scholarly journals Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5409-5415 ◽  
Author(s):  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
Jean-Pierre Bourquin ◽  
Michael N. Dworzak ◽  
Christine von Neuhoff ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Independent Predictor ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Event Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
High Dose Cytarabine ◽  
Pediatric Aml

Abstract Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) and inv(16)/t (16;16) subtypes requires intensification remained to be determined. In the 2 successive studies (AML-BFM-1998 and AML-BFM-2004), 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study AML-BFM-1998 but not in AML-BFM-2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n = 78) compared with without HAM (n = 53): OS 92% ± 3% versus 80% ± 6%, plogrank0.047, EFS 84% ± 4% versus 59% ± 7%, plogrank0.001, and CIR 14% ± 4% versus 34% ± 7%, p(gray)0.006. These differences were not seen for inv(16) (n = 43 and 46, respectively): OS 93% ± 4% versus 94% ± 4%, EFS 75% ± 7% versus 71% ± 9% and CIR 15% ± 6% versus 23% ± 8% (not significant). The subtype t(8;21), but not inv(16), was an independent predictor of worse outcome without HAM reinduction. Based on our data, a 5-year OS of > 90% can be expected for CBF-AML, when stratifying t(8;21), but not inv(16), patients to high-risk chemotherapy, including HAM reinduction.

scholarly journals Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia

Blood ◽  
2018 ◽  
Vol 132 (2) ◽  
pp. 187-196 ◽  
Author(s):  
Raphael Itzykson ◽  
Nicolas Duployez ◽  
Annette Fasan ◽  
Gauthier Decool ◽  
Alice Marceau-Renaut ◽  
...  
Keyword(s):  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Event Free Survival ◽  
Clonal Interference ◽  
Core Binding Factor ◽  
Free Survival ◽  
Ras Pathway ◽  
Binding Factor ◽  
Key Points ◽  
Acute Myeloid

Key Points Presence of ≥2 independent subclones in the receptor tyrosine kinase/RAS pathway, defining clonal interference, is found in 28% of CBF AMLs. Clonal interference predicts shorter event-free survival independently of clinical variables and presence of specific signaling mutations.

Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation?

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 209-219 ◽  
Author(s):  
Peter Paschka ◽  
Konstanze Döhner
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Genetic Alterations ◽  
High Dose ◽  
Core Binding Factor ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Binding Factor ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered in the setting of repetitive cycles. For many years, high-dose cytarabine was the standard treatment in CBF-AML resulting in favorable long-term outcome in approximately half of the patients. Therefore, CBF-AML patients are generally considered to be a favorable AML group. However, a substantial proportion of patients cannot be cured by the current treatment. Additional genetic alterations discovered in CBF-AML help in our understanding of the process of leukemogenesis and some of them may refine the risk assessment in CBF-AML and, importantly, also serve as targets for novel therapeutic approaches. We discuss the clinical and genetic heterogeneity of CBF-AML, with a particular focus on the role of KIT mutations as a prognosticator, and also discuss recent efforts to target the KIT kinase in the context of existing therapeutic regimens.

Core Binding Factor Acute Myeloid Leukemia of the Elderly Treated with Conventional Chemotherapy: A Collaborative Study of the French CBF AML Intergroup

