scholarly journals High-Risk Additional Chromosomal Abnormalities in CML Herald Death By Blast Crisis Already at Low Blast Levels

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 666-666 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Astghik Voskanyan ◽  
Michael Lauseker ◽  
Markus Pfirrmann ◽  
Lida Kalmanti ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Blast Crisis ◽  
Intensive Therapy ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Low Risk ◽  
University Hospital ◽  
Additional Chromosomal Abnormalities

Background. The end phase or metamorphosis is one of the remaining challenges of chronic myeloid leukemia (CML) management. Blast crisis (BC) is a late marker. Earlier diagnosis may improve outcome. The detection of additional chromosomal abnormalities (ACA) at low blast levels might allow earlier treatment when outcome is better. Methods. We made use of 1536 Ph+CML-patients in chronic phase followed in the randomized CML study IV (Hehlmann et al, Leukemia 2017) for a median of 8.6 years. 1510 cytogenetically evaluable patients were analyzed for ACA and blast increase (Flow chart). According to impact on survival ACA were grouped into high-risk (+ 8; +Ph; i(17q); +17; +19 +21; 3q26; 11q23; -7; complex) and low-risk (all other). Prognosis with +8 alone was clearly better than with +8 accompanied by further abnormalities, but still worse than with low-risk ACA. +8 alone was therefore included in the high-risk group. The presence of high- and low-risk ACA was linked to 6 thresholds of blast increase (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox proportional hazards model. Results. 139 patients (9.2%) displayed ACA at any time before BC diagnosis, 88 (5.8%) had high-risk and 51 (3.4%) low-risk ACA. ACA emerged after a median of 17 (0-133) months. 79 patients developed BC. 43 (61%) of 71 cytogenetically evaluable patients with BC had high-risk ACA. 3-year survival after emergence of high-risk ACA was 48%, after emergence of low-risk ACA 92%. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die (ratios: 3.66 in blood; 6.84 in marrow) compared to no ACA in contrast to low-risk ACA. This effect was not observed anymore at blast increases to 20-30% (Figure). 38 patients with high-risk ACA died, 36 with known causes of death which were almost exclusively BC (n=26, 72%) and progression-related transplantation (n=8, 22%). Only 2 patients died of CML-unrelated causes. Conclusions. High-risk ACA herald death by BC already at low blast levels and may help to define CML end phase in a subgroup of patients at an earlier time than is possible with current blast thresholds. Cytogenetic monitoring is indicated when signs of progression surface and response to therapy is unsatisfactory. More intensive therapy may be indicated at emergence of high-risk ACA. Disclosures Hehlmann: Novartis: Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Fabarius:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. Baerlocher:Novartis: Research Funding. Burchert:Novartis: Research Funding. Brümmendorf:Novartis: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Ariad: Consultancy; Pfizer: Consultancy, Research Funding; University Hospital of the RWTH Aachen: Employment. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Saussele:BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy.

scholarly journals High-risk additional chromosomal abnormalities at low blast counts herald death by CML

Leukemia ◽  
2020 ◽  
Vol 34 (8) ◽  
pp. 2074-2086 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
◽  
Astghik Voskanyan ◽  
Michael Lauseker ◽  
Markus Pfirrmann ◽  
...  
Keyword(s):  
High Risk ◽  
Chromosomal Abnormalities ◽  
Cox Model ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Response To Therapy ◽  
Low Risk ◽  
Diagnostic Systems ◽  
Impact On Survival ◽  
Additional Chromosomal Abnormalities

Abstract Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, −7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1–15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20–30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.

scholarly journals Polygenic risk scores predict diabetic complications and their response to therapy

2019 ◽  
Author(s):  
J. Tremblay ◽  
M. Haloui ◽  
F. Harvey ◽  
R. Tahir ◽  
F.-C. Marois-Blanchet ◽  
...  
Keyword(s):  
High Risk ◽  
Prediction Model ◽  
Risk Group ◽  
Intensive Therapy ◽  
Cardiovascular Death ◽  
Response To Therapy ◽  
Low Risk ◽  
Number Needed To Treat ◽  
Genome Wide Association Studies ◽  
Increased Risk

