Impactof NOTCH1, FBXW7 and SETD2 Mutations On Early Treatment Response In Childhood T-Cell Acute Lymphoblastic Leukemia：A China Children’s Leukemia Group Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4937-4937
Author(s):  
Wei Wei ◽  
Xiaojuan Chen ◽  
Yao Zou ◽  
Lixian Chang ◽  
Zhu Xiaofan
Keyword(s):  
T Cell ◽  
High Risk ◽  
Treatment Response ◽  
Lymphoblastic Leukemia ◽  
High Risk Group ◽  
Missense Mutations ◽  
Early Treatment Response ◽  
Notch1 Mutations

Abstract T-cell lymphoblastic leukemia (T-ALL) is an aggressive malignancy accounting for about 15% of newly diagnosed acute lymphoblastic leukemia (ALL) in children. Although the prognosis has been improved by intensified therapies, the outcome of high risk patients is still not optimistic. Activating NOTCH1 and/or FBXW7 mutations have been reported to be the leading genetic abnormality in T-ALL with good prognosis but few studies about the role of NOTCH1 and FBXW7 in T-ALL were conducted in China and their mutation distributions and clinical prognosis are still unclear. On the other hand, loss of function mutations of SETD2, a histone methyltransferase specific for trimethylation of histone H3 on Lys36 (H3K36me3), has been found in renal cell carcinoma, gliomas and early T cell precursor ALL (ETP-ALL). SETD2 is a potential tumor suppressor gene and may play a deleterious role in human cancer. We attempted to investigate the role of these mutations in Chinese T-ALL children. Thirty-seven bone marrow samples from childhood patients with newly diagnosed T-ALL (26 boys and 11 girls; age＜14 years) enrolled into the China Children’s Leukemia Group (CCLG) ALL-2008 trail from September 2010 to December 2012 were analyzed for SETD2, NOTCH1, FBXW7 mutations. All exons of SETD2, exons 25-28, 34 of NOTCH1 and exons 5, 7-12 of FBXW7, including intron-exon boundaries, were sequenced by Sanger method. NOTCH1 mutations were observed in 43.2% (n=16) of the T-ALL patients. Thirteen missense mutations were found in HD-N domain, HD-C domain and TAD domain of NOTCH1 while only frameshift insertions and deletions were identified in PEST domain. Besides missense mutations, five inframe insertions were also observed in HD-N domain of NOTCH1. We only found one FBXW7 synonymous mutation in our patients, which was extremely low compared with that in other studies. SETD2 somatic mutations were found in 8.1% (n=3, one female and two males) of 37 T-ALL patients. Of the three patients, two patients had truncated SETD2 protein because of nonsense mutation (c.6229 C＞T) and frameshift insertion (c.7516_7517insTTATA) respectively. Both SETD2 and NOTCH1 mutations were found in one patient. In our study, no significant relationships between NOTCH1 status and age, sex, mediastinal or Central Nervous System (CNS) involvement, immunophenotype and cytogenetics were observed. However, White Blood Cell (WBC) count at diagnosis in patients without NOTCH1 mutation were much higher (221×109/L vs 76.95×109/L, P=0.015). Patients with NOTCH1 mutations had a better early treatment response: higher prednisone good response rate (81.2% vs 47.6%, p=0.048), higher incidence of bone marrow M1 status (blast cell＜5%) on day 15 (73.3% vs 33.3%, p=0.04), and higher rate of favorable minimal residual disease (MRD) level on day 88 (100% vs 59.9%, p=0.012). In contrast, patients without NOTCH1 mutations were more likely to fall into the high risk group (71.4% vs 21.4%, p= 0.006) according to our treatment protocol. After a median follow-up of 11 months, 1 patient did not reach complete remission (CR), 2 patients died during induction and 2 patients relapsed in 6 months. Patients who suffered relapse and induction failure are all in the NOTCH1 wild type group. SETD2 mutations seemed to have no relationship to sex, age, WBC, cytogenetics, CNS and mediastinal involvement. In contrast to previous study that found SETD2 mutations only in EPT ALL patients, none of our SETD2 mutated patients were ETP ALL, two were cortical-T ALL and one was pre-T ALL. All of the patients with SETD2 mutations were alive without the disease at the last follow-up. However, all of the patients were in the high risk group. The patient who had both NOTCH1 and SETD2 mutations responded poorly to prednisone. Although the other two patients without NOTCH1 mutations had good response to prednisone, favorable BM status on day 15 and low MRD on day 33, they had very high MRD levels (0.21% and 0.44% respectively) on day 88. NOTCH1 activating mutations were found in 43.2% of pediatric T-ALL patients enrolled in the CCLG ALL-2008 study with good treatment response while FBXW7 mutation rate was much lower. SETD2 mutation was a recurrent event in pediatric T ALL not only in ETP ALL. It seems that patients with SETD2 mutations have high risk of poor response to chemotherapy regardless of NOTCH1 status. Further studies are needed to find out the prognostic significance of SETD2 mutation in pediatric T ALL. Disclosures: No relevant conflicts of interest to declare.

Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1151-1157 ◽  
Author(s):  
Stephen Breit ◽  
Martin Stanulla ◽  
Thomas Flohr ◽  
Martin Schrappe ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
T Cell ◽  
Treatment Response ◽  
Early Treatment ◽  
Lymphoblastic Leukemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Early Treatment Response ◽  
The Impact ◽  
Notch1 Mutations

Abstract Activating mutations of the transmembrane receptor NOTCH1 are common in precursor T-cell lymphoblastic leukemia (T-ALL). We systematically analyzed the impact of activating NOTCH1 mutations on early treatment response and long-term outcome in 157 patients with T-ALL of the pediatric ALL–Berlin-Frankfurt-Munster (BFM) 2000 study. We confirm previous results that NOTCH1 mutations occur in more than 50% of T-ALL in children. In 82 patients (82/157; 52.2%), activating NOTCH1 mutations were identified either in the heterodimerization (55/82; 67.1%), in the PEST (13/82; 15.9%), or in both domains (14/82; 17.0%). The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favorable minimal residual disease (MRD) kinetics, which was independent from sex, age, white blood cell count, and T-cell immunophenotype at the time of diagnosis. Furthermore, activating NOTCH1 mutations specified a large subgroup of patients with an excellent prognosis. These findings indicate that in the context of the ALL-BFM 2000 treatment strategy, NOTCH1 mutations predict a more rapid early treatment response and a favorable long-term outcome in children with T-ALL.

Activating NOTCH1 Mutations Are Associated with Good Treatment Response in Childhood T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1444-1444
Author(s):  
Stephen Breit ◽  
Martin Stanulla ◽  
Thomas Flohr ◽  
Martin Schrappe ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Confidence Interval ◽  
Treatment Response ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Impact ◽  
Notch1 Mutations

Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15 % of pediatric ALL. Very rare cases of T-ALL (< 1 %) harbor the chromosomal translocation t(7;9) that involves NOTCH1, a gene encoding a single-pass, heterodimeric transmembrane receptor. NOTCH1 has an essential function in early intrathymic T-cell development. Recently, it has been demonstrated that more than 50 % of childhood T-ALLs carry activating mutations within the NOTCH1 gene (Weng et al., Science 2004). In the present study, we systematically analyzed the impact of activating NOTCH1 mutations on treatment response in 108 pediatric T-ALLs, registered in the ongoing ALL-BFM 2000 trial. In 56 cases (51.8%) activating NOTCH1 mutations were identified, located either in the heterodimerization (38/56 mutations; 65.5%), in the PEST (10/56; 17.9%) or in both domains (8/56; 14.3%). The presence of activating NOTCH1 mutations was significantly correlated with good prednisolone (p = 0.001, c2 or Fisher’s exact test) and MRD response (p = 0.002). T-ALLs with NOTCH1 mutations were 3.7 times more likely to show a good prednisolone response (95% confidence interval = 1.64–8.33; p = 0.002) and 4.8 times more likely to show a favorable MRD response (95% confidence interval = 2.04–11.11; p = 0.0003) when compared to patients with wild type NOTCH1. Patients with mutated NOTCH1 were thus underrepresented in the high risk group of the ALL-BFM 2000 protocol. This influence of NOTCH1 mutational status on risk stratification was independent from other commonly used criteria, like age and initial white blood cell count (WBC) at the time of diagnosis. Considering the impact of NOTCH1 mutations on long term prognosis, we analyzed those 49 patients of this cohort with a median follow-up of > 4 years. Eight patients relapsed within this follow-up period, 2 patients with mutated and 6 with wild type NOTCH1. With this small number of relapses, this trend towards a favorable influence of activating NOTCH1 mutations on EFS did not reach statistical significance. In conclusion, T-ALLs with NOTCH1 mutations are demonstrated to be more sensitive than those without to the ALL-BFM 2000 treatment strategy and may show a lower rate of relapse.

Abstract 19763: Role of HAS-BLED Score on Major Bleeding in Atrial Fibrillation Undergoing Percutaneous Coronary Intervention With Drug-eluting Stents

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yoshitaka Ito ◽  
Kazuhiro Naito ◽  
Katsuhisa Waseda ◽  
Hiroaki Takashima ◽  
Akiyoshi Kurita ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
High Risk ◽  
Anticoagulant Therapy ◽  
Major Bleeding ◽  
Stent Implantation ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk

Background: While anticoagulant therapy is standard management for atrial fibrillation (Af), dual antiplatelet therapy (DAPT) is needed after stent implantation for coronary artery disease. HAS-BLED score estimates risk of major bleeding for patients on anticoagulation to assess risk-benefit in Af care. However, it is little known about usefulness of HAS-BLED score in Af patient treated with coronary stents requiring DAPT or DAPT plus warfarin (triple therapy: TT). The aim of this study was to evaluate the role of HAS-BLED score on major bleeding in Af patients undergoing DAPT or TT. Methods: A total of 837 consecutive patients were received PCI in our hospital from Jan. 2007 to Dec. 2010, and 66 patients had Af or paroxysmal Af at the time of PCI. Clinical events including major bleeding (cerebral or gastrointestinal bleeding) were investigated up to 3 years. Patients were divided into 2 groups based on HAS-BLED score (High-risk group: HAS-BLED score≥4, n=19 and Low-risk group: HAS-BLED score<4, n=47). DAPT therapy was required for a minimum 12 months after stent implantation and warfarin was prescribed based on physicians’ discretion. Management/change of antiplatelet and anticoagulant therapy during follow-up periods were also up to physicians’ discretion. Results: Baseline characteristics were not different between High-risk and Low-risk group except for age. Overall incidence of major bleeding was observed in 8 cases (12.1%) at 3 years follow-up. Major bleeding event was significantly higher in High-risk group compared with Low-risk group (31.6% vs. 4.3%, p=0.002). However, management of DAPT and TT was not different between the 2 groups. Among component of HAS-BLED score, renal dysfunction and bleeding contributed with increased number of the score. Conclusion: High-risk group was more frequently observed major bleeding events compared with Low-risk group in patients with Af following DES implantation regardless of antiplatelet/anticoagulant therapy.

scholarly journals Body Mass Index Is Not Associated with Early Treatment Response or Clinical Outcome in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1299-1299
Author(s):  
Hesham Eissa ◽  
Yinmei Zhou ◽  
John C Panetta ◽  
Emily Browne ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Treatment Response ◽  
Body Mass ◽  
Early Treatment ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Cell Phenotype ◽  
Early Treatment Response

