Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013)
[en] The primary objective of this trial was to assess the feasibility, toxicity profile, and antitumor activity of gemtuzumab ozogamicin (GO) combined with a chemotherapy remission-induction regimen in adults with untreated high-risk myelodysplastic syndrome (HR-MDS) or secondary acute myeloid leukemia (sAML). In this phase II trial, 30 patients with median age of 58 years received 1 day of GO as a 1-h infusion at the dose level of 5 mg/m² on day 7 of the remission-induction course further consisting of a continuous infusion of cytarabine 100 mg/m²/day for 10 days and idarubicin 12 mg/m²/day on days 1, 3, and 5. A consolidation course, consisting of intermediate-dose cytarabine (A) and idarubicin (I) followed by hematopoietic stem cell transplantation (HSCT) was planned for patients in complete remission (CR). The primary endpoints were response rate (CR/CRi) and severe toxicity rate. The secondary endpoint(s) were survival and progression-free survival (PFS) from start of treatment. Thirteen patients (43 %) achieved CR (eight patients) or CR with incomplete hematopoietic recovery (CRi) (five patients). In patients who achieved CR or CRi, the median timeto recovery of neutrophils to 0.5x109/1 and of platelets to >50x109/1 was 29 and 30 days, respectively. Grade 3 to 4 severe toxicities occurred in nine patients. The most prominent was liver toxicity, as shown by elevated bilirubin levels in 16 patients and one case of nonfatal veno-occlusive disease (VOD). All 13 patients with CR/CRi received consolidation therapy, which was followed by allogeneic HSCT in five patients and autologous HSCT in three patients. According to the statistical design of the study, the idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) regimen did not show sufficient activity to warrant further exploration of this regimen in adult patients with HR-MDS or sAML.
Disciplines :
Hematology
Author, co-author :
DE WITTE, Theo
SUCIU, Stefan
MEERT, Liv
HALKES, Constantijn
SELLESLAG, Dominik
BRON, Dominique
AMADORI, Sergio
WILLEMZE, Roel
MUUS, Petra
BARON, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > Hématologie clinique
Language :
English
Title :
Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013)
Stone RM (2009) How I, treat patients with myelodysplastic syndromes. Blood 113(25):6296–6303
Oosterveld M, Suciu S, Muus P, Germing U, Delforge M, Belhabri A et al (2015) Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies. Ann Hematol 94(1):23–34
Malcovati L, Hellstrom-Lindberg E, Bowen D, Ades L, Cermak J, Del Canizo C et al (2013) Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 122(17):2943–2964
Fenaux P, Morel P, Rose C, Lai JL, Jouet JP, Bauters F (1991) Prognostic factors in adult de novo myelodysplastic syndromes treated by intensive chemotherapy. Br J Haematol 77(4):497–501
Hast R, Hellstrom-Lindberg E, Ohm L, Bjorkholm M, Celsing F, Dahl IM et al (2003) No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease. Leuk Off J Leuk Soc Am Leuk Res Fund UK 17(9):1827–1833
Germing U, Hildebrandt B, Pfeilstocker M, Nosslinger T, Valent P, Fonatsch C et al (2005) Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS). Leuk Off J Leuk Soc Am Leuk Res Fund UK 19(12):2223–2231
Estey E, Thall P, Beran M, Kantarjian H, Pierce S, Keating M (1997) Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90(8):2969–2977
de Witte T, Muus P, De PB, Haanen C (1990) Intensive antileukemic treatment of patients younger than 65 years with myelodysplastic syndromes and secondary acute myelogenous leukemia. Cancer 66(5):831–837
de Witte T, Suciu S, Peetermans M, Fenaux P, Strijckmans P, Hayat M et al (1995) Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leuk Off J Leuk Soc Am Leuk Res Fund UK 9(11):1805–1811
Parker JE, Pagliuca A, Mijovic A, Cullis JO, Czepulkowski B, Rassam SM et al (1997) Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia. Br J Haematol 99(4):939–944
