The Genes for Tissue Factor F3 and Nuclear Receptor 4A Are Down-Regulated in Early Death Acute Promyelocytic Leukemia Patients

Abstract Introduction: Acute promyelocytic leukemia (APL) patients are successfully treated via differentiation therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Attempts to apply ATRA-based differentiation therapy to non-APL acute myeloid leukemia (AML) patients have not been effective so far (Johnson & Redner, 2015). Furthermore, 10-30% of the APL patients suffer an early death (ED) within 30 days, due to hemorrhages, infections, differentiation syndrome and thrombosis. Different risk factors have been identified, but the underlying mechanisms and successful treatment of ED in APL patients still have not been established (Kwaan et al., 2014, Lehmann et al., 2017). Hence, it is highly important to identify novel risk factors to understand the mechanistic processes in APL ED patients. Methods: To identify target genes, 50 bp single-read RNA sequencing (RNAseq) of 6 ED and 9 APL controls (cohort #1; n=15) and 4 ED and 5 APL controls (cohort #2; n=9) was executed. Samples were taken from patients with confirmed diagnosis of APL before beginning of treatment. Cohort #1 consisted of 15 patients: median age 60 years (range 37-73 years), 10 high-risk patients and 5 low/intermediate-risk patients according to Sanz score. Patients of cohort #1 were treated according to the AIDA2000 protocol of the Study Alliance Leukemia (SAL) study group. Cohort #2 consisted of 9 patients: median age 55 years (range 36-79 years), 4 high-risk patients and 5 low/intermediate-risk patients. Most patients of cohort 2 were treated according to the AIDA2000 (SAL) or APL0406 protocol. Gene validation was performed via RT-qPCR. PML-RARα variants were determined by Mentype AMLplexQS (Biotype). Survival and RT-qPCR analyses were performed with 64 non-APL AML patients´ samples treated within the clinical trial of the AMLSG HD98B study (Schlenk et al., 2004). In this trial, all patients received ICE (idarubicin, cytarabine, etoposide) chemotherapy. The patients were randomly assigned to ATRA or no ATRA. In our cohort, 26 patients had received ICE-ATRA, whereas 38 only ICE. Amaxa nucleofector technology was used for overexpression of PML-RARα bcr1 or bcr3 variant in U937 cells. NB4 or AML cells treated with 1 µM ATRA up to 72 h or 1-2 µM ATO up to 48 h were analyzed via flow cytometry, CellTiter-Glo viability assay, RT-qPCR or Western blot. Results: RNAseq of cohorts 1 and 2 showed F3 (Tissue Factor) and members of nuclear receptor 4A family, NR4A1/2/3, significantly downregulated in ED compared to control APL cases. GSEA analysis further identified a gene family including F3 and members of nuclear receptor 4A family, NR4A1/2/3, co-regulated upon leukotriene and thrombin treatment. Downregulation of F3 was further validated by RT-qPCR. Analysis of PML-RARα variants in APL control and ED cases (n=38, Chi-square p < 0.041) showed a significant enrichment of the short variant bcr3 in ED APL. Artificial overexpression of the short bcr3 and long bcr1 PML/RARα variant in U937 further revealed a correlation between bcr3 and downregulation of NR4A2/3. Moreover, treatment of the APL NB4 cell line with ATRA or ATO induced further downregulation of F3 but upregulation of NR4A2/3 transcripts. ATRA treatment induced the same effects on F3 and NR4A3 protein levels, while ATO led not only to a decrease of F3 but also NR4A3 protein levels. We next sought to address the role of F3 and NR4A in non-APL AML. In 5 non-APL AML cell lines high F3 transcript and protein levels were positively correlated with a better response to ATRA treatment in vitro. Consistently, analyzing samples taken from the AMLSG HD98B trial, AML patients with high F3 but also NR4A3 transcript levels treated with ICE chemotherapy showed a significantly prolonged overall survival upon additional ATRA treatment in vivo (Log-rank p < 0.008). Conclusions: Expression of F3 and NR4A1/2/3 is downregulated in APL ED and decreased expression of NR4A2/3 is associated with short PML-RARα variant bcr3, which is significantly enriched in ED APL. Since NR4A members are associated with coagulation and inflammation, they may be important F3-related factors, contributing to the bcr3 ED APL phenotype. As ATRA and ATO treatment is known to further inhibit F3 expression, alternative therapies not inhibiting F3 expression could be worthwhile in APL ED patients. Moreover, F3 and NR4A3 expression levels seem to be highly relevant as marker for the prediction of ATRA response in non-APL AML patients. Figure. Figure. Disclosures Platzbecker: Celgene: Research Funding. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership. Schlenk:Pfizer: Research Funding, Speakers Bureau.

Download Full-text

Early Mortality in Acute Promyelocytic Leukemia May Be Higher Than Previously Reported.

Blood ◽

10.1182/blood.v114.22.1015.1015 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1015-1015 ◽

Cited By ~ 6

Author(s):

Ash A Alizadeh ◽

James S. McClellan ◽

Jason R. Gotlib ◽

Steven Coutre ◽

Ravindra Majeti ◽

...

