scholarly journals Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710

Blood ◽  
2010 ◽  
Vol 116 (19) ◽  
pp. 3751-3757 ◽  
Author(s):  
Bayard L. Powell ◽  
Barry Moser ◽  
Wendy Stock ◽  
Robert E. Gallagher ◽  
Cheryl L. Willman ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Rank Test ◽  
Consolidation Therapy ◽  
Free Survival ◽  
End Point ◽  
To Receive ◽  
Disease Free

Abstract Arsenic trioxide (As2O3) is a highly effective treatment for patients with relapsed acute promyelocytic leukemia (APL); its role as consolidation treatment for patients in first remission has not been defined. We randomized 481 patients (age ≥ 15 years) with untreated APL to either a standard induction regimen of tretinoin, cytarabine, and daunorubicin, followed by 2 courses of consolidation therapy with tretinoin plus daunorubicin, or to the same induction and consolidation regimen plus two 25-day courses of As2O3 consolidation immediately after induction. After consolidation, patients were randomly assigned to one year of maintenance therapy with either tretinoin alone or in combination with methotrexate and mercaptopurine. Ninety percent of patients on each arm achieved remission and were eligible to receive their assigned consolidation therapy. Event-free survival, the primary end point, was significantly better for patients assigned to receive As2O3 consolidation, 80% compared with 63% at 3 years (stratified log-rank test, P < .0001). Survival, a secondary end point, was better in the As2O3 arm, 86% compared with 81% at 3 years (P = .059). Disease-free survival, a secondary end point, was significantly better in the As2O3 arm, 90% compared with 70% at 3 years (P < .0001). The addition of As2O3 consolidation to standard induction and consolidation therapy significantly improves event-free and disease-free survival in adults with newly diagnosed APL. This trial was registered at clinicaltrials.gov (NCT00003934).

A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARα transcript after consolidation therapy: The Japan Adult Leukemia Study Group (JALSG) APL97 study

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 59-66 ◽  
Author(s):  
Norio Asou ◽  
Yuji Kishimoto ◽  
Hitoshi Kiyoi ◽  
Masaya Okada ◽  
Yasukazu Kawai ◽  
...  
Keyword(s):  
Complete Remission ◽  
Acute Promyelocytic Leukemia ◽  
Randomized Study ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Maintenance Chemotherapy ◽  
Free Survival ◽  
Significant Difference ◽  
Disease Free

To examine the efficacy of intensified maintenance chemotherapy, we conducted a prospective multicenter trial in adult patients with newly diagnosed acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Of the 302 registered, 283 patients were assessable and 267 (94%) achieved complete remission. Predicted 6-year overall survival in all assessable patients and disease-free survival in patients who achieved complete remission were 83.9% and 68.5%, respectively. A total of 175 patients negative for PML-RARα at the end of consolidation were randomly assigned to receive either intensified maintenance chemotherapy (n = 89) or observation (n = 86). Predicted 6-year disease-free survival was 79.8% for the observation group and 63.1% for the chemotherapy group, showing no statistically significant difference between the 2 groups (P = .20). Predicted 6-year survival of patients assigned to the observation was 98.8%, which was significantly higher than 86.2% in those allocated to the intensified maintenance (P = .014). These results indicate that the intensified maintenance chemotherapy did not improve disease-free survival, but rather conferred a significantly poorer chance of survival in acute promyelocytic leukemia patients who have become negative for the PML-RARα fusion transcript after 3 courses of intensive consolidation therapy.

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia

2021 ◽  
pp. 107815522110247
Author(s):  
Kyle Zacholski ◽  
Bryan Hambley ◽  
Erin Hickey ◽  
Sarah Kashanian ◽  
Andrew Li ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Survival Rates ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
All Trans Retinoic Acid ◽  
Grade 3 ◽  
Disease Free

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

A randomized trial of amsacrine and rubidazone in 39 patients with acute promyelocytic leukemia.

