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)

A 6-year-old boy with CML in blastic crisis was transplanted with BM and PBSC from his HLA-mismatched MLC-positive mother following CD34-positive selection. Preconditioning for transplant was with thiotepa, cyclophosphamide, rabbit anti-human thymocyte globulin, and TBI followed by infusion of 2.6 x 10(6)/kg of CD34-positive BM and PBSC. Engraftment was confirmed by FISH analysis, and GVHD was not observed. On day 50, he relapsed and died despite three transfusions of donor lymphocytes without GVHD prophylaxis. CD34-positive cell selection for HLA-mismatched transplantation may prevent severe acute GVHD.
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PMID:Allogeneic bone marrow and peripheral stem cell transplantation from a haplo-identical mother and CD34 positive selection for CML. 886 62

A 58-year-old man was referred to our hospital because of his refractory leukemia. Laboratory examinations showed mild anemia and leukocytosis but no blast was seen in the blood. The patient's bone marrow was hyperplastic and 64.8% of marrow cells were lymphoblastoid cells. They were positive for CD10, CD19, CD34 and HLA-DR antigen. Cytogenetic analysis revealed the Ph chromosome in 17 of 20 metaphases. A Southern blot analysis demonstrated no rearrangement of M-BCR gene. A diagnosis of Ph-positive ALL was made. The patient received chemotherapy and reached a complete remission. At that time, however, his marrow cells had Ph chromosome in 7 of 7 metaphases and rearrangement of m-BCR was positive in PCR analysis. He died of septic shock during the intensive consolidation therapy. Clinically this patient seems to have de novo Ph-positive ALL though his marrow cells had Ph chromosome in all metaphases at the time of complete remission. Recently the rare cases of Ph-positive CML with an m-BCR breakpoint are reported in the literature. This patient may have such a type of CML in blastic phase.
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PMID:[A patient with clinically de novo Ph-positive acute lymphoblastic leukemia had Ph chromosome in all metaphases at the time of hematological remission]. 891 71

Between October 1991 and May 1994, 42 patients were treated with cyclophosphamide, thiotepa, and total body irradiation followed by an allogeneic transplantation of marrow depleted of T cells with soybean agglutinin and E-rosetting. Patients included in this study had acute myelogenous leukemia (13), chronic myelogenous leukemia (12), acute lymphocytic leukemia (nine), Hodgkin's disease or non-Hodgkin's lymphoma (four), multiple myeloma (three), or myelodysplastic syndrome (one). The mean age was 34 (range 8 to 51 years). Nineteen patients had a matched sibling donor and 18 received marrow from 6/6 matched unrelated donors while five received transplants from unrelated donors disparate at one DR locus (5/6 match). Time to granulocyte engraftment (AGC > or = 500/mm3) occurred at a mean of 16.5 days for related and 11.4 days for unrelated transplant recipients, and was related to the increased use of G-CSF in the unrelated population. There was no correlation with number of mononuclear cells, T cells, or CD34-positive cells infused, the rate of engraftment or the incidence of transplant complications. Multivariate analysis determined that G-CSF administration and a diagnosis other than ALL were the only factors associated with a faster rate of engraftment. Patients receiving unrelated donor transplants, those with ALL, or those who had a low T cell number infused (< or = 8.0 x 10(3) cells/kg) experienced delayed hospital discharge. The regimen resulted in excellent rates of engraftment (95.2%) with only one failure to engraft and one graft rejection. The incidence of grade III-IV acute graft-versus-host disease was 0% with sibling and 26.1% with unrelated donors. There were no cases of veno-occlusive disease. Fifty percent of patients are alive with a mean follow-up of 26.4 months. We conclude that this regimen is well tolerated and results in excellent engraftment with a low incidence of severe graft-versus-host disease and few therapy-related toxicities.
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PMID:Minimizing graft rejection in allogeneic T cell-depleted bone marrow transplantation. 893 45

