The Level of Histone Deacetylase 7 in Pediatric ALL and Its Effect on Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5099-5099
Author(s):  
Bei Hou ◽  
Huyong Zheng
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Histone Deacetylase ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Altered Expression ◽  
Expression Levels ◽  
Pediatric All

Abstract Background Leukemia is the most common pediatric malignancy and a major cause of mortality and morbidity in children. Nearly 15,000 children are newly diagnosed with leukemia in China each year and among them, acute lymphoblastic leukemia (ALL) accounts for more than 75%. Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment . With increasing focus on precision medicine, HDACs have emerged as promising therapeutic target in pediatric ALL. Methods We detect the histone deacetylase 7(HDAC7) expression in the bone marrow samples of 254 children with newly diagnosed acute lymphoblastic leukemia (ALL) at Hematology Oncology Center of Beijing Children`s Hospital from January 2010 to the end of 2012 via qRT-PCR using the TaqMan gene expression probes. 3 patients that have been completely remission for 3 years are used as normal control. We find out that the expression levels of HDAC7 are associated with the unfavorable events (such as induction failure, relapse and/or death due to any cause ) occurence rates and 5-EFS. Results Here we find that the HDAC7 expression levels are associated with the unfavorable events occurence rates and 5-EFS. We find that in the intermediate risk group of 157 patients, the patients who have lower level of HDAC7 expression have higher unfavorable event occurence rates than the higher expression of HDAC7 group (p=0.001). The group of higher HDAC7 expression have higher 5-EFS than the lower group in both the intermediate risk group(p=0.001) and the T-ALL group(n=18). Conclusion We conclude that HDAC7 has a potent anti-oncogenic effect on specific pediatric B-cell leukemia, indicating that its deregulation may contribute to the pathogenesis of the disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals IKZF1 Deletion Is An Independent Predictor of Outcome In Pediatric Acute Lymphoblastic Leukemia Treated According to the ALL-BFM 2000 Protocol

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 409-409
Author(s):  
Petra Breithaupt ◽  
Barbara Meissner ◽  
Martin Zimmermann ◽  
Anja Möricke ◽  
André Schrauder ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
High Risk ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Risk Group ◽  
Independent Predictor ◽  
Lymphoblastic Leukemia ◽  
Time Points ◽  
Pediatric All

Abstract Abstract 409 Alteration of the IKZF1 gene – encoding the transcription factor IKAROS, a key player in lymphoid development and tumor suppression – has been reported to be associated with a poor outcome in pediatric precursor B-cell ALL, especially in cases positive for the BCR-ABL1 fusion gene. In order to assess the prognostic value of IKZF1 deletions in a representative cohort of pediatric ALL patients treated on the German ALL-BFM 2000 study protocol, we screened 409 patients by applying a multiplex