Low-dose donor CD8+ cells in the CD4-depleted graft prevent allogeneic marrow graft rejection and severe graft-versus-host disease for chronic myeloid leukemia patients in first chronic phase

Abstract

Summary:mixed chimerism 5,6 and leukemic relapse, 7-10 especially in patients with chronic myelogenous leukemia (CML). Based on previous experiences in animals and humans,The role of the T cell subpopulations in aGVHD, graftlow doses of CD8 + lymphocytes infused together with versus-leukemia (GVL) effect and graft failure has been the marrow graft seem to enhance engraftment after studied in experimental animal models and in clinical proallogeneic T cell-depleted marrow transplantation.tocols of selective T cell depletion. [11][12][13][14] It is accepted that From April 1994 to February 1997, 12 patients with both CD4 + and CD8 + lymphocytes are involved in the allochronic myelogenous leukemia in first chronic phase reactive response after BMT, causing aGVHD. 15 Selective receiving a bone marrow transplant (BMT) from an depletion of CD8 + cells from the marrow graft in combi-HLA-identical sibling were included in a pilot study of nation with in vivo cyclosporin A induces a low rate of T cell subset depletion. Total depletion of CD4 + cells of GVHD with about 10% of graft failure after BMT using the marrow graft and partial depletion of CD8 + cells HLA-identical sibling donors. [16][17][18][19] Depletion of both CD4 + was performed by immunomagnetic separation. In and CD8 + cells leads to a low rate of aGVHD even in unorder to improve the engraftment rate, we infused a low related donor BMT, but leukemic relapse still remains a fixed number of CD8 + lymphocytes (0.25 × 10 6 /kg). All problem. 20 the patients were at high risk of developing acute graftIn animal models, it has been postulated that CD8 + cells versus-host disease (GVHD), with a recipient age of Ͼ30 may be important to ensure engraftment after BMT. 21 years, and/or donor sensitized by previous pregnancies Moreover, patients transplanted using a low fixed number or transfusions. All of them received cyclosporin A and of lymphocytes in the graft after physical depletion of T methotrexate post-BMT. No graft failure was observed.cells showed a stable and durable engraftment in the The grade III-IV GVHD rate was 16.6%, and the actumajority of cases, with an effective prevention of arial survival at 3 years is 81.8%. Immunological recovaGVHD. 22,23 ery showed persistent CD8 + HLA-DR + lymphocytosis 8We have developed a program of allogeneic bone marmonths after transplant. Relapses were not observed.row transplantation for patients with CML and with high This experience shows the importance of CD8 + cells to risk of aGVHD, using selective depletion of T cell subsets, ensure correct engraftment, decreasing the GVHD rate.by total immunomagnetic CD4 + depletion and partial CD8 + Keywords: T cell subset depletion; CD8 + lymphocytes; depletion. We infused a low fixed number of CD8 + cells GVHD prevention; graft failure with the graft to attempt an effective prevention of aGVHD, ensuring engraftment and without increasing the rate of leukemic relapses. We have previously reported 24,25 our initial experience Acute graft-versus-host disease (aGVHD) is an import...

Increasing mixed haematopoietic chimaerism after BMT with total depletion of CD4+ and partial depletion of CD8+ lymphocytes is associated with a higher incidence of relapse

“…At the end of the study period our global incidence of MC was about 40%, whereas an unexpected absence of MC was found by Gallardo et al 24 in their series using a similar method of T cell depletion.…”

Therapy-related Changes of CD20+ and CD45RO+ Lymphocyte Subsets in Chronic Myeloid Leukemia (CML): An Immunohistochemical and Morphometric Study on Sequential Trephine Biopsies of the Bone Marrow

“…In particular, the fact that T-cell numbers are significantly decreased in relation to total hematopoiesis merits attention. It is tempting to speculate that a breakdown in immune homeostasis may have occurred in CML, generating a suppression of activation of immunocompetent cells and consequently may further the expansion of the leukemic clone (11,12).…”

“…Interest in the lymphocyte population in chronic myelogenous leukemia (CML) has been reawakened because of problems related to cell lineage involvement (1-7), lymphoid blast crisis (8 -10), and occurrence of acute graft-versus-host disease (aGVHD) complicating allogeneic bone marrow transplantation (11)(12)(13). There is convincing cytogenetic, enzymatic, and molecular biologic evidence suggesting a clonal transformation of B-and T-lymphocytes; however, a conflict of opinion arises concerning its exact extent (2)(3)(4)(5)(6)(7).…”

“…There is convincing cytogenetic, enzymatic, and molecular biologic evidence suggesting a clonal transformation of B-and T-lymphocytes; however, a conflict of opinion arises concerning its exact extent (2)(3)(4)(5)(6)(7). It is generally accepted that certain subsets of T-lymphocytes (CD4 ϩ and CD8 ϩ ) are involved in the alloreactive response after transplantation causing aGVHD as a most hazardous complication (11,12). Contrasting this progress in the understanding of important biological features regarding the lymphoid cell population in CML, little knowledge exists about their exact quantity in comparison to the normal bone marrow (14).…”

Comparison of the classic Glucksberg criteria and the IBMTR Severity Index for grading acute graft-versus-host disease following HLA-identical sibling stem cell transplantation

“…Partial T cell depletion of the graft was done in 20 cases (18%), with a final T cell content of 1-3 ϫ 10 5 /kg CD3 ϩ cells. 7,8 One hundred patients survived у21 days with engraftment after transplant and were evaluable for this study. …”