Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The molecules detected by CD34 and CD56 monoclonal antibodies are simultaneously expressed in approximately 20% of childhood acute myeloid leukemia (AML) cases, and this phenotype is associated with t(8;21)(q22;q22) karyotype. By contrast, bone marrow samples from normal donors (n = 5) and patients with CD56- malignancies in remission (n = 8) contained fewer than 1 in 10,000 CD34+/CD56+ cells. CD34+/CD56+ cells were readily identified when leukemic blasts were admixed with normal bone marrow cells at a 1:10(4) ratio. Cells expressing both markers (0.01-0.8% of mononuclear cells) were also found in bone marrow samples from two of three children with CD34+/CD56+ AML studied, who were in remission by morphologic criteria. In one of these patients, detection of residual disease by flow cytometry anticipated overt hematologic relapse. A second patient, in whom minimal residual disease was detected prior to and following autografting, died of unrelated causes while in morphologic remission. The third patient had no detectable residual disease prior to and following autografting, and is still in morphologic and immunologic remission 100+ days post-transplant. The expression of CD56 on CD34+ cells is leukemia-associated and offers a means of identifying extremely small numbers of these cells by flow cytometry. This sensitive approach can now be used to assess the efficacy of treatment and detect early relapse in patients with CD34+/CD56+ AML.
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PMID:N-CAM (CD56) expression by CD34+ malignant myeloblasts has implications for minimal residual disease detection in acute myeloid leukemia. 768 98

The t(8;21) (q22;q22) translocation is a recurring chromosomal abnormality observed in about 20-40% of AML patients with subtype FAB M2 (AML-M2). The molecular facet of this translocation is represented by the formation of a new hybrid gene, the AML1-ETO, which is regularly transcribed in a chimaeric mRNA and translated into a new fusion protein believed to have a key role in the pathogenesis of this type of leukaemia. We looked for the presence of AML1-ETO transcripts, by RT-PCR, in 49 unselected patients affected by AML-M2 diagnosed at various Italian Institutions. A hybrid transcript was detected in 11 cases (23%). Minimal residual disease status was investigated in three patients in continuous complete remission (CCR) after a median follow-up of 44 months; at least one sample from each subject was found positive for the AML1-ETO transcript suggesting a long-term persistence of t(8;21) leukaemic cells. In two female patients in CCR a 'clonality' analysis was performed on peripheral blood DNA by exploiting the X chromosome inactivation pattern of the human androgen-receptor gene (HUMARA); in both cases the results were consistent with the presence of a polyclonal haemopoiesis. Our data confirm that the persistence of residual cells expressing the AML1-ETO transcripts is a frequent occurrence even in patients with long-term remission; on the other hand, clonality assays indicate that in t(8;21) leukaemias long-term remission haemopoiesis is sustained by a polyclonal bone marrow reconstitution.
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PMID:Polyclonal haemopoieses associated with long-term persistence of the AML1-ETO transcript in patients with FAB M2 acute myeloid leukaemia in continous clinical remission. 779 58

A murine model for acute myeloid leukemia (mAML) was used to study graft-vs.-leukemia (GVL) effects on residual leukemic cells across both major (MHC) and minor histocompatibility antigens (mHA) barriers. In addition, the therapeutic effect of recombinant human interleukin-2 (rhIL-2)-administered postsyngeneic and allogeneic bone marrow transplantation (BMT) was examined. SJL/J mice inoculated with mAML cells were exposed later to total body irradiation (TBI) and transplanted with bone marrow cells (BMC) mixed with spleen cells derived from normal syngeneic (SJL/J), congenic (B10.S), or allogeneic (C57BL/6) donor mice. One-half of the mice in each group received low dose rhIL-2 for 3 days starting 1 day post-BMT. Spleen cells from treated recipients were transferred to secondary naive SJL/J mice for in vivo detection of residual tumor cells. At a tumor load of 10(5) cells per animal, none of the mice rescued with SJL/J or B10.S cells was cured since 100% of secondary recipients developed leukemia. Concomitant treatment of recipients of B10.S cells with rhIL-2 induced GVL effects since none of the secondary recipients developed leukemia after 2 years. All adoptive recipients of mice rescued with C57BL/6 cells remained free of leukemia after 2 years whether or not rhIL-2 was injected. The potency of the GVL effects observed across mHA and MHC were tumor-cell dose dependent since fewer animals inoculated with 10(6) mAML cells were cured. Only marginal GVL effects were noticed following syngeneic BMT and rhIL-2. Our results sustain the importance of the GVL effects in the treatment of myeloid leukemia and demonstrate that immunotherapy with rhIL-2 following BMT can enhance the therapeutic effect induced by the allograft.
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PMID:Enhancement of GVL effect with rhIL-2 following BMT in a murine model for acute myeloid leukemia in SJL/J mice. 787 38

