Transplantation of allogeneic CD34+-selected cells followed by early T-cell add-backs: favorable results in acute and chronic myeloid leukemia.

BACKGROUND The aim of this study was to investigate preservation of anti-leukemic activity and protection from opportunistic infections after transplantation of allogeneic + cells in patients with hematologic malignancies and bad prognosis. Methods Thirty-three patients [median age 42 years, range 23-55 years, diagnosis AML/myelodysplastic syndrome (MDS) 14, ALL nine, CML seven and multiple myeloma (MM) three] received myeloablative conditioning followed by infusion of selected CD34+ cells from matched unrelated donors (31) or HLA-identical siblings (two). Early donor lymphocyte infusions (DLI; 0.5 and 1.0 x 10(6) CD3+ cells/kg) were given while patients were on immunosuppressive therapy. RESULTS Ninety-seven per cent of patients engrafted and 24 of 29 patients surviving more than 30 days received at least one pre-emptive DLI. Three patients (10%) developed acute (a)GvHD (two grade I-II, one grade III-IV) spontaneously, and 16 patients (67%) developed aGvHD after DLI (12 grade I-II, four grade III-IV). Eight of 24 evaluable patients developed chronic (c)GvHD (33%, six limited, two extensive). After a median follow-up of 590 days (range 138-1610 days) 18 patients were alive (55%), 16 in complete remission (CR), one in hematologic and one in molecular relapse. Seven patients died after relapse (21%) and eight died from transplantation-related causes (24%). Patients with myeloid malignancies had a significantly better survival than patients with ALL or MM (74%+/-10 vs. 30%+/-13, P<0.05). DISCUSSION Early pre-emptive low-dose DLI following transplantation of selected CD34+ cells from unrelated donors after myeloablative conditioning is feasible and effective without undue toxicity, especially in patients with myeloid malignancies.

[1]  L. To,et al.  Selected CD34 blood cell allografts for older patients: low transplant-related mortality, graft failure and acute GvHD. , 2003, Cytotherapy.

[2]  J. Madrigal,et al.  Factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients , 2003, Bone Marrow Transplantation.

[3]  H. Einsele,et al.  Infectious complications after allogeneic stem cell transplantation: epidemiology and interventional therapy strategies , 2003, Annals of Hematology.

[4]  D. Pillay,et al.  Reconstitution of the Epstein-Barr virus-specific cytotoxic T-lymphocyte response following T-cell-depleted myeloablative and nonmyeloablative allogeneic stem cell transplantation. , 2003, Blood.

[5]  S. Mackinnon,et al.  Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. , 2003, Blood.

[6]  M. Shlomchik,et al.  Memory CD4+ T cells do not induce graft-versus-host disease. , 2003, The Journal of clinical investigation.

[7]  F. Baron,et al.  Low incidence of acute graft-versus-host disease after non-myeloablative stem cell transplantation with CD8-depleted peripheral blood stem cells: an update. , 2003, Haematologica.

[8]  T. Luft,et al.  Addition of a low fixed number of CD3+ cells to CD34-enriched allografts: effects on engraftment, graft-versus-host disease, and survival after related and unrelated peripheral stem cell transplantation. , 2003, Journal of hematotherapy & stem cell research.

[9]  N. Young,et al.  Cyclosporine is required to prevent severe acute GVHD following T-cell-depleted peripheral blood stem cell transplantation , 2003, Bone Marrow Transplantation.

[10]  D. Milligan,et al.  Polyoma viruria following T-cell-depleted allogeneic transplants using Campath-1H: incidence and outcome in relation to graft manipulation, donor type and conditioning , 2003, Bone Marrow Transplantation.

[11]  A. Elmaagacli,et al.  Outcome of transplantation of highly purified peripheral blood CD34+ cells with T-cell add-back compared with unmanipulated bone marrow or peripheral blood stem cells from HLA-identical sibling donors in patients with first chronic phase chronic myeloid leukemia. , 2003, Blood.

[12]  G. Kobbe,et al.  Quantitative real‐time reverse‐transcription polymerase chain reaction for diagnosis of BCR‐ABL positive leukemias and molecular monitoring following allogeneic stem cell transplantation , 2003, European journal of haematology.

