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

We have developed an in vivo model of human chronic myeloid leukemia (CML). A peripheral blood (PB) sample of Philadelphia (Ph) chromosome-positive CML cells in lymphoid blast crisis was transplanted intravenously (IV) into sublethally irradiated severe combined immunodeficient (SCID) mice, and this resulted in engraftment with systemic proliferation. Growth of leukemia was monitored by PB cell morphology and by flow cytometric analysis of murine PB cells labelled with an anti-human leukocyte antigen (HLA) monoclonal antibody. Human cells were first detected in the PB at 4 weeks and comprised a mean of 57% of the total nucleated cells in the PB of these mice by 15 weeks. The Ph chromosome was retained and the population has been successfully passaged. BCR/ABL fusion gene expression was detected in a subsequent passage. Experiments are underway to use this in vivo model to assess the antileukemic activity of BCR/ABL antisense oligonucleotides.
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PMID:Human Philadelphia chromosome-positive chronic myeloid leukemia: a potential model for antisense therapy. 850 May 81

A 25-yr-old Caucasian man presented in 1988 with Philadelphia chromosome (Ph) negative, bcr-abl rearranged, chronic phase chronic myeloid leukemia (CML). He was treated with human leukocyte antigen matched sibling allogeneic bone marrow transplantation but relapsed 5 yrs later. At this time he was given donor leukocyte infusions from the original bone marrow donor, seeking an immune anti-leukemic effect. This treatment induced graft versus host disease and severe bone marrow aplasia, requiring immunosuppression and repeat donor marrow infusion (without prior conditioning). Graft versus host disease was controlled and full donor hematopoiesis was restored, resulting in complete eradication of the leukemic clone at a molecular level. The patient remains in complete clinical and molecular remission and off all immunosuppression 24 mths later. This emphasizes a potentially powerful graft versus leukemia effect in CML.
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PMID:Donor leukocyte infusions in the treatment of chronic myeloid leukemia in relapse post bone marrow transplantation. 871 72

We report a 47-year-old Japanese woman with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) combined with acute type adult T-cell leukemia (ATL). The susceptibility for HAM/TSP and acute type of ATL is hitherto explained by human leukocyte antigen (HLA) haplotype-linked immune responsiveness to HTLV-I. This patient's HLA (A24Cw1B54DR4DQ4/A24Cw3B51DR8DQ1) included a HAM-associated HLA haplotype. This suggests that HAM patients with HAM-associated HLA haplotype can also develop the acute type of ATL.
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PMID:Human T-cell lymphotropic virus type-I (HTLV-I)-associated myelopathy/tropical spastic paraparesis with acute type of adult T-cell leukemia. 877 79

At present, allogeneic bone marrow transplantation (BMT) is the only curative treatment for chronic myeloid leukemia (CML) in chronic phase (CP). The graft-vs.-leukemia (GVL) effect appears to play an important role in this treatment. Direct evidence for a GVL effect has been reported in Ph1-positive CML patients who relapsed after allogeneic BMT and who were treated with leukocyte transfusion from the original marrow donor. Alpha-interferon (alpha-IFN) may have facilitated this GVL effect since many patients were treated with it also. We investigated whether leukemia-reactive cytotoxic T lymphocytes (CTLs) can be generated from human leukocyte antigen (HLA)-genotypically identical sibling bone marrow (BM) donors who donated marrow for two patients with Ph1-positive CML in CP and one patient with Ph1-positive acute lymphoblastic leukemia (ALL). We also investigated alpha-IFN's ability to facilitate the generation of CTLs. In the absence of alpha-IFN, CTL lines with only low cytotoxicity and no CTL clones could be generated. In the presence of alpha-IFN, however, alloreactive, leukemia-reactive CTL lines with high cytotoxicity could be generated, and CD8+ CTL clones could be established with HLA class I restricted minor histocompatibility antigen (mHa)-specific recognition. In a cell-mediated clonogenic cytotoxicity assay, the CTL clones showed specific growth inhibition of leukemic precursor cells from the recipient and a second CML patient, but the clones did not inhibit growth of hematopoietic precursor cells (HPCs) from the donor. The normal HPCs from an unrelated donor with the HLA class I restriction molecule were also recognized by the CTL clones, illustrating that the antigen recognized is not leukemia-specific. The mechanism of the immunomodulating effect by alpha-IFN is not clear. Addition of alpha-IFN to medium did not alter the expression of HLA or adhesion molecules on CML cells. In the treatment of CML, administration of alpha-IFN as adjuvant immunotherapy after allogeneic BMT may increase GVL reactivity.
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PMID:Minor histocompatibility antigen-specific, leukemia-reactive cytotoxic T cell clones can be generated in vitro without in vivo priming using chronic myeloid leukemia cells as stimulators in the presence of alpha-interferon. 907 52

