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PubMed1988

Heterogeneity in protein patterns of cells from terminal blast crisis in chronic granulocytic leukemia: discrimination between lymphatic and myeloid lineages.

Terminal blast crisis cells of chronic granulocytic leukemia are biochemically distinct. Triton-X-114 detergent phase lysates revealed that myeloid types express predominantly proteins of a 24 kd apparent molecular weight range, whereas lymphatic types do not express these molecules but a 55 kd protein band. These biochemical differences, observed in the poorly differentiated blast crisis cells, are also found in well differentiated hemopoietic malignancies such as chronic lymphatic leukemia, or in mature granulocytes isolated from healthy individuals. The results support the concept of the different lineages of blast crisis cells in chronic granulocytic leukemia but question the role of these proteins in cell differentiation. In addition, the presence or absence of these proteins provide a helpful tool for classifying blast crises of chronic granulocytic leukemia.

Antibodies, Monoclonal↗
PubMed1996

Laboratory preparation of a deglycosylated ricin toxin A chain containing immunotoxin directed against a CD7 T lineage differentiation antigen for phase I human clinical studies involving T cell malignancies.

An immunotoxin consisting of a monoclonal antibody specific for CD7, a cell surface determinant expressed on T acute lymphocytic leukemia (T-ALL) blast cells, was linked to the potent plant toxin deglycosylated ricin toxin A chain (dgRTA) and is currently under evaluation in phase I clinical trials. Scale-up production of this immunotoxin, called DA7, was simplified using a two-step purification protocol that resulted in a highly purified immunotoxin meeting FDA criteria for IND approval. The anti-CD7 antibody, 3Ale, an IgG2b, was coupled to toxin using two different heterobifunctional cross-linkers, (1) N-succinimidyl-3-(2-pyridyl-dithiolproprionate) (SPDP), considered a standard croslinker and (2) 4-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)tolu ene (SMPT), designed to hinder the in vivo breakdown of the toxin/antibody disulfide bond. Since experiments revealed that SPDP-DA7 had similar pharmacokinetics and biodistribution in mice and higher yields than DA7 made with a hindered cross-linker, SPDP-DA7 was scaled up for clinical study. Yield of SPDP-DA7 was 25% relative to starting material. Fractions were collected containing a toxin: antibody ratio of 1:1 to 4:1 rather than only a 1:1 ratio since studies showed that this heterogenous fraction was just as toxic to proliferating CD7-expressing leukemia cells as a homogeneous 1:1 fraction. In vitro, the concentration of heterogenous SPDP-DA7 selectively inhibiting 50% activity (IC50) of the CD7+ CEM cell line was 0.01 microgram/ml to 0.05 microgram/ml for inhibiting activated T cells or T cell lines. In vivo, SPDP-DA7 showed a significant anti-tumor effect against CEM cells administered to scid/scid mice, but even more importantly was effective against primary T cell leukemias taken from patients and injected into scid/scid mice.

Animals↗
PubMed1988

Transposition of the oncogene c-ets-1 in a t(11;19)(q23;p13) cell line transient during clonal evolution of blast crisis chronic myeloid leukemia.

A patient with Ph-negative chronic myeloid leukemia showed active karyotypic evolution when he entered blast crisis. One cell line, which predominated briefly in an accelerated myeloid phase, was characterized by the t(11;19)(q23;p13). Chromosome in situ hybridization demonstrated movement of the oncogene c-ets-1 from the der (11q-) to the der (19p+). The breakpoint at 19p13 was in the vicinity of the human insulin receptor gene locus (INSR). No rearrangements of the c-ets and INSR genes were found in Southern blot analyses. Myeloid lineage was indicated by cell morphology and absence of immunoglobulin JH gene rearrangement and was supported by loss of the germ line bcr-3' gene. Chromosome rearrangements involving 11q23 and movement of c-ets-1 characterize monocytic and lymphoid leukemias and have not previously been reported in myeloid blast crisis of chronic myeloid leukemia.

Cell Transformation, Neoplastic↗
PubMed1993

Hypercalcemia in the blastic phase of chronic myeloid leukemia associated with elevated parathyroid hormone-related protein.

