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

The detection of chimerism, residual molecular and cytogenetic disease following transplantation of peripheral blood stem cells (PBSCT) with a nonmyeloablative conditioning (n = 9) and the transplantation of highly purified CD34(+) stem cells (CD34(+) PBSCT) (n = 16) were compared to unmanipulated bone marrow transplantation (BMT) (n = 69) and unmanipulated PBSCT (n = 50) after myeloablative conditioning in patients with first chronic phase of chronic myelogenous leukemia (CML) (n = 137), second chronic phase of CML (n = 4), acute lymphoblastic leukemia (n = 2) and acute myeloid leukemia (n = 1). A molecular relapse (MR) as defined by two consecutive positive polymerase chain reaction assays for the detection of M-bcr-abl transcripts (n = 141) and cbfbeta-myh11 transcripts (n = 1) in a 4-week interval was found in 10 of 16 patients (63%) after CD34(+) PBSCT, and in 27 of 69 patients (39%) after BMT, whereas only three of 50 patients (6%) after PBSCT (P < 0.001) and one of eight patients (13%) after PBSCT with reduced conditioning suffered from a MR. A cytogenetic relapse occurred in five of 16 patients (31%) after CD34(+)PBSCT and 21 of 69 patients (30%) after BMT (NS) compared to two of 50 patients (4%) after PBSCT and none of the eight patients after PBSCT with reduced conditioning (P < 0.05). The lowest treatment-related mortality was seen in the 16 patients after CD34(+) PBSCT, who are all currently alive with a median follow-up of 15 months, whereas the survival rate for BMT, PBSCT and PBSCT with reduced conditioning were 65%, 63% and 58%, respectively. Multivariate analysis including all potential influential factors of post-transplant residual disease recurrence showed that patients after CD34(+) PBSCT had a significantly higher risk (two times) to develop a MR than patients after BMT (P < 0.03), whereas patients after unmanipulated PBSCT had a significant lower risk (eight times) for the occurrence of a MR post transplant (P < 0.001). Patients after BMT and CD34(+) PBSCT had the lowest rates of complete chimerism (CC) at 3 months after transplant. Only five of nine patients (55%) after CD34(+) PBSCT and 19 of 33 patients (58%) after BMT achieved CC compared to 19 of 22 (86%) patients after PBSCT and seven of eight (88%) patients after PBSCT with reduced conditioning (P < 0.05).
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PMID:A comparison of chimerism and minimal residual disease between four different allogeneic transplantation methods in patients with chronic myelogenous leukemia in first chronic phase. 1147 37

Persistence of BCR-ABL rearrangements was demonstrated by D-FISH technique in chronic myeloid leukemia (CML) patients in complete cytogenetic response (CCR) after allogeneic bone marrow transplantation (BMT) or interferon-alpha therapy (IFN-alpha). Samples from bone marrow aspirate or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, fluorescent interphase in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement remains unexpressed in a small percentage of cells whatever the treatment (IFN-alpha or BMT), and this in spite of the negativity of the RT-PCR-based classical molecular remission criterion. These data corroborate those obtained by other investigators and point to the need for follow-up of CML patients in CCR over an extensive period, at the DNA level to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse and guide the therapeutic decision. Experimental models suggesting the persistence of positive BCR-ABL cells are discussed and tentative explanations of tumor "dormancy" are proposed.
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PMID:Persistence of transcriptionally silent BCR-ABL rearrangements in chronic myeloid leukemia patients in sustained complete cytogenetic remission. 1169 48