Abstract Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with survival rates exceeding 90% in recent trials. Obesity is increasingly prevalent in the general population, and studies in children with ALL have correlated obesity with higher risk of persistent minimal residual disease (MRD) at the end of induction as well as worse outcome. We, therefore, determined whether obesity affected treatment response in children with ALL who were enrolled in a recent trial including MRD-guided therapy. Methods: Patients enrolled in the Total XV study at St. Jude Children's Research Hospital from 2000 to 2007 were included in the analysis. The protocol used MRD levels prospectively for risk assignment together with age, white blood cell counts, and cytogenetic profiles. Drug dosages were based on actual (rather than ideal) body surface area. Body mass index (BMI) was calculated by using height and weight for patients older than 2 years at diagnosis. Four BMI categories (underweight, normal, overweight, and obese) based on Center for Disease Control and Prevention guidelines were used. The association between BMI categories at diagnosis and MRD, cumulative incidences of refractory/relapsed disease (CIR), and event-free survival (EFS) were evaluated. The changes in BMI percentile from diagnosis to the end of induction were also calculated. Results: Among 409 patients enrolled, 26 who were younger than 2 years with no available BMI and 9 with Down syndrome were excluded. Of the 374 evaluable patients, 26 (7.0%) were underweight; 245 (65.5%) had normal BMI; 45 (12.0%) were overweight; and 58 (15.5%) were obese. Older age at diagnosis (P = 0.008) and being on the standard/high-risk treatment arm (P = 0.040) were associated with higher BMI categories. Among the 4 BMI categories, there was no significant difference in the proportion of patients with MRD ≥1% on day 19 of remission-induction therapy (P = 0.437) or MRD ≥0.01% at the end of induction (P = 0.182). There were also no differences in CIR (P = 0.259) or EFS (P = 0.158) among the 4 categories. EFS was significantly worse in male patients (P = 0.027) and in those with T-cell phenotype (P = 0.006), standard/high risk (P < 0.001), MRD ≥1% on day 19 (P < 0.001), or MRD ≥0.01% at the end of induction (P < 0.001). We reanalyzed the data by using 2 BMI categories (non-obese and obese). No significant differences were observed in the proportions of patients with MRD ≥1% on day 19 (P = 0.766) or MRD ≥0.01% at the end of induction (P = 0.177), and there was no difference in CIR between the 2 categories (P = 0.395). Although not statistically significant, EFS was marginally worse in obese patients (P=0.053). EFS among 4 or 2 BMI categories was evaluated by using a multiple Cox regression model including treatment arm, sex, race, and BMI categories as variables. No differences were observed for analysis by 4 (P = 0.368) or 2 (P = 0.151) BMI categories. In these analyses, only treatment arm (standard/high risk) remained a significant predictor (all P < 0.001). BMI percentile change from diagnosis to the end of induction also lacked significant association with MRD, CIR, and EFS. Conclusion: In contrast to published reports, body mass index had no effect on early treatment response as measured by MRD, incidence of relapse, or EFS in children with ALL enrolled in the Total XV study. These results indicate that obesity should not be considered an adverse prognostic factor in children with ALL in the context of contemporary treatment programs. Figure 1. Association of BMI with MRD, CIR, and EFS Figure 1. Association of BMI with MRD, CIR, and EFS Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Clinical Significance of Alterations of the NOTCH1, FLT3 and p53 Genes in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4434-4434
Author(s):  
Myoung-ja Park ◽  
Tomohiko Taki ◽  
Akira Shimada ◽  
Manabu Sotomatsu ◽  
Ryoji Hanada ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Poor Prognostic Factor ◽  
Cell Acute Lymphoblastic Leukemia ◽  
P53 Genes ◽  
Notch1 Mutations

