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Annals of Hematology

, Volume 94, Issue 3, pp 375–378 | Cite as

Salvage therapy with ARA-C and gemtuzumab ozogamicin in AML patients relapsing after stem cell transplantation

  • Maya Koren-MichowitzEmail author
  • Hannah Maayan
  • Arie Apel
  • Noga Shem-Tov
  • Ronit Yerushalmi
  • Yulia Volchek
  • Abraham Avigdor
  • Avichai Shimoni
  • Arnon Nagler
Original Article

Abstract

Acute myeloid leukemia (AML) relapse is often associated with a poor outcome, especially after allogeneic stem cell transplantation (Allo-SCT). In patients relapsing early after SCT treatment, options are further limited by the fear for increased toxicity. We report our experience with ARA-C and gemtuzumab ozogamicin (GO) combination in relapsed post-SCT AML patients. Therapy consisted of ARA-C (1 gr/m2) for 4 days followed by one dose of GO 9 mg/m2 on day 5 and was supported by donor stem cells when possible. Responding patients not developing graft versus host disease (GVHD) were eligible for immunotherapy with donor lymphocyte infusion (DLI) or a second Allo-SCT. Sixteen patients, median age 53 years (range 31–63), are included in this analysis. Patients underwent SCT for high-risk AML (n = 11) or AML relapse (n = 5), and 81 % had an early post-SCT relapse. Responses were achieved in 60 % of evaluable patients (CR-5 CRp-4). Median probabilities of survival (OS) and event-free survival (EFS) in the entire cohort, responding and non-responding patients were 103 and 76 days, 183 and 97 days, and 79 and 16 days, respectively. At 1-year follow-up, 25 % of patients were alive; however, all had relapse. Treatment resulted in grade 3–4 neutropenia and thrombocytopenia in all patients, and 27 % each had grade 3–4 hyperbilirubinemia or elevation of liver enzymes. One patient died during treatment due to intracranial hemorrhage. Of the six patients proceeding to second SCT or receiving DLI, three patients developed mild veno-occlusive disease (VOD). Combination therapy with ARA-C and GO after SCT results in short-term disease control and limited toxicity and could be considered for patients who are candidates for further immunotherapy.

Keywords

Acute myeloid leukemia relapse Stem cell transplantation Gemtuzumab ozogamicin ARA-C 