The detection of BCR-ABL specific RNA by RT-PCR has been shown to predict relapse when positive 6 months after allogeneic stem cell transplantation (SCT) for chronic myelogenous leukemia (CML). In the present study, the focus was on evaluation of residual disease during the first weeks following SCT. In this study, 177 blood or marrow samples were obtained from 33 patients who received allogeneic (20 patients) or autologous (13 patients) SCT on day 0, day 30 and every 3 months for 1 year. T-cell depletion (TCD) was performed in 4 cases. On day 0 (day of graft infusion), 10/30 evaluable patients had negative RT-PCR (33%) regardless of pretransplant characteristics. On day 30, 14/18 patients (77%) from the allogeneic group had negative RT-PCR versus 0% in the autologous group. 2/4 patients who received TCD allogeneic grafts had day 30-positive PCR. Five patients in the allogeneic group had at least one positive RT-PCR sample between day 30 and day 90: 3 of them subsequently relapsed suggesting possible correlation between early positivity and relapse. Our results show that disappearance of MRD can be achieved within 3 months after transplantation in the majority of patients treated with allogeneic but not after autologous SCT. This suggests that the GVL effect might be operational early during the first weeks following transplantation.
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PMID:Survey of early disapearance of BCR/ABL fusion transcript after allogeneic or autologous stem cell transplantation for chronic myelogenous leukemia. 1169 49

The activated tyrosine kinase, which arises as a result of the balanced t(9,22) translocation in chronic myeloid leukemia (CML), is thought to be essential for the development of the leukemic phenotype. Recently, designer drugs have been introduced which specifically inhibit such specific kinases. Among these, STI571 (Glivec) has entered clinical trials and shown promising activities in chronic phase (CP), accelerated phase (AP) and blast crisis (BC) as evidenced by significant hematological and cytogenetic responses in CML patients. To evaluate the effect of STI571 at the molecular level we have employed quantitative real-time PCR (RQ-PCR) to measure the amount of BCR-ABL fusion transcript in a series of 19 patients treated with STI571, either in CP(11) or in (AP)(8) of the disease for 3--9 months (median 6 months). Employing this method, which is able to detect at least one BCR-ABL+ cell in 500,000, in serial blood and bone marrow specimens we found decreases in transcript levels in 10/11 CP patients, but only in 1/8 of the AP patients. When present such decreases were gradual and became evident only after 3 months of STI571 treatment, and their kinetics in blood closely mirrored those seen in parallel marrow samples. Moreover, decreases were between 10- and 100-fold in 11/13 patients, with only two patients reaching residual disease levels below 10(-2) (a 900-fold decrease). Thus, no patient reached PCR negativity. We conclude that the RQ-PCR method is a highly suitable tool for following the effect of STI571 in CML and that further validation of the method, performed in a prospective manner, will contribute significantly to the elucidation of the proper role of STI571 in CML.
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PMID:Kinetics of BCR-ABL fusion transcript levels in chronic myeloid leukemia patients treated with STI571 measured by quantitative real-time polymerase chain reaction. 1187 78

Detection of BCR-ABL transcripts in chronic myeloid leukaemia (CML) is used to confirm the diagnosis and to monitor residual disease. Quantitative techniques are required to predict response to therapy or early relapse. We have evaluated an assay in which transcription-mediated amplification (TMA) of BCR-ABL and ABL transcripts is achieved using reverse transcriptase and RNA polymerase. The products are quantified in the hybridisation protection assay (HPA) using acridinium ester-labelled DNA probes and chemiluminescence. The method is a single tube procedure which uses small amounts of RNA (<500 ng/triplicate analysis), is technically simple (requiring just two waterbaths and a luminometer), rapid (total assay time <4 h) and sensitive (capable of detecting one BCR-ABL-positive K562 cell in the presence of 10(4)-10(5) BCR-ABL-negative cells). BCR-ABL signals from patient RNA samples were quantified relative to known amounts of K562 RNA and normalised to levels of ABL. BCR-ABL/ABL ratios ranged from 0.15 to 1.59 (median 0.65) in RNA from diagnostic blood or bone marrow of 18 CML patients and were < or =0.0001 in 20 normal controls. Sequential samples analysed from six CML patients post-allogeneic bone marrow transplantation who relapsed and received donor lymphocyte infusions showed BCR-ABL/ABL ratios which reflected patient status or treatment. A BCR-ABL/ABL ratio of 0.01 served as a useful arbitrary indicator value, with results above and below this value generally correlating with relapse or remission, respectively.
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PMID:Transcription-mediated amplification and hybridisation protection assay to determine BCR-ABL transcript levels in patients with chronic myeloid leukaemia. 1189 44

