Evaluation of tolerance to mercaptopurine in patients with inflammatory bowel disease and gastrointestinal intolerance to azathioprine / Evaluación de la tolerancia a la mercaptopurina en los pacientes con enfermedad inflamatoria intestinal e intolerancia gastrointestinal a la azatioprina

Background Thiopurines such as azathioprine (AZA) and mercaptopurine (MP) are commonly utilized to treat inflammatory bowel disease (IBD). Their use is frequently restricted due to gastrointestinal intolerance (GI). Previous retrospective studies have reported that AZA-intolerant patients may benefit from a switch to MP; yet the effectiveness of this strategy has not been prospectively evaluated.AimsTo assess GI tolerance to MP in patients who are intolerant to AZA, and to identify clinical predictors of GI intolerance to AZA or MP.MethodsA prospective, observational, single-cohort study was performed in 92 thiopurine-naïve IBD patients. They were started on a 50mg dose of AZA and escalated to 2.5mg/kg per day by week 2. Those with GI intolerance were rechallenged with a 50% dose of AZA, after which another dose escalation attempt was made. If symptoms persisted, they were switched to MP.ResultsThirty (32.6%) of the recruited patients suffered from GI intolerance to AZA. Of these, 15 did not present recurrence of symptoms after rechallenge with lower doses. Of 15 intolerant patients, 14 were switched to MP. Within the MP cohort, 8 patients (57%) were also intolerant to MP, 5 (36%) had no symptoms, and 1 (7%) was lost to follow-up. Female gender was the only independent predictor of GI intolerance to AZA.ConclusionsUp to half of the AZA-intolerant patients tolerated a 50% dose rechallenge that was successfully escalated. A switch to MP was tolerated in over a third of cases whom rechallenge failed. Our strategy (challenge–rechallenge–switch) achieved an overall GI tolerance to thiopurines in most of the patients. (AU)

Antecedentes Las tiopurinas como la azatioprina (AZA) y la mercaptopurina (MP) se utilizan comúnmente para tratar la enfermedad inflamatoria intestinal (EII). Su uso está frecuentemente restringido debido a la intolerancia gastrointestinal. Estudios retrospectivos anteriores han informado que los pacientes intolerantes a la AZA pueden beneficiarse de un cambio a MP; sin embargo, la eficacia de esta estrategia no ha sido evaluada prospectivamente.ObjetivosEvaluar la tolerancia gastrointestinal a MP en pacientes que son intolerantes a AZA e identificar predictores clínicos de intolerancia gastrointestinal a AZA o MP.MétodosSe realizó un estudio prospectivo, observacional y de cohorte única en 92 pacientes con EII que nunca habían recibido tiopurinas. Comenzaron con una dosis de 50mg de AZA y se aumentó a 2,5mg/kg por día en la semana 2. En aquellos con intolerancia gastrointestinal se administró una dosis del 50% de AZA que se fue incrementando en función de la tolerancia. Si los síntomas persistían, se cambiaba a MP.ResultadosTreinta (32,6%) de los pacientes reclutados presentaron intolerancia gastrointestinal a la AZA. De estos, 15 no presentaron recurrencia de los síntomas después de la nueva exposición. De los 15 pacientes que no toleraron una dosis más baja, 14 recibieron MP. De los que recibieron MP, 8 pacientes (57%) también eran intolerantes a MP, 5 (36%) no tenían síntomas y uno (7%) se perdió durante el seguimiento. El género femenino fue el único predictor independiente de intolerancia gastrointestinal a la AZA.ConclusionesHasta la mitad de los pacientes intolerantes a la AZA toleran una nueva exposición al 50% de la dosis. Se toleró un cambio a MP en más de un tercio de los casos en los que la reexposición fracasó. Nuestra estrategia logró la tolerancia gastrointestinal a tiopurinas en la mayoría de los pacientes. (AU)

Novel variant in Nudix hydrolase 15 gene influences 6-mercaptopurine toxicity in childhood acute lymphoblastic leukemia patients.

