Mutations Based on Next-Generation Sequencing May be Complementally to Prognostic Risk in Myelodysplastic Syndromes

Objective: Established the value of somatic mutations based on next-generation sequencing (NGS) and explore factors associated with prognosis in myelodysplastic syndromes (MDS). Methods: From March 2012 to September 2019, 90 newly diagnosed MDS patients were treated and analysed by a sensitive NGS assay for mutations in 87 candidate genes and target regions. IPSSR higher risk include IPSS-R Intermediate, High, Very High subgroups (risk score >3.5), and IPSSR lower risk include IPSSR risk score ≤3.5. Results: A total of 90 MDS patients were recruited for this study (median age: 51.5 years; range: 16-70 years). Eighty-two (91.1%) patients harbored at least one mutation (median, 3 per patient; range, 0-11), and the most common mutations were found successively in the ASXL1 (28.9%), TP53 (21.1%), TET2 (18.9%), U2AF1 (17.8%), RUNX1 (15.6%), SETBP1 (13.3%), DNMT3A (13.3%), IDH1 (12.2%), NRAS (12.2%), KMT2D (11.1%), CBL (11.1%) and PTPN11 (11.1%) genes. The median follow-up was 32 months (range: 10-96 months). Thirty-seven (92.5%) had at least one point mutation in 40 patients with normal karyotype. ASXL1 and U2AF1 mutations had more frequently platelet levels of <50×109/L (P=0.047, P=0.023; respectively) and hemoglobin concentrations at <80 g/L (P=0.048, P=0.042; respectively). Compared with the lower risk MDS, more TP53 mutations (28% vs. 12.5%, P=0.048), RUNX1 mutations (22% vs. 7.5%, P=0.039), IDH1 mutations (18% vs. 5%, P=0.041), and IDH2 mutations (8% vs. 0, P=0.047) were found in the higher risk MDS. During the follow-up period, 37 (41.4%) patients translate to AML at a median follow-up of 24.5 months (range: 2-96 months). The median time of progress to AML from MDS diagnosis was 46 (2-96) months in MLD, 21 (2-37) months in EB1, and 18.5 (2-73) months in EB2. At 3-year follow-up, the probability of overall survival (OS) and cumulative incidence of AML transformation (CIAT) were 72.3% (95%CI 67.2%-77.8%) and 36.2% (95%CI 30.9%-41.5%), respectively. The univariate analysis results showed that ≥50 years old, IPSSR higher risk, ASXL1mutation, TP53 mutation, TET2 mutation, U2AF1 mutation, RUNX1 mutation, IDH1 mutation, IDH2 mutation, and ≥3 molecular mutations were poor factors for OS. The univariate analysis results associated with CIAT showed that IPSSR higher risk, TP53 mutation, RUNX1 mutation, IDH1 mutation, and IDH2 mutation were poor factors for CIAT.Multivariate adjust analysis showed that IPSSR higher risk, ASXL1 mutation, TP53 mutation, and RUNX1 mutation were independent prognosis factors associated with OS (HR=0.113, 95% CI: 0.093-0.199, P=0.003; HR=0.215, 95% CI: 0.103-0.623, P=0.025; HR=0.147, 95% CI: 0.084-0.506, P=0.012; HR=0.317, 95% CI: 0.122-0.661, P=0.013; respectively), and IPSSR higher risk, TP53 mutation, RUNX1 mutation, IDH1 mutation, and IDH2 mutation were independent prognosis factors associated with CIAT (HR=2.905, 95% CI: 1.155-6.312, P=0.023; HR=2.636, 95% CI: 1.024-5.023, P=0.004; HR=2.350, 95% CI: 1.043-5.789, P=0.024; HR=2.061, 95% CI: 1.036-4.078, P=0.003; HR=2.814, 95% CI: 1.073-5.359, P=0.005; respectively). Patients with mutations in one or more of the three independent survival prognostic genes (TP53, RUNX1, or ASXL1) defined as "mutation high risk" (n=48) and those without anyone of the three prognostic genes defined as "mutation low risk" (n=42). OS were significantly longer in the IPSSR both lower risk and higher risk patients with mutations low risk cohort than IPSSR lower risk patients with mutations high risk cohort (3-year OS, 95.7% vs. 47.1%, P=0.001; 79.9% vs. 47.1%, P=0.045; respectively). In the IPSSR lower risk with mutations high risk group, OS was significantly improved in the allo-HSCT cohort (3-year OS, 75.0% vs. 30.0%, P=0.042). In the IPSSR higher risk with mutations low risk group, no significant difference existed between the transplant and non-transplant arms for the probabilities of OS (3-year OS, 83.3% vs. 75.8%, P=0.972). Conclusions: Somatic mutations are common in MDS and are associated with prognosis. Mutation high risk may be complementally to IPSSR prognostic risk in MDS patients, and allo-HSCT can improved the survival in the IPSSR lower risk with mutations high risk group. Key words: myelodysplastic syndromes; somatic mutations; Prognostic dichotomization based on 3.5 of the revised international prognostic scoring system; overall survival; allogeneic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

