Mutation Status of Imatinib Mesylate-Resistants CML Patients and Clinical Outcomes: A French Multicenter Retrospective Study for the fiLMC Group.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 275-275 ◽  
Author(s):  
Selim Corm ◽  
Franck Nicollini ◽  
Dominique Borie ◽  
Nathalie Sorel ◽  
Thibault Leguay ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Median Survival ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Rank Test ◽  
Mutation Status ◽  
Abl Kinase ◽  
Survival Difference ◽  
Significant Difference

Abstract Imatinib mesylate (IM) is highly effective in newly diagnosed CML. Unfortunately, acquired abl-kinase domain mutations are commonly identified to be associated to resistance or relapse in patients with advanced disease. Distinct mutation exhibit varying degrees of resistance, and mutation occurring in the ATP-binding loop (P loop) or in positions in direct contact with IM (i.e. T315) may be correlated with subsequent disease progression. In this study, we investigated the bcr-abl mutation status of imatinib-resistant CML patients and correlated to the disease outcome. Patients and methods: From CML patients diagnosed in 5 French centers, 67 IM-resistants patients presenting mutations by direct sequencing of the abl kinase domain at time of resistance or relapse were included in this study. When starting IM monotherapy (J1) at 400 to 600 mg per day, 45 patients were in chronic phase of CML, 12 patients were in accelerated phase of the disease and 7 patients were in blast crisis. The median duration of IM is 29 months (range 3–54) and the median delay between diagnosis and J1 is 34 months (range 0–168). At the end of the study, 23 patients were dead. According to the mutation status, a Kaplan-Meier curve was construct for time to death to J1, and survival were compared using log rank test. Results: By direct sequencing, 17 patients presented mutations in the P-loop (residues 252 to 255), 10 patients presented the T315M mutation alone, 1 patient had the T315 and the M351 mutations, and 39 patients presented mutations in other kinase domains. According to the mutation status, survival difference between patients presenting P-loop mutations or mutations in an other abl-kinase (including T315), no significant difference was observed (p=0.07). However, survival difference between patients presenting P-loop mutations, T315 mutation and mutations in an other abl-kinase domains was highly significant (p=0.0031, figure). The median survival for the P-loop and T315 mutated patients was of 39 months and 29 months respectively, and median survival not reached for others. Conclusion: By this study we confirm that either the T315 mutation or mutations in the P-loop had a poor prognosis. Detailed correlation analysis of mutation status according to clinical features and response to increased IM-dose will be reported. Figure Figure

Clinical Characteristics and Outcome of 20 Imatinib Mesylate Resistant Patients with T315I BCR-ABL Mutation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1954-1954
Author(s):  
Wan-Seok Kim ◽  
Il-Young Kweon ◽  
Soo Hyun Kim ◽  
Hyun Gyung Goh ◽  
Jeong Lee ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Clinical Characteristics ◽  
Chromosomal Abnormalities ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Low Grade ◽  
Advanced Phase ◽  
Significant Difference ◽  
T315i Mutation