We describe a case of hypercalcemia without lytic bone lesions complicating myeloid blast crisis of chronic myeloid leukemia (CML). Serum levels of parathyroid hormone-related protein (PTHrP) were elevated during the initial hypercalcemic period and became undetectable during chemotherapy-induced chronic phase, only to become elevated again during subsequent recurrent blastic periods repeatedly associated with hypercalcemia. Previously reported cases of hypercalcemia complicating CML are reviewed. It is suggested that PTHrP was responsible for the hypercalcemia in this case and may be an important mediator of hypercalcemia in CML.

Adult↗
PubMed1999

Chronic myelogenous leukemia in nonlymphoid blastic phase: analysis of the results of first salvage therapy with three different treatment approaches for 162 patients.

BACKGROUND: The prognoses of patients with chronic myelogenous leukemia in blastic phase (CML-BP) are extremely poor. Treatment of patients with nonlymphoid CML-BP is associated with very low response rates, a median survival of 2-3 months, and significant toxicities. The aim of this study was to evaluate the results of therapy in CML-BP with different treatments in relation to response rate, survival, and toxicity. METHODS: A total of 162 adults patients with a diagnosis of nonlymphoid CML-BP referred from 1986 to 1997 were included in this analysis. Only first salvage therapy was considered for the purpose of this analysis. The blastic phase of CML was defined by the presence of 30% or more blasts in the blood or bone marrow, or extramedullary disease. Ninety patients were treated with intensive chemotherapy, 31 with decitabine, and 41 with other single agents. RESULTS: Thirty-six patients (22%) had an objective response. Response rates were similar among patients treated with intensive chemotherapy (28%) or with decitabine (26%). In aggregate, other single agents showed objective response rates of 7%. The median duration of remission for all patients was 29 weeks and the median overall survival 22 weeks. Patients treated with decitabine showed a trend toward better survival, despite a higher percentage of older patients (P < 0.004). The median survival times were 29 weeks with decitabine, 21 weeks with intensive chemotherapy, and 22 weeks with other agents. When only older patients were considered, survival was significantly better with decitabine versus other treatments (P < 0.01). A multivariate analysis of prognostic factors for survival confirmed the independent, significant favorable effect of decitabine therapy (P = 0.047). In all groups complications of myelosuppression were the most significant side effects. Severe nonhematologic toxicities were not observed in patients treated with decitabine; they occurred in 20% and 17% of patients treated with intensive chemotherapy or other single agents, respectively. CONCLUSIONS: Compared with intensive chemotherapy, decitabine showed favorable results, with similar objective response rates, a better nonhematologic toxicity profile, and a trend for better survival, particularly among older patients. Studies will now attempt to combine decitabine with other promising approaches, such as homoharringtonine, low dose cytarabine, and interferon-alpha, in all CML phases.

Adolescent↗
PubMed1989

Specific binding of radioiodinated human GM-CSF to the blast cells of acute myeloblastic leukemia.

We describe here the presence of two classes of binding sites for GM-CSF expressed on blasts freshly isolated from five AML patients and one patient with CML in blastic phase: one of high-affinity (38-177 per cell, KD 8-150 pM) and one of low-affinity (121-806 per cell, KD 503-2683 pM). No correlation is observed between the receptor number, receptor affinity, and the growth stimulatory effect of GM-CSF on leukemic blast progenitors. Blasts from two cases showed no or negligible response to GM-CSF but expressed comparable numbers of receptors when compared with the numbers expressed by the sensitive blasts. Our data suggest that significant proliferative effects of GM-CSF can occur at low levels of high-affinity receptor occupancy. Lack of responsiveness to GM-CSF in some AML patients is not correlated to the absence of GM-CSF receptors on leukemic cells. Reduction in the growth of blast progenitors at high concentrations of GM-CSF may be attributed to the differentiating activity of GM-CSF via low-affinity receptors on leukemic cells.

Binding, Competitive↗
PubMed1991

Clinical effect of granulocyte colony-stimulating factor on neutrophils and leukemic cells in myelogenous leukemia: analysis.

