Galia Avrahami

Role of 18F-FDG PET/CT in staging and follow-up of lymphoma in pediatric and young adult patients

Objective: To assess the role of 18F-Fluorodeoxyglucose (18F-FDG) PET/CT in pediatric patients with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Materials and Methods: 31 patients, mean age 12.9 ± 5.1, HD (n = 24), and NHL (n = 7) underwent 18F-FDG PET/CT at diagnosis (n = 31 studies) and later in the course of the disease (n = 75 studies). The findings of PET/CT were correlated with diagnostic CT and clinical follow-up. Results: PET/CT findings resulted in a change of disease staging in 10 patients (32.3%), upstaging in 7 (22.6%) and downstaging in 3 (9.6%). On a lesion analysis, 164 disease sites were detected by PET/CT of which 38 were overlooked by DCT. At mid-treatment, PET was negative in 28 out of 31 patients (90%) with negative predictive value of 96% as all latter patients except for 1, were disease free (mean 15.4 ± 8.8 months). The positive predictive value of persistent increased 18F-FDG uptake was 100% as 3 patients with latter findings had active disease. On the CT part, 76 residual masses were identified in 22 patients. Increased 18F-FDG uptake was detected in 11 masses in 4 patients who had active disease. Remaining 65 PET negative masses were false positive findings. The positive predictive value of residual CT mass was 14%. Conclusions: PET/CT is associated with change in staging in approximately 1 out of 3 pediatric patients with HD and NHL. When used for monitoring response to treatment, a negative study is associated with disease-free period, even when residual mass is detected. A positive PET study indicates residual malignant disease.

Long-term results of the Israeli National Studies in childhood acute lymphoblastic leukemia: INS 84, 89 and 98

Long-term results of the Israeli National Studies in childhood acute lymphoblastic leukemia: INS 84, 89 and 98

miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia.

Our aim was to identify miRNAs that can predict risk of relapse in pediatric patients with acute lymphoblastic leukemia (ALL). Following high‐throughput miRNA expression analysis (48 samples), five miRs were selected for further confirmation performed by real time quantitative PCR on a cohort of precursor B‐cell ALL patients (n = 138). The results were correlated with clinical parameters and outcome. Low expression of miR‐151‐5p, and miR‐451, and high expression of miR‐1290 or a combination of all three predicted inferior relapse free survival (P = 0.007, 0.042, 0.025, and <0.0001, respectively). Cox regression analysis identified aberrant expression of the three miRs as an independent prognostic marker with a 10.5‐fold increased risk of relapse (P = 0.041) in PCR‐MRD non‐high risk patients. Furthermore, following exclusion of patients harboring IKZF1 deletion, the aberrant expression of all three miRs could identify patients with a 24.5‐fold increased risk to relapse (P < 0.0001). The prognostic relevance of the three miRNAs was evaluated in a non‐BFM treated precursor B‐cell ALL cohort (n = 33). A significant correlation between an aberrant expression of at least one of the three miRs and poor outcome was maintained (P < 0.0001). Our results identify an expression profile of miR‐151‐5p, miR‐451, and miR‐1290 as a novel biomarker for outcome in pediatric precursor B‐cell ALL patients, regardless of treatment protocol. The use of these markers may lead to improved risk stratification at diagnosis and allow early therapeutic interventions in an attempt to improve survival of high risk patients.

Extended triple intrathecal therapy in children with T‐cell acute lymphoblastic leukaemia: a report from the Israeli National ALL‐Studies

Owing to the increased central nervous system (CNS) relapse risk in T‐cell acute lymphoblastic leukaemia (ALL), it is unclear whether preventive cranial radiation (pCRT) can be safely omitted. In this study, pCRT was replaced by extended triple intrathecal therapy (TIT) in prednisone good early responders – medium‐risk (MR) group, accounting for 76% of T‐ALL patients. From 1989 to 2003, 143 T‐ALL patients aged 1–18 years were enrolled in the Israel National Studies (INS) 89 (n = 84) and INS 98 (n = 59) trials, based on ALL‐Berlin–Frankfurt–Munster (BFM) 86/90 and ALL‐BFM 95 protocols, respectively. Five‐year event‐free survival (EFS) of the MR group in the INS 89 (n = 60) was 70 ± 5·9% and the INS 98 (n = 43), 83·7 ± 5·6% (P = 0·12); the cumulative incidence (CI) of any CNS relapse was 5·0 ± 2·8% and 2·3 ± 2·3% (P = 0·50), respectively. There was no difference in outcome between MR patients with a white blood cell count (WBC) ≥100 × 109/l treated with extended TIT (n = 17) or pCRT (n = 10). For all T‐ALL patients, 5‐year EFS was 61·9 ± 5·3% in INS 89 and 72·9 ± 5·8% in INS 98, (P = 0·21); the CI of any CNS relapse was 7·1 ± 2·8% and 1·7 ± 1·7% (P = 0·142), respectively. Outcome of T‐ALL MR patients given extended TIT in the context of BFM‐based protocols with long‐term follow‐up appeared to be comparable to studies in which a larger proportion of patients was irradiated, and was associated with low risk of CNS relapse, regardless of the WBC.