Serial peripheral blood specimen from eight adult patients after sex-mismatched bone marrow transplantation (BMT) for Chronic Myeloid Leukemia (CML) (N = 3). Ewing sarcoma (N = 1), Acute Myeloid Leukemia (AML) in second remission (N = 1), Acute Lymphoid Leukemia (ALL) (N = 1), of multiple myeloma (N = 2) were analyzed by the simultaneous immunophenotypic (moAbs/ APAAP-staining) and genotypic analysis (for X and Y chromosomes) of interphase cells to characterize mixed chimerism, residual host cells, and leukemic relapse. Although a stable donor chimerism for T cells, myelomonocytic cells, and granulocytes was developed in seven of the eight patients at Days +21 to +28 post BMT, 0.5 to 1% host cells of different lineages remained continuously in five of the eight patients post BMT (> day 100). In two patients, one with common ALL and the other with multiple myeloma and long-term stable mixed chimerism, a tumor cell relapse was detected first in a sample at Day +176 and confirmed at Day +294. These malignant cells were genotypically of host origin and presented phenotypes identical to those at diagnosis. In the three patients with CML, residual host cells were identified as CD13 (Patient 3) of CD13/CD34 (Patient 4) positive and in one case as CD4/CD8 positive (Patient 7). Since no exclusive antigenic marker is available for this discrimination in these CML patients, normal host hematopoiesis can interfere with the identification of residual disease. Therefore, the identification of the bcr-abl transcripts by a two-step reverse transcriptase-polymerase chain reaction (RT-PCR) was included in this analysis. Patient 3 was bcr-abl positive at [Days +21, +28, +35, and +311, but negative at Days +121 and +400; Patient 4 was bcr-abl positive at only Day +166 post BMT. These results are interpreted as signaling a continuing risk of relapse. In Patient 7, the bcr-abl RT-PCR was negative at Days +142, +166, and +237. Thus, the combination of the simultaneous immunophenotypic and genotypic analysis and the bcr-abl detection by RT-PCR clearly improves the discrimination between malignant cells and normal residual host cells.
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PMID:Qualitative assessment of mixed chimerism after allogeneic bone marrow transplantation with regard to leukemic relapse. 893 46

Induction of apoptosis by growth factor deprivation or gamma-irradiation-induced DNA damage was directly studied in proliferating primary haemopoietic cells derived from CD34-positive cells of 13 CML patients and 12 normal controls. CD34-positive cells were cultured in the presence of appropriate concentrations of SCF and G-CSF for 5-7 d. After gamma irradiation with 500 rad or growth factor deprivation, the fraction of apoptotic cells was assessed by two independent methods applying either measurement of cells incorporating FITC-labelled dUTP by terminal transferase or assessment of the fraction of cells with a less than 2N DNA content in flow cytometry. Proliferating CML cells were not resistant to the induction of apoptosis either after gamma irradiation or subsequent to growth factor deprivation. A similar fraction of normal and CML cells underwent apoptosis 48 h after withdrawal of growth factors. CML cells displayed an increased susceptibility to induction of apoptosis after DNA damage. A significantly higher proportion of apoptotic cells were detected in samples derived from CML patients after irradiation with 0.5 Gy. These results, in conjunction with conflicting observations by other investigators, on the induction of apoptosis by gamma irradiation in various bcr-abl positive cells, suggest that bcr-abl-dependent effects on apoptosis strongly depend on the cells used. Our observations in CML cells derived exclusively from newly diagnosed CML patients demonstrate that bcr-abl expression per se is not sufficient to induce resistance to apoptosis.
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PMID:Primary proliferating immature myeloid cells from CML patients are not resistant to induction of apoptosis by DNA damage and growth factor withdrawal. 894 91

