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Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study

Leukemia volume 18, pages 989–997 (2004)Cite this article

Abstract

To assess the efficacy of an original DAC-7 regimen: daunorubicine (DNR) 60 mg/m2/day, days 1–3; cytarabine (AraC) 200 mg/m2/day, days 1–7; cladribine (2-CdA) 5 mg/m2/day, days 1–5, 400 untreated adult acute myeloid leukemia patients (including 63 with preceding myelodysplastic syndrome), aged 45 (16–60) years were randomized to either DAC-7 (n=200) or DA-7 (without 2-CdA, n=200). The overall CR rate equaled 72% for DAC-7 and 69% for DA-7 arm (P=NS). After a single course of DAC-7 induction, the CR rate equaled 64% and was significantly higher compared to 47% in the DA-7 arm (P=0.0009). Median hospitalization time during the induction was 7 days shorter for DAC-7 compared to the DA-7 group (33 vs 40 days, P=0.002). Toxicity was comparable in both groups. The probability of 3-year leukemia-free survival (LFS) for DAC-7 and DA-7 group equaled 43 and 34%, respectively (P=NS). There was a trend toward higher LFS rate for patients aged >40 years receiving DAC-7 compared with DA-7 regimen (44 vs 28%, P=0.05). This study proves that addition of 2-CdA increases antileukemic potency of DNR+AraC regimen, thus resulting in a higher CR rate after one induction cycle when compared to DA-7, without additional toxicity. It shortens hospitalization time and may improve long-term survival in patients aged >40 years.

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References

  1. Rees JK, Gray G, Wheatley K . Dose intensification in acute myeloid leukemia: great effectiveness at lower cost. Principal report of a Medical Research Council's AML 9 study. Br J Haematol 1996; 94: 89–94.

    Article  CAS  Google Scholar 

  2. Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG et al. Randomized comparison of DAT vs ADE as induction chemotherapy in children and young adults with acute myeloid leukaemia. Results of the Medical Research Council's 10th AML trials (MRC AML 10). Blood 1997; 89: 2311–2318.

    CAS  PubMed  Google Scholar 

  3. Yates J, Glidewell OJ, Wiernik P, Cooper MR, Steinberg D, Dosik H et al. Cytosine arabinoside with daunorubicin or adriamycin therapy with acute myelocytic leukemia: a CALGB study. Blood 1982; 60: 454–463.

    CAS  PubMed  Google Scholar 

  4. Arlin Z, Case DC, Moore J, Wiernik P, Feldman E, Saletan S et al. Randomized multi-center trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Leukemia 1990; 4: 177–183.

    CAS  Google Scholar 

  5. Lowenberg B, Sucio S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R et al. Mitoxantrone vs daunorubicin in induction–consolidation chemotherapy, the value of low-dose cytarabine for maintenance of remission as well as in assessment of prognostic factors in acute myeloid leukaemia in the elderly: final report of the EORTC LCG-HOVON randomised phase III study AML-9. J Clin Oncol 1998; 16: 1–11.

    Article  Google Scholar 

  6. Vogler WR, Velez-Garcia E, Weiner RS, Flaum MA, Bartolucci AA, Omura GA et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group. J Clin Oncol 1992; 10: 1103–1111.

    Article  CAS  Google Scholar 

  7. Wiernik PH, Banks PL, Case Jr DC, Arlin ZA, Periman PO, Todd MB et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 1992; 79: 313–319.

    CAS  Google Scholar 

  8. Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D, Cobcroft R et al. Australian Study Group: etoposide in acute non-lymphocytic leukemia. Blood 1990; 75: 27–32.

    CAS  PubMed  Google Scholar 

  9. Robak T . Purine nucleoside analogues in the treatment of myeloid leukemias. Leukemia Lymphoma 2003; 44: 391–409.

    Article  CAS  Google Scholar 

  10. Gandhi V, Plunkett W . Cell cycle-specific metabolism of arabinosyl nucleosides in K 562 human leukemia cells. Cancer Chemother Pharmacol 1992; 31: 11–17.

