scholarly journals Young CML Patients Treated Frontline with Imatinib or Second Generation TKIs: Clinical Characteristics and Outcome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3078-3078
Author(s):  
Mario Annunziata ◽  
Roberto Latagliata ◽  
Alessandra Iurlo ◽  
Massimo Breccia ◽  
Isabella Capodanno ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Second Generation ◽  
Low Risk ◽  
Blast Transformation ◽  
Molecular Response ◽  
Costal Margin ◽  
Secondary Resistance ◽  
Significant Difference

Abstract Median age of CML patients at diagnosis is reported to be around 66 years. Few data about the characteristics and outcome of patients younger than 40 years are available, and the clinical trials of dasatinib and nilotinib as first line treatment were not stratified by age. We retrospectively analyzed 251 young patients with CML in chronic phase from 12 different Italian Institutions, diagnosed between October 2001 and October 2016. Up to 2011 all patients were treated frontline with imatinib while from January 2011 onwards with imatinib or a second generation TKI (nilotinib or dasatinib), based on clinical judgment. At diagnosis median age was 32,6 years [interquartile range (IQR) 27,6- 36,9]; 143 (57%) were male. Splenomegaly was found in 129 out of 233 evaluable patients, in 29,2% of the cases spleen was palpable >5 cm below the costal margin. The risk score was low in most of the cases (low risk Sokal 71%, low risk Eutos 91,3% vs high risk Sokal 9,8%, high risk Eutos 8,7%). Clinical features of the patients in treatment with different inhibitors are summarized in table 1. There were two main statistically significant differences in the group of patients treated with dasatinib: a higher proportion of high risk (30,8%) according to Eutos score and a lower median Hb level at diagnosis (8,5 gr/dL). These features probably reflected the trend of using dasatinib in patients with a more aggressive disease, as this drug was shown to be more potent since the first in vitro studies. Out of 251 patients 179 were treated with imatinib, 57 (22%) with nilotinib, 15 (5,9%) with dasatinib. Median follow up of the whole cohort was 76,5 months (IQR 41- 116); as expected, the follow up was longer in the imatinib group compared to the nilotinib and dasatinib groups (100 months vs 39,6 and 23,0 respectively). In the whole cohort, the cumulative incidence of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMolR) were 90,4% and 75,7% respectively; a deep molecular response (negative nested PCR, MR4.0, MR4,5) was achieved by 52.2% of patients, without differences among the 3 groups. Primary resistance occurred in 12,4% of patients, without differences among the 3 groups: secondary resistance occurred in 15.9% of patients, with a higher rate in the imatinib group (19,5%) as compared with nilotinib (7,0%) and dasatinib (6,7%) (p=0.047). Treatment discontinuation due to toxicity was observed in 6.0% of patients, without differences among the 3 groups. Blast transformation occurred in 7 out of 251 patients (2,8%), all in the imatinib group, after a median time from the diagnosis of 31 months (range 4-110). The 4-year cumulative Event-Free Survival (EFS) and Overall Survival (OS) were 72,4% (95%CI 66,7 - 78,5) and 98,1% (95%CI 96,4 - 99,8) respectively, without differences among the 3 groups. All deaths were related to blast transformation in imatinib group. In conclusion, as expected in a younger population, response to treatment and OS were excellent. However, the 4-year EFS was lower than expected, in spite of the presence of patients with predominantly low risk score. Furthermore, while the higher rate of secondary resistance in the imatinib group probably reflects the longer follow-up, it is worth of note that no statistically significant difference was observed between imatinib and 2nd generation TKI groups in terms of OS and EFS. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2113-2113 ◽  
Author(s):  
Susan Branford ◽  
Rebecca Lawrence ◽  
Andrew Grigg ◽  
John Francis Seymour ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Low Risk ◽  
Initial Slope ◽  
Molecular Response ◽  
Average Dose ◽  
Major Molecular Response ◽  
First Line ◽  
Significant Difference

Abstract A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3–96m). The event rate was compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis indicated BCR-ABL was <0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed >2 fold rise from nadir to a level >0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3–53m). Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of <600mg in the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a median of 9m (r 3–42m). An event occurred in 8 pts with MMR at a median of 36m (r12–57m) after commencing imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4–220). The probability of an event if MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) >6 to 12m was 12% (n=40) and c) 12 to 18m was 19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r 3–87m), 38m (r 6–87m), 40m (r 9–78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by 6m was significantly lower than in pts with MMR achieved by >6 to 18m, P=0.04. CMR occurred in 55 pts who were followed for a median of 24m (r 3–55m) after its attainment. Only 1 event occurred in these 55 pts, which was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for 45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference in the probability of CMR by 60m of imatinib dependent on the time to MMR, P<0.0001 (Figure). All pts failed to achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those with MMR at >6 to 12m and >12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and deeper responses. It remains possible however, that early molecular response reflects a more biologically favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved. Figure Figure

