T-cell–depleted allogeneic bone marrow transplantation followed by donor lymphocyte infusion in patients with multiple myeloma: induction of graft-versus-myeloma effect

Abstract

Previous trials of allogeneic bone marrow transplantation (BMT) in patients with multiple myeloma (MM) have demonstrated high response rates but also high transplantation-related mortality (TRM) and high relapse rates. Exploitation of this strategy remains of interest because donor lymphocyte infusions (DLIs) can induce a potent graft-versus-myeloma (GVM) effect. CD6 T-cell-depleted allogeneic BMT was combined with prophylactic CD4 ؉ DLI administered 6 to 9 months after BMT in an effort to reduce TRM and to induce a GVM response after BMT. Twenty-four patients with matched sibling donors and chemotherapy-sensitive disease underwent BMT. CD6 T-cell depletion of donor bone marrow was the sole method of graft-versus-host disease (GVHD) prophylaxis. GVHD after BMT was minimal, 1 (4%) grade III and 4 (17%) grade II GVHD. Fourteen patients received DLI, 3 in complete response and 11 with persistent disease after BMT. Significant GVM responses were noted after DLI in 10 patients with persistent disease, resulting in 6 complete responses and 4 partial responses. After DLI, 50% of patients developed acute (> II) or extensive chronic GVHD. Two-year estimated overall survival and current progression-free survival (PFS) for all 24 patients is 55% and 42%, respectively. The 14 patients receiving DLI had an improved 2-year current PFS (65%) when compared with a historical cohort of MM patients who underwent CD6-depleted BMT survived 6 months with no GVHD and did not receive DLI (41%) (P ‫؍‬ .13). Although this study suggests that prophylactic DLI induces significant GVM responses after allogeneic BMT, only 58% of patients were able to receive DLI despite T-cell-depleted BMT. Therefore, less toxic transplantation strategies are needed to allow a higher proportion of patients to receive DLI and the benefit from the GVM effect after transplantation. (Blood. 2001;98: 934-939)

Donor lymphocyte infusions for multiple myeloma: clinical results and novel perspectives

“…4-8 DLI alone have been demonstrated to induce response rates in 40-67% of patients with MM. [9][10][11][12][13][14][15][16][17][18][19][20] Experience was collected with DLI as prophylaxis 9-12 for myeloma relapse or as relapse treatment 13-20 after allo-HSCT.…”

“…CD8 þ -depleted DLIs as consolidation treatment, 6-9 months after T-cell depleted allogeneic HSCT, resulting in response rate of 71%, with 43% CR. 9 Badros et al 10 conducted a trial employing nonmyeloablative HSCT and unmanipulated allogeneic PBSCT grafts from sibling in 16 poor risk, chemotherapy-refractory patients. Patients without evidence for GVHD (n ¼ 14) received DLI with dose escalation on days 21, 42 and 112.…”

“…4-8 DLI alone have been demonstrated to induce response rates in 40-67% of patients with MM. [9][10][11][12][13][14][15][16][17][18][19][20] Experience was collected with DLI as prophylaxis 9-12 for myeloma relapse or as relapse treatment 13-20 after allo-HSCT.Although a graft-versus-myeloma (GVM) effect has been documented in several case reports and small populations, 13-18 the results must be interpreted with respect to additional chemotherapy preceding DLI administration 19 or interferon (IFN)-a 15,19 for immunological modulation. IFN-a might enhance the GVM effect by increasing the expression of cell-surface molecules necessary for the interaction of effector cells with the neoplastic plama cell 21,22 or by a direct antimyeloma effect.…”

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

“…Several studies have illustrated that depletion of CD8 + T cells from the DLI may preserve the beneficial GVL reactivity without the induction of GVHD, indicating that the CD4 + T lymphocytes may play an essential role in the antileukemic reactivity. [5][6][7][8][9][10] The mechanism by which the CD4 + T cells contribute to the GVL response is, however, not known. CD4 + T cells have been suggested to elicit the antileukemic response via the induction of minor histocompatibility antigen (mHag)-specific CD8 + T cells.…”

Allogeneic stem cell transplantation for multiple myeloma: is there a future?

“…Additionally, in vitro or in vivo T-cell depletion has been associated with higher relapse rates and a need for subsequent DLI after allotransplant. 49,50 However, in a large series of patients with hematological disorders including MM undergoing allo-SCT, the presence of GVHD is associated with only modest reduction in relapse risk in MM and AML, suggesting the presence of graft-vs-tumor effect in the absence of GVHD. 51 Similarly, in another study of high-risk relapsed MM patients undergoing allo-SCT, OS and PFS were comparable to other studies in the absence of GVHD.…”