The prognosis of Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is poor. While umbilical cord blood transplantation has been used successfully for hematopoietic reconstitution, patients' size may be a limiting factor. We report an 11-year-old, 55-kg patient with Ph+ ALL, who received human leukocyte antigen-identical sibling donor cord blood transplantation (5.94 x 10(6) CD34+ cells) during the second ALL relapse. On days 25, 41, 75 and 103, successful engraftment was confirmed by cytogenetic studies. However, the leukemia relapsed on day 117 and the patient died on day 146 due to refractory ALL. In conclusion, based on the documented engraftment in our patient, we believe cord blood transplantation may be successfully employed in adolescent or possibly even adult patients.
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PMID:Cord blood transplantation for acute lymphoblastic leukemia in a pediatric patient. 908 Jul 60

The translocation (6;9)(p23;q34) is a rare cytogenetic aberration found in patients with acute myeloid leukemia (AML). The clinical, morphologic, and immunophenotypic findings of eight t(6;9) acute leukemias are described. The patients included six men and two women with a mean age of 38.5 years. The leukemias were classified in the French-American-British (FAB) system as AML FAB M2 in four cases and as FAB M4 in four cases. Underlying myelodysplasia was evident in six cases. Bone marrow basophilia was found at presentation in six of the seven cases studied. In two cases with basophilia, darkly stained granules were also present in many eosinophils. In one case, initial basophilia was absent, but was present at relapse, as were eosinophils containing darkly stained granules. Iron stains were available in five cases; four showed increased incorporation and three had ringed sideroblasts. All cases studied by flow cytometry (six at presentation and three at relapse) expressed CD13, CD33, and human leukocyte antigen-DR. At presentation, five cases were CD34 negative. In one case at presentation, a subset of blasts (18%) weakly expressed CD34. Three cases studied at relapse were positive for CD34. Two of seven cases studied were terminal deoxynucleotidyl transferase positive. The t(6;9)(p23;q34) was the only cytogenetic abnormality in five cases. Trisomy 8 was found in two cases, and ring 12 was present in one case. Three patients are living with refractory leukemia 6 weeks to 6 months after initial diagnosis, and three patients died of complications of allogeneic bone marrow transplantation. Only one patient is alive without evidence of disease 3 years after bone marrow transplantation. t(6;9) leukemia is an unusual type of AML that is associated with poor prognosis, early age of onset, basophilia, myelodysplasia with frequent ringed sideroblasts, and a CD34-negative initial phenotype.
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PMID:Acute myeloid leukemia with t(6;9) (p23;q34): association with myelodysplasia, basophilia, and initial CD34 negative immunophenotype. 912 11

Every year 2,800 children are diagnosed with leukemia and between 30% and 60% will relapse and need a bone marrow transplant. In addition, children with hematologic, genetic, or immunologic diseases may also require a transplant to be cured. Unfortunately, only 30% of these children will have a human leukocyte antigen-matched sibling donor. The current options for alternative donor sources include matched unrelated donor, mismatched related donor, and unrelated cord blood donor. Compared to a matched sibling donor, each of these options has an increased risk for graft failure and graft-versus-host disease (GVHD). For patients who receive stem cells from matched unrelated donors or mismatched related donors, the risk of graft failure is 5% to 10% and the risk of GVHD approaches 80%. After unrelated cord blood transplants, the graft failure rate is 8%, but this is potentially offset by less severe GVHD. Challenges for nurses include providing anticipatory guidance for patients and families undergoing these novel therapies and devising treatment strategies to manage the complications. Graft failure, GVHD, and infections pose the most significant risks associated with alternative donor transplants.
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PMID:Alternative donor sources in pediatric bone marrow transplantation. 932 95