1991 ◽  
Vol 9 (9) ◽  
pp. 1556-1561 ◽  
Author(s):  
P Fenaux ◽  
G Tertian ◽  
S Castaigne ◽  
H Tilly ◽  
G Leverger ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Confidence Interval ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Early Death ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
The Difference ◽  
To Receive ◽  
Disease Free

Thirty-nine patients with untreated acute promyelocytic leukemia (APL) were randomly allocated to receive rubidazone (zorubicin) 200 mg/m2/d, days 1 to 4 plus cytarabine (Ara C) 200 mg/m2/d, days 1 to 7 (arm A, 21 patients), or amsacrine (Amsa) 150 mg/m2/d, days 1 to 4 plus Ara C 200 mg/m2/d, days 1 to 7 (arm B, 18 patients). Prophylaxis of disseminated intravascular coagulation was made by platelet transfusions and heparin. In case of leukemic resistance, patients received a second course with 2 days of rubidazone (arm A) or Amsa (arm B) and 3 days of Ara C. Patients who achieved complete remission (CR) received three consolidation courses with the two drugs used for induction and maintenance therapy for 3 years. Two patients in arm A and one in arm B were allografted in first CR. Initial characteristics were similar in both arms. In arm A, 18 patients (86%) reached CR, two had hypoplastic death, and one had leukemic resistance after two courses. In arm B, 12 patients (66%) achieved CR, two had early death (CNS bleeding, one case; ventricular fibrillation, one case), and four had resistant leukemia after two courses. The difference in CR rate between the two arms was not significant. In arm A, disease-free survival (DFS) showed a plateau at 54.3% after 34 months (95% confidence interval [CI], 32.1% to 74.9%), with eight CRs longer than 34 months. In arm B, DFS was significantly shorter (P less than .03), showing a plateau at 16.7% after 38 months (95% confidence interval, 4.7% to 44.6%), and only two prolonged CRs were seen. The difference in DFS remained significant after censoring allografted patients and patients who died in CR (one in arm A, two in arm B). Our results suggest that Amsa-Ara C combinations may be inferior to anthracycline-Ara C combinations in the treatment of APL, because they seem to provide shorter DFS and, possibly, a higher incidence of initial leukemic resistance. However, studies with larger numbers of patients are required.

United States Multicenter Study of Arsenic Trioxide in Relapsed Acute Promyelocytic Leukemia

2001 ◽  
Vol 19 (18) ◽  
pp. 3852-3860 ◽  
Author(s):  
Steven L. Soignet ◽  
Stanley R. Frankel ◽  
Dan Douer ◽  
Martin S. Tallman ◽  
Hagop Kantarjian ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Consolidation Therapy ◽  
Free Survival ◽  
Polymerase Chain ◽  
Torsades De Pointe ◽  
To Receive

PURPOSE: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL). PATIENTS AND METHODS: Forty patients experiencing first (n = 21) or ≥ second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study. RESULTS: Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/μL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes. CONCLUSION: This study establishes ATO as a highly effective therapy for patients with relapsed APL.

Minimizing Therapy for Patients with Acute Promyelocytic Leukemia: Efficacy of Single Cycle of Arsenic-Based Consolidation Therapy.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1932-1932
Author(s):  
Steven D. Gore ◽  
Lawrence Morris ◽  
Ivana Gojo ◽  
Marcel P. Devetten ◽  
Katarzyna Jamieson ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Consolidation Therapy ◽  
Event Free Survival ◽  
Rt Pcr ◽  
Single Cycle ◽  
Free Survival ◽  
Disease Free