Acute lymphoblastic leukemia (ALL) is the most frequent pediatric cancer. 6-Mercaptopurine (6-MP) is a key component of ALL treatment. Its use, however, is also associated with adverse drug reactions, particularly myelosuppression. Thiopurine S-methyltransferase (TPMT) and, more recently, Nudix hydrolase 15 (NUDT15) deficiency, due to no-function variants in their respective genes, are well known for their role in the development of this toxicity. Two novel genetic variants, rs12199316 in TPMT and rs73189762 in the NUDT15 gene, were recently identified by targeted sequencing. The latter is particularly interesting because of its potential association with 6-MP intolerance. Here, we assessed the relationship of this variant with the risk of myelosuppression and 6-MP dose intensity in 275 patients treated with Dana Farber Cancer Institute ALL protocols at the Sainte Justine University Health Center. Carriers of the NUDT15 rs73189762 variant allele were at a higher risk of myelosuppression, as shown by absolute phagocyte count reduction during consolidation II and maintenance phases of therapy. Reduction in 6-MP dose intensity was observed in patients with both rs73189762 and known no-function variants in the NUDT15 and TPMT genes. This finding supports the initial observation and suggests that 6-MP dose reduction might be beneficial for individuals with this genotype combination.

Efficacy of optimised thiopurine therapy in patients with moderate-to-severe ulcerative colitis: retrospective long-term follow-up from two randomised trials.

OBJECTIVE: The long-term outcome of thiopurine therapy in patients with ulcerative colitis (UC) enrolled in prospective trials have not been evaluated. We aimed to assess the effects of optimised thiopurine maintenance therapy for UC. METHODS: Long-term data were obtained from patients from our center enrolled in two randomised, prospective, open-label, controlled studies comprising 66 thiopurine-naïve moderate-to-severe patients with UC consisting of a low dose azathioprine (AZA)/allopurinol combination or AZA monotherapy. Following the randomised trials, treatment was adjusted according to adverse effects and metabolites. Patients requiring optimisation initially on AZA monotherapy treatment were switched to low dose AZA in combination with allopurinol, low dose 6-mercaptopurin in combination with allopurinol, or 6-mercaptopurin treatment alone, and those treated with low dose AZA in combination with allopurinol were switched to low dose 6-mercaptopurin in combination with allopurinol or 6-mercaptopurin alone. RESULTS: A total of 62 patients were included in the analysis; 31 were initially treated with AZA monotherapy and 31 with low dose AZA in combination with allopurinol. Initial treatment was tolerated by 67% patients (7 AZA monotherapy and 28 low dose AZA in combination with allopurinol), increasing to 94% (58 patients) post-adjustment. After a median 52-month follow-up period, 38 (93%) out of the 41 primary responding patients-maintained clinical remission without steroids, biologics or surgery. The four intolerant patients and the 17 not responding to optimisation were more likely to require colectomy (odds ratio 16.36; 95% confidence interval 3.08-87.03, p < 0.0001). CONCLUSION: Optimised thiopurine therapy demonstrated effective long-term treatment for patients with ulcerative colitis.

Chemotherapeutic metabolism presenting as a recalcitrant case of hand-foot syndrome and mucositis.

INTRODUCTION: Mercaptopurine (6MP) and methotrexate (MTX) are commonly used for maintenance chemotherapy for acute lymphoblastic leukemia (ALL). These medications have been associated with various side effects such as myelosuppression, colitis, and thyroiditis in addition to numerous cutaneous adverse events. Cutaneous side-effects most reported include mucositis, alopecia, xerosis, and pruritus. We report an interesting case of hand-foot syndrome to 6MP in a child on maintenance therapy for B-cell ALL from an alteration in medication metabolism. CASE: We report a 10-year-old male on maintenance chemotherapy for pre-Bcell ALL who presented to the hospital with worsening oral lesions and erythematous, fissured plaques on the palms and soles. Maintenance therapy consisted of IV vincristine and 5-day pulse of steroids every 12 weeks, daily 6MP, and weekly MTX, which were increased to ≥ 150% of standard dosing due to persistent absolute neutrophil counts > 1500. Metabolites obtained on admission demonstrated elevated 6MMP metabolites at 35,761 (normal < 5700). TPMT and NUDT15 enzyme activity were normal and no alterations in genotyping were discovered. OUTCOME: Patient's oral chemotherapy, including both 6MP and MTX, were stopped and allopurinol 100 mg daily was initiated, which lead to overall improvement. DISCUSSION: Clinical findings of acute mucositis and worsening of hand-foot syndrome, in the setting of inadequate myelosuppression in a child on maintenance therapy for ALL should raise concerns to consider altered metabolism pathway leading to toxic metabolite buildup. Allopurinol can play in improving cutaneous manifestation and chemotherapeutic dosing in patients with altered metabolism.

