scholarly journals Asparaginase-Associated Pancreatitis in Acute Lymphoblastic Leukemia: Results From the NOPHO ALL2008 Treatment of Patients 1-45 Years of Age

2020 ◽  
Vol 38 (2) ◽  
pp. 145-154 ◽  
Author(s):  
Cecilie U. Rank ◽  
Benjamin O. Wolthers ◽  
Kathrine Grell ◽  
Birgitte K. Albertsen ◽  
Thomas L. Frandsen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Age Groups ◽  
Older Children ◽  
Pediatric Hematology ◽  
Hazard Ratios ◽  
Increased Risk ◽  
Leukemic Relapse ◽  
First Time ◽  
Risk Of Relapse

PURPOSE Asparaginase-associated pancreatitis (AAP) is common in patients with acute lymphoblastic leukemia (ALL), but risk differences across age groups both in relation to first-time AAP and after asparaginase re-exposure have not been explored. PATIENTS AND METHODS We prospectively registered AAP (n = 168) during treatment of 2,448 consecutive ALL patients aged 1.0-45.9 years diagnosed from July 2008 to October 2018 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. RESULTS Compared with patients aged 1.0-9.9 years, adjusted AAP hazard ratios (HRa) were associated with higher age with almost identical HRa (1.6; 95% CI, 1.1 to 2.3; P = .02) for adolescents (10.0-17.9 years) and adults (18.0-45.9 years). The day 280 cumulative incidences of AAP were 7.0% for children (1.0-9.9 years: 95% CI, 5.4 to 8.6), 10.1% for adolescents (10.0 to 17.9 years: 95% CI, 7.0 to 13.3), and 11.0% for adults (18.0-45.9 years: 95% CI, 7.1 to 14.9; P = .03). Adolescents had increased odds of both acute (odds ratio [OR], 5.2; 95% CI, 2.1 to 13.2; P = .0005) and persisting complications (OR, 6.7; 95% CI, 2.4 to 18.4; P = .0002) compared with children (1.0-9.9 years), whereas adults had increased odds of only persisting complications (OR, 4.1; 95% CI, 1.4 to 11.8; P = .01). Fifteen of 34 asparaginase-rechallenged patients developed a second AAP. Asparaginase was truncated in 17/21 patients with AAP who subsequently developed leukemic relapse, but neither AAP nor the asparaginase truncation was associated with increased risk of relapse. CONCLUSION Older children and adults had similar AAP risk, whereas morbidity was most pronounced among adolescents. Asparaginase re-exposure should be considered only for patients with an anticipated high risk of leukemic relapse, because multiple studies strongly indicate that reduction of asparaginase treatment intensity increases the risk of relapse.

Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1332-1339 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Olle Björk ◽  
Anders Glomstein ◽  
Göran Gustafsson ◽  
Niels Keiding ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Control Group ◽  
Cox Regression Analysis ◽  
Cell Counts ◽  
Increased Risk ◽  
Risk Of Relapse

Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P = .00003), high WBC at diagnosis (P = .03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P = .002), and high average neutrophil counts during maintenance therapy (P = .0009), with a significant interaction between sex and randomization group (P = .0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P = .001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P < .0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P = .03; boys 19.3 v 18.0 U/mL, P = .04). Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Risk-Directed Treatment Intensification Significantly Reduces the Risk of Relapse Among Children and Adolescents With Acute Lymphoblastic Leukemia and Intrachromosomal Amplification of Chromosome 21: A Comparison of the MRC ALL97/99 and UKALL2003 Trials

2013 ◽  
Vol 31 (27) ◽  
pp. 3389-3396 ◽  
Author(s):  
Anthony V. Moorman ◽  
Hazel Robinson ◽  
Claire Schwab ◽  
Sue M. Richards ◽  
Jeremy Hancock ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Survival Rates ◽  
Chromosome 21 ◽  
Treatment Intensification ◽  
Runx1 Gene ◽  
Increased Risk ◽  
First Remission ◽  
Risk Of Relapse

