摘要:

Although serial detection of bcr-abl positive cells by PCR appears able to identify distinct patient groups with different risks of relapse following BMT, there remain many unanswered questions regarding the clinical utility and biological significance of PCR detectable cells in this disease. Many of the studies summarized have conflicting results and the influence of various clinical parameters which are known to affect the risk of relapse post-BMT has not yet been consistently associated with the ability to detect bcr-abl positive cells by PCR. These clinical parameters include GVHD, T-cell depletion and intensity of immunosuppression following BMT. Prospective studies with larger patient numbers will be necessary to define the impact of these factors in PCR status and relapse. The answers to all these questions will increase our understanding of the biology of chronic myelogenous leukemia and help provide more effective therapies for the future.

ISSN:1042-8194    

DOI:10.3109/10428199309147350

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Formation of the Philadelphia (Ph1) chromosome, which contains the hybridbcr-ablgene, is thought to be the initial event in chronic myelogenous leukemia (CML). The positions of the breakpoint within the breakpoint cluster region (bcr) on thebcr-ablgene in 22 chronic-phase cases of Ph1-positive CML were determined using conventional Southern blots, and the splicing pattern were also determined the species of the fusedbcr-ablmRNA in 79 CML cases using the polymerase chain-reaction procedure (RT-PCR). The location of the breakpoint within the bcr locus was assigned to one of five zones. Breakpoints in zones 1 and 2 were grouped as 5', and those in zones 3,4 and 5 as 3'. Nine patients had 5' breakpoints and 13 patients had 3' breakpoints. The platelet counts of 3' patients were significantly higher than those of 5' patients (1395 vs 274×109/L; p<0.03). The megakaryocyte counts from bone marrow histological sections in 3' patients (n= 12) and 5' patients (n= 7) were 63.4/mm2and 19.5/mm2, with a significant difference at p<0.006. The mean number of megakaryocyte progenitor cells assayed byin vitrocloning was 128.3/2×105bone marrow cells for 3' patients (n= 7) compared with 46.3 for 5' patients (n= 4). Using the RT-PCR technique, the bcr exon 2/ablexon 2 fused mRNA (b2-a2) was detected in 18 patients, the bcr exon 3/ablexon 2 fused mRNA (b3-a2) was detected in 45 patients, and both types of mRNA were detected in 16 patients. The platelet counts of patients who expressed b3-a2 mRNA or both types were significantly higher than the counts of patients who expressed only b2-a2 (813 vs 379×109/1; p<0.01). The megakaryocyte counts from bone marrow histological sections in patients with b3-a2 type (n= 19) and with b2-a2 type (n= 7) were 67.1/mm2and 27.7/mm2, respectively, with difference being significant at p<0.02. All these findings suggest that Ph1- positive CML patients with 3' breakpoints or with b3-a2 type mRNA have higher thrombopoietic activity than patients with 5' or b2-a2 type.

ISSN:1042-8194    

DOI:10.3109/10428199309147351

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

High grade B cell non-Hodgkin's lymphoma (NHL) is an increasingly important problem in individuals infected with the human immunodeficiency virus (HIV). Fifty percent of these tumours harbour the Epstein-Barr virus (EBV) and there is an equal frequency of EBV A and B-subtypes in the tumours. This contrasts with the recent report that only A-type EBV is associated with Hodgkin's disease. Such studies are challenging the traditional models of EBV-associated lymphomagenesis and showing the way for further studies in this field. This article reviews the studies of EBV subtypes in HIV-associated NHL and uses this new knowledge to discuss the role of EBV in lymphomagenesis.