Abstract Current strategies for the treatment of patients with acute promyelocytic leukemia provide event-free survival of 75 – 85%. Most multicenter studies have used large doses of anthracyclines and multiple cycles of treatment. Based on the extremely high efficacy of arsenic trioxide (ATO) as single agent re-induction therapy, we conducted a Phase II study which minimized anthracycline exposure and treatment duration in newly diagnosed APL patients. The study design was modified from a previous trial which successfully used a single cycle of consolidation chemotherapy (Am. J. Heme.2005;79:119–27). All patients received ATRA for 60 days with daunorubicin (DRN, 60 mg/m2/dose IV) on days 4, 6, 8 unless urgent cytoreduction was required. Consolidation, begun between days 60 and 67, consisted of cytarabine 0.667 gm/m2/day IV continuous infusion days 1 – 3, DRN 60 mg/m2/dose IV days 1 – 3, and ATO 0.15 mg/kg IV for 30 doses, administered five days per week beginning on day 8 of consolidation on an outpatient basis. A second module of ATO was planned for patients with a positive qualitative rt-PCR for PML-RARα (sensitivity 1/10000) following recovery from consolidation. Patients whose initial WBC was &lt; 10,000 per microliter proceeded to ATRA maintenance given for 15 days every three months for 8 cycles. Patients with WBC counts greater than 10,000 per microliter also received 6-mercaptopurine and methotrexate as part of the maintenance regimen. Forty-five patients received induction therapy. Median age was 50; relapse risk categories (Sanz et al. Blood. 2000;96:1247–1253): Low, 36%; Intermediate, 29%; High, 32%. Four patients expired during induction. Of the 41 remaining patients, 4 patients withdrew consent prior to consolidation due to difficulty traveling to the treatment center. 27/31 patients tested following induction achieved molecular remission at that time point (qualitative rt-PCR). 37 patients received consolidation therapy. No patients expired during consolidation, and no patients required a second module of ATO therapy. Only two events have been recorded in patients who underwent consolidation treatment: one patient with Hemoglobin SC disease expired during maintenance therapy due to intrahepatic sickle crisis, possibly related to methotrexate administration, while one patient developed central nervous system relapse. The table compares overall, event free- and disease-free survival of this series to three recent series, including the ATO-containing arm of C9810. Although median follow-up of the current series is shorter, to date the results are comparable to these three studies which employed more extensive therapy. No cases of secondary MDS or AML have been reported to date. Echocardiographic monitoring pre- and post-induction therapy in 24 patients revealed a decrement in ejection fraction post-induction of ≥ 10% in nine patients, including &gt; 20% in three patients to EF values of 20 – 30%, with biopsyproven anthracycline-induced cardiomyopathy documented by biopsy in two patients, indicating possible cardiac sensitization by ATRA to anthracycline. These data suggest that the inclusion of ATO in primary APL management may allow further minimization of conventional cytotoxic chemotherapy without compromising cure rates, and demonstrate the critical need to determine the minimum curative therapy for APL patients. Series Total anthracycline dose administered (mg/m2 DRN equivalent)a Age (median) Sanz Relapse risk: High (percent) Follow- up (years, median) Overall survival Disease- Free Survival Event- Free Survival a Daunorubicin= 1. Mitoxantrone = 2.5. Idarubicin = 5. b nr indicates not reported c Selected based on Sanz risk score 90.5 92.9 83.6 Current 360 50 32 1.8 86 87 77 C9710 ATO arm 500 nrb 24 2.4 82 84 nr PETHEMA LPA99 525 – 625c 37 25 5.4 APL2000 Ara-C arm 495 43 46 5.2 90.5 nr 85.6

scholarly journals Single Cycle of Arsenic Trioxide–Based Consolidation Chemotherapy Spares Anthracycline Exposure in the Primary Management of Acute Promyelocytic Leukemia

2010 ◽  
Vol 28 (6) ◽  
pp. 1047-1053 ◽  
Author(s):  
Steven D. Gore ◽  
Ivana Gojo ◽  
Mikkael A. Sekeres ◽  
Lawrence Morris ◽  
Marcel Devetten ◽  
...  
Keyword(s):  
Maintenance Therapy ◽  
Arsenic Trioxide ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Cytotoxic Agents ◽  
Single Cycle ◽  
Free Survival ◽  
All Trans Retinoic Acid ◽  
Primary Management

Purpose Event-free survival following all-trans-retinoic acid (ATRA) –based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. Patients and Methods After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m2, cardiac ejection fraction decreased by ≥ 20% in 20% of patients. Conclusion These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.

