Skip to main content
SpringerLink
Log in

Re-induction chemotherapy using FLAG–mitoxantrone for adult patients with relapsed acute leukemia: a single-center experience from United Arab Emirates

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

We studied the outcome of 47 adult patients with relapsed acute leukaemia (AML = 25 and ALL = 22) treated with FLAG–mitoxantrone regimen. Median time to relapse was 10.7 months (range 1.9–27.7). Complete remission (CR2) was 60.1% which was significantly more frequent in ALL compared to AML (P = 0.049). WBC count < 100 × 109/L at initial diagnosis and time to relapse > 1 year were significantly predictor for CR2 in AML (P = 0.005 for both). Induction death was significantly higher in ALL compared to AML (P = 0.039). Median follow-up was 4.0 months (0.9–119.8) for AML and 2.1 months (range 0.6–118.1) for ALL. Nine patients underwent allogeneic stem-cell transplantation (allo-SCT). Estimated overall survival (OS) at 12 and 18 months was 60.5 and 34.6%, respectively, for AML, and 39.9 and 29.9%, respectively, for ALL. For AML patients failure to achieve CR, WBC count at initial diagnosis > 5 × 109/L and poor cytogenetic risk group was significant predictors of poor OS (P = 0.010, P = 0.025, and P = 0.015, respectively). For ALL patients failure to achieve of CR, WBC count at relapse < 5 × 109/L (CR patients) and lack of any type of consolidation therapy were significant predictor of poor OS (P < 0.001, P = 0.008, P = 0.008, respectively).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    Article  CAS  PubMed  Google Scholar 

  2. Juliusson G, Antunovic P, Derolf A, Lehmann S, Möllgård L, Stockelberg D, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood. 2009;113:4179–87.

    Article  CAS  PubMed  Google Scholar 

  3. Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, et al. European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3);453–74.

    Article  CAS  Google Scholar 

  4. Annino L, Vegna ML, Camera A, Specchia G, Visani G, Fioritoni G, et al. GIMEMA Group. Treatment of adult acute lymphoblastic leukemia (ALL): long-term follow-up of the GIMEMA ALL 0288 randomized study. Blood. 2002;99(3):863–71.

    Article  CAS  PubMed  Google Scholar 

  5. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, et al. ECOG.; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106(12):3760–7.

    Article  CAS  PubMed  Google Scholar 

  6. Ronson A, Tvito A, Rowe JM. Treatment of relapsed/refractory acute lymphoblastic leukemia in adults. Curr Oncol Rep. 2016;18(6):39.

    Article  CAS  PubMed  Google Scholar 

  7. Breems DA, Van Putten WL, Huijgens PC, Ossenkoppele GJ, Verhoef GE, Verdonck LF, et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23(9):1969–78.

    Article  PubMed  Google Scholar 

  8. Tavernier E, Boiron JM, Huguet F, Bradstock K, Vey N, Kovacsovics T, et al. GET-LALA Group; Swiss Group for Clinical Cancer Research SAKK; Australasian Leukaemia and Lymphoma Group. Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial. Leukemia. 2007;21(9):1907–14.

    Article  CAS  PubMed  Google Scholar 

  9. Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Medical Research Council of the United Kingdom Adult ALL Working Party.; 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):944–50.

    Google Scholar 

  10. Gökbuget N, Dombret H, Ribera JM, Fielding AK, Advani A, Bassan R, et al. International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia. Haematologica. 2016;101(12):1524–33.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kozlowski P, Åström M, Ahlberg L, Bernell P, Hulegårdh E, Hägglund H, et al. High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003–2007. Haematologica. 2012;97(9):1414–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Rosen PJ, Rankin C, Head DR, Boldt DH, Luthardt FW, Norwood T, et al. phase II study of high dose ARA-C and mitoxantrone for treatment of relapsed or refractory adult acute lymphoblastic leukemia. Leuk Res. 2000;24(3):183–7.

    Article  CAS  PubMed  Google Scholar 

  13. Virchis A, Koh M, Rankin P, Mehta A, Potter M, Hoffbrand AV, et al. Fludarabine, cytosine arabinoside, granulocyte-colony stimulating factor with or without idarubicin in the treatment of high risk acute leukaemia or myelodysplastic syndromes. Br J Haematol. 2004;124:26–32.

    Article  CAS  PubMed  Google Scholar 

  14. Suki S, Kantarjian H, Gandhi V, Estey E, O’Brien S, Beran M, et al. Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia. Cancer. 1993;2(7):2155–60.