ligation-dependent probe amplification (MLPA) assay covering all eight IKZF1 exons (P335-A3 ALL-IKZF1 probemix; MRC-Holland, Amsterdam, The Netherlands). In ALL-BFM 2000, risk group stratification (standard, SR; intermediate, MR; high, HR) was based on minimal residual disease (MRD) analysis at two different time points (TP) and required two MRD targets with sensitivities of ≤10−4 (Flohr et al. Leukemia 2008). SR patients were MRD-negative on treatment days 33 (TP1) and 78 (TP2). HR patients had residual disease (≥10−3) at TP2. MRD MR patients had positive MRD detection at either one and or both time points but at a level of <10−3 at TP2. Although MRD-based stratification criteria were introduced in ALL-BFM 2000, established high-risk parameters were also retained: patients with prednisone poor-response or ≥5% leukemic blasts in the bone marrow on day 33 or positivity for a t(9;22) or t(4;11) or their molecular equivalents (BCR/ABL1 or MLL/AF4 fusion RNA) were stratified into the high-risk group independent of their MRD results. First results on MRD and outcome were published earlier (Conter et al. Blood 2010). Out of the 409 patients analyzed in our study, 46 (11%) displayed a deletion in at least one of the eight IKZF1 exons. Forty-three out of the 46 cases showed heterozygous deletions, while 3 patients displayed homozygous loss of IKZF1 exons. MLPA results of 11 patients were validated with results derived from copy number/LOH analyses using Affymetrix SNP 6.0 arrays. IKZF1 deletion was significantly more common in precursor B compared to T cell ALL (13% vs. 4%, P = 0.03) and less frequent in TEL/AML1-positive ALL (3% vs. 13%, P = 0.004). Out of 11 BCR/ABL1-positive samples, only two were characterized by an IKZF1 deletion. Forty-four patients with IKZF1-deleted ALL had results of MRD analyses available for both informative time points (day 33 after induction and day 78 after consolidation). Despite a trend towards increasing incidence of IKZF1 deletion in patients with slow response, the distribution of IKZF1-deleted ALL patients over the risk groups was not significantly different from non-deleted ALL (SR: 40.9 vs. 41.9; MR: 45.5 vs. 52.3; HR: 13.6 vs. 5.7%; P = 0.153). Regarding treatment outcome, patients with an IKZF1 deletion had a significantly lower 5-year event-free survival (EFS) compared to non-deleted patients (0.78±0.06 vs. 0.86±0.02; P = 0.015). This result was due to a higher cumulative incidence of relapses in IKZF1-deleted patients (0.16±0.05 vs. 0.10±0.02; P = 0.031). In multivariate Cox regression analyses including known prognostic variables (gender, immunophenotype, WBC count at diagnosis, TEL/AML1 status, risk group criteria of ALL-BFM 2000), IKZF1 deletion conferred a risk of 2.16 (95% confidence interval 1.14 – 4.10; P = 0.018) for an event when compared to non-deleted patients. We conclude that IKZF1 deletion is an independent predictor of treatment outcome for patients enrolled on the ALL-BFM 2000 protocol and represents a candidate marker to be integrated in future algorithms for early risk stratification in pediatric ALL. Disclosures: No relevant conflicts of interest to declare.