AbstractType 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals, we combined 9 PRS gathering genomic variants associated to cardiovascular and renal diseases and their key risk factors into one logistic regression model, to predict micro- and macrovascular endpoints of diabetes. Its clinical utility in predicting complications of diabetes was tested in 4098 participants with diabetes of the ADVANCE trial followed during a period of 10 years and replicated it in three independent non-trial cohorts. The prediction model adjusted for ethnicity, sex, age at onset and diabetes duration, identified the top 30% of ADVANCE participants at 3.1-fold increased risk of major micro- and macrovascular events (p=6.3×10−21 and p=9.6×10−31, respectively) and at 4.4-fold (p=6.8×10−33) increased risk of cardiovascular death compared to the remainder of T2D subjects. While in ADVANCE overall, combined intensive therapy of blood pressure and glycaemia decreased cardiovascular mortality by 24%, the prediction model identified a high-risk group in whom this therapy decreased mortality by 47%, and a low risk group in whom the therapy had no discernable effect. Patients with high PRS had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel polygenic prediction model identified people with diabetes at low and high risk of complications and improved targeting those at greater benefit from intensive therapy while avoiding unnecessary intensification in low-risk subjects.

The Clinical Significance of Early Imatinib Induced ABCB1 Overexpression in Chronic Phase CML Patients: A TIDEL II Sub-Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 348-348 ◽  
Author(s):  
Laura N Eadie ◽  
Timothy P. Hughes ◽  
Deborah L White
Keyword(s):  
Research Funding ◽  
Therapeutic Option ◽  
Blast Crisis ◽  
Drug Transporters ◽  
Chronic Phase ◽  
Response To Therapy ◽  
Molecular Response ◽  
The Impact ◽  
Post Therapy

Abstract Recent data from the TIDEL II trial indicate first-line imatinib (IM) treatment, with selective switching to nilotinib (NIL) for failure to meet specific molecular targets or for intolerance, results in excellent molecular response and overall survival in chronic phase Chronic Myeloid Leukaemia (CP-CML) patients. Drug transporters, particularly OCT-1 and ABCB1, have previously been demonstrated to impact IM response. Furthermore, ABCB1 overexpression has been implicated in IM and NIL resistance in vitro. In this TIDEL II sub-study the level of ABCB1 mRNA expression was retrospectively assessed by PCR at day 0 and day 22 post the start of IM therapy and where relevant, at cessation. A change in the level of expression of ABCB1 compared with baseline after 22 days exposure to IM was observed in all patients (Range: 0.6-12.3 fold; median: 2 fold), suggesting IM exposure resulted in altered ABCB1 expression that was variable between patients; this change was not related to the level of BCR-ABL1 expression (p=0.29 at day 0 and p=0.84 at 1 mo). Assessing the impact of >2 fold rise in ABCB1 expression after 22 days IM exposure on subsequent molecular response, and comparing this with patients where a <2 fold rise was observed revealed significant differences in outcome between the 2 groups (Table 1). Table 1.% of patients achieving:Over the first 22 days of treatmentEarly Molecular ResponseMMR by 12 moEvent Free SurvivalMR4.5<2 fold rise in ABCB1 (n=22)86%64%77%64%>2 fold rise in ABCB1 (n=22)60%14%37%5%p -value0.0060.0010.018<0.001 Importantly, change in ABCB1 mRNA over the first 22 days of treatment was predictive of MMR by 24 mo (Figure 1). These data support previous in vitro findings of ABCB1-mediated IM export and provide the first in vivo evidence for up regulation of ABCB1 in response to IM therapy. Because ABCB1-mediated export of NIL has also been demonstrated, we assessed the correlation between response to NIL therapy and changes in ABCB1 expression following 22 days IM exposure. Of the patients who demonstrated a >2 fold rise in ABCB1 compared with baseline, 16 of the remaining 20 patients (2/22 died at 3.2 mo (Cardiac event) and 3.7 mo (Blast Crisis)) switched to sequential NIL therapy because of sub-optimal response to IM (no prior MMR). Importantly, 0/16 patients receiving NIL subsequently achieved confirmed MMR, suggesting that NIL may provide a poor therapeutic option for patients with up-regulation of ABCB1. These data highlight the potential importance for monitoring increases in ABCB1 expression early in therapy in order to predict those patients likely to achieve poor molecular responses. We next determined the impact of ABCB1 expression on Event Free Survival (EFS) and demonstrated that the fold change in ABCB1 levels at day 22 was predictive for achieving EFS: 77% of patients with <2 rise in ABCB1 vs 37% of patients with >2 rise in ABCB1; p =0.018. Furthermore a sustained >2 fold rise in ABCB1 mRNA compared with levels at diagnosis was observed in 3/3 patients prior to progression to blast crisis and ABCB1 mRNA increased by >2 fold post therapy in 9/12 patients prior to development of KD mutations. Previous studies investigating the correlation between ABCB1 expression and response to therapy have focussed on absolute levels of ABCB1, usually at 12 mo post-therapy initiation when leukaemic cell burden would be low, and have observed no significant difference in ABCB1 expression in optimal vs sub-optimal responders. Conversely, our rapid PCR based assay performed pre and 22 days post the start of IM therapy in CP-CML patients provides a potent early predictor of subsequent IM response. The findings detailed here also suggest that NIL is likely a poor subsequent therapeutic option for patients with up-regulated ABCB1 expression in response to IM. Importantly, these data highlight the fact that better understanding of the effects of TKIs on factors with the potential to influence treatment outcome (such as drug transporter expression) can be used to personalise therapy. Overarchingly, these data exemplify the importance of drug transporters in the setting of TKI therapy and patient response, and, following validation in further studies, provide a new, effective and easily translatable prognostic biomarker based on ABCB1. Disclosures Hughes: Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. White:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

