scholarly journals The Effect of NUDT15, TPMT, APEX1, and ITPA Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia

Children ◽  
2021 ◽  
Vol 8 (3) ◽  
pp. 224
Author(s):  
Jae Min Lee ◽  
Ye Jee Shim ◽  
Do-Hoon Kim ◽  
Nani Jung ◽  
Jung-Sook Ha
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Febrile Neutropenia ◽  
Maintenance Therapy ◽  
Synergistic Effects ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Genetic Variations ◽  
Allele Carrier ◽  
Clinical Effects ◽  
Pediatric Acute Lymphoblastic Leukemia

Mercaptopurine (MP) is a commonly used maintenance regimen for childhood acute lymphoblastic leukemia (ALL). However, 6-MP has a narrow therapeutic index, which causes dose-limiting toxicities in hematopoietic tissues. Recent studies reported several candidate pharmacogenetic markers such as TPMT, NUDT15, ITPA, and APEX1, which predict the possibility of 6-MP related toxicities. The aim of this study is to evaluate the effect of major variants of these genes on 6-MP intolerances and toxicities in pediatric acute lymphoblastic leukemia (ALL) patients. A total of 83 pediatric ALL patients were included (56 males and 27 females). The NUDT15 c.415C>T (rs116855232), NUDT15 c.55_56insGAGTCG (rs746071566), ITPA c.94C>A (rs1127354), ITPA c.IVS2+21A>C (rs7270101), APEX c.190A>G (rs2307486), and TPMT variants were analyzed by sanger sequencing. Correlations between indexes of 6-MP-related toxicities or 6-MP intolerance (absolute neutrophil count [ANC] at several time point, days of ANC < 1 × 103/mm3, days of ANC < 0.5 × 103/mm3, frequency of febrile neutropenia, maximum AST and ALT, 6-MP dose and 6-MP dose intensity during maintenance therapy) and genetic variations were analyzed. The NUDT15 c.415C>T allele carrier showed significantly low 6-MP doses at the final maintenance therapy period than the wild type carrier (p = 0.007). The 6-MP dose intensities at the sixth and final maintenance period were also significantly low in NUDT15 c.415C>T carriers (p = 0.003 and 0.008, respectively). However, indexes for neutropenia, days of febrile neutropenia, maximum AST, and ALT levels were not associated with the presence of c.415C>T as well as other analyzed variants. When analyzing the effect of the coexistence of NUDT15 c.415C>T and ITPA c.94C>A, no significant differences were found between the NUDT15 c.415C>T carrier and carrier with both variations. The NUDT15 c.415C>T was the most useful marker to predict 6-MP intolerance among analyzed variants in our study population. Although we could not find association of those variants with 6-MP induced toxicities and the synergistic effects of those variants, a well-planed larger scale study would be helpful in clarifying new candidates and their clinical effects.

Asparaginase May Affect Mercaptopurine Tolerability in the Context of Multi-Agent Therapy for Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 179-179
Author(s):  
Chengcheng Liu ◽  
Deqing Pei ◽  
Cheng Cheng ◽  
Jun J Yang ◽  
Kristine R Crews ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Linear Regression ◽  
Maintenance Therapy ◽  
Linear Regression Model ◽  
Lymphoblastic Leukemia ◽  
Dose Intensity ◽  
Low Risk ◽  
Remission Induction ◽  
P Values

