Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Infusions of large numbers (> 10(8)/kg) of donor leukocytes can induce remissions in patients with chronic myeloid leukemia (CML) who relapse after marrow transplantation. We wanted to determine if substantially lower numbers of donor leukocytes could induce remissions and, if so, whether this would reduce the 90% incidence of graft-versus-host disease (GVHD) associated with this therapy. Twenty-two patients with relapsed CML were studied: 2 in molecular relapse, 6 in cytogenetic relapse, 10 in chronic phase, and 4 in accelerated phase. Each patient received escalating doses of donor leukocytes at 4- to 33-week intervals. Leukocyte doses were calculated as T cells per kilogram of recipient weight. There were 8 dose levels between 1 x 10(5) and 5 x 10(8). Lineage-specific chimerism and residual leukemia detection were assessed using sensitive polymerase chain reaction (PCR) methodologies. Nineteen of the 22 patients achieved remission. Remissions were achieved at the following T-cell doses: 1 x 10(7) (n = 8), 5 x 10(7) (n = 4), 1 x 10(8) (n = 3), and 5 x 10(8) (n = 4). To date, 15 of the 17 evaluable patients have become BCR-ABL negative by PCR. The incidence of GVHD was correlated with the dose of T cells administered. Only 1 of the 8 patients who achieved remission at a T-cell dose of 1 x 10(7)/kg developed GVHD, whereas this complication developed in 8 of the 11 responders who received a T-cell dose of > or = 5 x 10(7)/kg. Three patients died in remission, 1 secondary to marrow aplasia, 1 of respiratory failure and 1 of complications of chronic GVHD. Sixteen patients who were mixed T-cell chimeras before treatment became full donor T-cell chimeras at the time of remission. Donor leukocytes with a T-cell content as low as 1 x 10(7)/kg can result in complete donor chimerism together with a potent graft-versus-leukemia (GVL) effect. The dose of donor leukocytes or T cells used may be important in determining both the GVL response and the incidence of GVHD. In many patients, this potent GVL effect can occur in the absence of clinical GVHD.
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PMID:Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. 763 30

Eight patients who had hematologic relapse of chronic myelogenous leukemia (CML) after undergoing allogeneic bone marrow transplantation (BMT) were treated with leukocyte infusions from the original bone marrow donors. All patients had previously received marrow grafts from HLA-identical siblings. Six patients were in the accelerated phase of their disease and two were in blast crisis. Each patient received a predetermined T-cell dose within a narrow range of 2.5 to 5.0 x 10(8) T cells/kg. Three patients also received short courses of therapy with alpha interferon to control elevated white blood cell counts within the first several weeks after leukocyte transfusions. Seven of eight evaluable patients developed graft-versus-host disease (GVHD) at a median of 32 days after the initial infusion. One patient had fatal GVHD. A second patient had grade 3 acute GVHD, which has responded to immunosuppressive therapy. The remaining patients all had mild grade I GVHD. Six patients continue to require modest doses of prednisone more than 6 months after infusion. Four patients developed marrow aplasia, which in three patients required marrow boosts from the original donors. Two of these three patients have normal hematopoietic function, whereas the third patient remains growth factor and transfusion dependent. Both patients treated in blast crisis have died, one from GVHD and one from disease progression. All six patients in the accelerated phase are alive and in cytogenetic remission at a median of 42 weeks after infusion. Five of these six patients are in molecular remission. This study demonstrates that leukocyte infusions that administered a defined T-cell dose can exert a profound graft-versus-leukemia effect and are an effective form of salvage immunotherapy in allogeneic marrow transplant recipients. This therapeutic approach appears to be a viable alternative to existing chemotherapeutic and immunomodulatory strategies for the treatment of relapsed CML.
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PMID:Salvage immunotherapy using donor leukocyte infusions as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation: efficacy and toxicity of a defined T-cell dose. 840 Feb 84

