CD22 Expression in Pediatric B-Lineage Acute Lymphoblastic Leukemia.

Abstract Abstract 4119 While the majority of pediatric patients with newly diagnosed B-lineage acute lymphoblastic leukemia (ALL) are cured with standard chemotherapy regimens, treatment is associated with multiple toxicities, and ALL remains the most frequent cause of cancer mortality in childhood. CD22, a B-lineage surface glycoprotein involved in B cell signaling and adhesion, is expressed in most cases of B-lineage ALL. We are conducting clinical trials of anti-CD22 immunotoxins [RFB4(dsFv)-PE38] for pediatric ALL. To assess eligibility for such targeted therapy, CD22 expression by ALL cells was studied in peripheral blood and/or bone marrow aspirate samples from 50 patients with relapsed ALL. The level of CD22 expression by ALL cells was quantitated by measuring mean anti-CD22 antibody binding per ALL cell (ABC) under saturating conditions using flow cytometry and the BD Biosciences QuantiBRITE system for fluorescence quantitation. Patients ranged in age from 3 to 22 years (median 10 years) and included 27 males and 23 females. CD22 expression was detected in all samples, and the vast majority of cases demonstrated expression of CD22 in 100% of leukemic blasts. CD22 antigen density in ALL cells varied widely among patients at baseline (range 451 - 14,519; mean 4276; median 3824; standard deviation 2976; see graph). CD22-directed immunotoxin therapy was initiated in 29 of the 50 patients, 19 of whom had samples quantitated for CD22 expression levels both before and after immunotoxin therapy. Most patients exhibited limited variation in the mean number of anti-CD22 molecules bound per ALL cell when comparing multiple specimens. In conclusion, CD22 expression varies widely in pediatric B-lineage ALL and persists despite repeated exposure to CD22-directed therapy. (MedImmune, LLC, sponsored the clinical studies of anti-CD22 immunotoxin CAT-8015.) Disclosures: No relevant conflicts of interest to declare.

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Detection of Common Chimeric Fusion Transcripts in Acute Lymphoblastic Leukemia (ALL) Patients Using Multiplex Reverse Transcriptase Polymerase Chain Reaction Assay: A North Indian Tertiary Care Centre Experience

Blood ◽

10.1182/blood.v118.21.4234.4234 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4234-4234 ◽

Cited By ~ 1

Author(s):

Neelam Varma ◽

Prateek Bhatia ◽

Jogeshwar Binota ◽

Ram Kumar Marwaha ◽

Subhash Varma ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Tertiary Care ◽

Rna Extraction ◽

Rt Pcr ◽

Pcr Assay ◽

Fusion Transcripts ◽

Pediatric All ◽

B Lineage

Abstract Abstract 4234 Introduction: Chromosomal abnormalities constitute an important parameter to identify prognostically relevant subgroups in acute lymphoblastic leukemia (ALL). Many western studies report the incidence of common chimeric fusion transcripts as 30–35%, however the data regarding the Indian patients is very scarce. Aims and Objectives: The aim of the present study was to detect presence of common chimeric fusion transcripts of t(12;21), t(9;22), t(1;19) and t(4;11) in adult and pediatric ALL cases using the Multiplex RT-PCR assay. Materials and Methods: This prospective study included 100 consecutive ALL cases diagnosed during last one year; 54 patients were <12 years of age. Diagnosis of ALL was made on the basis of bone marrow (BM) examination and flowcytometric immunophenotypic (FCM-IP) analysis. Approximately 2 ml of peripheral blood (PB) sample or 0.5 ml of BM sample was collected in EDTA. RNA extraction and cDNA synthesis was performed using commercial kits, according to standard protocols. RT-PCR assay was carried out using primers specific to the fusion transcripts of TEL-AML1 t(12;21); BCR-ABL t(9;22); E2A-PBX t(1;19) and MLL-AF4 t(4;11). The results of RT-PCR and FCM-IP were blinded and compared later. Results: Out of the 100 cases enrolled in the study, 54% were pediatric and 46% adult cases. Among the pediatric ALL cases, 49 were diagnosed as B-lineage ALL, 3 T-lineage ALL and 2 Biphenotypic ALL. Whereas among the adult ALL cases, 30 were diagnosed as B-lineage ALL, 12 T-lineage ALL and 4 Biphenotypic ALL. A total of 26% showed positivity for various fusion transcripts: 13% each pediatric and adult cases being positive. Of the 12 positive pediatric B-lineage ALL cases, 8 were positive for TEL-AML1 transcripts, 1 for BCR-ABL transcripts, 1 for E2A-PBX transcripts and 2 for MLL-AF4 transcripts. Out of the 11 positive adult cases, 7 were positive for BCR-ABL transcripts, 2 were positive for TEL-AML1 transcripts and 1 each for E2A-PBX transcripts and MLL-AF4 transcripts. BCR-ABL transcripts were detected in 1 out of 2 pediatric biphenotypic ALL and 2 out of 4 adult biphenotypic ALL cases. None of the pediatric cases was positive for the MLL-AF4 transcripts. None of the 4 transcripts were detected in any T-lineage ALL. Conclusion: Results of our study are comparable to those of other western and Asian studies, with TEL-AML1 transcripts being the most common fusion transcripts seen in pediatric B-ALL cases and BCR-ABL in adult cases. However two Indian studies had reported much lower incidence of TEL-AML1 and MLL-AF4 transcript in B-ALL cases. Identification of good prognostic groups and rationalization of therapy assumes great importance in our set ups as many patients are economically under-privileged. Relationship of these transcripts to the prognosis of our ALL patients will be evaluated in future. Disclosures: No relevant conflicts of interest to declare.