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In CLL with Complex Aberrant Karyotype Distinct Entities Can Be Deciphered by Molecular Genetic and Cytogenetic Parameters

Blood ◽

10.1182/blood.v112.11.3138.3138 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3138-3138 ◽

Cited By ~ 1

Author(s):

Frank Dicker ◽

Susanne Schnittger ◽

Torsten Haferlach ◽

Wolfgang Kern ◽

Claudia Haferlach

Keyword(s):

High Risk ◽

Lower Risk ◽

Tp53 Mutation ◽

Risk Group ◽

Molecular Genetic ◽

Tp53 Gene ◽

High Risk Group ◽

Complex Karyotype ◽

Tp53 Mutations ◽

The Poor

Abstract Metaphase cytogenetics have recently defined important prognostic subgroups in CLL. In addition to the poor prognosis FISH markers del(17p) and del(11q), the presence of translocations and a complex aberrant karyotype, defined by chromosome banding analyses, have been associated with shorter overall survival in a retrospective analysis. Thus far, a complex aberrant karyotype is defined by a number of three or more chromosomal aberrations, therefore, we aimed at characterizing an unselected CLL cohort of 92 patients with complex aberrant karyotype in more detail with molecular genetic, cytogenetic, and immunophenotypic parameters. Median age at diagnosis was 62.5 years (range: 33.4–83.3 years), the male/female ratio was 2.8. An unmutated IgVH status (<= 2% mutations) was detected in 51 (60.7%) of 84 analyzed samples. A positive CD38 expression (>= 30% CD38 positive cells) was detected in 55 (64%) of 86 samples and TP53 gene mutations by denaturing high performance liquid chromatography of exons 4–9 of TP53 in 29 (36.7%) of 79 samples. As the main approach for prognostication in CLL uses FISH for del(17p), del(11q), +12, del(13q) sole and normal, we related our cohort with complex aberrant karyotype into these different FISH categories. The poor prognosis markers del(17p) and del(11q) were detected with frequencies of 39.1% (n=36) and 22.8% (n=21), respectively, accounting for almost two third of all samples (n=57, 61.9%). An overlap between del(17p) and del(11q) was detected in 5 of the 36 del(17p) cases. The intermediate risk FISH marker +12 and low risk FISH markers del(13q) as sole abnormality and “normal karyotype” appeared with an incidence of 8.7% (n=8), 21.7% (n=20) and 7.6% (n=7), respectively. The high incidence of del(11q) and del(17p) in complex karyotype seems likely, as genes implicated in sensing DNA damage and in regulating apoptosis, ATM and TP53, are candidate genes in these deleted regions. As TP53 mutations have been suggested as independent poor prognostic markers, we also added TP53 gene mutation analysis to the FISH stratification. Del(17p) was associated with TP53 mutation in 26 (86.7%) of 30 analyzed cases, whereas the three residual TP53 mutations were associated with del(11q) (n=1) and del(13q) as sole abnormality (n=2). Therefore, we chose to merge samples with high risk features within the complex karyotype into one group (n=59), i.e., samples with del(17p), del(11q) or TP53 mutation, and compared these samples to the remaining samples (n=33). Effectively, the high risk group compared to the other cohort was significantly associated with an unmutated IgVH (p=0.02, Fisher’s exact test) and with an increased, median amount of cytogenetic aberrations (4.9 vs. 3.7 aberrations, p=0.005, t-test). However, no significant difference between the two groups regarding a CD38 positive status was detected (p=0.257). The prognostic impact of high risk features (del(17p), del(11q) and TP53 mutation) within the group defined above vs the lower risk group was analyzed with log-rank statistics with respect to time from diagnosis of CLL to initial treatment (TTT). 34 patients from the high risk group and 18 patients from the low risk group were available for analysis. The high risk features within the complex karyotype were significantly associated with a higher risk of early treatment in log-rank statistics with a median TTT of 12.2 month in the higher risk group compared to 70.1 month in the lower risk group (p=0.005). In conclusion, based on poor risk cytogenetic and molecular genetic features within the group of CLL with complex aberrant karyotype, we characterized patients with a higher risk of early treatment initiation. This group includes samples with del(17p), del(11q) and TP53 mutations.