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 553-553
Author(s):  
Thomas Prebet ◽  
Nicolas Boissel ◽  
Christian Recher ◽  
Xavier Thomas ◽  
Jacques Delaunay ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
The Elderly ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Wbc Count ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia with rearrangements of CBFα or β (CBF-AML) are associated with a younger age and with a good prognosis when treated with intensive chemotherapy. CBF are infrequent in elderly patients (Appelbaum BJH 2006) and are associated with a better outcome as compared to other AMLs. Complete Remission (CR) rate and Event Free Survival (EFS) seemed to be lower than what was observed for younger patients. However, only limited data are available on the characteristics and outcome of CBF-AML in the elderly. We presents the results of a retrospective analysis of 150 patients with t(8;21) or inv(16) older than 60 years who received conventional induction chemotherapy in 17 centres of the french CBF AML intergroup (GOELAMS/ALFA groups). All patients received conventional anthracyclin + cytarabine induction therapy. Post-remission therapy consisted of low dose maintenance chemotherapy (87 patients 58%), intermediate or high dose cytarabine (47 patients, 31%) or Melphalan with autologous (SCT: 9 patients 6%). Median age was 67 years (range 60–82y). Inv(16) was found in 88 pts (58%) and t(8;21) in 62pts (42%). Additionnal chromosomal abnormalities were identified in 66 patients (44%) including 16 with trisomy 22 (11%) only in pts with Inv(16), 19 (13%) with loss of sex chromosome and 7 (5%) with del 9q mostly found in t(8;21). 132 patients achieved CR after 1 or 2 induction courses (88% CR rate), 3 pts had refractory diseasea and 15 died early (10%). 17 pts (11%) required ICU transfer during induction. Induction mortality was significantly related to poor performance status (p<0.001) and High WBC count at diagnosis(p=0.015). With a median follow-up of 17 months, Overall Survival (OS) and EFS were respectively 24 and 19 months. By multivariate analysis of factors influencing OS and LFS are presented in the Table. Outcome was favorable for Inv(16) patients (OS=27 months, EFS=22 months) compared to t(8;21) patients (OS=21 months, EFS=14 months). Interestingly, the benefit of intensive consolidation was limited to t(8;21) AML (EFS NR vs 11 months, p=0.002). No impact of age as a continuous variable could be demonstrated. After relapse, Median Overall survival was 5 months with a significantly better outcome in Inv(16) patients and if relapse was delayed (more than 12 months after CR1). No impact of age on outcome after relapse could be demonstrated. This large series of elderly patients with CBF-AML show that these patients must be offered standard induction which leads to high CR rate whatever the age. Nevertheless, the majority of them relapse with conventional post-remission treatment and the impact of intensive chemo seems limited. Alternative strategies of post-remission therapy are thus warranted including new cytotoxic drugs as well as targeted molecules. Variable RR Overall survival p= RR Event Free Survival p= High WBC count 2.56 [1.464–4.491] 0.001 2 [1.104–3.562] 0.022 ECOG (0–1 vs 2–4) 5.12 [2.878–9.112] < 0.001 2.76 [1.457–5.215] 0.002 Deletion 9q 5.06 [2.125–12.05] < 0.001 3.32 [1.445–7.629] 0.005 ICU admittance during induction 5.18 [2.744–9.764] < 0.001 2.86 [1.216–6.717] 0.016 use of High Dose Cytarabine 0.373 [0.196–0.708] 0.003 NS NS

Excess Reduction of Anthracyclines Results in Inferior Event-Free Survival in Core Binding Factor Acute Myeloid Leukemia in Children; A Report From the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 409-409 ◽  
Author(s):  
Daisuke Tomizawa ◽  
Akio Tawa ◽  
Tomoyuki Watanabe ◽  
Akiko Moriya Saito ◽  
Kazuko Kudo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Risk Stratification ◽  
Cumulative Dose ◽  
Myeloid Leukemia ◽  
Event Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Intensive Use ◽  
Acute Myeloid