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

High Risk ◽

Early Death ◽

Promyelocytic Leukemia ◽

Early Mortality ◽

Low Risk ◽

Intermediate Risk ◽

Risk Patients

Abstract Abstract 1015 Poster Board I-37 Background: Early mortality, mostly from hemorrhagic complications, occurs in less than 10% of patients currently treated in clinical trials for acute promyelocytic leukemia (APL). However, data about the proportion of patients developing such complications prior to clinical trial enrollment are scarce in the literature (Sanz M, et al Blood 2009). Approximately 5% of newly diagnosed patients with APL have been reported not to be eligible for participation in clinical trials due to very poor clinical condition, and their outcome has never been reported. However, enrollment on clinical trials may be difficult in specific clinical situations, such as after hours/weekend admissions and/or emergent requirement for therapy. This study reports the incidence, time of occurrence and clinical features of APL patients with a focus on early mortality. Methods: 150 consecutive APL patients treated at Stanford University between 8/1986 and 7/2009 were identified. Thirteen patients were excluded for lack of appropriate clinical information. Clinical features of patients with APL were analyzed for factors that might be relate to prognosis, including age, gender, white blood cell count, platelet count, fibrinogen, PTT, and INR. Continuous variables were compared with the t-test and categorical variables by Fisher's exact test or X-square statistic. The Kaplan–Meier method was applied to assess overall survival time. Results: Of the 137 patients included in this analysis, the median age at diagnosis was 45 (1-93) years and 78 (57%) were females. Using the PETHEMA criteria, there were 37, 46 and 20 patients with high-, intermediate- and low-risk disease (34 patients could not be classified based on partial/missing data). With a median follow-up time of 748 (0-6,235) days for the entire cohort, 52 (38%) have died. 19 (14%) and 11 (8%) of these patients died within 7 and 3 days of presentation, respectively. Patients with high-risk features had a 13% and 24% chance of dying with 3 and 7 days of presentation, respectively, with significantly inferior outcomes (p=0.045) when compared to those with intermediate-risk patients (6% and 13%) and low-risk disease (5% and 5%). Patients with unknown risk category faired similarly to low-risk patients. The most common cause of early mortality in these 19 patients was intracranial hemorrhage (n=11). Patients with early death (ED) (either <=3 or <=7 days) tended to be older than APL patients with non-early deaths (>7d), or APL patients alive as of their last follow-up (median age 54 years vs. 50 years vs. 39 years), and were more likely to have higher risk disease, though coagulopathy appeared not significantly different amongst the groups. Median fibrinogen, PTT and INR for each individual group are presented on Table 1. The 3-year overall survival (% +/- SE) of the low, intermediate, and high risk patients was 90+/-7, 74+/-7, and 64+/-8, respectively, though early mortality (death within 7 days) was a major determinant of this stratification (p=0.045). Conclusions: Risk of early death in APL patients appears to be higher than previously reported in clinical trials, where trial registration may exclude patients requiring urgent therapeutic interventions. In this cohort, 25% and 13% patients with high- and intermediate-risk APL died within 7 days of presentation, respectively. Risk group stratification was very predictive of risk of early death. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

Risk factors for recurrence amongst high intermediate risk patients with endometrioid adenocarcinoma

Journal of Gynecologic Oncology ◽

10.3802/jgo.2012.23.4.257 ◽

2012 ◽

Vol 23 (4) ◽

pp. 257 ◽

Cited By ~ 6

Author(s):

Agnes Y. Bahng ◽

Christina Chu ◽

Paul Wileyto ◽

Stephen Rubin ◽

Lilie L. Lin

Keyword(s):

Risk Factors ◽

Endometrioid Adenocarcinoma ◽

Intermediate Risk ◽

Risk Patients ◽

Risk Factors For Recurrence

Download Full-text

Remission in Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide (varitrinox) As the First Line in Colombia

Blood ◽

10.1182/blood-2020-137143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 3-3

Author(s):

Gustavo Milone ◽

Samuel Sarmiento Doncel ◽

Carol Agudelo Rico ◽

Fabiola Vizcarra Reyes ◽

Gina Alejandra Diaz Mosquera ◽

...

Keyword(s):

