Our goal was to study the induction of CYP1B mRNA expression in channel catfish (Ictalurus punctatus). CYP1B belongs to the cytochrome P450 superfamily of genes, is involved in the oxidation of ...endogenous and exogenous compounds, and could potentially be a useful biomarker in fish for exposure to AhR ligands. The full-length catfish CYP1B cDNA is 2417 nt to the polyA tail and encodes a putative protein of 536 amino acids. It has 67% amino acid similarity to carp and zebrafish CYP1B and 68% similarity to carp CYP1B2. Male channel catfish were collected from three Mississippi Delta sites: Lake Roebuck, Itta Bena; Bee Lake, Thornton; and Sunflower River, Indianola. Total RNA was isolated from wild-caught catfish gill, blood, gonad and liver tissues. Quantitative real-time reverse transcriptase PCR was used to determine relative induction of CYP1B in wild catfish compared to laboratory control and BaP-exposed catfish (20 mg/kg i.p. after 4 days). BaP exposure significantly induced CYP1B message in blood, gonad, and liver of laboratory catfish. In these same tissues of wild catfish from sites with relatively low sediment contaminants, CYP1B message was not statistically increased relative to laboratory control catfish. CYP1B transcript abundance was higher in gills compared to other tissues in both laboratory and wild catfish. When primary cultured gill cells were treated with increasing concentrations of BaP, TCDD, and PCBs 77, 126 and 169, CYP1B mRNA was induced more than 10-fold while PCB153 and 4,4'DDT did not cause significant CYP1B induction. Our results suggest that catfish CYP1B is induced by the classic AhR ligands.
Introduction: Bendamustine is an alkylator with anti-metabolite properties that shows incomplete cross resistance with other alkylators such as cyclophosphamide. The combination of cyclophosphamide, ...clofarabine and etoposide is often used in the treatment of children with relapsed leukemia, most of whom have significant prior exposure to cyclophosphamide. We evaluated the maximum tolerated dose (MTD) and safety profile of bendamustine when used in combination with clofarabine and etoposide in pediatric patients with relapsed or refractory hematologic malignancies.
Methods: Patients are eligible if they are younger than 22 years-old, have relapsed or refractory hematologic malignancies following 2 or more prior regimens, and have adequate organ function. Using the rolling 6 design, participants received bendamustine at one of 3 dose levels (escalating doses of 30, 40, or 60mg/m2/day) on Days 1-5 in combination with clofarabine (40 mg/m2/day), etoposide (100 mg/m2/day), and dexamethasone (8 mg/m2/day) daily on Days 1-5. We obtained pharmacokinetic (PK) studies to assess for potential time-dependent changes in bendamustine clearance over the 5 day course in this combination regimen since most PK studies of bendamustine have been conducted in adult patients with dose schedules of 90-120 mg/m2/day for 2 days.
Results: Sixteen patients (12 males and 4 females) with median age 11 years (range 4 to 17 years) were enrolled: 10 B-cell acute lymphoblastic leukemia (B-ALL), 1 early T-cell precursor (ETP) leukemia, 1 gamma delta T-cell ALL, 2 Hodgkin lymphoma, and 2 T-cell non-Hodgkin lymphoma. Six patients were treated on dose level 1, six on dose level 2, and four on dose level 3. One patient with hyperleukocytosis died from severe systemic inflammatory response syndrome (SIRS). Dose limiting toxicity was failure to recover peripheral blood counts on Day 42. The recommended dose of bendamustine in this combination is 30mg/m2 daily over 5 days. Ten responses were observed: 6 complete remissions (CR), 1 durable minimal residual disease (MRD)-negative CR without platelet recovery in the patient with ETP-ALL, and 3 partial remissions. Eight patients proceeded to transplant. Nine patients died (5 from progressive disease, 2 from transplant complications, 1 from SIRS and 1 from complications of subsequent salvage chemotherapy). Six patients are alive at a median follow up of 12 months (range 2 to 29 months).
Conclusions: Bendamustine is well tolerated in combination with clofarabine and etoposide and shows efficacy in multiple relapsed and refractory hematologic malignancies. Dose reductions on the first day of therapy are warranted in patients at risk of tumor lysis syndrome to avoid severe systemic inflammatory response.
Bhojwani:Amgen: Other: Blinatumumab global pediatric advisory board 2015.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
▪
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.
