Late Development of Cytogenetic Abnormalities in Ph Negative Cells of Chronic Myeloid Leukemia Patients Treated with Imatinib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1108-1108
Author(s):  
Michael Deininger ◽  
François-Xavier Mahon ◽  
Francois Guilhot ◽  
Giuseppe Saglio ◽  
Philipp le Coutre ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Acute Leukemia ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Imatinib Treatment ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Late Event

Abstract Abstract 1108 Poster Board I-130 Clonal cytogenetics abnormalities in Ph negative metaphases (CCA/Ph-) are observed in a variable fraction of Chronic Myeloid Leukemia (CML) patients (pts) after they obtain a Complete Cytogenetic Remission (CCyR). It is not known whether such abnormalities develop soon after CCyR or if they can appear as a late event. Cytogenetic analysis remains the only methodology able to detect such abnormalities and its use in pts in CCyR after several years of imatinib therapy is being questioned. The Imatinib Long Term Effect (ILTE) study enrolled 948 CML pts in 24 centers around the world (Europe, North/South America, Africa, Middle East and Asia); in order to be eligible, pts had to achieve a CCyR within 2 years after starting imatinib. These pts are being followed for long term side effects such as loss of CCyR, toxicities including second cancers, and survival. Within the ILTE cohort, 384 eligible pts received imatinib for > 5 years and remained in CCyR at 5 years. In 309 cases, at least one standard routine cytogenetic analysis after 5 years of treatment was available. The median duration of imatinib treatment is 6.5 years in this group of pts. A cytogenetic abnormality in the Ph negative metaphases was detected in 18 cases (5.8%; 99% Confidence Interval: 0-10.1%); the number of available cytogenetics analyses positive for CCA/Ph- varied from 1 to 12 per patient. The percentages of pts positive for CCA/Ph- in the the different participating centers ranged between 0 and 28.6%. Of the 18 cases positive for CCA/Ph-, 10 were diagnosed within the first 5 years of treatment, and 8 cases afterwards. Three pts (17%) developed abnormalities during the first 2 years of treatment, 5 (28%) during the third or fourth year, 4 (22%) during the fifth or sixth year, and 6 (33%) during year 7, 8 or 9. Abnormalities were: deletion of Y chromosome (7 cases), trisomy 8, del 7q (2 cases each), monosomy 7, trisomy 6, del 9q, Y duplication, del 13, del 18. With a median follow up of 4.5 years after first detection, none of the patients have developed acute leukemia or myelodysplasia. In addition none of these 18 pts lost his/her CCyR status. CCA/Ph-are detectable in a low but consistent proportion of CML pts in CCyR; their occurrence is not limited to the first 5 years of treatment. Our study supports the notion that patients with CCA/Ph- have a favorable prognosis, despite the similarity of the abnormalities to those observed in acute leukemia and myelodysplasia, suggesting CCA/Ph- to be quite slow in their evolution. These data suggest that the search for CCA/Ph- should not be limited to the first years of imatinib treatment. Disclosures No relevant conflicts of interest to declare.

Distinct Impact of Imatinib on Growth In Prepubertal and Pubertal Children with Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2277-2277
Author(s):  
Haruko Shima ◽  
Mika Tokuyama ◽  
Akihiko Tanizawa ◽  
Chikako Tono ◽  
Kazuko Hamamoto ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Effects ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Growth Impairment ◽  
Clinical Records

