The Addition of Bortezomib to Standard Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without Therapeutic Benefit: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 899-899 ◽  
Author(s):  
Richard Aplenc ◽  
Soheil Meshinchi ◽  
Lillian Sung ◽  
Todd A. Alonzo ◽  
Jessica Pollard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Oncology Group ◽  
Standard Chemotherapy ◽  
Free Survival ◽  
Risk Patients ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction: Despite the very high intensity of current chemotherapy regimens for children with acute myeloid leukemia (AML), approximately 50% of patients will experience disease relapse. New therapeutic strategies to improve clinical outcomes have centered on improving the efficacy of standard chemotherapy with novel agents such as gemtuzumab and other agents designed to augment standard chemotherapy. Bortezomib, a proteasome inhibitor, is one such agent. The Children's Oncology Group (COG) Phase III clinical trial AAML1031 tested the hypothesis that the addition of bortezomib to standard chemotherapy would improve treatment outcomes in pediatric patients with newly diagnosed AML. Methods: The COG AAML1031 trial randomized patients younger than 30 years of age with de novo AML to either standard chemotherapy (Arm A) or standard chemotherapy with bortezomib (Arm B). Patients with high allelic ratio FLT3 ITD were offered enrollment on a standard chemotherapy plus sorafenib (Arm C, n = 102) and are excluded from this efficacy analysis. All patients received induction chemotherapy with cytarabine, daunorubicin, and etoposide (ADE). Risk stratification occurred at the end of ADE induction and was based on the presence of high risk cytogenetic/molecular markers and/or minimal residual disease (MRD) >0.1% determined by multidimensional flow cytometry. Low risk patients received three additional courses of chemotherapy consisting of a second course of ADE, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. High risk patients received a second course of cytarabine/mitoxantrone, a third course of cytarabine/etoposide, and then allogeneic stem cell transplant (SCT) from the best available donor. Bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each cycle with one dose de-escalation to 1 mg/m2 allowed for dose limiting toxicity. Results: A total of 1097 patients were randomized to either standard therapy (Arm A, n = 542) or standard chemotherapy with bortezomib (Arm B, n = 555). No statistically significant differences in sex, age, race, ethnicity, WHO classification, initial blast count, or initial CNS status was observed between arms. Remission induction rate did not differ between treatment arms 89% vs 91%, p = 0.457. MRD was negative in 75% of patients on both treatment arms at the end of Induction I and mean MRD measures did not differ significantly: 2.8% vs 1.9%, p = 0.247. For all patients, event free survival (EFS) and overall survival (OS) at 3 years were 44.4% ± 3.8% and 60.6% ± 4.4%. EFS was not significantly different between Arms A and B (44.0% ± 5.2% vs 44.6% ± 5.6%, p = 0.285) (Figure 1). Likewise, OS was similar between arms (59.0 ± 6.7 vs 62.2 ± 6.0, p = 0.732) (Figure 1). One year cumulative treatment related mortality (TRM) was 14.6 ± 9.3 and 10.8 ± 7.5, p = 0.49 for Arms A and B, respectively. No significant differences were seen in OS, disease-free survival, and TRM from the end of Induction I in low and high risk groups. Cox proportional hazards analysis demonstrated that initial WBC count at diagnosis was the only consistently identified risk factor for OS, DFS, and TRM. Targeted toxicity monitoring identified increased toxicity risks in Arm B for peripheral neuropathy (Induction I/II), dose reductions (all chemotherapy courses), and PICU admissions (Induction I/II) and Intensification I). Serial monitoring of cardiac ejection fraction/shortening fraction in all patients did not demonstrate a clinically meaningful difference in drop in ejection fraction/shortening fraction by treatment arm. No other consistent differences in targeted toxicity rates were identified. Conclusions: The addition of bortezomib to standard chemotherapy increased toxicity but did not improve EFS or OS in children with newly diagnosedAML Consequently, bortezomib should not be used in children with de novo AML in combination with standard chemotherapy. Future work will evaluate the role of intensifying Induction II therapy for patients with high risk AML, further refine risk stratification, and define a more optimal role for allogeneic donor SCT in pediatric AML. Figure 1 Figure 1. Disclosures Loken: Hematologics: Employment, Equity Ownership.