High Risk ◽

Arsenic Trioxide ◽

Acute Promyelocytic Leukemia ◽

Conflicts Of Interest ◽

Promyelocytic Leukemia ◽

Remission Induction ◽

Intermediate Risk ◽

Newly Diagnosed ◽

First Line ◽

Risk Patients

Acute promyelocytic leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML) in which a chromosomal translocation t (15; 17) (q22; q12) is generated by fusing produces a hybrid PML / RARα gene, generating an altered signal . The combination of transretinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of newly diagnosed standard risk patients with acute promyelocytic leukemia (APL) in several countries. The objective of the present study is to describe the frequency of remission in patients with acute promyelocytic leukemia who were administered as a first line Arsenic Trioxide (varitrinox) during the period from November 2017 to June 2020 in Colombian patients. Methods: Retrospective observational and descriptive study of 12 patients diagnosed with acute promyelocytic leukemia treated with ATO Arsenic trioxide (Varitrinox) as first line, the source of information was provided by the treating hematologists (medical records) by filling out the technical concept format. Active pharmacovigilance scientist in Colombia, this format keeps the identification information of the patient anonymized and the confidentiality of the data is guaranteed as well as compliance with the rules of good clinical practice. Results: Twelve patients with age range between 22 and 69 years with a median age of 34.0 were analyzed. It was found in the analysis that 100% had induction hematologic remission with a median of 45 days. 75% of patients received ATO + ATRA and were at low and intermediate risk, the remaining 25% received ATRA + ATO + Chemotherapy and were at high risk, and intermediate risk. 91.7% of molecular remission in consolidation was obtained and it was measured in cycle 3 by means of PCR (undetectable), 8.3% (n = 1) was positive 3% and is finishing consolidation. Regarding the most frequent adverse events, intravascular coagulation (n = 9), neutropenia (n = 6) and thrombocytopenia (n = 6) were observed. 75% of patients are disease-free, 16.7% are on maintenance (they received ATO + ATRA + Induction chemotherapy) and 8.3% are on consolidation. So far, none of the patients under study have died. Conclusions: Our results support the use of ATO (Varitrinox) in newly diagnosed APL patients (as first line), as a care strategy for low, intermediate and high risk patients. The role of ATRA-ATO is guaranteed in other studies where they manage patients of different risks. Key words: Arsenic trioxide, leukemia promyelocytic acute, leukemia myeloid acute, remission induction, tretinoin. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Incidence, Outcome and Risk Factors of Pseudotumor Cerebri after All- Trans Retinoic Acid and Anthracycline-Based Chemotherapy in Patients with Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood.v112.11.2992.2992 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2992-2992 ◽

Cited By ~ 1

Author(s):

Pau Montesinos ◽

Edo Vellenga ◽

Aleksandra Holowiecka ◽

Chelo Rayon ◽

Gustavo Milone ◽

...

Keyword(s):

Risk Factors ◽

Retinoic Acid ◽

Side Effects ◽

High Risk ◽

Pseudotumor Cerebri ◽

Promyelocytic Leukemia ◽

Consolidation Therapy ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Risk Patients

Abstract Background: Pseudotumor cerebri associated with all-trans-retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) have been frequently described in pediatric patients. However, the incidence, outcome and risk factors of pseudotumor cerebri in APL are not well-known. We analyze the incidence and risk factors of this complication in a large series of patients with newly diagnosed APL enrolled in three consecutive trials of the PETHEMA Group (LPA96, LPA99 and LPA2005). Mehods: AIDA regimen (ATRA 45 mg/m2/d [25mg/m2/d in patients younger than 20] until CR and idarubicin 12 mg/m2/d on days 2, 4, 6 and 8) was given as induction therapy. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy: idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3). Since November 1999 (LPA99 trial), for patients with intermediate or high risk of relapse (Sanz et al, Blood 2000), consolidation was slightly intensified by increasing idarubicin doses in courses #1 and #3, and by simultaneously administering 25 mg/m2 ATRA together with chemotherapy in all three courses. Since July 2005, consolidation therapy in the ongoing LPA 2005 trial included the following modifications: the administration of ATRA for all patients; for low- and intermediate-risk patients, mitoxantrone has been reduced from five to three days in the second course; and for high-risk patients, cytarabine has been added to idarubicin in the first and third course. Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 25 mg/m2/d ATRA for 15 days every three months. Diagnosis of pseudotumor cerebri was made in the presence of signs and symptoms of intracranial hypertension without clinical or radiological evidence of infective or space occupying lesions. Results: Of 1034 patients enrolled between November 1996 and July 2008, 32 (3%) experienced pseudotumor cerebri. Headaches without pseudotumor were present in 252 patients (25%). Thirty cases of pseudotumor occurred during induction therapy and 2 cases manifested only during consolidation. In all, 9 of 32 patients (28%) had recurrent pseudotumor cerebri after reinitiating ATRA. All these side effects were transient, reversible, and never a cause of death. CR rates were 96% and 90% in patients with and without pseudotumor cerebri, respectively (p=0.32). The incidence of pseudotumor cerebri among patients younger than 18 years, 18–25 years, 25–50 years and older than 50 years was 13%, 7%, 2% and 0.3%, respectively (p<0.0001). There was a trend toward a correlation between fibrinogen <170 mg/dL and worse general state (ECOG>1) at presentation and development of pseudotumor cerebri (p=0.08 and p=0.06, respectively). We did not found any significant association between pseudotumor cerebri and WBC, platelets, relapse risk-score, hemoglobin, creatinine, PETHEMA trial, gender, morphological subtype, PML/RARA isoform, FLT3 mutations, and surface antigens (CD2, CD11b, CD13, CD15, CD34, CD56, and CD117). Conclusion: This study shows an overall incidence of pseudotumor cerebri of 3% among APL patients treated with ATRA and anthracycline-based regimens, with higher incidences in children and young adults (13% and 7%, respectively). No other prognostic factors could be demonstrated. The development of pseudotumor cerebri was not associated with a worse induction outcome. Side effects were reversible and transient, but roughly a third of patients had recurrent pseudotumor cerebri after reinitiating ATRA

Download Full-text

Clinical Significance of Mitochondrial DNA Content in Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood-2021-151265 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3474-3474

Author(s):

Antonio R. Lucena-Araujo ◽

Diego A Pereira-Martins ◽

Juan L Coelho-Silva ◽

Isabel Weinhäuser ◽

Pedro Luis Franca-Neto ◽

...