Bioequivalence study followed by model-informed dose optimization of a powder for oral suspension of 6-mercaptopurine.

BACKGROUND: 6-Mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukemia (ALL) and is conventionally available as 50 mg tablets. A new 6MP powder for oral suspension (PFOS 10 mg/mL) was developed recently by IDRS Labs, India, intended for pediatric use. A comparative pharmacokinetics of PFOS with T. mercaptopurine was conducted to determine the dose equivalence. METHODS: An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy adult subjects. Post hoc, a population pharmacokinetic (PopPK) model was developed using the healthy volunteer data to perform simulations with various PFOS doses and select a bioequivalent dose. Further, to confirm the safety of PFOS in pediatrics, a simulation of 6MP and 6-thioguanine exposures was performed by incorporating the formulation-specific parameters derived from the healthy volunteer study into the PopPK model in childhood ALL available in literature. RESULTS: The 6MP PFOS had 47% higher oral bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to 50 mg tablets. The simulated 6-thioguanine nucleotide concentrations in children using the dose adjusted for PFOS were between 114 and 703.6 pmol/8 × 108 RBC, which was within the range reported in pediatric ALL studies. CONCLUSION: 6MP PFOS 10 mg/mL should be administered at a 20% lower dose than the tablet to achieve comparable exposure. 6MP PFOS addresses an unmet medical need for a liquid formulation of 6MP in the Indian subcontinent.

Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study.

BACKGROUND: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity. AIMS: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival. METHODS: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient. RESULTS: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase. CONCLUSIONS: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.

Understanding thiopurine methyltransferase polymorphisms for the targeted treatment of hematologic malignancies.

INTRODUCTION: Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurines (mercaptopurine (MP) and tioguanine (TG)), chemotherapeutic agents used in the treatment of acute lymphoblastic leukemia (ALL). Polymorphisms in TPMT gene encode diminished activity enzyme, enhancing accumulation of active metabolites, and partially explaining the inter-individual differences in patients' clinical response. AREAS COVERED: This review gives an overview on TPMT gene and function, and discusses the pharmacogenomic implications of TPMT variants in the prevention of severe thiopurine-induced hematological toxicities and the less known implication on TG-induced sinusoidal obstruction syndrome. Additional genetic and non-genetic factors impairing TPMT activity are considered. Literature search was done in PubMed for English articles published since1990, and on PharmGKB. EXPERT OPINION: To titrate thiopurines safely and effectively, achieve the right degree of lymphotoxic effect and avoid excessive myelosuppression, the optimal management will combine a preemptive TPMT genotyping to establish a safe initial dose with a close phenotypic monitoring of TPMT activity and/or of active metabolites during long-term treatment. Compared to current ALL protocols, replacement of TG by MP during reinduction phase in TPMT heterozygotes and novel individualized TG regimens in maintenance for TPMT wild-type subjects could be investigated to improve outcomes while avoiding risk of severe hepatotoxicity.

Maintenance therapy and risk of osteonecrosis in children and young adults with acute lymphoblastic leukemia: a NOPHO ALL2008 sub-study.