ISSN:1042-8194    

DOI:10.3109/10428199309147352

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Adhesion molecules such as CD2 and its ligand CD58 (LFA-3), as well as CD1 la/18 (LFA-1) and CD54 (ICAM-1) regulate not only cell to cell attachment but also participate in lymphocyte activation, recirculation, and effector function including cytolytic activity towards tumor cells. We have investigated the role of CD2/CD58 and CDlla/18/CD54 interactions in cellular immune responses directed towards freshly recovered human T cell leukemias. Downregulation of CD54 and CD58 were observed to correlate with enhanced numbers of blasts in circulation and lack of susceptibility to killing by autologous cytotoxic lymphocytes. Furthermore, culturing tumor cells with recombinant TNF-alpha conditioned medium resulted in reinduction of CD54 and CD58 expression and susceptibility to lymphocyte mediated lysisin vitro. Our findings support the view that adhesion molecules play a pivotal role for tumor cell biologyin vivoand stress the point that successful immunotherapy of malignant disease may be facilitated by influencing not only the immune response itself but also adhesion molecules on the malignant tumor targets.

ISSN:1042-8194    

DOI:10.3109/10428199309147353

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Thec-kilproto-oncogene encodes a receptor tyrosine kinase that is considered to play important roles in hematopoiesis. The proto-oncogenec-kitproduct is expressed on various types of human cell lines derived from leukemic cells of erythroid, megakaryocytic and mast-cell lineages. Also, thec-kitproduct is detectable in blast cells in most cases of acute myeloblastic leukemia (AML) and in some cases of chronic myelogenous leukemia (CML) in blastic crisis (BC). By contrast, little or no expression ofc-kitis observed in human leukemia cell lines of lymphoid lineage and in blast cells in acute lymphoblastic leukemia (ALL). Tyrosine phosphorylation and activation of thec-kitproduct with the ligand forc-kit(stem cell factor: SCF) results in proliferation of some human leukemia cell lines, such as M07E, and blast cells in a substantial fraction of AML cases. In addition, SCF appears to have an activity in inducing differentiation of certain types of leukemic cells. In some cases, further, thec-kitproduct is found to be activated in leukemic cells even before the stimulation with SCF. These results suggest thatc-kitmay be involved in excessive proliferation and aberrant differentiation of human leukemia cells.

ISSN:1042-8194    

DOI:10.3109/10428199309147354

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Twenty-seven patients with B-cell chronic lymphocytic leukemia (CLL) or a related lymphoid malignancy were treated with high-dose cytosine arabinoside (ara-C) at a dosage of 3 gm/m2administered over 2 hours every 12 hours at one to four doses per course, which were repeated at 4-week intervals. Median patient age was 60 years. Fifty-four percent of CLL patients had Rai stage III or IV disease and the median number of prior therapies was three. Two patients achieved a complete response, five had a partial response, and two had clinical improvement for an overall response rate of 33%. The median duration of response was 9 months. Myelosuppression and infection were the main toxicities. Intracellular levels of the active metabolite ara-C triphosphate varied among patients, but comparisons of pharmacokinetic parameters revealed no significant differences between responders and non-responders. We conclude that high-dose ara-C has modest activity in CLL and that its use in combination with other agents in the treatment of CLL is warranted.

ISSN:1042-8194    

DOI:10.3109/10428199309147355

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

The pharmacology of fludarabine triphosphate (F-ara-ATP) in leukemic lymphocytes was studied during a phase II trial of fludarabine in 24 patients with chronic lymphocytic leukemia (CLL). Fludarabine was given as a 30-min i.v. infusion at a dose of 25 or 30 mg/m2daily for 5 days. The concentrations of F-ara-ATP, the active metabolite of fludarabine, were determined in leukemic lymphocytes at intervals up to 24 hr after the first infusion. A median peak concentration of 19μM (range, 6-52μM) was generally reached 4hr after the beginning of the infusion. No significant relationship was observed between clinical response and the median peak level of F-ara-ATP or the retention of F-ara-ATP in leukemic lymphocytes.In vitroincubation of CLL cells with the parent nucleoside of fludarabine, arabinosyl-2-fluoroadenine (F-ara-A), indicated that F-ara-ATP accumulated in a linear fashion in response to the product of the F-ara-A concentration times the duration of incubation. Exposing cells longer with lower F-ara-A concentrations or shorter with higher F-ara-A concentrations resulted in similar intracellular levels of F-ara-ATP as long as the products of fludarabine concentration and time of exposure were equal. These results and the fact that the fludarabine dose rate currently administered is well tolerated suggest that it may be the optimal dose rate for F-ara-ATP accumulation in CLL cells.

