Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report the case of a 42-year-old male patient who was diagnosed with a large tumor of the right thoracic aperture 30 months after unrelated hematopoietic stem cell transplantation (HSCT) for accelerated phase of Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML). Biopsy revealed an immature lymphoid neoplasia with blastic tumor cell morphology and immunoreactivity for CD34, CD79a, CD43, and CD30 as well as slight positivity for TdT and CD20. Bcr-Abl rearrangement was found in interphase tumor cell nuclei by fluorescence in situ hybridization (FISH). Furthermore, a translocation t(14;18)(q32;q21) was amplified by polymerase chain reaction (PCR). Bone marrow (BM) examination showed regular hematopoiesis including a negative FISH analysis for Bcr-Abl and complete donor chimerism. Nested PCR from peripheral blood (PB), but not conventional PCR, was positive for the b3a2 Bcr-Abl transcript. Neither radiation nor intensive chemotherapy was capable of achieving a tumor remission, and the patient died from progressive disease 6 months later. Postmortem examinations showed a shift of immunophenotype with appearance of myeloperoxidase-positive tumor cells and loss of lymphoid antigens. In addition, there were characteristic cytogenetic findings of multiple Ph chromosomes and a clonal loss of P53 tumor suppressor gene. The latter was already deleted before HSCT. We conclude that lymphoid neoplasia occurring in our patient should be interpreted as an extramedullary, very immature blast crisis of CML expressing lymphoid differentiation markers rather than a true de novo NHL.
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PMID:Extramedullary blast crisis of chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation mimicking aggressive, translocation t(14;18)-positive B-cell lymphoma. 1257 66

Age >or=50 years has been reported to be an adverse risk factor for allogeneic BMT, and consequently many of these patients are either not transplanted or treated on nonmyeloablative protocols. To study if older patients perform poorly relative to younger adults following myeloablative allogeneic transplants, we compared the outcomes of consecutive adults aged >or=50 years (n=51) to those <50 years (n=262) who received BU, CY+/-etoposide and allogeneic transplantation for AML, CML, MDS and NHL from 1984 to 2000. Median ages were 53 (range 50-66) and 35 (range 18-49) years for older and younger patients, respectively. Patients were low-risk if they had AML in CR1, CML in first chronic phase, refractory anemia, or NHL in remission or sensitive relapse at the time of transplantation. All others were high-risk. In patients with low-risk disease, there was no significant difference in overall survival (OS) between older and younger adults (P=0.64), while older patients tended to have a shorter OS among high-risk patients (P=0.06). The 3-year OS was 53% (95% CI, 29-77%) compared to 60% (95% CI, 50-69%) for older and younger patients with low-risk disease, respectively. The corresponding 3-year OS were 27% (95% CI, 11-43%) and 37% (95% CI, 25-45%) for high-risk patients. In low-risk patients, the incidence of acute and chronic graft-versus-host disease, and treatment-related mortality were similar in older and younger patients, while older patients experienced more treatment-related deaths by day 100. On multivariable analysis, age >or=50 years was a significant adverse factor only when high-risk patients were considered. We conclude that when radiation-free conditioning is used, age >or=50 years is not a significant adverse risk factor for allogeneic BMT in patients with low-risk disease, and that such patients should not be excluded from conventional myeloablative approaches until the efficacy of nonmyeloablative transplantation is better established.
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PMID:Radiation-free regimens result in similar outcomes of allogeneic hematopoietic progenitor cell transplantation in patients aged >or=50 years compared to younger adults with low-risk disease. 1262 88

The multiple tumor syndrome is an unusual pathologic condition, which consists in association of multiple malignancies in the same patient. Seven cases are discussed: two women, five men, aged 32-70 years. The period between the two neoplasias was 2-23 years (in 6 cases). In one case the two malignancies appeared concomitantly. The hematological malignancies were: multiple myeloma: 2 cases; chronic granulocytic leukemia: 2 cases; chronic lymphatic leukemia: 3 cases. In four cases, the solid tumor followed the hematological malignancy at variable periods (2 and 4 years). In other two cases, the solid tumors preceded the hematological malignancy with 2 years, 23 years respectively. The solid tumors were genital cancers, malignant melanoma, spino-cellular carcinoma, thyroid cancer, hemangiosarcoma. In a single case the second tumor was a hematological malignancy too (NHL-diffuse lymphocytic lymphoma). Possible implications of previous therapy and environmental factors are discussed.
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PMID:The multiple tumor syndrome. Personal experience. 1263 87