Stroma-supported long-term cultures (LTC) of chronic myeloid leukemia (CML) progenitor cells have previously revealed differences between normal and malignant stem cells with respect to their maintenance and adhesive properties. Using the cobblestone area forming cell (CAFC) assay and LTC, we have examined the frequencies of stem cell subsets, their ability for long-term progenitor cell production and the relative frequencies of malignant and normal progenitor cells before and after a 5-6 week culture period. Cells were obtained from bone marrow (BM) and peripheral blood (PB) samples of patients in chronic phase CML. CD34-enriched cells were sorted by FACS on the basis of CD34 and CD38 expression and overlaid on confluent stromal layers of murine FBMD-1 cells. The presence of the bcr/abl chimeric gene was detected by fluorescent in situ hybridization (FISH) using differently labelled bcr and abl-specific probes. In the CD34pos/CD38pos subset of CML-PB, representing 64-95% of CD34pos cells, CAFC frequencies at week 1 (wk-1) were much higher than those of CAFC wk-5 (1.10(4)/10(5) cells vs 1.10(3)/10(5)). In contrast, in the CD34pos/CD38neg subset, representing 2-3% of CD34pos cells, the frequency of CAFC wk-1 was only 1.10(2)/10(5) cells, but a high CAFC frequency (10(3)-10(4)/10(5)) was detected after 5 weeks of culture. CAFC frequencies in the CD34pos subset obtained from CML-BM were 10- to 100-fold lower than those from CML-PB, but displayed a similar distribution over CD38pos, CD38dim and CD38neg cells. Analysis of the percentage of Philadelphia chromosome-positive (Ph+) and Ph- cells by FISH on freshly sorted cells revealed that normal cells were not enriched in any CD34pos/CD38 subset. In addition, Ph- as well as Ph+ cells were maintained with similar efficiency throughout 5 week LTC. These results demonstrate that immature normal and malignant stem cells in CML have a comparable distribution on the basis of CD34 and CD38 expression. The ability to maintain immature normal and malignant hemopoietic cells with similar efficiency in LTC provides a model enabling a direct comparison of differential effects of cytokines or drugs on either normal or malignant immature stem cells in CML.
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PMID:Efficient long-term maintenance of chronic myeloid leukemic cobblestone area forming cells on a murine stromal cell line. 900 28

Five patients with Ph+ chronic myeloid leukemia and no detectable diploid cells in the marrow received 6 g hydroxyurea twice daily for 7 days followed by G-CSF to harvest Ph-cells 1-84 months after diagnosis. Three were in first chronic phase, and two in accelerated phase. One stopped hydroxyurea after 4 doses due to intractable vomiting and was not apheresed, while two stopped hydroxyurea after 9 and 11 doses because of mucositis and skin rash. Two tolerated all doses; one with no significant side effects, and one with mucositis and painful plantar rash. The nadir leukocyte, neutrophil, and platelet counts were 0.4-0.8, 0-0.1, and 2-19 x 10(9)/L respectively. Apheresis was commenced when the leukocytes were 1.2-3.8 x 10(9)/L 9-10 days after starting G-CSF, and 6 aphereses were performed. Four collections were 100% Ph+, and two 22% and 90% Ph-. The total nucleated cell, CD34+/CD34-subset, CD34+/CD33+ subset, and CFU-GM yields per kg per collection were 0.48-2.38 (median 1.18) x 10(8), 0-0.48 (median 0.012) x 10(6), 0.028-10.19 (median 0.92) x 10(6), and 0.29-41.81 (median 21.78) x 10(4) respectively. We conclude that hydroxyurea in the dose we used is poorly tolerated, and is associated with significant adverse effects including severe myelosuppression. It is possible to harvest diploid cells during recovery, but achievement of Ph-negativity appears to be erratic and cell yields are poor.
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PMID:High-dose hydroxyurea and G-CSF to collect Philadelphia-negative cells in chronic myeloid leukemia: preliminary results. 902 92

We conducted a retrospective study to assess the changes in bone marrow (BM) stromal antigenic profile and fibrosis in chronic myeloid leukemia (CML) under combined interferon-alpha (IFN) and Ara-c therapy. Bone marrow biopsies were taken before therapy and twice (at 4 and 15 months) during therapy in 10 CML patients and compared with non-CML samples. Collagen and reticulin fibrosis was assessed by histochemical methods and phenotypic changes were studied by immunohistochemistry (APAAP) with antibodies directed against endothelial cell antigens, cell adhesion molecules, and HLA-DR. It was found that: (1) BM endothelial cells in patient and in control specimens showed a specific pattern of antigen expression: high expression of FVIII and CD34 (except on sinusoids for the latter), variable expression of UEA I, and no expression of HLA-DR and E-selectin. (2) Compared to non-CML controls, CML specimens at diagnosis showed an increased reticulin fibrosis and a decreased expression of CD61 on megakaryocytes and of CD31 on vessels and hemopoietic cells. (3) Treatment did not influence BM fibrosis, the vascular content of the BM, or the expression of the antigens tested except an increase in the number of CD34+ sinusoids (5/10 patients), an increase in the number of HLA-DR+, and a decrease in the number of CD34+ hemopoietic cells (6/10). (4) On therapy, difficulty in aspiration and/or reduced BM fragment numbers were noted in 8 of 10 patients whose bone marrow was still normocellular or slightly hypercellular. In conclusion, CML samples at diagnosis showed increased fibrosis and decreased CD31 and CD61 expression compared to controls. During the period of observation, combined therapy did not modify BM fibrosis; however, an increase in CD34+ sinusoids and a decrease in CD34+ hemopoietic cells were noted.
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PMID:Evolution of bone marrow fibrosis and stromal antigenic expression in chronic myeloid leukemia on alpha interferon and Ara-C therapy. 904 64