Purpose To evaluate the effect on outcome of intensifying therapy for patients with acute lymphoblastic leukemia (ALL) and an intrachromosomal amplification of chromosome 21 (iAMP21). Patients and Methods We report two cohorts of patients treated on Medical Research Council ALL97 or United Kingdom (UK) ALL2003. iAMP21 was identified retrospectively in ALL97 and was not used to guide therapy. However, in UKALL2003, iAMP21 was determined prospectively, and patients were allocated to the most intensive treatment arm (regimen C), which included augmented Berlin-Frankfurt-Munster consolidation, escalating Capizzi maintenance, double delayed intensification, and an option for first remission transplantation. The presence of iAMP21 was determined by fluorescence in situ hybridization using probes specific for the RUNX1 gene. Results iAMP21 was identified in 2% of patients with B-cell precursor ALL treated on UKALL2003 and ALL97. The event-free survival, relapse, and overall survival rates at 5 years for iAMP21 patients treated on ALL97 and UKALL2003 were 29% and 78%, 70% and 16%, and 67% and 89%, respectively (all P < .01). Patients treated on ALL97 had an increased risk of relapse compared with patients treated on UKALL2003 (hazard ratio, 7.2; 95% CI, 2.91 to 17.87; P < .001). Conclusion iAMP21 patients with ALL benefitted from receiving more intensive therapy in UKALL2003. In UKALL2011, they will continue to be treated as cytogenetic high risk, receive intensive chemotherapy (regimen C), and will only be recommended for transplantation if they do not achieve a complete remission by the end of induction therapy. This study illustrates how the discovery and characterization of disease-specific genetic aberrations can be used to tailor therapy more precisely.

scholarly journals Asparaginase Enzyme Activity Levels and Toxicity in Childhood Acute Lymphoblastic Leukemia: a NOPHO ALL2008 study

2021 ◽  
Author(s):  
Line Stensig Lynggaard ◽  
Cecilie Utke Rank ◽  
Stefan Nygaard Hansen ◽  
Sofie Gottschalk Højfeldt ◽  
Louise Tram Henriksen ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Acute Lymphoblastic Leukemia ◽  
Cox Model ◽  
Lymphoblastic Leukemia ◽  
Time Dependent ◽  
Activity Levels ◽  
Blood Samples ◽  
Pediatric Hematology ◽  
Leukemic Relapse ◽  
Protocol Compliance

Asparaginase treatment is a mainstay in contemporary treatment of acute lymphoblastic leukemia (ALL), but substantial asparaginase-related toxicity may lead to jeopardized protocol compliance and compromises survival. We investigated the association between risk of asparaginase-associated toxicities (AspTox) and asparaginase enzyme activity (AEA) levels in 1,155 children aged 1.0-17.9 years, diagnosed with ALL between July 2008 and March 2016 and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Patients with ≥2 blood samples for AEA measurement drawn 14 ± 2 days after asparaginase administration were included (6,944 trough values). AEA was measurable (or above &gt;0 IU/L) in 955 patients while 200 patients (17.3%) had asparaginase inactivation and few AspTox recorded. A time-dependent multiple Cox model of time to any first asparaginase-associated toxicity adjusted for sex and age was used. For patients with measurable AEA, we found a hazard ratio (HR) of 1.17 per 100 IU/L increase in median AEA (95% CI, 0.98-1.41; p=0.09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12-1.75; p=0.002), 0.99 (95% CI, 0.70-1.40; p = 0.96), and 1.36 (95% CI, 1.04-1.77; p=0.02) per 100 IU/L increase in median AEA, respectively. No significant decrease in the risk of leukemic relapse was found: HR 0.88 per 100 IU/L increase in AEA (95% CI, 0.66-1.16; p=0.35). In conclusion, these results emphasize that overall AspTox and relapse are not associated with AEA levels, yet the risk of pancreatitis and osteonecrosis increases with increasing AEA levels.

scholarly journals Thromboembolism in acute lymphoblastic leukemia: results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years

