vs placebo plus intensive induction and consolidation therapy followed by single agent continuation in patients aged 18–75 years with newly diagnosed FLT3-ITD+ AML; Proceedings of the 27th Congress of European Hematology Association (EHA 2022); Wien, Austria. 9–12 June 2022.
    1. Borlenghi E., Cattaneo C., Cerqui E., Archetti S., Bertoli D., Bellotti D., Gramegna D., Soverini G., Oberti M., Schieppati F., et al. Postremission therapy with repeated courses of high-dose cytarabine, idarubicin, and limited autologous stem cell support achieves a very good long-term outcome in European leukemia net favorable and intermediate-risk acute myeloid leukemia. Hematol. Oncol. 2020;38:754–762. doi: 10.1002/hon.2806.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi