Reinventing Bone Marrow Transplantation

Introduction

Bone marrow transplantation (BMT) was initially developed as a means to deliver supralethal doses of chemotherapy and radiation for the treatment of malignancies.[1,2] Myelosuppression is the dose-limiting toxicity for numerous chemotherapeutic drugs and whole-body irradiation. Many malignancies exhibit a steep dose-response relationship to chemotherapy or radiotherapy. Marrow transplantation enables doses to be escalated beyond those that produce severe bone marrow toxicity, allowing doses of many chemotherapeutic agents, particularly alkylating agents, and whole-body irradiation to be increased three- to fivefold above conventional maximally tolerated levels.

Until recently, marrow transplantation was considered a supportive-care modality for restoring hematopoiesis. It has become clear, however, that high-dose therapy does not eradicate the malignancy in many patients, and that the therapeutic benefit of allogeneic marrow transplantation relates largely to an associated immune-mediated graft-vs-malignancy effect.

Extensive clinical and experimental data support the presence of a graft-vs-malignancy effect (Table 1). Most of the data relates to the effects of allogeneic transplantation in leukemia, or graft-vs-leukemia (GVL) effects. These include a reduced risk of relapse in transplant recipients with acute and chronic graft-vs-host disease (GVHD)[3-5] and a higher relapse risk after syngeneic marrow transplantation.[6-8] T-cell–depleted allotransplants are also associated with an increased risk of relapse, particularly in patients with chronic myelogenous leukemia (CML).[4] The most direct evidence of GVL is the finding that, in many patients who relapse after allogeneic transplantation, remission can be reinduced simply by infusing additional donor lymphocytes.[9-11]

Malignancies differ with respect to their susceptibility to GVL effects. In both acute myelogenous leukemia (AML) and CML, syngeneic transplants are associated with an increased rate of relapse, as compared with transplants from human lymphocyte antigen (HLA)–identical siblings; this indicates the involvement of allogeneic minor histocompatibility target antigens.[4] T-lymphocytes are critical effector cells in CML, in which T-cell–depleted transplants are associated with a fivefold increase in the risk of relapse.

Minimal residual disease can be detected (using polymerase chain reaction [PCR]–based techniques for the bcr-abl rearrangement) in most patients with CML following high-dose chemoradiation.[12,13] The malignant cells are eliminated in most patients who receive an unmodified marrow graft during the first 6 months posttransplant, presumably due to the GVL effect. With syngeneic or T-cell-depleted marrow transplantation, GVL does not occur, and if residual leukemia cells are demonstrated, patients generally relapse.

Approximately 70% of CML patients who relapse following transplantation achieve a complete remission after additional donor lymphocyte infusions.[9,14,15] Similar results have been achieved with donor lymphocyte infusions for HLA-identical sibling or matched unrelated donors.[16] The best results occur when relapses occur into chronic phase and when infusions are administered early in the course of relapse.[17] Responding patients generally become negative for minimal residual leukemia cells by PCR analysis, and these responses are usually durable.

Acute myelogenous leukemia is also subject to graft-vs-malignancy effects, but these are not as dramatic as those observed in CML. The relapse rate for AML is increased threefold with syngeneic transplantation but is only modestly affected by T-cell depletion.[18,19] Approximately one-third of patients with AML or myelodysplasia respond to donor lymphocyte infusions, but these remissions are generally transient, and disease typically recurs within the following year.

Among the leukemias, acute lymphocytic leukemia (ALL) is affected the least by GVL, possibly due to the pace of the disease and the limited capacity of the leukemic lymphoblasts to stimulate an effective immune response.[20,21] Only rare patients with ALL have benefited from donor lymphocyte infusions.

Relatively few patients have received allogeneic transplants for indolent lymphoid malignancies, but available data indicate that potent graft-vs-malignancy effects against these disorders do occur. Allogeneic transplants are associated with a much lower relapse rate than purged autologous transplants for low-grade lymphoma[22,23] and CLL.[24,25] Selected patients who have CLL,[26] lymphoma,[27,28] or multiple myeloma[29-31] have also responded to donor lymphocyte infusions or modification of immunosuppressive therapy.

