Serum endocan and endothelial dysfunction in childhood acute lymphoblastic leukemia survivors: a tertiary center experience

Background: An increased risk of cardiovascular complications is reported in survivors of childhood acute lymphoblastic leukemia (ALL). Early identification of impaired vascular health may allow for early interventions to improve outcomes. Aim: The study was conducted to assess the endothelial dysfunction in ALL survivors using a new marker, serum endocan, and measurement of the mean common carotid arteries intima media thickness (cIMT). Methods: A case-control study was conducted on 100 childhood ALL survivors (aged 6–18 years), with 80 healthy age and sex-matched children as a control group. Lipid profile, hepatitis markers, and serum ferritin where measured, in addition to the measurement of serum endocan. and cIMT by B-mode high-resolution ultrasonography for all study participants. Results: Triglycerides, total cholesterol, post prandial glucose, and serum ferritin were significantly higher in ALL survivors than controls ( p < 0.05). Dyslipidemia was detected in 6% of ALL survivors. ALL survivors showed statistically higher serum endocan levels (470.41 ± 556.1 ng/l, versus, 225.94 ± 185.2 ng/l, respectively) and increased cIMT levels compared with the control group (0.650 ± 0.129 mm versus 0.320 ± 0.095 mm, respectively) p < 0.05. Serum endocan was positively correlated with cIMT and blood cholesterol. Conclusions: The survivors of childhood ALL demonstrated an elevated level of serum endocan and increased cIMT. These can be used as predictors of endothelial dysfunction, and, as a consequence, the risk of developing premature atherosclerosis.

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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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Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols

Blood ◽

10.1182/blood-2008-12-193250 ◽

2009 ◽

Vol 114 (7) ◽

pp. 1314-1318 ◽

Cited By ~ 27

Author(s):

Martin Stanulla ◽

Elke Schaeffeler ◽

Anja Möricke ◽

Sally A. Coulthard ◽

Gunnar Cario ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasm ◽

Childhood Acute Lymphoblastic Leukemia ◽

Tpmt Activity ◽

Malignant Neoplasms ◽

Thiopurine Methyltransferase ◽

Childhood All ◽

Increased Risk ◽

Secondary Malignant Neoplasm

AbstractThiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.

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Genetic Mediators of Neurocognitive Outcomes in Survivors of Childhood Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2012.46.7944 ◽

2013 ◽

Vol 31 (17) ◽

pp. 2182-2188 ◽

Cited By ~ 57

Author(s):

Kevin R. Krull ◽

Deepa Bhojwani ◽

Heather M. Conklin ◽

Deqing Pei ◽

Cheng Cheng ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Lymphoblastic Leukemia ◽

Linear Models ◽

Lymphoblastic Leukemia ◽

Response Speed ◽

Attention Problems ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Increased Risk ◽

Neurocognitive Outcomes

Purpose Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive problems, with significant interindividual variability in outcome. This study examined genetic polymorphisms associated with variability in neurocognitive outcome. Patients and Methods Neurocognitive outcomes were evaluated at the end of therapy in 243 survivors treated on an institutional protocol featuring risk-adapted chemotherapy without prophylactic cranial irradiation. Polymorphisms in genes related to pharmacokinetics or pharmacodynamics of antileukemic agents, drug metabolism, oxidative stress, and attention problems in noncancer populations were examined as predictors of outcome, using multiple general linear models and controlling for age at diagnosis, sex, race, and treatment intensity. Results Compared with national norms, the cohort demonstrated significantly higher rates of problems on direct assessment of sustained attention (P = .01) and on parent ratings of attention problems (P = .02). Children with the A2756G polymorphism in methionine synthase (MS) were more likely to demonstrate deficits in attentiveness (P = .03) and response speed (P = .02), whereas those with various polymorphisms in glutathione S-transferase demonstrated increased performance variability (P = .01) and reduced attentiveness (P = .003). Polymorphisms in monoamine oxidase (T1460CA) were associated with increased attention variability (P = .03). Parent-reported attention problems were more common in children with the Cys112Arg polymorphism in apoliopoprotein E4 (P = .01). Conclusion These results are consistent with our previous report of association between attention problems and MS in an independent cohort of long-term survivors of childhood ALL treated with chemotherapy only. The results also raise the possibility of an impact from genetic predispositions related to oxidative stress and CNS integrity.