Clinical experiences with recombinant granulocyte colony-stimulating factor (rhG-CSF) in 13 acute (AML) and four chronic (CML) myelogenous leukemia patients are reported. Sixteen patients received rhG-CSF in support of treatment for life threatening infections and one CML patient in support of induction chemotherapy. After their first induction chemotherapy, six out of eight AML patients showed a rapid increase of neutrophils, recovered from infections and achieved complete remission (CR). One patient, in whom both neutrophils and blasts had increased during rhG-CSF administration, achieved CR through the next administration of chemotherapy (CR rate 87.5%). The last of the eight AML patients showed no increase of neutrophils, and died of interstitial pneumonitis. Two of five AML patients who received rhG-CSF after reinduction chemotherapy for relapsed or refractory leukemia achieved CR, a rate of 40%. In one of the two, the administration of rhG-CSF prior to induction chemotherapy seemed advantageous in achieving CR. During rhG-CSF administration, an increase of blastic cells in peripheral blood was observed in four out of all 13 AML patients. One of three CML patients, with a lymphoid crisis, showed an increase only of neutrophils, and recovered from infection. The other two showed increases of both neutrophils and blasts. One patient with CML in blastic crisis, undergoing induction chemotherapy with rhG-CSF administration, returned to the chronic phase. These clinical experiences suggest rhG-CSF to be effective in supporting infection therapy and in possibly enhancing the sensitivity of myelogenous leukemic blasts to antileukemic agents.

Adolescent↗
PubMed1987

T cell-derived blast crisis in chronic myelocytic leukemia.

We describe herein the occurrence of a T cell-derived blast crisis of chronic myelocytic leukemia which presented as a typical T cell leukemia on clinical (thymic mass and high white blood cells) and immunological grounds (T6+ T4+ T8+), with rearranged T cell receptor genes and germ line immunoglobulin genes. A Philadelphia chromosome was detected in all blast cell mitoses. The significance of T cell involvement during the chronic and acute phases of chronic myelocytic leukemia is discussed.

Adult↗
PubMed2002

Cutting edge: B7/CD28 interactions regulate cell cycle progression independent of the strength of TCR signaling.

The role of B7/CD28 signals in Ag-induced cell cycle progression of CD4(+) T cells was examined using the technique of CFSE dye dilution and flow cytometry. In wild-type T cells, proliferation was directly related to the concentration of Ag available to the APC. Consistent with this, the rate of G(0)-->G(1) cell cycle progression varied with the concentration of Ag. However, cell division by T cell blasts occurred at a constant rate, independent of Ag concentration. G(0)-->G(1) phase progression by CD28-deficient CD4(+) T cells or wild-type T cells cultured in the presence of neutralizing anti-B7 mAbs was slowed, confirming that a synergy does exist between TCR and CD28 signaling in the initial activation of the T cells. However, unlike the TCR, the strength of CD28 stimulation was also shown to play a unique role in controlling the rate of cell division by T cell blasts.

Animals↗
PubMed2004

Clofarabine.