In-Vitro Efficacy of the Deoxyguanoside Analogs Forodesine (BCX-1777) and ARA-G in Pediatric Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2038-2038
Author(s):  
Irene Homminga ◽  
Michel C. Zwaan ◽  
Amel Seghouani ◽  
Chantal Y. Manz ◽  
Shanta Bantia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Nucleoside Transporter ◽  
Nucleotide Synthesis ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Expression Levels ◽  
Lc50 Value ◽  
Pediatric All

Abstract Abstract 2038 Poster Board II-15 Purine nucleoside phosphorylase (PNP) deficiency in humans is associated with elevated deoxyguanosine (dGuo) plasma levels. DGuo is converted into dGTP inducing apoptosis in T-cells and this provides the rationale for the development of deoxyguanosine analogues as a potential treatment option for T-cell malignancies. Forodesine (BCX-1777; BioCryst-Mundipharma) is an efficient blocker of PNP activity, thereby boosting the conversion of dGuo into dGTP and raising intracellular dGTP levels. AraG (9-b-D-arabinofuranosyl-guanine) is a compound that is resistant to PNP-mediated degradation that is efficiently converted into AraGTP. AraGTP becomes incorporated in the DNA, blocking DNA synthesis and promoting apoptosis. In a phase II clinical trial, the AraG prodrug Nelarabine enforced a complete remission rate of 55% for pediatric T-ALL patients at 1st relapse. (Berg, JCO 2005). Clinical data of Forodesine treatment in pediatric ALL patients are not yet available. As tested on primary pediatric acute lymphoblastic leukemia (ALL) patient samples (4 T-ALL, 2 BCP-ALL), 1μM of Forodesine is sufficient to completely block PNP and abolish rapid dGuo degradation resulting in a median 7.9 (range 0.5-378) fold raise of intracellular dGTP levels. Accumulation of dGTP is comparable for T-ALL (n=31) and BCP-ALL (n=11) patient samples. This reflects equal intrinsic ability of salvage nucleotide synthesis for both T-ALL and BCP-ALL cells. Cytotoxic effect of Forodesine was tested on primary leukemia cells from newly diagnosed pediatric ALL patients in-vitro by incubating cells with Forodesine (1μM) in the presence of increasing concentrations of dGuo (0.001-50μM). In accordance with selective T-cell toxicity, T-ALL cells were more sensitive to Forodesine/dGuo treatment (median T-ALL LC50 value: 1.1μM dGuo/1μM Forodesine, n=27, p=0.001) compared to BCP-ALL cells, which had a median LC50 value of 8.8μM dGuo/1μM Forodesine (n=30). All patients that responded demonstrated dGTP accumulation (1.5-222.1 fold), although the raise of dGTP levels did not correlate with Forodesine/dGuo toxicity (r2= 0.10, p=0.22). Studying in-vitro responsiveness to AraG, T-ALL cells were more sensitive compared to BCP-ALL cells (p=0.0002) with a median AraG LC50 value of 20.5μM for T-ALL samples (n=24) versus 48.3μM for BCP-ALL samples (n=20). Remarkably, TELAML1 positive BCP-ALL cases were insensitive to AraG treatment (median LC50 value >50μM, n=9). No correlation was identified between in-vitro Forodesine/dGuo and AraG cytotoxicities (r2=0.05, p=0.29). Most patient samples that displayed AraG resistance still responded to Forodesine/dGuo treatment. This may be explained by the fact that the uptake of both drugs may be facilitated by different transporters. Using RQ-PCR we could demonstrate that AraG toxicity, in contrast to Forodesine, was significantly associated with ENT1 (equilibrative nucleoside transporter 1) expression levels (p=0.008), which was previously identified as strong predictor for AraC cytotoxicity in pediatric ALL (Stam RW. et al., Blood 2003). AraG cytotoxicity strongly correlated with AraC cytotoxicity (r2=0.71, p<0.0001). We found no significant correlation between Forodesine sensitivity and the expression levels of other nucleoside transporters (CNT1, CNT2, CNT3, ENT2), kinases (dCK, dGK), nucleotidases (NT5C1A, NT5C2, PNI) or other enzymes that are involved in dGuo metabolism (PNP, RRM1, RRM2). In conclusion, T-ALL cells are more sensitive to Forodesine/dGuo treatment in-vitro than BCP-ALL cells that have nearly 8 fold higher dGuo LC50 values. Resistance to AraG treatment does not preclude responsiveness to Forodesine treatment and vice versa, indicating that Forodesine and AraG rely on different cellular mechanisms for cytotoxicity, possibly involving differences in dependence on the nucleoside transporter ENT1. Disclosures: No relevant conflicts of interest to declare.

Relative Expression of Ikaros Isoforms Has a Prognostic Impact in Phildelphia-Negative Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1282-1282
Author(s):  
Jana Volejnikova ◽  
Ester Mejstrikova ◽  
Jan Stary ◽  
Jan Trka ◽  
Eva Fronkova
Keyword(s):  
Dna Binding ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
High Expression ◽  
Rapid Screening ◽  
Prognostic Impact ◽  
Altered Expression ◽  
Relative Expression ◽  
Lymphoid Lineage

