Acute myeloid leukemia - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main AML page for regimens that include active anticancer treatment.
=First-line induction therapy, older or "unfit" patients=
==Best supportive care==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Löwenberg et al. 1989 	1983-1986 	Phase 3 (C)	Cytarabine, Daunorubicin, Vincristine	Seems to have shorter OS
Fenaux et al. 2009 (AZA PH GL 2003) 	2003-2007 	Phase 3 (C)	Azacitidine 	Shorter OS (primary endpoint)Median OS: 16 vs 24.5 mo(HR 2.13, 95% CI 1.27-3.57)
Harousseau et al. 2009 (FIGHT-AML-301) 	2004-2007 	Phase 3 (C)	Tipifarnib 	Did not meet primary endpoint of OSMedian OS: 109 vs 107 days(HR 0.98, 95% CI 0.81-1.19)
Amadori et al. 2016 (EORTC/GIMEMA AML-19)	2004-2013 	Phase 3 (C)	Gemtuzumab ozogamicin 	Shorter OS (primary endpoint)Median OS: 3.6 vs 4.9 mo(HR 1.45, 95% CI 1.11-1.89)
Kantarjian et al. 2012 (DACO-016) 	2006-2009 	Phase 3 (C)	Decitabine 	Might have shorter OS (primary endpoint)Median OS: 5 vs 7.7 mo(HR 1.18, 95% CI 0.96-1.45)
Dombret et al. 2015 (AZA-AML-001) 	2010-2014 	Phase 3 (C)	Azacitidine 	Might have shorter OS (primary endpoint)Median OS: 6.5 vs 10.4 mo(HR 1.18, 95% CI 0.97-1.45)
No active antineoplastic treatment, although some trials consider Hydroxyurea (Hydrea) to be a component of best supportive care.
===References===
#Löwenberg B, Zittoun R, Kerkhofs H, Jehn U, Abels J, Debusscher L, Cauchie C, Peetermans M, Solbu G, Suciu S, Stryckmans P; EORTC Leukemia Group. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989 Sep;7(9):1268-74. link to original article EuroPMC
#FIGHT-AML-301: Harousseau JL, Martinelli G, Jedrzejczak WW, Brandwein JM, Bordessoule D, Masszi T, Ossenkoppele GJ, Alexeeva JA, Beutel G, Maertens J, Vidriales MB, Dombret H, Thomas X, Burnett AK, Robak T, Khuageva NK, Golenkov AK, Tothova E, Mollgard L, Park YC, Bessems A, De Porre P, Howes AJ; FIGHT-AML-301 Investigators. A randomized phase 3 study of tipifarnib compared with best supportive care, including hydroxyurea, in the treatment of newly diagnosed acute myeloid leukemia in patients 70 years or older. Blood. 2009 Aug 6;114(6):1166-73. Epub 2009 May 21. link to original article EuroPMC NCT00093990
#AZA PH GL 2003: Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):562-9. Epub 2009 Dec 21. link to original article EuroPMC NCT00071799
#DACO-016: Kantarjian HM, Thomas XG, Dmoszyńska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012 Jul 20;30(21):2670-7. Epub 2012 Jun 11. link to original article link to PMC article EuroPMC NCT00260832
##Subgroup analysis: Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: A subgroup analysis of the DACO-016 trial. Am J Hematol. 2018 May;93(5):E125-E127. Epub 2018 Feb 24. link to original article EuroPMC
#AZA-AML-001: Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher 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, Döhner 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. Epub 2015 May 18. link to original article link to PMC article EuroPMC NCT01074047