scholarly journals Clinical Investigation of Stratified Therapy in Childhood Acute Promyelocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5286-5286 ◽  
Author(s):  
Yuming Zhang ◽  
Xiaoqing Feng ◽  
Cuiling Wu ◽  
Wenling Guo ◽  
Huiping Li ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Promyelocytic Leukemia ◽  
Risk Group ◽  
Disease Free Survival ◽  
High Risk Group ◽  
Promyelocytic Leukemia ◽  
Free Survival ◽  
Standard Risk ◽  
Disease Free

Abstract OBJECTIVE: The aim of this study was to investigate the clinical biological features, treatment strategy, prognosis and long-term survival in children with acute promyelocytic leukemia（APL）. Focus on the effect of stratified therapy in childhood APL. METHODS: The clinical data of 42 cases of APL with t (15;17) from April 2004 to December 2012 were analyzed retrospectively. Patients were stratified into three risk-group based on white blood cell count and platelet count at diagnosis: standard, intermediate and high-risk group. Induction treatment consisted of all-trans retinoic acid（ATRA）and Idarubicin（IDA）), followed by multi-drug chemotherapy consolidation and a long term maintenance therapy including ATRA,6-Mercaptopurine（6-MP), Methotrexate（MTX）. The complete remission (CR) rate, overall survival (OS) rate, disease free survival (DFS) rate, hematologic and cytogenetic cumulative incidence of relapse (CIR) were compared among the three groups, the stratified therapy in childhood APL and its correlation with clinical prognosis was analyzed. The statistical analyses were performed by SPSS. RESULTS: 42 patients were enrolled (median age 5.8 years, range 1.5-14, 64% males and 36% females), 11 in standard-risk group, 18 in intermediate-risk group, 13 in high-risk group. Immunophenotyping analysis indicated that MPO, CD33, CD13 and CD117 were commonly expressed antigens while HLA-DR and CD34 were mostly the negative markers on APL cells. Of the 42 patients receiving treatment, 38 children (90.5%) achieve complete remission. 1 patient from the high risk group died of intracranial hemorrhage, 1 patient from the Standard Risk group died of anthracycline cardiotoxicity, 1 patient from the intermediate group died of severe infection. The estimated overall survival (OS) rates at 3 and 5 years were （74.2±6.7%）and（70±7.4%）respectively, the disease free survival (DFS) rates were（71±3.8%）and（57±8.1%）respectively. The 3 and 5-year cumulative incidence of relapse (CIR) were 18% and 27%. OS for three groups were (86±7.4%),（71±4、8%）and（57±4.7%）respectively, the 5-year DFS were (82±6.3%), (61±5.3%)and(50±7.2%) and 5-year CIR were 6.7%、18%、35%.There were significant differences in 5-year OS, DFS and CIR rates of three groups (P< 0.05). CONCLUSION: The results indicated that ATRA combined with Anthracycline is effective and safe for treatment of newly diagnosed childhood APL. Prognosis of childhood APL was associated with clinical types. It indicates that stratified therapy according to different risk group can improve the OS and EFS rate and decrease the CIR rate while minimizing chemotherapy-related toxicity. Now, real-time quantitative polymerase chain reaction (RQ-PCR), which can performed to detect PML-RARα fusion transcripts, has become an important means for minimal residual disease (MRD) assays, but it is rarely used in children. Compared with RQ-PCR, clinical risk-adapted classification is a simple, validated and highly predictive index for the determination of stratified therapy in childhood acute promyelocytic leukemia. Disclosures No relevant conflicts of interest to declare.

ΔNp73/TAp73 Expression Ratio Is Associated with Poor Outcome in Acute Promyelocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3536-3536
Author(s):  
Antonio R Lucena-Araujo ◽  
Alexandre Krause ◽  
Rafael Henriques Jacomo ◽  
Priscila S Scheucher ◽  
Guilherme A dos Santos ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Promyelocytic Leukemia ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
Expression Ratio ◽  
Free Survival ◽  
The Mean ◽  
Induced Apoptosis ◽  
Disease Free