Abstract Most CML patients are sensitive to imatinib mesylate (IM), however, a small fraction develop resistance, mostly through the emergence onset of BCR-ABL mutation. Dasatinib and nilotinib, novel tyrosine kinase inhibitors (NTKIs), are active against most of IM resistant BCR-ABL kinase domain mutants except T315I. Although T315I mutation has been highly resistant to IM and both NTKIs, precise clinical characteristics and outcome have not been known yet. A total of 81 patients with various phases of CML who were intolerant or were resistant to IM (M:F-52:29, median age: 43 years, range; 12–74 years) were enrolled in this study between May 2005 and Sep 2006. Eighty one patients had received dasatinib and/or nilotinib in phase II or extended access program. At the time of IM failure and every 3 months during NTKIs treatment, mutations were screened by both ASO-PCR and direct sequencing. Clinical characteristics and outcome probabilities were statistically analyzed. T315I was detected in 20 of 31 patients (65%) harboring kinase domain mutations; 9 patients had mutation before NTKIs treatment and 11 patients were developing mutation after NTKIs treatment. Median age was 33 years (range, 19–74 years). Transcripts were Major BCR for all patients and 8 patients had received prior interferon therapy. 6 patients had additional chromosomal abnormalities (ACA) at diagnosis. At the time of T315I emergence, 8 patients were CP, 6 patients were AP, and 6 in BC (4 in myeloid and 2 in lymphoid). Median accumulate dose per day was 398.8 mg/day (range, 205.3–600.0 mg/day). 13 patients were received dasatinib, 5 received nilotinib and 2 received both dasatinib and nilotinib. The best response to NTKIs was complete cytogenetic response (CCyR) in 6 and complete hematologic response (CHR) in 8. Median overall survival (OS) from NTKIs start was 7.0 months for advanced phase and 12.3 months for chronic phase. The 3 year survival rate was 21.5%, with median value was 8.4 months in all patients. With NTKIs therapies [median follow-up, 9.7 months (range, 0.7–27.3 months)], 8 patients are alive (40%); 6 patients are alive with active disease and 2 patients are alive with ongoing response. 10 patients died of disease progression and 2 patients died of pneumonia. Low grade disease phase at discovery of T315I mutation (log-rank P=0.0237) demonstrated significantly favorable outcome but after NTKIs treatment, there was no difference in OS between disease phases (log-rank P=0.271). And there was no difference in OS between T315I mutation and other mutations (P=0.147). However the ACA at diagnosis (P=0.029) and achievement of best CCyR during NTKIs treatment (P=0.085) was different in OS. And there was significant difference in survival between patients with and without ACA and achievement of best CCyR during NTKIs treatment (log-rank P=0.0235), suggesting they have prognostic influences on survival as T315I mutation. In summary, our findings confirm that ACA at diagnosis and achievement of best CCyR during NTKIs treatment are statistically significant prognostic information with respect to survival probability at patients with T315I mutation. However T315I mutation was highly resistant to NTKIs as well as IM, and are associated with poor outcome. As diverse outcomes in patients with T315I mutation have been demonstrated, different strategies such as MK-0457 and/or novel T315I mutation inhibitor should be applied.

Variant Philadelphia-Positive Chronic Myeloid Leukemia, der(9) Deletions and Response to Imatinib Mesylate: A Retrospective Multicentric Analysis from the French Fi-LMC Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2113-2113
Author(s):  
S. Corm ◽  
Franck Nicolini ◽  
S. Richebourg ◽  
F. Huguet ◽  
D. Rea ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Survival Data ◽  
Disease Duration ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Rank Test ◽  
Primary Resistance ◽  
Multicentric Study ◽  
Abl Kinase ◽  
Sokal Score

Abstract Purpose: Major initial prognostic factors predicting chronic myeloid leukaemia (CML) response to imatinib mesylate (IM) therapy are represented by hema-tological status, Sokal score and duration of disease before IM. Before the era of IM, CML patients harbouring der(9) deletion classically had a worse outcome when compared to non deleted pts, but some preliminary studies suggest that this adverse factor might be reversed by IM. Additionally der(9) deletion seems to be more frequent in Variant Ph chromosome (vPh) patients (up to 30%) whereas its frequency is about 10% in classical Ph pts. We evaluated in this retrospective multicentric study the response to IM in vPh population and the possible impact of der(9) deletion on this response. 92 vPh patients treated by IM were selected from 11 hematology departments within the country. vPh chromosome was assessed by conventional karyotyping analysis and der(9) deletion by FISH. IM resistant patients were screened for ABL kinase site mutation by direct sequencing. Statistical analysis of survival and descriptive parameters were performed according to Kaplan Meyer method, log-rank test, Chi-2 and non parametric Kruskal Wallis tests. Results: among the vPh population 75% pts had a simple translocation and 25% had a more complex one (chromosomes 9, 22 and at least two other break-points). Initially 95% pts were in chronic phase (CP), 2.5% in accelerated phase (AP) and 2.5% in blastic crisis (BC).19 pts (33.3%) were scored in each Sokal score category (low, intermediate and high). At IM initiation: 83% were in CP (>35% Ph+ ), 8% were in major cytogenetic response (after interferon) and 9% were either in AP or in BC. 74 pts were screened for der(9) deletion, which was present in 16.2% of them. IM response and survival data were available for 53 pts with CP (with > 35% Ph+ ) at IM initiation. Median age of this CP population at diagnosis was 50.8 (19.5–79.4), median disease duration before IM initiation : 2 Mo (0–92.4), median follow-up after IM initiation : 24.8 Mo (6.1–69.9). 71.7% achieved RcyM including 67.9% in RcyC. 19 pts presented IM failure or suboptimal response (European LeukemiaNet consensus). 1 pt stopped IM for liver intolerance. We observed 9 (16.9%) primary resistance and 10 (18.9%) loss of response. 12% pts progressed towards AP/BC. 12 resistant pts were screened for ABL kinase site mutations : 3 of them harboured mutations. We found no difference for the overall survival between the populations with (n=9) and without (n=33) der(9q) deletions (median of survival not reached ). Respectively 1 pt (11%) and 3 pts (9%) died in these two cohorts. We found a trend for an increased rate of resistance in the der(9) deletion cohort (55.6% vs 30.3%) but the difference was not significative (p=0.16). We only found significant differences in the repartition of the Sokal score between these two cohorts with more frequent high scores for vPh patients (p=0.03). Resistance in vPh IM treated pts is high (35.8%) but the disease duration before IM was heterogenous. Der(9) deletions slightly increases the rate of IM resistance but we found no difference of survival between the two cohorts.

BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet

Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1208-1215 ◽  
Author(s):  
Simona Soverini ◽  
Andreas Hochhaus ◽  
Franck E. Nicolini ◽  
Franz Gruber ◽  
Thoralf Lange ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Abl Kinase

AbstractMutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.

Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4611-4614 ◽  
Author(s):  
Amie S. Corbin ◽  
Paul La Rosée ◽  
Eric P. Stoffregen ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Kinase ◽  
Cellular Assays ◽  
Kinase Domain Mutations

Abstract Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance.While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.

Denaturing- HPLC and HR-1 Melter-Based Detection of ABL Mutations in Patients with Chronic Myelogenous Leukemia (CML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4876-4876
Author(s):  
Il-Kwon Lee ◽  
Ju Hyun Yun ◽  
Nan Young Kim ◽  
Jeong-Hwa Choi ◽  
Yeo-Kyeoung Kim ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Catalytic Domain ◽  
Novel Mutation ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Functional Evaluation ◽  
Novel Mutations ◽  
Secondary Resistance

Abstract Imatinib mesylate is the first line of drug for CML since its ability to induce durable remissions in most patients with Philadelphia-positive leukemias and cytogenetic responses in most patients with chronic-phase CML. Although Imatinib mesylate has revolutionized current chronic myeloid leukemia therapy the phenomenon of relapse because of the emergence of resistance were observed. There were well-known mutations in kinase domain that confer resistance despite continued Imatinib mesylate chemotherapy and number of resistance-conferring mutation is increasing. In this study we systematically scanned kinase domain-encoding exon 5, 7, 8, 9, 10 and 11 from genomic DNA of 79 patients with CML to identify novel mutation using denaturing high-performance liquid chromatography (dHPLC) and HR-1 melter (Idaho Technology). In total 15 mutations in the regions were identified and three mutations are found to be novel and two were located in the catalytic domain region (F359I and E374K). Since these two mutations were identified in patients with primary and secondary resistance respectively, it might be classified into resistance-conferring mutation conditional on further functional evaluation. Also we found P499L mutation in the C-terminus and interestingly we detected E478Q in six patients with CML. Analysis with dHPLC and HR-1 screening after PCR amplification proved to be accurate and effective methods to isolate mutation. In addition dHPLC and HR-1 more sensitive compared to PCR direct sequencing methods since two mutations which were not detected by direct sequencing were confirmed only after subcloning of PCR products and sequencing. Taken together, we designed six PCR amplicons encompassing the kinase domain of abl kinase and screened for novel mutations patients with CML. Out of fourteen mutations identified two novel mutations in the catalytic domain need further investigation to understand if they contribute to the acquirance of imatinib mesylate resistance