Notes

Acknowledgments

The data was partially presented as an abstract at ASH 2012.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    James K, Mangan SML (2011) Salvage therapy for relapsed or refractory acute myeloid leukemia. Ther Adv Hematol 2(2):73–82. doi: 10.1177/2040620711402533 CrossRefGoogle Scholar
  2. 2.
    van der Velden VHJ, te Marvelde JG, Hoogeveen PG, Bernstein ID, Houtsmuller AB, Berger MS, van Dongen JJM (2001) Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood 97(10):3197–3204. doi: 10.1182/blood.V97.10.3197 CrossRefGoogle Scholar
  3. 3.
    Bross PF, Beitz J, Chen G, Chen XH, Duffy E, Kieffer L, Roy S, Sridhara R, Rahman A, Williams G, Pazdur R (2001) Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 7(6):1490–1496PubMedGoogle Scholar
  4. 4.
    Filanovsky K, Shvidel L, Shtalrid M (2010) Advantage of MIDAM protocol in treatment of elderly patients with refractory and relapsing acute myeloid leukemia. J Clin Oncol 28(7):e115–e116. doi: 10.1200/JCO.2009.26.7930, author reply e117-8PubMedCrossRefGoogle Scholar
  5. 5.
    Cortes J, Tsimberidou AM, Alvarez R, Thomas D, Beran M, Kantarjian H, Estey E, Giles FJ (2002) Mylotarg combined with topotecan and cytarabine in patients with refractory acute myelogenous leukemia. Cancer Chemother Pharmacol 50(6):497–500PubMedCrossRefGoogle Scholar
  6. 6.
    Alvarado Y, Tsimberidou A, Kantarjian H, Cortes J, Garcia-Manero G, Faderl S, Thomas D, Estey E, Giles FJ (2003) Pilot study of Mylotarg, idarubicin and cytarabine combination regimen in patients with primary resistant or relapsed acute myeloid leukemia. Cancer Chemother Pharmacol 51(1):87–90PubMedCrossRefGoogle Scholar
  7. 7.
    Apostolidou E, Cortes J, Tsimberidou A, Estey E, Kantarjian H, Giles FJ (2003) Pilot study of gemtuzumab ozogamicin, liposomal daunorubicin, cytarabine and cyclosporine regimen in patients with refractory acute myelogenous leukemia. Leuk Res 27(10):887–891PubMedCrossRefGoogle Scholar
  8. 8.
    Tsimberidou A, Cortes J, Thomas D, Garcia-Manero G, Verstovsek S, Faderl S, Albitar M, Kantarjian H, Estey E, Giles FJ (2003) Gemtuzumab ozogamicin, fludarabine, cytarabine and cyclosporine combination regimen in patients with CD33+ primary resistant or relapsed acute myeloid leukemia. Leuk Res 27(10):893–897PubMedCrossRefGoogle Scholar
  9. 9.
    Piccaluga PP, Martinelli G, Rondoni M, Malagola M, Gaitani S, Visani G, Baccarani M (2004) First experience with gemtuzumab ozogamicin plus cytarabine as continuous infusion for elderly acute myeloid leukaemia patients. Leuk Res 28(9):987–990PubMedCrossRefGoogle Scholar
  10. 10.
    Specchia G, Pastore D, Carluccio P, Spinosa G, Giannoccaro M, Rizzi R, Mestice A, Liso V (2007) Gemtuzumab ozogamicin with cytarabine and mitoxantrone as a third-line treatment in a poor prognosis group of adult acute myeloid leukemia patients: a single-center experience. Ann Hematol 86(6):425–428PubMedCrossRefGoogle Scholar
  11. 11.
    Chevallier P, Delaunay J, Turlure P, Pigneux A, Hunault M, Garand R, Guillaume T, Avet-Loiseau H, Dmytruk N, Girault S, Milpied N, Ifrah N, Mohty M, Harousseau J-L (2008) Long-term disease-free survival after gemtuzumab, intermediate-dose cytarabine, and mitoxantrone in patients with CD33+ primary resistant or relapsed acute myeloid leukemia. J Clin Oncol 26(32):5192–5197. doi: 10.1200/jco.2007.15.9764 PubMedCrossRefGoogle Scholar
  12. 12.
    Stone RM, Moser B, Sanford B, Schulman P, Kolitz JE, Allen S, Stock W, Galinsky I, Vij R, Marcucci G, Hurd D, Larson RA (2011) High dose cytarabine plus gemtuzumab ozogamicin for patients with relapsed or refractory acute myeloid leukemia: cancer and leukemia group B study 19902. Leuk Res 35(3):329–333PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Pilorge S, Rigaudeau S, Rabian F, Sarkozy C, Taksin AL, Farhat H, Merabet F, Ghez S, Raggueneau V, Terré C, Garcia I, Renneville A, Preudhomme C, Castaigne S, Rousselot P (2014) Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse. Am J Hematol 89(4):399–403. doi: 10.1002/ajh.23653 PubMedCrossRefGoogle Scholar