The EUTOS Survival Score Is Preferable over the Sokal Score for Prognosis of Long-Term Survival of Patients with Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 595-595 ◽  
Author(s):  
Markus Pfirrmann ◽  
Joerg Hasford ◽  
Susanne Saussele ◽  
Anna Turkina ◽  
Witold Prejzner ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Chronic Phase ◽  
Low Risk ◽  
Term Survival ◽  
Survival Score ◽  
Risk Patients ◽  
Sokal Score

Abstract Introduction: The in-study and out-study sections of the European Treatment and Outcome Study (EUTOS) registry comprise data on imatinib-treated adult patients with chronic myeloid leukemia (CML) who were prospectively enrolled in clinical studies or registries between 2002 and 2006. All patients diagnosed with chronic-phase Philadelphia chromosome-positive CML were eligible for analysis. The new EUTOS long-term survival (ELTS) score was developed in 2,205 in-study patients (Blood 2014; 124(21):153). Its purpose is the discrimination of three risk groups with clinically significantly different probabilities of dying from CML. The score was validated in 1,120 out-study patients. Aims: Up to now, many investigators still apply the Sokal score for the prognostic discrimination of CML-patients treated with tyrosine kinase inhibitors (TKIs). The Sokal score allocated more than 20% of chronic-phase patients to the high-risk group while it was 12% with the new ELTS score. Long-term outcome with tyrosine kinase inhibitors (TKIs) suggests that the allocation of more than 20% chronic-phase CML patients into a high-risk group is too pessimistic. The focus of this analysis was the comparison of risk group allocations and prognosis between the two scores. Methods: Survival time was calculated from the date of start of treatment to death or to the latest follow-up date. Survival was censored at the time of allogeneic stem cell transplantation in first chronic phase. Cumulative incidence probabilities (CIPs) of dying of CML were compared with the Gray test and overall survival probabilities with the log-rank test. As "death due to CML", only death after confirmed disease progression was regarded. Progression was defined in accordance with the recommendations of the ELN (Baccarani et al, Blood 2013). Level of significance was 0.05. Results: Both registries combined, the 3,325 patients had a median observation time of 6.1 years. Six-year overall survival probability was 91% (95% confidence interval (CI): 89-92%). Death was due to CML in 142 of 309 deceased patients (46%).The 6-year CIP of dying of CML was 4% (CI: 4-5%). From low to high risk groups, the Sokal score resulted in 6-year CIPs of 3% (n=1358 (41%), CI: 2-4%), 4% (n=1209 (36%), CI: 3-5%), and 8% (n=758 (23%), CI: 6-11%) and the ELTS score in 6-year CIPs of 2% (n=2030 (61%), CI: 2-3%), 6% (n=898 (27%), CI: 4-7%), and 13% (n=397 (12%), CI: 10-17%). Of the 758 patients allocated to high risk by the Sokal score, the ELTS score classified 165 (22%) as low risk and 265 (35%) as intermediate risk. Compared to the 328 high-risk patients (43%) according to both scores (6-year CIP of dying: 13%, CI: 9-17%), the CIPs of dying were significantly lower for the 165 low-risk patients (p=0.0062, 6-year CIP: 5%, CI: 2-9%) and for the 265 intermediate-risk patients (p=0.0050, 6-year CIP: 5%, CI: 3-9%). These 430 Sokal high but ELTS non-high-risk patients (6-year OS: 89%. CI: 86-92%) showed significantly higher OS probabilities than the 328 Sokal and ELTS high-risk patients (p=0.030, 6-year OS: 81%. CI: 76-85%). Of the 2030 patients identified as low risk by the ELTS score, the Sokal score allocated 603 (30%) to the intermediate- and 165 (8%) to the high-risk group. Without significant CIP differences to the latter group, at 6 years, the CIP of dying was 2% (CI: 1-3%) in the 1262 low-risk and also 2% in the 603 intermediate-risk patients (CI: 1-3%). The OS probabilities of the 768 non-low-risk patients according to the Sokal score (6-year OS: 93%. CI: 91-95%) were not significantly different from the 1262 classified as low-risk by both scores (6-year OS: 95%. CI: 93-96%). Conclusions: To be able to perform comparisons between the various prognostic groups suggested by the Sokal and the EUTOS survival score with a reasonable power, data of in- and out-study samples were combined. The Sokal score allocated an absolute difference of 12% (n=430) more patients to the high-risk groups than the EUTOS survival score. As these patients had significantly and clinically relevantly lower CIPs and higher OS probabilities, the allocation of the Sokal score was not appropriate. Contrarily, the long-term outcome of 768 patients assessed as low-risk by the ELTS and non-low-risk by the Sokal score was not different from the outcome of 1262 assesses as low-risk patients by both scores. For prognosis of long-term survival outcome, the use of the EUTOS survival score is recommended. Disclosures Pfirrmann: BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Hasford:Novartis: Research Funding. Saussele:Novartis Pharma: Honoraria, Other: Travel grant, Research Funding; BMS: Honoraria, Other: Travel grant, Research Funding; ARIAD: Honoraria; Pfizer: Honoraria, Other: Travel grant. Turkina:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy. Prejzner:Novartis Pharma: Honoraria; BMS: Honoraria. Steegmann:Novartis Pharma: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Simonsson:Novartis Pharma: Research Funding. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy. Zackova:Novartis Pharma: Consultancy; Bristol Myers Squibb: Consultancy. Janssen:Novartis: Research Funding; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; ARIAD: Consultancy. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Hehlmann:Novartis Pharma: Research Funding; BMS: Consultancy. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Ariad: Consultancy, Speakers Bureau.