Blood ◽  
2018 ◽  
Vol 131 (22) ◽  
pp. 2475-2484 ◽  
Author(s):  
Cecilie Utke Rank ◽  
Nina Toft ◽  
Ruta Tuckuviene ◽  
Kathrine Grell ◽  
Ove Juul Nielsen ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymph Nodes ◽  
Mediastinal Mass ◽  
Absolute Risk ◽  
Lymphoblastic Leukemia ◽  
Aged Patients ◽  
Pediatric Hematology ◽  
Hazard Ratios ◽  
Cerebral Sinus Venous Thrombosis ◽  
Age Range

Abstract Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P &lt; .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P &lt; .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P &lt; .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged lymph nodes, 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P &lt; .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P ≤ .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.

Genetically Defined Racial Differences Underlie Risk of Relapse in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 14-14
Author(s):  
Jun J. Yang ◽  
Wenjian Yang ◽  
Cheng Cheng ◽  
Meenakshi Devidas ◽  
Xueyuan Cao ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
American Indian ◽  
American Indians ◽  
Lymphoblastic Leukemia ◽  
Prognostic Features ◽  
Increased Risk ◽  
Hispanic Patients ◽  
Racial Ethnic ◽  
Risk Of Relapse

Abstract The effect of race or ethnicity on cure and survival outcomes among children with acute lymphoblastic leukemia (ALL) is controversial. For those studies that have demonstrated variability in survival associated with race or ethnicity, the cause of these differences remains unclear. We therefore used genome-wide germline single nucleotide polymorphism (SNP) genotypes to quantitatively estimate racial ancestral composition in children with ALL and examined associations between ancestries and the probability of ALL relapse. To infer population genomic structures, we applied principal components analysis (PCA) to genotypes at 219,955 germline SNPs in 893 individuals: 683 patients with ALL (450 from St. Jude Children’s Research Hospital [St. Jude] Total XIIIB and Total XV studies and 233 from Children’s Oncology Group [COG] P9906 protocol), and 210 HapMap samples (60 CEU, 60 YRI, 90 CHB/JPT, serving as references for white, black, and Asian races, respectively). The top ranked principal component (PC1) separated self-reported black patients (n=92) and the YRI HapMap group from all other racial/ethnic groups; PC2 separated self-reported Asian patients (n=19) and the CHB/JPT HapMap samples from non-Asian populations. PC3, on the other hand, primarily captured genetic variation characteristic of American Indian ancestry (assessed using publicly available data from American Indians, n=105). Interestingly, Hispanic patients with ALL (n=75) showed a continuous cline between the American Indians and whites, displaying a gradient of these two ancestries among Hispanics. The relationships between ancestries (PC1, PC2, and PC3) and outcome were assessed in the St. Jude cohort first and validated in the COG cohort, using Fine and Gray’s regression test and after stratification for risk-adapted treatment. Of the top three PCs, only PC3 exhibited a significant association with cumulative incidence of relapse in St. Jude (P=0.038), with higher PC3 values linked to higher risk for relapse. This relationship between PC3 and relapse was validated in the COG cohort (P=0.003), which included more Hispanic patients than the St. Jude cohort. When the St. Jude and COG cohorts were combined, only the American Indian/Hispanic-informative PC3 (not PC1 or PC2) was related to relapse (P=4.5×10−4). Further, PC3 remained significant even after accounting for self-reported race/ethnicity (P=0.044), or when the analysis was restricted to self-reported white patients (P=0.006). The proportions of patients with high risk clinical or biological features (i.e. high leukocyte count, unfavorable age, unfavorable genetic subtypes, and minimal residual disease at the end of induction therapy) did not differ between the high and low PC3 groups (PC3 &gt; or &lt; 0.005). Therefore, the higher relapse rates in patients with higher proportions of American Indian ancestry are not derived from overrepresentation of unfavorable prognostic features in this group. In a multivariate analysis, PC3 remained significantly associated with the risk of relapse (P=0.041) after adjusting for known risk factors, indicating a possible independent prognostic value of PC3. In conclusion, germline genetic variation that is related to American Indian ancestry is associated with increased risk of leukemia relapse, providing evidence for a genetic basis for racial/ethnic differences in cancer treatment outcome.

