Measuring mercaptopurine (6MP) adherence using red cell 6MP metabolite levels in children with acute lymphoblastic leukemia (ALL): A COG AALL03N1 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10514-10514
Author(s):  
Anna Lynn Hoppmann ◽  
Torrey Hill ◽  
Yanjun Chen ◽  
Wendy Landier ◽  
Lindsey Hageman ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Sociodemographic Factors ◽  
Self Report ◽  
Red Cell ◽  
Total N ◽  
Increased Risk ◽  
Proportional Subdistribution Hazards ◽  
Cluster 2 ◽  
Risk Of Relapse

10514 Background: Non-adherence to 6MP (monitored with medication event monitoring system [MEMs]) is associated with an increased risk of relapse in children with ALL.(JAMA Oncol, 2015) Self-report over-estimates true medication intake, particularly in non-adherent patients.(Blood, 2017) However, monitoring adherence using MEMs is logistically difficult. We investigated whether red cell 6MP metabolite levels (thioguanine nucleotide [TGN] and methylated mercaptopurine [MMP]) taken together, could identify non-adherent patients. Methods: The analysis included children with ALL in maintenance. To minimize variability in TGN and MMP levels due to pharmacogenetics, we excluded TPMT heterozygotes and homozygote mutants. We also excluded Asians to remove variability due to NUDT15. TGN and MMP levels were drawn at 6 consecutive monthly time points for each patient and averaged. TGN and MMP levels (pmol/8 x 108red cells) were standardized, adjusted for 6MP dose intensity, and then analyzed using cluster analysis (Spath, H. [1980]). Results: The 373 patients eligible for analysis yielded 5 clusters. Cluster #1 (n = 119; mean MMP: 15,656; mean TGN: 158); Cluster #2 (n = 211; MMP: 6,042; TGN: 135); and 3 very small outlying clusters (total N = 43). Adjusting for age, sex, race/ethnicity, cytogenetics and NCI risk, we found that patients in Cluster #2 were 2.6 times as likely to be non-adherent (MEMs-based adherence < 95%) compared to Cluster #1 (95% CI 1.5-4.4; P= 0.0007). Mean MEMs-based adherence was significantly higher for patients in Cluster #1 (94.3%) when compared to those in Cluster #2 (87.8%, p = 0.0002). Using Fine-Gray proportional subdistribution hazards models for competing risks and adjusting for clinical and sociodemographic factors, we found that patients in Cluster #2 were at a 2.3-fold higher risk of relapse compared with those in Cluster #1 (95%CI, 1.0-6.4, p = 0.058). Conclusions: These findings illustrate the potential for using a combination of red cell TGN and MMP levels in identifying non-adherent patients. We propose to use these and clinical and demographic factors associated with non-adherence in creating an adherence calculator.

Evaluation of Minimal Residual Disease (MRD) by Quantification of TEL-AML1 Transcripts Is a Powerful Prognostic Tool in Children with T(12;21) Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 322-322
Author(s):  
Jean-Michel Cayuela ◽  
Paola Ballerini ◽  
Marina Romeo ◽  
Vahid Asnafi ◽  
Marie-Francoise Auclerc ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Induction Treatment ◽  
Prognostic Tool ◽  
Time Points ◽  
Increased Risk ◽  
Level 2 ◽  
Risk Of Relapse