Risk-Stratified Therapy and the Intensive Use of Cytarabine Improves the Outcome in Childhood Acute Myeloid Leukemia: The AML99 Trial From the Japanese Childhood AML Cooperative Study Group

2009 ◽  
Vol 27 (24) ◽  
pp. 4007-4013 ◽  
Author(s):  
Ichiro Tsukimoto ◽  
Akio Tawa ◽  
Keizo Horibe ◽  
Ken Tabuchi ◽  
Hisato Kigasawa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Death Rate ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
Intermediate Risk ◽  
Free Survival ◽  
De Novo Aml ◽  
Acute Myeloid

Purpose To improve the prognosis in children with newly diagnosed acute myeloid leukemia (AML) by introducing a dose-dense intensive chemotherapy regimen and an appropriate risk stratification system. Patients and Methods Two hundred forty children with de novo AML were treated with continuous cytarabine-based induction therapy and stratified to three risk groups based on the initial treatment response, age, and WBC at diagnosis and cytogenetics. All of the patients were treated with intensive consolidation chemotherapy including three or four courses of high-dose cytarabine. Allogeneic hematopoietic stem-cell transplantation (HSCT) was indicated for only the intermediate-risk patients with matched related donors and for all the high-risk subsets. Results Two hundred twenty-seven children (94.6%) achieved a complete remission (CR). Four children demonstrated induction death. The median follow-up of the live patients was 55 months (range, 37 to 73 months). The 5-year overall survival of all 240 children was 75.6% (95% CI, 70.3% to 81.4%) and event-free survival was 61.6% (95% CI, 55.8% to 68.1%). The 5-year disease-free survival in each risk group were 71.3% (95% CI, 63.4% to 80.2%) in the low-risk group (n = 112), 59.8% (95% CI, 50.6% to 70.7%) in the intermediate-risk group (n = 92), and 56.5% (95% CI, 39.5% to 80.9%) in the high-risk group (n = 23). Eight children died during the first CR, including four after HSCT. Conclusion A high survival rate, 75.6% at 5 years, was achieved for childhood with de novo AML in the AML99 trial. The treatment strategy was well tolerated with only 1.7% induction death rate and 3.5% remission death rate. Low-risk children were successfully treated with chemotherapy alone.

CBFA2T3-GLIS2 Fusion Is Prevalent in Younger Patients with Acute Myeloid Leukemia and Associated with High-Risk of Relapse and Poor Outcome: A Children’s Oncology Group Report

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 13-13 ◽  
Author(s):  
Heather L Schuback ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Kristen L. Miller ◽  
Samir Kahwash ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Clinical Implications ◽  
Free Survival ◽  
Younger Patients ◽  
De Novo Aml ◽  
Disease Free ◽  
Acute Myeloid

