Advertisement

Annals of Hematology

, Volume 97, Issue 11, pp 2195–2204 | Cite as

Effects of preemptive interferon-α monotherapy in acute leukemia patients with relapse tendency after allogeneic hematopoietic stem cell transplantation: a case-control study

  • Xiao-Ji Lin
  • Hai-ping Dai
  • Ai-Jing Wang
  • Feng Chen
  • Xiao Ma
  • Ai-Ning Sun
  • Xia-Ming Zhu
  • Hui-Ying Qiu
  • Zheng-Min Jin
  • Miao Miao
  • Sheng-Li Xue
  • Xin-liang Mao
  • De-Pei WuEmail author
  • Xiao-Wen TangEmail author
Original Article

Abstract

Interferon-α (IFN-α) inhibits tumor growth and mimics graft-versus-leukemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the current case-control study, we compared treatment responses in acute leukemia patients with relapse tendency post-allo-HSCT receiving preemptive IFN-α after withdrawal of immunosuppressants (n = 31) vs. receiving no IFN-α (n = 67). In the IFN-α group, 25 patients responded to the treatment without progressing to hematological relapse. In the non-IFN-α group, only 22 patients responded to the treatment. The response rate differed significantly (80.6 vs. 32.8%, P < 0.001). The 2-year cumulative incidence of relapse was 31.6 and 61.2% in the IFN-α and the non-IFN groups, respectively (P = 0.006). The 2-year leukemia-free survival and overall survival rate was 57.4 vs. 28.4% (P < 0.001) and 67.6 vs. 32.9% (P = 0.001), respectively. Among the 31 patients in the IFN-α group, 18 patients (58.1%) developed graft-versus-host disease (GVHD): 6 acute and 12 limited chronic GVHD. Patients who developed GVHD had higher treatment response rate than patients without GVHD (88.9 vs. 53.8%, P = 0.022). In conclusion, preemptive IFN-α therapy is a safe and effective treatment to prevent disease progression in high-risk patients with relapse tendency post-allo-HSCT.

Keywords

Acute leukemia IFN-α Hematopoietic stem cell transplantation Recurrence Preemptive therapy 

Notes

Acknowledgments

This work was supported by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), National Key R&D Program of China (2016YFC0902800), National Natural Science Foundation of China (81270645), NSFC Major Project of International Cooperation and Exchanges (81320108023), Frontier Clinical Technical Project Of the Science and Technology Department of Jiangsu Province (BE201765), and the Application of Basic Research Programs of Suzhou Municipal Science and Technology Project (SYS201457).

Compliance with ethical standards

Informed consent was obtained from patients in compliance with institutional guidelines. This study was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University.

Conflict of interest

The authors have no conflicts of interest to report.