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Factors associated with effectiveness of trifluridine/tipiracil versus regorafenib in patients with pretreated metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.137 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 137-137 ◽

Cited By ~ 1

Author(s):

Peter Grell ◽

Simona Borilova ◽

Renata Schwanzerova ◽

Sabina Kukolikova ◽

Josef Dvorak ◽

...

Keyword(s):

High Risk ◽

Risk Group ◽

Progression Free Survival ◽

High Risk Group ◽

Median Line ◽

Free Survival ◽

Treatment Groups ◽

Factors Associated ◽

Patient Will

137 Background: Trifluridine/tipiracil (T) and regorafenib (R) are indicated for patients with refractory mCRC. Currently, no biomarkers are used to select which patient will benefit from which treatment. Methods: We retrospectively evaluated 212 patients who received T and/or R. Different factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. Results: T received 132, R 52, both drugs 28 patients. Median age was 64 (range 28-83), male 64%, PS 0 37%, median line of treatment 3, characteristic was similar between treatment groups. Median follow-up was 16.5 months. Median OS for T was 10.2, for R 6.9 months, P = 0.03. Factors significantly associated with OS were: ≥ 24 months from diagnosis of mCRC (0.49, P < 0.001), PS 0 (HR 1.54, P = 0.007), baseline WBC < 8 × 109/L (HR 0.47, P < 0.001), normal baseline CRP (HR 0.47, P < 0.001), ≥ 3 months from last therapy (fluoropyrimidine for T, anti-VEGF for R) (HR 0.66, P = 0.006). We developed a scoring system TASREG from these factors, 1 point for each factor, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS for all patients according to risk group was 4.6 for high risk, 7.9 intermediate, 11.8 months favorable risk (P < 0.001). Score was also significant for T and R group evaluated separately. Score was also significant for PFS. Factors associated with OS specific for T were neutropenia G≥2 (HR 0.34, P < 0.001); for R normal baseline LDH (HR 0,40. P < 0.001), no liver metastases (HR 0.45, P = 0.002), non-synchronous disease (HR 0,40, P < 0.001). Conclusions: We could find factors associated with better outcomes for both treatment groups and factors specific for T or R. TASREG is simple prognostic tool for patients with refractory mCRC.

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Critical Predictors for the Early Detection of Conversion From Unipolar Major Depressive Disorder to Bipolar Disorder: Nationwide Population-Based Retrospective Cohort Study (Preprint)

10.2196/preprints.14278 ◽

2019 ◽

Author(s):

Ya-Han Hu ◽

Kuanchin Chen ◽

I-Chiu Chang ◽

Cheng-Che Shen

Keyword(s):

Bipolar Disorder ◽

Major Depressive Disorder ◽

Cohort Study ◽

High Risk ◽

Retrospective Cohort ◽

Risk Group ◽

Population Based ◽

Major Depressive ◽

Risk Stratification Model

BACKGROUND Unipolar major depressive disorder (MDD) and bipolar disorder are two major mood disorders. The two disorders have different treatment strategies and prognoses. However, bipolar disorder may begin with depression and could be diagnosed as MDD in the initial stage, which may later contribute to treatment failure. Previous studies indicated that a high proportion of patients diagnosed with MDD will develop bipolar disorder over time. This kind of hidden bipolar disorder may contribute to the treatment resistance observed in patients with MDD. OBJECTIVE In this population-based study, our aim was to investigate the rate and risk factors of a diagnostic change from unipolar MDD to bipolar disorder during a 10-year follow-up. Furthermore, a risk stratification model was developed for MDD-to-bipolar disorder conversion. METHODS We conducted a retrospective cohort study involving patients who were newly diagnosed with MDD between January 1, 2000, and December 31, 2004, by using the Taiwan National Health Insurance Research Database. All patients with depression were observed until (1) diagnosis of bipolar disorder by a psychiatrist, (2) death, or (3) December 31, 2013. All patients with depression were divided into the following two groups, according to whether bipolar disorder was diagnosed during the follow-up period: converted group and nonconverted group. Six groups of variables within the first 6 months of enrollment, including personal characteristics, physical comorbidities, psychiatric comorbidities, health care usage behaviors, disorder severity, and psychotropic use, were extracted and were included in a classiﬁcation and regression tree (CART) analysis to generate a risk stratification model for MDD-to-bipolar disorder conversion. RESULTS Our study enrolled 2820 patients with MDD. During the follow-up period, 536 patients were diagnosed with bipolar disorder (conversion rate=19.0%). The CART method identified five variables (kinds of antipsychotics used within the first 6 months of enrollment, kinds of antidepressants used within the first 6 months of enrollment, total psychiatric outpatient visits, kinds of benzodiazepines used within one visit, and use of mood stabilizers) as significant predictors of the risk of bipolar disorder conversion. This risk CART was able to stratify patients into high-, medium-, and low-risk groups with regard to bipolar disorder conversion. In the high-risk group, 61.5%-100% of patients with depression eventually developed bipolar disorder. On the other hand, in the low-risk group, only 6.4%-14.3% of patients with depression developed bipolar disorder. CONCLUSIONS The CART method identified five variables as significant predictors of bipolar disorder conversion. In a simple two- to four-step process, these variables permit the identification of patients with low, intermediate, or high risk of bipolar disorder conversion. The developed model can be applied to routine clinical practice for the early diagnosis of bipolar disorder.