Abstract TEL-AML1 fusion transcripts are found in 25% of children with B-cell precursor ALL (BCP-ALL). From June 1993 to December 1999, 1195 children with BCP-ALL were included in the FRALLE 93 protocol. Out of these, 792 were evaluated for TEL-AML1 transcript expression. There is no difference in terms of initial features, DFS, EFS, survival between evaluated (792) and non evaluated (403) patients. Out of the 792 pts, 191 (24%) expressed TEL-AML1 transcripts at diagnosis. To assess the potential prognostic value of TEL-AML1 transcripts quantification, we have retrospectively analysed follow up marrow samples using Europe Against Cancer procedures for real time quantitative RT-PCR assay, on ABI PRISM 7700 (2 reference labs) and Light Cycler apparatus (1 reference lab). Out of the 191 TEL-AML1+ve pts, 83 were evaluated for MRD at different time points after induction therapy (median = D41 (34–55) (53 evaluable pts), at D111 (62–158) (62 pts), at D216 (159–325) (33 pts) and at D838 (365–1287) (49 pts). According to normalized Ct values, samples were attributed to 4 MRD level ranging from 0 to 3 and defined as follows: 0: Ct>40 ; 1 : 36<Ct≤40 ; 2 : 33<Ct≤36 ; 3 : Ct≤33, corresponding respectively to undetectable MRD ; MRD<10-4 ; 10-4≤MRD<10-3 ; MRD≥ 10-3, with respect to dilution of REH cDNA. Distribution of pts according to MRD level at different time points after induction treatment are summarized in the following table. Seventeen relapses have occurred at a median time of 41 months (17–73)(bone marrow: 7, BM + other: 5, testis: 3, CNS: 2). A level 2 positivity at the end of induction was associated with an increased risk of relapse of 3.31(95%CI:1.02 – 10.76, p =.047) while level 3 positivity was associated with a relative risk of 9.52 (95%CI: 2.91 – 31.08, p =.0002). Positivity at D111 was associated with an increased risk of relapse of 8.6 (2.0 – 38.5, p = 0.0042), whatever the level. Combination of data obtained at D41 and D111 allows to distinguish 3 subsets of pts with decreasing relapse-free survival: from 97.5% (95%CI: 85–100%) in pts with no positivity at D111 whatever the D41 result, to 75% (95%CI: 58–92%) in pts with MRD +ve at D111 with low level at D41 and 42% (95%CI: 14–69%) in pts with MRD +ve at D111 with level 2 or 3 at D41 (p<.0001). No other prognostic factor was found (age, sex, WBC, D8 steroid response, D21 bone marrow response) which renders the MRD profile unique in this matter. Conclusion: RQ-PCR-based MRD detection is a powerful prognostic tool in TEL-AML1+ve leukemia. Combination of two time points allows a relevant stratification of pts according to the risk of relapse, compatible with clinical decision making towards intensification or deescalation in the setting of controlled trials FU time point Number of pts in MRD classes (number of relapses) 0 1 2 3 Not evaluated D41 27 (3) 11 (2) 10 (4) 5 (4) 30 (4) D111 40 (2) 14 (6) 7 (2) 1 (1) 21 (6) D216 29 (2) 2 (1) 1 (0) 1 (1) 50 (13) D838 47 (8) 1 (0) 1 (1) 0 34 (8)

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 Does Body Mass Index (BMI) during Maintenance Influence Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL)? Results from COG-AALL03N1

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 213-213
Author(s):  
Aman Wadhwa ◽  
Yanjun Chen ◽  
Lindsey Hageman ◽  
Anna Hoppmann ◽  
Anne L Angiolillo ◽  
...  
Keyword(s):  
Morbid Obesity ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Morbidly Obese ◽  
Red Cell ◽  
Childhood All ◽  
Relapse Risk ◽  
Increased Risk ◽  
Race Ethnicity

Abstract Introduction: Higher BMI at ALL diagnosis is associated with an increased risk of post-induction residual leukemia (Orgel, Blood 2014) and relapse (Butturini, JCO 2007). However, children may experience significant changes in BMI during the pre-maintenance phases of ALL treatment (Withycombe, Pediatr Blood Cancer 2009), necessitating an examination of the association between BMI during maintenance and relapse risk. We hypothesized that higher BMI during maintenance would be associated with a greater risk of relapse. We also explored the association between BMI and red cell thioguanine (TGN) levels to understand whether BMI-associated variations in TGN biodistribution explained the BMI-relapse association. Methods: We used data from COG-AALL03N1 (primary aim was 6MP adherence) to examine the association between BMI during maintenance and relapse risk. Eligibility for enrollment on AALL03N1 included age ≤21y at ALL diagnosis and receiving maintenance therapy in first remission. The current analysis was limited to patients with wild-type thiopurine methyltransferase genotype. BMI (exposure variable) was calculated as sex- and age-based percentile per CDC normative data, and operationalized as normal/underweight [&lt;85%ile], overweight/obese [85-98%ile] and morbidly obese [≥99%ile]). Hazard of relapse (any site) was estimated using multivariable proportional subdistributional hazards regression after adjusting for age at study enrollment, sex, race/ethnicity, NCI risk group, cytogenetics, 6MP dose intensity (6MPDI), and time from initiation of maintenance. We compared fitted means of red cell TGN levels by BMI groups after adjusting for age at enrollment, sex, race/ethnicity, 6MPDI and time from initiation of maintenance using generalized estimated equations. The association between BMI and relapse risk, as well as between BMI and TGN levels, was also examined in a sub-cohort of patients with available 6MP adherence. Results: The sociodemographic and disease characteristics of the 676 study participants are summarized in the Table. Median BMI%ile was 88.5 (range, 0-100); normal/underweight: 43%, overweight/obese: 45%, and morbidly obese: 12%. As shown in the Figure, cumulative incidence of relapse at 2y from start of maintenance therapy was significantly greater among patients with morbid obesity (11.9±4.3%) when compared to those who were overweight/obese (5.4±1.6%) and underweight/normal weight (4.1±1.4%). After adjusting for the variables listed above, we found that patients with morbid obesity had a 3.2-fold greater hazard of relapse (95%CI=1.4-7.5, P=0.008) when compared to patients who were normal/underweight. After adjusting for age at enrollment, sex, race/ethnicity, 6MPDI, and time from initiation of maintenance, patients with morbid obesity had lower mean red cell TGN levels compared to normal/underweight patients (mean difference: -27.2±7.4 pmol/8 x 10 8 erythrocytes, P=0.0002). However, inclusion of TGN in the model did not alter the association between BMI and hazard of relapse (HR=3.8, 95%CI, 1.6-9.0, P=0.003). These findings did not change after adjusting for 6MP adherence in the sub-cohort with available adherence data (n=435). Conclusion: Morbid obesity during maintenance for childhood ALL is associated with relapse as well as lower systemic exposure to 6MP. However, lower TGN levels do not explain the relation between BMI and relapse risk. Therefore, there is a need to understand the mechanism of the relation between morbid obesity during maintenance and relapse risk in children with ALL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