Early Detection of Imminent Hematologic Relapse Due to BCR-ABL Kinase Domain Mutations in CML Patients on Imatinib Therapy by D-HPLC.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1088-1088
Author(s):  
Thomas Ernst ◽  
Philipp Erben ◽  
Thomas Schenk ◽  
Martin C. Mueller ◽  
Michael Emig ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Direct Sequencing ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Imatinib Therapy ◽  
Tyrosine Kinase Domain ◽  
Abl Kinase ◽  
Loop Region ◽  
Kinase Domain Mutations

Abstract Mutations of the BCR-ABL tyrosine kinase domain constitute the major cause of resistance in chronic myeloid leukemia (CML) patients (pts) on imatinib monotherapy. Sensitivity of conventional sequencing may allow the detection of a proportion of 10% mutated cells. We sought to improve the diagnostic armamentarium to screen for mutations prior to frank relapse. A total of 95 pts (chronic phase, CP, n=47; accelerated phase, AP, n=27; myeloid blast crisis, BC, n=19; lymphoid BC, n=2) who relapsed during imatinib therapy were screened for BCR-ABL kinase domain mutations applying denaturing high performance liquid chromatography (D-HPLC) and direct sequencing. Mutations were detectable in 47/79 (59%) pts with hematologic relapse and in 8/16 (50%) pts with cytogenetic relapse. 22 different point mutations affecting 18 amino acids and a novel deletion of 81bp of ABL exon 4 mapping to the P-loop region of the kinase domain were observed. To investigate the dynamics of the mutated clones D-HPLC was applied to 453 cDNA samples tracking back from relapse towards start of imatinib therapy. D-HPLC was optimized to detect 0.1–0.5% BaF3BCR-ABL cells harboring various mutations in a background of unmutated cells. Hematologic relapse occurred after a median of 12.9 mo (range 0.9–44.2) of imatinib therapy. However, BCR-ABL mutations became first detectable by D-HPLC at a median of 5.8 mo (range 0.0–30.5) after commencing imatinib (p<0.0001). Nine pts (18%; CP, n=4; AP, n=3, myeloid and lymphoid BC, n=1 each) showed evidence for BCR-ABL mutations even prior to imatinib therapy (T315I, n=4; M351T, n=3; M244V, Y253H, n=1 each). The median interval between first detection of the mutation and relapse was 5.6 mo in CP, 8.1 mo in AP, and 2.4 mo in myeloid BC. P-loop mutations were revealed at a median of 2.8 mo, activation loop mutations 2.9 mo, and T315I 6.3 mo prior to relapse. Cytogenetic relapse occured at a median of 19.2 mo (range 10.3–36.3) after start of imatinib therapy. BCR-ABL mutations became first detectable at a median time of 15.8 mo (range 0.0–26.4) after commencing imatinib (difference n.s., p=0.061). In two pts BCR-ABL mutations (M244V in AP, L324Q in CP) were observed in a small clone prior to imatinib therapy. Twenty-five CP pts in continuous complete cytogenetic remission were screened for BCR-ABL mutations to determine the predictive value of minor clones harboring mutations for consecutive relapse. No mutation was found in any of these pts. We conclude that (i) D-HPLC is a reliable and sensitive method to screen for BCR-ABL mutations before and during therapy with tyrosine kinase inhibitors. (ii) The observation of BCR-ABL mutations during imatinib therapy is predictive for relapse. (iii) Mutations may be detectable several months before hematologic relapse, and (iv) the sensitive detection of small mutated clones could provide clinical benefit by triggering early therapeutic interventions, which should be demonstrated in prospective clinical trials.

BCR-ABL Kinase Domain Mutations in the P-Loop and at Imatinib Contact Sites in CML Patients with Imatinib Resistance Are Associated with Higher Maximum Imatinib Doses.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2918-2918
Author(s):  
Oliver Pelz-Ackermann ◽  
Michael W.N. Deininger ◽  
Michael Cross ◽  
Kathrin Wildenberger ◽  
Rainer Krahl ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Wilcoxon Test ◽  
Independent Experiment ◽  
Imatinib Resistance ◽  
Low Level ◽  
Abl Kinase ◽  
Pcr Assays