Should adult medulloblastoma patients at low risk receive adjuvant chemotherapy? Long-term results of a prospective study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2018-2018
Author(s):  
E. Franceschi ◽  
A. Tosoni ◽  
M. Ermani ◽  
V. Blatt ◽  
P. Amistà ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Survival Rates ◽  
Low Risk ◽  
Long Term Results ◽  
High Risk Patients ◽  
Significant Difference ◽  
Risk Patients

2018 Background: Due to the rarity of medulloblastoma (MB) in adults, the few studies available on this condition are retrospective, and the follow-up tends to be short. Furthermore, the different therapeutic strategies used in these patients makes it difficult to assess survival rates and prognostic factors. Methods: Between January 1989 and February 2001, a prospective phase II trial was performed to evaluate the efficacy of treatment for adults with medulloblastoma. Patients were completely staged with a neuroradiological examination of the brain and neuraxis and by CSF cytology, according to Chang’s staging system. Low risk patients received radiotherapy alone, while high risk patients were given 2 cycles of upfront chemotherapy followed by radiotherapy and adjuvant chemotherapy. The results of the preliminary analysis of this study at a median follow-up of 3.7 years are reported elsewhere. The present papers reports on the long- term results of the same trial. Results: After a median follow up of 7.6 years, among a total of 36 enrolled adults with medulloblastoma, overall progression free survival (PFS) and overall survival (OS) at 5 years were 72% (range 59% to 84%) and 75% (62% to 91%), respectively. No difference was found between low and high risk patients in terms of PFS and OS at 5 years: in low-risk patients the 5-year PFS was 80% (range, 59–100%) and the 5-year OS, 80% (range, 58 - 100%); in high-risk patients the 5-year PFS was 69% (range, 54 -89%) and the 5-year OS, 73% (range, 58 - 92%). Conclusions: A long-term follow-up is essential to evaluate the real impact of treatments in adult patients with MB. Since there is no significant difference between low-risk and high-risk patients for PFS and OS, the use of chemotherapy is also questionable in low-risk patients. No significant financial relationships to disclose.

scholarly journals The role of asymmetric dimethylarginine (ADMA) in the follow-up of patients with precapillary pulmonary hypertension (PH)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
I Shafran ◽  
V Probst ◽  
J Campean ◽  
R Sadushi-Kolici ◽  
C Gerges ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
High Risk ◽  
Plasma Level ◽  
Plasma Levels ◽  
Asymmetric Dimethylarginine ◽  
Low Risk ◽  
Hemodynamic Assessment ◽  
Significant Difference

Abstract Introduction Asymmetric dimethylarginine (ADMA) interferes with L-arginine in the production of nitric oxide, a key mediator of endothelial cell function. ADMA is elevated in pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and is associated with unfavorable outcomes. Aim To assess the role of ADMA to monitor disease progression of PH patients treated with PAH-specific therapy. Methods ADMA was measured by competitive ELISA at baseline (BL) and follow-up (FU). Risk assessment including a clinical assessment, echocardiography, 6-minute walking test, NT-pro-BNP and hemodynamic assessment by right heart catheterization was performed accordingly. Risk was calculated according to the ESC/ERS 2015 guidelines by the SPHAR method. Results ADMA samples were collected from 113 patients treated at our institution between 2012 and 2019. 89 (79%) patients had PAH, 15 (13%) were diagnosed with CTEPH and 9 (8%) with group 3 – PH associated with lung disease. 69% were females. 15 (13.3%) patients had a low risk at baseline, 96 (85%) intermediate risk and 2 (1.8%) were high risk patients. 75% received oral medications, 31% received subcutaneous treprostinil. Median baseline ADMA was 0.738umol/l. At BL no significant difference of ADMA plasma levels was found among the different PH types (p=0.063), or between different risk categories (p=0.531). Change in ADMA plasma levels correlated with change in risk (p=0.002, rs 0.291) and with change in mixed venous saturation (p=0.034, rs −0.205). Change in ADMA plasma levels also correlated with risk at FU (p=0.011, rs 0.240). Patients categorized as low risk at FU had a median ADMA plasma level decrease of 22%, compared with −3 to 0% ADMA plasma level change in patients with moderate to high risk at FU (p=0.04). Patients who improved their risk category had a median decrease of ADMA plasma level of 23% vs. 2.3% in patients who did not improve (p=0.011). Decrease of ADMA plasma levels was a weak but significant discriminator for improvement of risk in ROC analysis (p=0.032, AUC 0.374). Conclusion ADMA plasma levels paralleled the hemodynamic and clinical benefit of PAH-specific treatments in patients with precapillary PH. ADMA could be used as a biomarker for monitoring treatment effects in precapillary PH. Funding Acknowledgement Type of funding source: None

scholarly journals Low Von Willebrand Factor: Cut-Off Value for Diagnosis and Risk Score to Predict Bleeding Incidence

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Ferdows Atiq ◽  
Esmee Wuijster ◽  
Moniek P.M. de Maat ◽  
Marieke J.H.A. Kruip ◽  
Marjon H. Cnossen ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Research Funding ◽  
Low Risk ◽  
Intermediate Risk ◽  
Spontaneous Bleeding ◽  
High Risk Patients ◽  
Risk Patients ◽  
Surgical Bleeding

