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

Abstract

One hundred and forty-six patients with acute leukaemia (81 with ANLL and 65 with ALL) received allogeneic bone marrow transplantation from their fully matched siblings. 121 patients underwent T-cell depletion (TCD) using Campath 1 monoclonal rat anti-human lymphocyte (CDw52) antibodies; 67 with Campath 1M and 54 with Campath 1G isotypes. Patients were conditioned for transplant using either total body irradiation combined with chemotherapy (125 patients) or busulfan and cyclophosphamide (21 patients). 112 recipients of T-cell depleted allografts received in addition total lymphoid irradiation (TLI) for prevention of rejection. Engraftment of neutrophils (> 0.5 x 10(9)/l) and platelets (> 25 x 10(9)/l) occurred on days 15 and 18, and on days 18 and 20 in recipients of Campath 1M and Campath 1G treated marrows respectively. Rejection was documented in 6.8% of T-cell depleted transplants. Leukaemia relapse-free survival at 2 years was 83% for patients transplanted in first CR, 76% in second CR (P2 = 0.34) and 42% in advanced leukaemia (P2 = 0.009). 81 marrow recipients, 38 with Campath 1M and 43 with Campath 1G treated marrow, received post-transplant graded increments of donor's peripheral blood lymphocytes (PBL) to induce graft-versus-leukaemia (GVL) effects. Administration of donor's PBL was associated with clinically significant GVHD and with decreased relapse rate especially in patients with ALL. Our data suggest that in patients receiving marrow allografts depleted of T cells by Campath 1 monoclonal antibodies, rejection can be reduced by adequate pregrafting immunosuppression. In patients with advanced disease, post-transplant cell-mediated immunotherapy (CMI) using donor's PBL may be beneficial; however, further studies are needed to define the optimal schedule of CMI for safe and effective prevention of relapse following TCD bone marrow transplantation in malignant haematological diseases.

Monitoring of lineage-specific chimaerism allows early prediction of response following donor lymphocyte infusions for relapsed chronic myeloid leukaemia

“…The reemergence of T cell depletion of BM grafts to prevent GVHD coupled with the use of DLI to treat minimal residual disease or the genetic manipulation of T lymphocytes with suicide genes which potentially enable the T cell response to be switched off when a detrimental GVHD reaction develops, are some of the novel approaches now reaching clinical application. 22,23 The monitoring of T cell chimaerism as an early marker for response using STR-PCR should be of benefit in monitoring new DLI therapy protocols, particularly in dose escalation studies for the treatment of molecular or cytogenetic relapse, where an early response indicator may eliminate the need for further infusions of T cells. The detailed monitoring of these new immunotherapeutic approaches at the molecular level should also increase the understanding of the effectors, mechanism and the kinetics of the GVL reaction.…”

Outcome of transplantation for standard‐risk leukaemia with grafts depleted of lymphocytes after conditioning with an intensified regimen

“…Graft failure occurred in 2-20% of HLA-identical T-cell-depleted sibling transplants compared to 0-2% of recipients of HLA-identical unmanipulated bone marrow (Champlin, 1993;Goldman et al, 1988;Maraninchi et al, 1987;Martelli & Aversa, 1993;Martin et al, 1985;Mitsuyasu et al, 1986;Naparstek et al, 1995;O'Reilly, 1992). In the present study graft failure occurred in 5% of cases which is less than previously reported in recipients of T-cell-depleted grafts Champlin, 1993;Kernan et al, 1989;O'Reilly, 1992;Patterson et al, 1986).…”

“…In general, T-cell depletion significantly reduces LFS after BMT and this is caused by higher relapse rates. LFS after T-cell-depleted BMT for leukaemia in CR1 or CP1 varied from 48% at 2 years to 25% at 7 years (Blaise et al, 1993;Marmont et al, 1991;Naparstek et al, 1995). In standard-risk recipients of HLA-identical unmanipulated grafts, LFS varied from 70% at 2 years to 40% at 10 years (Blaise et al, 1993;Chao & Blume, 1990;Chao et al, 1991;Clift et al, 1993;Goldman et al, 1988;Gratwohl et al, 1993;Marmont et al, 1991;Zhang et al, 1995;Zittoun et al, 1995).…”

The role of thiotepa in allogeneic bone marrow transplantation for genetic diseases

“…There was no significant difference in the number of cells infused between patients who received BM and the single patient who received PBSC (data not shown). 14 All patients received cyclosporin (3 mg/kg/day) i.v. from day Ϫ1 to day +100.…”

“…[12][13][14] This is an attractive approach, especially for diseases in which the stem cells are relatively resistant, [15][16][17] the aim being to attempt to reduce post-BMT disease recurrence with no risk of GVHD, and to avoid total body irradiation in the preparatory regimen as far as possible because of its hazardous after-effects which include growth retardation and increased likelihood of secondary malignancies. 18,19 Our attempt towards achieving more effective eradication of the patient's stem cells and reducing disease recurrence without increasing regimen-related toxicity (RRT) consisted of T cell-depleted allogeneic BMT preceded by the classical preparative protocol of busulfan (BU)-cyclophosphamide (CY) which we intensified by the addition of thiotepa (TTP).…”