Three-Dimensional Nuclear Telomeric Organization (3D) of Chronic Myeloid Leukemia Patients Predicts Accelerated Phase and Blast Crisis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2771-2771
Author(s):  
Fabio Morato Oliveira ◽  
Ferdinando de Paula Silva ◽  
Ana Paula N Rodrigues Alves ◽  
Belinda Pinto Simoes ◽  
Roberto P. Falcao ◽  
...  
Keyword(s):  
Chromosomal Abnormalities ◽  
Blast Crisis ◽  
Three Dimensional ◽  
Chronic Phase ◽  
Statistical Analyses ◽  
Telomere Dysfunction ◽  
3D Image ◽  
Disease Evolution ◽  
Additional Chromosomal Abnormalities ◽  
The Impact

Abstract Abstract 2771 One major cause of genomic instability and cellular apoptosis is telomere dysfunction. Telomere loss or dysfunction results in breakage–bridge –fusion cycles, aneuploidy, and ongoing chromosomal abnormalities. The three-dimensional (3D) nuclear organization of telomeres allows for a distinction between normal and tumor cells: nuclei of the latter tend to be disorganized and commonly contain telomeric aggregates. However, few studies have addressed the impact of telomeres dynamics in CML progression. The frequency of additional chromosomal abnormalities in CML is around 5% in chronic phase and increases to 50–80% in the advanced phases. Clonal evolution often precedes progression and is predictive for inferior therapeutic outcome. In order to better understand cellular and molecular mechanisms in CML progression, the objectives of this investigation were examine telomere dysfunction and alterations in the 3D nuclear telomere architecture. Eighteen CML patients, in total, 54 bone marrow samples (chronic phase, accelerated phase and blast crisis) were eligible for 3D nuclear telomeric investigation. The quantitative FISH (QFISH), cytologic diagnosis and the cytogenetic determination for additional chromosomal abnormalities were assessed according to standard protocols. 3D image analysis on 30 interphase nuclei per slide was obtained by using an Axio Imager A1 microscope (Carl Zeiss, USA). Sixty z-stacks were acquired at a sampling distance of x,y: 102 nm and z: 200 nm for each slice of the stack. AxioVision 4.8 software (Carl Zeiss, Canada) was used for 3D image acquisition, and deconvolution analysis. Three CML subgroups were defined on the basis of their 3D telomeric profiles. The telomeric parameters (number, length, telomere aggregates and nuclear volumes) were compared between these three subgroups. Distribution of telomere intensities in CML phases was compared between the patient's subgroups. All patients of a same subgroup displayed similar 3D telomeric profiles. Comparison with clinical diagnosis after the classification according to telomere profile showed that all CML patients were classified in the three distinct subgroups. Statistical analyses showed significant differences between the CML subgroups (P<0.001). Each of the quantitative telomere parameters exhibited significant differences. Furthermore, statistical analyses combining all 3D telomere parameters revealed significant differences between all subgroups (P<0.05). According to our data these profiles are correlated to the disease evolution and increased telomere dysfunction in these subgroups. It seems that the evolution of CML progresses from low to high level of telomere dysfunction, that is, from early stage to more aggressive stage, followed by disease transformation. We concluded that telomere 3D organization is a highly accurate tool to distinguish CML stages. We propose that monitoring 3D telomere dysfunction might be a very powerful marker to measure this transformation. Furthermore, it may be a better indicator of therapeutic response because an optimal response will lead to a normal cellular biology, including elimination of abnormal telomeric aggregates and the increase of normal 3D telomeric profiles. Financial support: FAPESP (2011/01647-2). Disclosures: No relevant conflicts of interest to declare.