    Article  CAS  Google Scholar 

  11. Gandhi V, Estey E, Keating MJ, Chucrallah A, Plunkett W . Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukemia: pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 1996; 87: 256–264.

    CAS  PubMed  Google Scholar 

  12. Kornblau SM, Gandhi V, Andreeff HM, Beran M, Kantarjian HM, Koller CA et al. Clinical and laboratory studies of 2-chlorodeoxyadenosine ± cytosine arabinoside for relapsed or refractory acute myelogenous leukemia in adults. Leukemia 1996; 24: 1563–1569.

    Google Scholar 

  13. Beutler E . Cladribine (2-chlorodeoxyadenosine). Lancet 1992; 340: 952–956.

    Article  CAS  Google Scholar 

  14. Estey EH, Plunkett W, Gandhi V, Rios MB, Kantarjian H, Keating MJ . Fludarabine and arabinosyl cytosine therapy of refractory and relapsed acute myelogenous leukemia. Leukemia Lymphoma 1993; 9: 343–350.

    Article  CAS  Google Scholar 

  15. Clavio M, Carrara P, Miglino M, Pierri I, Canepa L, Balleari E et al. High efficacy of fludarabine-containing therapy (FLAG–FLANG) in poor risk acute myeloid leukaemia. Hematology 1996; 81: 513–520.

    CAS  Google Scholar 

  16. Robak T, Wrzesien-Kus A, Lech-Maranda E, Kowal M, Dmoszynska A . Combination regimen of cladribine (2-chlorodeoxyadenosine), cytarabine and G-CSF (CLAG) as induction therapy for patients with relapsed of refractory myeloid leukemia. Leukemia Lymphoma 2000; 39: 121–129.

    Article  CAS  Google Scholar 

  17. Estey EH, Thall PF, Cortes JE, Giles FJ, O'Brien S, Pierce SA et al. Comparison of idarubicin+ara-C-, fludarabine+ara-C-, and topotecan+ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood 2001; 98: 3575.

    Article  CAS  Google Scholar 

  18. Holowiecki J, Robak T, Kyrcz-Krzemien S, Grosicki S, Hellmann A, Skotnicki A et al. Daunorubicin, cytarabine, and 2-CdA (DAC-7) for remission induction in ‘de novo’ adult acute myeloid leukaemia patients. Acta Haematol Polon 2002; 33: 839–847.

    Google Scholar 

  19. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the acute leukaemias: French–American–British (FAB) Co-operative Group. Br J Haematol 1976; 33: 451–458.

    Article  CAS  Google Scholar 

  20. Mitelman F (ed.). ISCN An International System for Human Cytogenetic Nomenclature. Basel: S Karger, 1995.

    Google Scholar 

  21. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/ Eastern Cooperative Oncology Group study. Blood 2000; 96: 4075–4083.

    CAS  PubMed  Google Scholar 

  22. Holowiecki J, Giebel S, Krzemien S, Krawczyk-Kulis M, Jagoda K, Kopera M et al. G-CSF administered in time-sequenced setting during remission induction and consolidation therapy of adult acute lymphoblastic leukemia has beneficial influence on early recovery and possibly improves long-term outcome: a randomized multicenter study. Leukemia Lymphoma 2002; 43: 315–325.

    Article  Google Scholar 

  23. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  24. Gooley TA, Leisenring W, Crowley J, Storer BE . Estimation of failure probabilities in the presence of competing risk: new representations of old estimators. Stat Med 1999; 18: 695–706.

    Article  CAS  Google Scholar 

  25. Dillman RO, Davis RB, Green M, Weiss RB, Gottlieb AJ, Caplan S et al. A comparative study of two different doses of cytarabine for acute myeloid leukaemia: a phase III trial of Cancer and Leukemia Group B. Blood 1991; 78: 2520–2526.

    CAS  PubMed  Google Scholar 

  26. Rowe JM, Tallman MS . Intensifying induction therapy in acute myeloid leukemia: Has a new standard of care emerged? Blood 1997; 90: 2121–2126.