The aim of the study was to test whether fractionated (weekly) idarubicin administration to multiply pretreated leukemia patients is effective and tolerable for outpatient treatment, and whether idarubicin alone can overcome P-glycoprotein (P-gp)-related resistance. P-gp was assessed with an immunocytological technique using the monoclonal antibody 4E3.16. P-gp. expression was characterized as a percentage of P-gp-positive blasts. Additionally, the function of P-gp was determined with the rhodamine-123 (R-123) accumulation test in combination with or without verapamil and expressed as the R123 accumulation ratio. Fractionated idarubicin (12 mg/m2/week) was given to 36 acute myelogenous leukemia (AML) patients, 12 acute lymphoblastic leukemia (ALL) patients, and eight chronic myelogenous leukemia (CML) patients in blast crisis. Furthermore, 11 AML and four ALL patients were treated with fractionated daunorubicin at a dose of 50 mg/m2/week. All patients had been pretreated with drugs inducing P-gp-related resistance including daunorubicin and/or doxorubicin or vindesine (CML patients). Of 71 pretreated patients, 51 (72%) had a P-gp value between 25 and 98%. Six of these patients with increased P-gp expression had a nonpumping P-gp; four of them were CD34 positive. Of 51 patients with increased P-gp expression, 30 (59%) were CD34 positive. With regard to idarubicin monotherapy, overall response was 33/56 (59%) patients, and 23/33 (70%) responding patients showed a P-gp expression between 25 and 95%. All idarubicin-responding patients with high P-gp expression before treatment showed a clear reduction of P-gp-positive blasts. No patients with P-gp expression between 34 and 85% treated with fractionated daunorubicin showed response or reduction of P-gp-positive blasts in bone marrow. This study demonstrates that P-gp-related resistance can be overcome in multiply pretreated leukemia patients with idarubicin alone, and that the protocol used here is tolerable for outpatient treatment.
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PMID:Idarubicin monotherapy in multiply pretreated leukemia patients: response in relation to P-glycoprotein expression. 906 74

A considerable proportion of cases of myeloproliferative and lymphoproliferative disorders exhibit renal involvement. However, it is unclear whether the cytologic features, immunophenotype or grade of malignancy of the cells infiltrating the kidney differ from those of the primary tumor. This study was performed on 120 autopsy cases with the following diagnoses: acute myelogenous leukemia (AML, n = 22; subtypes M1 + M2, n = 12, subtype M4, n = 10), chronic myelogenous leukemia (CML, n = 7), agnogenic myeloid metaplasia/myelofibrosis (AMM/MF, n = 6), acute lymphocytic leukemia (ALL, n = 6), chronic lymphocytic leukemia (CLL, n = 9), other low-grade non-Hodgkin's lymphomas (low-grade NHL, n = 24), high-grade NHL (n = 21) and multiple myeloma (MM, n = 25). Renal involvement was investigated by light microscopy and immunohistochemistry. It was found in 34% of the cases, and was most common in ALL (83%) and low-grade NHL (50%) and least common in high-grade NHL (10%) and MM (12%). Dense infiltration of almost the entire kidney was most commonly seen in AML, low-grade NHL and ALL. Infiltration was bilateral and involved both the cortex and medulla in the majority of cases. When involvement of other organs was compared with that of the kidney, the lung was found to be involved in approximately the same number of cases, but liver involvement was more common and heart involvement less common. Reactive lymphocytic infiltration of the kidney was found in 18 of the 120 cases (15%), and was distinguished from scanty tumorous infiltration by immunohistochemical staining. No major phenotypical differences were found between the tumor cells infiltrating the kidney and those of the primary tumors in the bone marrow or lymph nodes. However, in one case of CML, the cells infiltrating the kidney were negative for KP1 and chloroacetate esterase, but could be identified by reactivity for CD34. The grade of malignancy in NHL was similar in both the nodal and renal manifestations.
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PMID:Renal involvement in myeloproliferative and lymphoproliferative disorders. A study of autopsy cases. 906 78


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