Abstract Abstract 2277 Imatinib is now widely used for treating chronic-phase chronic myeloid leukemia (CML) in children as well as in adults, and long-term adverse effects of imatinib therapy in children are now gaining attention. One of its adverse effects is the negative impact on growth in children, suggested by 3 recently published case reports. However, the incidence or prospect of growth impairment resulting from imatinib treatment has not been fully elucidated. In this study, we retrospectively analyzed the clinical records of 48 children with chronic-phase CML who were treated with imatinib as a first-line therapy between 2001 and 2006. The median age at diagnosis was 9 years (2 to 15 years). Cumulative change in height while on imatinib was assessed using the height standard deviations score (height-SDS), the converted height data from age- and sex-adjusted Japanese norms. Our data indicated that growth impairment (decrease in height-SDS) was observed in 72.9% of the patients, with median maximum reduction in height-SDS of 0.61 during imatinib treatment. Growth impairment was noticeable in children who were prepubertal at the commencement of imatinib treatment, while only mild or no growth impairment (with no decrease of height-SDS) was observed in most patients who were pubertal at the commencement of imatinib treatment. Furthermore, in prepubertal children with growth impairment, growth velocity tended to recuperate concomitant with pubertal maturation, suggesting that imatinib has little impact on growth during puberty. To our knowledge, this is the first report to describe and compare the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. Although the introduction of imatinib was a breakthrough in CML therapy, the possibility of continuous remission after discontinuation of imatinib remains uncertain. Thus, the possibility of adverse effects of long-term exposure to imatinib has become a huge issue, especially when treating children. We consider that it is important to promote awareness of growth deceleration in children, especially in young children who started imatinib treatment before puberty and are inevitably going to be subject to prolonged exposure. Disclosures: No relevant conflicts of interest to declare.

Cytogenetic Clonal Evolution in Chronic Myeloid Leukemia during Imatinib Mesylate Treatment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4844-4844
Author(s):  
Hana Klamova ◽  
Jana Brezinova ◽  
Kyra Michalova ◽  
Zuzana Zemanova ◽  
Marek Trneny
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Clonal Evolution ◽  
Chronic Phase ◽  
Imatinib Treatment ◽  
Cytogenetic Abnormalities ◽  
Ph Chromosome ◽  
Cytogenetic Evolution

Abstract Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH). Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%). Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities. A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.

Expression of the CAMPATH-1 Antigen (CD52) on CD34+/CD38- Progenitor Cells in Patients with 5q- MDS and in a Subset of AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1728-1728
Author(s):  
Katharina Blatt ◽  
Harald Herrmann ◽  
Sabine Cerny-Reiterer ◽  
Susanne Herndlhofer ◽  
Wolfgang R. Sperr ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Lymphocytic Leukemia ◽  
Target Antigen ◽  
Blood Monocytes ◽  
Trisomy 8 ◽  
Monosomy 7

Abstract Abstract 1728 The target antigen CAMPATH-1 (CD52) is widely expressed in various hematopoietic lineages inlcuding lymphocytes, basophils, and blood monocytes. The anti-CD52 antibody Alemtuzumab is used successfully to treat patients with chemotherapy-refractory chronic lymphocytic leukemia. Based on its strong immunosuppressive effects, Alemtuzumab has also been considered for patients with aplastic anemia and hypoplastic myelodysplastic syndromes (MDS). Indeed, more recently, Alemtuzumab was found to induce major hematologic responses in a group of patients with MDS. Although the immunosuppressive effect was considered to play a role, the exact mechanisms underlying this drug effect remained speculative. In the current study, we asked whether CD34+ bone marrow (BM) progenitor cells in MDS and acute myeloid leukemia (AML) express the CAMPATH-1 antigen. Twelve patients with MDS (5 females, 7 males; median age: 70 years), 25 patients with AML (16 females, 9 males; median age: 62 years), and 34 control cases (normal reactive BM, n=12; idiopathic cytopenia of unknown significance, n=11; chronic myeloid leukemia, CML, n=4; chronic myelomonocytic leukemia, CMML, n=3; JAK2 V617F+ myeloproliferative neoplasms, MPN, n=4) were examined. Surface expression of CD52 on CD34+/CD38+ and CD34+/CD38- BM progenitor cells was analyzed by monoclonal antibodies and multicolor flow cytometry. In the group of MDS, CD52 was detectable on CD34+/CD38- stem cells in 3/4 patients with isolated 5q-. In most of the other MDS patients, CD52 was weakly expressed or not detectable on CD34+/CD38- cells. In AML, CD34+/CD38- cells displayed CD52 in 12/25 patients, namely 3 with complex karyotype including 5q-, 2 with inv(3), one with t(8;21), one with inv(16), one with del13q, one with trisomy 8, one with monosomy 7, and 2 with normal karyotype. Expression of CD52 mRNA in CD34+/CD38- AML stem cells was confirmed by qPCR in all patients tested (n=14). In addition, a good correlation was found between surface CD52 expression and CD52 mRNA expression in AML progenitor fractions. In patients with normal hematopoiesis (n=12) or idiopathic cytopenia (n=11), CD34+/CD38- cells stained weakly positive or negative for CD52. Almost in all cases tested, blood monocytes and blood basophils stained positive for CD52. Together, our data suggest that the target antigen CAMPATH-1 (CD52) is expressed on primitive CD34+/CD38- progenitor cells in MDS, preferentially in 5q- patients, and in a subset of patients with AML. These observations may have clinical implications and explain recently described effects of Alemtuzumab in patients with MDS. Our data also suggest that Alemtuzumab may be an interesting targeted drug in patients with refractory or relapsed AML in whom neoplastic stem cells express the target antigen CD52. Disclosures: No relevant conflicts of interest to declare.

