Precision Therapy Versus Standard Therapy in AML and MDS in Elderly

Summary

This is a randomized clinical trial that randomizes between treatment principles. The study will investigate if precision therapy determined by a tumour board is better than standard treatment for acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) in elderly. The tumour board will decide the precision therapy based on identified genetic changes that can guide customized therapy. There are currently 40-50 targeted therapies approved for various cancers in Norway. The precision therapy will be given in addition to the standard treatment. The primary study objective will be to evaluate the cost-effectiveness of a precision therapy strategy compared with standard treatment. Other objectives will mesaure efficacy and satety of the treatment, and impact on life quality of the patients.

Timeline

Start

2021-06-22

Primary completion

2026-06-10

Completion

2027-06-10

Publications

• Background Pfeilstocker M, Tuechler H, Sanz G, Schanz J, Garcia-Manero G, Sole F, Bennett JM, Bowen D, Fenaux P, Dreyfus F, Kantarjian H, Kuendgen A, Malcovati L, Cazzola M, Cermak J, Fonatsch C, Le Beau MM, Slovak ML, Levis A, Luebbert M, Maciejewski J, Machherndl-Spandl S, Magalhaes SM, Miyazaki Y, Sekeres MA, Sperr WR, Stauder R, Tauro S, Valent P, Vallespi T, van de Loosdrecht AA, Germing U, Haase D, Greenberg PL. Time-dependent changes in mortality and transformation risk in MDS. Blood. 2016 Aug 18;128(7):902-10. doi: 10.1182/blood-2016-02-700054. Epub 2016 Jun 22.
• Background Lowenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Dohner H, Gratwohl A, Pabst T, Verhoef G; Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON); German AML Study Group (AMLSG); Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. doi: 10.1056/NEJMoa0901409.
• Background Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011 Feb 10;29(5):487-94. doi: 10.1200/JCO.2010.30.1820. Epub 2011 Jan 10.
• Background Klepin HD, Rao AV, Pardee TS. Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol. 2014 Aug 20;32(24):2541-52. doi: 10.1200/JCO.2014.55.1564.
• Background Klepin HD. Geriatric perspective: how to assess fitness for chemotherapy in acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2014 Dec 5;2014(1):8-13. doi: 10.1182/asheducation-2014.1.8. Epub 2014 Nov 18.
• Background Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Recher C, Sandhu I, Bernal del Castillo T, Al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Dohner H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 2015 Jul 16;126(3):291-9. doi: 10.1182/blood-2015-01-621664. Epub 2015 May 18.
• Background Ma X. Epidemiology of myelodysplastic syndromes. Am J Med. 2012 Jul;125(7 Suppl):S2-5. doi: 10.1016/j.amjmed.2012.04.014.
• Background Platzbecker U. Treatment of MDS. Blood. 2019 Mar 7;133(10):1096-1107. doi: 10.1182/blood-2018-10-844696. Epub 2019 Jan 22.
• Background Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
• Background Prasad V, Gale RP. Precision medicine in acute myeloid leukemia: Hope, hype or both? Leuk Res. 2016 Sep;48:73-7. doi: 10.1016/j.leukres.2016.07.011. Epub 2016 Jul 22.
• Background Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, Taylor M, Shaw AT, Montez S, Meric-Bernstam F, Smith S, Tuch BB, Ebata K, Cruickshank S, Cox MC, Burris HA 3rd, Doebele RC. Larotrectinib in adult patients with solid tumours: a multi-centre, open-label, phase I dose-escalation study. Ann Oncol. 2019 Feb 1;30(2):325-331. doi: 10.1093/annonc/mdy539.