Introduction Although large studies have recently provided valuable insights on the diagnosis, bleeding phenotype, and treatment outcomes of VWD patients, these aspects remain poorly understood in individuals with low VWF. Firstly, there is no clear evidence which cut-off value should be used to diagnose low VWF. Although 0.50 IU/mL is the most recommended cut-off value, some centers use the lower limit of normal (0.60 IU/mL). Secondly, the incidence of post-surgical bleeding, postpartum hemorrhage (PPH) and traumatic- or spontaneous bleeding after diagnosis of low VWF are still unknown. Lastly, it is hard to predict which individuals with low VWF have an increased bleeding risk. Therefore, we investigated the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL, and the incidence of post-surgical bleeding, PPH and traumatic- and spontaneous bleeding after their initial diagnosis of "low VWF". Methods We performed a retrospective cohort study from January 2007 to November 2019 at the Erasmus MC, University Medical Center Rotterdam. All patients evaluated for the presence of a bleeding disorder with VWF antigen (VWF:Ag) and/or VWF activity (VWF:Act) and/or VWF collagen binding (VWF:CB) levels between 0.31-0.60 IU/mL, were included. Patients with VWF:Ag and/or VWF:Act and/or VWF:CB ≤0.30 IU/mL, acquired VWD and those with a concomitant bleeding disorder were excluded. For each individual we collected data from electronic patient files on baseline characteristics, reason for referral, family history of bleeding disorders, ISTH-BAT and laboratory measurements at diagnosis. Retrospective follow-up started from initial date of low VWF diagnosis through November 2019, during which we collected data on surgical procedures, pregnancies, and incidence of spontaneous- and traumatic bleeding. Results We included 439 patients; 269 patients with historically lowest VWF levels 0.31-0.50 IU/mL and 170 patients 0.51-0.60 IU/mL. Mean age at diagnosis was 28.8 ±17.7 years. Most patients were female (74.3%) and had blood group O (76.4%, Table 1). The bleeding score (BS) was similar in patients with historically lowest VWF levels of 0.31-0.50 IU/mL (3.7 ±3.0) and 0.51-0.60 IU/mL (4.0 ±2.9, p=0.209, Table 1). During the mean follow-up period of 6.3 ±3.7 years, 259 surgical procedures were performed in 146 patients, 81 deliveries in 56 women, and 109 spontaneous- or traumatic bleedings in 71 patients. The incidence of post-surgical bleeding was 7 (2.7%) during follow-up, whereas 8 deliveries (10%) were complicated by PPH. Overall, 65 out of 439 patients (14.8%) had a bleeding episode requiring treatment during follow-up, resulting in an incidence of bleeding requiring treatment of 0.5 ±1.9 per patient per decade. No difference was found in the incidence of bleeding requiring treatment between patients with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL (Figure 2A, p=0.154). We found that referral for a personal bleeding diathesis, a younger age at diagnosis and an abnormal BS at diagnosis were strong and independent risk factors for bleeding requiring treatment during follow-up, respectively HR=2.32 (95%CI: 1.16-4.63), HR=1.18 (95%CI: 1.01-1.38) and HR=1.77 (95%CI: 1.04-3.01). These risk factors were combined to develop a risk score to identify low VWF patients with an increased risk for bleeding requiring treatment (Figure 2B). The risk score performed excellent to differentiate in bleeding requiring treatment between low risk, intermediate risk and high risk patients (p<0.001, Figure 2C). The number of patients with bleeding requiring treatment was 8/126 (6.3%) in patients with low risk, 18/143 (12.6%) in intermediate risk and 39/170 (22.9%) in high risk patients (p<0.001). Likewise, the incidence of bleeding requiring treatment per patient per decade was 0.22 ±1.08 in low risk, 0.28 ±1.25 in intermediate risk and 0.87 ±2.61 in high risk patients (p=0.004, Figure 2D). Conclusion To conclude, there is no difference in the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL. Therefore, the cut-off value to diagnose low VWF should be set at 0.60 IU/mL. Furthermore, the risk score developed in the current study may assist to identify low VWF patients with low, intermediate and high risk for future bleeding. Disclosures Atiq: SOBI: Other: travel grant; CSL Behring: Research Funding. Kruip:Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Daiichi Sankyo: Research Funding; SOBI: Research Funding; Bayer: Speakers Bureau. Cnossen:Takeda: Research Funding; Shire: Research Funding; Baxter: Research Funding; Bayer: Research Funding; Sobi: Research Funding; CSL behring: Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Leebeek:CSL Behring: Research Funding; Shire/Takeda: Research Funding; Uniqure: Consultancy; Shire/Takeda: Consultancy; Novo Nordisk: Consultancy; SOBI: Other: Travel grant; Roche: Other: DSMB member for a study.

