[en] Clofarabine (CLO) is a nucleoside analogue with efficacy in relapsed/refractory acute lymphoblastic leukemia (ALL). This randomized phase III study aimed to evaluate whether CLO added to induction and consolidation would improve outcome in adults with newly diagnosed ALL. Treatment for younger (18-40 years) patients consisted of a pediatric inspired protocol and for older patients (41-70 years) of a semi-intensive protocol was used. 340 patients were randomized. After a median follow up of 70 months, 5-year EFS was 50% and 53% for arm A and B (CLO arm). For patients ≤40 years, EFS was 58% vs 65% in arm A vs B, while in patients >40 years EFS was 43% in both arms. CR rate was 89% in both arms and similar in younger and older patients. Minimal residual disease (MRD) was assessed in 200 patients (60%). Fifty-four of 76 evaluable patients (71%) were MRD negative after consolidation 1 in arm A vs 75/81 (93%) in arm B (p=0.001). Seventy (42%) patients proceeded to allogeneic hematopoietic stem cell transplantation in both arms. Five years OS was similar in both arms, 60% vs 61%. Among patients achieving CR, relapse rates were 28% and 24%, and non-relapse mortality was 16% vs 17% after CR. CLO treated patients experienced more serious adverse events, more infections, and more often went off-protocol. This was most pronounced in older patients. We conclude that, despite a higher rate of MRD-negativity, addition of CLO does not improve outcome in adults with ALL, which might be due to increased toxicity. The trial is registered at www.trialregister.nl as NTR2004.
Disciplines :
Hematology
Author, co-author :
Rijneveld, Anita W.
van der Holt, Bronno
de Weerdt, Okke
Biemond, Bart J.
Van de Loosdrecht, Arjan A.
van der Wagen, Lotte E.
Bellido, Mar
van Gelder, Michel
van der Velden, Walter J. F. M.
Selleslag, Dominik
van Lammeren-Venema, Daniëlle
Halkes, Constantijn J. M.
Fijnheer, Rob
Havelange, Violaine
Sluis, Geerte Van
Legdeur, Marie-Cecile J. C.
Deeren, Dries H.
Gadisseur, Alain Pa
Sinnige, Harm A. M.
Breems, Dimitri
JASPERS, Aurélie ; Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service d'hématologie clinique
Bailey C, Richardson LC, Allemani C, et al; CONCORD Working Group (US members). Adult leukemia survival trends in the United States by subtype: a population-based registry study of 370,994 patients diagnosed during 1995-2009. Cancer. 2018;124(19):3856-3867.
Dinmohamed AG, Szabo’ A, van der Mark M, et al. Improved survival in adult patients with acute lymphoblastic leukemia in the Netherlands: a population-based study on treatment, trial participation and survival. Leukemia. 2016;30(2):310-317.
Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119(1):34-43.
Fielding AK, Richards SM, Chopra R, et al; Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109(3):944-950.
Gokbuget € N, Kneba M, Raff T, et al; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868-1876.
Berry DA, Zhou S, Higley H, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3(7):e170580.
Giebel S, Stella-Holowiecka B, Krawczyk-Kulis M, et al; Study Group for Adult ALL of the European Leukemia Net. Status of minimal residual disease determines outcome of autologous hematopoietic SCT in adult ALL. Bone Marrow Transplant. 2010;45(6):1095-1101.
Raff T, Gokbuget € N, Luschen € S, et al; GMALL Study Group. Molecular relapse in adult standard-risk ALL patients detected by prospective MRD monitoring during and after maintenance treatment: data from the GMALL 06/99 and 07/03 trials. Blood. 2007;109(3):910-915.
Spinelli O, Peruta B, Tosi M, et al. Clearance of minimal residual disease after allogeneic stem cell transplantation and the prediction of the clinical outcome of adult patients with high-risk acute lymphoblastic leukemia. Haematologica. 2007;92(5):612-618.
Bonate PL, Craig A, Gaynon P, et al. Population pharmacokinetics of clofarabine, a second-generation nucleoside analog, in pediatric patients with acute leukemia. J Clin Pharmacol. 2004;44(11):1309-1322.
Gandhi V, Plunkett W, Bonate PL, et al. Clinical and pharmacokinetic study of clofarabine in chronic lymphocytic leukemia: strategy for treatment. Clin Cancer Res. 2006;12(13):4011-4017.
Jeha S, Gandhi V, Chan KW, et al. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004; 103(3):784-789.
Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24(12):1917-1923.
Jeha S, Kantarjian H. Clofarabine for the treatment of acute lymphoblastic leukemia. Expert Rev Anticancer Ther. 2007;7(2):113-118.
Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102(7):2379-2386.
Locatelli F, Testi AM, Bernardo ME, et al. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009;147(3):371-378.
Advani AS, Gundacker HM, Sala-Torra O, et al. Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia. Br J Haematol. 2010;151(5):430-434.
Bassan R, Fumagalli M, Chiaretti S, et al. Phase II trial with sequential clofarabine and cyclophosphamide for refractory and relapsed philadelphianegative adult acute lymphoblastic leukemia. Results of the GIMEMA LAL 1610 protocol. Leuk Lymphoma. 2019;60(14):3482-3492.
