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Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions

Leukemia volume 15, pages 1339–1346 (2001)Cite this article

Abstract

In this prospective study we analyzed pre-emptive donor leukocyte infusions (DLI) in 82 consecutive patients transplanted with partially T cell-depleted grafts for acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation and multiple myeloma. Donors were HLA-identical siblings. Patients without significant acute (>grade 1) and/or chronic GVHD were scheduled to be treated with DLI (35 patients) and 31 actually received DLI. Patients who developed acute GVHD >grade 1 and/or chronic GVHD were not scheduled to receive DLI and served as a comparison group (47 patients). The median interval between BMT and DLI was 22 weeks. The first six patients received 0.7 × 108 CD3+cells/kg body weight (b.w.). Five out of these six patients developed acute GVHD (grade 1: n = 2, grade 3: n = 2 and grade 4: n = 1) which was more frequent and more severe than we had anticipated. In the next 25 patients the number of T lymphocytes was diminished to 0.1 × 108 CD3+ cells/kg b.w. which resulted in less frequent and less severe GVHD. Eight patients in this group developed acute GVHD (grade 1: n = 4, grade 2: n = 4) and three patients had limited chronic GVHD. Patients in the DLI group needed more time to establish complete donor chimerism confirmed by a higher number of mixed chimeras at 6 months after BMT. The projected 3-year probability of disease-free survival was 77% for the 35 patients intended to treat with DLI and 45% for the patients of the comparison group (P = 0.024). Relapse rate at 36 months after transplantation was 18% in the patients who were intended to treat with DLI and 44% in the comparison group (P = 0.026). We conclude that pre-emptive DLI is feasible and generates favorable relapse rates in patients who are at high risk for relapse. Furthermore, the incidence and severity of GVHD disease after DLI is dependent on the number of CD3+ cells infused.

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References

  1. Blaise D, Gravis G, Maraninchi D . Long-term follow-up of T-cell depletion for bone marrow transplantation (letter) Lancet 1993 341: 51–52

    Article  CAS  Google Scholar 

  2. Bron D . Graft-versus-host disease Curr Opin Oncol 1994 6: 358–364

    Article  CAS  Google Scholar 

  3. Gardiner N, Lawler M, O'Riordan J, De'Arce M, McCann SR . Donor chimaerism is a strong indicator of disease-free survival following bone marrow transplantation for chronic myeloid leukaemia Leukemia 1997 3: 512–515

    Google Scholar 

  4. Miralbell R, Chapuis B, Nouet P, Helg C, Delorme H, Wacker P, Wyss M, Kurtz J . Conditioning the leukemic patient before allogeneic BMT: value of intensifying immunosuppression in the context of different levels of T lymphocyte depletion of the graft Bone Marrow Transplant 1993 11: 447–451

    CAS  PubMed  Google Scholar 

  5. Powles R, Singhal S, Treleaven J, Kulkarni S, Horton C, Mehta J . Identification of patients who may benefit from prophylactic immunotherapy after bone marrow transplantation for acute myeloid leukemia on the basis of lymphocyte recovery early after transplantation Blood 1998 91: 3481–3486

    CAS  PubMed  Google Scholar 

  6. Schattenberg A, Preijers F, Mensink E, Bär B, Schaap N, Geurts van Kessel A, van der Maazen R, de Witte T . Survival in first or second remission after lymphocyte depleted transplantation for philadelphia chromosome positive CML in first chronic phase Bone Marrow Transplant 1997 19: 1205–1212

    Article  CAS  Google Scholar 

  7. Slavin S, Or R, Naparstek E, Eckerstein A, Weiss L . Cellular mediated immunotherapy of leukemia in conjuction with autologous and allogeneic bone marrow transplantation in experimental animals and man Blood 1988 72: 407a

    Google Scholar 

  8. Slavin S, Or R, Kapelushnik Y, Drakos P, Ackerstein A, Vourka-Karussis U, Weiss L, Nagler A . Immunotherapy of minimal residual disease in conjunction with autologous and allogeneic bone marrow transplantation Leukemia 1992 6: (Suppl. 4) 164–166