Relapse remains a significant problem after allogeneic bone marrow transplantation (BMT). For patients with relapsed chronic myelogenous leukemia (CML), infusions of donor mononuclear cells (MNC) provide a potent graft-versus-leukemia (GVL) reaction inducing complete remissions in the majority of patients. Little is known about the efficacy of donor MNC infusions for patients who relapse with other diseases. We have studied the GVL effects of donor MNC in eight patients with relapsed acute leukemia or myelodysplasia (MDS). One patient with relapsed MDS achieved complete remission and another patient had a transient response. Five of six non-responders died of progressive leukemia and one non-responder died of complications during second BMT. Three patients developed grade I-II acute GVHD responsive to immunosuppression. These data, and review of the literature, suggest that GVL induction with donor MNC infusions is less effective for patients with relapsed acute leukemia than for patients with relapsed CML; too few patients with relapsed MDS have been treated to draw definite conclusions. However, some patients respond, and given the high mortality associated with alternative procedures such as second BMT, donor MNC infusions are a reasonable approach for relapsed acute leukemia and MDS after allogeneic BMT.
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PMID:Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation. 893 54

Nine children from 10 to 76 months (median 28.0), weighing 8.5 to 19.7 kg (median 13.0 kg) underwent peripheral blood stem cell separation (PBSCS) or peripheral blood mononuclear cell separation (PBMNCS), after insertion of a double-lumen central venous catheter (8-10 French). Separations were performed with a continuous flow blood separator (Fen-wall CS 3000 plus), running a specially adopted separation-program. In 7 children (5 with neuroblastoma IV, 1 with multifocal Ewing's sarcoma, and 1 with rhabdomyosarcoma IV), stem cells were mobilized by application of G-CSF at a dosage of 15-27.7 micrograms/kg body weight (median 16.25) subcutaneously following high-dose chemotherapy, according to the disease-related protocols, whereas 2 children had PBMNCS to induce graft vs. leukemia (GvL)-reaction in the HLA-identical sibling suffering from relapsed chronic myelogenous leukemia (CML: n = 1), or chronic myelomonocytic leukemia (CMML: n = 1) after allogeneic BMT. In all cases, the collecting procedure was performed after filling the cell separator with priming solution consisting of 2 U of irradiated and washed packed red cells, 250 ml human albumin, and 0.9% NaCl. In the 7 patients with solid tumors between 0.45 and 62.7 x 10(6) CD-34 positive cells/kg body weight were separated; the patient who had the lowest yield was separated twice after another mobilizing course. Three patients (2 with neuroblastoma IV and 1 with multifocal Ewing's-sarcoma) underwent a double transplantation with 1-3 portions of the collected stem cells within a 5- to 6-week interval. Two children had a rapid engraftment on both peripheral blood stem cell transplantations (PBSCTs). The third child, who had the lowest yield and was separated twice had prompt engraftment at the first PBSCT but delayed and incomplete engraftment at the second PBSCT. One patient after adoptive immunotransfer with PBMNCs for relapsed CML is now 40 months in complete cytogenetic and molecular biological remission, whereas the other patient treated for relapsed CMML did not respond to the PBMNC-transfusion. The results indicate that PBSCS and PBMNCS can be performed in children with a body weight below 20 kg.
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PMID:Feasibility of peripheral blood stem cell (PBSC) and peripheral blood mononuclear cell (PBMNC) separation in children with a body weight below 20 KG. 918 Sep 13