Abstract The cryptic CBA2T3-GLIS2 fusion generated by the inv(16)(p13.3q24.3) was initially identified in megakaryocytic leukemia and later implicated in other acute myeloid leukemia (AML) subtypes. Presence of this fusion may lead to altered expression of the potentially targetable sonic hedgehog and bone morphogenic protein pathways. We determined the prevalence of CBA2T3-GLIS2 in children treated on COG AAML03P1 and AAML0531 protocols, which collectively enrolled 1361 eligible children, adolescents, and young adults with de novo AML, and correlated the presence of this fusion with patient demographics, laboratory features, and clinical outcomes. We also determined the prevalence and clinical implications of CBA2T3-GLIS2 in 71 children with FAB M7 AML treated on 4 consecutive COG AML trials. Of the 1042 diagnostic samples available and tested for CBFA2T3-GLIS2, 45 (4.3%) were positive for the fusion. Fusion-positive patients were significantly younger than fusion-negative patients (2.1 vs. 10.3 years; P<0.001). CBFA2T3-GLIS2 was most prevalent in the youngest patients (10.6% for 0 to <2 year olds and 8.6% for 2 to <5 year olds) [Figure A]. In contrast, no fusion transcripts were identified in 299 unselected adult patients. All FAB subtypes were represented in fusion-positive patients. Overall, FAB M5 and M7 were equally prevalent in fusion-positive patients, and each subtype accounted for 20% of cases [Figure B]. There was a preponderance of MLL rearrangements (N=7) in fusion-positive patients, and 3 more patients had either t(8;21) or inv(16), and 25.6% (N=11) without karyotypic alterations (CN-AML). None of the fusion-positive patients had the t(7;12) or 12p abnormality. There were few common AML-associated mutations: 1 patient had FLT3ITD and 1 had the WT1 mutation (no NPM1 or biallelic CEBPA mutations were identified). Figure 1 Figure 1. Rates of morphologic complete remission (CR) at the end of induction course 1 were similar for fusion-positive and -negative patients (68.9% vs. 77.7%; P=0.17). However, fusion-positive patients were more likely to have minimal residual disease (MRD) by flow cytometry at this time point (50% vs. 28.9%; P=0.006) with a correspondingly higher relapse rate (RR) from remission of 58% vs. 35% (p=0.005). Disease-free survival for those with and without fusion was 42% vs. 58% (p=0.060) In a subset analysis of 193 patients with CN-AML, the prevalence of CBFA2T3-GLIS2 was 4.7%. Fusion-positive patients were younger than fusion-negative patients (1.6 vs. 13.1 years; P<0.001) and more likely to have MRD at the end of induction (85.7% vs. 40.8%; P=0.043). CN-AML fusion-positive patients had significantly worse 5-year OS (36% vs. 67% P=0.025) and EFS (18% vs. 51%, P=0.017) than fusion-negative patients. All fusion-positive patients in CR had a higher 5-year RR than fusion-negative patients (88% vs. 33%; P<0.001), with a corresponding disease-free survival (DFS) of 13% vs. 59% (P<0.001). Implications of CBFA2T3-GLIS2 were evaluated in 71 cases of children with FAB M7 AML where the fusion was identified in 12 patients (17%). Fusion-positive FAB M7 patients had significantly lower CR rate than fusion-negative patients (33.3% vs. 77.6%, P=0.005) and all were MRD positive at the end of induction (100% vs. 30%, P=0.001). All FAB M7 fusion-positive patients relapsed (100% vs. 36%, P=0.007), with a DFS of 0% vs. 60% (p=0.013). As CBFA2T3-GLIS2 was most common in younger patients, we compared clinical implications in children <2 years of age. Although CR rates in fusion-positive and -negative patients were similar (68.2% vs. 74.9%; P=0.50), fusion-positive patients were more likely than fusion-negative patients to have MRD at the end of course 1 (63.2% vs. 24.8%, P=0.006). Five-year RR rates in fusion-positive and -negative patients were 71% vs. 39% (P=0.012), with corresponding DFS of 29% vs. 56% (P=0.030). This study provides a comprehensive evaluation of incidence and prognostic implications of the CBFA2T3-GLIS2 fusion in pediatric de novo AML. Along with MLL rearrangements, 12p abnormalities, and the recently described NUP98-JARID1A fusion, this cryptic inversion 16, as defined by presence of the CBFA2T3-GLIS2 fusion, represents a distinct, recurrent chromosomal abnormality associated with poor prognosis in infant AML and is a potential therapeutic target. Disclosures No relevant conflicts of interest to declare.

BAALC expression predicts clinical outcome of de novo acute myeloid leukemia patients with normal cytogenetics: a Cancer and Leukemia Group B Study

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1613-1618 ◽  
Author(s):  
Claudia D. Baldus ◽  
Stephan M. Tanner ◽  
Amy S. Ruppert ◽  
Susan P. Whitman ◽  
Kellie J. Archer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Free Survival ◽  
De Novo Aml ◽  
Normal Cytogenetics ◽  
Group B ◽  
Leukemia Group ◽  
Acute Myeloid

AbstractCytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). Of adults with de novo AML, 45% lack cytogenetic abnormalities, and identification of predictive molecular markers might improve therapy. We studied the prognostic impact of BAALC (Brain And Acute Leukemia, Cytoplasmic), a novel gene involved in leukemia, in 86 de novo AML patients with normal cytogenetics who were uniformly treated on Cancer and Leukemia Group B 9621. BAALC expression was determined by comparative real-time reverse transcriptase–polymerase chain reaction in pretreatment blood samples, and patients were dichotomized at BAALC's median expression into low and high expressers. Low expressers had higher white counts (P = .03) and more frequent French-American-British M5 morphology (P = .007). Compared to low expressers, high BAALC expressers showed significantly inferior overall survival (OS; median, 1.7 vs 5.8 years, P = .02), event-free survival (EFS; median, 0.8 vs 4.9 years, P = .03), and disease-free survival (DFS; median, 1.4 vs 7.3 years, P = .03). Multivariable analysis confirmed high BAALC expression as an independent risk factor. For high BAALC expressers the hazard ratio of an event for OS, EFS, and DFS was respectively 2.7, 2.6, and 2.2. We conclude that high BAALC expression predicts an adverse prognosis and may define an important risk factor in AML with normal cytogenetics.