    PubMed  Google Scholar 

  9. van Leeuwen JE, van Tol MJ, Joosten AM, Wijnen JT, Verweij PJ, Khan PM, Vossen JM . Persistence of host-type hematopoiesis after allogeneic bone marrow transplantation for leukemia is significantly related to the recipient's age and/or the conditioning regimen, but it is not associated with an increased risk of relapse Blood 1994 83: 3059–3067

    CAS  PubMed  Google Scholar 

  10. Ringden O, Sundberg B, Lonnqvist B, Tollemar J, Gahrton G, Nilsson B . Allogeneic bone marrow transplantation for leukemia: factors of importance for long-term survival and relapse Bone Marrow Transplant 1988 3: 281–290

    CAS  PubMed  Google Scholar 

  11. Patterson J, Prentice HG, Brenner MK, Gilmore M, Janossy G, Ivory K, Skeggs D, Morgan H, Lord J, Blacklock HA, Hoffbrand AV, Apperley JF, Goldman JM, Burnett A, Gribben J, Alcorn M, Pearson C, McVickers I, Hann IM, Reid C, Wardle D, Gravett PJ, Bacigalupo A, Robertson AG . Graft rejection following HLA matched T-lymphocyte depleted bone marrow transplantation Br J Haematol 1986 63: 221–230

    Article  CAS  Google Scholar 

  12. Apperley JF, Jones L, Hale G, Waldmann H, Hows J, Rombos Y, Tsatalas C, Marcus RE, Goolden AW, Gordon Smith, Catovsky D, Galton DAG, Goldman JM . Bone marrow transplantation for patients with chronic myeloid leukaemia: T-cell depletion with Campath-1 reduces the incidence of graft-versus-host disease but may increase the risk of leukaemic relapse Bone Marrow Transplant 1986 1: 53–66

    CAS  PubMed  Google Scholar 

  13. Bortin MM, Horowitz MM, Rimm AA . Increasing utilization of allogeneic bone marrow transplantation. Results of the 1988–1990 survey Ann Intern Med 1992 116: 505–512

    Article  CAS  Google Scholar 

  14. Leclair B, Fregeau CJ, Aye MT, Fourney RM . DNA typing for bone marrow engraftment follow-up after allogeneic transplant: a comparative study of current technologies Bone Marrow Transplant 1995 16: 43–55

    CAS  PubMed  Google Scholar 

  15. Hale G, Waldmann H . Control of graft-versus-host disease and graft rejection by T cell depletion of donor and recipient with Campath-1 antibodies. Results of matched sibling transplants for malignant diseases Bone Marrow Transplant 1994 13: 597–611

    CAS  PubMed  Google Scholar 

  16. Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik J, Or R . Allogeneic cell therapy for relapsed leukemia after bone marrow transplantation with donor peripheral blood lymphocytes Exp Hematol 1995 23: 1553–1562

    CAS  PubMed  Google Scholar 

  17. Schaap N, Schattenberg A, Bär B, Preijers F, Geurts van Kessel A, van der Maazen R, de Boo T, de Witte T . Outcome of transplantation for standard risk leukaemia with grafts depleted of lymphocytes after conditioning with an intensified regimen Br J Haematol 1997 98: 750–759

    Article  CAS  Google Scholar 

  18. Van Rhee F, Lin F, Cullis JO, Spencer A, Cross NCP, Chase A, Garicochea B, Bungey J, Barret J, Goldman JM . Relapse of chronic myeloid leukemia after allogeneic bone marrow transplant: the case for giving donor leukocyte transfusions before the onset of hematologic relapse Blood 1994 83: 3377–3383

    CAS  PubMed  Google Scholar 

  19. Barrett AJ, Mavroudis D, Tisdale J, Molldrem J, Clave E, Dunbar C, Cottler F, Phang S, Carter C, Okunnieff P, Young NS, Read EJ . T cell-depleted bone marrow transplantation and delayed T cell add-back to control acute GVHD and conserve a graft-versus-leukemia effect Bone Marrow Transplant 1998 21: 543–551