References

  1. 1.
    Porter DL, Alyea EP, Antin JH, DeLima M, Estey E, Falkenburg JHF, Hardy N, Kroeger N, Leis J, Levine J, Maloney DG, Peggs K, Rowe JM, Wayne AS, Giralt S, Bishop MR, van Besien K (2010) NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 16:1467–1503CrossRefGoogle Scholar
  2. 2.
    Choi SJ, Lee JH, Lee JH, Kim S, Seol M, Lee YS, Lee JS, Kim WK, Chi HS, Lee KH (2004) Treatment of relapsed acute myeloid leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a high incidence of isolated extramedullary relapse. Leukemia 18:1789–1797CrossRefGoogle Scholar
  3. 3.
    Schmid C, Labopin M, Nagler A, Bornhäuser M, Finke J, Fassas A, Volin L, Gürman G, Maertens J, Bordigoni P, Holler E, Ehninger G, Polge E, Gorin NC, Kolb HJ, Rocha V, EBMT Acute Leukemia Working Party (2007) Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25:4938–4945CrossRefGoogle Scholar
  4. 4.
    Levine JE, Braun T, Penza SL, Beatty P, Cornetta K, Martino R, Drobyski WR, Barrett AJ, Porter DL, Giralt S, Leis J, Holmes HE, Johnson M, Horowitz M, Collins RH Jr (2002) Prospective trial of chemotherapy and donor leukocyte infusions for relapse of advanced myeloid malignancies after allogeneic stem-cell transplantation. J Clin Oncol 20:405–412CrossRefGoogle Scholar
  5. 5.
    Campana D, Leung W (2013) Clinical significance of minimal residual disease in patients with acute leukaemia undergoing haematopoietic stem cell transplantation. Br J Haematol 162:147–161CrossRefGoogle Scholar
  6. 6.
    Dominietto A, Pozzi S, Miglino M, Albarracin F, Piaggio G, Bertolotti F, Grasso R, Zupo S, Raiola AM, Gobbi M, Frassoni F, Bacigalupo A (2007) Donor lymphocyte infusions for the treatment of minimal residual disease in acute leukemia. Blood 109:5063–5064CrossRefGoogle Scholar
  7. 7.
    Tan Y, Du K, Luo Y et al (2014) Superiority of preemptive donor lymphocyte infusion based on minimal residual disease in acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Transfusion 54:1493–1500CrossRefGoogle Scholar
  8. 8.
    Tarlock K, Chang B, Cooper T, Gross T, Gupta S, Neudorf S, Adlard K, Ho PA, McGoldrick S, Watt T, Templeman T, Sisler I, Garee A, Thomson B, Woolfrey A, Estey E, Meshinchi S, Pollard JA (2015) Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia. Pediatr Blood Cancer 62:1048–1054CrossRefGoogle Scholar
  9. 9.
    Vilcek J (2006) Fifty years of interferon research: aiming at a moving target. Immunity 25:343–348CrossRefGoogle Scholar
  10. 10.
    Guilhot F, Chastang C, Michallet M et al (1997) Interferon alpha-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Eng J Med 337:223–229CrossRefGoogle Scholar
  11. 11.
    Arellano ML, Langston A, Winton E, Flowers CR, Waller EK (2007) Treatment of relapsed acute leukemia after allogeneic transplantation: a single center experience. Biol Blood Marrow Transplant 13:116–123CrossRefGoogle Scholar
  12. 12.
    Mo XD, Zhang XH, Xu LP, Wang Y, Yan CH, Chen H, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ (2015) Interferon-α: a potentially effective treatment for minimal residual disease in acute leukemia/myelodysplastic syndrome after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 21:1939–1947CrossRefGoogle Scholar
  13. 13.
    Armand P, Gibson CJ, Cutler C, Ho VT, Koreth J, Alyea EP, Ritz J, Sorror ML, Lee SJ, Deeg HJ, Storer BE, Appelbaum FR, Antin JH, Soiffer RJ, Kim HT (2012) A disease risk index for patients undergoing allogeneic stem cell transplantation. Blood 120:905–913CrossRefGoogle Scholar
  14. 14.
    Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED (1995) 1994 consensus conference on acute GVHD grading. Bone Marrow Transplant 15:825–828PubMedGoogle Scholar
  15. 15.
    Lee SJ, Vogelsang G, Flowers ME (2003) Chronic graft-versus-host disease. Biol Blood Marrow Transplant 9:215–233CrossRefGoogle Scholar
  16. 16.
    Yan CH, Liu DH, Liu KY, Xu LP, Liu YR, Chen H, Han W, Wang Y, Qin YZ, Huang XJ (2012) Risk stratification-directed donor lymphocyte infusion could reduce relapse of standard-risk acute leukemia patients after allogeneic hematopoietic stem cell transplantation. Blood 119:3256–3262CrossRefGoogle Scholar