Multi-Course of Moderate Dose Cytosine Arabinoside and Fludarabin in the Consolidation Therapy of Patients with De Novo Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4251-4251
Author(s):  
Huiying Qiu ◽  
Wu Depei ◽  
Aining Sun ◽  
Zhengming Jin ◽  
Miao Miao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Hematological Toxicity ◽  
Consolidation Therapy ◽  
Moderate Dose ◽  
Free Survival ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Abstract 4251 To investigate the long-term outcome of multi-course of moderate dose cytosine arabinoside and fludarabin in the consolidation therapy of patients with de novo acute myeloid leukemia (AML). Sixty-seven consecutive de novo AML patients, 38 males, 29 females, including M1 (5 cases), M2a (34 cases), M4 (11 cases), M5 (13 cases), M6 (2 cases), unclassified AML (1 cases), HAL (1 case), were enrolled in this retrospective analysis between 2006 to 2011. Their median age was 32.28 years (range 13–64 years). Cytogenetic analysis showed that 27 patients with normal karyotype, 11 patients with t(8; 21), 4 patients with inv(16), 16 patients with other karyotype. Forty-two cases were classified as low and intermediate risk groups based on karyotype analysis and fusion gene detection. Thirty-eight cases and twenth-nine cases achieved complete remission (CR) after one course and two course induction chemotherapy (such as cytarabine with idarubicin or daunorubicin and mitoxantrone etc), respectively. All patients received at least two-course consolidation therapy with moderate dose cytosine arabinoside (2g/m2) and fludarabin (30mg/m2) for 3 days (FA). Nineteen cases received two courses, 20 three courses, 20 four courses, 8 five courses and1 six courses. Quantitative RT-PCR and flow cytometry were used to detect minimal residual disease. Afterwards 3 patients underwent allogeneic stem cell transplantation. The median time for hematological recovery of neutrophils©ƒ500/microl and platelets©ƒ20,000/microl was 12 and 16 days, respectively. The median length of hospitalization was 18 days. Non-hematological toxicity consisted of mild gastrointestinal reaction and mild hepatic dysfunction, forty percent of patients experienced fever. There was no treatment-related mortality during consolidation. After follow up of 4–54 months, 10/19 (52.6%) cases were relapse-free survival (RFS) after two courses FA consolidation, 15/20 (75%) cases in three courses, 15/20 (75%) cases in four courses, respectively. 8 cases were all in RFS after five courses consolidation. 1 case was also in RFS after six courses FA consolidation. Three-year overall survival, event free survival and RFS was 67%, 67%, and 66%, respectively. Our results suggest that multi-course FA consolidation is effective in de novo AML patients with low-risk and moderate-risk diseases. To reduce the recurrence rate the number of courses should be increased. Non-hematological toxicity was mild and the toxicity is acceptable. Disclosures: No relevant conflicts of interest to declare.

6-Thioguanine, Cytarabine, and Daunorubicin (TAD) and High-Dose Cytarabine and Mitoxantrone (HAM) for Induction, TAD for Consolidation, and Either Prolonged Maintenance by Reduced Monthly TAD or TAD-HAM-TAD and One Course of Intensive Consolidation by Sequential HAM in Adult Patients at All Ages With De Novo Acute Myeloid Leukemia (AML): A Randomized Trial of the German AML Cooperative Group

2003 ◽  
Vol 21 (24) ◽  
pp. 4496-4504 ◽  
Author(s):  
Thomas Büchner ◽  
Wolfgang Hiddemann ◽  
Wolfgang E. Berdel ◽  
Bernhard Wörmann ◽  
Claudia Schoch ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Lactate Dehydrogenase Level ◽  
High Dose ◽  
Free Survival ◽  
Poor Risk ◽  
De Novo Aml ◽  
To Receive ◽  
Acute Myeloid

