Showing papers by "Sebastian Kreil published in 2003"
Heidelberg University1, University of Düsseldorf2, Leipzig University3, Dresden University of Technology4, University of Mainz5, Technische Universität München6, University of Regensburg7, München Klinik Bogenhausen8, University of Jena9, Goethe University Frankfurt10, University of Freiburg11, Bosch12, Charité13, University of Rostock14, Novartis15
TL;DR: It is concluded that treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels, and nested PCR may reveal residual BCR/ABL transcripts in samples that are negative by real-time PCR.
Abstract: We sought to determine dynamics of BCR-ABL mRNA expression levels in 139 patients with chronic myelogenous leukemia (CML) in early chronic phase, randomized to receive imatinib (n=69) or interferon (IFN)/Ara-C (n=70). The response was sequentially monitored by cytogenetics from bone marrow metaphases (n=803) and qualitative and quantitative RT-PCR from peripheral blood samples (n=1117). Complete cytogenetic response (CCR) was achieved in 60 (imatinib, 87%) vs 10 patients (IFN/Ara-C, 14%) after a median observation time of 24 months. Within the first year after CCR, best median ratio BCR-ABL/ABL was 0.087%, (imatinib, n=48) vs 0.27% (IFN/Ara-C, n=9, P=0.025). BCR-ABL was undetectable in 25 cases by real-time PCR, but in only four patients by nested PCR. Median best response in patients with relapse after CCR was 0.24% (n=3) as compared to 0.029% in patients with continuous remission (n=52, P=0.029). We conclude that (i) treatment with imatinib in newly diagnosed CML patients is associated with a rapid decrease of BCR-ABL transcript levels; (ii) nested PCR may reveal residual BCR-ABL transcripts in samples that are negative by real-time PCR; (iii) BCR-ABL transcript levels parallel cytogenetic response, and (iv) imatinib is superior to IFN/Ara-C in terms of the speed and degree of molecular responses, but residual disease is rarely eliminated.
126 citations
TL;DR: It is concluded that in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; RT- PCR results derived from PB and BM are comparable in CP CML; and low levels of residual disease with ratios BCR -ABL/ABL <0.1% are associated with continuous remission.
Abstract: A significant proportion of chronic myeloid leukemia (CML) patients achieve a major cytogenetic remission (MCR) to imatinib therapy after failing interferon (IFN) alpha-based protocols. We sought to determine levels of residual disease in patients with MCR using various molecular methods and to establish a relation between residual BCR-ABL transcript levels and rate of relapse in complete cytogenetic remission (CCR). Response was measured by conventional cytogenetic analysis, hypermetaphase and interphase fluorescence in situ hybridization (HM-FISH, IP-FISH) of bone marrow (BM) cells, qualitative nested and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts. We investigated 323 peripheral blood (PB) and BM samples from 48 CML patients who achieved a complete (Ph+ 0%; n=41) or partial (Ph+ 1-34%; n=7) cytogenetic remission after 3-20 months of imatinib therapy. Prior to imatinib, 35 patients were in chronic phase (CP), eight in accelerated phase (AP), four in myeloid and one in lymphoid blast crisis. HM-FISH results correlated with ratios BCR-ABL/ABL in PB and BM. In patients with CCR, residual disease was detectable by HM-FISH (31%), IP-FISH (18%), and RT-PCR (100%). During follow-up, BCR-ABL became undetectable in two patients (one CP, one AP) by both nested and quantitative RT-PCR. CCR is ongoing in 30 evaluable patients, 11 patients have relapsed. At the time of best response, median ratios BCR-ABL/ABL were 2.1% (range 0.82-7.8) in patients with subsequent relapse and 0.075% (range 0-3.9) in patients with ongoing remission (P=0.0011). All 16 CP patients, who achieved ratios BCR-ABL/ABL /=0.1% have relapsed (P=0.0036). We conclude that: (i) in patients with CCR to imatinib, HM-FISH and RT-PCR usually reveal residual BCR-ABL+ cells; (ii) RT-PCR results derived from PB and BM are comparable in CP CML; and (iii) low levels of residual disease with ratios BCR-ABL/ABL &<0.1% are associated with continuous remission.
96 citations
TL;DR: The increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph− cells in the PB of patients with CML.
Abstract: Telomeres are composed of TTAGGG repeats and associated proteins. In somatic cells, telomere repeats are lost with each cell division, eventually leading to genetic instability and cellular senescence. In previous studies, we described substantial and disease stage-specific telomere shortening in peripheral blood (PB) leukocytes from patients with chronic myeloid leukemia (CML). Here, we sought to determine whether age-adjusted telomere length in PB granulocytes (deltaTEL(gran)) is associated with response to treatment with the selective tyrosine kinase inhibitor imatinib. A total of 517 samples from 206 patients in chronic phase (CP), accelerated phase (AP), and blast crisis (BC) before and up to 706 days after initiation of imatinib therapy (median: 144 days) were analyzed by quantitative fluorescence in situ hybridization of interphase cells in suspension (Flow-FISH); telomere fluorescence was expressed in molecular equivalents of soluble fluorochrome units (MESF). Telomere length in samples from start of treatment up to day 144 was significantly shorter (mean +/- SE; -1.5 +/- 0.3 kMESF) compared to samples from patients treated for more than 144 days (-0.8 +/- 0.3 kMESF, p = 0.035). In patients with repeated measurements, a significant increase in telomere length under treatment was observed. Median telomere length in major remission was found to be significantly longer compared to patients without response to treatment measured either by cytogenetics (n = 246, p < 0.05), interphase FISH (n = 204, p = 0.002), or quantitative RT-PCR (n = 371, p < 0.05). In conclusion, the increase in telomere length under treatment with imatinib reflects a shift from Ph+ to Ph- cells in the PB of patients with CML.
30 citations
TL;DR: This work has described substantial and disease stage–specific telomere repeats in somatic cells that are composed of TTAGGG repeats and associated proteins and described their role in genetic instability and cellular senescence.
27 citations
01 Jan 2003
TL;DR: Imatinib (formerly STI571; Glivec) is an orally administered selective inhibitor of the BCR-ABL tyrosine kinase, and preliminary results from three international phase 11 studies are promising with good hematological and cytogenetical response rates and manageable side effects.
Abstract: Chronic myelogenous leukemia (CML) is characterized by a reciprocal translocation between long arms of chromosomes 9 and 22 that produces the Philadelphia chromosome The resulting chimeric BCR-ABL fusion gene is thought to be the molecular cause of the disease Typical symptom is the marked expansion of myeloid cells that mature normally The natural history of CML is progression from chronic phase to a rapidly fatal blast crisis within three to five years Blast crisis is often preceded by an accelerated phase in which increasing doses of initial therapy are required Treatment options have become more complex in recent years, allogeneic stem cell transplantation is still the only curative option Recent data show that interferonalpha prolongs life in CML patients, as compared to chemotherapy New therapies based on the causative molecular abnormality of CML are showing great promise Imatinib (formerly STI571; Glivec) is an orally administered selective inhibitor of the BCR-ABL tyrosine kinase Preliminary results from three international phase 11 studies are promising with good hematological and cytogenetical response rates and manageable side effects Combination with cytostatic drugs may help to overcome the problem of secondary resistance in advanced disease Longterm observation is required to demonstrate whether imatinib will prolong life in comparison with other methods of treatment