Abstract Background: Mercaptopurine (MP) and asparaginase (ASP) are critical components in the treatment of acute lymphoblastic leukemia (ALL). Dose-limiting toxicities of the two drugs are common, resulting in therapy interruption, which has been associated with inferior treatment outcome in some studies. However, the interaction between these drugs has not been clearly identified. Merryman et al (Pediatr Blood Cancer 2012) reported that in DFCI ALL 05-01, patients had lower blood counts and more dosage reductions of MP during consolidation therapy (with concomitant ASP treatment) than during continuation therapy (identical treatment without concomitant ASP). Among groups of homogeneously treated patients with ALL, variability in ASP exposure due to inactivating antibodies can affect ASP pharmacodynamics: we have reported that ASP antibodies were associated with lower plasma ASP activity and higher dexamethasone (DEX) clearance, leading to a lower risk of osteonecrosis and a higher risk of CNS relapse (Liu, Leukemia 2012; Kawedia, Blood 2012). Here we studied the possible effect of ASP antibodies on MP tolerability in St. Jude Children's Research Hospital Total XV, a clinical trial featured intensive ASP treatment. Methods: A total of 390 children with ALL treated on St. Jude Total XV protocol were evaluable. TPMT genotype was used to guide starting doses of MP. During maintenance treatment, planned MP doses were higher on the low-risk arm (LR; n = 202) than on the standard/high-risk arm (SHR; n = 188). MP dose intensity was estimated as (prescribed dose)/(protocol dose) for weeks 1-146 (boys) or 1-120 (girls) for patients on the LR and SHR arms of maintenance therapy. Native E.coli-ASP (Elspar) was administered intramuscularly at 10000 U/m2 thrice weekly for 6 or 9 doses during remission induction. During maintenance therapy, patients on the LR arm received ASP only during reinductions I (weeks 7-9) and II (weeks 17-19), whereas those on the SHR arm received 19 weekly doses at 25000 U/m2 during weeks 1-19. Patients were tested for serum anti-Elspar antibodies at days 5, 19, 34 of remission induction, day 1 of reinduction I and day 1 of reinduction II, and were grouped based on whether they were ever positive for antibodies at any time during therapy or not. The area under the antibody concentration-time curve (AUC) for the entire period up to week 19 was also estimated in 360 patients. Result: Overall MP dose intensity was higher in those with vs without ASP antibodies in patients on the LR (median 83 vs 75%, P = 0.003) and SHR arms (median 86 vs 76%, P = 3.3 × 10-5; Figure 1A), and MP dose intensity was correlated with ASP antibody AUC in patients on both treatment arms (LR, P = 7.7 × 10-3 and SHR, P = 2.4 × 10-4; Figure 1B). In a multivariate model including age, sex, risk arm, ancestry, TPMT status, NUDT15 genotype and ASP antibody status, TPMT genotype was the strongest determinant of MP dose intensity (-17% in heterozygotes, P = 1.9 × 10-8), followed by ASP antibody positivity (+8.9% dose intensity in those with antibodies, P = 5.8 × 10-6). The model also confirmed previously identified associations of higher MP dose intensity with higher African ancestry (Bhatia et al. Blood 2014) (P = 1.8 × 10-4) and lower Asian ancestry (P = 0.05) (Yang et al. J Clin Oncol 2015). Conclusion: Interindividual differences in ASP systemic exposure, as reflected by ASP antibodies, had a strong impact on MP tolerance, especially in patients on the SHR arm who received intensive ASP therapy. We have previously shown that patients who are positive for ASP antibodies not only have lower exposure to ASP but also to dexamethasone (Kawedia, Blood 2012; Liu, Leukemia 2012). These data further emphasize the capacity for variation in ASP exposure to impact yet another critical component of ALL therapy. Figure 1 Asparaginase antibodies associated with higher mercaptopurine tolerance in patients on the low-risk (n = 202) and standard/high-risk (n = 188) arms. P values were estimated using the (A) Mann-Whitney U test and (B) linear regression model. DI, dose intensity; MP, mercaptopurine; ASP, asparaginase; NEG, anti-asparaginase antibody negative; POS, anti-asparaginase antibody positive. Figure 1. Asparaginase antibodies associated with higher mercaptopurine tolerance in patients on the low-risk (n = 202) and standard/high-risk (n = 188) arms. / P values were estimated using the (A) Mann-Whitney U test and (B) linear regression model. DI, dose intensity; MP, mercaptopurine; ASP, asparaginase; NEG, anti-asparaginase antibody negative; POS, anti-asparaginase antibody positive. Disclosures Evans: Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Effective VCR/DEX pulse maintenance therapy in the KYCCSG ALL-02 protocol for pediatric acute lymphoblastic leukemia

2015 ◽  
Vol 103 (2) ◽  
pp. 202-209 ◽  
Author(s):  
Yasuhiro Okamoto ◽  
Yuki Koga ◽  
Jiro Inagaki ◽  
Shuichi Ozono ◽  
Koichiro Ueda ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia

Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. e19611-e19611
Author(s):  
A. J. Esbenshade ◽  
J. H. Simmons ◽  
T. Koyama ◽  
E. Koehler ◽  
R. B. Lindell ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia

scholarly journals Obesity and insulin resistance in pediatric acute lymphoblastic leukemia worsens during maintenance therapy

2013 ◽  
Vol 60 (8) ◽  
pp. 1287-1291 ◽  
Author(s):  
Adam J. Esbenshade ◽  
Jill H. Simmons ◽  
Tatsuki Koyama ◽  
Robert B. Lindell ◽  
Debra L. Friedman
Keyword(s):  
Insulin Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia

scholarly journals Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 594
Author(s):  
Sunitha Kodidela ◽  
Patchava Dorababu ◽  
Dimpal N. Thakkar ◽  
Biswajit Dubashi ◽  
Rajan Sundaram ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Genetic Variants ◽  
Low Dose ◽  
Lymphoblastic Leukemia ◽  
Hematologic Toxicity ◽  
Carrier Status ◽  
Allele Carrier ◽  
Dose Methotrexate ◽  
Grade 3

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3–4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3–4) was seen in 54.9% of patients. The NUDT15c.415T allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5–6.1); p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105’T’) carrier status along with NUDT15c.415T allele [HR = 2.7 (1.5–4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15c.415T allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

Germline Genetic Variations in Methotrexate Candidate Genes Are Associated with Pharmacokinetics and Outcome in Pediatric Acute Lymphoblastic Leukemia in China

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1595-1595 ◽  
Author(s):  
Shuguang Liu ◽  
Chao Gao ◽  
Ruidong Zhang ◽  
Xiaoxi Zhao ◽  
Lei Cui ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Candidate Genes ◽  
Oral Mucositis ◽  
Lymphoblastic Leukemia ◽  
Genetic Variations ◽  
Hazard Ratio ◽  
High Dose ◽  
Childhood All ◽  
Long Term Outcome ◽  
Pediatric Acute Lymphoblastic Leukemia

Abstract BackgroundMethotrexate (MTX) is a key chemotherapeutic agent in the treatment of pediatric acute lymphoblastic leukemia (ALL). Nevertheless, MTX can cause severe adverse effects and toxicities. The aim of the present study was to identify genetic polymorphisms in candidate genes of the MTX pathway associated with MTX pharmacokinetics, toxicity, and outcome in ALL in China. MethodsThree hundred and twenty-two Chinese children with ALL in the standard-risk and medium-risk treatment branches from the Beijing Children's Hospital-2003 and Chinese Childhood Leukemia Group-2008 protocols were enrolled in this study. Sequenom MassARRAY was used to genotype 12 single nucleotide polymorphisms (SNPs) in 4 candidate genes of the MTX/folate pathway. A total of 1268 high-dose MTX (HD-MTX) courses were analyzed. The plasma MTX levels were evaluated at 48 h after the first dose of HD-MTX infusion. Oral mucositis during the consolidation therapy period was recorded. Results No polymorphism was associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. Long-term outcome was better in SLCO1B1 rs4149056 T and TC allele carriers than patients with C allele (5-year RFS 92.3±1.6% vs. 27.8±23.2%,P<0.0001), in ABCB1 rs1128503 T and TC allele carriers than patients with C allele (92.7±1.6% vs. 78.2±6.9%, P=0.020), and in SCL19A1 rs2838958 AG and G allele carries than patients with A allele (93.9±1.6% vs. 83.0±4.2%, P =0.010). Multiple Cox regression analyses revealed an association of MRD at day 33 (hazard ratio 3.356; P=0.018), MRD at day 78 (hazard ratio 2.843; P=0.034), and SLCO1B1 rs4149056 (hazard ratio 8.073; P=0.002) with RFS in the study population. As to MTX pharmacokinetics, ABCB1 rs1128503 showed a significant association with serum MTX levels (P=0.004). SNPs (rs3788200, rs1131596, rs1051266) of the SLC19A1 gene were also associated with the plasma levels of MTX (P=0.003, 0.004, and 0.003, respectively). No association was found between oral mucositis with any polymorphism. Conclusions Genetic variations substantially influence the kinetics and response to HD-MTX therapy in childhood ALL. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document