Survival In Pediatric Acute Lymphoblastic Leukemia Research Articles

Relationship between Bax and Bcl-2 Protein Expression and Outcome of Induction Phase Chemotherapy in Pediatric Acute Lymphoblastic Leukemia.

Background:Overexpression of the antiapoptotic protein Bcl-2 causes apoptosis to stop and conversely the increased expression of the proapoptotic protein Bax makes lymphoblasts easy to destroy. The Bax/Bcl-2 ratio plays a role in the balance of apoptosis, immortality, resistance, and outcome of chemotherapy. We analyzed the relationship between the Bax/BCl-2 ratio and the outcome of induction phase chemotherapy in pediatric Acute Lymphoblastic Leukemia (ALL). Methods:This research was conducted with a prospective observational study on pediatric ALL aged 1-18 years who were newly diagnosed based on bone marrow aspiration (morphology and immunophenotyping) at Dr. Soetomo General Hospital, Surabaya on October 2020 to March 2021. Expression of Bcl-2, Bax, and Bax/Bcl-2 protein ratio was measured by the flow cytometry method from lymphoblast on bone marrow aspirate samples before and after induction phase chemotherapy according to the 2018 Childhood ALL Indonesian Protocol. The outcomes evaluated were survival and remission rate (lymphoblasts in the bone marrow less than 5%). We used the Mann-Whitney U test and Wilcoxon Signed Rank test to analyze the differences between protein expression with p<0.05 for a two-tailed test. Results:We included 17/26 pediatric ALL, consisting of 88% male, 94% LLA-L1, 76% B cell ALL and 24% T cell ALL. Mean expression of Bax, Bcl-2, and Bax/Bcl-2 protein ratio before chemotherapy among pediatric ALL who alive (N=11) and dead (N=6) were not significantly different (p>0.05). All children who completed the induction phase of chemotherapy went into remission. Bax and Bcl-2 expression before and after chemotherapy showed no difference (p>0.05). The Bax/Bcl-2 ratio increased from 1.74(SD 1.846) to 6.17(4.139) with p=0.021. Conclusion:Expression of Bax, Bcl-2, and Bax/Bcl-2 protein ratio at the beginning of diagnosis did not affect the survival of pediatric ALL after the induction phase of chemotherapy. The Bax/Bcl-2 protein ratio increased 3.5 times in pediatric ALL with remission outcomes, indicating proapoptotic dominance.

Distance to the pediatric oncology center does not affect survival in children with acute lymphoblastic leukemia: a report from CYP-C

Remoteness is associated with worse survival in adults with cancer. We aimed to determine whether remoteness is associated with cancer outcomes in pediatric acute lymphoblastic leukemia (ALL). Canadian children with ALL entered in the CYP-C registry were included. The predictive impact of remoteness on overall survival (OS), relapse, and treatment-related complications (infections, thrombosis, bleeding, and osteonecrosis) was estimated using multivariate regression models. We included 1383 children, of whom 277 (20.0%) lived remotely (>200 km from the pediatric oncology center). The median latency to see a pediatric oncologist was longer in children living remotely. The 5-year OS (95% CI) was similar for both groups (remote: 95.2% [93.7–96.3%] vs close: 94.1% [90.5–95.2%]). No difference was found in the relapse rate between both groups and in treatment-related complications. Remoteness did not affect survival in pediatric ALL. Further research is needed to determine which models of healthcare organization optimize cancer outcomes and patients’ satisfaction.