[13]  J. Gribben,et al.  Comparable outcome with T-cell-depleted unrelated-donor versus related-donor allogeneic bone marrow transplantation. , 2002, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[14]  Catherine J. Wu,et al.  Randomized trial of CD8+ T-cell depletion in the prevention of graft-versus-host disease associated with donor lymphocyte infusion. , 2002, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[15]  G. Ehninger,et al.  CD34+‐enriched peripheral blood progenitor cells from unrelated donors for allografting of adult patients: high risk of graft failure, infection and relapse despite donor lymphocyte add‐back , 2002, British journal of haematology.

[16]  E. Holler,et al.  The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation , 2002, Bone Marrow Transplantation.

[17]  C. Fegan,et al.  Adenovirus infections following allogeneic stem cell transplantation: incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. , 2002, Blood.

[18]  R. Brand,et al.  Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. , 2002, Blood.

[19]  J. Ritz,et al.  Infusion of CD4+ donor lymphocytes induces the expansion of CD8+ donor T cells with cytolytic activity directed against recipient hematopoietic cells. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[20]  Y. Beguin,et al.  Preemptive cellular immunotherapy after T-cell-depleted allogeneic hematopoietic stem cell transplantation. , 2002, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[21]  C. Craddock,et al.  High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution. , 2002, Blood.

[22]  N. Russell,et al.  Peripheral blood stem cell harvests from G-CSF-stimulated donors contain a skewed Th2 CD4 phenotype and a predominance of type 2 dendritic cells. , 2002, Experimental hematology.

[23]  Y. Komada,et al.  The Role of Donor Age in Naive T-cell Recovery Following Allogeneic Hematopoietic Stem Cell Transplantation: The Younger the Better , 2002, Leukemia & lymphoma.

[24]  D. Bunjes.  188 Re-labeled Anti-CD66 Monoclonal Antibody in Stem Cell Transplantation for Patients with High-risk Acute Myeloid Leukemia , 2002, Leukemia & lymphoma.

[25]  F. Baron,et al.  Pre-emptive immunotherapy with CD8-depleted donor lymphocytes after CD34-selected allogeneic peripheral blood stem cell transplantation. , 2002, Haematologica.

[26]  J. Edwards,et al.  CD34 selection using three immunoselection devices: comparison of T-cell depleted allografts. , 2001, Cytotherapy.

[27]  A. Grañena,et al.  Individually adjusted prophylactic donor lymphocyte infusions after CD34-selected allogeneic peripheral blood stem cell transplantation , 2001, Bone Marrow Transplantation.

[28]  T. Gentle,et al.  Respiratory virus infections in adult T cell-depleted transplant recipients: the role of cellular immunity. , 2001, Transplantation.

[29]  N. Schmitz,et al.  Second German consensus on immunogenetic donor search for allotransplantation of hematopoietic stem cells , 2001, Annals of Hematology.

[30]  A. Nagler,et al.  Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloablative regimen , 2001, Bone Marrow Transplantation.

[31]  M. Varughese,et al.  Pharmacokinetics of CAMPATH-1H in BMT patients. , 2001, Cytotherapy.

[32]  G. Kobbe,et al.  Treatment of severe steroid refractory acute graft-versus-host disease with infliximab, a chimeric human/mouse antiTNFα antibody , 2001, Bone Marrow Transplantation.

[33]  R. Storb,et al.  Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. , 2001, Blood.

[34]  D. Bunjes,et al.  The current status of T-cell depleted allogeneic stem-cell transplants in adult patients with AML. , 2001, Cytotherapy.

[35]  B. Löwenberg,et al.  Unrelated marrow transplantation for adult patients with poor-risk acute lymphoblastic leukemia: strong graft-versus-leukemia effect and risk factors determining outcome. , 2001, Blood.

[36]  D. Schendel,et al.  Ex vivo generation of cytotoxic T lymphocytes specific for one or two distinct viruses for the prophylaxis of patients receiving an allogeneic bone marrow transplant , 2001, Bone Marrow Transplantation.