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Abstract 19763: Role of HAS-BLED Score on Major Bleeding in Atrial Fibrillation Undergoing Percutaneous Coronary Intervention With Drug-eluting Stents

Circulation ◽

10.1161/circ.132.suppl_3.19763 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Yoshitaka Ito ◽

Kazuhiro Naito ◽

Katsuhisa Waseda ◽

Hiroaki Takashima ◽

Akiyoshi Kurita ◽

...

Keyword(s):

Atrial Fibrillation ◽

High Risk ◽

Anticoagulant Therapy ◽

Major Bleeding ◽

Stent Implantation ◽

Risk Group ◽

High Risk Group ◽

Low Risk

Background: While anticoagulant therapy is standard management for atrial fibrillation (Af), dual antiplatelet therapy (DAPT) is needed after stent implantation for coronary artery disease. HAS-BLED score estimates risk of major bleeding for patients on anticoagulation to assess risk-benefit in Af care. However, it is little known about usefulness of HAS-BLED score in Af patient treated with coronary stents requiring DAPT or DAPT plus warfarin (triple therapy: TT). The aim of this study was to evaluate the role of HAS-BLED score on major bleeding in Af patients undergoing DAPT or TT. Methods: A total of 837 consecutive patients were received PCI in our hospital from Jan. 2007 to Dec. 2010, and 66 patients had Af or paroxysmal Af at the time of PCI. Clinical events including major bleeding (cerebral or gastrointestinal bleeding) were investigated up to 3 years. Patients were divided into 2 groups based on HAS-BLED score (High-risk group: HAS-BLED score≥4, n=19 and Low-risk group: HAS-BLED score<4, n=47). DAPT therapy was required for a minimum 12 months after stent implantation and warfarin was prescribed based on physicians’ discretion. Management/change of antiplatelet and anticoagulant therapy during follow-up periods were also up to physicians’ discretion. Results: Baseline characteristics were not different between High-risk and Low-risk group except for age. Overall incidence of major bleeding was observed in 8 cases (12.1%) at 3 years follow-up. Major bleeding event was significantly higher in High-risk group compared with Low-risk group (31.6% vs. 4.3%, p=0.002). However, management of DAPT and TT was not different between the 2 groups. Among component of HAS-BLED score, renal dysfunction and bleeding contributed with increased number of the score. Conclusion: High-risk group was more frequently observed major bleeding events compared with Low-risk group in patients with Af following DES implantation regardless of antiplatelet/anticoagulant therapy.

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P9 Novel use of CHA2DS2VASC score to select patients to undergo repeat atrial fibrillation screening

European Heart Journal ◽

10.1093/ehjci/ehz872.015 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

Author(s):

W Sun ◽

B P Y Yan

Keyword(s):