“SOCIOECONOMIC FACTORS AFFECTING SURVIVAL IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA FROM NORTH-EAST INDIA”

Acute lymphoblastic leukemia (ALL) is a highly curable childhood cancer with a survival rate of nearly 80% in developed countries but is around 45% in developing countries. This retrospective study analyzed the association between demographic and socioeconomic factors with survival in pediatric ALL. All confirmed cases of pediatric ALL (age &lt;18 years) registered at Dr. B Borooah Cancer Institute between 2010 to 2017 were analyzed using data collected from hospital-based cancer registry and case records. Seventy-five confirmed cases of pediatrics ALL were eligible for the study. The median age of presentation was six years with a male: female ratio 1.9:1. Overall survival at 4-years was 43.8%, with a median survival of 25 months. A trend for higher 4-year overall survival was seen in female children (54.1% versus 37.9%, p=0.097). Patients from rural areas (44% versus 39.5%, p=0.308), with higher maternal education (83.3% versus 41.1%, p=0.161) and patients who did not abandon treatment (49.1% versus 31.2%, p=0.497) had better survival, but the differences were not significant. Four years overall survival in upper-middle, lower-middle, upper-lower, and lower class were 85.7%, 74.9%, 38.1%, and 7.7% respectively (upper-middleversus lower socioeconomic class, p=0.0001).Multivariate analyses confirmed a statistically significant relationship between socioeconomic status and survival, with the upper-middle group had a 90% decreased risk of death compared to the lower socioeconomic group. There is an urgent need for a proper definition of the problems of childhood ALL to introduce appropriate policies for improving survival in developing countries.

Impact of IKZF1 Deletions and IKZF1 Plus in Pediatric Acute Lymphoblastic Leukemia Outcome

Introduction: Survival of children with acute lymphoblastic leukemia (ALL) has improved in the last decades, achieving approximately 80% in Argentina. However, relapses remain the most frequent adverse event and the identification of patients with higher risk need to be refined. Deletions in IKZF1(IKZF1del) in addition with deletion of CDKN2A, CDKN2B,PAX5 or PAR1 region define a new subgroup of patients (IKZF1plus) with higher relapse rate and poor survival.Objectives: To analyze the characteristics of patients with IKZF1del and IKZF1plus, assessing the impact of the copy number alterations in several genes on survival of pediatric ALL treated with ALLIC strategy.Methods: This is a retrospective analysis performed in the population of patients admitted from October 2009 to May 2018. Samples of 432 patients with diagnosis of ALL were collected and analyzed by MLPA P-335 (MRC-Holland) for copy number alterations of IKZF1, EBF1, JAK2, CDKN2A, CDKN2B, PAX5, ETV6, BTG1, RB1 genes and PAR1 region. IKZF1plus cases were defined as those with IKZF1del with at least one additional deletion in: PAX5, CDKN2A, CDKN2B, PAR1 region. Patients were treated with 2 consecutive ALLIC protocols, according to studies stratification. Patient characteristics were compared with chi-square and Wilcoxon-sum-rank-test. Survival probability was analyzed with Kaplan-Meier calculation and survival results compared with Log-rank-test.Results: IKZF1 was not deleted in 345 cases, IKZF1del was detected in 87 cases and 47 of them were defined as IKZF1plus. Statistically significant higher WBC, MRD+ positivity on day 15, day 33 and week 12, more BCR-ABL+ and high-risk group cases, null response and higher relapse rate were observed in the IKZF1del group (total) when comparing with IKZF1 not del, and also when comparing IKZF1plus vs IKZF1 not del + IKZF1del only. EFS (SE) and DFS (SE) probabilities were: 73 (4)% and 75 (3)% for IKZF1 not del, 66 (9)% and 70 (9)% for IKZF1del, and 20 (10)% and 21 (10)% for IKZF1plus, respectively (p<0.00001).DFS of the standard-risk group was not influenced by the presence of only 1 case of IKZF1del detected in this risk-group of patients. However, DFS of intermediate-risk patients was 41 (11)% for IKZF1plus while 70 (7)% and 73 (4)% were achieved for IKZF1del and IKZF1 not del respectively (p=0,0083). Therefore, high-risk patients with IKZF1plus achieved DFS of 12 (19)% vs 65 (7)% and 50 (21)% for IKZF not del and IKZF1del respectively (p=0.0085). DFS of patients with IKZF1del + CDKN2Adel was 30 (10)% and CDKN2A not deleted 67 (9)% (p=0.0433). DFS of patients with IKZF1del + CDKN2Bdel was 42 (12)% and 66 (9)% for CDKN2B not del. DFS of cases with IKZF1del in addition to deletion of ETV6, BTG1, EBF1 orJAK2 did not show statistically significant differences when comparing with IKZF1del + normal copy number of these genes. In addition, DFS of cases with RB1del was 36 (13)% while cases without RB1del showed 70 (3)% (p=0.0071).Conclusions: 1- Patients with IKZF1del and IKZF1plus disclosed biological features related to poor outcome. 2- IKZF1plus was associated with a poor outcome in intermediate and high-risk groups according to ALLIC stratification. 3- The addition of CDKN2Adel to IKZF1del influence the outcome. However, CDKN2Bdel did not show the same effect. 4- Copy number alterations of ETV6, BTG1, EBF1 or JAK2 did not demonstrate prognostic impact. 5- RB1 showed negative influence in survival. 6- Identification of patients with IKZF1plus at diagnosis could be very useful for improving risk-group stratification of pediatric ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Absolute Lymphocyte Count (ALC) after Induction Treatment Predicts Survival of Pediatric Patients with Acute Lymphoblastic Leukemia.