The clinical efficacy of donor lymphocyte infusions (DLI) in patients with relapsed chronic myelocytic leukemia after allogeneic bone marrow transplantation has been demonstrated in several recent studies. Although it is presumed that allogeneic T cells mediate this graft-versus-leukemia (GVL) effect, the influence of DLI on the T cell compartment of recipients has not been determined. To characterize the immunologic effects of DLI and to identify T cell changes selectively associated with the GVL response, we analyzed the T cell receptor (TCR) repertoire in four patients with relapsed chronic myelocytic leukemia who achieved a complete remission after infusion of CD4+ lymphocytes from HLA-identical sibling donors. Only one of the four patients developed clinically significant graft-versus-host disease (GVHD) after infusion of donor lymphocytes. TCR repertoire was examined after PCR amplification of 24 Vbeta gene subfamilies in serial samples obtained over a 1-yr period before and after DLI. Results were compared to 10 normal donors. Before DLI, all four patients were found to have abnormal TCR Vbeta repertoire in peripheral T cells, associated with a large number of clonal and oligoclonal patterns. Abnormal TCR patterns persisted for at least 3 mo after DLI, but thereafter gradually began to normalize. By 1 yr after DLI, all patients demonstrated almost complete normalization of Vbeta repertoire with polyclonal representation within almost all Vbeta gene subfamilies. We also examined changes in the TCR Vbeta repertoire associated with the disappearance of Ph+ cells. In each patient, we were able to identify the expansion of at least 1 Vbeta gene subfamily that coincided with the time of the cytogenetic response. In one patient who was studied in greater detail, CDR3 size analysis of serial samples after DLI indicated that these changes were associated with the appearance of clonal T cells. This finding was confirmed through CDR3 sequence analysis and use of CDR3 clone-specific oligonucleotide probes. A putative GVL clone identified by this technique was not detectable in either donor or patient T cells before DLI, but persisted in peripheral T cells for approximately 1 yr. These experiments therefore provide evidence for the clonal expansion of allogeneic T cells that may be selective mediators of antileukemia activity without also mediating graft-versus-host disease.
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PMID:Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion. 925 85

Until recently, the only curative therapy for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT) has been second allogeneic BMT. Recently, donor mononuclear cells have been given to patients with relapsed CML to induce a potent graft-versus-leukemia reaction and re-establish complete remissions in the majority of patients without the need for a second transplant. The extraordinary success of donor mononuclear cell infusions shows that it is possible to manipulate and harness the graft-versus-leukemia (GVL) reaction for clinical benefit. The identity of the effector cells and target antigens is unclear, but intensive investigation is beginning to define the complex cytokine and cellular interactions that mediate GVL reactivity. Current clinical trials are investigating strategies that will retain and enhance the GVL effects while limiting toxicity from this therapy. Ultimately, the ability to harness the GVL potential of allogeneic donor cells without excessive toxicity from graft-versus-host disease will be a central challenge in BMT and cellular immunotherapy.
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PMID:Infusion of donor peripheral blood mononuclear cells to treat relapse after transplantation for chronic myelogenous leukemia. 952 29

Donor lymphocyte infusions (DLI) have been shown to enhance the graft-versus-leukaemia (GVL) effect and induce haematological and molecular remission in patients with relapsed CML following allogeneic bone marrow transplantation (BMT). The potent donor cell-mediated cytolysis following DLI may lead to a short period of aplasia before the re-establishment of donor haematopoiesis. The absence of detectable donor cells in patients prior to DLI infusion may result in permanent aplasia in certain patients. We report on four patients who relapsed 1, 3, 6.5 and 7 years post-BMT for chronic phase CML and were treated with DLI from their original BMT donor. Polymorphic short tandem repeats (STRs) were used to assess haematological chimaerism both prior to and following DLI. At the time of relapse, STR-PCR indicated the presence of donor cells in all four patients, at levels ranging from 1-40%. A clinical and molecular response was seen in 4/4 patients following a short period of cytopenia and all patients remain in clinical remission with a follow-up of 2 months-3 years post-DLI. STR-PCR indicated that a response was occurring during the period of pancytopenia when metaphase analysis was unsuccessful. Lineage-specific analysis of the cellular response to DLI was monitored using STR-PCR of peripheral blood (PB) and bone marrow (BM) lymphocyte-enriched fractions and CD2-positive and -negative T cell fractions. In one patient BM and PB CD34-positive and -negative fractions were also assessed. A change in the ratio of donor:recipient cells in the PB lymphocyte fraction was the earliest molecular indication of an anti-leukaemic response. Subsequent conversion to donor chimaerism occurred in the other lineages and the granulocyte fraction was the last lineage to convert. In conclusion, lineage-specific STR-PCR permits detailed monitoring of subtle changes in donor/recipient cell dynamics in specific lineages following DLI during the crucial pancytopenic phase and may be a useful predictor of haematological response to DLI therapy.
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PMID:Monitoring of lineage-specific chimaerism allows early prediction of response following donor lymphocyte infusions for relapsed chronic myeloid leukaemia. 957 12