  14. 14.
    Cohen AD, Luger SM, Sickles C, Mangan PA, Porter DL, Schuster SJ, Tsai DE, Nasta S, Gewirtz AM, Stadtmauer EA (2002) Gemtuzumab ozogamicin (Mylotarg) monotherapy for relapsed AML after hematopoietic stem cell transplant: efficacy and incidence of hepatic veno-occlusive disease. Bone Marrow Transplant 30(1):23–28PubMedCrossRefGoogle Scholar
  15. 15.
    Owonikoko T, Agha M, Balassanian R, Smith R, Raptis A (2007) Gemtuzumab therapy for isolated extramedullary AML relapse following allogeneic stem-cell transplant. Nat Clin Pract Oncol 4(8):491–495PubMedCrossRefGoogle Scholar
  16. 16.
    Tamai H, Shioi Y, Yamaguchi H, Okabe M, Wakita S, Mizuki T, Nakayama K, Inokuchi K, Tajika K, Dan K (2007) Treatment of relapsed acute myeloid leukemia with MLL/AF6 fusion after allogeneic hematopoietic stem cell transplantation with gemtuzumab ozogamicin with a long interval followed by donor lymphocyte infusion. Leukemia 22(6):1273–1274PubMedCrossRefGoogle Scholar
  17. 17.
    Sumi M, Ichikawa N, Nasu K, Shimizu I, Ueki T, Ueno M, Kobayashi H (2009) Gemtuzumab ozogamicin-induced long-term remission in a woman with acute myelomonocytic leukemia and bone marrow relapse following allogeneic transplantation. Int J Hematol 90(5):643–647. doi: 10.1007/s12185-009-0440-0 PubMedCrossRefGoogle Scholar
  18. 18.
    Ando T, Mitani N, Matsunaga K, Nakazora T, Gondo T, Yujiri T, Tanizawa Y (2010) Gemtuzumab ozogamicin therapy for isolated extramedullary AML relapse after allogeneic hematopoietic stem-cell transplantation. Tohoku J Exp Med 220(2):121–126. doi: 10.1620/tjem.220.121 PubMedCrossRefGoogle Scholar
  19. 19.
    Tachibana T, Tanaka M, Takasaki H, Numata A, Fujisawa S, Maruta A, Harada H, Mori H, Ishigatsubo Y, Kanamori H (2011) Successful treatment with gemtuzumab ozogamicin and donor lymphocyte infusion for acute myeloid leukemia relapsing after allogeneic stem cell transplantation. Int J Hematol 94(6):580–582. doi: 10.1007/s12185-011-0967-8 PubMedCrossRefGoogle Scholar
  20. 20.
    Pollyea DA, Artz AS, Stock W, Daugherty C, Godley L, Odenike OM, Rich E, Smith SM, Zimmerman T, Zhang Y, Huo D, Larson R, van Besien K (2007) Outcomes of patients with AML and MDS who relapse or progress after reduced intensity allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 40(11):1027–1032PubMedCrossRefGoogle Scholar
  21. 21.
    Shaw BE, Mufti GJ, Mackinnon S, Cavenagh JD, Pearce RM, Towlson KE, Apperley JF, Chakraverty R, Craddock CF, Kazmi MA, Littlewood TJ, Milligan DW, Pagliuca A, Thomson KJ, Marks DI, Russell NH (2008) Outcome of second allogeneic transplants using reduced-intensity conditioning following relapse of haematological malignancy after an initial allogeneic transplant. Bone Marrow Transplant 42(12):783–789PubMedCrossRefGoogle Scholar
  22. 22.
    Eapen M, Giralt SA, Horowitz MM, Klein JP, Wagner JE, Zhang MJ, Tallman MS, Marks DI, Camitta BM, Champlin RE, Ringden O, Bredeson CN, Martino R, Gale RP, Cairo MS, Litzow MR, deLima M (2004) Second transplant for acute and chronic leukemia relapsing after first HLA-identical sibling transplant. Bone Marrow Transplant 34(8):721–727PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Maya Koren-Michowitz
    • 1
    • 2
    Email author
  • Hannah Maayan
    • 1
  • Arie Apel
    • 1
  • Noga Shem-Tov
    • 1
  • Ronit Yerushalmi
    • 1
  • Yulia Volchek
    • 1
  • Abraham Avigdor
    • 1
    • 2
  • Avichai Shimoni
    • 1
    • 2
  • Arnon Nagler
    • 1
    • 2
  1. 1.Division of Hematology and Bone Marrow TransplantationThe Chaim Sheba Medical CenterTel HashomerIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael

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