Keyword(s):

Mitochondrial Dna ◽

Complete Remission ◽

Treatment Outcomes ◽

Acute Promyelocytic Leukemia ◽

Clinical Significance ◽

Research Funding ◽

Mononuclear Cells ◽

Promyelocytic Leukemia ◽

Atra Treatment ◽

Acute Leukemias

Abstract Used in the clinical practice for more than three decades, the all-trans retinoic acid (ATRA) rendered acute promyelocytic leukemia (APL) the most curable subtype of acute myeloid leukemia, and currently, its combination with arsenic trioxide (ATO) exceeded all expectations for a chemotherapy-free protocol. In terms of metabolic importance, ATRA can also modulate the mitochondria-mediated cellular metabolism and promote a shift from a glycolytic-driven metabolism to an oxidative phosphorylation profile, although this effect has never been demonstrated in APL. As part of the cellular metabolic machinery, mitochondrial DNA (mtDNA) content has been reported to be altered in different types of solid tumors with clinical implication on patient treatment outcomes, although its clinical significance in acute leukemias has not been investigated to the same extent. Particularly in acute promyelocytic leukemia (APL), the role of mtDNA content on prognostication is completely unknown. Considering that mostly APL samples display a glycolytic-driven metabolism, it is conceivable that APL patients harboring high mtDNA content may present a better response to ATRA-based therapies. To test this hypothesis, we determined the mtDNA content in samples from patients with APL enrolled in the International Consortium on Acute Promyelocytic Leukemia study (Rego et al. Blood. 2013 Mar 14;121(11):1935-43) and analyzed its relationship to treatment outcomes. Diagnostic bone marrow (BM) mononuclear cells from 156 consecutive patients with APL (median age: 35 years, range: 18-82 years; 45% male) were obtained at diagnosis. For comparison purposes, we also included peripheral blood (PB) from 293 age- and sex-adjusted healthy volunteers. First, we determined whether mtDNA content could be compared between PB mononuclear cells and BM. To do so, we measured the mtDNA content of 22 APL patients, for whom paired samples were available at the time of diagnosis and detected a strong correlation between PB and BM samples (Pearson correlation coefficient, r=0.78, 95% confidence interval, CI: 0.54 to 0.9). Next, we used the values of mtDNA higher than the 95 th percentile of healthy subjects (≥1.63. Note: this value represents a fold change relative to healthy control) to define APL patients with high mtDNA content. Patients that presented values within the range of normal control samples (<1.63) were classified as normal mtDNA content. The median follow-up among survivals was 40 months (95%CI: 34-47 months). Of the 131/156 patients who achieved complete remission, 18 patients (14%) relapsed. mtDNA content had no impact on complete remission achievement (84% for normal mtDNA versus 83% for high mtDNA; P=0.924) or overall survival (78% for normal mtDNA versus 80% for high mtDNA; P=0.69). In contrast, patients with high mtDNA content had a significantly high 5-year disease-free survival rate (86%, 95%CI: 78-95%) than patients with normal mtDNA content (61%, 95%CI: 46-82%). Considering non-relapse death as a competing cause of failure, the 5-year cumulative incidence of relapse (CIR) for patients with high and normal mtDNA content were 35% (95%CI: 16-49%) and 10% (95%CI: 2-17%), respectively. The multivariate Cox proportional hazards model showed that mtDNA content was independently associated with CIR (hazard ratio, HR: 0.31, 95%CI: 0.12-0.8) considering PETHEMA/GIMEMA risk of relapse subgroups and age as confounders. To functionally evaluate the metabolic alterations in APL cells upon ATRA treatment, NB4 cell line was treated with ATRA (1 µM) for 48 and 72 hours. In vitro analyses demonstrated (as expected) that the treatment with resulted in increased levels of myeloid maturation markers (CD11b/CD11c/CD15), with morphological changes being only observed at 72 hours. Metabolically, we observed an increase in mitochondrial mass and potential upon ATRA-treatment after 48 hours, which was also reflected by increase in the mtDNA content (2-fold increase in comparison with the vehicle). Together, these findings demonstrate an important, but not completely understood role for mtDNA content in APL. Disclosures Silveira: BMS/Celgene: Research Funding; Servier/Agios: Research Funding; Abbvie: Speakers Bureau; Astellas: Speakers Bureau. Pagnano: EMS: Other: Lecture; Jansenn: Other: Lecture; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pintpharma: Other: Lecture.

Download Full-text

PP2A Inhibition By CIP2A or SETBP1 Leads to Elevated Levels of AKT S473 Which Can be Used As a Biomarker of Outcome in Acute Myeloid Leukaemia

Blood ◽

10.1182/blood.v126.23.1396.1396 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1396-1396

Author(s):

Robert K Hills ◽

Claire M Lucas ◽

Laura J Scott ◽

Natasha Carmell ◽

Alison K Holcroft ◽

...