Faderl S, Balakrishnan K, Thomas DA, et al. Phase I and extension study of clofarabine plus cyclophosphamide in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2014;14(3):231-238.
Huguet F, Leguay T, Raffoux E, et al. Clofarabine for the treatment of adult acute lymphoid leukemia: the Group for Research on Adult Acute Lymphoblastic Leukemia intergroup. Leuk Lymphoma. 2015;56(4):847-857.
Karp JE, Ricklis RM, Balakrishnan K, et al. A phase 1 clinical-laboratory study of clofarabine followed by cyclophosphamide for adults with refractory acute leukemias. Blood. 2007;110(6):1762-1769.
Zeidan AM, Ricklis RM, Carraway HE, et al. Phase 1 dose-escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias. Br J Haematol. 2012;158(2):198-207.
Grigoleit GU, Kapp M, Tan SM, et al. Clofarabine-based salvage chemotherapy for relapsed or refractory acute leukemia before allogeneic stem cell transplantation: results from a case series. Leuk Lymphoma. 2009;50(12):2071-2074.
Lowenberg € B, Pabst T, Maertens J, et al; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and Swiss Group for Clinical Cancer Research (SAKK). Therapeutic value of clofarabine in younger and middle-aged (18-65 years) adults with newly diagnosed AML. Blood. 2017; 129(12):1636-1645.
Daenen S, van der Holt B, Dekker AW, et al; Dutch-Belgian Cooperative Group for Hematological Oncology. Intensive chemotherapy to improve outcome in patients with acute lymphoblastic leukemia over the age of 40: a phase II study for efficacy and feasibility by HOVON. Leukemia. 2012; 26(7):1726-1729.
Rijneveld AW, van der Holt B, Daenen SM, et al; Dutch-Belgian HOVON Cooperative group. Intensified chemotherapy inspired by a pediatric regimen combined with allogeneic transplantation in adult patients with acute lymphoblastic leukemia up to the age of 40. Leukemia. 2011;25(11): 1697-1703.
Bruggemann € M, van der Velden VH, Raff T, et al. Rearranged T-cell receptor beta genes represent powerful targets for quantification of minimal residual disease in childhood and adult T-cell acute lymphoblastic leukemia. Leukemia. 2004;18(4):709-719.
Denys B, van der Sluijs-Gelling AJ, Homburg C, et al. Improved flow cytometric detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 2013;27(3):635-641.
van der Velden VH, van Dongen JJ. MRD detection in acute lymphoblastic leukemia patients using Ig/TCR gene rearrangements as targets for real-time quantitative PCR. Methods Mol Biol. 2009;538:115-150.
Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21(6):1167-1173.
Miano M, Pistorio A, Putti MC, et al. Clofarabine, cyclophosphamide and etoposide for the treatment of relapsed or resistant acute leukemia in pediatric patients. Leuk Lymphoma. 2012;53(9):1693-1698.
Barba P, Sampol A, Calbacho M, et al. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012;87(6):631-634.
Salzer WL, Burke MJ, Devidas M, et al. Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: A report from the Children’s Oncology Group study AALL1131 [published correction appears in Cancer. 2021;127(21):4106–4107]. Cancer. 2018;124(6):1150-1159.
Cave’ H, van der Werff ten Bosch J, Suciu S, et al; European Organization for Research and Treatment of Cancer–Childhood Leukemia Cooperative Group. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer–Childhood Leukemia Cooperative Group. N Engl J Med. 1998;339(9):591-598.
Nyvold C, Madsen HO, Ryder LP, et al; Nordic Society for Pediatric Hematology and Oncology. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood. 2002;99(4):1253-1258.
van Dongen JJ, Seriu T, Panzer-Grumayer € ER, et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. 1998;352(9142):1731-1738.
Willemse MJ, Seriu T, Hettinger K, et al. Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL. Blood. 2002;99(12):4386-4393.
Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet. 1998;351(9102):550-554.
Coustan-Smith E, Sancho J, Hancock ML, et al. Clinical importance of minimal residual disease in childhood acute lymphoblastic leukemia. Blood. 2000;96(8):2691-2696.
Akabane H, Logan A. Clinical significance and management of MRD in adults with acute lymphoblastic leukemia. Clin Adv Hematol Oncol. 2020; 18(7):413-422.
Bassan R, Bruggemann € M, Radcliffe HS, Hartfield E, Kreuzbauer G, Wetten S. A systematic literature review and meta-analysis of minimal residual disease as a prognostic indicator in adult B-cell acute lymphoblastic leukemia. Haematologica. 2019;104(10):2028-2039.
Bruggemann € M, Raff T, Flohr T, et al; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):1116-1123.
Yilmaz M, Kantarjian H, Wang X, et al. The early achievement of measurable residual disease negativity in the treatment of adults with Philadelphianegative B-cell acute lymphoblastic leukemia is a strong predictor for survival. Am J Hematol. 2020;95(2):144-150.