PURPOSE: Osteonecrosis is a burdensome treatment-related toxicity that is mostly diagnosed during or soon after 6-mercaptopurine (6MP)/methotrexate (MTX) maintenance therapy for acute lymphoblastic leukemia (ALL), possibly indicating a pathogenic role of these drugs. METHODS: We prospectively registered symptomatic osteonecrosis during treatment of 1234 patients aged 1.0-45.9 years treated according to the Nordic Society of Hematology and Oncology (NOPHO) ALL2008 protocol. MTX/6MP metabolites were measured as part of the NOPHO ALL2008 maintenance therapy study. RESULTS: After a median follow-up of 5.6 years [interquartile range (IQR) 3.6-7.5], 68 patients had been diagnosed with symptomatic osteonecrosis. The cumulative incidence was 2.7% [95% confidence interval (CI) 1.6-3.8%] for patients aged < 10 years, 14.9% (95% CI 9.7-20.2%) for patients aged 10.0-17.9 years, and 14.4% (95% CI 8.0-20.8%) for patients aged ≥ 18 years. The median time from diagnosis of ALL to diagnosis of osteonecrosis in these age groups was 1.0 year (IQR 0.7-2.0), 2.0 years (IQR 1.1-2.4), and 2.2 years (IQR 1.8-2.8), respectively (p = 0.001). With 17,854 blood samples available for MTX and 6MP metabolite analysis, neither erythrocyte levels of 6-thioguanine (TG) nucleotides (p > 0.99), methylated 6MP metabolites (p = 0.37), MTX polyglutamates (p = 0.98) nor DNA-TG (p = 0.53) were significantly associated with the hazard of osteonecrosis in Cox models stratified by the three age groups and adjusted for sex. CONCLUSION: Maintenance therapy intensity determined by 6MP and MTX metabolites was not associated with the risk of developing osteonecrosis in the NOPHO ALL2008 cohort.

Prevalence of polymorphisms in thiopurine metabolism and association with adverse outcomes: a South Asian region-specific systematic review and meta-analysis.

Background: Prevalence and impact of thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) minor allele frequencies in South Asian population is unclear.Methods: We searched PubMed and Embase with keywords-TPMT and NUDT15 combined with South Asian countries. We included studies reporting frequency of TPMT and NUDT15 polymorphisms. We estimated the pooled prevalence of TPMT and NUDT15 polymorphisms and their impact on pooled odds ratio of adverse events with thiopurines.Results: We included 26 studies in our analysis. The pooled prevalence of NUDT15 and TPMT polymorphisms was 16.5% (95% CI: 13.09-20.58) and 4.57% (95% CI: 3.66-5.68), respectively. In patients with adverse effects, the pooled prevalence of NUDT15 and TPMT polymorphism was 49.51% (95% C.I. 21.69-77.64) and 9.47% (95% C.I. 5.39-16.11), respectively. The odds ratio (OR) of adverse events with presence of TPMT polymorphisms was 3.65 (95% C.I., 1.43-9.28). The pooled OR for adverse events in presence of NUDT15 polymorphism was 12.63 (95% C.I., 3.68-43.26).Conclusion: NUDT15 were reported more frequently than the TPMT polymorphisms in South Asian population and were more frequently associated with adverse events. These findings may have implications for preemptive testing amongst South Asian population and immigrants prior to starting thiopurines.

Outcome of T-cell acute lymphoblastic leukemia/lymphoma: Focus on near-ETP phenotype and differential impact of nelarabine.

Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is characterized by a distinct immunophenotype (CD1a-negative, CD8-negative, CD5-negative or weak-positive <75%, myeloid/stem-cell markers positive) and poor clinical outcomes. Near-ETP ALL is transcriptionally similar to ETP-ALL but CD5 expression level is not low enough to meet the criteria of ETP immunophenotype. Outcomes of near-ETP ALL are not well characterized. We reviewed 171 patients with newly-diagnosed T-ALL/LBL. Patients were categorized into three groups; ETP (N = 27), near-ETP (N = 24), and non-ETP ALL/LBL (N = 120). ETP-ALL/LBL was associated with a significantly worse survival compared with non-ETP ALL/LBL: 5-year overall survival (OS) rates 32% versus 63% (p < .001). Outcome was similar between near-ETP and non-ETP ALL/LBL: 5-year OS rates 56% versus 63% (p = .543). Landmark analysis showed that allogeneic stem cell transplant (allo-SCT) in first remission was beneficial in ETP-ALL/LBL (5-year event-free survival rates 36% versus 18%, p = .030) but not in near-ETP or non-ETP ALL/LBL. Multivariate analysis selected the following as significant independent prognostic factors for OS: age ≥ 60 years (HR 3.11; p = .003); elevated WBC ≥100 × 109 /L (HR 2.60; p = .005); and ETP immunophenotype (HR 2.29; p = .010). A survival advantage with adding nelarabine to hyper-CVAD was observed in non-ETP ALL (5-year OS rates 83% versus 38% with hyper-CVAD plus neralabine versus hyper-CVAD, p = .003). In conclusion, outcome of ETP-ALL/LBL was poor and improved with allo-SCT; outcome of near-ETP ALL/LBL was similar to non-ETP ALL/LBL; the addition of nelarabine to hyper-CVAD improved the survival in non-ETP ALL only.