Atrial Fibrillation ◽

High Risk ◽

Clinical Outcomes ◽

Cross Validation ◽

Risk Group ◽

Curve Analysis ◽

Low Risk ◽

Decision Curve Analysis ◽

Risk Patients

Abstract Background We have previously demonstrated unselected screening for atrial fibrillation (AF) in patients ≥65 years old in an out-patient setting yielded 1-2% new AF each time screen-negative patients underwent repeated screening at 12 to 18 month interval. Selection criteria to identify high-risk patients for repeated AF screening may be more efficient than repeat screening on all patients. Aims This study aimed to validate CHA2DS2VASC score as a predictive model to select target population for repeat AF screening. Methods 17,745 consecutive patients underwent 24,363 index AF screening (26.9% patients underwent repeated screening) using a handheld single-lead ECG (AliveCor) from Dec 2014 to Dec 2017 (NCT02409654). Adverse clinical outcomes to be predicted included (i) new AF detection by repeated screening; (ii) new AF clinically diagnosed during follow-up and (ii) ischemic stroke/transient ischemic attack (TIA) during follow-up. Performance evaluation and validation of CHA2DS2VASC score as a prediction model was based on 15,732 subjects, 35,643 person-years of follow-up and 765 outcomes. Internal validation was conducted by method of k-fold cross-validation (k = n = 15,732, i.e., Leave-One-Out cross-validation). Performance measures included c-index for discriminatory ability and decision curve analysis for clinical utility. Risk groups were defined as ≤1, 2-3, or ≥4 for CHA2DS2VASC scores. Calibration was assessed by comparing proportions of actual observed events. Results CHA2DS2VASC scores achieved acceptable discrimination with c-index of 0.762 (95%CI: 0.746-0.777) for derivation and 0.703 for cross-validation. Decision curve analysis showed the use of CHA2DS2VASC to select patients for rescreening was superior to rescreening all or no patients in terms of net benefit across all reasonable threshold probability (Figure 1, left). Predicted and observed probabilities of adverse clinical outcomes progressively increased with increasing CHA2DS2VASC score (Figure 1, right): 0.7% outcome events in low-risk group (CHA2DS2VASC ≤1, predicted prob. ≤0.86%), 3.5% intermediate-risk group (CHA2DS2VASC 2-3, predicted prob. 2.62%-4.43%) and 11.3% in high-risk group (CHA2DS2VASC ≥4, predicted prob. ≥8.50%). The odds ratio for outcome events were 4.88 (95%CI: 3.43-6.96) for intermediate-versus-low risk group, and 17.37 (95%CI: 12.36-24.42) for high-versus-low risk group. Conclusion Repeat AF screening on high-risk population may be more efficient than rescreening all screen-negative individuals. CHA2DS2VASC scores may be used as a selection tool to identify high-risk patients to undergo repeat AF screening. Abstract P9 Figure 1

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Pre-Enucleation Chemotherapy in Advanced Intraocular Retinoblastoma. Central America Follow Up: AHOPCA II

Journal of Global Oncology ◽

10.1200/jgo.2016.004440 ◽

2016 ◽

Vol 2 (3_suppl) ◽

pp. 75s-75s

Author(s):

Sandra Luna-Fineman ◽

Soad L. Alabi ◽

Mauricio E. Castellanos ◽

Yessika Gamboa ◽

Ligia Fu ◽

...

Keyword(s):

High Risk ◽

Adjuvant Chemotherapy ◽

Central America ◽

Conflicts Of Interest ◽

Risk Group ◽

High Risk Group ◽

Globe Rupture ◽

Neo Adjuvant Chemotherapy ◽

Standard Risk

Abstract 57a Purpose: A significant percentage of patients in Central America present with buphthalmos, carrying a high risk of globe rupture and orbital contamination. In 2007, AHOPCA introduced chemotherapy before enucleation in children with buphthalmos. Methods: Patients with advanced intraocular disease were considered standard-risk and underwent enucleation. Those with diffuse invasion of choroid, postlaminar optic nerve, or anterior chamber invasion received 4-6 cycles of adjuvant chemotherapy (vincristine, carboplatin, etoposide). Patients with buphthalmos or perceived to be at risk for abandonment were considered high-risk, given 2-3 cycles of chemotherapy before enucleation to compete 6 cycles regardless of pathology. All cases were discussed via online meetings. Results: From 2007 to 2014, 396 patients were enrolled; 240 had IRSS stage I (174 unilateral). 143 had upfront enucleation, 95 had pre-enucleation chemotherapy, 1 is pending enucleation and 1 abandoned before enucleation. The standard-risk group 69 had risk pathology and 76 had no risk factors; 125 had no events, 5 abandoned 11 relapsed/progressed and 2 died of toxicity. Of 95 high-risk group, 8 abandoned, 20 relapse/progressive, 6 had toxic deaths and 61 are alive at last follow-up (median time of 4 years). Of high risk group, 55 were unilateral, 82% are alive. At 7 years OS (abandonment-censored) was 95±0.02 and 79±0.04 for standard-risk and high-risk (p=0.008). Conclusion: AHOPCA addressed advanced intraocular disease with an innovative approach. In eyes with buphthalmos and patients with risk of abandonment, neo-adjuvant chemotherapy is effective, when followed by post-enucleation chemotherapy. This approach avoids ocular rupture and intensified therapy, and reduces refusal/abandonment rate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

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Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis

TH Open ◽

10.1055/s-0040-1705137 ◽

2020 ◽

Vol 04 (01) ◽

pp. e59-e65 ◽

Cited By ~ 30

Author(s):

Alex C. Spyropoulos ◽

Concetta Lipardi ◽

Jianfeng Xu ◽

Colleen Peluso ◽

Theodore E. Spiro ◽

...