The degree of tumor load reduction as measured by cytogenetic response is an important prognostic factor for chronic myelogenous leukemia (CML) patients on therapy. We sought to determine whether BCR-ABL transcript levels can predict chromosomal response. Residual disease was evaluated in 120 CML patients in chronic phase (CP) treated with the selective tyrosine kinase inhibitor imatinib after resistance or intolerance to interferon alpha (IFN). Median time of therapy was 401 days (range 111-704). BCR-ABL and total ABL transcripts were measured in 486 peripheral blood (PB) specimens with a real time RT-PCR approach using fluorescent-labeled hybridization probes (LightCycler technology) and results were expressed as the ratio BCR-ABL/ABL. Cytogenetic response was determined in 3-monthly intervals: From 101 evaluable patients, 42 achieved a complete (CR, 0% Philadelphia chromosome (Ph)- positive metaphases), 18 a partial (PR, 1-34% Ph+), 13 a minor (MR, 35-94% Ph+), and 26 no response (NR, >94% Ph+). All PB samples were RT-PCR positive. The proportion of Ph+ metaphases and simultaneous BCR-ABL/ABL ratios correlated with r = 0.74, P < 0.0001. In order to investigate whether early molecular analysis may predict cytogenetic response, quantitative RT-PCR data obtained after 1 and 2 months of therapy were compared with cytogenetic response at 6 months. BCR-ABL/ABL ratios after 1 month were not predictive, but results after 2 months correlated with the consecutive cytogenetic response (P = 0.0008). The probability for a major cytogenetic response was significantly higher in patients with a BCR-ABL/ABL ratio <20% after 2 months of imatinib therapy. We conclude that: (1) quantitative determination of residual disease with real time RT-PCR is a reliable and sensitive method to monitor CML patients on imatinib therapy; (2) BCR-ABL/ABL ratios correlate well with cytogenetic response; (3) in IFN-pretreated patients all complete responders to imatinib have evidence of residual disease with the limited follow-up available; and (4) cytogenetic response at 6 months of therapy in CP patients is predictable with real time RT-PCR at 2 months.
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PMID:Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha. 1220 Jun 66

Conventional cytogenetic (CC) study and molecular analysis were performed in 150 leukapheresis products from 36 patients diagnosed with chronic myelogenous leukemia who were included in an autologous stem cell transplantation program. The aims of the study were to evaluate the effectiveness of these two methods for the detection of residual disease in the harvest and to identify the factors influencing the number of cycling cells present in the apheresis products. Progenitor cell mobilization procedures performed late after diagnosis (>12 months), a short interval between interferon-alpha discontinuation and mobilization (<3.5 months), and an intensive mobilization regimen (idarubicin, cytarabine, and etoposide, ICE protocol) were associated with a low probability of obtaining 25 metaphases, which was achieved in only 41 instances (25% of the samples). In 38 samples, less than ten metaphases were obtained; a peripheral blood leukocyte count <1.0x10(9)/l at mobilization and mononuclear cell counts in the bag <0.5x10(8)/kg significantly increased the probability to obtain less than ten metaphases for CC analysis. Previous interferon-alpha treatment during > or =12 months and low mononuclear cell counts in the bag (<0.5x10(8)/kg) increased the probability of not obtaining mitosis for cytogenetic analysis. Molecular analysis by the polymerase chain reaction (PCR) technique did not give discriminate information in the samples not evaluable by cytogenetics due to the high frequency of PCR-positive results. We conclude that new techniques such as hypermetaphase fluorescence in situ hybridization (FISH), interphase FISH, or quantitative PCR need to be routinely employed in the study of leukapheresis samples of chronic myelogenous leukemia patients for a better assessment of the neoplastic contamination of the infused products.
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PMID:Prognostic factors influencing feasibility of cytogenetic and molecular analysis in leukapheresis products in chronic myelogenous leukemia patients. 1248 67