Adoptive immunotherapy with donor lymphocyte infusions (DLI) is an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. To identify the effector and target cell populations responsible for the elimination of the leukemic cells in vivo we developed an assay to measure the frequency of T lymphocyte precursor cells capable of suppressing leukemic progenitor cells. Target cells in this assay were CML cells that were cultured in the presence of stem cell factor, interleukin 3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. [3H]thymidine incorporation at day 7 represented the proliferation of the progeny of the CD34(+) CML progenitor cells, and not of the more mature CD34(-) CML cells. Effector cells were mononuclear cells, which were used in a limiting dilution analysis to measure the frequencies of CML progenitor cell-inhibitory lymphocyte precursors (PCILp) in peripheral blood of seven patients before and after DLI for relapsed CML. In the six patients who entered complete remission, a 5- to 100-fold increase of PCILp was found during the clinical response. In the patient with resistant relapse the frequency of PCILp was <10 per ml before and after DLI. Leukemia-reactive helper T lymphocyte precursor frequencies remained unchanged after DLI. A significant increase in cytotoxic T lymphocyte precursor frequency against more mature leukemic cells was found in only two responding patients. These results indicate that T cells specifically directed against CD34(+) CML progenitor cells mediate the antileukemic effect of DLI.
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PMID:T cells recognizing leukemic CD34(+) progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. 970 16

Donor leukocyte infusions (DLI) have turned out to be an efficient way to re-establish complete remission (CR) in chronic myeloid leukemia (CML) patients relapsing after allogeneic bone marrow transplantation (BMT). In these patients, absence of PCR bcr-abl fusion transcripts confirmed the potency of donor leukocytes to induce molecular response in relapsed CML. This ensured sustained remission and long-term survival. In this study, the capacity of DLI to induce molecular remission in acute leukemia relapse after BMT was analyzed. The results showed that following DLI, leukemic cell eradication gradually occurred over a prolonged time period. The time to complete disappearance of the molecular marker of the disease was 30 weeks in RT-PCR analysis. A sustained and persistent elimination of an AML1/ETO-positive leukemic clone in an AML-M2 patient was observed. In contrast, an AML-M5 with t(11;19) and an E2A/PBX1-positive ALL achieving cytogenetic and molecular bone marrow CR developed following DLI unusual sites of extramedullary leukemia relapse, despite continued bone marrow remission. This study adds further proof of the benefit of donor cell therapy in acute leukemia but shows that complete leukemic cell eradication appears to require a critical interval in order to establish effective immune responses at all sites where leukemic cells persist.
Leukemia 1998 Nov
PMID:Extramedullary relapse after favorable molecular response to donor leukocyte infusions for recurring acute leukemia. 982 40

Relapse is the commonest cause of treatment failure following bone marrow transplantation for malignant haematological disease. Treatment options are limited and often unsuccessful, with remissions, if achieved, being short-lived. Donor lymphocyte infusions have been used in the treatment of relapsing CML for several years, with good results being obtained. Use of this form of adoptive immunotherapy however, has been much less successful in patients with acute leukaemias, with acute lymphoblastic leukaemia appearing to be particularly resistant. We report the successful use of a donor lymphocyte infusion in a patient with isolated extramedullary relapse of acute lymphoblastic leukaemia post bone marrow transplantation.
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PMID:Use of donor lymphocytes in extramedullary relapse of childhood acute lymphoblastic leukaemia following bone marrow transplantation. 1110 19


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