##Subgroup analysis: Seymour JF, Döhner H, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Del Castillo TB, Al-Ali HK, Falantes J, Stone RM, Minden MD, Weaver J, Songer S, Beach CL, Dombret H. Azacitidine improves clinical outcomes in older patients with acute myeloid leukaemia with myelodysplasia-related changes compared with conventional care regimens. BMC Cancer. 2017 Dec 14;17(1):852. link to original article link to PMC article EuroPMC
##HRQoL analysis: Roboz GJ, Döhner H, Pocock C, Dombret H, Ravandi F, Jang JH, Selleslag D, Mayer J, Martens UM, Liesveld J, Bernal T, Wang MC, Yu P, Shi L, Guo S, La Torre I, Skikne B, Dong Q, Braverman J, Nehme SA, Beach CL, Wei AH. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Dec 1;106(12):3240-3244. Epub 2021 Sep 23. link to original article link to PMC article EuroPMC
#EORTC/GIMEMA AML-19: Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M, Annino L, Venditti A, Voso MT, Mazzone C, Magro D, De Fabritiis P, Muus P, Alimena G, Mancini M, Hagemeijer A, Paoloni F, Vignetti M, Fazi P, Meert L, Ramadan SM, Willemze R, de Witte T, Baron F; EORTC; GIMEMA. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016 Mar 20;34(9):972-9. Epub 2016 Jan 25. link to original article EuroPMC NCT00091234
=Maintenance after first-line therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Sauter et al. 1984 	1977-1982 	Phase 3 (C)	Maintenance chemotherapy	Did not meet primary endpoint of OS
Robles et al. 2000 (ECOG E5483) 	1984-1988 	Phase 3 (C)	LoDAC 	Might have shorter DFS
Breems et al. 2005 (HOVON/SAKK AML4) 	1987-1995 	Phase 3 (C)	Auto HSCT 	Did not meet efficacy endpoints of DFS/OS
Brune et al. 2006 	1998-2000 	Phase 3 (C)	HDC/IL-2 	Shorter DFS
Baer et al. 2002 (CALGB 9720) 	1998-03 to not reported	Phase 3 (C)	Low-dose IL-2 	Did not meet primary endpoint of CR rate1
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01)	2000-2006 	Phase 3 (C)	Gemtuzumab ozogamicin 	Did not meet primary endpoint of DFS2DFS60: 16% vs 17%(HR not reported)
Kolitz et al. 2010 (CALGB 19808) 	2001-2003 	Phase 3 (C)	Low-dose IL-2 	Did not meet primary endpoint of DFS3DFS60: 42% vs 53%(HR 1.33, 95% CI 0.92-1.92)
Petersdorf et al. 2013 (SWOG S0106) 	2004-2009 	Phase 3 (C)	Gemtuzumab ozogamicin 	Might have longer postconsolidation DFS (co-primary endpoint)Median postconsolidaton DFS: NYR vs 14 mo(HR 0.68, 95% CI 0.45-1.01)
Luger et al. 2021 (ECOG E2902) 	2004-2009 	Phase 3 (C)	Tipifarnib 	Might have shorter DFS (primary endpoint)Median DFS: 5.3 vs 8.9 mo(HR 1.43, 95% CI 1.00-2.04)
Hasle et al. 2012 (NOPHO-AML 2004) 	2004-2010 	Phase 3 (C)	Gemtuzumab ozogamicin 	Did not meet primary endpoint of relapse rate
Huls et al. 2019 (HOVON97) 	2009-2016 	Phase 3 (C)	Azacitidine 	Shorter DFS (primary endpoint)DFS12: 42% vs 64%(aHR 1.61, 95% CI 1.05-2.44)
Wei et al. 2020 (QUAZAR AML-001) 	2013-2017 	Phase 3 (C)	Oral azacitidine 	Shorter OS (primary endpoint)Median OS: 14.8 vs 24.7 mo(HR not reported4, p<0.001)
1Reported efficacy for CALGB 9720 is based on the 2008 update.
2Reported efficacy for HOVON 43 AML/SAKK 30/01 is based on the 2010 update.
3Reported efficacy for CALGB 19808 is based on the 2013 update.
4The proportional hazards assumption was violated, so hazard ratios were not reported.
No further antineoplastic treatment.