Chronic myeloid leukemia in blast crisis (BC) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) are associated with extremely poor outcome. Allogeneic transplantation during BC or active leukemia is most often unsuccessful due to high-rates of both treatment-related complications and relapse. Long-term results are significantly better if a second chronic phase or remission can be achieved prior to transplantation. Similarly, DLI given for the treatment of post-transplant relapse is more successful when given during a second remission. In this study we report our results with a previously unreported approach consisting of short-term treatment with imatinib mesylate (formerly, STI571) to induce or maintain remission, followed by allogeneic transplantation or DLI and the impact on transplantation/DLI outcome. Sixteen patients were treated either in preparation for transplantation (n = 12), for DLI (n = 1), or for both (n = 3). Ten had CML in BC; seven myeloid and three lymphoid BC. Six patients had Ph(+) ALL. The donors were matched unrelated (n = 9), matched siblings (n = 5) or haplo-identical (n = 2). Eleven of 15 patients given imatinib pre-transplant were transplanted in complete hematologic response. Engraftment and GVHD rates were not different from expected. Seven patients had grade II-III hepatic toxicity after transplantation. After a median follow-up of 10 months (range, 3-16 months) six remain alive, two after further therapy. The 1-year survival rate was 25%. Four patients were given imatinib prior to DLI, all had complete response. Two remain in remission >6 months from relapse. In conclusion, treatment with imatinib allows transplantation in a more favorable status or maintaining remission with low toxicity until transplantation is feasible. Pre-transplant imatinib seems safe and not associated with excess post-transplant complications. Imatinib may have substantial activity in combination with DLI. Further study of a larger group of patients is required to assess the impact on long-term outcome and the role of post-transplant imatinib in controlling residual disease.
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PMID:Imatinib mesylate (STI571) in preparation for allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusions in patients with Philadelphia-positive acute leukemias. 1259 25

Although controversial, purging of the autograft may be necessary to optimize transplant outcome, especially if better treatments become available to eliminate or control residual disease that may be left after the conditioning regimen. The intent of this study was to show that immunological purging with the cytotoxic cell line NK-92 effectively reduces the number of clonogenic cells and that the method can be performed in compliance with GMP. Owing to the easy quantification of bcr-abl transcripts, chronic myelogenous leukemia (CML) was used as a model disease for proof of principle. A detection level of 10(-7) bcr-abl+ cells and purging efficiency of four logs were achievable for the bcr-abl+ cell line, K562. Leukapheresis products collected from CML patients after stem cell mobilization were then tested. For all patients tested, residual CML cells were highly sensitive to purging by NK-92 with a purging efficacy of several logs. No adverse effect on hematopoietic progenitor cell function was noted. These results demonstrate the efficacy of NK-92 as a purging agent to decrease or eliminate malignant contamination of autologous stem cell grafts and establish proof of principle for ex vivo purging of CML autografts using cytotoxic effector cells.
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PMID:Ex vivo purging with NK-92 prior to autografting for chronic myelogenous leukemia. 1279 91

We developed and extensively validated a real-time PCR assay for the quantitation of bcr-abl to determine residual disease in patients with chronic myelogenous leukemia. This method quantitates the p210 and the p190 bcr-abl RNA fusion transcripts with results normalized to a housekeeping gene, using the 5'-exonuclease technique and the ABI PRISM 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). We parallel tested 372 clinical specimens and 50 peripheral blood samples from patients not known to have any myeloproliferative disorders. The results were 100% specific. Sensitivity studies showed that this method can detect bcr-abl in cell lines diluted to 0.0001% and can detect a single bcr-abl plasmid spiked into negative RNA. The between-run reproducibility showed a coefficient of variance (CV) of 12.3%, and within-run reproducibility showed a CV of 13.8%. This method can be used to reliably monitor the disease load in patients with bcr-abl-positive diseases.
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PMID:Comprehensive validation of a real-time quantitative bcr-abl assay for clinical laboratory use. 1286 71


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