Keyword(s):

Overall Survival ◽

Multivariate Analysis ◽

Conflicts Of Interest ◽

Blast Crisis ◽

Univariate Analysis ◽

Intermediate Risk ◽

Pp2a Activity ◽

Protein Levels ◽

Risk Patients ◽

Related Proteins

Abstract Many cells utilise reversible phosphorylation as a mechanism of post-translational modification for activating and deactivating key regulatory molecules involved in cell signalling. Many malignancies are characterised by overactive kinases e.g. BCR-ABL or FLT-3 in myeloid malignancy, or ERK or ErbB2 in solid tumours. A major phosphatase working in opposition to kinases is protein phosphatase 2A (PP2A) but why the cellular phosphatases such as PP2A simply do not counteract the overactive kinase activity is unclear. PP2A activity is regulated by inhibitor proteins SET, (which is stabilised by a binding protein SETBP1) and cancerous inhibitor of PP2A (CIP2A). In CML, we have shown that high levels of CIP2A at diagnosis is a prospective biomarker for future progression to blast crisis. High levels of CIP2A in other malignancies have also been reported to confer a poor prognosis. In CML, high CIP2A levels lead to the stabilisation of c-Myc and elevation of E2F1, as well as PP2A inactivation. In AML there are data suggesting that high SETBP1 levels may confer a poor outcome in AML, by PP2A inhibition via increased action of SET, though little is known of CIP2A in AML. The aim of the study was to investigate if CIP2A or network related proteins could predict clinical outcome in AML patients. CIP2A and network related proteins were investigated in 119 AML patient samples collected in the UK MRC/NCRI trials AML15, 16 and 17. These were stratified into intermediate or adverse risk, based on cytogenetics as previously defined (Grimwade et al, Blood. 1998: 92; 2322-33). Protein levels were studied in diagnostic mono-nuclear cell samples by flow cytometry. The diagnostic CIP2A protein level (mean fluorescence intensity (MFI)) for all patients was calculated. This range was 0-13.69, the interquartile range was 1.47-5.11, the median was 3 and the mean was 3.5. High CIP2A patients are defined as those patients with a CIP2A level greater than or equal to 3. In all AML samples studied high CIP2A was associated with inactive PP2A as shown by high levels of PP2AY307 (p=0.05), as well as elevated levels of c-Myc p=<0.0001 and E2F1 p=<0.0001, a similar finding to what we have observed in CML. We also found that AKTS473 and STAT5 were also elevated in high CIP2A AML patients (p=0.002 and p=0.006 respectively). Unlike CML, we found in AML patients high CIP2A was associated with high levels of SET (p=<0.0001) and SETBP1 (p=0.01). Younger intermediate AML patients had significantly higher diagnostic CIP2A levels than adverse risk patients (p=0.004). In the intermediate risk group, overall survival was dominated by the survival from relapse. For younger intermediate risk patients with high and low CIP2A levels, median survival from relapse (censored at transplant) was 56 days and 303 days respectively. Multivariate analysis adjusted for FLT3-ITD showed that a high CIP2A level predicted inferior survival from relapse (p=0.04, hazard ratio 4.02). Interestingly, high diagnostic CIP2A was strongly associated with the presence of a FLT3-ITD mutation (p=0.03). In adverse risk patients SETBP1 levels were elevated but CIP2A levels were lower. SETBP1 acts via SET as an alternative inhibitor of PP2A. In younger patients with adverse cytogenetics, high SETBP1 levels predict for an inferior overall survival (p=0.02). For all 119 AML patients those with detectable SETBP1 protein levels at diagnosis had an inferior overall survival (p=0.01). High SETBP1 was also associated with secondary AML. In univariate analysis, high levels of AKTphosphorylation at seine 473 (which is inversely correlated with PP2A activity)were associated with poor survival in all patients. Multivariate analysis of known predictors of outcome (age, cytogenetics, white count, secondary leukaemia, FLT3-ITD) together with CIP2A and related proteins (PP2AY307, SET, SETBP1, c-Myc E2F1, AKTS473, STAT5, and E2F1) was used to derive a prognostic model for survival. This ranked high levels of AKTS473 as the third most important predictor of outcome after age and cytogenetics. Our data suggest that AKTS473 levels are elevated as a result of PP2A inactivation (p=>0.0001) caused by high level of PP2A inhibitors, either CIP2A (p=0.003) or SETBP1 (p=0.03). In summary, AKT phosphorylation at S473 is a biomarker of PP2A inhibition by either CIP2A (intermediate risk) or SETBP1 (adverse risk patients). The diagnostic AKTS473 level appears to be a novel biomarker for survival in AML. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Final Analysis of MELISSE, a Large Multicentric Observational Study to Determine Risk Factors of Venous Thromboembolism in Patients with Multiple Myeloma Treated with Immunomodulator Drugs

Blood ◽

10.1182/blood.v118.21.1235.1235 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1235-1235 ◽