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Outcome of Relapse After Allogeneic Transplantation for Childhood Acute Lymphoblastic Leukemia In Complete Remission. A Study of the Pediatric Diseases and Acute Leukemia Working Parties of the EBMT Group

Blood ◽

10.1182/blood.v116.21.1291.1291 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1291-1291

Author(s):

Adriana Balduzzi ◽

Myriam Labopin ◽

Vanderson Rocha ◽

Nabila Elarouci ◽

Giorgio Dini ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Hematopoietic Cell Transplantation ◽

Conflicts Of Interest ◽

Pediatric Population ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Prognostic Impact ◽

Dismal Prognosis ◽

B Lineage ◽

Donor Lymphocyte Infusions

Abstract Abstract 1291 Introduction. Childhood acute lymphoblastic leukemia (ALL) relapse occurring after hematopoietic cell transplantation (HCT) has a very dismal prognosis. Its treatment is still controversial and ranges from palliative treatment or chemotherapy to donor lymphocyte infusions, second transplant or experimental approaches. Objectives. The aim of this study is to assess the actual outcome in a pediatric population. The primary endpoint of this study is the 2-year probability of survival of children with ALL relapsing after allogeneic HCT; the secondary endpoint is the relationship between outcome and time of relapse after transplant, for which the following categories were considered: <3, 3–6, 6–12, > 12 months. Patients. Patients younger than 18 years of age undergoing first HCT from any allogeneic donor for ALL in first (CR1) or second (CR2) remission between January 1st 1998 and December 31st 2007 reported to the EBMT were eligible for the study. Results. Out of 3628 transplanted children with ALL reported to the EBMT, 836 (median age 9 years, male 66%) relapsed at a median of 6 months (range 1–67; 25th, 75th 4, 12 months) after HCT. The HCT was performed in CR1 (60%) or CR2 (40%) for a B-lineage (60%) or T- (13%) or unknown (27%) immunophenotype ALL, from an HLA-matched related (44%), unrelated (59%) or mismatched related (7%) donor, with marrow (61%), peripheral (28%) or umbilical (11%) stem cells. Out of 836, 81% died at a median of 2 months (25th,75th centiles:1,7) and 19% were reported as alive at last follow-up at a median of 22 months after relapse (range: 1–130). The 3-year probability of overall survival (3y-OS) was 14% (SE 1). As to immunophenotype, disease phase and donor type, 3y-OS was 15% (SE 2) in B-lineage and 8% (SE 3) in T-ALL, 18% (SE 2) in patients transplanted in CR1 and 11% (SE 6) in CR2 and 17% (SE 2) in patients transplanted from an HLA-identical sibling and 12% (SE 2) from any other donor. According to time of relapse after transplant, 3-year OS was 6% (SE 2), 10% (SE 2), 15% (SE 2) and 27% (SE 4) in those who relapsed in the first quarter, second quarter, second semester or after the first year, respectively. Donor lymphocyte infusions were reported for 7% and a second HCT for 16% of the 836 relapsed children. The probability of undergoing a second HCT within 1 year after relapse was 17% (SE 1); this probability was 6% for relapses occurring <6 months and 25% for later relapses. 3y-OS of those who underwent a second HCT was 32% (SE 5). Conclusions. The multivariate analyses confirmed the prognostic role of disease phase and immunophenotype, but not of the type of donor, assessed the strong prognostic impact of the time elapsed in CR after HCT before relapse, being earlier relapses at worse outcome compared with later relapses, possibly due to the chance of undergoing a second HCT, which role per se was not statistically significant. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v116.21.4934.4934 ◽

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.

