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. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main AML page for current regimens.


First-line induction therapy, older or "unfit" patients

Best supportive care

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Löwenberg et al. 1989 1983-1986 Phase III (C) Cytarabine, Daunorubicin, Vincristine Seems to have inferior OS
Harousseau et al. 2009 (FIGHT-AML-301) 2004-2007 Phase III (C) Tipifarnib Did not meet primary endpoint of OS
Amadori et al. 2016 (EORTC/GIMEMA AML-19) 2004-2013 Phase III (C) Gemtuzumab ozogamicin Inferior OS
Kantarjian et al. 2012 (DACO-016) 2006-2009 Phase III (C) Decitabine Might have inferior OS
Dombret et al. 2015 (AZA-AML-001) 2010-2014 Phase III (C) Azacitidine Might have inferior OS

No active antineoplastic treatment, although some trials consider Hydroxyurea (Hydrea) to be a component of best supportive care.

References

  1. 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 PubMed
  2. 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 PubMed
  3. 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 contains verified protocol link to PMC article PubMed
    1. 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 PubMed
  4. 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 contains verified protocol link to PMC article PubMed
    1. 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 PubMed
  5. 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 PubMed

Maintenance after first-line therapy

Observation

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Sauter et al. 1984 1977-1982 Phase III (C) Maintenance chemotherapy Did not meet primary endpoint of OS
Robles et al. 2000 (ECOG E5483) 1984-1988 Phase III (C) LoDAC Might have inferior DFS
Breems et al. 2005 (HOVON/SAKK AML4) 1987-1995 Phase III (C) Auto HSCT Did not meet efficacy endpoints of DFS/OS
Brune et al. 2006 1998-2000 Phase III (C) HDC/IL-2 Inferior DFS
Baer et al. 2002 (CALGB 9720) 1998-NR Phase III (C) Low-dose IL-2 Did not meet primary endpoint of CR rate (*)
Löwenberg et al. 2009 (HOVON 43 AML/SAKK 30/01) 2000-2006 Phase III (C) Gemtuzumab ozogamicin Did not meet primary endpoint of EFS (*)
Kolitz et al. 2013 (CALGB 19808) 2000-2006 Phase III (C) Low-dose IL-2 Did not meet primary endpoint of DFS
Petersdorf et al. 2013 (SWOG S0106) 2004-2009 Phase III (C) Gemtuzumab ozogamicin Did not meet primary endpoint of DFS
Huls et al. 2019 (HOVON97) 2009-2016 Phase III (C) Azacitidine Seems to have inferior DFS

No further antineoplastic treatment. Reported efficacy for CALGB 9720 is based on the 2008 update. Reported efficacy for HOVON 43 AML/SAKK 30/01 is based on the 2010 update.

Preceding treatment

References

  1. 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 PubMed
  2. 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 contains protocol PubMed
  3. 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 PubMed
  4. 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 PubMed
  5. 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 contains protocol PubMed
    1. 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 PubMed
  6. 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 contains verified protocol PubMed
    1. 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 PubMed
  7. 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 PubMed
  8. CALGB 19808: 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 PubMed
  9. 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 contains protocol PubMed NTR1810