Abstract Activating mutations of the NOTCH1 gene have been reported in about 50% of T cell acute lymphoblastic leukemia (T-ALL). We performed mutation analysis of the NOTCH1, FLT3 and p53 genes by polymerase chain reaction followed by direct sequence. Mutations of the NOTCH1 were identified in 24 (30%) of 80 fresh samples and 10 (71.4%) of 14 T-ALL cell lines. Six missense mutations and 2 insertion in HD domain, 2 nonsense mutations and 6 insertions in PEST domains were found in 14 cell lines. Eight missense mutations, 9 insertions and one deletion in HD domains, 5 missense mutations, 3 nonsense mutations and 3 deletions in PEST domain were found in 80 fresh samples. The incidence of the NOTCH1 mutations is less frequent than that of previous reports. We observed about 95% of single nucleotide polymorphisms (5097 C/T) in HD domain, which is more frequent than 30% of previous report, possibly due to the racial difference. FLT3 internal tandem duplication, which is known as the poor prognostic factor in acute myeloid leukemia, were not identified in any T-ALL cell lines or fresh samples. Mutations of the p53 gene were found in 5 of 8 cell lines and 5 of 50 fresh samples. Mutations of both NOTCH1 and p53 genes were identified 3 of 8 cell lines and one of 50 fresh samples. In our study NOTCH1 mutations were not significantly associated with high WBC count and prognosis. Further studies are needed to find the association between novel genes and clinical features of pediatric T-ALL.

The Early Treatment Response of the Clinically Challenging Group of Childhood T-ALL without NOTCH1 Mutations Is Signified by a Specific mRNA Gene Profile.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2789-2789
Author(s):  
Andreas Kulozik ◽  
Stephen Breit ◽  
Stefan Pfister ◽  
Shangyou Liu ◽  
Martin Stanulla ◽  
...  
Keyword(s):  
Treatment Response ◽  
Early Treatment ◽  
Lymphoblastic Leukemia ◽  
Biological Significance ◽  
Molecular Transport ◽  
Cellular Growth ◽  
Specific Gene ◽  
Long Term Outcome ◽  
Early Treatment Response ◽  
Notch1 Mutations

Abstract Activating mutations within the NOTCH1 gene occur in more than 50% of childhood precursor T-cell lymphoblastic leukemia (T-ALL, Weng et al. Science 2004). Our previous work has shown that in the context of the ALL-BFM 2000 treatment strategy, activating NOTCH1 mutations significantly correlate with a good early treatment response and specified a subgroup of patients with an exceptionally favorable long term outcome. By contrast, most of the relapses occurred in those patients without NOTCH1 mutations, which thus represents a clinically important and challenging subgroup (Breit et al., Blood 2006). We now aimed to further differentiate this subgroup without NOTCH1 mutations by analyzing the mRNA expression profile of primary pediatric T-ALL bone marrow samples. We first validated the biological significance of these analyses by comparing samples with and without activating NOTCH1 mutations and confirmed that the presence of activating NOTCH1 mutations correlates with differential expression of multiple downstream signaling pathways that are known to be activated by NOTCH1. Importantly, the comparison of patients without NOTCH1 mutations and good or poor prednisolone response revealed a specific gene signature that differentiates wild-type NOTCH1 T-ALL with a favourable from those with an unfavourable early treatment response. These discriminatory signatures significantly enrich for specific gene ontology categories (e.g. cell death, cellular growth and proliferation, and molecular transport), suggesting functional relevance of these differentially expressed genes. The specific comparison of different T-ALL subgroups thus reveals prognostic gene expression signatures particularly in the clinically difficult patients without NOTCH1 mutations.

The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Over Chemotherapy As Post-Remission Treatment for Patients with High-Risk Acute Lymphoblastic Leukemia in First Remission

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1986-1986
Author(s):  
Jiong Hu ◽  
han-Bo Dou ◽  
Ling Wang ◽  
Wei Tang
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Relapse Rate ◽  
Lymphoblastic Leukemia ◽  
P Value ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Chemotherapy Group