    Article  CAS  Google Scholar 

  20. Helg C, Starobinski M, Jeannet M, Chapuis B . Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation Leuk Lymphoma 1998 29: 301–313

    Article  CAS  Google Scholar 

  21. Bortin MM, Rimm AA, Saltzstein EC, Rodey GE . Graft versus leukemia. Apparent independent antihost and antileukemia activity of transplanted immunocompetent cells Transplantation 1973 16: 182–188

    Article  CAS  Google Scholar 

  22. Truitt RL, Lefevre AV, Shih CC. Gale RP, Champlin R (eds) . Graft-vs-leukemia reactions Experimental Models and Clinical Trials Liss: New York 1987 pp 219–232

    Google Scholar 

  23. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringden O, Rozman C, Speck B . Graft-versus-leukemia reactions after bone marrow transplantation Blood 1990 75: 555–562

    CAS  PubMed  Google Scholar 

  24. Imamura M, Hashino S, Tanaka J . Graft-versus-leukemia effect and its clinical implications Leuk Lymphoma 1996 23: 477–492

    Article  CAS  Google Scholar 

  25. Johnson BD, Hanke CA, Truitt RL . The graft-versus-leukemia effect of post-transplant donor leukocyte infusion Leuk Lymphoma 1996 23: 1–9

    Article  CAS  Google Scholar 

  26. Slavin S, Weiss L, Morecki S, Weigensberg M . Eradication of murine leukemia with histo-incompatible marrow grafts in mice conditioned with total lymphoid irradiation (TLI) Cancer Immunol Immunother 1981 11: 155–158

    Article  Google Scholar 

  27. Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L, Collins NH, Boulad F, Castro Malaspina, Childs BH, Gillio AP, Kernan NA . Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease Blood 1995 86: 1261–1268

    CAS  PubMed  Google Scholar 

  28. Sullivan KM, Storb R, Buckner CD, Fefer A, Fisher L, Weiden PL, Witherspoon RP, Appelbaum FR, Banaji M, Hansen J, Martin P, Sanders JE, Singer J, Thomas D . Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms N Engl J Med 1989 320: 828–834

    Article  CAS  Google Scholar 

  29. Naparstek E, Or R, Nagler A, Cividalli G, Engelhard D, Aker M, Gimon Z, Manny N, Sacks T, Tochner Z, Weiss L, Samuel S, Brautbar C, Hale G, Waldmann H, Steinberg SM, Slavin S . T-cell-depleted allogeneic bone marrow transplantation for acute leukaemia using Campath-1 antibodies and post-transplant administration of donor's peripheral blood lymphocytes for prevention of relapse Br J Haematol 1995 89: 506–515

    Article  CAS  Google Scholar 

  30. de Witte T, Raymakers R, Plas A, Koekman E, Wessels H, Haanen C . Bone marrow repopulation capacity after transplantation of lymphocyte-depleted allogeneic bone marrow using counterflow centrifugation Transplantation 1984 37: 151–155

    Article  CAS  Google Scholar 

  31. Plas A, de Witte T, Wessels H, Haanen C . A new multichamber counterflow centrifugation rotor with high-separation capacity and versatile potentials Exp Hematol 1988 16: 355–359

    CAS  PubMed  Google Scholar 

  32. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, Lerner KG, Thomas ED . Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors Transplantation 1974 18: 295–304

    Article  CAS  Google Scholar 

  33. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE, Hackman R, Tsoi MS, Storb R, Thomas ED . Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients Am J Med 1980 69: 204–217

    Article  CAS  Google Scholar 

  34. Schattenberg A, de Witte T, Salden M, Vet J, van Dijk B, Smeets D, Hoogenhout J, Haanen C . Mixed hematopoietic chimerism after allogeneic transplantation with lymphocyte-depleted bone marrow is not associated with a higher incidence of relapse Blood 1989 73: 1367–1372