Abstract Abstract 3536 ΔNp73 is an alternative TP73 gene transcript lacking the transactivation (TA) domain that is generated via alternative splicing and/or P2 promoter. The encoded protein acts as a potent transdominant inhibitor of wild type TP53 and full-length TAp73. In several human malignancies the unbalanced expression of transcriptionally active (TAp73) and inactive (ΔNp73) variants correlates with treatment outcome. We have previously reported that higher ΔN/TA isoform expression ratio was associated with poorer prognosis and resistance to cytarabine induced apoptosis in patients with acute myeloid leukemia (AML) (Lucena-Araujo et al., 2008). In acute promyelocytic leukemia (APL), both isoforms are expressed, but the clinical significance remains unknown. The aim of this study was to determine whether the ΔN/TA expression ratio was associated with treatment outcome of APL patients and to investigate the mechanisms by which ΔNp73 may contribute to PML-RARa+ cell survival. Using isoform-specific probes for ΔNp73 and TAp73, their expression was analyzed in 166 APL patients by Real-time quantitative polymerase chain reaction (RQ-PCR). Patients were divided into tertiles for ΔN/TA expression ratio (median value=23.62; 33rd/66th percentiles=12.8/42.3) and their clinical and laboratory characteristics were compared. Patients in the highest tertile presented higher white blood cells (WBC) counts than those in intermediate/lower tertiles (p <0.001), but no significant differences were observed for age, gender, PML breakpoint, or platelets count. Higher ΔN/TA expression ratio values were significantly associated with the presence of FLT3-ITD (p =0.001). Treatment outcome was obtained for 131 APL patients enrolled in the APL99 (n=41) and IC-APL (n=90) trials. The mean follow-up was 29.1 months, ranging from 1 to 85.5 months. The mean overall survival (OS) of all patients was of 66.8 months [95%CI; 60.8 to 72.8], whereas it was of 67.1 months [56.5 to 77.7] for patients in the lower and 41.7 months [32 to 51.4] for those in the higher tertile for ΔN/TA expression ratio (p=0.014, Figure 1A). Univariate analysis identified WBC counts above 10,000/μl (p =0.003), FLT3-ITD mutation (p =0.011) and ΔN/TA expression ratio (p =0.014) as predictive factors for OS. However, in multivariate Cox analysis, these three prognostic factors were not independent. Until April 2011, a total of eight relapses (6.1%) were recorded. The disease free survival (DFS) rate at five-years for all patients was of 88.3% ± 4.2% and the mean DFS was of 76.1 months [71.2 to 80.9]. DFS was significantly shorter in patients at the higher tertile ΔN/TA expression ratio compared with patients at the lower tertile (72.1 ± 11.2% vs 97.1 ± 2.8%, respectively; p <0.001; Figure 1B) and was the only variable found to be significant in the univariate analysis. To test the functional significance of the association of PML-RARa with high ΔNp73 gene expression, primary murine bone marrow cells from hCG-PML-RARa transgenic mice were transfected with MSCV-based retroviral vector carrying the ΔNp73 cDNA upstream of IRES-GFP cassette (PML-pMIG-ΔN). Expression of ΔNp73 in PML-RARa+ cells increased cell proliferation rate by 2.5-fold compared to PML-RARa+ transfected with the empty vector (p =0.03). This increase resulted from accumulation of cells at the G2/M phase (5.79 ± 0.08% for PML-pMIG vs 9.8 ± 0.35% for PML-pMIG-ΔN, p <0.001), as well as at S phase of the cell cycle (27.74 ± 0.89% for PML-pMIG vs. 36.78 ± 0.81% for PML-pMIG-ΔN, p =0.001). In addition, transfection of ΔNp73 resulted in resistance to cytarabine-induced apoptosis. After 24h of culture with 50μg/ml of cytarabine (ED-50%), the fractional effect for the drug (% Anexin V-positive in (treated – untreated) cells /100 - % Anexin V-positive in non-treated cells) was 32.1% for PML-pMIG-ΔN and 54.8% for PML-pMIG (p <0.001). In conclusion, ΔN/TA expression ratio was associated with shorter OS and DFS in APL, which may reflect increased cell proliferation and apoptosis resistance due to ΔNp73 activity.Figure 1.Overall (A) and disease-free survival (B) in acute promyelocytic leukemia patients according to ΔN/TA expression ratio.Figure 1. Overall (A) and disease-free survival (B) in acute promyelocytic leukemia patients according to ΔN/TA expression ratio. Disclosures: No relevant conflicts of interest to declare.

