Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503)

W Blum, B L Sanford, R Klisovic, D J DeAngelo, G Uy, B L Powell, W Stock, M R Baer, J E Kolitz, E S Wang, E Hoke, K Mrózek, J Kohlschmidt, C D Bloomfield, S Geyer, G Marcucci, R M Stone, R A Larson, Alliance for Clinical Trials in Oncology, W Blum, B L Sanford, R Klisovic, D J DeAngelo, G Uy, B L Powell, W Stock, M R Baer, J E Kolitz, E S Wang, E Hoke, K Mrózek, J Kohlschmidt, C D Bloomfield, S Geyer, G Marcucci, R M Stone, R A Larson, Alliance for Clinical Trials in Oncology

Abstract

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.

Conflict of interest statement

The authors declare no conflicts of interests.

Figures

Figure 1
Figure 1
Disease-free survival of patients with core-binding factor (CBF) AML (blue) or non-CBF AML (red) who received maintenance decitabine.

References

    1. Champlin R, Jacobs A, Gale RP, Boccia R, Elashoff R, Foon K, et al. Prolonged survival in acute myelogenous leukaemia without maintenance chemotherapy. Lancet. 1984;1:894–896.
    1. Raza A, Preisler HD, Browman GP, Larson RA, Rustum YM, Goldberg J, et al. Long-term outcome of patients with acute myelogenous leukemia: the role of maintenance therapy, consolidation therapy and the predictive value of two in vitro assays. Leuk Lymphoma. 1993;10:57–66.
    1. Sauter C, Berchtold W, Fopp M, Gratwohl A, Imbach P, Maurice P, et al. Acute myelogenous leukaemia: maintenance chemotherapy after early consolidation treatment does not prolong survival. Lancet. 1984;1:379–382.
    1. Büchner T, Berdel WE, Schoch C, Haferlach T, Serve HL, Kienast J, et al. Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 2006;24:2480–2489.
    1. Büchner T, Hiddemann W, Berdel WE, Wörmann B, Schoch C, Fonatsch C, et al. 6-Thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol. 2003;21:4496–4504.
    1. Santini V, Kantarjian HM, Issa JP. Changes in DNA methylation in neoplasia: pathophysiology and therapeutic implications. Ann Intern Med. 2001;134:573–586.
    1. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20:2429–2440.
    1. Kantarjian H, Issa J-PJ, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803.
    1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–232.
    1. Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, et al. 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;28:562–569.
    1. Issa J-PJ, Garcia-Manero G, Giles FJ, Mannari R, Thomas D, Faderl S, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640.
    1. Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA. 2010;107:7473–7478.
    1. Cashen AF, Schiller GJ, O’Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010;28:556–561.
    1. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, et al. 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;30:2670–2677.
    1. Boumber Y, Kantarjian H, Jorgensen J, Wen S, Faderl S, Castoro R, et al. A randomized study of decitabine versus conventional care for maintenance therapy in patients with acute myeloid leukemia in complete remission [letter] Leukemia. 2012;26:2428–2431.
    1. Kolitz JE, George SL, Benson DM, Jr, Maharry K, Marcucci G, Vij R, et al. 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;120:1010–1017.
    1. Mrózek K, Prior TW, Edwards C, Marcucci G, Carroll AJ, Snyder PJ, et al. Comparison of cytogenetic and molecular genetic detection of t(8;21) and inv(16) in a prospective series of adults with de novo acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol. 2001;19:2482–2492.
    1. Linker CA, Ries CA, Damon LE, Sayre P, Navarro W, Rugo HS, et al. Autologous stem cell transplantation for acute myeloid leukemia in first remission. Biol Blood Marrow Transplant. 2000;6:50–57.
    1. Linker CA, Owzar K, Powell B, Hurd D, Damon LE, Archer LE, et al. Auto-SCT for AML in second remission: CALGB study 9620. Bone Marrow Transplant. 2009;44:353–359.
    1. Mrózek K, Carroll AJ, Maharry K, Rao KW, Patil SR, Pettenati MJ, et al. Central review of cytogenetics is necessary for cooperative group correlative and clinical studies of adult acute leukemia: the Cancer and Leukemia Group B experience. Int J Oncol. 2008;33:239–244.
    1. Whitman SP, Archer KJ, Feng L, Baldus C, Becknell B, Carlson BD, et al. Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a Cancer and Leukemia Group B study. Cancer Res. 2001;61:7233–7239.
    1. Thiede C, Steudel C, Mohr B, Schaich M, Schäkel U, Platzbecker U, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99:4326–4335.
    1. Marcucci G, Maharry K, Radmacher MD, Mrózek K, Vukosavljevic T, Paschka P, et al. Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B study. J Clin Oncol. 2008;26:5078–5087.
    1. Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, et al. Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study. J Clin Oncol. 2010;28:596–604.
    1. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–474.
    1. Cassileth PA, Lynch E, Hines JD, Oken MM, Mazza JJ, Bennett JM, et al. Varying intensity of postremission therapy in acute myeloid leukemia. Blood. 1992;79:1924–1930.
    1. Löwenberg B, Suciu S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R, et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy—the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report of the European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group randomized phase III study AML-9. J Clin Oncol. 1998;16:872–881.
    1. 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.
    1. Löwenberg B, Beck J, Graux C, van Putten W, Schouten HC, Verdonck LF, et al. Gemtuzumab ozogamicin as postremission treatment in AML at 60 years of age or more: results of a multicenter phase 3 study. Blood. 2010;115:2586–2591.
    1. Baer MR, George SL, Caligiuri MA, Sanford BL, Bothun SM, Mrózek K, et al. 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;26:4934–4939.
    1. Cortes JE, Kantarjian HM, O’Brien S, Giles F, Keating MJ, Freireich EJ, et al. A pilot study of interleukin-2 for adult patients with acute myelogenous leukemia in first complete remission. Cancer. 1999;85:1506–1513.
    1. Blaise D, Attal M, Reiffers J, Michallet M, Bellanger C, Pico JL, et al. Randomized study of recombinant interleukin-2 after autologous bone marrow transplantation for acute leukemia in first complete remission. Eur Cytokine Netw. 2000;11:91–98.
    1. Khatri VP, Baiocchi RA, Bernstein ZP, Caligiuri MA. Immunotherapy with low-dose interleukin-2: rationale for prevention of immune-deficiency-associated cancer. Cancer J Sci Am. 1997;3(Suppl 1):S129–S136.
    1. Stone RM, DeAngelo DJ, Janosova A, Galinsky I, Canning C, Ritz J, et al. Low dose interleukin-2 following intensification therapy with high dose cytarabine for acute myelogenous leukemia in first complete remission. Am J Hematol. 2008;83:771–777.
    1. Brune M, Castaigne S, Catalano J, Gehlsen K, Ho AD, Hofmann WK, et al. 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;108:88–96.
    1. Buyse M, Squifflet P, Lange BJ, Alonzo TA, Larson RA, Kolitz JE, et al. Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia. Blood. 2011;117:7007–7013.
    1. Liu S, Shen T, Huynh L, Klisovic MI, Rush LJ, Ford JL, et al. Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia. Cancer Res. 2005;65:1277–1284.

Source: PubMed

3
Subscribe