Abstract Abstract 1282 Poster Board I-304 Ikaros, encoded by the IKZF1 gene, is a zinc-finger transcription factor crucial for normal differentiation of the lymphoid lineage. Multiple isoforms of Ikaros are generated by alternative splicing in lymphoid progenitors. Recent studies based primarily on high-risk (HR) patients with ALL, including Philadelphia-positive cases, have shown an inferior prognosis of patients with Ikaros alterations, leading in most cases to the expression of short, non-DNA binding isoforms of IKZF1. There is only a limited information about the overall frequency and prognostic impact of IKZF1 alterations in non-selected, BCR/ABL-negative ALL cohorts. Using a simplified yet efficient approach based on expression assay described by Iaccobucci et al. together with Agilent-on-chip semi-quantitative electrophoresis, we examined the expression of IKZF1 transcript variants in diagnostic bone marow (BM) samples from 94 children with Ph- ALL. The patients were diagnosed between November 2002 and December 2004 and treated by ALL IC-BFM 2002 protocol. Based on the analysis of peripheral blood from healthy donors and remission BM samples, we determined physiological range for relative expression of IKZF1 isoforms. The ratio between non-DNA binding (IK4, IK4del, IK4A, IK8) and functional IK1 and IK2 isoforms was significantly elevated in 26 of 94 patients (28%). There were no associations between elevated short/long isoforms ratio and age, WBC, ALL IC risk group, TEL/AML1 or hyperdiploidy. Considering the key role of Ikaros in lymphoid lineage specification, we tested whether its altered expression was related to the expression of myeloid markers on leukemic blasts. Neither short/long isoforms ratio, nor single transcript variant expression had any relation to the level of myeloperoxidase (MPO), CD13, CD33, CD65, CD117, CD14 or CD15 expression estimated by flow cytometry. Patients having the short/long isoforms ratio more than 80% had a 5-year RFS 66.7±13.6% compared to 87.5±4.1% in other patients (p=0.04). The main difference between leukemic and normal samples was observed in the relative expression of IK6 dominant-negative isoform. Using a cut-off of 10%, 14 of 94 (15%) ALL samples had increased IK6 expression in relation to other isoforms. Only 2 of 94 patients (2%) expressed IK6 alone. Elevated relative IK6 expression in the range 10-20% (6 patients) had no prognostic impact. Using a cut-off of 20%, 5-year RFS survival was 90.2± 3.3% in the group with low IK6 expression compared to 37.5±17.1% in patients with the high expression (p<0.0001). With the cut-off of 50%, RFS was 20±17.9% in the IK6 high expression group compared to 89.4±3.3% in the group with low expression (p<0.0001). Of the 5 patients with IK6 expression higher than 50%, two were treated in ALL IC HR group (based on poor prednisone response), one in the intermediate risk and two in the standard risk group, based on WBC, age and BM status at day 15. Only 1 of 4 patients with available MRD would be classified as MRD-HR based on MRD higher than 10−3 at week 12. Surprisingly, elevated relative expression of IK4, IK4del, IK4A and IK8 (all non-DNA binding isoforms) had no prognostic impact. The absolute level of IKZF1 expression, which might have indicated IKZF1 haploinsufficiency, had no prognostic impact either. In conclusion, we showed that a substantial proportion of childhood Ph-negative ALL cases had an increased expression of short, non-DNA binding Ikaros transcripts. However, only elevated expression of the IK6 isoform had prognostic impact. Patients with IK6 expression higher than 50% (5% of all patients) had very poor prognosis. The method used in this study could serve as a rapid screening for a new subgroup of HR patients with ALL. Supported by GA UK 7393/2007, MSMT NPV 2B06064, VZ MSM 0021620813 and MZ 000064203. Disclosures No relevant conflicts of interest to declare.

Discovery of Subtype-Specific Mirnas and New MiR-Genes In Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3232-3232 ◽  
Author(s):  
Diana Schotte ◽  
Renee X de Menezes ◽  
Farhad Akbari Moqadam ◽  
Ellen Lange-Turenhout ◽  
Ronald W Stam ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Mirna Expression ◽  
Lymphoblastic Leukemia ◽  
Cell Type ◽  
Quantitative Real Time Pcr ◽  
Aberrant Expression ◽  
Stem Loop ◽  
Expression Levels ◽  
Genetic Subtypes ◽  
Pediatric All