Abstract Abstract 409 Background: Intensive combination chemotherapy of Ara-C and anthracyclines, together with optimal risk stratification, led to 70% probability of survival (pOS) in childhood acute myeloid leukemia (AML) nowadays. Therefore, one of the main subjects for AML chemotherapy in children is to reduce anthracyclines to avoid late cardiotoxicity which could occur in lower cumulative dose compared to adults. High-dose (HD) Ara-C has contributed to improved survival especially in core binding factor (CBF)-AML, and we hypothesized that the intensive use of HD Ara-C could compensate for reduction of anthracycline dose in children with CBF-AML. Patients & Methods: JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, is a nation-wide multi-institutional study and recruited 447 eligible children (age <18 years) with de novo AML from 11/1/2006 to 12/31/2010 (acute promyelocytic leukemia and Down syndrome patients excluded). Three patients including 2 children with t(8;21) who discontinued from the study during induction therapy are excluded from the efficacy analyses: one protocol violation, 1 changing to non-JPLSG member hospital at the patient's request, and 1 withdrawal of the JPLSG institutional membership. After 2 courses of common induction therapies, patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups. Patients with CBF-AML, t(8;21) or inv(16), and good bone marrow response to the first induction course were stratified to the low risk (LR) group, and further received 3 courses of chemotherapy; 4/5 courses consisted of HD Ara-C, and the total cumulative dose of anthracyclines, Mitoxantrone and Idarubicin, was reduced from 300 to 225 mg/m2 compared to the LR chemotherapy in the previous AML99 study (Tsukimoto I. J Clin Oncol 2009;27:4007–13). Conversion rate of 5:1 was used to compare the cumulative dose of Daunorubicin and Mitoxantrone/Idarubicin. Results: Three-year probability of event-free survival (pEFS) and 3y-pOS of all 444 patients was 55.3% (95%CI, 50.2 – 60.1%) and 73.2% (68.3 – 77.5%), respectively. The median follow-up period for living patients was 3.06 years (range, 0.84 – 5.36 years). One hundred fifty-five CBF-AML patients [34.9%; t(8;21), N=123 (27.7%); inv(16), N=32 (7.2%)] in the AML-05 and 89 patients [37.0%; t(8;21), N=77 (32.0%); inv(16), N=12 (5.0%)] in AML99 were compared. There were no differences in basic characteristics such as sex and age/WBC at diagnosis. CR rate was identical between the 2 cohorts (95.5% vs. 97.8%, p = 0.36). There was a tendency of lower 3y-pEFS in the AML-05 cohort [69.3% (95%CI, 60.8 – 76.3%) vs. 80.9% (71.1 – 87.7%), p = 0.078], however, 3y pOS did not differ [92.2% (85.8 – 95.8%) vs. 92.1% (84.2 – 96.2%), p= 0.94]. One hundred thirty-six CBF-AML patients were stratified to the LR group in AML-05; 8 patients were stratified to the HR group and allocated to allogeneic hematopoietic transplantation in 1CR because of poor treatment response (N=5) or FLT3-ITD positivity (N=3), and 11 patients were off protocol therapy before risk stratification because of various reasons. These 136 LR patients were compared with 83 CBF-AML patients in AML99 who fulfilled AML-05 LR criteria; 7/83 t(8;21) cases with WBC ≥ 50,000/μL in AML99 received intermediate risk (IR) chemotherapy with 375 mg/m2 of anthracyclines according to the protocol. The 3y-pEFS was significantly lower in the AML-05 cohort [69.6% (60.6 – 77.0%) vs. 83.1% (73.2 – 89.6%), p = 0.041], although the 3y-pOS was not different [92.6% (85.6 – 96.3%) vs. 94.0% (86.1 – 97.5%), p= 0.74]. Conclusions: The pEFS of children with CBF-AML treated with very low cumulative dose of anthracyclines were inferior to the historical control even treated with intensive use of HD Ara-C, therefore, caution is needed to reduce cumulative anthracycline doses to below 300mg/m2. However, the fact that nearly 70% of the CBF-AML patients are cured with lower dose of anthracyclines suggest the presence of underlying biological factors to be identified for future stratification of CBF-AML in children. Disclosures: No relevant conflicts of interest to declare.

scholarly journals MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

2017 ◽  
Vol 35 (35) ◽  
pp. 3964-3977 ◽  
Author(s):  
Emilia L. Lim ◽  
Diane L. Trinh ◽  
Rhonda E. Ries ◽  
Jim Wang ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oxidative Phosphorylation ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
Outcome Prediction ◽  
Classification Scheme ◽  
Event Free Survival ◽  
Free Survival ◽  
Pediatric Aml ◽  
Acute Myeloid

Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

Predictive Value of Molecular Remissions Post Consolidation Chemotherapy in Patients with Core Binding Factor (CBF) Acute Myeloid Leukemias – a Single Centre Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3693-3693
Author(s):  
Uday Deotare ◽  
Marwan Shaheen ◽  
Joseph M. Brandwein ◽  
Bethany Gill ◽  
Suzanne Kamel-Reid ◽  
...  
Keyword(s):  
Median Time ◽  
High Dose ◽  
Relapse Free Survival ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Post Induction ◽  
Binding Factor ◽  
High Dose Cytarabine ◽  
Time To Relapse