Preparation, Characterization, Pharmacokinetic, and Therapeutic Potential of Novel 6-Mercaptopurine-Loaded Oral Nanomedicines for Acute Lymphoblastic Leukemia.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy in children. It requires a long and rigorous course of chemotherapy treatments. 6-Mercaptopurine (6-MP) is one of the primary drugs used in chemotherapy. Unfortunately, its efficacy has been limited due to its insolubility, poor bioavailability and serious adverse effects. To overcome these drawbacks, we constructed 6-mercaptopurine (6-MP)-loaded nanomedicines (6-MPNs) with biodegradable poly(lactide-co-glycolide) (PLGA) to enhance the anticancer efficacy of 6-MP. METHODS: We prepared the 6-MPNs using a double-emulsion solvent evaporation method, characterizing them for the physicochemical properties. We then investigated the plasma, intestinal region and other organs in Sprague Dawley (SD) rats for pharmacokinetics. Additionally, we evaluated its anticancer efficacy in vitro on the human T leukemia cell line Jurkat and in vivo on the ALL model mice. RESULTS: The 6-MPNs were spherical in shape with uniform particle size and high encapsulation efficiency. The in vitro release profile showed that 6-MPNs exhibited a burst release that a sustained release phase then followed. The apoptosis assay demonstrated that 6-MPNs could improve the in vitro cytotoxicity in Jurkat cells. Pharmacokinetics profiles revealed that 6-MPNs had improved oral bioavailability. Tissue distribution experiments indicated that 6-MPNs increased the duodenum absorption of 6-MP, at the same time having a low accumulation of the toxic metabolites of 6-MP. The in vivo pharmacodynamics study revealed that 6-MPNs could prolong the survival time of the ALL model mice. The prepared 6-MPNs, therefore, have superior properties in terms of anticancer efficacy against ALL with reduced systemic toxicity. CONCLUSION: Our nanomedicines provide a promising delivery strategy for 6-MP; they offer a simple preparation method and high significance for clinical translation.

DNA-thioguanine nucleotide as a treatment marker in acute lymphoblastic leukemia patients with NUDT15 variant genotypes.

BACKGROUND: Large inter-individual variations in drug metabolism pose a challenge in determining 6-mercaptopurine (6MP) doses. As the last product of 6MP metabolism, DNA-thioguanine nucleotide (DNA-TGN) could reflect the efficacy of 6MP, especially in patients harboring variants in the 6MP metabolism pathway. The aim of this study was to investigate the clinical significance of DNA-TGN monitoring in Korean pediatric acute lymphoblastic leukemia (ALL) patients, focusing on the NUDT15 genotype. METHODS: The subjects of this study were patients who underwent ALL treatment with 6MP. Tests for the NUDT15 and TPMT genotypes were performed, and prospective DNA-TGN and erythrocyte TGN samples were collected after two weeks or more of 6MP treatment. DNA-TGN was quantified using the liquid chromatography-tandem mass spectrometry method. RESULTS: A total of 471 DNA-TGN measurements in 71 patients were analyzed, which ranged from 1.0 to 903.1 fmol thioguanine/µg DNA. The 6MP intensity demonstrated a significant relationship with DNA-TGN concentration (P<0.001). Patients harboring NUDT15 variants were treated with a lower dose of 6MP (P<0.001); however, there was no significant difference in DNA-TGN concentration when compared to patients carrying wild-type NUDT15 (P = 0.261). These patients also presented higher variation in DNA-TGN levels (P = 0.002) and DNA-TGN/6MP intensity (P = 0.019) compared to patients carrying wild-type NUDT15. DNA-TGN concentration did not show a significant correlation with WBC count (P = 0.093). CONCLUSIONS: Patients harboring NUDT15 variants demonstrated similar DNA-TGN concentrations even at low doses of 6MP and showed high variability in DNA-TGN. Particularly in patients with NUDT15 variants who need a reduced 6MP dose, DNA-TGN could be applied as a useful marker to monitor the therapeutic effect of 6MP.