scholarly journals Long Term Follow up from the NCRI AML17 Trial of Attenuated Arsenic Trioxide and ATRA Therapy for Newly Diagnosed and Relapsed Acute Promyelocytic Leukaemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 897-897
Author(s):  
Nigel H Russell ◽  
Alan K. Burnett ◽  
Robert K Hills ◽  
Sophie Betteridge ◽  
Michael Dennis ◽  
...  
Keyword(s):  
High Risk ◽  
Low Risk ◽  
Newly Diagnosed ◽  
Molecular Monitoring ◽  
Term Survival ◽  
Cns Disease ◽  
Significant Difference ◽  
Risk Of Relapse

Abstract Background: Two randomized studies have reported comparison of the "chemo-free" combination of ATO+ATRA with Anthracycline/ ATRA (AIDA) in APL. The GIMEMA-AMLSG-SAL trial, using a daily schedule improved both survival and relapse risk in patients with newly diagnosed, low or intermediate-risk APL. (Lo Coco et al., NEJM 2013; 369: 111-21). The NCRI AML17 trial using an attenuated dosing schedule in all risk groups resulted in a very low risk of relapse, significantly better EFS but no significant survival advantage Aims: The NCRI AML17 Trial compared AIDA vs the chemo-free combination of ATO (in an attenuated schedule) + ATRA. Here we present long term survival results for randomized patients and for 24 patients who received the same chemo-free schedule of ATO + ATRA after relapsing from the AIDA arm of the trial. Methods: From May 2009 to October 2013, 235 patients aged >16 who entered the AML17 trial with molecularly confirmed APL were randomized to either ATRA+ATO (8 week induction 0.3mg/kg d1-5 w1, 0.25mg/kgx2/w w2-8, followed by 4 consolidation courses of 0.3mg/kgx2 w1, 0.25mg/kgx2/ w2-4 (63 ATO doses) OR AIDA schedule: Idarubicin (Ida)12mg/m2 d2,4,6,8 + ATRA to d60) (induction) then Ida 5mg/m2 d1-4 + ATRA d1-15 (Course 2); Mitox. 10mg/m2 d1-4 + ATRA d1-15 (course 3); Ida 12mg/m2 d1 + ATRA d1-15 (Course 4). ATRA was 45mg/m2/d. Maintenance was not given. High risk patients could receive Gemtuzumab Ozogamicin (d1,6mg/m2). Another 70 patients were treated in AML17 with AIDA after closure of the randomization. 25/189 patients relapsed post AIDA and 24 were treated with a median of 4 cycles (range 1-5) of ATRA + ATO, 11/24 were later transplanted. Follow-up is complete to 1 January 2016. Results: The median age was 47y (16-77); 57 had WBC>10x109/L (27 AIDA, 30 ATRA+ATO) and 49 (24 AIDA, 25 ATRA+ATO) were >60y. The early results of the randomization for newly diagnosed patients have been reported (Burnett et al. Lancet Oncol. 2015, 16 (13):1295). 91% entered morphological CR with no significant difference in CR rate between the arms (Chemo-free 94%, Chemo 89%; OR 0.54 (0.21-1.34), p= 0.18). The OS at 4 years was 93% (Chemo-free) vs 89% (Chemo), HR 0.60 (0.26-1.42) p= 0.2, but EFS was significantly superior with ATRA+ATO (91% vs 70%, HR 0.35 (0.18-0.68) p=0.002). With a longer median follow-up of 53.4 months 5-year survival is now 93% (chemo-free) v 87% (chemo) (HR 0.61 (0.27-1.35) p=0.2). A significant reduction in relapse (2% vs 16% at 5 years, HR 0.19 (0.09-0.45) p=0.0005) translates to continuing significant RFS benefit for the chemo-free approach (96% vs 82%; HR 0.30 (0.13-0.67) p=0.004). This is seen both in low risk (95% vs 86% HR 0.45 (0.17-1.20) p=0.11) and high risk disease (100% vs 69% HR 0.10 (0.02-0.46) p=0.003), p=0.11 for heterogeneity. 25 patients relapsed following AIDA therapy, of whom 1 died in frank relapse before treatment could be initiated and 24 (5 with concomitant CNS involvement) were treated with the attenuated ATO + ATRA schedule. Of these 16 were treated at molecular relapse, reflecting the value of centralised MRD monitoring as part of the trial protocol. All 24 patients achieved molecular CR post ATO +ATRA. Eleven patients were transplanted (8 autograft, 3 allograft) including 4 of the 5 patients with CNS disease. 3 patients have had a second molecular relapse after ATO + ATRA salvage (1 transplanted and 2 not transplanted). The 3-year overall survival post-relapse is 96% with the only other death occurring post-transplant after 37 months. Summary/Conclusion: The combination of ATO + ATRA continues to show a very low risk of relapse irrespective of risk group resulting in significantly better RFS compared to AIDA and excellent survival but no survival benefit has emerged primarily because of effective salvage interventions for AIDA-treated patients with most patients treated at molecular relapse. Molecular monitoring for t(15;17) is therefore essential to optimize therapy with AIDA. For patients treated with frontline ATO+ATRA molecular monitoring is of questionable value once achievement of molecular CR has been documented, but molecular surveillance remains important in those with relapsed disease. The attenuated AML17 ATO dosing approach is effective both upfront and in patients relapsing post AIDA and these results question the role of transplantation as consolidation in patients achieving molecular CR2 with ATO + ATRA who do not have CNS disease at relapse. Disclosures Burnett: CTI Life Sciences, London: Employment. Hills:TEVA: Honoraria. Grimwade:TEVA: Research Funding.