Abstract Background: Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). Although this group represents a favorable cytogenetic AML subgroup, 30-40% of these patients nevertheless relapse after standard intensive chemotherapy. The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered as 2-4 repetitive cycles. Here we present retrospective data from a single centre, on this favourable AML subgroup. Methods: We analyzed retrospectively the outcome of 80 sequential patients with CBF-AML (46 t(8;21), 34 inv(16)/t(16;16)) treated over a 13 year period from 2000-2012. The median age was 48 years (range 20-80) with a median white cell count of 13x109/L(range 1-426x109/L). All patients underwent induction chemotherapy consisting of daunorubicin (60 mg/m2/d x 3 days) and continuous infusion cytarabine (100 or 200 mg/m2/d x 7 days, for ages <60y and ≥60y, respectively). Patients in CR then received 3 cycles of consolidation chemotherapy which included high dose cytarabine (3 or 1.5 g/m2 on days 1, 3 and 5, for ages <60y and ≥60y, respectively) with daunorubicin 45 mg/m2 on days 1 and 3 added during cycle 1. Results: Ninety percent of patients achieved morphological complete remission (CR) post induction, but 33.3% of these remained molecularly positive by quantitative reverse transcriptase polymerase chain reaction (qR-PCR). The majority of patients (93.6%) subsequently achieved molecular negativity by qR-PCR after the 3rd consolidation cycle. With a median follow-up of 5 years, the estimated 5-year relapse free survival (RFS) was 58% and 5-year overall survival (OS) was 66%. This is in keeping with the earlier AMLSG and UK MRC studies. Only 21% of patients relapsed and the median time to relapse was 10 months. Of the 16 patients who relapsed, 7 underwent allogeneic hematopoietic cell transplantation (HCT) from HLA- matched sibling or unrelated donors, and of these, 4 remain alive and in remission with a median follow up of 8 years. While relapse occurred in 2 of the 4 patients who did not achieve a molecular CR after 3 cycles of consolidation, 13 of 16 relapsing patients had been in a molecular CR after final consolidation and one patient was not evaluated. Therefore, molecular remission post consolidation does not guarantee long term disease free survival. Further molecular analyses and the roles of additional mutations in predicting relapse will be presented. Conclusion: Sustained remissions can be achieved in patients with CBF AML after 3 cycles of high dose cytarabine consolidation, but post consolidation molecular remission does not necessarily preclude relapse. Comprehensive molecular profiling may be better in predicting relapse risk in this group of patients. Table1: Patient characteristics & response N=80 Sex 45 M : 35 F Median age, years (range) 48 (20-80) WBC at diagnosis (x106 cells/L) (range) 13 (1-426) Cytogenetics t(8;21) inv16/t(16;16) 46 (58%) 34 (42%) Response post-induction chemotherapy CR Primary refractory 72 (90%) 8 (10%) Number of consolidation cycles (range) 3 (2-4) Molecular CR post –induction Yes No Not evaluated 16 (20%) 32 (40%) 32 (40%) Molecular CR post –consolidation –cycle 3 Yes No Not evaluated 59 (74%) 4 (5%) 17 (21%) Relapse Yes No Unknown 16 (20%) 59 (74%) 5 (6%) Median time to relapse, months (range) 10 (6-17) Median time to follow up, y (range) 5 (0.5-11.5) Figure 1 : Overall and Relapse free survival in CBF-AML patients. Figure 1 :. Overall and Relapse free survival in CBF-AML patients. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

Patients With t(8;21)(q22;q22) and Acute Myeloid Leukemia Have Superior Failure-Free and Overall Survival When Repetitive Cycles of High-Dose Cytarabine Are Administered

1999 ◽  
Vol 17 (12) ◽  
pp. 3767-3775 ◽  
Author(s):  
John C. Byrd ◽  
Richard K. Dodge ◽  
Andrew Carroll ◽  
Maria R. Baer ◽  
Colin Edwards ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
Group B ◽  
To Receive ◽  
Leukemia Group ◽  
Acute Myeloid

PURPOSE: To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS: Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either ≥ three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared. RESULTS: A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or ≥ three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P = .03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received ≥ three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P = .04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received ≥ three cycles of high-dose cytarabine. CONCLUSION: These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.

scholarly journals Clinical Outcomes Based on Measurable Residual Disease Status in Patients with Core-Binding Factor Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

2020 ◽  
Vol 10 (4) ◽  
pp. 250
Author(s):  
Wannaphorn Rotchanapanya ◽  
Peter Hokland ◽  
Pattaraporn Tunsing ◽  
Weerapat Owattanapanich
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Meta Analysis ◽  
Recurrence Free Survival ◽  
Negative Group ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
Measurable Residual Disease ◽  
Acute Myeloid

Measurable residual disease (MRD) response during acute myeloid leukemia (AML) treatment is a gold standard for determining treatment strategy, especially in core-binding factor (CBL) AML. The aim of this study was to critically review the literature on MRD status in the CBF-AML to determine the overall impact of MRD status on clinical outcomes. Published studies in the MEDLINE and EMBASE databases from their inception up to 1 June 2019 were searched. The primary end-point was either overall survival (OS) or recurrence-free survival (RFS) between MRD negative and MRD positive CBF-AML patients. The secondary variable was cumulative incidence of relapse (CIR) between groups. Of the 736 articles, 13 relevant studies were included in this meta-analysis. The MRD negative group displayed more favorable recurrence-free survival (RFS) than those with MRD positivity, with a pooled odds ratio (OR) of 4.5. Moreover, OS was also superior in the MRD negative group, with a pooled OR of 7.88. Corroborating this, the CIR was statistically significantly lower in the MRD negative group, with a pooled OR of 0.06. The most common cutoff MRD level was 1 × 10−3. These results suggest that MRD assessment should be a routine investigation in clinical practice in this AML subset.

Sign in / Sign up

Export Citation Format

Share Document