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

Blood ◽

10.1182/blood.v120.21.5124.5124 ◽

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.

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

Blood ◽

10.1182/blood.v124.21.2260.2260 ◽

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.

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LDL Discordance in Pediatric Survivors of Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v124.21.6003.6003 ◽

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.

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

Blood ◽

10.1182/blood.v124.21.939.939 ◽

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.

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Two Cases of Pediatric Acute Lymphoblastic Leukemia with t(5;14): a Challenging and Unique Entity

Blood ◽

10.1182/blood.v126.23.4870.4870 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4870-4870

Author(s):

Renee-Pier Fortin-Boudreault ◽

Elaine W. Leung ◽

Mylene Bassal

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Pediatric Patients ◽

Conflicts Of Interest ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Behavior Changes ◽

Low Grade ◽

Cell Transplant ◽

St Depression ◽

Pediatric All

Background: Pre-B acute lymphoblastic leukemia (B-ALL) with the t(5;14) translocation occurs in less than 1% of B-ALL diagnoses. This translocation links the IGH on chromosome 14 with IL-3, which results in hypereosinophilia. Interestingly, circulating blasts or cytopenias usually don't accompany the eosinophilia. Patients often present with symptoms related to the eosinophilia, which can be quite morbid, and can delay the diagnosis of ALL. Few pediatric patients with this association have been described in the literature. The presentation and outcome can be quite variable, although it is thought that the prognosis in those patients is worse than standard ALL. Objectives: To review the laboratory and clinical features of pediatric ALL with t(5;14). Methods: Cases of pediatric patients with ALL and t(5;14) diagnosed at the Children's Hospital of Eastern Ontario between 1995 and 2003 were reviewed. Results: We present two 11 year old children, a female and a male, who were diagnosed with B-ALL with t(5;14). The first one presented with a persisting low-grade fever and weight loss as well as asymptomatic lung infiltrates on the chest xray. The second patient presented with chest pain, fever, abdominal pain, as well as a petechial rash and splinter hemorrhages. His EKG showed ST depression, his troponins were elevated and an echocardiogram showed heart dysfunction. He went on and developed behavior changes and cerebral microinfarcts. Common to their presentation was the presence of hyperoesinophilia and absence of circulating blasts. Both had aggressive disease with persistent positive minimal residual disease (MRD) after consolidation and reinduction, which sent them to stem cell transplant. Conclusion: ALL with t(5;14) is a rare entity that usually presents with hypereosinophilia. While eosinophilia can be asymptomatic, it can also be the cause of important morbidity. Diagnosis can be delayed because of the absence of blasts in the peripheral blood and lack of severe cytopenia. Finally, due to its rarity, there is very little information available on how this cytogenic abnormality impacts prognosis, which seems to be worse than ALL without this translocation. Disclosures No relevant conflicts of interest to declare.

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Incidence and Clinical Relevance of TEL/AML1 Fusion Genes in Children With Acute Lymphoblastic Leukemia Enrolled in the German and Italian Multicenter Therapy Trials

Blood ◽

10.1182/blood.v90.2.571.571_571_577 ◽

1997 ◽

Vol 90 (2) ◽

pp. 571-577 ◽

Cited By ~ 5

Author(s):

Arndt Borkhardt ◽

Giovanni Cazzaniga ◽

Susanne Viehmann ◽

Maria Grazia Valsecchi ◽

Wolf Dieter Ludwig ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Fusion Gene ◽