Abstract Abstract 1986 For adult patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HLA-matched related donor (MSD) is recommended for standard and high-risk patients. The role of unrelated donor transplantation (URD) is not fully determined. In this single-center retrospective analysis, we included all consecutive adult patients with high-risk ALL in 1st complete remission (CR) without sibling donor between Jan 2007 to June 2012. Overall, 74 patients were included in the analysis in which 32 patients received URD allo-HSCT during 1st CR with busulfan-cyclophophamide preparation regimen and in vivo T cell depletion with anti-T-lymphoglobulin (ATG). The median time from remission to transplantation was 4.5 months (3∼13). Forty-two patients in the chemotherapy group with 1st CR more than 6 months received consolidation chemotherapy alone either due to lack of suitable URD (n=21), refuse to URD search (n=14), unwillingness to undergo transplantation with available URD (n=5) and donor refuse to donate (n=2). Salvage allo-HSCT was allowed after relapse and actually 5 patients in the chemotherapy group received transplantation from URD donor (n=2) or haplo-identical donor (n=2) in the subsequent remission. The clinical characteristics such age, sex, initial WBC, and Philadelphia chromosome are all distributed equally in the two groups. With a median follow-up of 18 months for the whole group, 30 patients relapsed with estimated 3-year relapse rate (RR) at 58.1±8.5%. The 3-year event-free survival (LFS), non-relapse mortality (NRM) and overall survival (OS) were 38.0±7.9%, 11.1±4.4% and 46.0±9.0% respectively. In the URD allo-HSCT group, RR was 30.6±11.4% which was significantly lower than chemotherapy group (80.5±10.1%, p<0.001) while NRM was higher (16.4±6.7% vs. 0, p=0.028). Overall, 3-year LFS was superior in URD allo-HSCT group compared to chemotherapy (57.8±10.6% vs. 19.5±10.5%; median not reached vs. 13 months, p=0.002) and 3-year OS was also improved in URD allo-HSCT group (63.5±13.3%, median not reached versus 31.6±10.6%, median 24 months, p=0.016). Based on our data, URD allo-HSCT significantly reduced the relapse rate in high-risk ALL and the benefit translated into improvement in both LFS and OS. Prospective randomized study based on availability of HLA matched URD is warranted to confirm the exact role of URD transplantation in adult ALL. Table 1. Patient's characteristics Chemotherapy URD-allo-HSCT P value No of patients N=42 N=32 Median Follow-up (months) 15 (7.7∼48) 22 (8.2∼49) Sex (M/F) 19/23 21/11 0.08 Age 24.5 (16∼60) 25 (16∼57) 0.10     >35 14 9 0.61     <=35 28 23 Initial WBC (×109/L) 80.3 (15.3∼97.9) 61.5 (3.2∼98.4) 0.12 Cytogenetics     Ph+ 8 10 0.33     Ph− 33 22 Table 2. Clinical outcome in different treatment strategies Chemotherapy URD-allo-HSCT P value No of patients N=42 N=32 OS 31.6 ± 10.6% 63.5 ± 13.3% 0.016     median 24.9 months not reached LFS 19.5 ± 10.5% 57.8 ± 10.6% 0.002     median 13.2 months not reached Relapse rate 80.5 ± 10.1% 30.6 ± 11.4% <0.001 NRM 0% 16.4 ± 6.7% 0.028 Disclosures: No relevant conflicts of interest to declare.

Clinical Relevance of NOTCH1 and FBXW7 Mutations in DCOG and COALL T-ALL Patient Cohorts.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1603-1603
Author(s):  
Linda Zuurbier ◽  
Irene Homminga ◽  
Jessica Buijs-Gladdines ◽  
Valerie de Haas ◽  
Martin Horstman ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Relevance ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Study Cohort ◽  
Activating Mutations ◽  
Inactivating Mutations ◽  
Notch1 Mutations