Abstract Abstract 3232 MicroRNAs (miRNAs) are non-coding RNAs that regulate the activity of protein-coding genes and some miRNAs have been shown to be dysregulated in cancer. The function of miRNAs differs per cell type and prominent miRNAs in e.g. B-cell lymphoma may not be important in acute lymphoblastic leukemia (ALL). To identify which miRNAs may be relevant in pediatric ALL the expression level of 397 different miRNAs was measured in leukemic cells (>90% purity) of 81 pediatric ALL and 17 normal hematopoietic control samples by stem-loop reverse-transcriptase (RT) quantitative real-time PCR. Except for BCRABL1-positive and B-other ALL, all major subtypes including T-ALL, MLL-rearranged, TELAML1-positive, E2APBX1-positive and hyperdiploid (>50 chromosomes) ALL presented with unique miRNA signatures that differ from each other and from those in healthy hematopoietic cells. The expression levels highly varied amongst subtypes and, for example, differed by 4000-fold for miR-708 in T-ALL (P<0.0001) and 1700-fold for miR-383 in TELAML1-positive ALL (P<0.0001) compared to other precursor B-ALL cases. Some subtypes shared similarities in their miRNA expression signatures suggesting a common underlying biology; e.g. miR-196b was highly expressed in 9/12 MLL-rearranged and 14/22 T-ALL patients. In particular, all T-ALL cases carrying CALM-AF10, MLL-AF6, SET-NUP214 or an inversion of chromosome 7 expressed high levels of miR-196b similar to MLL-rearranged ALL. These genetic subtypes have all been functionally linked to upregulation of HOXA cluster genes. In correspondence, miR-196b expression levels were also highly correlated with HOXA (Rs>0.7, p<0.003), which was not seen for HOXB and HOXC cluster genes. High levels of miR-196b coincide with reduced methylation of the DNA at CpG islands directly upstream of miR-196b in MLL-rearranged cases compared to non-MLL precursor B-ALL and normal bone marrow cases, suggesting an epigenetic origin for miR-196b overexpression in these patients. High-throughput sequencing (Solexa technology) of small RNA libraries representing 7 subtypes of ALL and 3 normal hematopoietic tissue types followed by application of stringent computational miRNA precursor prediction algorithms resulted into the identification of 28 novel and 431 candidate novel miR-genes (besides 554 known miR-genes) for which the expression levels differed between genetic subtypes of pediatric ALL and normal hematopoietic cells. Stem-loop RT-quantitative real-time PCR confirmed aberrant expression levels of newly discovered miR-genes in a different set of patients. These data may point to leukemia-associated miRNAs for which the (aberrant) expression level and activity may be cell type (e.g. MLL-subtype) specific. These subtype-specific (known and novel) miRNAs may have stayed unrecognized when analyzed in a set of genetically unspecified ALL cases. In conclusion, genetic subtypes of ALL display unique miRNA expression signatures. Functional studies are in progress for these discriminative miRNAs since this may provide new insights into the biology of ALL subtypes. Disclosures: No relevant conflicts of interest to declare.

Triptolide Induces Apoptosis In Acute Lymphoblastic Leukemia Cells by Inhibition of the Oncoprotein MDM2

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4934-4934
Author(s):  
Mei Huang ◽  
Lubing Gu ◽  
Muxiang Zhou
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Biological Action ◽  
Leukemic Cells ◽  
Transcriptional Level ◽  
Antitumor Effects ◽  
Mdm2 Expression ◽  
Pediatric All ◽  
Chinese Plant

Abstract Abstract 4934 Triptolide, a nature product derived from the Chinese plant Tripterygium wilfordii, is reported to exhibit antitumor effects in a broad range of cancers. Recent studies indicate that the antitumor activity of triptolide is associated with its biological action to inhibit expression of many oncoproteins and anti-apoptotic or survival factors that were expressed in the cancer cells. Herein, we demonstrate that triptolide induces apoptosis in a subgroup of acute lymphoblastic leukemia (ALL) cells that overexpress MDM2 oncoprotein by inhibiting the MDM2 expression. In pediatric ALL, overexpression of MDM2 by leukemic cells is typically associated with a wild-type (wt) p53 phenotype and resistance to conventional chemotherapeutic drugs such as doxorubicin. In the present study, we evaluated the role of triptolide in regulating MDM2 and in inducing apoptosis, as compared to doxorubicin, using ALL lines and primary ALL samples. In contrast to doxorubicin, which induced p53 activation and a subsequent upregulation of MDM2, triptolide strongly induced persistent inhibition of MDM2 followed by a steady-state activation of p53, which resulted in potent apoptosis of the MDM2-overexpressing ALL cells tested, even if they were doxorubicin-resistant. We discovered that triptolide's inhibition of MDM2 in ALL cells occurred at the post-transcriptional level through inhibition of mRNA synthesis. Because p53 function is inhibited by MDM2 in chemoresistant/MDM2-overexpressing ALL cells, potent killing of these cells by triptolide suggests that this naturally-derived agent may be a novel therapeutic for refractory ALL. Disclosures: No relevant conflicts of interest to declare.