The administration of interleukin-2 (IL-2) may induce complete remissions in acute myelogenous leukemia (AML) patients with a low proportion of residual bone marrow (BM) blasts. To confirm this preliminary observation, we treated 14 AML patients with advanced disease and with a residual BM blastosis that ranged between 7% and 24% with repeated 5-day cycles of high-dose recombinant IL-2 administered by daily continuous intravenous infusion. Patients who responded have been subsequently submitted to a monthly maintenance scheme with subcutaneous IL-2 at lower doses. While using this schedule and closely monitoring clinical and laboratory conditions, side effects were acceptable and no toxic deaths recorded. Eight of the 14 patients treated with high-dose IL-2 obtained a complete remission (CR). Five remain in persistent CR (four in third CR and one in fourth CR) after a median follow-up time of 32 months (14, 30, 32, 33, and 68 months, respectively). In all five patients, the IL-2-induced remission is the longest in the natural history of the disease. These findings show that IL-2 displays an antileukemic effect in AML with limited residual disease, and suggest that IL-2 should be considered a therapeutic option for resistant or relapsed AML patients.
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PMID:Interleukin-2 may induce prolonged remissions in advanced acute myelogenous leukemia. 791 30

Between March 1983 and December 1992, we performed 178 allogeneic BMTs for patients with hematopoietic stem cell disorders: 48 acute myelogenous leukemia (AML), 27 acute lymphoblastic leukemia (ALL), 40 chronic myelogenous leukemia (CML), 55 severe aplastic anemia (SAA), 6 myelodysplastic syndrome (MDS), 1 non-Hodgkin's lymphoma and 1 hybrid leukemia. Twenty-five of 48 AML are in disease-free survival (DFS). Fifteen of 27 ALL are in unmaintained remission. Twenty-four of 40 CML are in DFS. Forty-four out of 55 SAA patients are alive and well. Comparing the survival between standard (< or = CR1: 21 of 31 (68%)) and high risk (> or = CR2: 4 of 17 (24%)) AML, our data suggest that the preparative regimen for high risk AML was not potent enough to eradicate the residual disease in advanced AML. Although our cases are limited and the follow-up period is short, the result of ALL (overall: 56%, standard risk (adult < or = CR1, children < or = CR2: 10 of 14 (71%) and high risk (adult > or = CR2, children > CR2): 5 of 13 (38%)) and CML (overall: 60%; CP: 19 of 27 (70%), AP or BC: 5 of 13 (38%)) are promising. The probability of 5 year survival of SAA was 80 +/- 4 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Allogeneic bone marrow transplantation in Korea: 1983-92. 792 Mar 1

Modern clinical applications of cytometry include the determination of the most powerful antileukemic drugs in each patient at the time of diagnosis and the monitoring of residual disease during and off treatment. The precision of in vitro assays to test the susceptibility of cancer cells to cytotoxic drugs depends on the ability to maintain the cells' viability in culture. We found that bone marrow-derived allogeneic stromal cells are critical to prevent death by apoptosis of acute lymphoblastic leukemia (ALL) cells. Thus, we devised an in vitro drug sensitivity assay in which ALL cells are seeded onto stromal cells and viable leukemic cells are counted at the end of cultures by flow cytometry. Our preliminary results indicate that this assay is suitable for evaluating the drug sensitivity of leukemic lymphoblasts and testing the antileukemic activity of potentially effective compounds which have not yet been administered to patients with ALL. The identification of immunophenotypes expressed on leukemic cells but absent or extremely rare among normal hematopoietic progenitors allows close monitoring of the effects of drug treatment in vivo. Phenotypes that afford a detection level of 1 leukemic cell among 10,000 normal bone marrow cells have been identified in 90% of cases of T-ALL, 25% of B-lineage ALL, and 40% of acute myeloid leukemia (AML). In several studies, residual disease emerging during continuation therapy or off treatment almost invariably anticipated overt relapse by 1-7 months. These data indicate the reliability of immunologic techniques to detect occult leukemia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Applications of cytometry to study acute leukemia: in vitro determination of drug sensitivity and detection of minimal residual disease. 792

Emergence of drug resistance with conventional cytotoxic therapy is a major challenge towards the curability of many cancers, especially in patients undergoing autologous BMT with ex-vivo purged hematopoietic support. We have explored the potential role of photoradiation therapy in purging hematopoietic stem cells of various hematological malignancies. Benzoporphyrin derivative, monoacid ring A (BPD-MA), dihematoporphyrin ether (DHE), and MC-540 were evaluated for the "ex-vivo" purging of residual tumor cells from autologous bone marrow (BM) grafts. BPD-MA and DHE photosensitizing activity was tested against two human large cell lymphoma cell lines and colony forming-unit leukemia (CFU-L) derived from patients with acute myelogenous leukemia (AML). In mixing experiments four log elimination of tumor cell lines was observed after 1 hr of incubation with BPD-MA or DHE followed by white light exposure. By comparison, using the same concentration of BPD-MA or DHE, the mean recovery of normal BM progenitors was 4-5.2% for granulocyte-macrophage colony forming unit (CFU-GM) and 5-9.8% for burst forming unit erythroid (BFU-E). The T lymphoblastic leukemia cell line CEM and its vinblastine (VBL)-resistant subline CEM/VBL100, along with the acute promyelocyte leukemia cell line HL-60 and its vincristine (VCR)-resistant subline HL-60/VCR, were also tested. Our results demonstrated the preferential cytotoxicity of BPD-MA and DHE toward neoplastic cell lines and CFU-L from AML patients. In addition, DHE was slightly more effective in purging tumor cells expressing the p-170 glycoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Newer options for treating drug-resistant (MDR+) cancer cells using photoradiation therapy. 818 Jun 6