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Risk Score ◽

Lower Risk ◽

Risk Group ◽

High Risk Group ◽

Cutoff Score ◽

Risk Of Bleeding ◽

Increased Risk ◽

D Dimer

AbstractAn individualized approach to identify acutely ill medical patients at increased risk of venous thromboembolism (VTE) and a low risk of bleeding to optimize the benefit and risk of extended thromboprophylaxis (ET) is needed. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score has undergone extensive external validation in medically ill patients for in-hospital use and a modified model was used in the MARINER trial of ET also incorporating an elevated D-dimer. The MAGELLAN study demonstrated efficacy with rivaroxaban but had excess bleeding. This retrospective analysis investigated whether the modified IMPROVE VTE model with an elevated D-dimer could identify a high VTE risk subgroup of patients for ET from a subpopulation of the MAGELLAN study, which was previously identified as having a lower risk of bleeding. We incorporated the modified IMPROVE VTE score using a cutoff score of 4 or more or 2 and 3 with an elevated D-dimer (>2 times the upper limit of normal) to the MAGELLAN subpopulation. In total, 56% of the patients met the high-risk criteria. In the placebo group, the total VTE event rate at Day 35 was 7.94% in the high-risk group and 2.83% for patients in the lower-risk group. A reduction in VTE was observed with rivaroxaban in the high-risk group (relative risk [RR]: 0.68, 95% confidence interval [CI]: 0.51–0.91, p = 0.008) and in the lower-risk group (RR: 0.69, 95% CI: 0.40 -1.20, p = 0.187). The modified IMPROVE VTE score with an elevated D-dimer identified a nearly threefold higher VTE risk subpopulation of patients where a significant benefit exists for ET using rivaroxaban.

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Long-Term Outcome of Iron-Induced Cardiac Disease in Patients with Thalassemia Major Treated with Combined DFP/DFO or DFO Alone.

Blood ◽

10.1182/blood.v108.11.1764.1764 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1764-1764

Author(s):

Maria Eliana Lai ◽

Stefania Vacquer ◽

Alessia Pepe ◽

Aurelio Maggio ◽

Maria P. Carta ◽

...

Keyword(s):

High Risk ◽

Cardiac Disease ◽

Risk Group ◽

Thalassemia Major ◽

Left Ventricular ◽

Low Risk ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction

Abstract We conducted a 4-yr prospective trial to evaluate the long-term effects of combined deferiprone (DFP)/deferoxamine (DFO) on reversal of cardiac complications in thalassemia major compared to those of DFO alone. Twenty-eight patients (pts) with cardiac disease requiring medication were stratified according to their risk for cardiac death. Fourteen pts were high risk, serum ferritin (SF) > 2500 ug/L on two-thirds of occasions since the onset of cardiac disease. Of those with a SF < 2500 ug/L (low risk), six had progressive decrements of left ventricular ejection fraction (LVEF). Nine high-risk pts and six low-risk pts were placed on DFP/DFO (DFP, 75 mg/kg/d divided t.i.d.; DFO, 40 – 50 mg/kg over 8 – 12 h at night 5 – 7 d/wk. The others infused DFO alone. If SF fell below 500 ug/L, DFO infusions were reduced to 2 d/wk. Cardiac follow-up (including blood work and ECG) was done at 4-m intervals. M-mode and two-dimensional echocardiograms were done at 4- to 6-m intervals. Cardiac T2* was not available at the beginning of the study. All but eight patients (3 death, 1 refusal, 2 claustrophobic, 2 pacemaker) subsequently had at least one T2* assessment. Routine lab tests were done at 1- to 6-m intervals. Blood counts were done at 7- to 10-d intervals for those taking DFP. Mean follow-up was approximately 40 m. Compliance with DFO was significantly better among low-risk pts in both treatment groups (DFP/DFO, 82% vs 61%; DFO alone, 83% vs 52%) as was that with DFP (94% vs 76%). At baseline, no statistically significant differences were observed between the SF levels, LVEFs or left ventricular shortening fractions (LVSFs) of pts on DFP/DFO or DFO alone in either risk group except for the LVEFs of the low-risk group (DFP/DFO, 56.5% +/− 5.5%; DFO alone, 65.4% +/− 5.0%; p = 0.032). In the high-risk group, four cardiac events (3 deaths, 1 worsening of CHF) occurred in the group getting DFO alone vs none in the DFP/DFO-treated group. The latter pts showed a decrease in SF and an increase in both LVEF and LVSF at the end of study (EOS). The three pts who died (at 17 to 35 m) had increased SFs. These pts were not rescued by IV DFO (98 +/− 12 mg/kg/d). The two DFO-treated pts who survived had marginally improved T2*s (1.5 to 3.0 ms and 7.6 to 8.8 ms) over the year prior to EOS. Only one of the seven evaluable pts on DFP/DFO had a T2* < 10 ms, the others averaging 19.4 +/− 6.7 ms. Among the low-risk pts, those on DFP/DFO showed a reduction in SF and an improvement in both LVEF and LVSF. Those on DFO alone had increased SF but essentially no change in LVEFs or LVSFs. Five pts on DFP/DFO had T2* evaluations. In two pts, T2* rose from 9.0 to 37 ms (38 m) and from 9.3 to 11.8 ms (17 m). The remaining three had T2* values > 20 ms at EOS. Similar results were seen in low-risk pts on DFO alone. These finding clearly support the notion that DFP/DFO has a beneficial effect upon the heart, even in well established disease. Moreover, our finding of low T2* values associated with low SF levels indicates the importance of tailoring treatment to each individual.