Complete Molecular Remission (CMR 4.5) of CML Is Induced Faster by Dose – Optimized Imatinib and Predicts Better Survival - Results From the Randomized CML-Study IV

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 67-67 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Michael Lauseker ◽  
Benjamin Hanfstein ◽  
Martin C. Müller ◽  
Annette Schreiber ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Randomized Study ◽  
Chronic Phase ◽  
Low Risk ◽  
Molecular Remission ◽  
Log Reduction ◽  
Risk Patients ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 67 Dose optimized imatinib (IM) at doses of 400– 800mg has been shown to induce faster and deeper cytogenetic and molecular – responses than standard IM (400mg/day). Since complete molecular remission (CMR 4.5) identifies a subgroup of patients who may stay in remission even after discontinuation of treatment, it was of interest to analyse whether CMR 4.5 is reached faster with dose optimized IM and whether CMR 4.5 correlates with survival. CMR 4 and CMR 4.5 are defined as ≤ 0.01% BCR-ABL IS or ≥ 4. log reduction and ≤ 0.0032% BCR-ABL IS or ≥ 4.5 log reduction, respectively, from IRIS baseline as determined by real-time PCR. CML-Study IV is a five arm randomized study of IM 400 mg vs IM 400 mg + IFN vs. IM 400 mg + Ara C vs. IM after IFN failure vs. IM 800 mg. In the IM 800 arm, a 6 weeks run in period at IM 400 mg was followed by a dose increase to 800 mg and then by a dose reduction according to tolerability. Grade 3 or 4 adverse effects (AE) were to be avoided. From July 2002 to March 2012 a total of 1551 patients with newly diagnosed chronic phase CML were randomized of whom 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk, 36% were Euro score low risk, 52% intermediate and 12% high risk, 38% were Sokal low risk, 38% intermediate and 24% high risk. 113 patients were transplanted, 246 received 2nd generation TKI. 152 patients have died, 90 of CML or unknown reasons, 62 of not directly CML-related causes. After a median observation time of 67,5 months 6 years OS was 88.2% and PFS 85.6%. CCR, MMR, CMR 4 and CMR 4,5 were achieved significantly faster with dose optimized IM (400 – 800 mg). No significant differences in remission rates were observed between IM 400 mg and the combination arms IM 400 mg + IFN and IM 400 mg + Ara C, whereas IM after IFN failure thus far yielded significantly slower response rates. After 4 years CCR rates were for IM 400, IM 400 + IFN, IM 400 + Ara C, IM 400 after IFN, and IM 800, 80%, 75%, 73%, 59% and 80%, respectively, MMR rates 84%, 77%, 82%, 61% and 88%, CMR 4 rates 57%, 55%, 55%, 40% and 65%, and CMR 4.5 rates 40%,42%, 42%, 28% and 52%, respectively. CMR 4 was reached after a median of 27 months with IM 800 and 41.5 months with IM 400. CMR 4.5 was reached after a median of 41.5 months with IM 800 and 63 months with IM 400. EUTOS low risk patients reached all remissions faster than EUTOS high risk patients. The differences of CMR 4 rates between IM 800 and IM 400 at 3 years were 13% and at 4 years 8%, and of CMR 4.5 rates at 3 years 10% and at 4 years 13%. Grade 3 and 4 AE were not different between IM 400 and dose optimized IM 800. Independent of treatment approach, CMR 4 and more clearly CMR 4.5 at 3 years predicted better OS and PFS, if compared with patients without CMR 4 or CMR 4.5, respectively. CMR 4 and 4.5 were stable. After a median duration of CMR 4 of 3.7 years only 4 of 792 patients with CMR 4 have progressed. Life expectancy with CMR 4 and 4.5 was identical to that of the age matched population. We conclude that dose optimized IM induces CMR 4.5 faster than IM 400 and that CMR 4 and CMR 4.5 at 3 years are associated with a survival advantage. Dose optimized IM may provide an improved therapeutic basis for unmaintained treatment discontinuation in patients with CML. Disclosures: Hehlmann: Novartis: Research Funding. Müller:Novartis, BMS: Consultancy, Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hochhaus:Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding.