ISSN:1042-8194    

DOI:10.3109/10428199309147356

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

Three successive strategies used to treat acute myelogenous leukemia (AML) patients who entered complete remission are compared with respect to their long term efficacy (>5 years). Additionally, the ability of twoin vitroassays to identify patients who would be long term remitters was assessed. With respect to the proportion of patients in long term remission, 5 years of maintenance therapy, intensive consolidation therapy plus 3 years of additional therapy, and 4 courses of consolidation therapy produced equivalent results with 18 to 22% of patients in remission at 7 years. Patients whose leukemia cells retained high levels of cytosine arabinoside triphosphate (araCTP) and who received maintenance therapy were less likely to experience early relapse than comparably treated patients whose leukemia cells failed to retain araCTP. The failure of leukemia cells to clonein vitrowas also associated with a lower early relapse rate for patients who received maintenance therapy. Neither the ability of leukemia cells to retain araCTP nor their ability to clone in vitro were of prognostic significance for patients treated with 4 courses of intensive consolidation therapy.

ISSN:1042-8194    

DOI:10.3109/10428199309147357

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

In an attempt to improve the results of treatment in patients with relapsing or refractory acute myeloid leukemia (AML), we conducted a pilot study using a two-drug salvage regimen according to thein vitroclonogenic leukemic cell (CFU-L) drug sensitivity. Fourteen patients were included in the study, 10 with relapsing and 4 with refractory AML. Drug exposure was assessed for daunorubicin, cytosine arabinoside, etoposide, mitoxantrone and amsacrine. The two drugs with the best inhibitory effect on CFU-L were selected for the treatment. A complete remission was achieved in only 4 patients and a partial remission in 3 patients. Although the number of patients is too small for appropriate statistical analysis and for a definite conclusion to be drawn, the observed response rate with directed therapy did not appear better than that expected from empiric salvage regimen.

ISSN:1042-8194    

DOI:10.3109/10428199309147358

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor

摘要:

High dose hydroxyurea (HU) was used in a pilot study to assess its efficacy in mobilizing Philadelphia (Ph) chromosome negative progenitor cells in chronic myeloid leukaemia (CML). Five patients received 12g/M2oral HU in divided doses. Side effects were minimal, allowing outpatient administration. Nine to fourteen days later 4 patients achieved a mean leukocyte nadir of 3.5×109/L (Range 2.4-4.9) and a mean platelet nadir of 99×109/L (Range 95-108). Peripheral blood mononuclear cells (PB-MNC) sampled prior to the HU priming were 100% Ph positive. Between 10 and 18 days post HU, 3 patients achieved a marked reduction (80-100%) in the number of Ph positive metaphases in PB-MNC collected by apheresis. One patient failed to achieve any Ph suppression. Polymerase chain reaction analysis (PCR) for thebcr-ablfusion product remained positive in all samples.Rapid rises in CFU-GM numbers were associated with a return to 100% Ph positive metaphases however slower rises represented recovery with predominantly Ph negative cells, allowing apheresis collection of these cells.We conclude that HU induces a reproducible leukocyte nadir with sufficient stem cell mobilization for potential autologous transplantation. Higher doses of HU together with early and intensive apheresis is required to maximize Ph negative progenitor cell harvests.

ISSN:1042-8194    

DOI:10.3109/10428199309147359

出版商:Taylor&Francis    

年代:1993

数据来源: Taylor