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.

scholarly journals Whole Exome Sequencing of Pediatric Acute Lymphoblastic Leukemia Patients Identify Mutations in 11 Pathways: A Report from the Children's Oncology Group

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 455-455
Author(s):  
Mignon L. Loh ◽  
Jinghui Zhang ◽  
Deqing Pei ◽  
Yunfeng Dai ◽  
Xiaotu Ma ◽  
...  
Keyword(s):  
Lymphoblastic Leukemia ◽  
B Cell Development ◽  
Genetic Mutations ◽  
Ras Signaling ◽  
Childhood All ◽  
Cytoplasmic Transport ◽  
Whole Exome ◽  
Increased Risk ◽  
Equity Ownership ◽  
Risk Of Relapse

Abstract Survival for childhood acute lymphoblastic leukemia (ALL) now approaches 90% with risk adapted therapy based on National Cancer Institute risk group (NCI RG) at diagnosis, somatic lymphoblast genetics, and early response to therapy as measured by minimal residual disease (MRD). Recent studies have identified multiple somatic genetic mutations in ALL, some of which confer increased risk of relapse or identify opportunities for additional targeted therapies. However, there are few genome sequencing analyses of representative cohorts of childhood ALL treated on contemporary regimens. To define the mutational landscape of childhood B-ALL, we performed whole exome sequencing (WES) on diagnostic tumor and remission samples of 192 patients with B-ALL consecutively enrolled between 4/1/06-9/8/06 on the Children's Oncology Group AALL03B1 classification trial that enrolled 11,145 patients up to age 30, which included patients enrolled on clinical trials for standard-risk (SR) B-ALL (N=5226, age 1-10 years and white blood cell count (WBC) < 50,000/uL) and high-risk (HR) B-ALL (N=2907; age ≥10 years or WBC ≥50,000/uL). An 8-gene expression low density array card identified Ph-like patients, and single nucleotide polymorphism arrays and multiplex ligation assays were used to determine DNA copy number alterations. Approximately 2/3 NCI SR and 1/3 NCI HR patients with sufficient banked samples were selected to reflect a population-based cohort (Table 1). Comparison of those selected vs. those not revealed significantly more NCI SR patients with a higher WBC and MRD, and fewer with double trisomy 4 and 10. Selected NCI HR patients were younger, had a higher WBC, and had more ETV6/RUNX1. There were a total of 3576 non-silent mutations with a median of 15 mutations/case (range 1-134). One case had 102 non-silent mutations and a germline mutation in MSH3. The additional mutations clustered in 11 pathways (Table 2), several of which were novel including cell-matrix interaction (e.g. SSPO, FAT1) and intracellular trafficking/cytoplasmic transport (e.g. DYNC2H1, ANK3, UNC13C). Most commonly altered were B-cell development (49.4%), transcription factors (45.8%), tumor suppressor genes (32.7%), cytoplasmic transport (27.3%), and Ras signaling (26.7%). Several pathways Ras signaling, Jak/STAT, and transcription factor mutations/deletions were associated with genetic lesions commonly used for risk stratification. Other pathways (epigenetic, B-cell development, or tumor suppressor) occurred in all subtypes. The most commonly identified genetic mutations were NRAS (n=33), KRAS (n=26), FLT3 (n=13), PAX5 (n=10), CREBBP (n=10), XBP1 (n=9), WHSC1 (n=7), and UBA2 (n=7). XBP1 and UBA2 mutations were novel. XBP1 (X-Box binding Protein 1) encodes a transcription factor that regulates the unfolded protein response. UBA2 (ubiquitin like modifier activating enzyme 2) encodes a protein involved in sumoylation to regulate protein structure and intracellular localization. Univariable analysis revealed no significant associations with any of these pathways or mutations with an increased risk of relapse with the exception of IKZF1 mutations or deletions (n=36; p=0.0087). Multivariable analysis modeling including IKZF1, age, presenting WBC, gender, NCI RG, ETV6/RUNX1, BCR/ABL1, Ph-like, white race, and MRD revealed only BCR/ABL1 and MRD positivity being significantly predictive of relapse. However, the risk of relapse was significantly increased based on the number of mutations identified in any one single patient (HR 1.02, 95% CI 1.01-1.023, p < 0.0004). Of note, only 18 patients (NCI SR, n=8, NCI HR, n=10) were Ph-like in this cohort, likely explaining the lack of significance between Ph-like status and an increased risk of relapse in this analysis. In summary, WES of a consecutively enrolled cohort of NCI SR and HR patients revealed a large number of novel genetic mutations that could be broadly assigned to 11 classes. Outcomes for patients overall were not influenced by any one of these classes, demonstrating that sentinel genetic alterations currently used in risk stratification are of paramount importance in directing therapy intensification for ALL. These data provide important information about pathways commonly mutated in childhood ALL, identifying classes of drugs that can be considered for clinical testing to further improve outcome. Disclosures Loh: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Hunger:Amgen: Equity Ownership; Pfizer: Equity Ownership; Merck: Equity Ownership; Jazz Pharmaceuticals: Honoraria; Sigma Tau Pharmaceuticals: Honoraria; Erytech: Honoraria; Patent: Patents & Royalties: Dr. Hunger is a co-inventor of a patent (#8658,964) for the identification of novel subgroups in high risk B-ALL and outcome correlations and diagnostic methods related to the same; Spectrum Pharmaceuticals: Honoraria.