scholarly journals Clinical Risk Score for the Prediction of Incident Atrial Fibrillation: Derivation in 7 220 654 Taiwan Patients With 438 930 Incident Atrial Fibrillations During a 16‐Year Follow‐Up

2021 ◽  
Author(s):  
Tze‐Fan Chao ◽  
Chern‐En Chiang ◽  
Tzeng‐Ji Chen ◽  
Jo‐Nan Liao ◽  
Ta‐Chuan Tuan ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
High Risk ◽  
Risk Score ◽  
Risk Group ◽  
Low Risk ◽  
Intermediate Risk ◽  
Clinical Risk Score ◽  
Clinical Risk ◽  
Asian Patients

Background Although several risk schemes have been proposed to predict new‐onset atrial fibrillation (AF), clinical prediction models specific for Asian patients were limited. In the present study, we aimed to develop a clinical risk score (Taiwan AF score) for AF prediction using the whole Taiwan population database with a long‐term follow‐up. Methods and Results Among 7 220 654 individuals aged ≥40 years without a past history of cardiac arrhythmia identified from the Taiwan Health Insurance Research Database, 438 930 incident AFs occurred after a 16‐year follow‐up. Clinical risk factors of AF were identified using Cox regression analysis and then combined into a clinical risk score (Taiwan AF score). The Taiwan AF score included age, male sex, and important comorbidities (hypertension, heart failure, coronary artery disease, end‐stage renal disease, and alcoholism) and ranged from −2 to 15. The area under the receiver operating characteristic curve of the Taiwan AF scores in the predictions of AF are 0.857 for the 1‐year follow‐up, 0.825 for the 5‐year follow‐up, 0.797 for the 10‐year follow‐up, and 0.756 for the 16‐year follow‐up. The annual risks of incident AF were 0.21%/year, 1.31%/year, and 3.37%/year for the low‐risk (score −2 to 3), intermediate‐risk (score 4 to 9), and high‐risk (score ≥10) groups, respectively. Compared with low‐risk patients, the hazard ratios of incident AF were 5.78 (95% CI, 3.76–7.75) for the intermediate‐risk group and 8.94 (95% CI, 6.47–10.80) for the high‐risk group. Conclusions We developed a clinical AF prediction model, the Taiwan AF score, among a large‐scale Asian cohort. The new score could help physicians to identify Asian patients at high risk of AF in whom more aggressive and frequent detections and screenings may be considered.

Imatinib Mesylate (IM) Versus IM + Low Dose of Pegylated Interferon Alfa 2a (Peg-IFN 2a) In Newly-Diagnosed Chronic-Phase (CP) Chronic Myeloid Leukemia (CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4497-4497
Author(s):  
Luis Antonio Meillon ◽  
Salvador Campos-Cabrera ◽  
Nancy Delgado-Lopez ◽  
Angel A. Fernandez-Martinez ◽  
Jesus Medrano-Contreras ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Low Risk ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Primary Resistance ◽  
Initial Report

Abstract Abstract 4497 Background: IM 400mg daily is the current standard of treatment of CP CML. Almost 70% of patients achieve complete cytogenetic response (CCR) at 12 months (mo) (IRIS Trial) and the rate of Major Molecular Response (MMR) is 40% with IM 400mg daily (TOPS Trial). On the other hand, low doses of Peg-IFN 2a has the same efficacy and lower toxicity profile and cost as high dose, mainly when it is combined with other drugs (MRC and Hovon groups, Blood 2004; 103:4408). Combination of IM + Peg-IFN 2a or Cytarabine could increase the rate of response in CML. Aims: To evaluate the rates of CCR and MMR at 12 mo in Mexican patients with newly-diagnosed CP-CML treated with IM versus IM + Peg-IFN 2a. Methods: Between 2006 and 2008, 10 patients were randomized 1:1 and stratified by Sokal and Hasford risk groups. Cytogenetic and Molecular assesments were available for all patients. In the arm A of the study IM 400 mg daily was delivered. In the Arm B IM + Peg-IFN 2a was delivered at 400 mg daily + 90 μ g per week respectively. Peg-IFN 2a was started in the 7th week of treatment (Hochhaus A, et al ASCO 2003. Abstract #2287). Results: For this initial report, 10 patients were analyzed, median age was 35 years (25-55), 50% males; Sokal score was: low risk 70%, and high risk 30%. Hasford score was: low risk 40%, intermediate 30% and high risk 30%. All patients are alive with a median follow-up of 41 mo (30-48). CCR at 12 mo was obtained in 80% in both arms of treatment. MMR was obtained in 10% in patients with IM alone and 30% in patients with IM + Peg-IFN 2a. Overall the rate of primary resistance was 10% and the rate of suboptimal response was 10%. IM 400 mg was well tolerated. Peg-IFN 2a was tolerated in most patients, but needed discontinuation because increased cytopenias or other non hematologic toxicities. The median time of duration of treatment with Peg-IFN 2a was 6 mo (3-12). Conclusions: IM 400 mg and IM 400 mg + Peg-IFN 2a obtained similar rates of CCR. IM 400 mg + Peg-IFN 2a obtained a higher rate of MMR. The combination of IM 400 mg + Peg-IFN 2a is feasible. There is a slight increase in toxicity with this combination. Further follow-up is warranted for these patients. Disclosures: No relevant conflicts of interest to declare.

