Homozygous Deletion of the p16/MTS1 Gene in Pediatric Acute Lymphoblastic Leukemia Is Associated With Unfavorable Clinical Outcome

Abstract The p16 gene (MTS1, CDKN2, p16INK4A, CDKI) encoding an inhibitor of cyclin-dependent kinase 4 (cdk4) has been found to be deleted in various types of tumors, including leukemia, and is thought to code for a tumor suppressor gene. Our preliminary findings on eight pediatric patients with acute lymphoblastic leukemia (ALL) suggested that the survival of patients carrying a homozygous p16 gene deletion was significantly inferior to that of those without a deletion. The present study on 48 patients tested the hypothesis that the clinical outcome for pediatric ALL patients is correlated with the presence or absence of the p16 gene. Overall, nine of 48 children (18.3%) carried a homozygous p16 deletion. Such deletions were significantly more common (P = .003) among T-ALL patients (five of eight, 62.5%) than among precursor-B-ALL patients (four of 40, 10.0%). Of nine patients exhibiting p16 deletions, eight (88.9%) were classified as high-risk patients by the recognized prognostic factors of age, white blood cell count, and T-cell phenotype. The 4-year event-free survival in the study population as a whole was 72.7%. Without adjustment for other risk factors (univariate model), the presence of a homozygous p16 deletion was associated with a markedly increased probability of both relapse (P = .0003) and death (P = .002). These findings raise the question of whether the p16 deletion itself confers an increased risk of relapse after adjusting for the known risk factors. In this analysis, the estimated risk multiplier factor for relapse in patients carrying the p16 deletion was 14.0 (P = .0004) and for the risk of death 15.6 (P = .0008). We therefore conclude that the presence of a homozygous p16 deletion may well be an important risk factor for both relapse and death in childhood ALL, and that its prognostic effect is not a consequence of confounding by other factors already known to influence outcome in this disease.

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

10.36106/ijsr/0820971 ◽

2020 ◽

pp. 1-3

Author(s):

Partha Sarathi Roy ◽

Munlima Hazarika ◽

Rakesh Kumar Mishra ◽

BhargabJyoti Saikia ◽

Gaurav Kumar

Keyword(s):

Overall Survival ◽

Developing Countries ◽

Acute Lymphoblastic Leukemia ◽

Socioeconomic Factors ◽

Lymphoblastic Leukemia ◽

Childhood All ◽

Female Ratio ◽

Risk Of Death ◽

Lower Socioeconomic ◽

Pediatric All

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 <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.

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Study of Some Biochemical Parameters in Iraqi Children with Acute Lymphoblastic Leukemia

Baghdad Science Journal ◽

10.21123/bsj.12.2.371-378 ◽

2015 ◽

Vol 12 (2) ◽

pp. 371-378

Author(s):

Baghdad Science Journal

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Biochemical Parameters ◽

Serum Proteins ◽

Lymphoblastic Leukemia ◽

White Blood Cells ◽

Total Serum ◽

Childhood All ◽

Marrow Cavity ◽

Increased Risk

Leukemia or cancer of the blood is the most common childhood cancer, Acute lymphoblastic leukemia (ALL), is the most common form of leukemia that occurs in children. It is characterized by the presence of too many immature white blood cells in the child’s blood and bone marrow, Acute lymphoblastic leukemia can occur in adults too, treatment is different for children. Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional indications consist of fatigue (50%), pallor (25%), fever (60%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disturbance of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in approximately 75% of patients. About 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm3 occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection. The aim of this study was to investigate the differentiations in some biochemical parameters (Hb, PCV, total serum proteins Aspartate amino transferase(AST), Alanin amino transferase (ALT), and Malondialdehyde (MDA) in blood which can be conceder as a marker of ALL. Samples were collected from 50 patients (between 1-16 years old) diagnosed with ALL after one month treatment with induction therapy, compared with 30 control samples taken from healthy persons at the same age . The ALT and MDA showed a significant increase p < 0.001 and p

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Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

Blood ◽

10.1182/blood.v61.1.66.66 ◽

1983 ◽

Vol 61 (1) ◽

pp. 66-70

Author(s):

T Mohanakumar ◽

TW Coffey ◽

MP Vaughn ◽

EC Russell ◽

D Conrad

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Membrane Component ◽

Childhood All ◽

Antigen Present ◽

The Common ◽

Blood Elements ◽

Human Primate

Abstract A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.