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.

Systemic Exposure to Dexamethasone and Asparaginase Affects Risk of Relapse in Children with Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2550-2550
Author(s):  
Jitesh D. Kawedia ◽  
Chengcheng Liu ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Christian A Fernandez ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Confidence Interval ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Systemic Exposure ◽  
Hazard Ratio ◽  
Research Hospital ◽  
Cns Relapse ◽  
Increased Risk ◽  
Risk Of Relapse

Abstract Abstract 2550 Dexamethasone and asparaginase are key components of acute lymphoblastic leukemia (ALL) treatment. We previously observed that patients with a higher systemic exposure to asparaginase had a lower clearance and thus a higher systemic exposure to dexamethasone (Yang et al, J Clin Oncol; 26:1932–9, 2008). Whether interpatient dexamethasone pharmacokinetic variability contributes to relapse risk is not known. We determined the prognostic influence of dexamethasone plasma clearance and of anti-asparaginase antibody levels on risk of relapse via multivariate analyses after adjusting for standard clinical and biologic prognostic factors (treatment risk arm, age, race, initial leukocyte count, ALL immunophenotype, minimal residual disease and CNS status) in 410 children with ALL who were treated on a front-line clinical trial (St. Jude Total XV) and were evaluable for the pharmacologic measures through at least 22 weeks from diagnosis. Dexamethasone apparent clearance (average ± standard deviation) was significantly (p = 3 ×10−8) higher in patients with detectable serum levels of anti-asparaginase antibodies (17.7 ± 18.6 L/h/m2) compared to patients with no detectable antibodies (10.6 ± 5·99 L/h/m2), consistent with higher exposure to asparaginase being associated with higher exposure to dexamethasone. In multivariate analysis, higher dexamethasone clearance was associated with a higher risk of any relapse (hematologic, CNS, combined, and other; hazard ratio 1.56, 95% confidence interval, 1.1–2.19; p = 0.01) and of any CNS relapse (CNS and CNS + hematologic; hazard ratio 1.93, 95% confidence interval 1.1–3.37; p = 0.02). CNS relapse was also more frequent in patients with vs. those without anti-asparaginase antibodies (5-year cumulative risk of 4.9% vs. 1.8%; p = 0.02). Classification and regression tree analysis revealed that a dexamethasone clearance greater than 37.5 L/h/m2 might distinguish patients at higher risk of relapse (Figure). In conclusion, the presence of anti-asparaginase antibodies is associated with increased systemic clearance of dexamethasone. Lower exposure to dexamethasone and asparaginase are associated with an increased risk of relapse in children with ALL treated with contemporary therapy. The cumulative incidence of any relapse (A) and CNS relapse (B) was higher in patients with dexamethasone (Dex) clearance (CL) greater than 37.5 L/h/m2 than in those with lower clearance (p values based on log rank test). Disclosures: Evans: St. Jude Children's research Hospital: Employment, Patents & Royalties; NIH & NCI: Research Funding; Aldagen: Membership on an entity's Board of Directors or advisory committees. Relling:Sigma-Tau Pharmaceuticals, Inc: Investigator-initiated research; NIH: Research Funding; St. Jude Children's Research Hospital: Employment, Patents & Royalties.

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