Analysis of the GeneXpert System on the International Multicentre ICORG 08–02 Phase II Study of Nilotinib 300mg BID as Frontline Treatment in Patients with Early Chronic Phase Chronic Myeloid Leukemia (ECPCML),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3774-3774 ◽  
Author(s):  
Michael E O'Dwyer ◽  
Ronan Swords ◽  
Francis Giles ◽  
Mary Frances McMullin ◽  
Philipp D. le Coutre ◽  
...  
Keyword(s):  
High Risk ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Low Risk ◽  
Phase Iii ◽  
Additional Patient ◽  
Molecular Response ◽  
Grade Iii

Abstract Abstract 3774 BACKGROUND/METHODS: Data from the ENESTnd phase III trial showed superiority of nilotinib over imatinib leading to accelerated approval of nilotinib as initial treatment of ECPCML at a dose of 300mg BID. ICORG, the All-Ireland Cooperative Oncology Research Group, has been coordinating an international open-label, single stage, multicenter, investigator-initiated phase II study (ClinicalTrials.gov NCT00809211) of the safety and efficacy of nilotinib 300 mg BID in previously untreated patients with ECPCML. The primary study endpoint is the complete cytogenetic response (CCyR) rate at 6 months; secondary endpoints include the kinetics of molecular response, determined by RQ-PCR at baseline and 3 monthly from start of treatment as well as an evaluation of a novel rapid turnaround PCR system “GeneXpert” with IS BCR-ABL1/ABL1 RQ-PCR. The study closed to accrual with 61 patients (median age 54 years [range 20 –77]) enrolled; 53% have low risk Sokal score, 25% intermediate and 22% high risk. Median follow up is currently 12 months (range 1–30) and by November 2011 all patients will have had at least 6 months follow up. RESULTS: At the time of this analysis, 6 and 12 month follow up data were available in 43 and 31 patients, respectively. By intention to treat analysis, 41/43 (95%) have achieved CCyR within 6 months with all patients still on treatment at 12 months achieving CCyR. 26/43 (60%) and 25/31 (81%) of patients have achieved a major molecular response (MMR) (BCR-ABL1/ABL1 IS ≤ 0.1%) within 6 and 12 months, respectively, with 16/31 (52%) and 11/31 (35%) patients on treatment at least 12 months achieving BCR-ABL1/ABL1 IS ≤ 0.01% and ≤ 0.0032%, respectively. Sokal risk had no apparent effect on response with 12/16 (75%) low risk and 13/15 (87%) intermediate/high risk patients achieving MMR within 12 months, p=0.65. Thus far 4/6 (67%) high risk Sokal patients achieved BCR-ABL1/ABL1 IS ≤ 0.0032% within 12 months. No patients have suffered CML progression to date. 53 patients remain on study. Six patients have been removed from study due to adverse events: 4 patients due to persistent drug-related toxicity; 2 patients non drug-related events (death due to progressive multiple system atrophy and colorectal carcinoma, respectively). In addition, one patient was enrolled but never received study drug and an additional patient was lost to follow up. Treatment was generally well tolerated and toxicities easily managed. Haematologic toxicity was minimal with grade III/IV thrombocytopenia seen in 3 (5%) patients and only a single patient (2%) each with grade III/IV neutropenia and anemia, respectively. The most common grade III/IV non-haematologic toxicity was lipase elevation, seen in 14/61 (23%). No cases of acute pancreatitis were seen. Other grade III/IV non-hematologic toxicities were uncommon (< 5% patients). While treatment was interrupted at least once in 36/59 (61%) patients, the median duration of interruptions was short (5 days). At last follow up 49/59 (83%) of patients were taking ≥ 300mg BID. The study evaluation of the “GeneXpert” PCR system consisted of paired BCR-ABL1/ABL1 measurements performed by RQ-PCR methodologies aligned to International Standard (IS) and by the Xpert BCR-ABL Monitor system on 36 evaluable patients at diagnosis and at 128 subsequent three-monthly time-points. In patients expressing e13a2 or e14a2 BCR-ABL1 transcripts, both techniques had comparable results at diagnosis: IS median BCR-ABL1/ABL1 41.0% vs 44.0% median BCR-ABL1/ABL1 on the Xpert BCR-ABL Monitor. In the 122 paired analyses, correlation between methodologies, without automated system IS conversion, over a five log range (IS BCR-ABL1/ABL1 100–0.001%) was favourable (r2=0.845), however a progressive decline in correlation was noted with each decreasing log IS BCR-ABL1/ABL1 level. No significant difference was observed between the Xpert BCR-ABL Monitor and IS RQ-PCR in identifying MMR (44.3% vs 41.8%). CONCLUSION: In ECPCML, nilotinib 300mg BID induces high rates of CCyR and MMR with a substantial fraction of patients achieving responses in the range of complete molecular response (CMR). This regimen's toxicity is modest. The GeneXpert system provides a reliable and rapid means of assessing CML patients' response to tyrosine kinase inhibitor (TKI) therapy. Development of a reagent lot-specific conversion factor to the IS would enhance GeneXpert's applicability in monitoring TKI therapy in patients with CML. Disclosures: O'Dwyer: Novartis: Honoraria, Research Funding. Giles:Novartis: Consultancy, Honoraria, Research Funding. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau. Nagler:Novartis: Honoraria, Research Funding. Egan:Novartis: Employment. Conneally:Novartis: Honoraria.