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HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Blood ◽

10.1182/blood-2012-01-404723 ◽

2012 ◽

Vol 120 (15) ◽

pp. 3039-3047 ◽

Cited By ~ 14

Author(s):

Kevin Y. Urayama ◽

Anand P. Chokkalingam ◽

Catherine Metayer ◽

Xiaomei Ma ◽

Steve Selvin ◽

...

Keyword(s):

Genetic Variation ◽

Acute Lymphoblastic Leukemia ◽

Immune Modulation ◽

Lymphoblastic Leukemia ◽

Human Leukocyte ◽

Potential Interaction ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Increased Risk ◽

Ear Infections

Abstract The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.

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Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽

10.1182/blood.v99.12.4257 ◽

2002 ◽

Vol 99 (12) ◽

pp. 4257-4264 ◽

Cited By ~ 129

Author(s):

Smita Bhatia ◽

Harland N. Sather ◽

Olga B. Pabustan ◽

Michael E. Trigg ◽

Paul S. Gaynon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Brain Tumors ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasms ◽

Childhood All ◽

Second Neoplasms ◽

Increased Risk ◽

The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

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Risk Factors for Induction Related Mortality in Adults Patients with Acute Lymphoblastic Leukemia: Report from a Hispanic Population

Blood ◽

10.1182/blood-2018-99-119607 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5162-5162

Author(s):

Sergio I Inclan-Alarcon ◽

Christianne Bourlon ◽

Oscar Manuel Fierro-Angulo ◽

Jesus A Garcia-Ramos ◽

Santiago Riviello-Goya ◽

...

Keyword(s):

Risk Factors ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Prognostic Score ◽

Univariate Analysis ◽

Adult Patients ◽

Hispanic Population ◽

Increased Risk ◽

The Impact ◽

Hispanic Adult

Abstract Introduction Acute lymphoblastic leukemia (ALL) represents 20-30% of acute leukemia in adults. Higher incidence and inferior outcomes in Hispanic population have been described. In Latin Americans induction mortality (IM) is a major cause of death representing 20-50% vs.7-11% in developed countries. Our aim was to determine risk factors (RF) related to IM in ALL Hispanic adult patients. Methods We retrospectively analyzed clinical data of ≥18yo patients with ALL diagnosed and treated at our institution within 2009 and 2016. Results A total of 170 patients were included. Median age was 29 years (16-70), 64% were AYA, 96.8% had B-cell ALL, and 62.3% received Hyper-CVAD. IM rate was 13.4%. In 64.1% IM was related to an infectious cause. The most frequent infection was pneumonia (39.8%). Gram-negative etiology was more prevalent (35.5% vs. 10.2%), however, IM rate was higher in gram-positive infections (26.3% vs .13.6%; p=.028). RF related to IM in univariate analysis were: CNS involvement (OR4.6,95%IC2.8-9.5;p=<.001), tumor lysis syndrome (TLS) (OR 5.6, 95% CI 2.2-14.1; p=<.001), need for dialysis (OR 28.9, 95% CI 5.3-157.1; p=<.001), primary hypertension (OR 3.5, 95% CI 1.0-12.7; p=.052), shock status (OR 10.3, 95% CI 3.9-27.3; p=<.001), ECOG³2 (OR 1.9, 95% IC 1.1-3.4; p=.022), T-ALL (OR 2.2, 95% IC 1.1-4.3; p=.026), Hyper-CVAD (OR 1.9, 95% IC 1.1-3.8; p=0.51), ventilation assistance (OR 7.7, 95% IC 2.8-21; p=<.001), and vasopressor use (OR 7.6, 95% IC 2.8-20.6; p=<.001). In multivariate analysis TLS, need for dialysis and shock, kept statistical significance. Conclusions To our knowledge, this is the largest study that evaluates the impact over IM of biological, social, and economic factors in Hispanic adult patients with ALL. We identified factors not previously described such as hypertension and need for dialysis. Multicenter prospective studies most be urged to asses and validate these RF, and design a bedside prognostic score that can predict an increased risk of IM at ALL diagnosis. Disclosures No relevant conflicts of interest to declare.