Changes of Pro-Inflammatory Cytokines in Bone Marrow of MDS Patients in Response to Treatment with 5-Azacytidine

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2895-2895
Author(s):  
Alena Moudra ◽  
Sona Hubackova ◽  
Jiri Bartek ◽  
Zdenek Hodny ◽  
Anna Jonasova
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Complete Remission ◽  
Conflicts Of Interest ◽  
Response To Therapy ◽  
Low Risk ◽  
University Hospital ◽  
Healthy Controls ◽  
Risk Patients ◽  
The Difference

Abstract Introduction Treatment with 5-azacytidine (5-AC) is indicated for high-risk MDS patients. Besides the inhibitory effects of 5-AC on DNA and RNA methylation, 5-AC has been recently shown to induce DNA damage and apoptosis in cultured cells. However, in vivo effects of 5-AC remain to be elucidated. Several recent publications implicate aberrant bone marrow (BM) microenvironment and inflammation-related changes in the occurrence and/or progression of the MDS. To provide more insights into this emerging concept, we assessed: i) the extent to which inflammation related cytokines may contribute to MDS progression, and ii) potential changes of cytokine abundance in response to 5-AC therapy. Patients and methods We have collected BM samples from 30 high-risk MDS patients (IPSS int II or IPSS high, 16 females, 14 males) treated by 5-AC at the Hematology Clinic, General University Hospital in Prague. Patients' mean age was 72y (range 55-85) and the WHO 2008 diagnoses were: 15 RAEB II, 5 RAEB I, 2 CMML II, 2 RCMD, 1 U-MDS/MPN and 5 AML/MDS with < 30% myeloblasts. We analyzed BM aspirates collected before 5-AC therapy and at day 7 after the completion of respectively the 4th and 8th cycle at which time initial response was also assessed. BM plasma was immediately separated from cells and kept in liquid nitrogen until the time of analysis. As controls we used BM samples from 4 healthy subjects (males, mean age 42y, range 32-59), along with BM samples from 6 low-risk 5q- MDS patients (females, mean age 68y, range 46-80). For the presence of inflammation-related cytokines, BM plasma was analyzed using Human Inflammation 11-Plex (IFNγ, IL1α, IL1β, IL6, IL8, IL10, IL12p70, IL27, IP10, MCP1, and TNFα; YSLBio) via flow cytometry. For the purposes of data analysis, 5-AC treated patients were divided into 2 groups depending on their response to therapy: responders (hematological improvement, partial remission, complete remission, complete remission with incomplete BM recovery) and non-responders (stable disease, progressive disease). Obtained cytokine values were transformed using Box-Cox procedure, and repeated measurements, analyzed using linear models with mixed effects. Comparisons of 5-AC-treated patients, 5q- MDS low-risk patients and controls were subjected to a Kruskal-Wallis test. P-values less than 0.05 were considered as statistically significant. Analyses were conducted using the R statistical package, version 3.1.2, R Core Team (2014). Results Among the 11 cytokines analyzed, 3 (IL27, IP10 and MCP1) displayed significantly altered levels when comparing high-risk 5-AC treated patients, low-risk MDS patients and healthy controls. First, IL27 was elevated in low-risk MDS in comparison to 5-AC or healthy controls (p = 0.041); Figure 1. For IP10, 5-AC MDS patients before therapy showed higher levels (p = 0.005) compared to the low-risk group and healthy controls, respectively. The difference for IP10 was also significant after 4 cycles of 5-AC therapy (p = 0.005), but insignificant after 8 cycles (p = 0.288). The difference in IP10 levels between the two treated groups (4 vs. 8 cycles) were not significant, likely reflecting insufficient sample size, thereby masking the presumably lower levels of IP10 in responders (Figure 2). Further, the 5-AC treated patients showed higher levels of MCP1 than MDS low-risk patients and healthy controls, a difference apparent before therapy (p = 0.011), after 4 cycles (p = 0.003), but not after 8 cycles of therapy (p = 0.058). Also, MCP1 levels changed (p = 0.030) during the treatment, yet irrespective of clinical responses to therapy (Figure 3). Conclusions The IL27 level was higher in low-risk MDS patients compared to high-risk MDS 5-AC patients. Levels of IP10 and MCP1 were higher in high-risk MDS 5-AC patients. Levels of MCP1 changed significantly during the 8 cycles of 5-AC therapy. The observed correlation of IP10 with responses to 5-AC therapy should be further validated. Acknowledgment and Institutional support: This study was supported by grant from Internal Grant Agency of Ministry of Health of the Czech republic (Project NT14174-3) and by Institutional grant (Project RVO 68378050). Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