Abstract Objectives: Acquired resistance to imatinib (IM) in patients with chronic myeloid leukaemia (CML) is frequently due to mutations of the BCR-ABL kinase domain (KD). Current thinking holds that this results from the selection of pre-existing mutant clones on IM. As new BCR-ABL inhibitors with differential activity against KD mutant BCR-ABL have become available, precise quantification of key mutations even at a low level is required to adequately monitor responses. Here we report that the occurrence of G250E, Q252H, Y253F/H, E255K/V, T315I, F317L, F359V mutations at the time of IM resistance is independently associated with a high maximum IM dose. Patients and Methods: We have developed highly specific allele-specific ligation-PCR assays (L-PCR) to accurately quantify a panel of frequent KD mutations, including G250E, Q252H, Y253F/H, E255K/V, T315I, F317L, F359V. In limiting dilution experiments the L-PCR assays routinely detect between 0.05 and 0.1% of mutant allele in total BCR-ABL, and their average dynamic range is in the range of 4.5 log. Forty-three patients with imatinib failure were analyzed. The median age was 60 (range 20 – 75) years and the median disease duration 64 (range 3–213) months. Eleven patients were in blast crisis, 20 in accelerated phase and 12 in chronic phase. Results: Patients were treated with chemotherapy (48%) and/or interferon alpha (76%) prior to IM. The median maximal IM dose was 600 (range 500–800) mg and the median duration of total therapy until resistance was 15.5 (range 1 to 75) months. Eighteen patients (42%) had dose reductions due to toxicity. At the time of IM resistance, clonal evolution was present in 21/41 (47%) of the patients. L-PCR identified 50 mutations in 29/43 patients (67%) (table1). One, 2, 3 or 4 different mutations were identified in 14, 11, 2 and 2 patients, respectively. The T315I and E255K/V mutations accounted for 32/50 (64%) of all mutations, while Q252H and Y253H were not detected. Twelve mutations (24%) were confirmed by direct sequencing (DS) and an additional M315T mutation and a K247R polymorphism were detected. Thirty eight (76%) mutations were negative by DS for the corresponding mutation from the L-PCR panel but additional mutations (L248V, M351T, H396Rx2, L298Vx2) were identified. All 38 L-PCR positive mutations were confirmed in a second independent experiment. The mutated clone was significantly smaller in mutations with no confirmation by DS (median 0.2, range 0.05–12.63%) compared to positive by DS (median 40.76, range 13.58–100%, p=0.003, Wilcoxon test). The detection of one or more mutations was significantly more frequent in patients with a maximum IM dose of 800mg (n=15/17, 88%) compared to less than 800mg (14/26, 53%, p= 0.02 Fisher’s exact test). Multivariate analysis (Wald forward) confirmed that a maximum IM peak dose of 800mg is an independent prognostic parameter to detect a mutation from the L-PCR panel at the time of IM resistance. Conclusions:High sensitive testing with L-PCR detects mutations with 4-fold increased frequency compared to direct sequencing.Mutations, including p-loop and T315I, may be selected by exposure to higher drug levels.The predominance of T315I and E255K/V mutations at a low level is consistent with the findings in newly diagnosed patients with Ph+ALL (Pfeifer et al. Blood 2007).

scholarly journals Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate

Blood ◽  
2010 ◽  
Vol 116 (12) ◽  
pp. 2112-2121 ◽  
Author(s):  
Xiaoyan Jiang ◽  
Donna Forrest ◽  
Franck Nicolini ◽  
Ali Turhan ◽  
Joelle Guilhot ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Imatinib Mesylate ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Cd34 Cells ◽  
Cell Assays ◽  
Prospective Assessment ◽  
Kinase Domain Mutations

Abstract Imatinib mesylate (IM) induces clinical remissions in chronic-phase chronic myeloid leukemia (CML) patients but IM resistance remains a problem. We recently identified several features of CML CD34+ stem/progenitor cells expected to confer resistance to BCR-ABL-targeted therapeutics. From a study of 25 initially chronic-phase patients, we now demonstrate that some, but not all, of these parameters correlate with subsequent clinical response to IM therapy. CD34+ cells from the 14 IM nonresponders demonstrated greater resistance to IM than the 11 IM responders in colony-forming cell assays in vitro (P < .001) and direct sequencing of cloned transcripts from CD34+ cells further revealed a higher incidence of BCR-ABL kinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, P < .003). In contrast, CD34+ cells from IM nonresponders and IM responders were not distinguished by differences in BCR-ABL or transporter gene expression. Interestingly, one BCR-ABL mutation (V304D), predicted to destabilize the interaction between p210BCR-ABL and IM, was detectable in 14 of 20 patients. T315I mutant CD34+ cells found before IM treatment in 2 of 20 patients examined were preferentially amplified after IM treatment. Thus, 2 properties of pretreatment CML stem/progenitor cells correlate with subsequent response to IM therapy. Prospective assessment of these properties may allow improved patient management.