Cytogenetic Analysis of 1863 Chineses Patients with Chronic Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4888-4888
Author(s):  
Qitian Mu ◽  
Qiuling Ma ◽  
Yungui Wang ◽  
Xiangmin Tong ◽  
Zhimei Chen ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Monocytic Differentiation ◽  
Granulocytic Differentiation ◽  
Monosomy 7

Abstract Abstract 4888 Background: Cytogenetic analyses of chronic myeloid leukemia (CML) have been performed previously in a large number of reports, but systematical research based on large sample sizes is seldom available. In order to further elucidate the cytogenetic nature of CML, we analyzed retrospectively the cytogenetic profiles of 1863 Ph/BCR-ABL-positive CML patients from a research center in China. Results: Of 1266 newly diagnosed CML patients, the median age was 41 years, which is younger than the median age of diagnosis in western populations. The incidence of additional chromosome abnormalities(ACAs) was 3.1% in newly-diagnosed chronic phase(CP), 9.1% in CP after therapy, 35.4% in accelerated phase(AP) and 52.9% in blast phase(BP), reflecting cytogenetic evolution with CML progression. 5.3% patients harbored a variant Ph translocation. A higher prevalence of ACAs was observed in variant Ph translocations than in classical t(9;22) in the disease progression, especially in BP(88.2% vs. 50%, p=0.002). Moreover, a hyperdiploid karyotype and trisomy 8 were closely correlated with myeloid blast crisis(BC) while a hypodiploid karyotype and monosomy 7 were associated with lymphoid-BC. Among subsets of myeloid-BC, compared with myeloid-BC with granulocytic differentiation or monocytic differentiation, myeloid-BC with minimal differentiation had higher ACAs rate (80% vs.46.8%, p=0.009 and 80% vs. 42.9%, p=0.006). Conclusion: CML tends to afflict younger population in China. In the disease progression, the incident of ACAs was higher in variant Ph translocations than in classical t(9;22). Among subsets of myeloid-BC, myeloid with minimal differentiation had distinct cytogenetic features. Disclosures: No relevant conflicts of interest to declare.

Long-Term Follow-up Results Over 7 Years for Survival, and Safety with Imatinib Mesylate Accompany with Allogeneic Transplantation for Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4529-4529
Author(s):  
Jun Wang ◽  
Aining Sun ◽  
Wu Depei ◽  
Huiying Qiu ◽  
XiaoWen Tang
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Allogeneic Transplantation ◽  
Cytogenetic Response ◽  
Hematopoietic Stem ◽  
Long Term Follow Up