Burnett AK, Hills RK, Milligan DW, Goldstone AH, Prentice AG, McMullin MF et al (2010) Attempts to optimize induction and consolidation treatment in acute myeloid leukemia: results of the MRC AML12 trial. J Clin Oncol 28(4):586–595
Hofmann WK, Heil G, Zander C, Wiebe S, Ottmann OG, Bergmann L et al (2004) Intensive chemotherapy with idarubicin, cytarabine, etoposide, and G-CSF priming in patients with advanced myelodysplastic syndrome and high-risk acute myeloid leukemia. Ann Hematol 83(8):498–503
Lepelley P, Soenen V, Preudhomme C, Lai JL, Cosson A, Fenaux P (1994) Expression of the multidrug resistance P-glycoprotein and its relationship to hematological characteristics and response to treatment in myelodysplastic syndromes. Leuk Off J Leuk Soc Am Leuk Res Fund UK 8(6):998–1004
Sato H, Gottesman MM, Goldstein LJ, Pastan I, Block AM, Sandberg AA et al (1990) Expression of the multidrug resistance gene in myeloid leukemias. Leuk Res 14(1):11–21
Sonneveld P, van Dongen JJ, Hagemeijer A, van Kapel L, Nooter K, Schoester M et al (1993) High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype. Leuk Off J Leuk Soc Am Leuk Res Fund UK 7(7):963–969
Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM et al (1997) Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 89(9):3323–3329
de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G et al (2010) Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial. Haematologica 95(10):1754–1761
Hinman LM, Hamann PR, Wallace R, Menendez AT, Durr FE, Upeslacis J (1993) Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics. Cancer Res 53(14):3336–3342
Linenberger ML (2005) CD33-directed therapy with gemtuzumab ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance. Leuk Off J Leuk Soc Am Leuk Res Fund UK 19(2):176–182
Amadori S, Suciu S, Selleslag D, Stasi R, Alimena G, Baila L et al (2010) Randomized trial of two schedules of low-dose gemtuzumab ozogamicin as induction monotherapy for newly diagnosed acute myeloid leukaemia in older patients not considered candidates for intensive chemotherapy. A phase II study of the EORTC and GIMEMA leukaemia groups (AML-19). Br J Haematol 149(3):376–382
Amadori S, Suciu S, Willemze R, Mandelli F, Selleslag D, Stauder R et al (2004) Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups. Haematologica 89(8):950–956
Amadori S, Suciu S, Stasi R, Salih HR, Selleslag D, Muus P et al (2013) Sequential combination of gemtuzumab ozogamicin and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia: results of a randomized phase III trial by the EORTC and GIMEMA consortium (AML-17). J Clin Oncol Off J Am Soc Clin Oncol 31(35):4424–4430
Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret H et al (2001) Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol Off J Am Soc Clin Oncol 19(13):3244–3254
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108(2):419–425
Wattel E, Solary E, Hecquet B, Caillot D, Ifrah N, Brion A et al (1998) Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study. Br J Haematol 102(4):1015–1024
Ossenkoppele GJ, Graveland WJ, Sonneveld P, Daenen SM, Biesma DH, Verdonck LF et al (2004) The value of fludarabine in addition to ARA-C and G-CSF in the treatment of patients with high-risk myelodysplastic syndromes and AML in elderly patients. Blood 103(8):2908–2913
Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M et al (2014) 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 15(9):986–996
Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH et al (2011) Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol 29(4):369–377
Burnett AK, Russell NH, Hills RK, Kell J, Freeman S, Kjeldsen L et al (2012) Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol Off J Am Soc Clin Oncol 30(32):3924–3931
de Witte T, Suciu S, Verhoef G, Labar B, Archimbaud E, Aul C et al (2001) Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 98(8):2326–2331
van Der Velden VH, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS et al (2001) Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 97(10):3197–3204
Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN et al (2012) 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 379(9825):1508–1516