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Graft-Versus-Leukemia (GVL) Effect After Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) as Treatment for Acute Myeloid Leukemia (AML): a Survey From the Acute Leukemia Working Party of the EBMT.

Blood ◽

10.1182/blood.v114.22.3313.3313 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3313-3313

Author(s):

Frederic Baron ◽

Myriam Labopin ◽

Mohamad Mohty ◽

Nadezda Basara ◽

Dietger Niederwieser ◽

...

Keyword(s):

High Risk ◽

Lower Risk ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Working Party ◽

Cox Models ◽

Landmark Analysis ◽

Factors Associated ◽

The Impact ◽

Risk Of Relapse

Abstract Abstract 3313 Poster Board III-201 RIC allo-SCT has been increasingly used as treatment for AML patients (pts) ineligible for myeloablative allo-SCT. Previous studies have observed a lower risk of relapse in pts who experienced chronic GVHD after RIC allo-SCT versus in those who did not. The objective of the current study was to further investigate the association between chronic GVHD and relapse in a large cohort of pts given RIC allo-SCT as treatment for AML. Data from 1188 AML pts in first or second CR transplanted between 2000 and 2008 following a RIC regimen at EBMT affiliated centers were analyzed. Patients were given PBSC from HLA-identical sibling (MRD, n=879), or from HLA-matched unrelated donors (MUD, n=309). RIC was defined as Busulfan conditioning regimens containing ≤ 8mg/kg total dose, or TBI <6 Gy. Median pt age at transplantation was 55 (range, 18-76) yrs in pts given grafts from MRD, versus 57 (range, 19-72) yrs in those given grafts from MUD. 54 pts had good risk (4.5%), 564 standard-risk (47.5%), and 116 high-risk (9.8%) cytogenetics, while cytogenetic was unknown in 454 pts (38.2%). The impact of chronic GVHD on relapse risk, non-relapse mortality (NRM) and leukemia-free survival (LFS) was assessed by time-dependent multivariate Cox models and in a landmark analysis. Three-yr incidences of relapse, NRM and LFS were 35 ± 2%, 14 ± 2%, and 50 ± 2%, respectively, while 2-yr incidence of chronic GVHD was 49 ± 2%. In a landmark analysis at 18 months after allo-SCT, 5-year relapse rates were 10 ± 2% versus 19 ± 3% for patients with or without chronic GVHD (P=0.04), respectively. In multivariate Cox models, CR2 versus CR1 (P=.003), pt age > 55 yrs (P=.008), alemtuzumab use in the RIC (P=.048), TBI-based RIC (P=.006), high-risk cytogenetics (P=.001), and absence of chronic GVHD (P=.015) were each associated with higher risk of relapse. Factors associated with high NRM were MUD versus MRD (P=.003), grade II-IV acute GVHD (P<.001), and chronic GVHD (P=.002). Factors associated with lower LFS were CR2 versus CR1 (P=.003), pt age > 55 yrs (P=.007), alemtuzumab use in the RIC (P=.012), and high-risk cytogenetics (P=.003). In conclusion, in this cohort of AML patients transplanted in remission, chronic GVHD was associated with a lower risk of relapse while profound in-vivo T cell depletion with alemtuzumab was associated with higher relapse rate suggesting that GVL effects play a role in preventing AML relapse in patients given RIC allo-SCT. Therefore, closed surveillance of patients in this setting not presenting chronic GVHD such as decreasing of immunosuppression should be further investigated. Disclosures No relevant conflicts of interest to declare.