• Background Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012 Oct 12;338(6104):221. doi: 10.1126/science.1226344. Epub 2012 Aug 23.
• Background Ree AH, Nygaard V, Russnes HG, Heinrich D, Nygaard V, Johansen C, Bergheim IR, Hovig E, Beiske K, Negard A, Borresen-Dale AL, Flatmark K, Maelandsmo GM. Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain. Cancer Immunol Res. 2019 May;7(5):701-706. doi: 10.1158/2326-6066.CIR-18-0777. Epub 2019 Feb 25.
• Background Von Hoff DD, Stephenson JJ Jr, Rosen P, Loesch DM, Borad MJ, Anthony S, Jameson G, Brown S, Cantafio N, Richards DA, Fitch TR, Wasserman E, Fernandez C, Green S, Sutherland W, Bittner M, Alarcon A, Mallery D, Penny R. Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers. J Clin Oncol. 2010 Nov 20;28(33):4877-83. doi: 10.1200/JCO.2009.26.5983. Epub 2010 Oct 4.
• Background Tyner JW, Tognon CE, Bottomly D, Wilmot B, Kurtz SE, Savage SL, Long N, Schultz AR, Traer E, Abel M, Agarwal A, Blucher A, Borate U, Bryant J, Burke R, Carlos A, Carpenter R, Carroll J, Chang BH, Coblentz C, d'Almeida A, Cook R, Danilov A, Dao KT, Degnin M, Devine D, Dibb J, Edwards DK 5th, Eide CA, English I, Glover J, Henson R, Ho H, Jemal A, Johnson K, Johnson R, Junio B, Kaempf A, Leonard J, Lin C, Liu SQ, Lo P, Loriaux MM, Luty S, Macey T, MacManiman J, Martinez J, Mori M, Nelson D, Nichols C, Peters J, Ramsdill J, Rofelty A, Schuff R, Searles R, Segerdell E, Smith RL, Spurgeon SE, Sweeney T, Thapa A, Visser C, Wagner J, Watanabe-Smith K, Werth K, Wolf J, White L, Yates A, Zhang H, Cogle CR, Collins RH, Connolly DC, Deininger MW, Drusbosky L, Hourigan CS, Jordan CT, Kropf P, Lin TL, Martinez ME, Medeiros BC, Pallapati RR, Pollyea DA, Swords RT, Watts JM, Weir SJ, Wiest DL, Winters RM, McWeeney SK, Druker BJ. Functional genomic landscape of acute myeloid leukaemia. Nature. 2018 Oct;562(7728):526-531. doi: 10.1038/s41586-018-0623-z. Epub 2018 Oct 17.
• Background Haferlach T, Nagata Y, Grossmann V, Okuno Y, Bacher U, Nagae G, Schnittger S, Sanada M, Kon A, Alpermann T, Yoshida K, Roller A, Nadarajah N, Shiraishi Y, Shiozawa Y, Chiba K, Tanaka H, Koeffler HP, Klein HU, Dugas M, Aburatani H, Kohlmann A, Miyano S, Haferlach C, Kern W, Ogawa S. Landscape of genetic lesions in 944 patients with myelodysplastic syndromes. Leukemia. 2014 Feb;28(2):241-7. doi: 10.1038/leu.2013.336. Epub 2013 Nov 13.
• Background Stone RM, Mandrekar SJ, Sanford BL, Laumann K, Geyer S, Bloomfield CD, Thiede C, Prior TW, Dohner K, Marcucci G, Lo-Coco F, Klisovic RB, Wei A, Sierra J, Sanz MA, Brandwein JM, de Witte T, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Krauter J, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Larson RA, Dohner H. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017 Aug 3;377(5):454-464. doi: 10.1056/NEJMoa1614359. Epub 2017 Jun 23.
• Background Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, Levis MJ. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3-ITD-mutated, relapsed or refractory AML. Blood. 2018 Aug 9;132(6):598-607. doi: 10.1182/blood-2018-01-821629. Epub 2018 Jun 6.
• Background Stein EM, DiNardo CD, Fathi AT, Pollyea DA, Stone RM, Altman JK, Roboz GJ, Patel MR, Collins R, Flinn IW, Sekeres MA, Stein AS, Kantarjian HM, Levine RL, Vyas P, MacBeth KJ, Tosolini A, VanOostendorp J, Xu Q, Gupta I, Lila T, Risueno A, Yen KE, Wu B, Attar EC, Tallman MS, de Botton S. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019 Feb 14;133(7):676-687. doi: 10.1182/blood-2018-08-869008. Epub 2018 Dec 3.