====Preceding treatment====
*ECOG E5483: HiDAC, then amsacrine induction
*CALGB 9720 & CALGB 19808: ADE versus ADEP induction
*HOVON 43 AML/SAKK 30/01: IDAC consolidation x 1
*SWOG S0106: HiDAC consolidation x 3
*HOVON97: Intensive chemotherapy induction x 2
===References===
#Sauter C, Berchtold W, Fopp M, Gratwohl A, Imbach P, Maurice P, Tschopp L, von Fliedner V, Cavalli F; SAKK. Acute myelogenous leukaemia: maintenance chemotherapy after early consolidation treatment does not prolong survival. Lancet. 1984 Feb 18;1(8373):379-82. link to original article EuroPMC
#ECOG E5483: Robles C, Kim KM, Oken MM, Bennett JM, Letendre L, Wiernik PH, O'Connell MJ, Cassileth PA. Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia. 2000 Aug;14(8):1349-53. link to original article EuroPMC
#HOVON/SAKK AML4: Breems DA, Boogaerts MA, Dekker AW, Van Putten WL, Sonneveld P, Huijgens PC, Van der Lelie J, Vellenga E, Gratwohl A, Verhoef GE, Verdonck LF, Löwenberg B; HOVON; SAKK. Autologous bone marrow transplantation as consolidation therapy in the treatment of adult patients under 60 years with acute myeloid leukaemia in first complete remission: a prospective randomized Dutch-Belgian Haemato-Oncology Co-operative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK) trial. Br J Haematol. 2005 Jan;128(1):59-65. link to original article EuroPMC
#Brune M, Castaigne S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, Hogge DE, Nilsson B, Or R, Romero AI, Rowe JM, Simonsson B, Spearing R, Stadtmauer EA, Szer J, Wallhult E, Hellstrand K. Improved leukemia-free survival after postconsolidation immunotherapy with histamine dihydrochloride and interleukin-2 in acute myeloid leukemia: results of a randomized phase 3 trial. Blood. 2006 Jul 1;108(1):88-96. Epub 2006 Mar 23. link to original article EuroPMC
#CALGB 9720: Baer MR, George SL, Dodge RK, O'Loughlin KL, Minderman H, Caligiuri MA, Anastasi J, Powell BL, Kolitz JE, Schiffer CA, Bloomfield CD, Larson RA. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood. 2002 Aug 15;100(4):1224-32. link to original article EuroPMC NCT00003190
##Update: Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, Kolitz JE, Powell BL, Moore JO, Stone RM, Anastasi J, Bloomfield CD, Larson RA. Low-dose interleukin-2 immunotherapy does not improve outcome of patients age 60 years and older with acute myeloid leukemia in first complete remission: Cancer and Leukemia Group B Study 9720. J Clin Oncol. 2008 Oct 20;26(30):4934-9. Epub 2008 Jun 30. link to original article link to PMC article EuroPMC
#HOVON 43 AML/SAKK 30/01: Löwenberg 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, Döhner H, Gratwohl A, Pabst T, Verhoef G; HOVON; AMLSG; SAKK. High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med. 2009 Sep 24;361(13):1235-48. Erratum in: N Engl J Med. 2010 Mar 25;362(12):1155. Dosage error in published abstract; MEDLINE/PubMed abstract corrected; Dosage error in article text. link to original article EuroPMC ISRCTN77039377
##Update: Löwenberg B, Beck J, Graux C, van Putten W, Schouten HC, Verdonck LF, Ferrant A, Sonneveld P, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, Breems D, de Muijnck H, Schaafsma R, Verhoef G, Döhner H, Gratwohl A, Pabst T, Ossenkoppele GJ, Maertens J; HOVON; AML; SAKK. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood. 2010 Apr 1;115(13):2586-91. Epub 2010 Jan 26. link to original article EuroPMC
#NOPHO-AML 2004: Hasle H, Abrahamsson J, Forestier E, Ha SY, Heldrup J, Jahnukainen K, Jónsson ÓG, Lausen B, Palle J, Zeller B; Nordic Society of Paediatric Haematology and Oncology (NOPHO). Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004. Blood. 2012 Aug 2;120(5):978-84. Epub 2012 Jun 22. link to original article EuroPMC NCT00476541
#SWOG S0106: Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 2013 Jun 13;121(24):4854-60. Epub 2013 Apr 16. link to original article link to PMC article EuroPMC NCT00085709
