Bone marrow transplantation in acute lymphoblastic leukemia

Gale, Robert Peter; Butturini, Anna

doi:10.1007/978-1-4613-1493-6_13

Cited by 8 publications

(9 citation statements)

References 35 publications

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“…Splenectomized mice surviving >30 days were included in the present analysis of the role of various T-lymphocyte subsets in the bone marrow inoculum on graft vs leukemia effects b Leukemia was determined in the peripheral blood (lymphocytes >20000/mm 3) c NS, not significant may be associated with a significant reduction in the incidence of relapse of leukemia, as compared with syngeneic, autologous or allogeneic bone marrow transplant procedures not associated with GVHD [3,20]. These studies have raised the possibility that GVL effects may be mediated by alloimmune effector mechanisms of donor origin, recognizing host residual tumor cells of host origin as target cells, similar to the mechanism of GVHD.…”

Section: Discussionmentioning

confidence: 99%

Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia

Weiss¹,

Weigensberg²,

Morecki³

et al. 1990

Cancer Immunol Immunother

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It is now widely accepted that immunocompetent lymphocytes in allogeneic bone marrow grafts exert an antileukemic effect that contributes to the cure of leukemia. Graft vs leukemia (GVL) effects independent of graft vs host disease were investigated in allogeneic bone marrow chimeras tolerant of host and donor alloantigens. The role of Thy1.2, L3T4 and Lyt2 T lymphocytes as effector cells of GVL were investigated in (BALB/c x C57BL/6)F1 mice inoculated with murine B-cell leukemia and subsequently conditioned with total lymphoid irradiation and cyclophosphamide (200 mg/kg). Mice were reconstituted with C57BL/6 bone marrow cells depleted of well-defined T-cell subsets or enriched for stem cells by the soybean agglutination method. Detection of residual tumor cells, an indicator for efficacy of GVL, was carried out by adoptive transfer of peripheral blood or spleen cells obtained from treated chimeras into secondary naive BALB/c recipients at different time intervals following bone marrow transplantation. Treatment of the primary marrow inoculum with monoclonal anti-Thy1.2 or anti-Lyt2 abolished the GVL effects and all secondary BALB/c recipients developed leukemia within 60 days. On the other hand, the treatment with monoclonal anti-L3T4 did not influence the effect of GVL and all treated recipients remained without leukemia. The data suggest that T cells may mediate GVL effects in the absence of graft vs host disease and in circumstances where tolerance to conventional alloantigens is elicited. Effector cells of GVL across the major histocompatibility complex (MHC) in the murine B-cell leukemia tumor model system appear to be Thy1.2+ Lyt2+ L3T4-. Induction of GVL effects by allogeneic cells tolerant of host MHC suggests that these effects may be independent of graft vs host disease.

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Section: Discussionmentioning

confidence: 99%

Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia

Weiss¹,

Weigensberg²,

Morecki³

et al. 1990

Cancer Immunol Immunother

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“…The T cells causing graft-versus-host disease are derived from the donor bone marrow. They appear to be necessary in the initial post-graft period to ensure marrow engraftment and to provide a graft-versus-leukemia effect (28,29) but could be subsequently eliminated. An anti-human CD5-ricin A-chain immunotoxin has been used for this purpose with modest clinical success (30).…”

Section: Discussionmentioning

confidence: 99%

In vivo T-cell ablation by a holo-immunotoxin directed at human CD3.

Neville

Scharff

Srinivasachar

1992

Proc. Natl. Acad. Sci. U.S.A.