• Background Cerrano M, Itzykson R. New Treatment Options for Acute Myeloid Leukemia in 2019. Curr Oncol Rep. 2019 Feb 4;21(2):16. doi: 10.1007/s11912-019-0764-8.
• Background Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon B, Lee YS, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016 Nov 24;375(21):2023-2036. doi: 10.1056/NEJMoa1605949.
• Background Lambert J, Pautas C, Terre C, Raffoux E, Turlure P, Caillot D, Legrand O, Thomas X, Gardin C, Gogat-Marchant K, Rubin SD, Benner RJ, Bousset P, Preudhomme C, Chevret S, Dombret H, Castaigne S. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019 Jan;104(1):113-119. doi: 10.3324/haematol.2018.188888. Epub 2018 Aug 3.
• Background Cortizas EM, Zahn A, Safavi S, Reed JA, Vega F, Di Noia JM, Verdun RE. UNG protects B cells from AID-induced telomere loss. J Exp Med. 2016 Oct 17;213(11):2459-2472. doi: 10.1084/jem.20160635. Epub 2016 Oct 3.
• Background Fountzilas E, Tsimberidou AM. Overview of precision oncology trials: challenges and opportunities. Expert Rev Clin Pharmacol. 2018 Aug;11(8):797-804. doi: 10.1080/17512433.2018.1504677. Epub 2018 Aug 10.
• Background Le Tourneau C, Delord JP, Goncalves A, Gavoille C, Dubot C, Isambert N, Campone M, Tredan O, Massiani MA, Mauborgne C, Armanet S, Servant N, Bieche I, Bernard V, Gentien D, Jezequel P, Attignon V, Boyault S, Vincent-Salomon A, Servois V, Sablin MP, Kamal M, Paoletti X; SHIVA investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015 Oct;16(13):1324-34. doi: 10.1016/S1470-2045(15)00188-6. Epub 2015 Sep 3.
• Background DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, Letai A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019 Jan 3;133(1):7-17. doi: 10.1182/blood-2018-08-868752. Epub 2018 Oct 25.
• Background Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, Panayiotidis P. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020 Jun 11;135(24):2137-2145. doi: 10.1182/blood.2020004856.
• Background DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei AH, Konopleva M, Dohner H, Letai A, Fenaux P, Koller E, Havelange V, Leber B, Esteve J, Wang J, Pejsa V, Hajek R, Porkka K, Illes A, Lavie D, Lemoli RM, Yamamoto K, Yoon SS, Jang JH, Yeh SP, Turgut M, Hong WJ, Zhou Y, Potluri J, Pratz KW. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971.
• Background Burd A. Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 studies. Annual meeting of the American Society of Hematology. San Diego; 2018
• Background Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Lowenberg B, Bloomfield CD. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017 Jan 26;129(4):424-447. doi: 10.1182/blood-2016-08-733196. Epub 2016 Nov 28.
• Background Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006 Jul 15;108(2):419-25. doi: 10.1182/blood-2005-10-4149. Epub 2006 Apr 11.
• Background Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. Blood. 2016 Jul 21;128(3):462-463. doi: 10.1182/blood-2016-06-721662. No abstract available.
• Background Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, Tsimberidou AM, Vnencak-Jones CL, Wolff DJ, Younes A, Nikiforova MN. Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer: A Joint Consensus Recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn. 2017 Jan;19(1):4-23. doi: 10.1016/j.jmoldx.2016.10.002.

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Indications