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Thiopurine methyltransferase Genotype Is Not a Risk Factor for Secondary Malignant Neoplasias after Treatment for Childhood Acute Lymphoblastic Leukemia on Berlin-Frankfurt-Muenster Protocols.

Blood ◽

10.1182/blood.v108.11.150.150 ◽

2006 ◽

Vol 108 (11) ◽

pp. 150-150 ◽

Cited By ~ 3

Author(s):

Martin Stanulla ◽

Elke Schaeffeler ◽

Anja Moericke ◽

Gunnar Cario ◽

Michel Eichelbaum ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Brain Tumors ◽

Patient Population ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Tpmt Activity ◽

Malignant Neoplasms ◽

Acute Leukemias ◽

Childhood All ◽

Increased Risk

Abstract The thiopurines mercaptopurine and thioguanine are important components of contemporary polychemotherapeutic treatment protocols for acute leukemias. Thiopurines are prodrugs that undergo intestinal and hepatic metabolism. Activation occurs via a multistep pathway to form thioguanine nucleotides, which are thought to be the major cytotoxic compound through triggering cell cycle arrest and apoptosis. This process is in competition with direct inactivation of thiopurines or their metabolites by thiopurine S-methyltransferase (TPMT). TPMT is a cytosolic enzyme that is ubiquitously expressed in the human body and catalyzes the S-methylation of thiopurines. The TPMT locus is subject to genetic polymorphism, with heterozygous individuals (5 to 11% of Caucasians) having intermediate TPMT activity, and homozygous individuals (0.3 to 0.5% of Caucasians) having low TPMT activity. At least 20 variant TPMT alleles (*2 to *18) have been described so far that confer decreased enzyme activities compared to the TPMT*1 wild-type allele. TPMT genotype is highly concordant with TPMT phenotype. With regard to long-term adverse effects, patients who have diminished TPMT activity were shown to be at increased risk of developing chemotherapy-induced acute myeloid leukemia and radiation-induced second brain tumors tumors after exposure towards mercaptopurine during therapy for childhood acute lymphoblastic leukemia (ALL). To investigate if such an association is generalizable to other entities of secondary malignant neoplasms (SMN) and different treatment approaches for ALL, we collected specimens of 72 patients who developed a SMN after ALL treatment on Berlin-Frankfurt-Muenster (BFM) protocols, analyzed their TPMT genotype and compared genotype frequencies to these in the general ALL patient population. The 72 patient cohort consisted of 49 hematological SMN (half of them received cranial irradiation), 12 brain tumors, and 11 other solid SMN. Neither in the entire patient group nor in subgroup analyses, differences in allele frequencies of TPMT variants conferring diminished enzyme activity were detectable when comparing SMN patients to the overall ALL patient population. Thus, low TPMT activity does not seem to play a major role in the etiology of SMN after treatment for childhood ALL according to BFM treatment strategies. Factors potentially helpful for the explanation of the previously described relationsship of TPMT activity with SMN will be presented.