Purpose: To examine the efficacy of prolonged maintenance chemotherapy versus intensified consolidation therapy for patients with acute myeloid leukemia (AML). Materials and Methods: Eight hundred thirty-two patients (median age, 54 years; range, 16 to 82 years) with de novo AML were randomly assigned to receive 6-thioguanine, cytarabine, and daunorubicin (TAD) plus cytarabine and mitoxantrone (HAM; cytarabine 3 g/m2 [age < 60 years] or 1 g/m2 [age ≥ 60 years] × 6) induction, TAD consolidation, and monthly modified TAD maintenance for 3 years, or TAD-HAM-TAD and one course of intensive consolidation with sequential HAM (S-HAM) with cytarabine 1 g/m2 (age < 60 years) or 0.5 g/m2 (age ≥ 60 years) × 8 instead of maintenance. Results: A total of 69.2% patients went into complete remission (CR). Median relapse-free survival (RFS) was 19 months for patients on the maintenance arm, with 31.4% of patients relapse-free at 5 years, versus 12 months for patients on the S-HAM arm, with 24.7% of patients relapse-free at 5 years (P = .0118). RFS from maintenance was superior in patients with poor risk by unfavorable karyotype, age ≥ 60 years, lactate dehydrogenase level greater than 700 U/L, or day 16 bone marrow blasts greater than 40% (P = .0061) but not in patients with good risk by complete absence of any poor risk factors. Although a survival benefit in the CR patients is not significant (P = .085), more surviving patients in the maintenance than in the S-HAM arm remain in first CR (P = .026). Conclusion: We conclude that TAD-HAM-TAD-maintenance first-line treatment has a higher curative potential than TAD-HAM-TAD-S-HAM and improves prognosis even among patients with poor prognosis.

Impact of Molecular Clonality on Survival in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1385-1385
Author(s):  
Wade L Schulz ◽  
Thomas JS Durant ◽  
Henry Rinder ◽  
Christopher A Tormey ◽  
Richard Torres ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Tumor Heterogeneity ◽  
De Novo ◽  
Prognostic Significance ◽  
Recurrent Mutations ◽  
Early Survival ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background: Tumor heterogeneity has been documented in several malignancies and is generally associated with more aggressive disease and poorer prognosis. While heterogeneity has been documented in acute myeloid leukemia (AML), risk prognosis in AML is currently assessed by cytogenetics and the presence of recurrent mutations in genes such as FLT3 and NPM1, which are typically tested on a single gene basis. Prior approaches to identify molecular clonality have been laborious and therefore of limited clinical utility. The advent of next generation sequencing (NGS), however, allows for the rapid assessment of subclones within tumor populations. Currently, the prognostic significance of tumor heterogeneity in AML is not well defined. Therefore, this pilot study assessed the clinical significance of molecular clonality in AML using data generated by an NGS platform. Methods: We selected patients with de novo AML who had blood or bone marrow submitted for sequencing at initial diagnosis. Patients who subsequently elected for comfort measures only without receiving AML-directed therapy were excluded. Study patients were sequenced with a 25 gene NGS panel on the Ion Torrent platform. This panel included genes that have been shown to be frequently mutated in AML and which lead to increased cellular proliferation or impaired differentiation, with particular emphasis on therapeutic and prognostic mutations. Germline mutations, identified by allelic fraction and/or minor allele frequency, were excluded. Remaining somatic mutations were analyzed with software employing a variational Bayesian algorithm to predict tumor heterogeneity such that patients were assessed for the presence of tumor heterogeneity (≥2 predicted clones) at the time of diagnosis. Heterogeneity was recorded and compared to several clinical parameters, including post-chemotherapy survival at 120 days, patient age, gender, karyotype, and association with the recurrent genetic mutations NPM1, FLT3-ITD, and CEBPA. Results: Twenty patients met the study criteria of de novo AML and elected to receive therapy. The mean age at diagnosis was 59 years (38-77 years); overall survival was 75% at 120 days. Half of the patients (n=10) were determined to have ≥2 clones. Patients with either a complex karyotype or the FLT3-ITD mutation were classified as high risk (n=11). While survival at 120 days was lower in the high risk group (64%) compared to normal risk subjects (89%), this difference did not reach statistical significance (p=0.19). By contrast, patients with tumor heterogeneity (≥2 clones) had significantly lower 120 day survival (50%) when compared to AML patients with a single clone (100%) (p=0.01). There was no correlation between patients with multiple clones and high risk classification (p=0.18). Conclusions: These pilot data present some of the first prospective evidence that heterogeneity detected by NGS is an adverse prognostic indicator for early survival in de novo AML post-chemotherapy. This finding may not be surprising given that the presence of tumor heterogeneity has been shown to confer adverse prognostic risk in several solid malignancies. Still, this early impact of molecular clonality in AML may have important consequences on choice of therapy. Further prospective studies are needed to confirm our findings and to determine the long-term outcomes in AML patient subsets, as well as examining whether a distinct approach to therapy in AML patients with clonal heterogeneity leads to improved early survival. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Pretransplant comorbidity as an outcome predictor in adult patients younger than 60 years of age receiving standard induction chemotherapy for de novo acute myeloid leukemia