    Article  Google Scholar 

  15. Wierzbowska A, Robak T, Pluta A, Wawrzyniak E, Cebula B, Hołowiecki J, et al. Polish Adult Leukemia Group. Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G-CSF (CLAG-M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group. Eur J Haematol. 2008;80(2):115–26.

    Google Scholar 

  16. Lee SR, Yang DH, Ahn JS, Kim YK, Lee JJ, Choi YJ, et al. The clinical outcome of FLAG chemotherapy without idarubicin in patients with relapsed or refractory acute myeloid leukemia. J Korean Med Sci. 2009;24(3):498–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yavuz S, Paydas S, Disel U, Sahin B. IDA-FLAG regimen for the therapy of primary refractory and relapse acute leukemia: a single-center experience. Am J Ther. 2006;13(5):389–93.

    Article  Google Scholar 

  18. Hänel M, Friedrichsen K, Hänel A, Herbst R, Morgner A, Neser S, et al. Mito-flag as salvage therapy for relapsed and refractory acute myeloid leukemia. Onkologie. 2001;24(4):356–60.

    Google Scholar 

  19. Gandhi V, Estey E, Keating MJ, Plunkett W. Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol. 1993;11(1):116–24.

    Article  CAS  PubMed  Google Scholar 

  20. Gandhi V, Estey E, Du M, Nowak B, Keating MJ, Plunkett W. Modulation of the cellular metabolism of cytarabine and fludarabine by granulocyte-colony-stimulating factor during therapy of acute myelogenous leukemia. Clin Cancer Res. 1995;1(2):169–78.

    CAS  PubMed  Google Scholar 

  21. Tosi P, Visani G, Ottaviani E, Manfori S, Zinzani PL, Tura S. Fludarabine + Ara-C + G-CSF: cytotoxic effect and induction of apoptosis on fresh acute myeloid leukemia cells. Leukemia. 1994;8(12):2076–82.

    CAS  PubMed  Google Scholar 

  22. Fleischhack G, Hasan C, Graf N, Mann G, Bode U. IDA-FLAG (idarubicin, fludarabine, cytarabine, G-CSF), an effective remission-induction therapy for poor-prognosis AML of childhood prior to allogeneic or autologous bone marrow transplantation: experiences of a phase II trial. Br J Haematol. 1998;102(3):647–55.

    Article  Google Scholar 

  23. Eom KS, Min WS, Kim HJ, Cho BS, Choi SM, Lee DG, et al. FLANG salvage chemotherapy is an effective regimen that offers a safe bridge to transplantation for patients with relapsed or refractory acute myeloid leukemia. Med Oncol. 2011;28(Suppl 1):S462–70.

    Article  CAS  PubMed  Google Scholar 

  24. Luo S, Cai F, Jiang L, Zhang S, Shen Z, Sun L, et al. Clinical study of Mito-FLAG regimen in treatment of relapsed acute myeloid leukemia. Exp Ther Med. 2013;5(3):982–6.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Martin MG, Augustin KM, Uy GL, Welch JS, Hladnik L, Goyal S, et al. Salvage therapy for acute myeloid leukemia with fludarabine, cytarabine, and idarubicin with or without gemtuzumab ozogamicin and with concurrent or sequential G-CSF. Am J Hematol. 2009;84(11):733–7.

    Article  CAS  PubMed  Google Scholar 

  26. Amadori S, Arcese W, Isacchi G, Meloni G, Petti MC, Monarca B, et al. Mitoxantrone, etoposide, and intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of refractory acute myeloid leukemia. J Clin Oncol. 1991;9(7):1210–4.

    Article  CAS  PubMed  Google Scholar 

  27. Wrzesień-Kuś A, Robak T, Wierzbowska A, Lech-Marańda E, Pluta A, Wawrzyniak E, et al. Polish Adult Leukemia Group. A multicenter, open, noncomparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, granulocyte colony-stimulating factor and mitoxantrone as induction therapy in refractory acute myeloid leukemia: a report of the Polish Adult Leukemia Group. Ann Hematol. 2005;84(9):557–64.

    Google Scholar 

  28. Kohrt HE, Patel S, Ho M, Owen T, Pollyea DA, Majeti R, et al. Second-line mitoxantrone, etoposide, and cytarabine for acute myeloid leukemia: a single-center experience. Am J Hematol. 2010;85(11):877–81.