Abstract Abstract 1603 Poster Board I-629 Introduction Ten to fifteen percent of all pediatric leukemic cancers are addressed to T-cell acute lymphoblastic leukemia (T-ALL). Despite improved therapy, about 30% of these cases relapse and ultimately die due to the persistent of disease. Many chromosomal aberrations are known to be involved in T-ALL nowadays and there is evidence for some of these factors to be associated with prognosis. Aberrant activation of the NOTCH1 pathway is a frequent phenomenon in T-ALL. NOTCH1 is a transmembrane protein that as a transcription factor promotes self-renewal, proliferation and differentiation. Hyperactivation of NOTCH1 has been linked to the presence of activating mutations in NOTCH1 itself and inactivating mutations in FBXW7. FBXW7 normally targets NOTCH1, among other proteins, for ubiquitin-mediated proteasomal degradation. Several studies investigated the clinical relevance for NOTCH1 and/or FBXW7 mutations, but results are contradictory. We attempted to clarify this by screening two cohorts for these mutations in relation to clinical and molecular cytogenetic parameters. Patients We performed a retrospective analysis on 146 pediatric T-ALL patients who were enrolled on Dutch DCOG ALL7, ALL8 or ALL9 protocols(n=72), or the German COALL-97 protocol (n=74). DCOG patients had a median follow-up time of 67 months whereas the median follow-up for COALL patients was 52 months. The DCOG study comprised 51 males and 21 females and the COALL study cohort contained 49 males and 25 females. Results We were able to screen for NOTCH1 and FBXW7 mutations in 141 out of 146 pediatric T-ALL patients. NOTCH1 and FBXW7 mutations were observed in 56% (n=79) and 16% (n=23) of the patients, respectively. Together, 63% (n=89) of our pediatric T-ALL patients have a mutation in NOTCH1 and/or FBXW7. Mutations were mainly observed as single mutations in the HD domain of NOTCH1 and less frequently in the closely associated juxtamembrane domain (n=40) or found in combination with PEST domain mutations (n=9) or FBXW7 inactivating mutations (n=13). Isolated PEST domain mutations (n=17) or FBXW7 mutations (n=10) were observed as well. Mutations in FBXW7 were located in the WD40-protein binding domain. A higher incidence of NOTCH1 with or without FBXW7 mutations was observed for TLX3 rearranged T-ALL (p=0.039 and p=0.008, respectively). NOTCH1 mutations w/wo FBXW7 mutations were observed at a lower frequency in TAL or LMO rearranged T-ALL (p=0.004 and p=0.004, correspondingly). NOTCH1 mutations w/wo FBXW7 mutations were less frequently associated with a mature T-cell development status. We did not identify any association with clinical parameters including age, gender and white blood cell count. Like the German BFM study group (see abstract submitted by first author Corinne Kox), we identified a good response for NOTCH1/FBXW7 mutant patients to prednisone in vivo for 34 patients treated on DCOG ALL-7 or ALL-8 protocols (p=0.003). In relation to outcome, NOTCH1 and/or FBXW7 mutated patients demonstrated a trend to poor outcome (DCOG EFS p=0.156 and RFS p=0.101, COALL EFS p=0.903 and RFS p=0.230). Conclusion We identified NOTCH1 activating mutations in two third of all pediatric T-ALL patients which enrolled in the DCOG and COALL study. Based on data for selected patients groups, these patients had a significantly better in vivo prednisone response compared to wild type patients. However, NOTCH1 and/or FBXW7 mutations do not show to have a prognostic significance within the DCOG and COALL T-ALL studies. Disclosures No relevant conflicts of interest to declare.