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7055-7055
Author(s):  
S. Kim ◽  
J. Lee ◽  
J. Lee ◽  
D. Kim ◽  
S. Lim ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Outcome Predictor ◽  
Free Survival ◽  
Pre Treatment ◽  
De Novo Aml ◽  
Acute Myeloid

7055 Background: Comorbidity has been evaluated as an outcome predictor in elderly patients receiving induction chemotherapy for acute myeloid leukemia (AML) as well as in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for various hematologic disorders. In this single-institute retrospective study, we investigated the prognostic significance of comorbidity in younger AML patients. Methods: A total of 276 patients, aged 14 to 59 years, who received standard induction chemotherapy consisting of cytarabine plus daunorubicin or idarubicin for de novo AML excluding M3 subtype between 2000 and 2007 were included. Pre-treatment comorbidity score, assessed by the HCT specific comorbidity index (HCT-CI), was calculated using clinico- pathologic data, which were retrieved from Asan Medical Center Leukemia Registry Database. The HCT-CI score was 0 in 113 patients (40.9%), 1 in 94 (34.1%), and ≥ 2 in 69 (25.0%). Results: In the univariate analyses, the HCT-CI score was not a significant prognostic factor for induction of complete remission (CR), whereas survival outcomes such as overall survival (OS), relapse-free survival (RFS) and event-free survival (EFS) were significantly different according to the HCT-CI scores (Table). The multivariate models showed that the HCT-CI score was an independent prognostic factor for EFS (P=0.044), but not for OS (P=0.301) and RFS (P=0.119). Other independent prognostic factors were age (P=0.001 for OS, P=0.002 for RFS, P=0.006 for EFS), initial leukocyte counts (P=0.006 for CR, P<0.001 for OS, P=0.039 for RFS), initial uric acid levels (P=0.004 for RFS, P=0.001 for EFS), and cytogenetic risk groups (P=0.012 for CR, P<0.001 for OS, P<0.001 for RFS, P=0.005 for EFS). Conclusions: Pre-treatment comorbidity may provide additional prognostic information over established prognostic factors in patients younger than 60 years of age receiving standard induction chemotherapy for de novo AML. [Table: see text] No significant financial relationships to disclose.

Amount of spontaneous apoptosis detected by Bax/Bcl-2 ratio predicts outcome in acute myeloid leukemia (AML)

Blood ◽  
2003 ◽  
Vol 101 (6) ◽  
pp. 2125-2131 ◽  
Author(s):  
Giovanni Del Poeta ◽  
Adriano Venditti ◽  
Maria Ilaria Del Principe ◽  
Luca Maurillo ◽  
Francesco Buccisano ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Free Survival ◽  
Spontaneous Apoptosis ◽  
Free Survival ◽  
De Novo Aml ◽  
French American British ◽  
Disease Free ◽  
Acute Myeloid

The inability to undergo apoptosis is a crucial mechanism of multidrug resistance in acute myeloid leukemia (AML), and the analysis of mitochondrial apoptotic proteins may represent a significant prognostic tool to predict outcome. Bcl-2 and Bax oncoproteins were evaluated in 255 de novo AML patients (pts) by flow cytometry using an anti–bcl-2 monoclonal antibody (MoAb) and an anti-bax MoAb. The results were expressed as an index (bax/bcl-2) obtained by dividing bax mean fluorescence intensity (MFI) and bcl-2 MFI. Lower bax/bcl-2 ratio was associated with French-American-British (FAB) M0-M1 classes (P = .000 01) and CD34 more than 20% (P < .000 01). There were striking inverse correlations between CD34 or CD117 MFI and bax/bcl-2 values (r = −.40, P < .000 001 andr = −.29, P = .000 002), confirming that immaturity is consistent with this index. Moreover, lower bax/bcl-2 levels were correlated with poor-risk cytogenetics (P = .0002). A significant higher complete remission (CR) rate was found in pts with higher bax/bcl-2 levels (79% versus 45%; P = .000 01). Also, both a longer overall survival (OS) and disease-free survival (DFS) were observed in pts with higher bax/bcl-2 levels (P = .000 01 and = .019). Noteworthy, bax/bcl-2 levels accurately predicted the clinical response and outcome of pts with normal or unknown cytogenetics. Indeed, within this subset of 147 pts, higher bax/bcl-2 ratio was significantly associated both with a higher CR rate (86% versus 42%;P < .000 01) and a longer OS (P = .0016). The independent prognostic value of bax/bcl-2 ratio was confirmed in multivariate analysis. Therefore, mitochondrial oncoproteins, such as bcl-2 and bax, represent both sensitive indicators of clinical outcome and potential targets of novel proapoptotic molecules in order to circumvent chemoresistance.