Detection of Five Common Fusion Oncogenes in Pakistani Children with Acute Lymphoblastic Leukemia and Their Association with Clinical Pattern and Treatment Outcome

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5124-5124
Author(s):  
Zafar Iqbal ◽  
Sabir Noreen ◽  
Aleem Aamer ◽  
Awan Tashfeen ◽  
Tahir Naeem ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
White Cell Count ◽  
Total Leukocyte Count ◽  
Age Group ◽  
Response To Chemotherapy ◽  
Pediatric All

Abstract Abstract 5124 Background & Objectives: Acute lymphoblastic leukemia (ALL) is a complex genetic disease involving many fusion oncogenes (FGs) (Xu et al., 2012). The frequency of various FO can vary in different ethnic groups & these FGs have important implications for prognosis & treatment outcome (van-Dongen et al, 1999). Methods: We studied FGs in 101 pediatric ALL patients using Interphase FISH & RT-PCR (van-Dongen et al, 1999), & their association with clinical features & treatment outcome. Results: Five most common FGs i. e. BCR-ABL [t(9;22)], TCF3-PBX1 [t(1;19)], ETV6-RUNX1 [t(12;21)], MLL-AF4 [t(4;11)] & SIL-TAL1 (del 1p32) were found in 89/101 (88. 1%) patients. Frequency of BCR-ABL was 44. 5% (45/101) (Table 1). BCR-ABL positive patients had a significantly lower survival (43. 73 ± 4. 24 weeks) (Figure 1)& higher white cell count as compared to others except patients with MLL-AF4. The highest relapse-free survival (RFS) was documented in ETV6-RUNX1 (14. 167 months) followed closely by those cases in which no gene was detected (13/100). RFS in BCR-ABL, MLL-ASF4, TCF-PBX4 & SIL-TAL1 was less than 10 months (7. 994, 3. 559, 5. 500 & 8. 080 months respectively) (Figure 2 & 3). BCR-ABL: Frequency of occurrence was directly proportional to age (3 less than 2 year age group, 16 in the 2–7 year age group & 26 in the older than 7 group. Total leukocyte count (TLC) was higher when compared to patients with other oncogenes. Organomegaly was not common. BCR-ABL positivity was associated with low remission rates & shortened survival. ETV6-RUNX1: The median age of the patients was 1. 85 years. The gene frequency was highest in patients younger than 2 years. TLC was not very high & patients had a good prognosis. MLL-AF4: 17 patients had MLL-AF4 gene rearrangement with a median age of 9 years. Five patients were younger than 2 years, two between 2 & 7 years, & ten patients were in the 7–15 age group. Majority of our patients were older unlike the usual occurrence where most of the patients are infants. TCF3-PBX1: This FG occurs in around 2% of patients. Only two female patients were diagnosed with this translocation. Both the patients were over 2 years of age. It was associated with an inferior outcome in the context of response to chemotherapy & a higher risk of CNS relapse although small numbers preclude any firm conclusions. SIL-TAL1: Patients were older than 2 years, with the majority falling in the age range 7 to 15 years. The immunophenotype data were available in all SIL-TAL1 patients showing this fusion gene was associated with T-ALL with organomegaly being observed frequently. Discussion & Conclusion: This is the first study from Pakistan correlating molecular markers with disease biology & treatment outcome in pediatric ALL. Our study revealed the highest reported frequency of BCR-ABL FO in pediatric ALL, in consistent with various other reports from Pakistan & rest of the world ((Iqbal & Akhtar, 2007; Faiz et al., 2011; (Gaynon et al., 1997; Iacobucci et al., 2012).) which, consequently, was associated with poor overall survival. The data indicates an immediate need for incorporation of tyrosine kinase inhibitors in the treatment of BCR-ABL+ pediatric ALL in this population & the development of facilities for stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Aggravated Bone Density Decline after Symptomatic Osteonecrosis in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2260-2260
Author(s):  
Marissa den Hoed ◽  
S.M.F. Pluijm ◽  
Mariël L. Te Winkel ◽  
Hester A. de Groot-Kruseman ◽  
Marta Fiocco ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Acute Lymphoblastic Leukemia ◽  
Side Effects ◽  
Bone Mineral ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Bone Destruction ◽  
Mineral Density ◽  
Pediatric All ◽  
Cessation Of Treatment