Risk Stratification of Untreated Mantle Cell Lymphoma Patients Using MIPI, Ki67 Proliferative Index and Cytogenetics

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1785-1785 ◽  
Author(s):  
Ashley D. Staton ◽  
Irl Brian Greenwell ◽  
Jeffrey M Switchenko ◽  
Joseph Maly ◽  
Kristie Blum ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Markers ◽  
Chromosomal Abnormalities ◽  
Cell Lymphoma ◽  
Low Risk ◽  
Ki67 Index ◽  
Advisory Committees ◽  
Mantle Cell

Abstract Background:There are multiple prognostic markers used to risk stratify pts with mantle cell lymphoma (MCL) including the MCL International Prognostic Index (MIPI) which divides newly diagnosed patients into three groups based on available clinical and laboratory data.Complex karyotype (CK) defined as equal to or greater than 3 chromosomal abnormalities has also been associated with inferior outcomes in MCL although its association with MIPI is lesswell-described. We conducted a multicenter analysis of MCL pts to assess the relative contributions of MIPI, CK and Ki67 as predictors of progression-free (PFS) and overall survival (OS). Methods:Untreated pts atleast18 years of age with MCL from 5 academic centers diagnosed between 1993 and 2015 who had available data describing MIPI, Ki67, and cytogenetics were included. Patients with 3 or more chromosomal abnormalities were defined as having CK. High Ki67 was defined as immunohistochemistry staining >30%. We described the associations between MIPI risk group, CK, Ki67, and other clinical factors of interest as predictors of PFS and OS in univariate and multivariable models. Results:Of 92 eligible MCL patients, 30 (32.6%) had low-risk, 36 pts (39.1%) had intermediate-risk, and 26 pts (28.3%) had high-risk MIPI scores. Ki67 index was >30% in 44.6% of patients, and 17.4% had CK. Neither Ki67 > 30% (p=0.548) norpresence of CK (p=0.409) wereassociated with MIPI risk category. In the low-risk MIPI subgroup, 37% of patients had Ki67 > 30% and 10% had CK. Induction regimens included: R-HyperCVAD (n=15), R-CHOP/R-DHAP (n=7), Nordic regimen (n=13), R-CHOP (n=10), B-R (n=19), and others (n=28). Thirty-two patients (39%) had an autologous stem cell transplant (ASCT) in first remission. Median PFS for the entire cohort was 3.8 years, and median OS has not yet been reached. Median PFS for was 2.2 years, 2.5 years, and 7.9 years for patients with high-, intermediate-, and low- risk MIPI scores, respectively, at diagnosis. Median PFS was 2.4 years for patients with Ki67 > 30% and 7.9 years for patients with Ki67 < 30%. Median PFS was 1.3 years for patients with CK and 4.3 years for patients without CK. High risk MIPI (p=0.042), CK (p=0.002), and Ki67 index > 30% (p=0.002) were all associated with inferior PFS in a univariable analyses (See Figure). In a multivariable analysis (See Table) Ki67 >30% (HR=3.66, p<0.001), and complex karyotype (HR=3.9, p=0.002) were associated with inferior PFS while autologous stem cell transplantation in first CR was associated with improved PFS (HR=0.21, p=0.002). MIPI risk score was not independently associated with PFS. Conclusions:Our findings suggest that Ki67> 30% and CK are independently associated with inferior outcomes in MCL. In this analysis, MIPI risk score was not independently associated with PFS or OS when considering these additional prognostic markers, which needs to be confirmed in other retrospective and prospective cohort studies. Our high-risk MIPI patients, in general, have an improved outcome compared to prior reports. (Hoster2008, 2014;Lex2014), suggesting that alternative markers may play an important role in MCL risk-assessment. Efforts to incorporate additional patients and develop a new prognostic model in MCL are underway. Figure Figure. Figure Figure. Disclosures Danilov: Pharmacyclics: Consultancy; Astra Zeneca: Research Funding; Takeda: Research Funding; GIlead Sciences: Research Funding; ImmunoGen: Consultancy; Dava Oncology: Honoraria; Prime Oncology: Honoraria. Hamadani:Janssen: Consultancy; Celgene: Honoraria, Research Funding; Takeda Pharmaceuticals: Research Funding. Flowers:TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Infinity: Research Funding; Millenium/Takeda: Research Funding; Mayo Clinic: Research Funding; NIH: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; ECOG: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding.