A Risk Score Integrating BAALC, ERG and WT1 Expression Can Be Used To Improve Risk Stratification In Acute Promyelocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1323-1323
Author(s):  
Anna Hecht ◽  
Florian Nolte ◽  
Daniel Nowak ◽  
Verena Nowak ◽  
Benjamin Hanfstein ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Score ◽  
Risk Group ◽  
Risk Groups ◽  
Low Risk ◽  
Expression Levels ◽  
Improve Risk Stratification

Abstract Introduction With current therapy regimens over 75% of patients with de novo acute promyelocytic leukemia (APL) can be cured. Approaches to further improve patient outcome by stratifying patients at the time of initial diagnosis according to their individual risk and to adjust therapy accordingly have been based on clinical features only. Molecular markers have not been established for risk stratification as yet. Recently, we have shown that high expression levels of the genes brain and acute leukemia, cytoplasmic (BAALC) and ets related gene (ERG) are associated with inferior outcome in APL patients. In addition, data indicate that aberrant expression of the gene Wilms’ tumor 1 (WT1) is a negative prognostic factor with regard to overall survival (OS) after complete remission (CR) and relapse free survival (RFS) in APL. In this study we evaluated the prognostic relevance of a combined score integrating the expression levels of the above mentioned genes to further improve risk stratification in APL patients. Methods Expression levels of BAALC, ERG and WT1 of 62 patients with newly diagnosed APL were retrospectively analyzed in bone marrow mononuclear cells using multiplex reverse transcriptase quantitative real-time PCR (qRT-PCR). Median age of patients was 47 years (range: 19 to 82y). All patients gave informed consent. Patients were diagnosed and treated in the German AML Cooperative Group (AMLCG) study with a treatment of simultaneous ATRA and double induction chemotherapy including high-dose ara-C, consolidation and maintenance chemotherapy. The following gene expression levels were identified as negative risk factors in preceding studies: BAALC expression ≥25th percentile (BAALChigh), ERG expression >75th percentile (ERGhigh) and WT1 expression ≤25th percentile or ≥75th percentile (WT1low/high). A risk score was developed as follows: for the presence of one of the mentioned risk factors one scoring point was assigned to a respective patient, i.e. a maximum of 3 points (one point for BAALChigh, ERGhigh and WT1low/high, respectively) and a minimum of 0 points (i.e. presenting with none of the aforementioned risk factors) could be allocated to one patient. Accordingly, patients were divided into four risk groups: 7 patients scored 0 points (= low risk), 27 patients scored 1 point (= intermediate 1 risk), 19 patients scored 2 points (= intermediate 2 risk) and 9 patients scored 3 points (= high risk). Subsequently, OS, RFS and relapse free interval (RFI) were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the four risk groups (p<0.05). Results The integrative risk score divided patients into four groups with significantly different outcome. The low risk group showed a RFS of 100% at 10 years of follow-up compared to the intermediate 1 risk group with 81%, the intermediate 2 risk group with 58% and the high risk group with a RFS of 42% only (median survival: 4.6y) (p=0.02). In accordance, the RFI differed significantly between the four groups: low risk 100%, intermediate 1 risk 100%, intermediate 2 risk 89% and high risk 71% (p=0.049). There was no statistically significant difference between the 4 groups with regard to OS in the entire patient cohort. However, there was a clear trend towards a difference in OS in patients who achieved a CR after induction therapy: low risk 100%, intermediate 1 risk 81%, intermediate 2 risk 68% and high risk 53% survival at 10 years of follow-up (p=0.09). Conclusion Integration of expression levels of the genes BAALC, ERG and WT1 into a scoring system identifies 4 risk groups with significantly different outcome with regard to RFS and RFI. It might be a promising approach to guide therapeutic decisions in patients with APL. However, multivariate analyses and validation of these data in an independent patient cohort is warranted. Disclosures: No relevant conflicts of interest to declare.