Abstract Abstract 4529 Objective: To observe the efficacy and safety of imatinib mesylate (IM) accompany with allogeneic transplantation for chronic myeloid leukemia (CML). Methods: During the period from January 2003 to August 2011,we retrospectively observed 95 patients with CML receiving IM for a minimum of 4 months before allogeneic hematopoietic stem cell transplantation (HSCT). Patients with advanced CML received IM from 3 month after transplantation for 12 months. Results: Among 95 enrolled patients (CML-CP 76, CML-AP 10, CML-BP 9), types of transplantation: sib-matched HSCT 64, unrelated-HSCT 19, haplo-HSCT 12. For the whole patients, 7 year overall survival (OS) is 80.5%, and disease free survival (DFS) is 74.5%. Complete hematologic response (CHR) is 93.6%, complete cytogenetic response (CCR) is 84.5%, major cytogenetic response (MCR) is 60.3% at 7 year. For CML-CP1, OS is 83.2% and CML-AP/BC is 33.3% (P<0.05). Compared patients of advanced CML achieving CP2 after IM and with no CP2,the former has better results of CCR or MCR, OS and PFS (P<0.05). The total treatment related mortality (TRM) is 16.8%. Cox multivariate regression analysis of prognostic factors indicates that status of CML and severe acute graft-versus-host disease (aGVHD III-‡W) retain independent predictive value. No increase in rates of serious adverse events was observed with continuous use of IM for up to 7 years. Conclusions: For chronic myeloid leukemia, combining with imatinib mesylate and allogeneic transplantation is a good strategy, with favorable long-term follow-up results and acceptable TRM, especially for the patients with advanced CML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Achieving Complete Cytogenetic Response and BCR-ABL PCRIS <1% within 12 Moths Are Important Goals for Imatinib Therapy in Newly Diagnosed, TKI-Naive Chronic Myeloid Leukemia Accelated Phase Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3158-3158
Author(s):  
Hawk Kim ◽  
Eun-Jung Jang ◽  
Sung-Eun Lee ◽  
Won Sik Lee ◽  
Sukjoong Oh ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Platelet Count ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Hematopoietic Stem ◽  
Long Term Outcome

Abstract Background; Accelerated phase of chronic myeloid leukemia (AP-CML) is not clearly defined yet. There are different definitions to classify AP. In European Leukemia Net (ELN) 2013 recommendation, considerable therapeutic approach of de novo AP would be hematopoietic stem cell transplantation (HSCT) followed by frontline tyrosine kinase inhibitor (TKI). To explore long-term efficacy of frontline imatinib (IM) treatment and early predictors of long-term outcome, we analyzed a total of 73 patients who received frontline IM.. Method; AP defined as a definition of ELN recommendation.. A progression to blastic phase and loss of response were considered as progression. Patients who had received HCT were censored at the time of HCT when calculating overall survival (OS) and progression-free survival (PFS). Results; Of 83 patients who diagnosed as AP, 73 patients received IM and other 10 patients had HSCT (n=7) or no treatment (n=3). Of 73 IM-treated patients, 36 patients maintained IM therapy and 37 patients discontinued IM with switch to 2G TKI (n=23) or HSCT (n=14). Analysis of baseline characteristics revealed prior cytogenetic response (CyR), and molecular response at 6 and 12 months for prediction of survivals. Clinical factors for better survival including Sokal score (p=0.203), Hasford sore (p=0.832), peripheral blood (PB) basophil count (p=0.374), spleen size (p=0.656), bone marrow (BM) promelocyte (p=0.839), BM basophil (p=0.478 were not significant. PB blast<10% (p=0.0670), PB eosinophil count>5% (p=0.031), platelet count >20x109/L (p=0.008), PB promyelocyte<2% (p=0.171), PB blast+promelocyte<20% (p=0.095), BM blast+promelocyte<20% (p=0.006), BM blast<10% (p=0.020) at diagnosis, achieving CCyR (p<0.001), achieving BCR-ABL PCRIS <10% (MR1.0) at 3M (p=0.020), BCR-ABL PCRIS <1% (MR2.0) at 6M (p=0.005) and MR2.0 at 12M (p=0.001) were included in multivariate analysis. Platelet count >20x109/L at diagnosis (p=0.002), achieving CCyR (p=0.007) and MR2.0 at 12M (p=0.048) were significant prognostic factors in multivariate analysis. Probability of 10Y OS for patients who acheived CCyR vs. no CCyR were 85.2% vs. 0% (p<0.001); median survival for patients without CCyR was 31.737 (95% CI, 16.269-47.147) months (Figure 2). Probabilities of 10Y OS for MR1.0 at 6M and MR2.0 at 12M were 81.3% vs. 59.7% (p=0.016) and 96.5% vs. 57.4% (p=0.003), respectively. However, time to CCyR<6M was not significant 10Y OS rate 75% vs. 67.6%, p=0.173). The 10Y PFS probability in patients who had acheived CCyR was 66.0% vs. 0% (p<0.001); median PFS for patients without CCyR was 9.462 (95% CI, 1.978-16.946) months. Probabilities of 10Y PFS in MR1.0 at 6M and MR2.0 at 12M were 63.2% vs. 44.9% (p=0.076) and 77.1% vs. 39.8% (p=0.005), respectively. Median PFS for patients not achieving MR1.0 at 6M and MR2.0 at 12M were 30.555 (95% CI, 0.0-61.252) and 22.867 (95% CI, 0.0-50.208), respectively. Time to CCyR<6M was not significant for PFS (10Y PFS rate 50.8% vs. 58.5%, p=0.828). Conclusion: Achievement of CCyR or achievement of MR1.0 at 12M was important goals not only in progression but also in survival. Therefore if a patient doesnÕt achieve the goals, the treatments need to be changed. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