It has been suggested that HLA-G antigens may provide tumor cells with an effective immune escape mechanism. So far mostly solid tumors have been analyzed; HLA-G antigen was only exceptionally detected. To further examine HLA-G expression, patients were chosen with different forms of leukemia: AML (25), CML (4), ALL (9), CLL (8), HCL (2) and NHL (3). Using flow cytometry with three HLA-G specific mAbs (87G, 01G and MEM-G/9), western blotting with two specific mAbs (4H84 and MEM-G/1) and RT-PCR, neither HLA-G antigen nor mRNA for any HLA-G isoform was detected. These results strongly suggest that HLA-G antigen is not expressed in freshly isolated human leukemia cells and therefore is not involved in their escape from immune attack.
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PMID:Analysis of HLA-G expression in malignant hematopoetic cells from leukemia patients. 1268 64

Hematopoietic stem cell transplants (HSCTs) are considered the best treatment option for many hematological malignancies, and transplant numbers have increased five-fold during the last decade. Only a few controlled prospective studies are available, and different opinions prevail. Data from 118 167 HSCT (36% allogeneic, 64% autologous) collected within the EBMT activity survey from 1990 to 2001 were used to assess trends over time, transplant rates and coefficient of variation (CV) of transplant rates among European countries for acute myeloid leukemia (AML; 18.5%), acute lymphocytic leukemia (ALL; 12%), chronic myeloid leukemia (CML; 11.5%), myelodysplastic syndromes (MDS; 3%), lymphoproliferative disorders (LPS; 36.3%) and multiple myeloma (MM; 18.7%). Transplant rates increased in all countries and for all indications from 1990 to 2001 from 1.7-fold (CML) to 24.8-fold (MM). Transplant rates have declined for CML since 1999. Autologous HSCT are the preferred choice for LPS and MM, allogeneic HSCT for ALL and myeloid malignancies. CVs of less than 50% suggest consensus for allogeneic HSCT in AML, ALL, CML, MDS and NHL, for autologous HSCT in LPS and MM. These data give an overview of the current status of HSCT for hematological malignancies in Europe and provide objective information for health-care providers and patient counselling.
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PMID:Hematopoietic stem cell transplantation for hematological malignancies in Europe. 1275 Jul 9

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.
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PMID:Apoptosis induced by molecular targeting therapy in hematological malignancies. 1464 49

We assessed the prognostic importance of the platelet count 100 days post transplant of 107 consecutive patients receiving ablative allogeneic bone marrow transplant (BMT) between 7/96 and 12/00 who survived at least 100 days. Diagnoses included AML (n=36), chronic myelogenous leukemia (n=27), NHL (n=14), ALL (n=16), MDS (n=9), aplastic anemia (n=3), and one Hodgkin's disease and myelofibrosis each. In total, 64% were in remission or in chronic phase or had aplastic anemia (good risk), and 36% had active disease at the time of transplant (bad risk). In all, 70% were matched sibling transplants and 30% were matched unrelated donor transplants. The mean follow-up for the patients remaining alive is 48 months. Survival was powerfully influenced by the 100-day platelet count: 4-year survival was 19% for patients with a platelet count <30 x 10(9)/l; 41% for patients with a platelet count of 30-50; and 72% for those with a platelet count >50 (P<0.001; log-rank test). In a multivariable analysis, the most powerful risk factors for mortality after allogeneic BMT were low 100-day platelet count (P<0.001) and bad risk disease (P=0.009). We conclude that the platelet count 100 days post transplant is a powerful predictor of overall survival.
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PMID:Prognostic importance of the platelet count 100 days post allogeneic bone marrow transplant. 1468 14