[37]  M. Sivakumaran.  Modulation of Th1/Th2 subsets by granulocyte-colony stimulating factor. , 2001, Blood.

[38]  H. Gadner,et al.  Selection of CD34-Positive Blood Cells for Allogeneic Transplantation: Approaches to Optimize D34-Cell Recovery, Purity, Viability, and T-cell Depletion , 2000, Oncology Research and Treatment.

[39]  J. Sierra,et al.  Unrelated donor marrow transplantation for acute myeloid leukemia: an update of the Seattle experience , 2000, Bone Marrow Transplantation.

[40]  P. Vyas,et al.  Longitudinal monitoring of immune reconstitution by CDR3 size spectratyping after T-cell-depleted allogeneic bone marrow transplant and the effect of donor lymphocyte infusions on T-cell repertoire. , 2000, Blood.

[41]  J. Klein,et al.  T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. , 2000, Blood.

[42]  R. Storb,et al.  T-cell reconstitution after stem-cell transplantation—by which organ? , 2000, The Lancet.

[43]  G. Hale,et al.  Immune reconstitution after allogeneic bone marrow transplantation depleted of T cells. , 2000, Transplantation.

[44]  S. Heimfeld,et al.  Granulocyte-colony stimulating factor mobilizes T helper 2-inducing dendritic cells. , 2000, Blood.

[45]  R. Handgretinger,et al.  Unrelated peripheral blood stem cell transplantation with ‘megadoses’ of purified CD34+ cells in three children with refractory severe aplastic anemia , 2000, Bone Marrow Transplantation.

[46]  R. Collins,et al.  transplantation with unrelated donor leukocyte infusions Treatment of relapsed leukemia after unrelated donor marrow , 2013 .

[47]  C. Schmoor,et al.  Quantitative lymphocyte subset reconstitution after allogeneic hematopoietic transplantation from matched related donors with CD34+ selected PBPC grafts, unselected PBPC grafts or BM grafts , 1999, Bone Marrow Transplantation.

[48]  M. Martelli,et al.  The Role of Megadose CD34+ Progenitor Cells in the Treatment of Leukemia Patients without a Matched Donor and in Tolerance Induction for Organ Transplantation , 1999, Annals of the New York Academy of Sciences.

[49]  S. Mackinnon,et al.  Comparison of immune reconstitution after unrelated and related T-cell-depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions. , 1999, Blood.

[50]  J. Garcia-conde,et al.  Allogeneic transplantation of selected CD34+ cells from peripheral blood: experience of 62 cases using immunoadsorption or immunomagnetic technique , 1998, Bone Marrow Transplantation.

[51]  D. Neuberg,et al.  Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant. , 1998, Blood.

[52]  G. Hale,et al.  Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants. CAMPATH Users. , 1998, Blood.

[53]  J. Briones,et al.  Rapid engraftment without significant graft-versus-host disease after allogeneic transplantation of CD34+ selected cells from peripheral blood. , 1997, Blood.

[54]  Robert H. Collins,et al.  Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  B. Hendry,et al.  The pharmacokinetics of anti-thymocyte globulin (ATG) following intravenous infusion in man. , 1996, Clinical nephrology.

[56]  J. Ferrara,et al.  Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. , 1995, Blood.

[57]  E D Thomas,et al.  1994 Consensus Conference on Acute GVHD Grading. , 1995, Bone marrow transplantation.

[58]  H. Heimpel,et al.  In vivo/ex vivo T cell depletion for GVHD prophylaxis influences onset and course of active cytomegalovirus infection and disease after BMT. , 1995, Bone marrow transplantation.

[59]  P. Beatty,et al.  Unrelated donor marrow transplantation therapy for chronic myelogenous leukemia: initial experience of the National Marrow Donor Program. , 1993, Blood.

[60]  W. Wilmanns,et al.  Donor Leukocyte Transfusions for Treatment of Recurrent Chronic Myelogenous Leukemia in Marrow Transplant Patients , 1990 .

[61]  W. Lehmacher,et al.  Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. , 1990, Blood.

[62]  R. Storb,et al.  Transplantation of marrow from an unrelated donor to a patient with acute leukemia. , 1980, The New England journal of medicine.