Clofarabine [Clofarex] is a purine nucleoside in development with Bio-envision, the Southern Research Institute and ILEX Oncology as an anticancer agent. Clofarabine's nucleoside structure is such that both the purine and ribose rings are halogenated, which allows it to inhibit DNA synthesis at two critical junctures: DNA polymerase I and RNA reductase. An intravenous infusion and an oral formulation are undergoing clinical development. Clofarabine was originated by the Southern Research Institute. In August 1998 Bioenvision signed a co-development agreement with the Southern Research Institute, under which it obtained the right to manufacture, market and distribute clofarabine worldwide, except Japan and Southeast Asia. In addition, the company appears to have licensed rights from the Institute that cover the development and marketing of other purine nucleoside analogues that have relevance in the treatment of leukaemia and lymphoma. Bioenvision will pay royalties to the Southern Research Institute for sales of clofarabine. Bioenvision extended its option in May 2004 to manufacture, market and distribute clofarabine in Japan and Southeast Asia, and is seeking a co-marketing partner to convert the option into a license agreement following the terms agreed upon between Bioenvision and the Southern Research Institute. Bioenvision and ILEX Products (a wholly owned subsidiary of ILEX Oncology) signed an agreement in February 2004 that converted ILEX's option (agreed in March 2001) to market and distribute clofarabine in the US and Canada. As part of the deal, Bioenvision received a $US3.5 million payment from ILEX in December 2003. In March 2004, Genzyme Corporation announced that it had signed a merger agreement with ILEX Oncology under which ILEX shareholders will receive shares of Genzyme common stock valued at approximately $US1 billion in equity value. Genzyme's business combination with ILEX is expected to be completed by the middle of 2004, Genzyme will, therefore, acquire a considerable boost to its product portfolio. Bioenvision obtained the exclusive option from the Southern Research Institute in September 2003 to manufacture, market and distribute clofarabine in Japan and Southeast Asia. Bioenvision stated it was actively seeking a co-marketing partner to convert this option into a license. Bioenvision announced in June 2003 that it had formed two separate agreements with Ferro Pfanstiehl Laboratories. The agreements cover worldwide development and supply of clofarabine, excluding the US and Canada. Ferro Pfanstiehl has more than 25 years of experience in potent compound manufacturing. The US FDA granted clofarabine fast-track designation for the treatment of refractory or relapsed acute lymphoblastic leukaemia in children in September 2003. Clofarabine has also been granted orphan drug status by the US FDA for the treatment of adult and paediatric patients with acute lymphocytic leukaemia (ALL) or acute myeloid leukaemia (AML). In December 2001, clofarabine was granted orphan drug status in the EU for the treatment of adult and paediatric patients with ALL. A single-agent phase II study has been completed in patients with acute leukaemia and myelodysplastic syndromes. Results of a phase II study of clofarabine in the treatment of acute myelogenous leukaemia in older adults who are not considered suitable for intensive chemotherapy have been very positive, with a 64% response rate in these patients being reported. In May 2004, Bioenvision announced that it had decided to stop enrollment at 25 evaluable patients (initially anticipated to be approximately 37 patients) because of the encouraging interim results. It said the trial would conclude earlier than expected and be completed by the end of June 2004. The pivotal trial will enroll approximately 65 patients with AML considered unsuitable for intensive chemotherapy. Bioenvision currently has phase II trials ongoing in adult and paediatric patients with acute leukaemia and chronic lymphocytic leukaemia (CLL). In addition, Bioenvision-sponsored phase I/II clinical trials of clofarabine in patients with CLL and non-Hodgkin's lymphoma are underway in Europe. In July 2002, ILEX began two US multicentre, open-label, phase II trials in children with relapsed or refractory AML or ALL. Children enrolled in the studies receive an intravenous infusion of clofarabine over 2 hours for five consecutive days every 2-6 weeks. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), an overall response rate of 28% was reported for clofarabine therapy in heavily pretreated children with acute leukaemia. In September 2003, a multicentre European phase II trial (BIOV-111) was initiated in children with relapsed/refractory ALL. In December 2003, the first of 65 patients received treatment. As part of the global development programme, Bioenvision and ILEX are also conducting a phase II study in adult patients with AML. The companies are planning to investigate the potential use of clofarabine in combination with DNA-damaging agents, because clofarabine has been shown to inhibit DNA repair and may, therefore, potentiate the effects of DNA damaging drugs. A phase I/II trial of clofarabine in combination with cytarabine (Ara-C) in adult patients with first relapse AML, ALL, CML blast crisis and myelodysplastic syndrome was initiated at the University of Texas MD Anderson Cancer Centre in October 2002. Clofarabine has completed US phase I trials, and has reported favourable results in patients with leukaemia and solid tumours, including breast, colorectal and prostate cancers. A phase I/II trial in patients with solid tumours was initiated in July 2002. In addition, ILEX said it intended to develop an oral formulation of clofarabine for the treatment of colorectal cancer.

Adenine Nucleotides↗
PubMed1976

Prediction of relapse and remission in AML by marrow culture criteria.