    CAS  PubMed  Google Scholar 

  27. Bishop JS, Matthews JP, Young GA, Szer J, Gillett A, Joshua D et al. A randomized trial of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996; 87: 1710–1717.

    CAS  PubMed  Google Scholar 

  28. Büchner T, Hiddemann W, Wörmann B, Loffler H, Gassmann W, Haferlach T et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanin: a randomized trial by the German AML Cooperative Group. Blood 1999; 93: 4116–4124.

    PubMed  Google Scholar 

  29. Weick JK, Kopecky TJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP et al. A randomized investigation of high-dose vs standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996; 88: 2841–2951.

    CAS  Google Scholar 

  30. Hansen OP, Pedersen-Bjergaard J, Ellegaard G, Brincker H, Boesen AM, Christensen BE et al. A clarubicine plus cytosine arabinoside vs daunorubicin plus cytosine arabinoside in previously untreated patients of acute myeloid leukemia: A Danish National Phase III Trial. For the Danish Society of Hematology Study Group on AML. Leukemia 1991; 5: 510–516.

    CAS  Google Scholar 

  31. Berman E, Arlin ZA, Gaynor J, Miller W, Gee T, Kempin SJ et al. Comparative trial of cytarabine and thioguanine in combination with amsacrine or daunorubicin in patients with untreated acute nonlymphocytic leukemia: results of the L-16M protocol. Leukemia 1989; 3: 115–121.

    CAS  Google Scholar 

  32. Tallman MS, Hakimian D . Purine nucleoside analogs: emerging roles in indolent lymphoproliferative disorders. Blood 1995; 86: 2463–2474.

    CAS  Google Scholar 

  33. Robak T, Blonski JZ, Kasznicki M, Blasinska-Morawiec M, Krykowski E, Dmoszynska A et al. Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood 2000; 96: 2723–2729.

    CAS  PubMed  Google Scholar 

  34. Genini D, Adachi S, Chao Q, Rose DW, Carrera CJ, Cottam HB et al. Deoxyadenosine analogues induce programmed cell death in chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. Blood 2002; 96: 3537–3543.

    Google Scholar 

  35. Gandhi V, Plunkett W . Cellular and clinical pharmacology of fludarabine. Clin Pharmacokinet 2002; 41: 93–103.

    Article  CAS  Google Scholar 

  36. Santana VM, Mirro J, Kearns C, Schell MJ, Crom W, Blakley RL . 2-chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin Oncol 1992; 10: 364–370.

    Article  CAS  Google Scholar 

  37. Santana VM, Hurvitz CA, Blakley RL, Crom WR, Luo X, Roberts WM et al. Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia. Blood 1994; 84: 1237–1242.

    CAS  Google Scholar 

  38. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994; 331: 896–903.

    Article  CAS  Google Scholar 

  39. Wahlin A, Markevärn B, Golovleva I, Nilsson M . Prognostic significance of risk group stratification in elderly patients with acute myeloid leukaemia. Br J Haematol 2001; 115: 25–33.

    Article  CAS  Google Scholar 

  40. Estey EH, Shen Y, Thall PF . Effect of time to complete remission on subsequent survival and disease-free survival time in AML, RAEB-t, and RAEB. Blood 2000; 95: 72–77.

    CAS  PubMed  Google Scholar 

  41. Fagioli F, Bacigalupo A, Frassoni F, Van Lint MT, Occhini D, Guala N et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission: the effect of FAB classification and GVHD prophylaxis. Bone Marrow Transplant 1994; 13: 247–252.

    CAS  PubMed  Google Scholar 

  42. Michel G, Gluckman E, Esperou-Bourdou H, Reiffers J, Pico JL, Bordigoni P et al. Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation – a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 1994; 12: 1217–1222.

    Article  CAS  Google Scholar 

  43. Cahn JY, Labopin M, Sierra J, Blaise D, Reiffers J, Ferrant A et al. No impact of high-dose cytarabine on the outcome of patients transplanted for acute myeloblastic leukaemia in first remission. Br J Haematol 2000; 110: 308–314.