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Survival, Prognostic Factors, and Rates of Leukemic Transformation in a Multicenter Study of 303 Untreated Patients with MDS and Del(5q).

Blood ◽

10.1182/blood.v114.22.945.945 ◽

2009 ◽

Vol 114 (22) ◽

pp. 945-945 ◽

Cited By ~ 3

Author(s):

Ulrich Germing ◽

Michael Lauseker ◽

Barbara Hildebrandt ◽

Argiris Symeonidis ◽

Jaroslav Cermak ◽

...

Keyword(s):

High Risk ◽

Median Survival ◽

Research Funding ◽

Risk Group ◽

Competing Risk ◽

Refractory Anemia ◽

Red Cell ◽

Kaplan Meier ◽

Red Cell Transfusion

Abstract Abstract 945 In 2001, the WHO defined the category MDS with del(5q) due to unique cytogenetic, morphologic, hematologic, clinical, prognostic and therapeutic features. The survival of these patients, as well as patients with refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ring sideroblasts is favorable in comparison to other MDS types. Data on disease progression to a more advanced MDS category or to acute leukemia (AML) are sparse and have not been examined in detail. In order to address this issue we collated data of all patients with MDS and del(5q) characterized by low or intermediate-1 IPSS risk score that had been included into various collaborating MDS registries. Patients were followed from diagnosis and data on cell counts, transfusion dependency, and MDS progression were documented. No patients received treatment other than best supportive care. The status of 62 patients was censored at the time of the initiation of Lenalidomide therapy. AML progression was defined as >20% marrow blasts. Estimates of survival probability were calculated with the Kaplan-Meier method. The cumulative incidence of progression to AML was calculated both with the Kaplan-Meier method and with the competing risk method where “death without progression to AML” is considered as competing event, not as censoring. For both events the cumulative incidences are estimated simultaneously. This method has the advantage that it takes into account that there is a difference between end of follow-up and death. Depending on the number of competing events, the curves are lower than those calculated with the Kaplan-Meier estimator. We identified 303 patients, median age at diagnosis 65 years (28-91), 71% were females. Median follow up time was 3 years. Median survival was 71.5 months. Patients with del(5q) as a sole chromosomal aberration had a median survival of 73 months as compared to 19.3 months in patients with more than 1 additional aberrations. Patients who had red cell transfusion need at diagnosis had a median survival of 39 months vs. 97 months in transfusion independent patients (p=0.00005). Transfusion need at diagnosis was the most important parameter for survival. Patients in the WPSS very low risk group had a median survival of 107 months, as compared to 73 and 56 months in the low and intermediate risk group and 37 months in the high risk group. 44 of the 303 patients (15%) progressed to AML (>20% marrow blasts). The cumulative AML progression rate calculated with the Kaplan-Meier method was 7% at 2 years and 18.2% at 5 years. The cumulative risk of AML progression calculated with the competing risk method was 6.6% at 2 years and 15.1% at 5 years. Factors associated with the risk of AML transformation were intermediate-I IPSS risk and high risk WPSS score, marrow blast count >5%, and red-cell transfusion need at diagnosis. Survival and progression rates did not differ among the participating centers. In conclusion, survival of patients with MDS and del(5q) is high and is comparable to patients with RCUD and RARS, but is associated with a risk of AML-transformation similar to RCMD without del(5q). Further cytogenetic and molecular studies are warranted in order to identify patients at greater risk of progression. Disclosures: Germing: Novartis, Celgene: Honoraria, Research Funding. Lauseker:Celgene: Research Funding. Hildebrandt:Celgene: Research Funding. Symeonidis:Celgene: Research Funding. Cermak:Celgene: Research Funding. Pfeilstöcker:Celgene: Research Funding. Nösslinger:Celgene: Research Funding. Sekeres:Celgene: Research Funding. Maciejewski:Celgene: Research Funding. Haase:Celgene: Research Funding. Schanz:Celgene: Research Funding. Seymour:Celgene: Research Funding. Weide:Celgene: Research Funding. Lübbert:Celgene: Research Funding. Platzbecker:Celgene: Research Funding. Valent:Celgene: Research Funding. Götze:Celgene: Research Funding. Stauder:Celgene: Research Funding. Blum:Celgene: Research Funding. Kreuzer:Celgene: Research Funding. Schlenk:Celgene: Research Funding. Aul:Celgene: Research Funding. Kündgen:Celgene: Research Funding. Hasford:Celgene: Research Funding. Giagounidis:Celgene: Research Funding.

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