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Evans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We performed a genome-wide association study of primary erythrocyte TPMT activity in children with leukemia (n = 1026). Adjusting for age and ancestry, TPMT was the only gene that reached genome-wide ...significance (top hit rs1142345 or 719A>G, P = 8.6 × 10
−61
). Additional genetic variants (besides the 3 SNPs rs1800462, rs1800460 and rs1142345 defining TPMT clinical genotype) did not significantly improve classification accuracy for TPMT phenotype. Clinical mercaptopurine tolerability in 839 patients was related to TPMT clinical genotype (P = 2.4 × 10
−11
). Using 177 lymphoblastoid cell lines (LCLs), there were 251 SNPs ranked higher than the top TPMT SNP (rs1142345 P = 6.8 × 10
−5
), showing the limitation of LCLs for pharmacogenomic discovery. In a GWAS, TPMT activity in patients behaves as a monogenic trait, further bolstering the utility of TPMT genetic testing in the clinic.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background: Genetic polymorphisms in the TPMT gene cause inter-individual variability in 6MP metabolism and tolerability. In the context of ALL maintenance therapy (SJCRH Total XII) that was heavily ...reliant upon 6MP and methotrexate (MTX) and without individualizing 6MP based on TPMT genetics, dose-limiting toxicity due to TPMT defects resulted in interruptions of 6MP and MTX administration, which have been associated with worse ALL outcomes in some studies (McLeod, Br J Haematol 1999; Welch, Cancer Chemother Pharmacol 1996). Overall 6MP dose intensity (i.e. prescribed dose /protocol dose) was 83% (Relling, Blood 1999).
Here we characterized the dose intensity (DI) and tolerance of 6MP among patients with different TPMT genotypes in a more contemporary ALL regimen that included multiple agents in addition to 6MP and MTX. Our goal was to determine the tolerability of 6MP in patients with heterozygous vs wild-type TPMT in the context of multi-agent ALL therapy.
Method: 388 children with ALL on the SJCRH Total XV protocol were evaluable for this study. TPMT genotype was analyzed at day 5 of remission induction using PCR and exome sequencing. Of the 388 patients, 347 (89%) were classified as wild-type and 41 (11%) carried a low activity allele, including *2, *3A, *3C and 677G>A (Udaka, Genet Test 2005). No homozygous deficient patients were identified.
It was generally recommended that patients with TPMT heterozygosity receive a starting 6MP dose of 50-60 mg/m2/d regardless of risk arm. Wild-type patients on the low-risk (LR) arm (n = 202) received daily 6MP at 75 mg/m2, while those on the standard/high-risk (SHR) arm (n = 186) started with 50 mg/m2/d in weeks 1-16, then increased to 75 mg/m2/d until week 120 (girls) or week 146 (boys). No 6MP was given during reinductions I (weeks 7-9) and II (weeks 17-19). The daily dosage, days of treatment, and DI of 6MP were analyzed for each phase of maintenance therapy.
6MP dosages were re-evaluated every 8-16 weeks to maintain a desired degree of leukopenia. Dosage was decreased if patients had myelosuppression (WBC < 1000/mm3, ANC < 300/mm3 and platelet < 5 × 104/mm3). Dosage increases were considered if patients missed less than 25% of therapy but had persistently high WBC (> 4000/mm3) and ANC (> 1000/mm3).
In addition to the two reinductions, SHR patients received weekly asparaginase during weeks 1-19 and monthly cyclophosphamide/cytarabine until week 68. After week 20, patients received daily 6MP and weekly MTX with addition of monthly vincristine/dexamethasone (VCR/DEX) pulses until week 96, after which only 6MP and MTX were given.
Result: The median cumulative DI was 83% (range 14-135%) in wild-type and 68% (range 5-102%) in heterozygotes, similar to that reported for SJCRH Total XII (Relling, Blood 1999). The DI of each phase differed by TPMT genotype (Fig 1). During week 10-16, wild-type patients on the SHR arm had lower median DI (77%, range 12-173%) than those on the LR arm (85%, range 0-110%; P = 6.4 × 10-5) despite the lower protocol dose in the SHR arm, supporting the practice of lowering the protocol 6MP dose during the early intensive weeks of therapy for the SHR arm, and suggesting the higher dose of 75 mg/m2/d is well tolerated even during early intensive therapy for the LR arm.
The DI was similar in weeks 20-95 (6MP/MTX plus monthly VCR/DEX pulses) and in weeks 96-146 (6MP/MTX only) after stratifying by genotype and risk arm (Fig 1), suggesting that VCR/DEX pulses do not alter 6MP tolerance.
TPMT heterozygotes received lower median daily 6MP doses (61 mg/m2) than wild-type (73 mg/m2; P = 3.2 × 10-7) during maintenance therapy. By using the lowered daily dose in heterozygotes, we prevented dose interruptions: the median percentage of days with no 6MP therapy was similar in heterozygotes and wild-type (12% vs 11% missed, P = 0.5).
Conclusion: Using the approach of lowering the 6MP dose from 75 to 50 mg/m2/d during early intensive therapy for SHR patients results in reasonable DI in both groups. The lower tolerated daily dose of 6MP 60 mg/m2 in heterozygotes, compared to 75 mg/m2 in TPMT wild-type patients, supports the recommendation for a lower starting dose of 6MP for TPMT heterozygotes. 6MP DI was similar during phases that did vs did not include VCR/DEX, and similar in this contemporary regimen that includes VCR/DEX pulses compared to older studies without VCR/DEX pulses.
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*P-value of comparison between TPMT genotypes, and #P-value of comparison between weeks 20-95 and weeks 96-146.
Evans:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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