The regulation of apoptosis is an important potential target for anticancer therapy. The mitochondrial Bcl-2 protein inhibits apoptosis and is therefore an important mediator of resistance to treatment with traditional cytotoxic chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen (Genasense, Aventis Pharmaceuticals / Genta Inc) is a 18mer antisense-oligonucleotide (ASO), which specifically binds to the first 6 codons of the human bcl-2 mRNA, resulting in degradation and destruction of the mRNA by RNAse H. Subsequently there is a significant decrease of bcl-2 translation. A growing number of preclinical and clinical studies suggests that the combination of cytotoxic therapy with Oblimersen results in synergistic anticancer efficacy in many hematologic and solid tumors. Due to its low toxicity profile, oblimersen is an ideal combination partner with conventional chemotherapy. Three randomized phase-III trials (malignant melanoma, chronic lymphocytic leukemia, multiple myeloma) have recently finished recruitment. The results of these studies will be available by the end of 2003. Based on preclinical data, a lot of nonrandomized phase-II studies on several different tumor types like AML, CML, NHL, prostate cancer and breast cancer are underway. The manipulation of proapoptotic and antiapoptotic factors in favor of proapoptotic factors by inhibition of the bcl-2 protein translation in order to enhance the efficacy of anticancer treatments represents a promising new treatment concept in oncology.
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PMID:[Proapoptotic therapy with oblimersen (bcl-2 antisense oligonucleotide)--review of preclinical and clinical results]. 1471 45

We report results of unrelated cord blood transplants (UCBT) in 29 pediatric recipients in one center and the risk factors associated with survival. Median age: 9 years (0.5-20); diagnosis: ALL (9), AML (4), CML (1), HD (3), HLH (1), NHL (3), NBL (2); B-thal (1), FA (1), FEL (1), Krabbe (1), WAS (1), SAA (1); median follow-up: 11 months; conditioning: total body irradiation (TBI)-ablative (14), chemotherapy-ablative (6) and reduced intensity chemotherapy (9); GVHD prophylaxis: MMF/FK506 (18), cyclosporin A (CsA)+steroids+/-MMF (7) or CsA+methotrexate (MTX) (4); median total nucleated cells (TNC): 3.8 x 10(7)/kg (1.1-11); median CD34+: 2.3 x 10(5)/kg (0.2-9.9); and HLA match: 2 (6/6), 5 (5/6), 22 (4/6). Neutrophil engraftment by cumulative incidence curves 63% (median 28 (95% confidence interval (CI) 18-32)). Probability of >/=grade II acute graft-versus-host disease (aGVHD) by day +60 27%, >/=grade III aGVHD 20% and chronic graft-versus-host disease 3%. Estimated 1-year overall survival (OS) 46% (95% CI 30-71) and standard risk 60% (95% CI 29-100%). Variables associated with improved survival by multivariate analysis include non-TBI-ablative conditioning (P=0.024), CD34+/kg (P=0.038) and gender (P=0.048). These results suggest that CD34/kg cell dose and non-TBI-ablative conditioning may be important variables influencing OS following UCBT in pediatric recipients. Given the small number of patients, these results should be viewed cautiously.
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PMID:Outcomes of unrelated cord blood transplantation in pediatric recipients. 1510 15

A CD8 murine monoclonal antibody-coated high-density microparticle (HDM) has been developed, which allows for the rapid depletion of CD8+ T cells from apheresis products by gravity sedimentation. We conducted a study to determine the efficacy and safety of CD8 depletion of donor lymphocyte infusions (DLI) to treat relapse after stem cell transplantation using the Eligix CD8-HDM Cell Separation System. Patients were targeted to receive 3 x 10(7) CD4+ T cells/kg. Nine patients were enrolled, three with CML, three myeloma, two CLL, and one NHL. A median of 1 x 10(10) mononuclear cells were obtained by apheresis and processed. The median depletion of CD8+ cells was 99.3% (97.8->99.5%). CD8 depletion was highly specific, with a median recovery of CD4+ cells of 75%. A median of 2.9 x 10(7) CD4+ cells/kg was infused. No infusional toxicity was noted. All CML patients achieved a complete molecular remission. A CLL patient demonstrated a complete response. One patient developed GVHD (grade II acute GVHD and subsequently chronic GVHD). The CD8-HDM Cell Separation System appears to be highly selective and effective in depleting CD8+ T cells from DLI apheresis products, and CD8-depleted DLI is capable of mediating a graft-versus-leukemia effect while minimizing GVHD.
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PMID:CD8+ cell depletion of donor lymphocyte infusions using cd8 monoclonal antibody-coated high-density microparticles (CD8-HDM) after allogeneic hematopoietic stem cell transplantation: a pilot study. 1513 87


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