Absolute Lymphocyte Count (ALC) has been recently established as a prognostic factor of survival in pediatric Acute Lymphoblastic Leukemia (ALL). A retrospective analysis of 132 patients treated according the BFM - ALLIC 2002 protocol was performed in a single institution. A possible association between ALC values and Overall Survival (OS) or Event-Free Survival (EFS) was evaluated at multiple time points during induction chemotherapy. ALC higher than 350 cells/μL measured on the 33th day of induction was associated with better Overall- and Event-Free Survival in both Kaplan-Meier (OS 88.6% vs. 40%; p<0.001 / EFS 81.6% vs. 30%; p<0.001) and Cox regression (OS HR 8.77 (3.31-23.28); p<0.001) and EFS HR 6.61 (2.79-15.63); p<0.001) analyses. There was no association between survival and measured ALC values from earlier time points (day of diagnosis, days 8 and 15) of induction therapy. Patients with low ALC values tend to have higher risk (MR or HR groups) and a higher age at diagnosis (>10years). With help of day 33 ALC values of 350 cells/μL cutoff it was possible to refine day 33 flow cytometry (FC) Minimal Residual Disease (MRD) results within the negative cohort: higher ALC values were significantly associated with better survival. ALC on day 33 (350 cells/μL) remained prognostic for OS and EFS in multivariate analysis after adjusting it for age, cytogenetics, immunophenotype and FC MRD of induction day 33. According to these findings ALC on day 33 of induction is a strong predictor of survival in pediatric ALL.

Methylenetetrahydrofolate reductase C677T and overall survival in pediatric acute lymphoblastic leukemia: a systematic review

A summary of the evidence pertaining to the association between methylenetetrahydrofolate reductase (MTHFR) C677T and overall survival in pediatric acute lymphoblastic leukemia (ALL) is not currently available. We thus reviewed the literature on the association between MTFHR C677T and overall survival in pediatric ALL. We searched PubMed/MEDLINE, Scopus and ISI Web of Knowledge literature databases without language restrictions to identify observational studies among children diagnosed between ages 0 and 19 years that assessed MTHFR 677 polymorphisms in relation to ALL survival. We identified six studies comprising 909 pediatric patients with ALL. The magnitude of relative risk (RR) for pediatric ALL mortality varied by genotype comparison and study population, ranging from RR = 0.84 (95% confidence limits [CL]: 0.24, 3.0) for a TT vs. CT/CC comparison to RR = 7.0 (95% CL: 0.98, 49) for a TT vs. CC comparison. The current evidence suggests that individuals with MTHFR 677 variants (i.e. at least one T allele) may have a higher relative risk of pediatric ALL mortality, with greater statistical support for MTHFR 677TT. With more detailed supporting evidence, MTHFR 677 genotyping at diagnosis could provide an option for individualizing therapy and further reducing pediatric ALL mortality in certain populations.