Bone marrow culture studies in semi-solid agar have been performed on 250 patients presenting with acute myeloid leukemia. The detection of a spectrum of qualitative defects in the proliferation, differentiation and biophysical characteristics of leukemic colony forming cells (CFU-c) has permitted a detailed analysis of the relapse-remission status based on transition from qualitatively abnormal cell growth in vitro to a normal pattern of proliferation and differentiation. Changes in vitro generally preceded clinical or morphological evidence of the onset of relapse or remission and serve as a valuable additional parameter in monitoring clinical status. Marked cyclic changes in CFU-c incidence appeared to characterize the remission phase of AML and were frequently associated with fluctuations in marrow blast cell count which can lead to mis-diagnosis of incipient relapse. Detection of qualitative defect in marrow culture serves to distinguish patients with preleukemic disorders at high risk of termination in acute myeloid leukemia from patients with clinically similar disease who have not undergone further progression over a 2-4 year period of observation.

Bone Marrow↗
PubMed1977

DNA-synthesizing cells in human fetal thymus.

Fragments and suspensions of human fetal thymus were incubated in the presence of 3H-TdR to permit study of the distribution and morphology of DNA-synthesizing cells. Results of light and EM autoradiography showed that 1. although DNA-synthesizing cells were present in the medulla, the vast majority of these cells were localized in the thymic cortex, 2. cells with the typical EM appearance of small lymphocytes and lymphoid blast cells both synthesized DNA, and 3. cells in S-phase were predominantly 8 to 12 mum in size.

Autoradiography↗
PubMed2001

Elevated Bcr-Abl expression levels are sufficient for a haematopoietic cell line to acquire a drug-resistant phenotype.

A characteristic feature of chronic myeloid leukaemia (CML) is the inevitable advancement from a treatable chronic phase to a fatal, drug-resistant stage referred to as blast crisis. The molecular mechanisms responsible for this disease transition remain unknown. As increased expression of Bcr-Abl has been associated with blast crisis CML, we have established transfectants in 32D cells that express low and high levels of Bcr-Abl, and assessed their drug sensitivity. Cells with high Bcr-Abl expression levels are resistant to conventional cytotoxic drugs, and also require higher levels of STI571 (an inhibitor of Bcr-Abl), to induce cell death. Co-treatment with cytotoxic drugs and STI571 increased the sensitivity of the drug-resistant cells. Despite the drug-resistant phenotype, high Bcr-Abl levels concomitantly increased the expression of p53, p21, Bax and down-regulated Bcl-2. These cells maintain a survival advantage irrespective of a reduced proportion of cycling cells and the pro-apoptotic shift in gene expression. In addition, the level of Bcr-Abl expression (high or low) does not alter the growth factor independence and elevated Bcl-xL expression observed. Our study indicates that drug resistance can be primarily attained by increased Bcr-Abl expression, and highlights the potential of therapy which combines STI571 with conventional cytotoxic drugs.

Antineoplastic Agents↗
PubMed1999

Secondary T-acute lymphoblastic leukaemia mimicking blast crisis in chronic myeloid leukaemia.

A 34-year-old man with chronic myeloid leukaemia (CML) firstly developed a lymphoid blast crisis of B-cell type. After a second chronic phase which lasted for > 4 years with maintenance chemotherapy of hydroxyurea, 6-mercaptopurine and methotrexate, he developed a T-cell acute lymphoblastic leukaemia of TcR-gammadelta+ type. Cytogenetic analysis revealed disappearance of the t(9;22) translocation and appearance of new abnormalities consistent with the diagnosis secondary acute leukaemia. To our knowledge, secondary leukaemia in CML has not previously been reported.

Adult↗
PubMed1988

Interleukin 4 inhibits the proliferation but not the differentiation of activated human B cells in response to interleukin 2.