Outcome and Toxicities of Modified Augmented Berlin-Frankfurt-Muenster (ABFM) Therapy Used in the Treatment of Acute Lymphoblastic Leukemia in Adolescent and Young Adult Patients, Single Center Experience From Saudi Arabia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3569-3569
Author(s):  
Suhaib Radi ◽  
Anas Merdad ◽  
Mona Al-Dabbagh ◽  
Ahmed Almohanad Absi ◽  
Ahmad Alsaeed ◽  
...  
Keyword(s):  
Overall Survival ◽  
Saudi Arabia ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Complete Remission ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Inclusion Criteria

Abstract Abstract 3569 Introduction: Acute lymphoblastic leukemia (ALL) is a neoplasm of precursor lymphoid cells known as lymphoblasts. ALL is the most common cancer in children. The prognosis among Adolescents and young adults (AYA) is intermediate between children, who have a very good prognosis with a 5-year survival rate of 80%, and adults, who have a worse prognosis with an overall survival of about 30–50%. We found no studies in Saudi Arabia which assessed the use of a Berlin-Frankfurt-Muenster (BFM) to treat patients in the AYA group. The purpose of this study is to measure the outcome and toxicities of the BFM protocol used in treatment of ALL patients in the AYA population seeking treatment at Princess Noorah Oncology Center (PNOC), at the National Guard Hospital, Jeddah, Saudi Arabia. PNOC is a tertiary referral center for the Western region of the Kingdom of Saudi Arabia. Patients referred between the ages of 14 to 25 were treated according to an augmented modified version of the Berlin-Frankfurt-Muenster (BFM) protocol. Patients' treatments were based on risk factor stratification. High risk category was identified based on the presence of one of following factors: phenotype of the leukemia (i.e. T-cell ALL is considered high risk), lack of response to therapy on day 29 of induction, cytogenetics, presence of extramedullary disease e.g. testicular or CNS disease and whether they have received steroid treatment prior to the first diagnostic marrow. High risk group was treated with doubled blocks of interim maintenance, delayed intensification the first of delayed intensification blocks included a high dose methotrexate at the dose of 5g/m2 which was first started at our center in 2008. Methodology: This study is a retrospective chart review. Patients who met the inclusion criteria within the last five years were included. The inclusion criteria were those with confirmed ALL (excluding mature B cell phenotype) aged between 14 to 25 years, and were treated with the Modified Augmented Berlin-Frankfurt-Muenster (ABFM) therapy protocol. 45 patients were indentified who fulfilled the above criteria 4 were excluded due to the lack of data and loss to follow up. Data were analyzed using SPSS version 19. Results: The mean age of 41 patients treated was 16.4 years (range; 14 – 25 years). Of 41 patients treated, 23 (56%) were males. Only one patient (2%) had CNS involvement at presentation. B cell ALL compromised 61% of the patients while 39% were T cell ALL. All 41 (100%) patients achieved complete remission after induction therapy however two patients (5%) required extended induction to achieve a complete remission status. Five (12.2%) patients relapsed at a median follow up of 30 months. Two (4.9%) patients died while in complete remission from treatment related causes. The probability of Overall Survival (OS) is 95.1% and 87.8% at 2 and 3 years, respectively. The probability of Event-free Survival (EFS) of our 41 patients is 90.2% and 82.9% at 2 and 3 years respectively. Thirty three (81%) patients developed febrile neutropenia with a total of 50 documented episodes. Thirty two (64%) of the febrile neutropenia episodes occurred during induction and re-intensification phases those two blocks were associated with a statistically significant increased risk of neutropenia (P < 0.001)compared to other blocks. Five (12%) of patients developed fungal infections there is one patient who developed two separate episodes of fungal infection. Four fungal infection episodes occurred during induction and re-intensification phases which constituted the highest risk phases for the development of fungal infections. In 38% of febrile neutropenic episodes an infectious agent was identified in 8% of episodes the isolate was a fungus. Eight patients (20%) developed Venous Thromboembolism (VTE) with a total of 9 episodes. Discussion & Conclusion: In our study population the OS & EFS were comparable to other reported groups despite the relatively increased numbers of T cell ALL (39%) patients compared to the reported average of 15–25%. The reported incidence of VTE is similar to the incidence reported by other groups while the incidence of fungal infections is relatively more than we would have expected. Complete remissions, survival, relapse and death rates are comparable to international studies. However new measures are required to lower the increased rates of fungal infections & VTE for future patients. Disclosures: No relevant conflicts of interest to declare.

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