Randomized Trial of Preoperative Chemoradiation Versus Surgery Alone in Patients With Locoregional Esophageal Carcinoma

2001 ◽  
Vol 19 (2) ◽  
pp. 305-313 ◽  
Author(s):  
Susan G. Urba ◽  
Mark B. Orringer ◽  
Andrew Turrisi ◽  
Mark Iannettoni ◽  
Arlene Forastiere ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Randomized Trial ◽  
Median Survival ◽  
Transhiatal Esophagectomy ◽  
Preoperative Chemoradiation ◽  
Survival Difference ◽  
Significant Survival ◽  
Significant Difference ◽  
Resectable Esophageal ◽  
Cervical Esophagogastric Anastomosis

PURPOSE: A pilot study of 43 patients with potentially resectable esophageal carcinoma treated with an intensive regimen of preoperative chemoradiation with cisplatin, fluorouracil, and vinblastine before surgery showed a median survival of 29 months in comparison with the 12-month median survival of 100 historical controls treated with surgery alone at the same institution. We designed a randomized trial to compare survival for patients treated with this preoperative chemoradiation regimen versus surgery alone.MATERIALS AND METHODS: One hundred patients with esophageal carcinoma were randomized to receive either surgery alone (arm I) or preoperative chemoradiation (arm II) with cisplatin 20 mg/m2/d on days 1 through 5 and 17 through 21, fluorouracil 300 mg/m2/d on days 1 through 21, and vinblastine 1 mg/m2/d on days 1 through 4 and 17 through 20. Radiotherapy consisted of 1.5-Gy fractions twice daily, Monday through Friday over 21 days, to a total dose of 45 Gy. Transhiatal esophagectomy with a cervical esophagogastric anastomosis was performed on approximately day 42.RESULTS: At median follow-up of 8.2 years, there is no significant difference in survival between the treatment arms. Median survival is 17.6 months in arm I and 16.9 months in arm II. Survival at 3 years was 16% in arm I and 30% in arm II (P = .15). This study was statistically powered to detect a relatively large increase in median survival from 1 year to 2.2 years, with at least 80% power.CONCLUSION: This randomized trial of preoperative chemoradiation versus surgery alone for patients with potentially resectable esophageal carcinoma did not demonstrate a statistically significant survival difference.

scholarly journals Allografting for Bosutinib, Imatinib, Nilotinib, Dasatinib, and Interferon Resistant Chronic Myeloid Leukemia without ABL Kinase Mutation

2011 ◽  
Vol 2011 ◽  
pp. 1-4
Author(s):  
B. Uz ◽  
O. Bektas ◽  
E. Eliacik ◽  
H. Goker ◽  
Y. Erbilgin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Current Treatment ◽  
Hematopoietic Stem ◽  
Abl Kinase ◽  
Kinase Domain Mutation ◽  
Kinase Mutation

The current treatment of chronic phase chronic myeloid leukemia (CML) consists of oral tyrosine kinase inhibitors (TKIs). However, high-risk CML may present with an aggressive course which may result in blastic crisis or a “difficult-to-manage” state with available treatments. The aim of this paper is to report a patient with complicated CML resistant to treatment and progressed despite the administration of bosutinib, imatinib mesylate, nilotinib, dasatinib, interferon alpha 2a, cytotoxic chemotherapy, and allogeneic hematopoietic stem cell transplantation. The striking point of this case story is that no Abl kinase domain mutation against TKIs has been detected during this very complicated disease course of CML. Meanwhile, challenging cases will always be present despite the hope and progress in CML in the TKI era.

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