Cited By ~ 1

Author(s):

Xavier Leleu ◽

Laurent Daley ◽

Philippe Rodon ◽

Cyrille Hulin ◽

Charles Dauriac ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

High Risk ◽

Incidence Rate ◽

Research Funding ◽

Final Analysis ◽

Vte Prophylaxis ◽

High Risk Patients ◽

Increased Risk ◽

Risk Patients

Abstract Abstract 1235 Background. Immunomodulator drugs (IMiDs) are associated with an increased risk of thromboembolic events (TE). Multiple Myeloma patients (MM) that can not benefit from novel agents, including IMiDs, only have 9 months survival. IMiDs must be stopped when TE occurs with the consequence of potential shortened life expectancy. MELISSE was designed to prospectively evaluate the incidence and risk factors of venous TE (VTE) associated with IMiDs in MM. We have presented the interim analysis of MELISSE at ASH 2010. A reduced incidence rate of early VTE was observed when a prophylaxis for VTE was started as compared to patients that had no prophylaxis. Interestingly, we also reported that most of the patients had received aspirin, while aspirin is not considered to exert any venous prophylactic effect. LMWH was primarily proposed to patients with high risk of TE according to physician's evaluation. We present the final analysis of MELISSE with updated results at 1 year. Method. A total of 524 MM treated with IMiDs-based therapy were included in 52 IFM centers. VTE prophylaxis was recommended prior to start IMiDs, the choice of which was left at the discretion of the investigator. Patients gave written informed consent according to the declaration of Helsinki. The physicians were to record the risk of VTE occurrence, categorized as low, moderate and high, based on guidelines and their own appreciation of the risk. Occurrence of any VTE was to be recorded along with the management of the event and the patient's outcome. The data were collected at entry in the study, and then after 4 and 12 months. Results. The median age was 70 years old, with 64.67% of patients >65 years old. Overall 36.0% had thalidomide-based and 64.0% had lenalidomide-based therapy, with 180 patients in first line and the remaining patients in 2nd and 3rd lines of therapy. The observed repartition of TE risk factors was as expected in a European population with myeloma. The risk of VTE was assessed as high in 14.2% patient and small or intermediate otherwise. Interestingly, approximately 70% of patients rated as low and intermediate risk received aspirin as a routine prophylaxis for VTE as compared to 20% in high risk patients. LMWH was primarily given to high risk patients, 45.8%. Surprisingly, 16.0% of patients had no VTE prophylaxis. Investigators recorded 29 (5.5% annual incidence rate) TE at 12 months, including 12 associated with PE. The incidence rate of TE was similar within the first 4 months (early occurrence, 3.5%) versus after 4 months (late, 2.5%). We have not identified any risk factor that would explain early versus late occurrence of VTE. Interestingly, the incidence of VTE was higher in patients that had no prophylaxis treatment, 8.5%, as compared to 4.4% and 5.9% in the LMWH and aspirin groups, respectively. There was no PE recorded in patients that were on LMWH prophylaxis. The VTE was equally breakdown across the 3 groups of risk factors. The bleeding adverse events were reported for 27 patients, mainly patients with aspirin. We isolated a model with 3 variables that independently predicted a higher risk to develop VTE in the multivariate model, and that comprised the male gender [OR 4.31 (95% CI 1.60 – 13.90)], the smoking habit [6.76 (1.73–22.42)] and the association to EPO [2.66 (1.04–6.58)]. Aspirin showed no significance, but with a p value at 0.55. The multivariate analysis is limited as certain subgroups with high risk factors might have received the optimal VTE prophylaxis, such as patients with bed rest and patients with prior history of VTE. These 2 groups rarely had aspirin. Survival data will be updated and presented at ASH 2011. Conclusion. This study further demonstrates that TE prophylaxis is required for MM treated with IMiDs-based therapy. There is a slight increase risk of VTE/PE with the use of aspirin as compared to LMWH, but a significant increase in bleeding events. Although we have identified risk factors of VTE in MM treated with IMiDs, for the first time, we could not identified VTE risk factors to guide investigators between LMWH and aspirin-based prophylaxis. The optimal dose and duration of LMWH remains to be determined. Disclosures: Leleu: LeoPharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; Roche: Research Funding; Amgen: Honoraria; Novartis: Research Funding. Daley:LeoPharma: Employment. Hulin:Janssen: Honoraria; Celgene: Honoraria. Lamblin:LeoPharma: Employment. Natta:LeoPharma: Employment.

