High-dose cytarabine in acute myeloid leukemia treatment: a systematic review and meta-analysis

Wei Li, Xiaoyuan Gong, Mingyuan Sun, Xingli Zhao, Benfa Gong, Hui Wei, Yingchang Mi, Jianxiang Wang, Wei Li, Xiaoyuan Gong, Mingyuan Sun, Xingli Zhao, Benfa Gong, Hui Wei, Yingchang Mi, Jianxiang Wang

Abstract

The optimal dose, scheme, and clinical setting for Ara-C in acute myeloid leukemia (AML) treatment remain uncertain. In this study, we performed a meta-analysis to systematically assess the impact of high-dose cytarabine (HDAC) on AML therapy during the induction and consolidation stages. Twenty-two trials with a total of 5,945 de novo AML patients were included in the meta-analysis. Only patients less than 60 year-old were included in the study. Using HDAC in induction therapy was beneficial for RFS (HR = 0.57; 95% CI, 0.35-0.93; P = 0.02) but not so for CR rate (HR = 1.01; 95% CI, 0.93-1.09; P = 0.88) and OS (HR = 0.83; 95% CI, 0.66-1.03; P = 0.1). In consolidation therapy, HDAC showed significant RFS benefits (HR = 0.67; 95% CI, 0.49-0.9; P = 0.008) especially for the favorable-risk group (HR = 0.38; 95% CI, 0.21-0.69; P = 0.001) compared with SDAC (standard dose cytarabine), although no OS advantage was observed (HR = 0.84; 95% CI, 0.55-1.27; P = 0.41). HDAC treatment seemed less effective than auto-BMT/allo-BMT treatment (HR = 1.66, 95% CI, 1.3-2.14; P<0.0001) with similar OS. HDAC treatment led to lower relapse rate in induction and consolidation therapy than SDAC treatment, especially for the favorable-risk group. Auto-BMT/allo-BMT was more beneficial in prolonging RFS than HDAC.

Conflict of interest statement

Competing Interests: In this article we declared that Jianxiang Wang acts as consultant of Novartis and Bristol Myers Squibb. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. ALL authors have no conflict of interest to declare.

Figures

Figure 1. Flow chart explaining the selection…
Figure 1. Flow chart explaining the selection of eligible studies included in the meta-analysis.
Figure 2. Effect of HDAC versus SDAC…
Figure 2. Effect of HDAC versus SDAC in induction therapy.
A: Effect of HDAC versus SDAC in induction therapy on CR rate. B: Overall survival benefit of HDAC in induction therapy. C: Relapse free survival benefit of HDAC in induction therapy.
Figure 3. Overall survival benefit of HDAC…
Figure 3. Overall survival benefit of HDAC in consolidation therapy.
A: Total overall survival benefit of HDAC in consolidation therapy. B: Overall survival benefit of different subgroups of HDAC in consolidation therapy.
Figure 4. Relapse free survival benefit of…
Figure 4. Relapse free survival benefit of HDAC in consolidation therapy.
A: Total relapse free survival benefit of HDAC in consolidation therapy. B: Relapse free survival benefit of different subgroups of HDAC in consolidation therapy.
Figure 5. Effect of HDAC versus BMT…
Figure 5. Effect of HDAC versus BMT on overall survival.
Figure 6. Effect of HDAC versus BMT…
Figure 6. Effect of HDAC versus BMT on relapse free survival.