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High Resolution Melting Analyses For Genetic Variants in ARID5B and IKZF1 with Childhood Acute Lymphoblastic Leukemia Susceptibility Loci In Taiwan

Blood ◽

10.1182/blood.v122.21.4958.4958 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4958-4958

Author(s):

Ching-Tien Peng

Keyword(s):

Acute Lymphoblastic Leukemia ◽

High Resolution ◽

High Resolution Melting ◽

Lymphoblastic Leukemia ◽

Melting Curve ◽

Childhood Acute Lymphoblastic Leukemia ◽

Control Group ◽

Genotype Distribution ◽

Childhood All ◽

B Lineage

Introduction Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease including multiple subtypes, defined on the basis of cell lineage and chromosome anomalies. Previous genome-wide association (GWA) studies report that several ARID5B and IKZF1 single nucleotide polymorphisms (SNPs) are associated with the incidence of ALL. However, high resolution melting analysis (HRM) supplies a faster and more convenient technique to detect SNPs. We applied HRM to detect the SNPs in ARID5B and IKZF1 gene. Method Seventy-nine pediatric ALL patients and 80 healthy controls were enrolled. Polymorphic variants of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) were detected by HRM method. The SNPs were further analyzed the association with childhood ALL. Result We evaluated 6 mutations by PCR amplicons (81 -176 bp) using the 96-well Light Cycler system. The primer detail was listed in Table 1. The melting curve data showed the difference in normalized temperature and we easily and accurately extended application of HRM analysis to genotyping of IKZF1 (Figure 1) and ARID5B (Figure 2) gene variants. The genotype distribution and the allele frequencies of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) gene polymorphisms among cases and controls and their association with the risk of childhood ALL were shown in Table 2. The distribution of genotype rs7073837 in ARID5B was significantly different between the ALL group and the control group (P = 0.046), while the distributions for IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs10740055, and rs7089424) were not significantly different. In addition, we analyzed the association for those SNPs with B lineage ALL and found rs7073837 in ARID5B conferred a higher risk for B lineage ALL (odds ratio, OR = 1.70, 95% confidence interval, CI = 1.01-2.87, P = 0.049). Conclusion HRM was a practical method to detect SNPs in ARID5B and IKZF1 gene. We determined the rs7073837 in ARID5B was associated with the risk of childhood B lineage ALL. Disclosures: No relevant conflicts of interest to declare.

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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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Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2013.53.0808 ◽

2014 ◽

Vol 32 (9) ◽

pp. 949-959 ◽

Cited By ~ 142

Author(s):

Deepa Bhojwani ◽

Noah D. Sabin ◽

Deqing Pei ◽

Jun J. Yang ◽

Raja B. Khan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Multivariable Analysis ◽

Brain Magnetic Resonance Imaging ◽

Childhood Acute Lymphoblastic Leukemia ◽

Intrathecal Therapy ◽

High Dose ◽

Asymptomatic Patients ◽

A Genome ◽

Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

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TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v91.5.1716 ◽

1998 ◽

Vol 91 (5) ◽

pp. 1716-1722 ◽

Cited By ~ 13

Author(s):

Karlheinz Seeger ◽

Hans-Peter Adams ◽

Dirk Buchwald ◽

Birgit Beyermann ◽

Bernhard Kremens ◽

...

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Prognostic Significance ◽

Philadelphia Chromosome ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Long Term Results ◽

Childhood All ◽

Cryptic Translocation

Abstract The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1–positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph1)-positive leukemia. Thus, the incidence ofTEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1–positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

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TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽

10.1182/blood.v88.11.4252.4252 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4252-4258 ◽

Cited By ~ 33

Author(s):

TW McLean ◽

S Ringold ◽

D Neuberg ◽

K Stegmaier ◽

R Tantravahi ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Chromosomal Translocation ◽

Fusion Transcript ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Polymerase Chain ◽

B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

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

Blood ◽

10.1182/blood.v89.11.4161 ◽

1997 ◽

Vol 89 (11) ◽

pp. 4161-4166 ◽

Cited By ~ 77

Author(s):

Ursula R. Kees ◽

Paul R. Burton ◽

Changlong Lü ◽

David L. Baker

Keyword(s):

Risk Factors ◽

Acute Lymphoblastic Leukemia ◽

Clinical Outcome ◽

Lymphoblastic Leukemia ◽

Homozygous Deletion ◽

Cell Phenotype ◽

P16 Gene ◽

Childhood All ◽

Risk Of Death ◽

Increased Risk

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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