Reduced intensity of early intensification does not increase the risk of relapse in children with standard risk acute lymphoblastic leukemia - a multi-centric clinical study of GD-2008-ALL protocol.

BACKGROUND: The prognosis of childhood acute lymphoblastic leukemia (ALL) is optimistic with a 5-year event-free survival (EFS) rate of 70-85%. However, the major causes of mortality are chemotherapy toxicity, infection and relapse. The Guangdong (GD)-2008-ALL collaborative protocol was carried out to study the effect of reduced intensity on treatment related mortality (TRM) based on Berlin-Frankfurt-Münster (BFM) 2002 backbone treatment. The study was designed to elucidate whether the reduced intensity is effective and safe for children with ALL. METHODS: The clinical data were obtained from February 28, 2008 to June 30, 2016. A total of 1765 childhood ALL cases from 9 medical centers were collected and data were retrospectively analyzed. Patients were stratified into 3 groups according to bone marrow morphology, prednisone response, age, genotype, and karyotype information: standard risk (SR), intermediate risk (IR) and high risk (HR). For SR group, daunorubicin was decreased in induction IA while duration was reduced in Induction Ib (2 weeks in place of 4 weeks). Doses for CAM were same in all risk groups - SR patients received one CAM, others got two CAMs. RESULTS: The 5-year and 8-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) were 83.5±0.9% and 83.1±1.0%, 71.9±1.1% and 70.9±1.2%, and 19.5±1.0% and 20.5±1.1%, respectively. The 2-year treatment-related mortality (TRM) was 5.2±0.5%. The 5-year and 8-year OS were 90.7±1.4% and 89.6±1.6% in the SR group, while the 5-year and 8-year EFS were 81.5±1.8% and 80.0±2.0%. In the SR group, 74 (15.2%) patients measured minimal residual disease (MRD) on Day 15 and Day 33 of induction therapy. Among them, 7 patients (9.46%) were MRD positive (≥ 0.01%) on Day 33. The incidence of relapse in the MRD Day 33 positive group (n=7) was 28.6%, while in the MRD Day 33 negative group (n=67) was 7.5% (p=0.129). CONCLUSIONS: The results of GD-2008-ALL protocol are outstanding for reducing TRM in childhood ALL in China with excellent long term EFS. This protocol provided the evidence for further reducing intensity of induction therapy in the SR group according to the risk stratification. MRD levels on Day 15 and Day 33 are appropriate indexes for stratification.

Adding Thiopurine After Loss of Response to Infliximab Versus Early Combination in Treating Crohn's Disease: A Retrospective Study.

BACKGROUND: Although combining thiopurine with infliximab (IFX) is considered to improve the clinical efficacy of IFX when treating Crohn's disease (CD), it also increases the risk of adverse events (AEs). We compared the efficacy and safety of delayed thiopurine addition after loss of response (LOR) to IFX with the efficacy and safety of an earlier combination of thiopurine and IFX. METHODS: This retrospective study analyzed patients with CD who started IFX as a first-line biologic at Kyushu University Hospital between June 2002 and July 2018. Patients were assigned to either the early-combination (EC) group, who started IFX and thiopurine simultaneously, or the late-combination (LC) group, who were treated with IFX alone until they developed LOR. We compared the cumulative IFX continuation rates and AE incidence between the two groups. RESULTS: One hundred seventy-six patients were enrolled in this study; 49 were enrolled in the EC group, and 127 were enrolled in the LC group. Disease activity at baseline did not significantly differ between the groups, nor did the cumulative IFX continuation rates differ between the groups (P = 0.30); however, the AE rate was significantly higher in the EC group than in the LC group (38.7% vs. 21.2%; P = 0.02). The severe AE rate was also higher in the EC group than in the LC group (18.3% vs 3.1%; P = 0.001). CONCLUSION: Considering the risk-benefit balance, delayed addition of thiopurine after LOR to IFX might be an alternative strategy when using IFX to treat CD.