  17. 17.
    Terwey TH, Hemmati PG, Nagy M, Pfeifer H, Gökbuget N, Brüggemann M, le Duc TM, le Coutre P, Dörken B, Arnold R (2014) Comparison of chimerism and minimal residual disease monitoring for relapse prediction after allogeneic stem cell transplantation for adult acute lymphoblastic leukemia. Biol Blood Marrow Transplant 20:1522–1529CrossRefGoogle Scholar
  18. 18.
    Horn B, Soni S, Khan S, Petrovic A, Breslin N, Cowan M, Pelle-Day G, Cooperstein E, Baxter-Lowe LA (2009) Feasibility study of preemptive withdrawal of immunosuppression based on chimerism testing in children undergoing myeloablative allogeneic transplantation for hematologic malignancies. Bone Marrow Transplant 43:469–476CrossRefGoogle Scholar
  19. 19.
    Platzbecker U, Wermke M, Radke J, Oelschlaegel U, Seltmann F, Kiani A, Klut IM, Knoth H, Röllig C, Schetelig J, Mohr B, Graehlert X, Ehninger G, Bornhäuser M, Thiede C (2012) Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 26:381–389CrossRefGoogle Scholar
  20. 20.
    Anguille S, Lion E, Willemen Y, van Tendeloo VFI, Berneman ZN, Smits ELJM (2011) Interferon-α in acute myeloid leukemia: an old drug revisited. Leukemia 25:739–748CrossRefGoogle Scholar
  21. 21.
    Smits EL, Anguille S, Berneman ZN (2013) Interferon α may be back on track to treat acute myeloid leukemia. Oncoimmunology 2:e23619CrossRefGoogle Scholar
  22. 22.
    Gesundheit B, Shapira MY, Resnick IB, Amar A, Kristt D, Dray L, Budowski E, Or R (2009) Successful cell-mediated cytokine-activated immunotherapy for relapsed acute myeloid leukemia after hematopoietic stem cell transplantation. Am J Hematol 84:188–190CrossRefGoogle Scholar
  23. 23.
    Singhal S, Powles R, Treleaven J, Mehta J (1997) Sensitivity of secondary acute myeloid leukemia relapsing after allogeneic bone marrow transplantation to immunotherapy with interferon-alpha 2b. Bone Marrow Transplant 19:1151–1153CrossRefGoogle Scholar
  24. 24.
    Kumar AJ, Hexner EO, Frey NV, Luger SM, Loren AW, Reshef R, Boyer J, Smith J, Stadtmauer EA, Levine BL, June CH, Porter DL, Goldstein SC (2013) Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation. Biol Blood Marrow Transplant 19:1094–1101CrossRefGoogle Scholar
  25. 25.
    Liga M, Triantafyllou E, Tiniakou M, Lambropoulou P, Karakantza M, Zoumbos NC, Spyridonidis A (2013) High alloreactivity of low-dose prophylactic donor lymphocyte infusion in patients with acute leukemia undergoing allogeneic hematopoietic cell transplantation with an alemtuzumab-containing conditioning regimen. Biol Blood Marrow transplant 19:75–81CrossRefGoogle Scholar
  26. 26.
    Odom LF, August CS, Githens JH, Humbert JR, Morse H, Peakman D, Sharma B, Rusnak SL, Johnson FB (1978) Remission of relapsed leukaemia during a graft-versus-host reaction. A “graft-versus-leukaemia reaction” in man? Lancet 2:537–540CrossRefGoogle Scholar
  27. 27.
    Higano CS, Brixley M, Bryant EM et al (1990) Durable complete remission of acute non lymphocytic leukemia associated with discontinuation of immunosuppression following relapse after allogeneic bone marrow transplantation. A case report of a probable graft-versus-leukemia effect. Transplantation 50:175–177CrossRefGoogle Scholar
  28. 28.
    Collins RH Jr, Rogers ZR, Bennett M et al (1992) Hematologic relapse of chronic myelogenous leukemia following allogeneic bone marrow transplantation: apparent graft-versus-leukaemia effect following abrupt discontinuation of immunosuppression. Bone Marrow Transplant 10:391–395PubMedGoogle Scholar
  29. 29.
    White JM, Devereux S, Pagliuca A et al (2006) Koebnerizing sclerodermatous graft-versus-host disease caused by donor lymphocyte infusion and interferon-alpha. Br J Dermatol 155:621–623CrossRefGoogle Scholar
  30. 30.
    Klingemann HG, Grigg AP, Wilkie-Boyd K, Barnett MJ, Eaves AC, Reece DE, Shepherd JD, Phillips GL (1991) Treatment with recombinant interferon (alpha-2b) early after bone marrow transplantation in patients at high risk for relapse [corrected]. Blood 78:3306–3311PubMedGoogle Scholar