scholarly journals SARS-CoV-2 Seroprevalence in Healthcare Workers in Germany: A Follow-Up Study

2021 ◽  
Vol 18 (9) ◽  
pp. 4540
Author(s):  
Johannes Korth ◽  
Benjamin Wilde ◽  
Sebastian Dolff ◽  
Jasmin Frisch ◽  
Michael Jahn ◽  
...  
Keyword(s):  
High Risk ◽  
Healthcare Workers ◽  
Risk Group ◽  
Close Contact ◽  
Virus Transmission ◽  
High Risk Group ◽  
Low Risk ◽  
University Hospital ◽  
Intermediate Risk ◽  
Igg Antibody

SARS-CoV-2 is a worldwide challenge for the medical sector. Healthcare workers (HCW) are a cohort vulnerable to SARS-CoV-2 infection due to frequent and close contact with COVID-19 patients. However, they are also well trained and equipped with protective gear. The SARS-CoV-2 IgG antibody status was assessed at three different time points in 450 HCW of the University Hospital Essen in Germany. HCW were stratified according to contact frequencies with COVID-19 patients in (I) a high-risk group with daily contacts with known COVID-19 patients (n = 338), (II) an intermediate-risk group with daily contacts with non-COVID-19 patients (n = 78), and (III) a low-risk group without patient contacts (n = 34). The overall seroprevalence increased from 2.2% in March–May to 4.0% in June–July to 5.1% in October–December. The SARS-CoV-2 IgG detection rate was not significantly different between the high-risk group (1.8%; 3.8%; 5.5%), the intermediate-risk group (5.1%; 6.3%; 6.1%), and the low-risk group (0%, 0%, 0%). The overall SARS-CoV-2 seroprevalence remained low in HCW in western Germany one year after the outbreak of COVID-19 in Germany, and hygiene standards seemed to be effective in preventing patient-to-staff virus transmission.

Determinants of Choice of Front-Line Tyrosine Kinase Inhibitor for Chronic Phase CML: A Study from the "Registro Italiano LMC & Campus CML"

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Mario Tiribelli ◽  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Isabella Capodanno ◽  
Maria Cristina Miggiano ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Multivariable Analysis ◽  
Chronic Phase ◽  
Front Line ◽  
Line Therapy ◽  
Concomitant Medications

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged &lt;45 (69.1%) while imatinib was used in 76.9% of patients over 65 (p&lt;0.001). There was a predominance of imatinib use across all Sokal (51.1% in low, 61.3% in intermediate and 51.4% in high) and ELTS (50.3% in low, 60.4% in intermediate and 66.5%) risk categories. We observed a prevalent use of 2G-TKIs in patients presenting with higher WBC counts (55.1% if WBC &gt;100,000/mm3 vs 38.2% if WBC &lt;100,000/mm3; p&lt;0.001), lower Hb (53.8% if Hb &lt;10 g/dl vs 41.9 if Hb &gt;10 g/dl; p=0.001) and bigger spleen (65.1% if spleen &gt;5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p&lt;0.001). There was a decreasing use of 2G-TKIs with higher number of concomitant drugs: 64.4% for 0, 47.7% for 1-2, 27.0% for 3-5 and 13.6% for &gt;5 drugs, respectively (p&lt;0.001). Concordantly, there was a significant higher use of imatinib in patients with hypertension (69.8%), diabetes (70.0%), COPD (73.7%), previous neoplasms (73.0%), AMI (86.3%) or stroke (97.2%) history (p&lt;0.001 for all conditions). Lastly, we observed a wider use of imatinib (61.1%) in patients diagnosed in years 2018-19, compared to those of the period 2012-17 (53.7%; p=0.01). In multivariable analysis, factors correlated with imatinib use were age &gt; 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

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