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Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽

10.1182/blood.v74.1.409.bloodjournal741409 ◽

1989 ◽

Vol 74 (1) ◽

pp. 409-415 ◽

Cited By ~ 1

Author(s):

SB Murphy ◽

SC Raimondi ◽

GK Rivera ◽

M Crone ◽

RK Dodge ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Clinical Features ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Term Survival ◽

Childhood All ◽

Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

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Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

Blood ◽

10.1182/blood.v61.1.66.bloodjournal61166 ◽

1983 ◽

Vol 61 (1) ◽

pp. 66-70

Author(s):

T Mohanakumar ◽

TW Coffey ◽

MP Vaughn ◽

EC Russell ◽

D Conrad

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Membrane Component ◽

Childhood All ◽

Antigen Present ◽

The Common ◽

Blood Elements ◽

Human Primate

A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.

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Association between the TPMT*3C (rs1142345) Polymorphism and the Risk of Death in the Treatment of Acute Lymphoblastic Leukemia in Children from the Brazilian Amazon Region

Genes ◽

10.3390/genes11101132 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1132

Author(s):

Darlen Cardoso de Carvalho ◽

Luciana Pereira Colares Leitão ◽

Fernando Augusto Rodrigues Mello Junior ◽

Alayde Vieira Wanderley ◽

Tatiane Piedade de Souza ◽

...

Keyword(s):

Native American ◽

Acute Lymphoblastic Leukemia ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Brazilian Amazon ◽

Childhood All ◽

Risk Of Death ◽

Native American Ancestry ◽

High Contribution ◽

Tpmt Gene

Acute lymphoblastic leukemia (ALL) is the leading cause of death from pediatric cancer worldwide. However, marked ethnic disparities are found in the treatment of childhood ALL with less effective results and higher mortality rates being obtained in populations with a high level of Native American ancestry. Genetic variations of the patient can affect resistance to ALL chemotherapy and potentially play an important role in this disparity. In the present study, we investigated the association of 16 genetic polymorphisms with the cell and metabolic pathways of the chemotherapeutic agents used in the treatment of ALL with the risk of death in treating childhood ALL in patients with a high contribution of Amerindian ancestry, coming from the Brazilian Amazon. The study included 121 patients with B-cell ALL treated with the BFM-2002 protocol. We are the first to identify the association between the TPMT gene rs1142345 polymorphism and the high risk of death in treating childhood ALL. Patients with the CC genotype had an approximately 25.5 times higher risk of dying during treatment of the disease than patients with other genotypes (p = 0.019). These results may help elucidate how the patient’s genetic characteristics contribute to the mortality disparity in populations with a high contribution of Native American ancestry. The rs1142345 variant of the TPMT gene could be used as a potential marker to early stratify patients at high risk of death in treating childhood ALL in the investigated population.

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Clinical significance of p53 mutations in relapsed T-cell acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v84.9.3105.3105 ◽

1994 ◽

Vol 84 (9) ◽

pp. 3105-3112 ◽

Cited By ~ 77

Author(s):

MB Diccianni ◽

J Yu ◽

M Hsiao ◽

S Mukherjee ◽

LE Shao ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Lymphoblastic Leukemia ◽

P53 Mutation ◽

P53 Mutations ◽

Risk Of Death ◽

Increased Risk ◽

Cell Acute Lymphoblastic Leukemia ◽

First Remission ◽

First Relapse

Abstract In T-cell acute lymphoblastic leukemia (T-ALL), p53 gene mutations were found in 12 of 51 patients in first relapse (24%). In a retrospective study, bone marrow samples at diagnosis were obtained from 9 of the 12 relapsed patients with p53 mutation; only one patient was found to harbor a p53 mutation at diagnosis. No further p53 mutations were identified in 18 unpaired diagnosis T-ALL samples. This is the first report of a p53 mutation in T-ALL at diagnosis. p53 mutations in relapsed T-ALL were clinically relevant. Patients with p53 mutations experience a shorter duration of survival than those patients without p53 mutations. Additionally, patients with p53 mutations were significantly less likely to have achieved a complete second remission from reinduction therapy than those patients without p53 mutations and experience a shorter duration of survival from relapse even when a second reinduction is obtained. Though primarily identified only at relapse, p53 mutations were also associated with a decreased duration of first remission and overall decrease in survival from diagnosis. Patients with p53 mutations had a 3.8-fold increase in risk of death than those patients without p53 mutations. These findings suggest that p53 mutation is associated with poor clinical outcome that is characterized by (1) a shortened duration of survival after first relapse; (2) a reduced response to reinduction therapy; (3) a shortened duration of first remission; and, hence, (4) an overall decreased duration of survival and increased risk of death.

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