    CAS  PubMed  Google Scholar 

  35. Schattenberg A, Bär B, Vet J, Van Dijk B, Smeets D, de Witte T . Comparison of chimerism of red cells with that of granulocytes, T lymphocytes, and bone marrow cells in recipients of marrow depleted of lymphocytes using counterflow centrifugation Leuk Lymphoma 1991 5: 171–177

    Article  CAS  Google Scholar 

  36. McCann SR, Lawler M . Mixed chimaerism; detection and significance following BMT Bone Marrow Transplant 1993 11: 91–94

    CAS  PubMed  Google Scholar 

  37. Bär BM, Schattenberg A, Van Dijk BA, De Man AJ, Kunst VA, de Witte TM . Host and donor erythrocyte repopulation patterns after allogeneic bone marrow transplantation analysed with antibody-coated fluorescent microspheres Br J Haematol 1989 72: 239–245

    Article  Google Scholar 

  38. De Man AJ, Foolen WJ, Van Dijk BA, Kunst VA, de Witte TM . A fluorescent microsphere method for the investigation of erythrocyte chimaerism after allogeneic bone marrow transplantation using antigenic differences Vox Sang 1988 55: 37–41

    Article  CAS  Google Scholar 

  39. Hendriks EC, De Man AJ, van Berkel YC, Stienstra S, de Witte T . Flow cytometric method for the routine follow-up of red cell populations after bone marrow transplantation Br J Haematol 1997 97: 141–145

    Article  CAS  Google Scholar 

  40. Bär BM, Schattenberg A, Mensink EJ, Geurts van Kessel A, Smetsers T, Knops G, Linders E, de Witte T . Donor leukocyte infusions for chronic myeloid leukemia relapsed after allogeneic bone marrow transplantation J Clin Oncol 1993 11: 513–519

    Article  Google Scholar 

  41. Kaplan EL, Meier P . Nonparametric estimation from incomplete observations Am Stat Assoc 1958 53: 457–466

    Article  Google Scholar 

  42. Johnson BD, Truitt RL . Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease Blood 1995 85: 3302–3312

    CAS  PubMed  Google Scholar 

  43. Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L, Collins NH, O'Reilly RJ . Adoptive immunotherapy using donor leukocytes following bone marrow transplantation for chronic myeloid leukemia: is T cell dose important in determining biological response? Bone Marrow Transplant 1995 15: 591–594

    CAS  PubMed  Google Scholar 

  44. Drobyski WR, Keever CA, Roth MS, Koethe S, Hanson G, McFadden P, Gottschall JL, Ash RC, van Tuinen P, Horowitz MM . Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose Blood 1993 82: 2310–2318

    CAS  PubMed  Google Scholar 

  45. Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, Van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H . Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients Blood 1995 86: 2041–2050

    CAS  Google Scholar 

  46. Schaap N, Schattenberg A, Bär B, Mensink E, de Man A, Geurts van Kessel A, de Witte T . Red blood cell phenotyping is a sensitive technique for monitoring chronic myeloid leukaemia patients after T-cell-depleted bone marrow transplantation and after donor leucocyte infusion Br J Haematol 2000 108: 116–125

    Article  CAS  Google Scholar 

  47. Porter DL, Collins RH, Shpilberg O, Drobyski WR, Connors JM, Sproles A, Antin JH . Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions Biol Blood Marrow Transplant 1999 5: 253–261

    Article  CAS  Google Scholar 

  48. Schattenberg A, Schaap N, van deWiel van Kemenade E, Bär B, Preijers F, van der Maazen R, Roovers E, de Witte T . In relapsed patients after lymphocyte depleted bone marrow transplantation the percentage of donor T lymphocytes correlates well with the outcome of donor leukocyte infusion Leuk Lymphoma 1999 32: 317–325

    Article  CAS  Google Scholar 

  49. Drobyski WR, Hessner MJ, Klein JP, Kabler BC, Vesole DH, Keever TC . T-cell depletion plus salvage immunotherapy with donor leukocyte infusions as a strategy to treat chronic-phase chronic myelogenous leukemia patients undergoing HLA-identical sibling marrow transplantation Blood 1999 94: 434–441

