Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma.
Donor lymphocyte infusions (DLIs) have been demonstrated to induce clinical responses in patients with relapsed multiple myeloma after allogeneic bone marrow transplantation, but the immunologic mechanisms involved have not been well characterized. In patients with chronic myelocytic leukemia (CML), remissions following DLI are invariably associated with conversion to complete donor hematopoiesis, suggesting that the target antigens of this response are expressed on both normal and CML-derived hematopoietic stem cells. In the present study, we examined hematopoietic chimerism and the complexity of the T-cell receptor (TCR) repertoire in 4 patients with relapsed multiple myeloma who received infusions of donor CD4+ lymphocytes. Three of 4 patients had a clinical response that began 1 to 2 months after DLI. All 3 responding patients developed lymphocytosis at the initiation of response that was due to a 2- to 4.5-fold increase in the number of CD3+ T cells. In 1 patient, this was due primarily to increases in CD3+ and CD8+ cells; in 2 patients, to increased numbers of CD3+ and CD8+ and CD3+ and CD4+ T cells. In all responding patients, conversion to complete donor hematopoiesis occurred in the first 2 months after DLI. The single nonresponding patient remained it 100% recipient hematopoiesis. The TCR repertoire complexity was examined by polymerase chain reaction amplification of complementary-determining region 3 (CDR3) derived from 24 Vbeta gene subfamilies. In 2 patients, the initiation of myeloma response and conversion to complete donor hematopoiesis was associated with normalization of TCR complexity. Complete donor chimerism and normal TCR complexity remained stable in all patients and did not change with subsequent relapse or development of graft-versus-host disease (GVHD). Thus, conversion to full donor chimerism was temporally associated with the antimyeloma effect of DLI but not with the development of GVHD. Nevertheless, the maintenance of stable donor hematopoiesis did not prevent disease relapse and was not associated with prolonged remission. The selective relapse of myeloma cells without concomitant return of mixed hematopoietic chimerism suggests that myeloma tumor cells in some patients develop resistance to immune destruction.
Center for Hematologic Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
E
E
Orsini
E P
EP
Alyea
A
A
Chillemi
R
R
Schlossman
S
S
McLaughlin
C
C
Canning
R J
RJ
Soiffer
K C
KC
Anderson
J
J
Ritz
D000818:Animals; D015703:Antigens, CD / Q000097:blood; D001782:Blood Donors; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D020350:Graft vs Tumor Effect / Q000276:immunology*; D006410:Hematopoiesis; D006801:Humans; D016130:Immunophenotyping; D017710:Lymphocyte Transfusion; D008218:Lymphocytosis / Q000209:etiology; D009101:Multiple Myeloma / Q000150:complications / Q000276:immunology / Q000628:therapy*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D012008:Recurrence; D013997:Time Factors; D018183:Transplantation Chimera / Q000097:blood*
D015703:Antigens, CD; D016693:Receptors, Antigen, T-Cell, alpha-beta