  31. 31.
    Samson D, Volin L, Schanz U, Bosi A, Gahrtron G (1996) Feasibility and toxicity of interferon maintenance therapy after allogeneic BMT for multiple myeloma: a pilot study of the EBMT. Bone Marrow Transplant 17:759–762PubMedGoogle Scholar
  32. 32.
    Mehta J, Powles R, Singhal S, Tait D, Swansbury J, Treleaven J (1995) Cytokine-mediated immunotherapy with or without donor leukocytes for poor-risk acute myeloid leukemia relapsing after allogeneic bone marrow transplantation. Bone Marrow Transplant 16:133–137PubMedGoogle Scholar
  33. 33.
    Papewalis C, Jacobs B, Wuttke M, Ullrich E, Baehring T, Fenk R, Willenberg HS, Schinner S, Cohnen M, Seissler J, Zacharowski K, Scherbaum WA, Schott M (2008) IFN-alpha skews monocytes into CD56+-expressing dendritic cells with potent functional activities in vitro and in vivo. J Immunol 180:1462–1470CrossRefGoogle Scholar
  34. 34.
    Diamond MS, Kinder M, Matsushita H, Mashayekhi M, Dunn GP, Archambault JM, Lee H, Arthur CD, White JM, Kalinke U, Murphy KM, Schreiber RD (2011) Type I interferon is selectively required by dendritic cells for immune rejection of tumors. J Exp Med 208:1989–2003CrossRefGoogle Scholar
  35. 35.
    Luft T, Pang KC, Thomas E et al (1998) Type I IFNs enhance the terminal differentiation of dendritic cells. J Immunol 161:1947–1953PubMedGoogle Scholar
  36. 36.
    Paquette RL, Hsu NC, Kiertscher SM, Park AN, Tran L, Roth MD, Glaspy JA (1998) Interferon-alpha and granulocyte-macrophage colony-stimulating factor differentiate peripheral blood monocytes into potent antigen-presenting cells. J Leukoc Biol 64:358–367CrossRefGoogle Scholar
  37. 37.
    Lapenta C, Santini SM, Logozzi M, Spada M, Andreotti M, di Pucchio T, Parlato S, Belardelli F (2003) Potent immune response against HIV-1 and protection from virus challenge in hu-PBL-SCID mice immunized with inactivated virus-pulsed dendritic cells generated in the presence of IFN-alpha. J Exp Med 198:361–367CrossRefGoogle Scholar
  38. 38.
    Tosi D, Valenti R, Cova A, Sovena G, Huber V, Pilla L, Arienti F, Belardelli F, Parmiani G, Rivoltini L (2004) Role of cross-talk between IFN-alpha-induced monocyte-derived dendritic cells and NK cells in priming CD8+ T cell responses against human tumor antigens. J Immunol 172:5363–5370CrossRefGoogle Scholar
  39. 39.
    Grigg A, Kannan K, Schwarer AP, Spencer A, Szer J (2001) Chemotherapy and granulocyte colony stimulating factor-mobilized blood cell infusion followed by interferon-alpha for relapsed malignancy after allogeneic bone marrow transplantation. Intern Med J 31:15–22CrossRefGoogle Scholar
  40. 40.
    Benjamin R, Khwaja A, Singh N, McIntosh J, Meager A, Wadhwa M, Streck C, Ng C, Davidoff AM, Nathwani AC (2007) Continuous delivery of human type I interferons (alpha/beta) has significant activity against acute myeloid leukemia cells in vitro and in a xenograft model. Blood 109:1244–1247CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xiao-Ji Lin
    • 1
    • 2
    • 3
    • 4
  • Hai-ping Dai
    • 1
    • 2
    • 3
    • 4
  • Ai-Jing Wang
    • 1
    • 2
    • 3
    • 4
  • Feng Chen
    • 1
    • 2
    • 3
    • 4
  • Xiao Ma
    • 1
    • 2
    • 3
    • 4
  • Ai-Ning Sun
    • 1
    • 2
    • 3
    • 4
  • Xia-Ming Zhu
    • 1
    • 2
    • 3
    • 4
  • Hui-Ying Qiu
    • 1
    • 2
    • 3
    • 4
  • Zheng-Min Jin
    • 1
    • 2
    • 3
    • 4
  • Miao Miao
    • 1
    • 2
    • 3
    • 4
  • Sheng-Li Xue
    • 1
    • 2
    • 3
    • 4
  • Xin-liang Mao
    • 5
  • De-Pei Wu
    • 1
    • 2
    • 3
    • 4
    Email author
  • Xiao-Wen Tang
    • 1
    • 2
    • 3
    • 4
    Email author
  1. 1.Jiangsu Institute of HematologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina
  2. 2.Institute of Blood and Marrow TransplantationSuzhouChina
  3. 3.Collaborative Innovation Center of HematologySoochow UniversitySuzhouChina
  4. 4.Key Laboratory of Thrombosis and Hemostasis of Ministry of HealthSuzhouChina
  5. 5.Department of Pharmacology, College of Pharmaceutical SciencesSoochow UniversitySuzhouChina

Personalised recommendations