    CAS  PubMed  Google Scholar 

  50. Porter DL, Roth MS, Lee SJ, McGarigle C, Ferrara JL, Antin JH . Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation Bone Marrow Transplant 1996 18: 975–980

    CAS  PubMed  Google Scholar 

  51. Collins RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R, Goodman SA, Wolff SN, Hu W, Verfaillie C, List A, Dalton W, Ognoskie N, Chetrit A, Antin JH, Nemunaitis J . Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation J Clin Oncol 1997 15: 433–444

    Article  Google Scholar 

  52. Keil F, Haas OA, Fritsch G, Kalhs P, Lechner K, Mannhalter C, Reiter E, Niederwieser D, Hoecker P, Greinix HT . Donor leukocyte infusion for leukemic relapse after allogeneic marrow transplantation: lack of residual donor hematopoiesis predicts aplasia Blood 1997 89: 3113–3117

    CAS  PubMed  Google Scholar 

  53. Baurmann H, Nagel S, Binder T, Neubauer A, Siegert W, Huhn D . Kinetics of the graft-versus-leukemia response after donor leukocyte infusions for relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation Blood 1998 92: 3582–3590

    CAS  PubMed  Google Scholar 

  54. Alyea EP, Soiffer RJ, Canning C, Neuberg D, Schlossman R, Pickett C, Collins H, Wang Y, Anderson KC, Ritz J . Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant Blood 1998 91: 3671–3680

    CAS  PubMed  Google Scholar 

  55. Champlin R, Ho W, Gajewski J, Feig S, Burnison M, Holley G, Greenberg P, Lee K, Schmid I, Giorgi J . Selective depletion of CD8+ T lymphocytes for prevention of graft-versus-host disease after allogeneic bone marrow transplantation Blood 1990 76: 418–423

    CAS  PubMed  Google Scholar 

  56. Giralt S, Hester J, Huh Y, Hirsch-Ginsberg C, Rondon G, Seong D, Lee M, Gajewski J, van Besien K, Khouri I . CD8-depleted donor lymphocyte infusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation Blood 1995 86: 4337–4343

    CAS  PubMed  Google Scholar 

  57. Bonini C, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L, Ponzoni M, Rossini S, Marvilio F, Traversari C, Bordignon C . HSV-TK gene transfer into donor lymphocytes for control of allogeneic graft-versus-leukemia Science 1997 276: 1719–1724

    Article  CAS  Google Scholar 

  58. Verzeletti S, Bonini C, Marktel S, Nobili N, Ciceri F, Traversari C, Bordignon C . Herpes simplex virus thymidine kinase gene transfer for controlled graft-versus-host disease and graft-versus-leukemia: clinical follow-up and improved new vectors Hum Gene Ther 1998 9: 2243–2251

    Article  CAS  Google Scholar 

  59. Falkenburg JH, Wafelman AR, Joosten P, Smit WM, van Bergen CAM, Bongaerts R, Lurvink E, van der Hoorn M, Kluck P, Landegent JE, Kluin-Nelemans H, Fibbe WE, Willemze R . Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes Blood 1999 94: 1201–1208

    CAS  PubMed  Google Scholar 

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  1. Department of Hematology, University Medical Center St Radboud Nijmegen, Nijmegen, The Netherlands

    N Schaap, A Schattenberg, B Bär & T de Witte

  2. Central Hematology Laboratory, University Medical Center St Radboud Nijmegen, Nijmegen, The Netherlands

    F Preijers & E van de Wiel van Kemenade

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Schaap, N., Schattenberg, A., Bär, B. et al. Induction of graft-versus-leukemia to prevent relapse after partially lymphocyte-depleted allogeneic bone marrow transplantation by pre-emptive donor leukocyte infusions. Leukemia 15, 1339–1346 (2001). https://doi.org/10.1038/sj.leu.2402203

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