Patients with hematologic malignancy or severe aplastic anemia after myeloablative chemo- and radiotherapy were given granulocyte colony-stimulating factor (G-CSF)-mobilized, cryopreserved allogeneic peripheral blood stem cells (PBSCs) from 15 healthy donors who were either human leukocyte antigen (HLA)-matched siblings (n = 13) or haploidentical offspring (2). Polymerase chain reaction-amplified short tandem repeat genotyping was used for early confirmation of donor engraftment after PBSC transplantation (PBSCT). A standard cyclosporine A/methotrexate combination was used to prevent acute graft-versus-host disease (GVHD). All donors, including one in the third trimester of pregnancy, tolerated G-CSF administration and 3-day PBSC harvesting procedures well. Engraftment was prompt for all patients; it was verified using a panel of 12 human polymorphic short tandem repeat loci from bone marrow as early as 7 days posttransplantation. This status was maintained until relapse, when mixed chimerism was detected using the polymerase chain reaction. A minimum resurgence of recipient cells to 1% of the population was required to detect chimerism. The median times to recovery of the absolute neutrophil count to greater than 0.5 x 10(9)/L and the sustained platelet count to greater than 20 x 10(9)/L without transfusion were 10 and 12 days after PBSCT, respectively. Six patients experienced acute GVHD, Grade I in two patients and Grade II in four, including two HLA-haploidentical recipients. Chronic GVHD was noticed in three of the 11 patients who were followed for at least 100 days after PBSCT. Ten patients were still alive at the latest follow-up and have been disease free for a median of 278 days (range 60-671). Five patients died from causes other than graft failure: three from leukemia relapse and two from transplant-related complications. The results confirm that G-CSF can be safely administered to healthy donors and that engraftment after allogeneic PBSCT is fast and durable. Complete chimerism can be detected early by genomic analysis. PBSCT may offer an alternative to bone marrow transplantation.
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PMID:Allogeneic peripheral blood stem cell transplantation and early detection of donor engraftment by polymerase chain reaction. 958 76

Immunocompetent donor-derived T lymphocytes play a crucial role in the elimination of residual leukemic cells post allogeneic bone marrow transplantation. Because this graft versus leukemia (GVL) effects is absent after autologous stem cell transplantation (ASCT), a high rate of relapse ensues. We introduced cell-mediated immunotherapy at the stage of minimal residual disease in lymphoma patients to help effect a GVL-like reaction by adoptive transfer of immunocompetent human leukocyte antigen-matched donor peripheral blood lymphocytes (PBL). Thirteen consecutive patients with high-risk lymphoma were treated with allogeneic cell therapy (AlloCT) after having undergone ASCT. In the absence of graft-versus-host disease, cell therapy-induced graft-versus-lymphoma reaction was amplified by human recombinant interleukin 2 (rIL-2) during 3 days to activate donor PBL in vivo, followed by infusion of in vitro rIL-2 activated donor lymphocytes combined with 3-day rIL-2 therapy. Nine of the patients underwent the treatment protocol well. In the four other patients, in whom the AlloCT resulted in marrow aplasia due to elimination of host hematopoietic cells, treatment with donor marrow cell infusion without further conditioning was performed. Adoptive cell therapy in the form of AlloCT may turn out to be an effective therapeutic modality for the treatment of resistant residual disease in lymphoma patients.
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PMID:Allogeneic cell-mediated and cytokine-activated immunotherapy for malignant lymphoma at the stage of minimal residual disease after autologous stem cell transplantation. 980 40

Sodium phenylacetate (PA) and sodium phenylbutyrate (PB) are aromatic fatty acids that can effect differentiation in a variety of cell lines at doses that may be clinically attainable. We have studied the impact of these two agents on lineage- and differentiation stage-specific antigen expression, proliferation, apoptosis, and clonogenic cell survival in primary cultures of bone marrow samples from patients with myeloid neoplasms at presentation and in remission and from normal volunteers. PB inhibited the proliferation of primary acute myeloid leukemia cells in suspension culture with an ID50 of 6.6 mM, similar to its ED50 in cell lines. At higher doses (>/=5 mM), PB also induced apoptosis. PB inhibited clonogenic leukemia cell growth with a median ID50 of less than 2 mM; however, colony-forming units-granulocyte/macrophage from patients with myelodysplasia and normal volunteers were inhibited with a similar ID50. In contrast to PB, its metabolite PA had no significant effect on either acute myeloid leukemia proliferation or apoptosis. Expression of the monocytic marker CD14 was increased in monocytic and myelomonocytic leukemias in response to PB, and to a lesser extent, PA. Surprisingly, both agents appeared to increase expression of the progenitor cell antigen CD34, as well as the DR locus of the human leukocyte antigen. These data indicate that PB, but not its metabolite PA, has significant cytostatic and differentiating activity against primary neoplastic myeloid cells at doses that may be achievable clinically.
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PMID:Impact of the putative differentiating agents sodium phenylbutyrate and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells. 981 60


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