Inhibition of the NAMPT-Triggered Deacetylation of HCLS1 Protein: A New Therapeutic Option in Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1001-1001 ◽  
Author(s):  
Bardia Samareh ◽  
Inna Zimmer ◽  
Andrew Zikic ◽  
Olga Klimenkova ◽  
Houra Loghmani-Khouzani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Therapeutic Option ◽  
Sirtuin 1 ◽  
Imatinib Treatment ◽  
Granulocytic Differentiation ◽  
Hematopoietic Stem ◽  
Inhibition Of Proliferation ◽  
Nicotinamide Phosphoribosyltransferase

Abstract G-CSFR-triggered phosphorylation and activation of the hematopoietic-specific lyn-substrate 1 (HCLS1) protein is important for the granulocytic differentiation of hematopoietic stem cells (HSCs) (Skokowa J. et al., Nat Med 2012). G-CSF also activates protein deacetylation via Nicotinamide phosphoribosyltransferase (NAMPT)/NAD+/sirtuin 1 (SIRT1) pathway (Skokowa J. et al., Nat Med 2009). SIRT1 is NAD+-dependent protein deacetylase playing an important role in the regulation of gene transcription. Interestingly, having strong pro-differentiation effects on myeloid progenitors, both HCLS1 and NAMPT are markedly hyper-activated in myeloid leukemias, inducing proliferation and survival of undifferentiated blasts. Knowing this, we investigated whether HCLS1 could be activated by NAMPT/NAD+/SIRT1 pathway via deacetylation in HSCs. Indeed, we found that HCLS1 is deacetylated in HSCs by NAMPT/SIRT1 and that G-CSF treatment of these cells induced deacetylation and phosphorylation of HCLS1 via NAMPT/SIRT1. Moreover, we found that deacetylation of HCLS1 is important for myeloid differentiation and proliferation of HSCs. We further demonstrated that HCLS1 protein was activated by deacetylation in blasts of chronic myeloid leukemia (CML) patients, as compared to HSCs of healthy individuals. This was in line with elevated mRNA and protein levels of NAMPT and HCLS1. We further investigated, whether inhibition of NAMPT-triggered deacetylation of HCLS1 has any effect on the survivial and differentiation of CML blasts in vitro. We found that treatment of CML blasts with the specific NAMPT inhibitor FK866 resulted in increased acetylation of HCLS1. In addition, treatment of CML blasts with the FK866 in a dose of 10nM resulted in marked inhibition of proliferation and elevated cell death, which was consistent between different patients and was comparable to the effects of Imatinib treatment. In CFU assay in the presence of FK866 (10nM) no CFU colonies were grown. Even at a dose of 3nM FK866 drastically suppressed total colony counts. This inhibitory effect was further amplified by combination of FK866 with Imatinib. Addition of 10nM of FK866 to CFU culture medium was not toxic for CD34+ cells of healthy donors. Taken together, we demonstrated that NAMPT and HCLS1 have dose-dependent effects on hematopoietic cells and that NAMPT activates HCLS1 functions by SIRT1-triggered deacetylation. Inhibition of NAMPT in CML blasts markedly reduced their survival, proliferation and differentiation. In conclusion, we suggest a possible therapeutic application of NAMPT inhibition in the treatment of CML patients via deactivation of HCLS1 function by acetylation. This therapy could be applied in combination with Imatinib, or in Imatinib-resistant CML patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals TKI Treatment Discontinuation: How Many Patients Could Stop Tyrosine Kinase Treatment According to Discontinuation Trials Criteria? Incidence and Prognostic Impact of Deep Molecular Response in a Cohort of Chronic Myeloid Leukemia Patients of South Brazil's Hematology Centers