Possible Mechanisms for the Graft-vs-Malignancy Effect

The relationship between the graft-vs-malignancy effect and GVHD suggests that the target antigens for graft-vs-malignancy may be minor histocompatibility antigens shared by the malignant cells and the tissues involved in GVHD (Table 2). Following donor lymphocyte infusion, many patients achieve a GVL response, ie, remission of their leukemia, without developing GVHD. Although this finding is consistent with the premise that different target antigens may be involved in each process, it could also result from greater sensitivity of leukemic cells than visceral tissues to a common immunologic mechanism.

Graft-vs-leukemia activity may also be due to reactivity against polymorphic hematopoietic lineage-related antigens or leukemia-specific targets. Minor histocompatibility antigens restricted to hematopoietic tissues have been described.[32,33] There is little evidence of a leukemia-specific response; donor-derived T-cell clones from allogeneic chimeras typically react against both host normal hematopoietic cells and leukemia cells.[34-36]

Overexpressed or abnormally expressed cellular constituents may also serve as target antigens for GVL. Proteinase-3, a serine protease present in myeloid primary granules, is overexpressed in CML and some cases of AML; it may serve as a target for an antileukemic immune response. Peptide antigens derived from proteinase-3 can stimulate generation of autologous or allogeneic T-cell cytotoxicity against the leukemia.[37,38]

A major question is whether graft-vs-tumor effects occur in nonhematopoietic malignancies. Pilot studies in breast cancer have reported antitumor responses in patients with GVHD, suggesting a graft-vs-adenocarcinoma effect.[39,40] In order to justify the added morbidity related to allogeneic transplantation, further studies are required to determine whether immunodominant tissue-restricted minor histocompatibility antigens are present in nonhematopoietic tumors and whether a clinically meaningful graft-vs-tumor effect occurs.

Effector Cells Producing GVL and GVHD

The effector cells producing GVHD and GVL effects are incompletely defined. Both CD4+ and CD8+ T-cells participate in the initiation of GVHD. Natural killer (NK) cells and other populations are subsequently recruited, and cytokines are involved as mediators of tissue injury.[41-44]

In animals, both CD4+ and CD8+ effectors of GVL have been described. In most models, CD8+ cells appear to the principal effectors of GVL effects.[34,45-48]

In human BMT recipients, both CD4+ and CD8+ cytotoxic antileukemic T-cell lines or clones have been described. In patients with CML who received transplants, several recent studies have identified CD4+ T-cell lines or clones that either inhibit the growth of leukemia progenitors or are directly lytic.[36,46,49,50] Natural killer cells have also been implicated as mediators of GVL effects.[48,51-54]

Results of Donor Lymphocyte Infusions

After infusion of donor lymphocytes, little change in peripheral blood counts occurs initially. However, after a median of 4 months, responding patients may suddenly become hypoplastic, followed by recovery of blood counts from donor-derived hematopoietic cells and a return to complete chimerism.[9,14,55] Antileukemic effectors presumably proliferate in vivo following the infusion, and most likely must reach a threshold level to eradicate the leukemia cells and the normal, host-derived hematopoietic cells.[56]

Marrow aplasia may occur unless sufficient donor-derived normal progenitors are present to restore hematopoiesis.[57] Consistent with this premise, CML patients treated during advanced relapse, in which the marrow is completely replaced with leukemic cells, develop marrow aplasia more frequently than do patients treated during cytogenetic or early hematologic relapse.[17]

Most patients who become aplastic recover after a second infusion of donor hematopoietic stem cells from either marrow or mobilized peripheral blood. A critical factor following donor lymphocyte infusion is the kinetics of leukemia growth. Rapid regrowth of leukemic cells may outpace the development of an effective immune antileukemic response.