IDH Mutations and Trisomy 8 In Myelodysplastic Syndromes and Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4009-4009
Author(s):  
Domenica Caramazza ◽  
Terra Lasho ◽  
Christy Finke ◽  
Naseema Gangat ◽  
David Dingli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Trisomy 8 ◽  
Idh Mutations ◽  
De Novo Aml ◽  
Idh2 Mutation ◽  
Acute Myeloid

Abstract Abstract 4009 Trisomy 8 is the most common among sole cytogenetic abnormalities in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In the very first paper published on isocitrate dehydrogenase (IDH) mutations in AML, 13 of the 16 IDH1 mutations detected were associated with normal karyotype, 2 with trisomy 8 and one with trisomy 13. Trisomy 8 was also recurrent in patients with IDH1/IDH2-mutated post-MDS AML. In the current study we examined the prevalence and disease distribution of IDH1 and IDH2 mutations in a large (n=157) group of patients with hematologic malignancies and isolated trisomy 8. The Mayo Clinic cytogenetic database allowed identification of 157 patients with isolated trisomy 8. Archived bone marrow cell pellets were used to extract DNA for IDH1 and IDH2 mutation analysis. Eighteen IDH mutations were identified: 15 IDH2 (14 R140Q and one R140W) and 3 IDH1 (2 R132C and one R132G). Seventeen of the 18 IDH mutations occurred in myeloid malignancies whereas one (IDH2R140W) occurred in a patient with angioimmunoblastic lymphoma who was not previously exposed to chemotherapy or radiotherapy, and in whom the IDH2 mutation disappeared after effective lymphoma chemotherapy. Among the 17 IDH-mutated myeloid malignancies, disease-specific IDH1/IDH2 mutational frequencies were as follows: 27% (3/11) for post-MDS AML, 25% (3/12) for therapy-related MDS/AML, 15% (8/54) for de novo MDS, 13% (2/15) for de novo AML and 3% (1/32) for myeloproliferative neoplasm (MPN). In contrast, IDH mutational frequencies were significantly lower among 64 additional patients with AML or MDS without isolated trisomy 8: 7% in de novo AML (n=28), 0% in de novo MDS (n=21), 0% in post-MDS AML (n=11) and 0% in therapy-related MDS/AML (n=4). In the 54 patients with trisomy 8-associated de novo MDS, prognosis was similar between IDH mutated (n=8; median survival 14 months) and unmutated (n=46; median survival 16 months) cases (p=0.7). The majority of IDH-mutated cases with de novo MDS belonged to high risk MDS disease category. However, 3 of the 8 IDH-mutated patients with de novo MDS and 2 of the 3 with therapy-related MDS did not display excess bone marrow blasts. The current study suggests a possible association between IDH mutations and trisomy 8 in AML and MDS but not in MPN or MDS/MPN. The fact that the mere presence of trisomy 8 did not result in a more than expected incidence of IDH mutations in MPN or MDS/MPN makes it unlikely that such an association would be secondary to trisomy 8-associated genetic or biologic changes. Instead, it is possible that IDH mutations, which have been shown to cluster with high-risk disease in both MPN and MDS associated with 5q-, promote a selective advantage for the survival of the clone that harbors trisomy 8. Consistent with this contention, we were able to demonstrate in one of our patients with relapsed AML, the presence of IDHR132C both at initial AML diagnosis and time of relapse, whereas the trisomy 8 abnormality was seen only at the time of relapse. Regardless, the presence of molecular heterogeneity among patients with trisomy 8-associated AML or MDS might explain the controversial prognostic influence of the specific cytogenetic abnormality. Disclosures: No relevant conflicts of interest to declare.

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