    Article  CAS  Google Scholar 

  29. Forman SJ, Rowe JM. The myth of the second remission of acute leukemia in the adult. Blood. 2013;121(7):1077–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Thiel A, Schetelig J, Pönisch W, Schäfer-Eckart K, Aulitzky W, Peter N, et al. East German Study Group. Mito-FLAG with Ara-C as bolus versus continuous infusion in recurrent or refractory AML—long-term results of a prospective randomized intergroup study of the East German Study Group Hematology/Oncology (OSHO) and the Study Alliance Leukemia (SAL). Ann Oncol. 2015;26(7):1434–40.

    Article  CAS  PubMed  Google Scholar 

  31. Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M, Jakubas B, Palynyczko G, Lewandowski K, et al. Polish Adult Leukemia Group. Fludarabine, cytarabine, and mitoxantrone (FLAM) for the treatment of relapsed and refractory adult acute lymphoblastic leukemia. A phase study by the Polish Adult Leukemia Group (PALG). Ann Hematol. 2006;85(10):717–22.

    Article  CAS  Google Scholar 

  32. Kern W, Schleyer E, Braess J, Wittmer E, Ohnesorge J, Unterhalt M, et al. Efficacy of fludarabine, intermittent sequential high-dose cytosine arabinoside, and mitoxantrone (FIS-HAM) salvage therapy in highly resistant acute leukemias. Ann Hematol. 2001;80(6):334–9.

    Article  CAS  PubMed  Google Scholar 

  33. Kantarjian HM, Estey EH, O’Brien S, Anaissie E, Beran M, Rios MB, et al. Intensive chemotherapy with mitoxantrone and high-dose cytosine arabinoside followed by granulocyte–macrophage colony-stimulating factor in the treatment of patients with acute lymphocytic leukemia. Blood. 1992;790(4):876–81.

    Google Scholar 

  34. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376(9757):2009–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cao C, Han Y, Ren Y, Wang Y. Mitoxantrone-mediated apoptotic B16-F1 cells induce specific anti-tumor immune response. Cell Mol Immunol. 2009;6(6):469–75.

    Article  Google Scholar 

  36. Hassan IB, Kristensen J, Alizadeh H, Bernsen R. Outcome of patients with acute lymphoblastic leukemia (ALL) following induction therapy with a modified (pulsed dexamethasone rather than continuous prednisone) UKALL XII/ECOG E2993 protocol at Tawam Hospital, United Arab Emirates (UAE). Med Oncol. 2013;30(2):519.

    Article  CAS  PubMed  Google Scholar 

  37. Mitchell C, Richards S, Harrison CJ, Eden T. Long-term follow-up of the United Kingdom Medical Research Council protocols for childhood acute lymphoblastic leukaemia, 1980–2001. Leukemia. 2010;24(2):406–18.

    Article  CAS  PubMed  Google Scholar 

  38. Jackson G, Taylor P, Smith GM, Marcus R, Smith A, Chu P, et al. A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation. Br J Haematol. 2001;112(1):127–37.

    Article  Google Scholar 

  39. Kantarjian HM, Keating MJ, Walters RS, McCredie KB, Freireich EJ. The characteristics and outcome of patients with late relapse acute myelogenous leukemia. J Clin Oncol. 1988;6(2):232–8.

    Article  CAS  PubMed  Google Scholar 

  40. Weltermann A, Fonatsch C, Haas OA, Greinix HT, Kahls P, Mitterbauer G, et al. Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse. Leukemia. 2004;18(2):293–302.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Research Affairs, United Arab Emirates University. The authors would like to thank the staff at The National Cancer Registry, and the Medical Record Department, at Tawam Hospital, Al Ain, UAE. The authors would like to thank Mrs. Mary Kutty Jacob and to the medical students, FMHS, UAEU, who participated in the data collection.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Faculty of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al Ain, United Arab Emirates

    Inaam Bashir Hassan

  2. Department of Hematology, Oncology Tawam Hospital, Al Ain, United Arab Emirates

    Inaam Bashir Hassan, Khalid Al Qawasmeh & Arif Alam

  3. Mediclinic North Wing, Dubai, United Arab Emirates

    Jorgen Kristensen

Authors
  1. Inaam Bashir Hassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorgen Kristensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Khalid Al Qawasmeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Arif Alam
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Inaam Bashir Hassan.

Ethics declarations

Conflict of interest

No relevant conflicts of interest to declare.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hassan, I.B., Kristensen, J., Al Qawasmeh, K. et al. Re-induction chemotherapy using FLAG–mitoxantrone for adult patients with relapsed acute leukemia: a single-center experience from United Arab Emirates. Int J Hematol 108, 390–401 (2018). https://doi.org/10.1007/s12185-018-2478-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-018-2478-3

Keywords

Search

Navigation