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5542-5542
Author(s):  
Laura Fogliatto ◽  
Marcelo Eduardo Zanella Capra ◽  
Mariza Shaan ◽  
Tito Vanelli Costa ◽  
Luis Carlos Zanandrea Contin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Event Free Survival ◽  
Free Survival ◽  
The Future ◽  
Tki Discontinuation

Abstract Sustained deep molecular response (MR4.5) after imatinib treatment defines a subgroup of patients with chronic myeloid leukemia (CML) with better outcome and that probably would be able to stop treatment in the future, according to results of clinical TKI discontinuation trials. Most of these trials showed that patients with a long-term imatinib treatment and low Sokal risk have a higher probability of maintain a deep molecular remission after stopping treatment. OBJECTIVES The main objective is to review the molecular responses, overall survival and event free survival of CP CML patients that have been treated with imatinib in 14 hematology centers in South Brazil. Using our data basis we also would like to see how many of them present long-term imatinib treatment, sustained deep molecular remission and correlate these findings with the Sokal risk groups. These data would allow us to predict patient profile that could be able to discontinue the treatment in the future in a prospective clinical trial. PATIENTS AND METHODS This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) that have been treated in 14 hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. MR(4.5) was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction. All tests were performed at a central standardized according to ELN. Event-free-survival (EFS) was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Overall survival (OS) was measured from the start of imatinib until death of any cause or to the date patient was last known to be alive. RESULTS Data from 474 patients was analyzed. After a median observation time of 46 months, 5-year overall survival (OS) was 86%, 5-year event-free-survival was 53%. Of the 474 patients, 258 had adequate PCR evaluations during treatment. 118 of 258 (45,7%) patients achieved MR(4.5) and 69 of 258 (27%) had sustained response for at least two years after a minimum time of treatment of 3 years. The cumulative incidence of MR(4.5) after 9 years was 76% (median, 3 years). In the group that achieved MR(4.5), there was only 1 (0,8%) death and 1 (1,1%) progression compared to 8 deaths (5,7%) and 8 progressions (7,5%) in the group without MR(4.5); these differences were significant with p=0,03 and 0,02 respectively. In the subgroup of 69 patients that had had been treated with imatinib for 3 year or more and sustained deep response (RM4,5) for at least two years, 21 pts had low Sokal risk, 7 pts intermediate Sokal risk and only 4 pts a high Sokal risk. Unfortunately, in 37 pts the Sokal risk could not be accessed due to missing information. CONCLUSION In our series MR(4.5) is reached in the majority of patients with long-term imatinib treatment. MR(4.5) is a predictor of outcome with only one disease progression and one death due to CML in this group of patients. Unfortunatly PCR are not available for all patients in our clinical practice, but this situation are improving. Regarding the 69 patients with TKI discontinuation trial criteria, we find out that 21 patients fulfill such criteria. In the future, according to the results of current stop trials it could be possible include this selected group of CP CML patients in a prospective clinical trial. Disclosures No relevant conflicts of interest to declare.

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