Growth and pubertal patterns in young survivors of childhood acute lymphoblastic leukemia.

Abstract Background: Survivors of acute lymphoblastic leukemia (ALL) may experience endocrine dysfunction. This study evaluated growth and pubertal patterns in survivors of childhood ALL. Methods: Longitudinal assessment of anthropometric measurements and pubertal status was performed in a retrospective cohort of survivors (n=183). Median age at last endocrine visit was 16.1 years (range 8.2–27.6); median follow-up time was 8.7 years (range 3–21.4). Results: Treatment with chemotherapy+prophylactic cranial radiation (pCRT, n=29) was associated with lower mean height standard deviation score (SDS) than chemotherapy alone (n=154) (p=0.001) and higher prevalence of adult short stature (13% vs. 2.2%). Mean age at pubertal onset was normal (girls: 10.3±1.3 years; boys: 12.0±1.3 years). Precocious puberty, diagnosed in 8.7% of patients, was more prevalent in pCRT-treated girls. Rates of overweight and obesity were 22.9% and 9.3%, respectively. Predictors of endocrine disorders were pCRT (p=0.031) and female gender (p=0.041); of obesity, higher body mass index (BMI)-SDS at diagnosis (p=0.001); and of short stature, lower height-SDS at diagnosis (p=0.038). Conclusions: Most childhood ALL survivors given chemotherapy alone attain normal adult height and puberty. Childhood ALL survivors are at increased risk of overweight, especially those with increased BMI at diagnosis. Clinicians should screen for overweight early in survivorship and introduce early interventions.

Abstract B34: Increased risk of relapse in non-high-risk children with pediatric B-lineage acute lymphoblastic leukemia can be predicted at diagnosis by microRNA expression

Aim: microRNAs (miRNAs) have been implicated in many malignancies. Our aim was to identify specific miRNAs that can predict risk of relapse in pediatric acute lymphoblastic leukemia (ALL) patients treated on BFM protocols, better than the current risk group stratification. Currently, the main method for risk group stratification is based on the amount of minimal residual disease (MRD) assessed at specific time points by real time quantitative PCR (RQ-PCR). Material and methods: Following microRNA expression analysis, we decided to focus on miR-151-5p and miR-451 that significantly correlated with known prognostic factors in ALL. Validation was performed by measuring the expression levels of miR-151-5p and miR-451 by RQ- PCR on a cohort of B-lineage ALL patients treated by a Berlin-Frankfurt-Munster (BFM) protocol following exclusion of Philadelphia positive patients (n=123). Results: Low expression of miR-151-5p, miR-451 or of both together resulted in significantly worse relapse free survival (RFS) (61%, 64% and 43%, respectively) compared to RFS rates when either or both miRNAs were highly expressed (83%, 82% and 82%, respectively) (p=0.023, 0.03 and 0.0001, respectively). Multivariate Cox regression analysis identified low expression of both miRNAs as an independent prognostic marker. Patients expressing low expression levels of both miRs had a 8.8-fold increased risk for relapse (p=0.003). Deletion of IKZF1 gene is a known adverse prognostic marker in B-lineage ALL. In 88 patients, IKZF1 status was analyzed and 9 patients were found to harbor the deletion. The expression of both miRs could still identify an adverse group of patients with only 50% RFS within the group with no deletion (p Even in a non-BFM treated B-lineage ALL cohort from The Netherlands, the expression levels of both miRs significantly correlated with outcome (p=0.003). Conclusion: Our results identify miR-151-5p and miR-451 as novel biomarkers for outcome in pediatric B-lineage ALL patients, regardless of treatment protocol. This may lead to improved risk group stratification and better RFS. Citation Format: Smadar Avigad, Iedan RN Verly, Gertjan JL Kaspers, Jacqueline Cloos, Anat Ohali, Michal Hameiri-Grossman, Keren Shichrur, Eva Fronkova, Jan Trka, Drorit Luria, Yona Kodman, Hadar Mirsky, Dafna Gaash, Marta Jeison, Galia Avrahami, Sarah Elitzur, Gil Gilad, Batia Stark, Isaac Yaniv. Increased risk of relapse in non-high-risk children with pediatric B-lineage acute lymphoblastic leukemia can be predicted at diagnosis by microRNA expression. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B34.