Download Full-text

RADT-07. STEREOTACTIC RADIOSURGERY OF PATIENTS WITH BRAIN METASTASES AND POOR PROGNOSIS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.761 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii182-ii183

Author(s):

Maciej Harat ◽

Maciej Blok ◽

Joanna Kowalewska ◽

Iza Miechowicz

Keyword(s):

Risk Factors ◽

High Risk ◽

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Poor Prognosis ◽

Early Death ◽

Neurological Deficits ◽

High Risk Patients ◽

Risk Of Death ◽

Risk Patients

Abstract PURPOSE/OBJECTIVE(S) Stereotactic radiosurgery (SRS) in patients with risk factors other than the number of intracranial metastases remains controversial. Here we define factors related to early death after SRS alone and compared SRS alone with WBRT in high-risk patients. The aim of our study was to verify if optimal brain treatment may extend survival in patients with poor prognosis and select optimal candidates. MATERIALS AND METHODS In this prospectively collected data, 180 patients with brain metastases and adverse prognostic factors not previously treated with WBRT were analyzed. SRS patients were divided into training (n=82) and validation (n=48) cohorts and compared to retrospective data of WBRT patients (n=50). Overall survival (OS) and probability of 3-month survival in relation to risk factors were defined by univariable and multivariable analyses. RESULTS In multivariable analysis, GPA (OR 0.44, 95%CI 0.21-0.95; p=0.001), extensive extracranial disease (OR 0.13, 95%CI 0.02-0.66; p=0.013), and serious neurological deficits (OR 0.13, 95%CI 0.04-0.45; p=0.001) were associated with early death. If one factor was favorable, 73% (training) and 92% (validation) of patients survived 3 months. Patients with coexisting GPA< 2, serious neurological deficits, and extracranial extensive disease had the highest risk of death within 3 months (AUC 0.822 training; 0.932 validation). Median survival of the WBRT and SRS cohorts was 86 days (interquartile range (IQR): 38-172 days) and 201 days (IQR: 86-not reached), respectively (p< 0.0001). OS in very high-risk patients (GPA< 2) was significantly longer in the SRS vs. WBRT group (123 vs. 58 days; p=0.008). CONCLUSIONS Extracranial oligometastatic disease, intact neurological status, or GPA ≥2 should be present to justify SRS in patients with 1-10 brain metastases. SRS alone is a viable treatment option in comparison to WBRT and most importantly survival benefits may be expected even for high-risk patients (GPA< 2).

Download Full-text

Evaluating the Utilization of All-Trans Retinoic Acid and Arsenic Trioxide during Consolidation Therapy for Patients Receiving Treatment for Acute Promyelocytic Leukemia

Blood ◽

10.1182/blood-2019-131817 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3901-3901

Author(s):

Laura A Bowers ◽

Maho Hibino ◽

Rebecca Garcia Hunt ◽

Leslie Renee Ellis ◽

Rupali Bhave ◽

...

Keyword(s):

Research Funding ◽

Promyelocytic Leukemia ◽

Intermediate Risk ◽

Consolidation Therapy ◽

Monotherapy Group ◽

Free Survival ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Secondary Endpoints

Background. Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) accounting for approximately 10% of AML cases. Advancements in the management of APL have led to complete remission (CR) rates of 90-100% and 5-year overall survival (OS) rates between 86-97%. Standard treatment of APL consists of induction and consolidation, with or without post-consolidation therapy, which is directed by risk group, age, and cardiovascular risk. A standard consolidation option consists of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (NCCN Guidelines, AML Version 3.2019). Frequently patients are unable to obtain consolidation with ATRA due to the high prescription co-pay and limited financial assistance. This study assessed the efficacy, safety, and financial impact of APL consolidation therapy with ATRA/ATO compared to ATO monotherapy at a single institution. Methods. This single-center, retrospective, chart-review study assessed adult patients with APL who received ATRA/ATO induction, followed by consolidation with ATRA/ATO or ATO monotherapy between November 2012 to January 2018. The primary efficacy endpoint was OS. Secondary endpoints included event-free survival (EFS), relapse-free survival (RFS), hematologic CR or molecular CR (CRm), incidence of adverse drug events, and outpatient accessibility of ATRA. Numerical data were expressed as medians and interquartile range (IQR) and categorical data were evaluated using the Fisher Exact test. The Log-rank test was used for time to event data and analyzed using the Kaplan-Meier method. A P-value of < 0.05 was defined as statistically significant. Results. The final analysis included 31 patients, 25 patients received standard ATRA/ATO and 6 patients received ATO monotherapy. Patients in the ATRA/ATO group had a median age of 47 years (range 19 - 72); 8 had low risk and 15 had intermediate risk APL. Patients in the ATO monotherapy group had a median age of 73 years (range 70 - 83); 4 had low risk and 1 had intermediate risk APL. Patients in the ATO monotherapy group had more comorbidities, with all patients having a Charlson Comorbidity Index of 4 or higher compared to only 44% of the ATRA/ATO group (p=0.02). A dose reduction for ATO was required for 50% and 28% of patients in the ATO monotherapy and ATRA/ATO groups, respectively due to peripheral neuropathy. During consolidation, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group (Table 1). Five of six patients (83.3%) and 24 of 25 patients (96%) were alive at last follow-up in the ATO monotherapy and ATRA/ATO groups with a median follow-up of 33.3 months and 35.5 months, respectively (Graph 1). Secondary endpoints are provided in Table 2. There was 1 death in each group, both due to unknown causes. All adverse events occurred in a higher proportion of patients in the ATRA/ATO group (Graph 2). The incidence of headache was significantly higher in the ATRA/ATO group, occurring in 68% of patients and leading to ATRA discontinuation for 1 patient (Table 3), compared to 0 events in the ATO monotherapy group (p=0.004). Barriers to access occurred in 19.4% (6 of 31) of all patients. In addition to the 4 patients who required omission of ATRA upfront due to cost, 2 additional patients discontinued ATRA during consolidation due to affordability (Table 3). Conclusions. Patients in the ATO monotherapy group were on average older, had more comorbid conditions, and received a lower cumulative dose of ATO during consolidation. The standard dose of ATO during consolidation is 12 mg/kg administered over 4 cycles. In our study, patients in the ATO monotherapy group received a median of 5.4 mg/kg of ATO over 2 cycles compared to 11.6 mg/kg over 4 cycles in the ATRA/ATO group. Despite discrepancies in age, comorbidities, and total dose of ATO received, outcomes were similar in the ATRA/ATO and ATO monotherapy groups. Although limited by a small sample size and retrospective design, this study suggests that elimination of ATRA from consolidation may be an acceptable option for patients that are unable to obtain ATRA or that experience intolerable side effects. These findings also suggest that lower cumulative doses of ATO during consolidation may produce similar efficacy with lesser toxicity. Future large, multicenter studies are necessary to confirm the efficacy and safety of these findings. Table Disclosures Manuel: Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau. Pardee:Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding.