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We have evaluated the in vivo efficacy of anti-CD3-CRM9, a holo-immunotoxin constructed with a diphtheria toxin binding-site mutant. Eighty percent of established human T-cell subcutaneous tumors in nude mice completely regressed following intraperitoneal ih'ection of immunotoxin at a dose set at half the minimum lethal dose assayed in toxin-sensitive animals. Similar regressions produced by a "7Cs source required a dose in excess of 500 cGy. The high degree of in vivo T-cell ablation produced by this immunotoxin is apparently due to maintenance of the toxin translocation function provided by CRM9 and a necessary intracellular routing function supplied by CD3. This immunotoxin may be useful in treating conditions caused by pathologic oligoclonal T-cell expansion such as graft-versus-host disease, autoimmune diseases, and possibly AIDS.The protein toxins, of which diphtheria toxin (DT) may be considered the prototype, have their effector or enzymatic functions on domains separate from the receptor-mediated entry functions (1)(2)(3)(4). By mixing and splicing toxin domains with binding domains derived from growth factors or monoclonal antibodies, a wide variety of immunotoxins, toxins with altered cellular specificity, have been created (5, 6). The goal has been to maximize in vivo targeted cell killing for therapeutic and experimental purposes (5).Recently, Youle and coworkers (7-9) have introduced highly efficacious holoimmunotoxins based on DT binding mutants. These immunotoxins were equal in potency to immunotoxins made with wild-type DT when directed at the human transferrin receptor or a component of the human T-cell receptor complex, CD3. Because the binding of the mutants was only 1/100th to 1/1000th that of native DT, non-target cell toxicity was similarly reduced. We showed that intracellular routing of DT-based immunotoxins via intracellular DT receptors or alternative receptors is an important determinant of their efficacy (10). CD3 and the transferrin receptor apparently are routed along the same path as the DT receptor. Consequently, CRM9 immunotoxins, which lack the DT binding site, are routed appropriately when directed at CD3 and the transferrin receptor (10). Because CD3 is highly restricted to mature T cells, immunotoxins directed toward this epitope should be useful in producing pan-T-cell ablation in vivo. We have evaluated anti-CD3-CRM9 for this purpose.

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“…1,2 Relapse rate correlates with diagnosis and stage of disease, 3,4 since patients transplanted either in relapse or after chemotherapy induction failure demonstrated a significantly higher risk for relapse compared to patients transplanted in complete remission. 5 The management of patients relapsing after HSCT is still controversial.…”

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confidence: 99%

Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant

Blau

Basara

Bischoff

et al. 2000

Bone Marrow Transplant

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Summary:We report 27 patients with relapsed acute or chronic leukemia who underwent a second hematopoietic stem cell transplant (HSCT) from a related or unrelated donor. Seventeen patients were diagnosed with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL) and four with chronic myeloid leukemia (CML). Ages ranged from 22 to 49 years (median 37); 13 patients were female and 14 male. Relapse was diagnosed between 1 and 45 months after the first HSCT. Sixteen patients who relapsed had received an autologous transplant initially and 11 an allogeneic transplant. Ten patients relapsed within 6 months and 17 patients later than 6 months. Chemotherapy was used as reinduction for relapse after HSCT in 16 patients who had received an autologous transplant and in three who had received an allogeneic transplant, since the latter did not respond to reduction of immunosuppression to induce a graft-versus-leukemia (GVL) reaction. Five of these 19 patients (26%) achieved complete remission (CR), seven patients did not respond to chemotherapy and seven achieved a partial remission (PR). The stem cell source for the second HSCT included bone marrow (n = 12) and PBSC (n = 4) from genotypically identical unrelated donors, PBSC (n = 7) and bone marrow (n = 3) from related donors. Currently eight of the 27 patients are alive and diseasefree after the second HSCT. One patient is alive and disease-free after two allogeneic transplants (day +1538), eight patients, who relapsed after an autologous transplant followed by an allogeneic transplant (days +248 to +1140), acute myeloid leukaemia (n = 6) and chronic myeloid leukemia (n = 2) are alive and diseasefree. The overall disease-free survival is 30% (8/27). The overall disease-free survival of autologous transplant patients subsequently undergoing an allogeneic transplant is 43% (P = 0.049). It is suggested that a second HSCT is possible for patients with leukemia relapse following the first autologous transplant. A second transplant might also be offered to patients relapsing after the first allogeneic HSCT. Keywords: second allogeneic bone marrow transplant; conditioning regimen; relapse rate; acute leukemia; diseasefree survivalThe relapse rate in patients transplanted for acute or chronic leukemia still ranges from 20-60%, accounting for one important cause of treatment failure. 1,2 Relapse rate correlates with diagnosis and stage of disease, 3,4 since patients transplanted either in relapse or after chemotherapy induction failure demonstrated a significantly higher risk for relapse compared to patients transplanted in complete remission. 5 The management of patients relapsing after HSCT is still controversial. 6,7 The therapeutic modalities for the treatment of leukemia relapse following allogeneic transplantation have been reviewed recently. [8][9][10] Options such as immunotherapy, donor lymphocyte infusion (DLI) or a second allograft after myeloablative conditioning have been explored. 10 Despite the high treatment-related mortality with a second HSC ...

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Bone marrow transplantation in acute lymphoblastic leukemia

Cited by 8 publications

References 35 publications

Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia

Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia

In vivo T-cell ablation by a holo-immunotoxin directed at human CD3.

Second allogeneic hematopoietic stem cell transplantation as treatment for leukemia relapsing following a first transplant

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