Abstract
It remains unclear in adult acute myeloid leukaemia (AML) whether leukaemic expression of CD33, the target antigen for gemtuzumab ozogamicin (GO), adds prognostic information on GO effectiveness at different doses. CD33 expression quantified in 1583 patients recruited to UK-NCRI-AML17 (younger adults) and UK-NCRI-AML16 (older adults) trials was correlated with clinical outcomes and benefit from GO including a dose randomisation. CD33 expression associated with genetic subgroups, including lower levels in both adverse karyotype and core-binding factor (CBF)-AML, but was not independently prognostic. When comparing GO versus no GO (n=393, CBF-AMLs excluded) by stratified subgroup-adjusted analysis, patients with lowest quartile (Q1) %CD33-positivity had no benefit from GO (relapse risk, HR 2.41 (1.27–4.56), P=0.009 for trend; overall survival, HR 1.52 (0.92–2.52)). However, from the dose randomisation (NCRI-AML17, n=464, CBF-AMLs included), 6 mg/m2 GO only had a relapse benefit without increased early mortality in CD33-low (Q1) patients (relapse risk HR 0.64 (0.36–1.12) versus 1.70 (0.99–2.92) for CD33-high, P=0.007 for trend). Thus CD33 expression is a predictive factor for GO effect in adult AML; although GO does not appear to benefit the non-CBF AML patients with lowest CD33 expression a higher GO dose may be more effective for CD33-low but not CD33-high younger adults.
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References
Rashidi A, Walter RB . Antigen-specific immunotherapy for acute myeloid leukemia. Expert Rev Hematol 2016; 9: 335–350.
Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 2011; 29: 369–377.
Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol 2012; 30: 3924–3931.
Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 2013; 121: 4854–4860.
Delaunay J, Recher C, Pigneux A, Witz F, Vey N, Blanchet O et al. Addition of gemtuzumab ozogamycin to chemotherapy improves event-free survival but not overall survival of AML patients with intermediate cytogenetics not eligible for allogeneic transplantation: results of the GOELAMS AML 2006 IR study. Blood (ASH annual meeting abstracts) 2011; 118, abstr 79.
Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN 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.
Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf SH, Othus M et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 2014; 15: 986–996.
Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol 2014; 32: 3021–3032.
Pollard JA, Loken M, Gerbing RB, Raimondi SC, Hirsch BA, Aplenc R et al. CD33 expression and its association with gemtuzumab ozogamicin response: results from the randomized phase III Children’s Oncology Group Trial AAML0531. J Clin Oncol 2016; 34: 747–755.
Olombel G, Guerin E, Guy J, Perrot JY, Dumezy F, de Labarthe A et al. Impact of blast CD33 expression on the effect of gemtuzumab ozogamicin (GO) in adult acute myeloid leukemia (AML): an ALFA-0701 study. Blood 2016; 127: 2157–2160.
Pollard J, Alonzo TA, Loken M, Gerbing RB, Ho PA, Bernstein ID et al. Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML. Blood 2012; 119: 3705–3711.
Ehninger A, Kramer M, Röllig C, Thiede C, Bornhauser M, von Bonin M et al. Distribution and levels of cell surface expression of CD33 and CD123 in acute myeloid leukemia. Blood Cancer J 2014; 4: e218.
Burnett AK, Russell NH, Hills RK, Kell J, Cavenagh J, Kjeldsen L et al. A randomized comparison of daunorubicin 90mg/m2 vs 60mg/m2 in AML induction: results from the UK NCRI AML 17 trial in 1206 patients. Blood 2015; 125: 3878–3885.
Freeman SD, Virgo P, Couzens S, Grimwade D, Russell N, Hills RK et al. Prognostic relevance of treatment response measured by flow cytometric residual disease detection in older patients with acute myeloid leukemia. J Clin Oncol 2013; 31: 4123–4131.
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003; 21: 4642–4649.
Walter RB, Raden BW, Kamikura DM, Cooper JA, Bernstein ID . Influence of CD33 expression levels and ITIM-dependent internalization on gemtuzumab ozogamicin-induced cytotoxicity. Blood 2005; 105: 1295–1302.
Walter RB, Gooley TA, van der Velden VH, Loken MR, van Dongen JJ, Flowers DA et al. CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood 2007; 109: 4168–4170.
Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso M et al. 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; 34: 972–979.
Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 2010; 28: 275–280.
van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res 2005; 11: 6520–6527.
Walter RB, Appelbaum FR, Estey EH, Berstein ID . Acute myeloid leukemia stem cells and CD33-targeted immunotherapy. Blood 2012; 119: 6198–6208.
Jawad M, Seedhouse C, Mony U, Grundy M, Russell N, Pallis M . Analysis of factors that affect in vitro chemosensitivity of leukemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia. Leukemia 2010; 24: 74–80.
Burnett AK, Cavenagh J, Russell NH, Hills R, Kell J, Jones G et alon behalf of the UK NCRI AML Study Group. Defining the dose gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukaemia: a comparison of 3mg/m2 with 6mg/m2 in the NCRI AML17 Trial. Haematologica 2016; 101: 724–731.
Paubelle E, Marceau A, Zylbersztejn F, Dussiot M, Moura IC, Cornillet-Lefebvre P et al. HFE gene mutation status predicts response to gemtuzumab ozogamicin in AML. Blood (ASH annual meeting abstracts) 2015; 126, abstr 1307.
Stein EM, Tallman MS . Emerging therapeutic drugs for AML. Blood 2016; 127: 71–78.
Kung Sutherland MS, Walter RB, Jeffrey SC, Burke PJ, Yu C, Kostner H et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 2013; 122: 1455–1463.
Acknowledgements
We are grateful to NIHR and Cancer Research UK for research funding for this trial, to Pfizer Japan for supplying Gemtuzumab Ozogamicin at a discounted price, to the staff of the Haematology Trials Office and Cardiff Experimental Cancer Medicine Centre for supporting the trial and to our co-investigators and research nurses who provided diagnostic samples from the NCRI AML Trial centres (listed in Supplementary Appendix).
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AKB has served on advisory boards for Wyeth/Pfizer during the study. The remaining authors declare no conflict of interest.
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Presented in part as an oral abstract at the 2015 Annual Meeting of the American Society of Hematology, Orlando, Fl, December 5–8, 2015.
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Khan, N., Hills, R., Virgo, P. et al. Expression of CD33 is a predictive factor for effect of gemtuzumab ozogamicin at different doses in adult acute myeloid leukaemia. Leukemia 31, 1059–1068 (2017). https://doi.org/10.1038/leu.2016.309
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DOI: https://doi.org/10.1038/leu.2016.309
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