The combined effect of IL-4 and IL-2 on proliferation of anti-IgM antibody or Staphylococcus aureus strain Cowan I (SAC)-preactivated B cells was investigated. It was observed that in most cases, rIL-2 used at optimal concentration induced higher levels of tritiated thymidine ([3H]TdR) uptake than rIL-4 used at optimal concentration. When rIL-4 and rIL-2 were added together, it was repeatedly found that B cell proliferation induced by rIL-2 was significantly reduced and was, in most cases, comparable with the proliferation induced by rIL-4 alone. Cell cycle studies demonstrated that rIL-4 significantly reduced the number of cells entering S and G2/M phases of the cell cycle upon rIL-2 stimulation. B cell blasts preincubated for 24 or 48 h with rIL-4 displayed a reduced proliferation in response to rIL-2. In contrast, preculture of resting B cells with rIL-4 did not impair their subsequent proliferation in response to rIL-2 plus insolubilized anti-IgM antibody. This suggests that rIL-4 can only exert its inhibitory effect once B cells have received an activation signal. The differentiative activity of rIL-2 measured on B cell blasts preactivated for 2 d with SAC was not altered by rIL-4, which suggests that rIL-4 did not exert its inhibitory activity on rIL-2-induced B cell proliferation by enhancing rIL-2-mediated differentiation. Delayed addition of a neutralizing anti-IL-4 antiserum demonstrated that a period of contact of at least 24 h between IL-4 and B cell blasts was necessary for the development of the antagonistic effect of IL-4 on IL-2-mediated growth of activated B cells. These data demonstrate that IL-4 antagonizes the B cell growth-promoting effect of IL-2 without affecting the differentiation of preactivated B cells in response to IL-2.

B-Lymphocytes↗
PubMed2006

CrossLink: visualization and exploration of sequence relationships between (micro) RNAs.

CrossLink is a versatile tool for the exploration of relationships between RNA sequences. After a parametrization phase, CrossLink delegates the determination of sequence relationships to established tools (BLAST, Vmatch and RNAhybrid) and then constructs a network. Each node in this network represents a sequence and each link represents a match or a set of matches. Match attributes are reflected by graphical attributes of the links and corresponding alignments are displayed on a mouse-click. The distributions of match attributes such as E-value, match length and proportion of identical nucleotides are displayed as histograms. Sequence sets can be highlighted and visibility of designated matches can be suppressed by real-time adjustable thresholds for attribute combinations. Powerful network layout operations (such as spring-embedding algorithms) and navigation capabilities complete the exploration features of this tool. CrossLink can be especially useful in a microRNA context since Vmatch and RNAhybrid are suitable tools for determining the antisense and hybridization relationships, which are decisive for the interaction between microRNAs and their targets. CrossLink is available both online and as a standalone version at http://www-ab.informatik.uni-tuebingen.de/software.

Computer Graphics↗
PubMed1981

Proliferation of human lymphoid cells. Lymphocytopoiesis and cell cycle parameters in isolated perfused human spleens.

Parameters of the cell cycle of lymphoid cells and the rate of production of small lymphocytes and mature plasma cells were estimated in human spleens. 12 normal and 1 enlarged spleen with lymphatic hyperplasia were labelled either by a pulse or continuously with 3H-TdR-thymidine during normothermic perfusion of the isolated spleens. Biopsies of splenic tissue were taken at different intervals and evaluated autoradiographically. The mean initial labelling index of immunoblasts was 73% and for plasmoblasts 52%. The labelling index for small lymphocytes and mature plasma cells increased initially from 0% to 1%, and up to 25% respectively after 14 h. The duration of the S-phase, as determined by double labelling, was 8.26 h for lymphoid blasts. Data from the percentage labelled mitosis curve resulted in a minimal tG2 of about 1 h and tG2 + tM of about 4 h. The estimated generation time was about 11.5 h. The results found on the hyperplastic spleen were comparable to those on the normal spleen.

Adult↗
PubMed1984

Chronic myeloid leukaemia presenting as femoral head necrosis.

A 17-year-old male whose initial presentation of chronic myeloid leukaemia (CML) was necrosis of the right femoral head is reported. This is the first case report to our knowledge of CML presenting with such a lesion and is of further interest in that almost all reported cases of destructive bony lesions in this disease have been associated with blast transformation. Our patient in contrast has remained in stable chronic phase for over 30 months.

Adolescent↗