References

    1. Löwenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med. 341(14): 1051–1062.
    1. Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, et al. (1996) A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood. 87: 1710–1717.
    1. Moore JO, George SL, Dodge RK, Amrein PC, Powell BL, et al. (2005) Sequential multiagent chemo- therapy is not superior to high-dose cytarabine alone as postremission intensification therapy for acute myeloid leukemia in adults under 60 years of age: Cancer and Leukemia Group B Study 9222. Blood. 105(9): 3420–7.
    1. Miyawaki S, Ohtake S, Fujisawa S, Kivoi H, Shinaqawak K, et al. (2011) A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in post remission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study. Blood. 117(8): 2366–72.
    1. Löwenberg B (2013) Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood. 121(1): 26–28.
    1. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 17(24): 2815–2834.
    1. Matthews JP, Bishop JF, Young GA, Juneia SK, Lowenthal RM, et al. (2001) Patterns of failure with increasing intensification of induction chemotherapy for acute myeloid leukaemia. Br J Haematol. 113(3): 727–36.
    1. Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, et al. (1996) A randomized investig- ation of high-dose versus standard-dose cytosine arabinoside with daunorubicin inpatients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood. 88(8): 2841–51.
    1. Büchner T, Berdel WE, Schoch C, Haferlach T, Serve HL, et al. (2006) Double induction containing either two courses or one course of high–dose cytarabine plus mitoxantrone and post remission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol. 24(16): 2480–9.
    1. Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, et al. (1999) Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood. 15 93(12): 4116–24.
    1. Büchner T, Berdel WE, Haferlach C, Haferlach T, Schnittger S, et al. (2009) Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Mye- loid Leukemia Coo-perative Group. J Clin Oncol. 27(1): 61–9.
    1. Bradstock KF, Matthews JP, Lowenthal RM, Baxter H, Catalano J, et al. (2005) A randomized trial of high-versus conventional-dose cytarabine in consolidation chemotherapy for adult de novo acute myeloid leukemia in first remission after induction therapy containing high-dose cytarabine. Blood. 105(2): 481–8.
    1. Fopp M, Fey MF, Bacchi M, Cavalli F, Gmuer J, et al. (1997) Post-remission therapy of adult acute myeloid leukaemia: one cycle of high-dose versus standard-dose cytarabine. Leukaemia Project Group of the Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol. 8(3): 251–7.
    1. Cassileth PA, Lynch E, Hines JD, Oken MM, Mazza JJ, et al. (1992) Varying intensity of post- remission therapy in acute myeloid leukemia. Blood. 79(8): 1924–30.
    1. Mayer RJ, Davis RB, Schiffer CA, Berq DT, Powell BL, et al. (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. 331(14): 896–903.
    1. Ohtake S, Miyawaki S, Fujita H, Kiyoi H, Shinaqawa K, et al. (2011) Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study. Blood. 117(8): 2358–65.
    1. Büchner T, Hiddemann W, Berdel WE, Wörmann B, Schoch C, et al. (2003) 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. 21(24): 4496–504.
    1. Schoch C, Haferlach T, Haase D, Fonatsch C, Löffler H, et al. (2001) Patients with de novo acute myeloid leukaemia and complex karyotype aberrations show a poor prognosis despite intensive treatment: a study of 90 patients. Br J Haematol. 112(1): 118–26.
    1. Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, et al. (1998) frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res. Sep 15 58(18): 4173–9.
    1. Thomas X, Elhamri M, Raffoux E, Renneville A, Pautas C, et al. (2011) Comparison of high-dose cytarabine and timed-sequential chemotherapy as consolidation for younger adults with AML in first remission: the ALFA-9802 study. Blood. 118(7): 1754–1762.
    1. Tsimberidu AM, Stavroyianni N, Viniou N, Papaioannou M, Tiniakou M, et al. (2003) Comparison of Allogeneic Stem Cell Transplantation, High-Dose Cytarabine, and Autologous Peripheral Stem Cell Transplantation as Postremission Treatment in Patients with De Novo Acute Myelogenous Leukemia. Cancer. 97(7): 1721–1731.
    1. Harousseau JL, Cahn JY, Pignon B, Witz F, Milpied N, et al. (1997) Chemotherapy as Postremission Therapy in Adult Acute Myeloid Leukemia Comparison of Autologous Bone Marrow Transplant- ation and Intensive. Blood. 90(8): 2978–2986.
    1. Cassileth PA, Arington DP, Appelbaum FR, Lazarus HM, Rowe JM, et al. (1998) Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 339: 1649–56.
    1. Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, et al. (1995) autologous or allogeneic bone marrow transplantion compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 332: 217–23.
    1. Brunet S, Esteve J, Berlanga J, Ribera JM, Bueno J, et al. (2004) Treatment of primary acute myeloid leukemia: results of a prospective multicenter trial including high-dose cytarabine or stem cell transplantation as post-remission strategy. Haematologica. 89: 940–949.
    1. Bassan R, Raimondi R, Lerede T, D’emilio A, Buelli M, et al. (1998) Outcome assessment of age group-specific (±50 years) post-remission consolidation with high-dose cytarabine or bone marrow autograft for adult acute myelogenous leukemia. Haematologica. 83: 627–635.
    1. Schiller GJ, Nimer SD, Territo MC, Ho WG, Champlin RE, et al. (1992) Bone Marrow Transplant- ation Versus High-Dose Cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in First Remission. J Clin Oncol. 10(1): 41–46.
    1. Harousseau JL, Milpied N, Briere J, Desablens B, Leprise PY, et al. (1991) Double Intensive Consolid -ation Chemotherapy in Adult Acute Myeloid Leukemia. J Clin Oncol. 9: 1432–1437.
    1. Kern W, Estey EH (2006) High-dose cytosine arabinoside in the treatment of acute myeloid leukemia. Cancer. 107: 116–24.
    1. Löwenberg B, Pabst T, Vellenga E, van Putten W, Schouten HC, et al. (2011) Cytarabine dose for acute myeloid leukemia. N Engl J Med. 364: 1027–1036.
    1. Farag SS, Ruppert AS, Mrózek K, Mayer RJ, Stone RM, et al. (2005) Outcome of induction and postremission therapy in younger adults with acute myeloid leukemia with normal karyotype: a cancer and leukemia group B study. J Clin Oncol. 23(3): 482–93.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다