IL-2 has been used after autologous BMT (ABMT) with the aim of inducing graft versus leukemia (GVL) effect. Our studies in mice have shown that IL-2 therapy induces GVL effect when employed after BMT with bone marrow (BM) that has been activated with IL-2 in vitro (ABM). The present study was carried out to define the time of optimal GVL effect after BMT so that the immunomodulatory approaches could be concentrated at the time of maximum GVL effect. Our data show that GVL effect was induced if IL-2 was instituted immediately after BMT with ABM in mice with acute myeloid leukemia; institution of IL-2 1 week after BMT with ABM did not induce GVL effect. IL-2 therapy instituted immediately or 1 week after BMT with fresh bone marrow (FBM) did not induce any GVL effect. A significant increase in the NK activity was noticed whether IL-2 was instituted immediately or 1 week after BMT, either with FBM or with ABM. To evaluate the ability of IL-2 in the eradication of residual disease from the autograft and the host, BM with variable infiltration with leukemia was activated with IL-2 and used for BMT in leukemic mice. The GVL effect of BM with minimal leukemic infiltration (absence of morphologically demonstrable disease) was comparable to the GVL effect of normal BM. These findings suggest that: (a) maximum GVL effect after BMT with ABM is concentrated in the early post-transplant period possibly because of minimal residual disease during this time; (b) an increase in the NK activity induced by IL-2 therapy may not predict for an improved GVL effect; and (c) for optimum GVL effect, BM with minimal leukemic infiltration should be activated with IL-2 before BMT.
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PMID:Graft versus leukemia effect after transplantation with interleukin-2-activated bone marrow. Correlation with eradication of residual disease. 833 64

High-dose therapy and bone marrow transplantation has been shown to be a potentially curative modality for patients with hematologic malignancies. Several obstacles to the use of this approach include the availability of histocompatible siblings and the increased toxicity even in HLA-matched patients owing to graft-versus-host disease and interstitial pneumonitis. The use of autologous marrow in support of high-dose therapy has lower toxicity; however, there is the issue that residual tumor cells may be reinfused into the patient. There are several laboratory studies demonstrating that residual tumor cells persist in the marrow despite histologic remission. In addition, case reports suggest that contaminated marrow has led to widespread early relapse owing to reinfusion of tumor cells. A variety of techniques have been developed that can deplete up to 5 logs of tumor cells from the marrow. These techniques include very specific immunologic as well as less specific pharmacologic purging. Both approaches have been refined so that normal hematopoietic stem cell reconstitution is relatively preserved. Although a large number of studies have been reported that have utilized ex vivo marrow purging, few have examined whether there has been an impact on disease-free survival. Although randomized studies have not been performed to date, several recent studies in ANLL and B-cell NHL strongly suggest that there is a relationship between the quality of elimination of the disease ex vivo in the marrow and disease-free survival. With further improvements in marrow treatment, whereby all detectable cells are depleted, as determined by highly sensitive molecular biologic techniques, and randomized trials involving purged and unpurged BM, the question of the impact of ex vivo marrow treatment can be better answered.
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PMID:Developments in purging in autotransplantation. 834 86

The very rapid development in the last few years of techniques based on use of the polymerase chain reaction (PCR) for characterizing molecular lesions in leukaemia and lymphoma now offers the opportunity for monitoring residual disease at a sensitivity of one malignant cell in 10(5) or 10(6) normal cells. Maximal specificity is presumably achieved when the DNA sequences amplified are truly leukaemia-specific, such as BCR/ABL in chronic myelogenous leukemia, RARA PML/RARA in t(15;17) acute myelogenous leukemia, DEK/CAN in t(6;9) AML, PBX1/E2A in t(1;19) acute lymphoblastic leukemia (ALL), or TAL-1 deletions in other T-ALLs. Comparable sensitivity may be achieved by using immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements if a clonospecific probe can be generated. However, the presence of similar sequences in IgH genes from normal B lymphocytes may decrease the specificity. For clinical purposes the crucial issues are the following. Can PCR techniques be used for confirmation of diagnosis and evaluation of extent of disease? Can PCR data obtained in remission provide information about the probability of cure or of relapse? Can techniques be developed to quantitate the PCR product and thereby increase its predictive value? These and other issues were addressed at the 4th Workshop of the Molecular Biology/BMT Study Group that took place in Bristol UK on 9-10 May 1992.
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PMID:Molecular evidence of minimal residual disease after treatment for leukaemia and lymphoma: an updated meeting report and review. 835 Jun 33


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