Lymphoblastic Leukemia ◽

Prognostic Impact ◽

Dna Index ◽

Childhood All ◽

Pediatric All ◽

Aml1 Gene ◽

B Lineage ◽

The Impact

The molecular approach for the analysis of leukemia associated chromosomal translocations has led to the identification of prognostic relevant subgroups. In pediatric acute lymphoblastic leukemia (ALL), the most common translocations, t(9; 22) and t(4; 11), have been associated with a poorer clinical outcome. Recently the TEL gene at chromosome 12p13 and the AML1 gene at chromosome 21q22 were found to be involved in the translocation t(12; 21)(p13; q22). By conventional cytogenetics, however, this chromosomal abnormality is barely detectable and occurs in less than 0.05% of childhood ALL. To investigate the frequency of the molecular equivalent of the t(12; 21), the TEL/AML1 gene fusion, we have undertaken a prospective screening in the running German Berlin-Frankfurt-Münster (BFM) and Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) multicenter ALL therapy trials. We have analyzed 334 unselected cases of pediatric ALL patients consecutively referred over a period of 5 and 9 months, respectively. The overall incidence of the t(12; 21) in pediatric ALL is 18.9%. The 63 cases positive for the TEL/AML1 chimeric products ranged in age between 1 and 12 years, and all but one showed CD10 and pre-B immunophenotype. Interestingly, one case displayed a pre-pre–B immunophenotype. Among the B-lineage subgroup, the t(12; 21) occurs in 22.0% of the cases. Fifteen of 61 (24.6%) cases coexpressed at least two myeloid antigens (CD13, CD33, or CDw65) in more than 20% of the gated blast cells. DNA index was available for 59 of the 63 TEL/AML1 positive cases; a hyperdiploid DNA content (≥1.16) was detected in only four patients, being nonhyperdiploid in the remaining 55. Based on this prospective analysis, we retrospectively evaluated the impact of TEL/AML1 in prognosis by identifying the subset of B-lineage ALL children enrolled in the closed German ALL-BFM-90 and Italian ALL-AIEOP-91 protocols who had sufficient material for analysis. A total of 342 children were investigated for the presence of TEL/AML1 fusion gene and 99 cases (28.9%) were positive. The patients expressing the TEL/AML1 fusion mRNA appeared to have a better event-free survival (EFS) than the patients who lacked this chimeric product. Whereas three of the TEL/AML1 positive cases (3.0%) have relapsed to date, 27 patients without TEL/AML1 rearrangement (11.1%) suffered from relapse. To date, the only subset of B-lineage ALL with a favorable prognosis has been the hyperdiploid group (DNA index ≥1.16 <1.6). Our findings reinforce the need to include the molecular screening of the t(12; 21) translocation within ongoing prospective ALL trials to prove definitively its prognostic impact.

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Low Epression of MiR-18a Distinguishes Pediatric and Adult Acute Lymphoblastic Leukemia from Each Other

Blood ◽

10.1182/blood.v126.23.4991.4991 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4991-4991

Author(s):

Neda Mosakhani ◽

Mohamed El Missiry ◽

Emmi Vakkila ◽

Päivi Heikkilä ◽

Sakari Knuutila ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Immune Cell ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Tissue Samples ◽

Inflammatory Microenvironment ◽

Qrt Pcr ◽

Response To Chemotherapy ◽

Pediatric All

Abstract In several adult solid cancers the presence or absence of an inflammatory microenvironment has turned out to be an important prognostic factor. Acute lymphoblastic leukemia (ALL) is seen in both adults and children but the response to chemotherapy and survival is significantly worse in adults than children. Therefore, we wanted to study whether the expression of immune system associated molecular markers would be different in adult and pediatric ALL patients at the time of diagnosis. IDO and FOXP3 were studied from paraffin embedded tissue samples by immunohistochemistry in 12 pediatric and 10 adult bone marrow samples. Inflammation associated miRNA analysis were performed in 19 adult and 79 pediatric ALL patients and involved miR-10, miR-15, miR-16, miR-17-92 cluster, miR-33, miR-146a, miR-150, miR-155, miR-181a, miR-222, miR-223, and miR-339. miRNAs were first analysed by Agilent's miRNA microarray and thereafter validated by qRT-PCR. miRNAs not expressed in at least 75% of one group of samples were excluded. Significance (p <0.05; q<0.1) of differential expression was estimated by t-test for those miRNAs with at least a 2.0 fold change. Sufficient RNA for qRT-PCR was available for 42 pediatric and 19 adult patients. The adult and pediatric ALL patients had quantitatively and qualitatively similar expression of IDO and FOXP3 in leukemic bone marrow samples (p=0.26 and 0.74, respectively). Out of studied miRNAs only miR-18a differed significantly in microarray analysis between adult and pediatric ALL being lower in children (FC -3.74; p 0,0037). Results were confirmed by qRT-PCR (upregulated in adults, FC 3.71, p 0.003161). The other members of the miR-17-92 cluster did not differ significantly. We conclude that pediatric and adult ALL patients have remarkably similar pattern of immune cell associated markers in bone marrow at diagnosis. This is in line with recent evidence that the outcome of the adult ALL patients can be significantly improved if treated with pediatric protocols. However, the low expression of miR-18a in pediatric ALL is interesting and demands further studies. Disclosures No relevant conflicts of interest to declare.

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