Abstract Background: Osteonecrosis (ON) and decline of bone mineral density (BMD) are serious side effects during and after treatment of childhood acute lymphoblastic leukemia (ALL). It is unknown whether ON and low BMD co-occur in the same patients, and whether these two osteogenic side effects can influence each other’s development during pediatric ALL treatment. Methods: BMD and the incidence of symptomatic ON were prospectively assessed in 466 patients with ALL (4-18 years of age) treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Symptomatic ON was defined as persistent pain in arms or legs not caused by vincristine administration, and confirmed by magnetic resonance imaging. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) were measured by dual X-ray absorptiometry at ALL diagnosis, after 32 weeks of treatment, at cessation of treatment (109 weeks) and 1 year after cessation of treatment. BMD was expressed as age-matched and gender-matched standard deviation scores (SDS; Z-score). Multivariate linear mixed models were adjusted for age at diagnosis. Results: Thirty patients (6.4%) suffered from ON. At cessation of treatment, mean BMDLS was -1.28 SDS (SD: 1.27, n=332; p<0.01) and BMDTB was -0.74 SDS (SD: 1.29, n=65; p<0.01) lower in ALL patients compared to their healthy peers. At baseline, BMDLS and BMDTB did not differ between patients who developed or who did not develop ON (mean BMDLS ON+: -0.90 vs. ON-: -1.14, p=0.36; mean BMDTB ON+: 0.07 vs. ON-: 0.25 p=0.65). At cessation of treatment, patients with ON seem to have a trend for a lower mean BMDLS (ON+: -1.68 vs. ON-: -1.31, p=0.18) and they have a lower mean BMDTB (ON+: -1.91 vs. ON-: -0.59, p=0.01) than patients without ON. Multivariate analyses showed that BMDTB change during follow-up was significantly different for patients with ON than without ON (interaction group time, p=0.04). Between BMD measurements before and after the diagnosis, patients with ON seemed to have a more rapid decline of BMDTB than in patients of the same age without ON (mean BMDTB difference -1.13 vs. -0.62, p=0.10). Conclusion: We conclude that symptomatic ON and low BMD during antileukemic treatment co-occur in pediatric ALL patients. BMD status at ALL diagnosis does not seem to precede ON. However, the development of ON seems to aggravate BMD decline during antileukemic treatment, most likely due to bone destruction and the advised physical immobilization. Disclosures No relevant conflicts of interest to declare.

LDL Discordance in Pediatric Survivors of Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 6003-6003
Author(s):  
Galit Rosen ◽  
Gabriel Q Shaibi
Keyword(s):  
Cardiovascular Disease ◽  
Acute Lymphoblastic Leukemia ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Cardiovascular Disease Risk ◽  
Heart Association ◽  
Cardiac Risk ◽  
Cardiac Events ◽  
Pediatric All

Abstract Background: Survivors of childhood acute lymphoblastic leukemia (ALL) have a four-fold excess risk of mortality secondary to cardiovascular events compared to the general population. While it is well-known that LDL has a role in atherogenesis and subsequent cardiac events, recent studies consistently show that LDL particle number (LDLp) is a stronger, independent predictor of coronary heart disease in adults compared to LDL-cholesterol (LDLc), especially when the values are discordant. There is emerging evidence that LDL discordance also occurs in children. We studied this phenomenon in pediatric ALL survivors and identify associated risk factors. Methods: Complete data were available from 64 patients enrolled in the Phoenix Children’s Hospital pediatric cancer survivorship registry. Patients were 12.9±3.5 years of age (range: 7.7-22.7 years) with a mean time off therapy of 5.5±2.6 years (range 2.3-11.4 years). LDLc and LDLp were assessed by NMR spectroscopy. Patients were assessed by a registered dietician for calcium, fat, and fruit intake as well as physical activity. Ideal LDLc and LDLp were defined as <160 mg/dL and <1600 nmol/L, respectively, based on American Heart Association guidelines for people with standard cardiac risk. Discordance was classified based on ideal vs. not-ideal status for each parameter. Results: Mean BMI was 22.7±5.7 kg/m2 (range 14-38 kg/m2); mean BMI percentile was 73.1±26.1% (0.9-99.5%) with 42% of patients considered overweight or obese at the time of evaluation. Mean LDLc and LDLp were 79±25.5 mg/dL (29-164 nmol/L) and 1124±517 nmol/L (411-2837 nmol/L), respectively, with 89% (n=56) of survivors exhibiting ideal LDLc and 47% (n=30) of survivors exhibiting ideal LDLp. In a subgroup of patients with ideal LDLc, 40.6% (n=26) exhibited not-ideal LDLp and were classified as discordant. Regression analysis showed that after adjusting for age and gender, BMI (p<0.00001) and LDLc (p<0.00001) were significant independent predictors of LDLp while lifestyle factors and time off therapy were not significant predictors of LDLp. When patients were grouped as concordant (ideal LDLc and LDLp, n=30) or discordant (ideal LDLc and elevated LDLp, n=25), BMI was 17.6% higher in the discordant group (25.0±5.4 kg/m2 vs. 20.6±5.0 kg/m2, p=0.003). Conclusion: In this population of pediatric ALL survivors, LDLc measurements may not provide a complete assessment of cardiovascular disease risk. Given that LDLp is an early predictor of cardiovascular outcomes, conventional lipid testing may underestimate the true cardiovascular disease risk in ALL survivors. Survivors may benefit from early, expanded screening and targeted intervention. Further studies should focus on the broader pathophysiology of cardiovascular disease in pediatric ALL survivors. Disclosures No relevant conflicts of interest to declare.