Prognostic Impact of Splenomegaly on Survival of Chinese with Primary Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3210-3210
Author(s):  
Jingya Wang ◽  
Junqing Xu ◽  
Robert Peter Gale ◽  
Zefeng Xu ◽  
Bing Li ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Scoring System ◽  
Scoring Systems ◽  
Primary Myelofibrosis ◽  
Low Risk ◽  
Prognostic Impact ◽  
European Descent ◽  
Rbc Transfusion

Abstract Median survival of persons with primary myelofibrosis (PMF) is about 7 years but ranges from <2 to >10 years. Different scoring systems were developed to predict survival of persons with PMF including the International Prognostic Scoring System (IPSS), the Dynamic IPSS (DIPSS), and the DIPSS-Plus. These scoring systems were developed predominately in persons of European descent and include few Asians. Recently, we analyzed a large dataset of Chinese with PMF to test validity of these scoring systems and determine if additional clinical or laboratory variables improved the prognostic accuracy of these scoring systems in Chinese with PMF who constitute a substantial proportion of people with PMF worldwide. We found frequencies of splenomegaly and anemia were significantly different between Chinese and persons of European descent with PMF and that splenomegaly, not included in the European-derived scoring systems, was an important independent predictor of survival in Chinese. Based on these data we developed a modified prognostic scoring system for Chinese subjects which included splenomegaly. The aim of our current study is to validate the prognostic value of this modified DIPSS for Chinese with PMF in a larger cohort of 874 subjects diagnosed August, 1984 to October, 2013 at the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and evaluate the prognostic impact of splenomegaly on survival. All cases were blind re-reviewed by the pathologist and diagnosis based on the 2008 World Health Organization criteria. 495 subjects (57%) had splenomegaly below the left costal margin. Splenomegaly subjects were younger (P=0.006) and had significantly higher hemoglobin concentrations (P<0.001) and levels of WBCs (P<0.001), platelets (P<0.001) and blood blasts (P=0.012). 217 subjects (62%) in the splenomegaly cohort had JAK2V617Fvs. 115 subjects (50%; P=0.003) in the no splenomegaly cohort. Distributions of RBC-transfusion-dependence (P<0.001) and DIPSS risk-cohorts (P=0.024) were also significantly different. Frequencies of constitutional symptoms and cytogenetic abnormalities were not significantly-different. Median follow-up is 22 months (range, 1-288 months); 215 subjects (25%) died during follow-up. We calculated DIPSS scores at diagnosis. Risk distribution according to the DIPSS for PMF was low risk in 182 subjects (21%), intermediate-1 risk in 398 subjects (46%), intermediate-2 risk in 281 subjects (32%) and high-risk in 13 subjects (2%). Corresponding median survivals are not reached, 110, 37 and 21 months. Using the DIPSS model survival curves of intermediate-2 and high-risk subjects are not significantly different (P=0.054). In our cohort, only 2% subjects were classified as high-risk in the DIPSS scoring system. The modified DIPSS for Chinese used three independent risk factors for briefer survival: DIPSS scores (low-risk, 0; intermediate-1 risk, 1; intermediate-2 risk, 2; and high-risk, 3), platelet levels <100´10E9/L and no palpable splenomegaly. The revised risk categorization was low-risk (score 0-1), intermediate-risk (score 2-3) and high-risk (score 4-5). Using the modified DIPSS median survivals are 288, 61 and 28 months. In univariate analyses, variables significantly correlated with survival were male gender (P=0.001), age >65 years (P<0.001), hemoglobin concentration < 100g/L (P<0.001), platelets <100×10E9/L (P<0.001), blood blasts ≥1% (P<0.001), no splenomegaly (P<0.001), RBC-transfusion-dependence (P<0.001) and DIPSS (P<0.001). Median survival in subjects with splenomegaly is 110 months compared with 64 months in subjects without splenomegaly.In multivariate analyses variables significantly correlated with survival were male gender (hazard ratio [HR]=1.63; 95% CI, 1.23-2.15; P=0.001), platelets >100×10E9/L (HR=1.58; 95% CI, 1.19-2.11; P=0.002), no splenomegaly (HR=1.45; 95% CI, 1.10-1.90; P=0.008), RBC-transfusion-dependence (HR =1.51; 95% CI, 1.11-2.06; P=0.009) and DIPSS (HR=1.90; 95% CI, 1.55-2.31; P<0.001). Our study confirms the predictive value of the modified DIPSS with splenomegaly as a variable in a large cohort of Chinese with PMF. Moreover, we found splenomegaly was strongly associated with several laboratory abnormalities. In contrast to persons of predominately European descent, splenomegaly is an important independent favorable prognostic variable in Chinese with PMF. Disclosures No relevant conflicts of interest to declare.

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