    Article  CAS  Google Scholar 

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Acknowledgements

The study was supported in part by grant number 4 P05B 139 18 from ‘Komitet Badan Naukowych’, Warsaw, Poland. We thank all the physicians, nurses and laboratory staff in the PALG centers for providing patient care.

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Authors and Affiliations

  1. University Department of Haematology and BMT, Silesian Medical University, Katowice, Poland

    J Holowiecki, S Grosicki, S Kyrcz-Krzemien, S Giebel, B Stella-Holowiecka & K Jagoda

  2. Department of Haematology, Medical University of Lodz, Poland

    T Robak & A Wierzbowska

  3. Department of Haematology, Medical University of Gdansk, Poland

    A Hellmann & W Baran

  4. Department of Haematology, Collegium Medicum, Jagiellonian University, Cracow, Poland

    A Skotnicki & B Jakubas

  5. Department of Haematology, Oncology and Internal Diseases, Medical University of Warsaw, Poland

    W W Jedrzejczak & M Paluszewska

  6. Department of Internal Diseases, Institute of Haematology and Transfusion Medicine, Warsaw, Poland

    L Konopka

  7. Department of Haematology and Proliferative Diseases, Wroclaw Medical Academy, Poland

    K Kuliczkowski, O Haus & M Kielbinski

  8. Department of Haematology, Pomorian Medical Academy, Szczecin, Poland

    B Zdziarska

  9. Department of Haematology and BMT, Lublin Medical Academy, Poland

    A Dmoszynska

  10. Department of Haematology, Institute of Haematology and Transfusion Medicine, Warsaw, Poland

    B Marianska

  11. Department of Internal Medicine, Provincial Specialistic Hospital, Rzeszow, Poland

    A Pluta

  12. Department of Internal Medicine, J Strus Hospital, Poznan, Poland

    K Zawilska

  13. Department of Haematology and Proliferative Diseases, Medical Academy Poznan, Poland

    M Komarnicki

  14. Department of Haematology, Bialystok Medical Academy, Poland

    J Kloczko

  15. Department of Clinical Hematology, Military Medical Academy, Warsaw, Poland

    K Sulek

  16. Department of Clinical Genetics, Bydgoszcz Medical Academy, Poland

    O Haus

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on behalf of the Polish Adult Leukaemia Group (PALG)

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Correspondence to J Holowiecki.

Appendix

Appendix

The following members of the Polish Adult Leukaemia Group (PALG) are also co-authors of this publication: Ewa Zuk (Department of Haematology, Pomorian Medical Academy, Szczecin, Poland), Małgorzata Krawczyk-Kulis (University Department of Haematology and BMT, Silesian Medical University, Katowice, Poland), Małgorzata Kopera (University Department of Haematology and BMT, Silesian Medical University, Katowice, Poland), Agata Wrzesien-Kus (Department of Haematology, Medical University of Lodz, Poland), Małgorzata Wach (Department of Haematology and BMT, Lublin Medical Academy, Poland), Anna Czyz (Department of Internal Medicine, J. Strus Hospital, Poznan, Poland), Katarzyna Mazgajska (Department of Haematology, Bialystok Medical Academy, Poland), Grazyna Pałynyczko (Department of Internal Diseases, Institute of Haematology and Transfusion Medicine, Warsaw, Poland), Stanisław Maj (Department of Haematology, Institute of Haematology and Transfusion Medicine, Warsaw, Poland), Jadwiga Dwilewicz-Trojaczek (Department of Haematology, Oncology and Internal Diseases, Warsaw Medical Academy, Poland), Ewa Starzak (Department of Internal Medicine, Provincial Specialistic Hospital, Rzeszow, Poland).

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Holowiecki, J., Grosicki, S., Robak, T. et al. Addition of cladribine to daunorubicin and cytarabine increases complete remission rate after a single course of induction treatment in acute myeloid leukemia. Multicenter, phase III study. Leukemia 18, 989–997 (2004). https://doi.org/10.1038/sj.leu.2403336

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