Download Full-text

VTE Incidence in RRMM Patients Treated with NOVEL Agents: A Monocentric Real Life Experience

Blood ◽

10.1182/blood-2019-131015 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4972-4972

Author(s):

Gaetano Giuffrida ◽

Concetta Conticello ◽

Valeria Calafiore ◽

Enrica Antonia Martino ◽

Silvia Giamporcaro ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Research Funding ◽

Real Life ◽

Low Risk ◽

Novel Agents ◽

Vte Prophylaxis ◽

High Risk Patients ◽

Risk Patients ◽

Low Incidence

INTRODUCTION: Venous thromboembolism (VTE) is very common in patients with malignancies. Compared to the general population, patients with multiple myeloma (MM) have a 9-fold increased risk of developing VTE. In patients treated with thalidomide or lenalidomide, current guidelines recommend systematic VTE prophylaxis with ASA in low risk patients while vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) or unfractionated heparin (UFH) in high-risk patients, based on the type of anti-MM treatment that patients receive and patient-related individual risk factors (e. g. history of VTE). However, little is known on VTE prophylaxis in patients treated with next generation anti-myeloma drugs, such as pomalidomide, carfilzomib and monoclonal antibodies daratumumab and elotuzumab. Here, we describe the incidence of VTE in MM patients treated with third generation novel agents in real life. In addition, we stratify patients on drugs category-based regimens to evaluate strategy of VTE prophylaxis between different groups of patients. MATERIALS AND METHODS: A retrospective cohort of 137 patients affected by relapsed and/ or refractory multiple myeloma treated with novel agents was analyzed. Patients were followed at the Division of Hematology of Catania from April 2013 to June2019. Our series includes 75 patients exposed to Pomalidomide and Dexametasone (PomaD), 46 patients receiving Carfilzomib, Lenalidomide and desamethasone regimen (KRd), 14 patients exposed to Daratumumab(Dara), 27 patients to Daratumumab, Bortezomib and desamethasone (DaraVD), 4 patients to Daratumumab lenalidomide and desamethasone (DaraRd), and12 patients exposed to Elotuzumab and Lenalidomide (EloRd). Several patients were exposed to multiple lines of treatment with novel agents: the total number of analyzed treatments are 178. Patients were stratified to high or low risk for VTE: risk factors taken into account were obesity, history of VTE, central venous catheter, inhered thrombophilia, surgical procedures and comorbidities such as infections, immobilization, cardiac disease, chronic renal disease. Low risk patients had no or one risk factor; in case of two or more risk factors, the patients were classified as high risk. Low-dose aspirin (ASA 100 mg per os once daily) or equivalent was prescribed in low risk patients, low-molecular-weight heparin (LMWH) or equivalent was given to high risk patients. Only Dara treatment did not include standard prophylaxis in patients without risk factors. RESULTS: Real life observation revealed a low incidence of VTE (6 VTE-4,3%) in patients exposed to novel agents together with a standard prophylaxis in case of risk of thromboembolic complications. Forty patients were at high risk of VTE, while 97 patients were classified as low risk; VTE/PE occurred in 2 high risk patients who refused to make correct LMWH prophylaxis due to the discomfort of the subcutaneous administration, developing distal DVT respectively after cycle 1 and 2 of KRd. Two low risk patients treated with PomaD developed DVT of lower extremities during cycle 2 and 4; 2 low risk patients had pulmonary embolism during PomaD cycle 8. CONCLUSIONS: Low incidence of VTE in patients with RRMM receiving PomaD, KRd, EloRd, DaraVD, DaraRd, Dara or EloRd treatment is probably due to a correct risk assessment and subsequent prophylaxis in case of therapies including immunomodulators or in case of patients with high risk for thromboembolic complications. These data support the use of VTE risk stratification-based prophylactic strategies in myeloma patients treated with new drugs. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.

Download Full-text