Genetic and Metabolic Determinants of Methotrexate Induced Mucositis in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 939-939
Author(s):  
Marissa den Hoed ◽  
E. Lopez-Lopez ◽  
Mariël L. Te Winkel ◽  
Wim Tissing ◽  
Jasmijn de Rooij ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Plasma Homocysteine ◽  
Nucleotide Polymorphisms ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Plasma Folate ◽  
Pediatric All ◽  
Erythrocyte Folate ◽  
Grade 3

Abstract Introduction: Methotrexate (MTX) is an important and effective chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia (ALL). However MTX can induce toxicity, which can lead to amendments of treatment and subsequent impaired survival. The aim of this study was to identify metabolic and genetic determinants of MTX toxicity. Patients and Methods: In this prospective study, 134 Dutch pediatric ALL patients were treated with four high dosages MTX (HD-MTX: 5 g/m2) every other week according to the DCOG-ALL10 protocol. Toxicity was prospectively scored and a National Cancer Institute (NCI) grade ≥3 was considered clinically relevant toxicity. Plasma MTX levels were measured at 24 and 48 hours after each HD-MTX infusion. Erythrocyte folate, plasma folate and plasma homocysteine levels were determined at the start of protocol M. Seventeen single nucleotide polymorphisms (SNPs) in 7 candidate genes in the MTX pathway were analyzed. Results: Grade ≥3 mucositis occurred in 20% of the patients, skin toxicity in 7%, diarrhea in 3%, and neurotoxicity in 3%. Mucositis occurred especially after the first course compared to the other courses (p=0.006). Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher baseline levels of erythrocyte folate (median 1.2 μmol/L vs. 1.4 μmol/L, p<0.008). Wildtype rs7317112 in the ABCC4 gene was the only SNP associated with a higher frequency of mucositis (AA (39%) vs. AG/GG (15%), p=0.016). Conclusion: Mucositis is the most frequent occurring toxicity during the HD-MTX phase in pediatric ALL treatment, and occurs especially after the first MTX course. Only a higher baseline erythrocyte folate, which reflects the accumulation of MTX polyglutamates in mucosal cells, and the wild-type variant of rs7317112 SNP in ABCC4 were determinants of mucositis in pediatric ALL during MTX-HD treatment. Disclosures No relevant conflicts of interest to declare.

Treatment of Acute Lymphoblastic Leukemia in Children and Adolescents: Peaks and Pitfalls

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 374-380 ◽  
Author(s):  
Nita L. Seibel
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Children And Adolescents ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Cooperative Groups ◽  
Newly Diagnosed ◽  
Success Story ◽  
Pediatric Oncologist ◽  
Leukemia In Children ◽  
Improved Outcome

AbstractSurvival of children with acute lymphoblastic leukemia (ALL) is often described as the success story for oncology. The improvements in the treatment of ALL represent the work of cooperative groups at their best. Fifty years ago a pediatric oncologist would have never considered using the term “cure” in a discussion with a family whose child was diagnosed with ALL. Today the term is not only used in the initial discussion but referred to frequently thereafter. However, as we all know, cure is not assured and is not obtained without sequelae. This review will focus on the improvements in treatment for newly diagnosed ALL in children and adolescents according to risk group and some of the challenges that remain despite the improved outcome.

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