Inferior Outcome in Patients with Acute Promyelocytic Leukemia and High Expression of the Ets Related Gene: Role in Leukemogenesis and Potential Implications for Future Therapeutic Approaches?,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3531-3531
Author(s):  
Anna Hecht ◽  
Florian Nolte ◽  
Daniel Nowak ◽  
Verena Nowak ◽  
Benjamin Hanfstein ◽  
...  
Keyword(s):  
Overall Survival ◽  
Molecular Marker ◽  
Acute Promyelocytic Leukemia ◽  
Disease Free Survival ◽  
Promyelocytic Leukemia ◽  
High Expression ◽  
Related Gene ◽  
Term Survival ◽  
Free Survival ◽  
Disease Free

Abstract Abstract 3531 Introduction: In acute promyelocytic leukemia (APL) the translocation t(15;17) leading to the fusion transcript PML-RARα is necessary but not sufficient to generate leukemia. However, additional molecular alterations leading to overt APL remain elusive. The introduction of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) in the treatment of APL has resulted in long term survival in about 75% of patients with de novo APL, but still, relapse occurs in about 15% of cases. However, markers identifying patients at high risk for relapse are not well established yet. The ets related gene (ERG) is a downstream effector of mitogenic signaling transduction. It is involved in key steps regulating cell proliferation, differentiation and apoptosis. High expression of ERG has been shown to be associated with inferior overall survival (OS) and disease free survival (DFS) in different types of hematologic malignancies such as acute myeloid leukemia and T cell acute lymphoblastic leukemia. The aim of this study was to evaluate the role of ERG expression in APL development and to elucidate its value as a prognostic molecular marker in APL patients. Methods: Bone marrow (BM) mononuclear cells were obtained from 86 APL patients (50 female, 36 male) after informed consent. Median age of patients was 47 years with a range from 19 to 82 years. All patients were diagnosed and treated in the German AML Cooperative Group (AMLCG) study. The treatment consisted of simultaneous ATRA and double induction (TAD/HAM) chemotherapy including high-dose ara-C, one cycle of consolidation chemotherapy (TAD) and 3 years monthly maintenance chemotherapy. BM cells were analyzed in triplicates by multiplex reverse transcriptase quantitative real-time PCR (qRT-PCR) on a LightCycler 480 (Roche, Mannheim, Germany). Glucose-6-phosphat isomerase (GPI) served as a housekeeping gene. The comparative cycle threshold (CT) method was used to determine relative ERG expression levels and the cycle number difference (ΔCT=GPI-ERG) was calculated using the mean of ΔCT from the replicates, that is μ(ΔCT) and expressed as 2μ(ΔCT). cDNA from KG1a cells served as a calibrator in each run. Statistical analyses were performed using SAS version 9.2. ERG expression groups were defined as follows: ERG expression higher than the 75th percentile (ERGhigh) and ERG expression lower than the 75th percentile (ERGlow). Time to complete remission (CR), disease free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the curves. Significance was set at p < 0.05. Results: For patients who achieved CR high ERG expression was significantly associated with an inferior OS as compared to lower ERG expression (49% vs. 80% at 10 years, p=0.02). The effect on DFS was even stronger: only 28% of patients in the ERGhigh group survived without relapse after a follow-up of 10 years as compared to 75% of patients in the ERGlow group (p=0.001). However, the expression of ERG did not have an influence on whether patients achieved CR, neither on how fast they achieved CR. Conclusion: In univariate analysis high ERG expression was significantly associated with inferior outcome concerning overall survival and disease free survival. Therefore, ERG expression might serve as a molecular marker for risk stratification. It might identify patients who could benefit from intensified treatment regimens such as maintenance therapy or allogeneic stem cell transplantation. However, multivariate analyses and validation of these data in an independent patient cohort is warranted. Disclosures: No relevant conflicts of interest to declare.

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