#CALGB 19808: Kolitz JE, George SL, Marcucci G, Vij R, Powell BL, Allen SL, DeAngelo DJ, Shea TC, Stock W, Baer MR, Hars V, Maharry K, Hoke E, Vardiman JW, Bloomfield CD, Larson RA; Cancer and Leukemia Group B. P-glycoprotein inhibition using valspodar (PSC-833) does not improve outcomes for patients younger than age 60 years with newly diagnosed acute myeloid leukemia: Cancer and Leukemia Group B study 19808. Blood. 2010 Sep 2;116(9):1413-21. Epub 2010 Jun 3. link to original article link to PMC article EuroPMC NCT00006363
##Update: Kolitz JE, George SL, Benson DM Jr, Maharry K, Marcucci G, Vij R, Powell BL, Allen SL, Deangelo DJ, Shea TC, Stock W, Bakan CE, Hars V, Hoke E, Bloomfield CD, Caligiuri MA, Larson RA; Alliance for Clinical Trials in Oncology. Recombinant interleukin-2 in patients aged younger than 60 years with acute myeloid leukemia in first complete remission: results from Cancer and Leukemia Group B 19808. Cancer. 2014 Apr 1;120(7):1010-7. Epub 2013 Dec 31. link to original article link to PMC article EuroPMC
# HOVON97: Huls G, Chitu DA, Havelange V, Jongen-Lavrencic M, van de Loosdrecht AA, Biemond BJ, Sinnige H, Hodossy B, Graux C, Kooy RVM, de Weerdt O, Breems D, Klein S, Kuball J, Deeren D, Terpstra W, Vekemans MC, Ossenkoppele GJ, Vellenga E, Löwenberg B; Dutch-Belgian Hemato-Oncology Cooperative Group. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood. 2019 Mar 28;133(13):1457-1464. Epub 2019 Jan 10. link to original article EuroPMC NTR1810
#QUAZAR AML-001: Wei AH, Döhner H, Pocock C, Montesinos P, Afanasyev B, Dombret H, Ravandi F, Sayar H, Jang JH, Porkka K, Selleslag D, Sandhu I, Turgut M, Giai V, Ofran Y, Kizil Çakar M, Botelho de Sousa A, Rybka J, Frairia C, Borin L, Beltrami G, Čermák J, Ossenkoppele GJ, La Torre I, Skikne B, Kumar K, Dong Q, Beach CL, Roboz GJ; QUAZAR AML-001 Trial Investigators. Oral Azacitidine Maintenance Therapy for Acute Myeloid Leukemia in First Remission. N Engl J Med. 2020 Dec 24;383(26):2526-2537. link to original article EuroPMC NCT01757535
##Update: Wei AH, Döhner H, Sayar H, Ravandi F, Montesinos P, Dombret H, Selleslag D, Porkka K, Jang JH, Skikne B, Beach CL, Prebet T, Zhang G, Risueño A, Ugidos M, See WL, Menezes D, Roboz GJ. Long-term survival with oral azacitidine for patients with acute myeloid leukemia in first remission after chemotherapy: Updated results from the randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial. Am J Hematol. 2023 Apr;98(4):E84-E87. Epub 2023 Feb 6. link to original article EuroPMC
#ECOG E2902: Luger SM, Wang VX, Rowe JM, Litzow MR, Paietta E, Ketterling RP, Lazarus H, Rybka WB, Craig MD, Karp J, Cooper BW, Makary AZ, Kaminer LS, Appelbaum FR, Larson RA, Tallman MS. Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial. Leuk Res. 2021 Dec;111:106736. Epub 2021 Oct 28. link to original article link to PMC article EuroPMC NCT00093470
#VIALE-M: NCT04102020
=Maintenance after allogeneic HSCT=
==Best supportive care==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Oran et al. 2020 (VZ-AML-PI-0129)	2009-2017 	Phase 3 (C)	Azacitidine 	Did not meet primary endpoint of RFSMedian RFS: 1.28 vs 2.07 years(aHR 1.37, 95% CI 0.91-2.04)
Awaiting publication (VIALE-T) 	2020-ongoing 	Phase 3 (C)	Azacitidine & Venetoclax	TBD if different primary endpoint of OS
No further antineoplastic treatment.
====Preceding treatment====
*Allogeneic HSCT consolidation
===References===
#VZ-AML-PI-0129: Oran B, de Lima M, Garcia-Manero G, Thall PF, Lin R, Popat U, Alousi AM, Hosing C, Giralt S, Rondon G, Woodworth G, Champlin RE. A phase 3 randomized study of 5-azacitidine maintenance vs observation after transplant in high-risk AML and MDS patients. Blood Adv. 2020 Nov 10;4(21):5580-5588. link to original article link to PMC article EuroPMC NCT00887068
#VIALE-T: NCT04161885
Category:Acute myeloid leukemia regimens
Category:Disease-specific pages
Category:Acute leukemias
Category:Null regimens