Environmental and Socioeconomic Factors in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3950-3950
Author(s):  
Cetin Timur ◽  
Oznur Yilmaz ◽  
Asim Yoruk ◽  
Muferet Erguven ◽  
Timucin Imdadoglu ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Base Stations ◽  
Control Group ◽  
Healthy Children ◽  
Pediatric Hematology ◽  
Genes And Environment ◽  
Increased Risk ◽  
Significant Difference ◽  
Leukemia Group

Abstract In our study, we aimed to evaluate environmental and socio-economic conditions in children with Acute Lymphoblastic Leukemia (ALL) and to point at possible etiologic factors that can affect leukemia risk. The parents of 105 children diagnosed and treated as ALL between the years 1997 –2007 in our clinic of Pediatric Hematology-Oncology were questioned in terms of environmental and socio-economical factors and results were compared with control group that consisted of 102 healthy children with similar age and gender. Educational level and monthly income were similar between the groups. Occupational exposure of fathers to dust and chemicals were significantly higher in leukemia group (OR:2.00; %95 CI=1.41–3.50, p:0.015). Living near transformer stations (OR: 4.08; %95 CI= 1.3–12.76, p: 0.034) and high-voltage power lines (OR: 2.43; %95 CI= 1.05–5.63, p:0.01) is found to be associated with increased risk of leukemia in children. There was no significant difference in terms of living near base stations (p&gt;0.05). Exposure to industrial air pollution was significantly higher in leukemia group and was related to an elevated risk of ALL (OR: 26.77; %95 CI= 3.53–202.80, p:0.001). There was no significant difference in terms of exposure to insecticides and pesticides between the groups (p:&gt;0.05). In conclusion, leukemia is a disease with multi-factorial etiology that occurs as a result of interactions of genes and environment. The list of possible chemical, physical and biologic agents suspected to play a role in its etiology increase with developing technology and environmental pollution. However there are no sufficient data and more extended studies have to be carried out.

scholarly journals Dexamethasone exposure and asparaginase antibodies affect relapse risk in acute lymphoblastic leukemia

Blood ◽  
2012 ◽  
Vol 119 (7) ◽  
pp. 1658-1664 ◽  
Author(s):  
Jitesh D. Kawedia ◽  
Chengcheng Liu ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Christian A. Fernandez ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Acute Lymphoblastic Leukemia ◽  
Multivariate Analyses ◽  
Lymphoblastic Leukemia ◽  
Central Nervous System Relapse ◽  
Relapse Risk ◽  
Increased Risk ◽  
The Impact ◽  
Risk Of Relapse

Abstract We have previously hypothesized that higher systemic exposure to asparaginase may cause increased exposure to dexamethasone, both critical chemotherapeutic agents for acute lymphoblastic leukemia. Whether interpatient pharmaco-kinetic differences in dexamethasone contribute to relapse risk has never been studied. The impact of plasma clearance of dexamethasone and anti–asparaginase antibody levels on risk of relapse was assessed in 410 children who were treated on a front-line clinical trial for acute lymphoblastic leukemia and were evaluable for all pharmacologic measures, using multivariate analyses, adjusting for standard clinical and biologic prognostic factors. Dexamethasone clearance (mean ± SD) was higher (P = 3 × 10−8) in patients whose sera was positive (17.7 ± 18.6 L/h per m2) versus nega-tive (10.6 ± 5.99 L/h per m2) for anti–asparaginase antibodies. In multivariate analyses, higher dexamethasone clearance was associated with a higher risk of any relapse (P = .01) and of central nervous system relapse (P = .014). Central nervous system relapse was also more common in patients with anti–asparaginase antibodies (P = .019). In conclusion, systemic clearance of dexamethasone is higher in patients with anti–asparaginase antibodies. Lower exposure to both drugs was associated with an increased risk of relapse.

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