A Retrospective Review of Mercaptopurine Metabolism Reveals High Rate of Patients With Suboptimal Metabolites Successfully Corrected With Allopurinol.

Skewed drug metabolism of 6-mercaptopurine (6-MP) can jeopardize antileukemic effects and result in toxicities during the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Allopurinol can alter 6-MP metabolism to maximize therapeutic effects while reducing toxicities. Over 75% of our patients with acute lymphoblastic leukemia or lymphoblastic lymphoma experienced a 6-MP-related toxicity. Review of metabolite date a showed 6-methylmercaptopurine nucleotide levels were >10,000 in 55% of the cohort, suggesting 6-MP shunting. Allopurinol was initiated in 12 of 23 shunters with resolution of toxicities. We propose an algorithm to incorporate allopurinol into chemotherapy regimens for patients with inappropriate 6-MP metabolism.

Childhood acute lymphoblastic leukemia mercaptopurine intolerance is associated with NUDT15 variants.

BACKGROUND: Mercaptopurine-induced neutropenia can interrupt chemotherapy and expose patients to infection during childhood acute lymphoblastic leukemia (ALL) treatment. Previously, six candidate gene variants associated with mercaptopurine intolerance were reported. Herein, we investigated the association between the mean tolerable dose of mercaptopurine and these genetic variants in Taiwanese patients. METHODS: In total, 294 children with ALL were treated at the National Taiwan University Hospital from April 1997 to December 2017. Germline variants were analyzed for NUDT15, SUCLA2, TPMT, ITPA, PACSIN2, and MRP4. Mean daily tolerable doses of mercaptopurine in the continuation phase of treatment were correlated with these genetic variants. RESULTS: Mercaptopurine intolerance was significantly associated with polymorphisms in NUDT15 (P value < 0.0001). Patients with SUCLA2 variants received lower mercaptopurine doses (P value = 0.0119). The mean mercaptopurine doses did not differ among patients with TPMT, ITPA, MRP4, and PACSIN2 polymorphisms (P value = 0.9461, 0.5818, and 0.7951, respectively). After multivariable linear regression analysis, only NUDT15 variants retained their clinically significant correlation with mercaptopurine intolerance (P value < 0.0001). CONCLUSION: In this cohort, the major genetic determinant of mercaptopurine intolerance was NUDT15 in Taiwanese patients. IMPACT: NUDT15 causes mercaptopurine intolerance in children with ALL. The NUDT15 variant is a stronger predictor of mercaptopurine intolerance than TPMT in a Taiwanese cohort. This finding is similar with studies performed on Asian populations rather than Caucasians. Pre-emptive genotyping of the patients' NUDT15 before administering mercaptopurine may be more helpful than genotyping TPMT in Asians.

Thiopurines and their optimization during infliximab induction and maintenance: A retrospective study in Crohn's disease.

BACKGROUND AND AIM: Combining therapy with a thiopurine is favored when commencing infliximab in Crohn's disease; however, the optimal 6-thioguanine nucleotide (TGN) level and how long to continue thiopurines after induction are uncertain. We aimed to compare outcomes after induction and during maintenance in combination therapy versus infliximab monotherapy in Crohn's and to examine whether TGN levels were associated with outcomes. METHODS: Crohn's patients induced with infliximab with or without concomitant thiopurines were retrospectively identified. Response to induction and clinical outcomes in subsequent 6-month maintenance semesters were analyzed. A TGN level ≥235 pmol/8 × 108 red blood cells was considered therapeutic. RESULTS: In 89 patients, response to induction was higher in combination therapy than monotherapy (74 vs 47%, P = 0.04). This benefit was only seen in patients with a therapeutic TGN (odds ratio 3.72, confidence interval 1.07-13.0, P = 0.04). Combination therapy during induction yielded a three times longer time to subsequent need for treatment escalation or treatment failure compared with monotherapy (29 vs 9 months, P = 0.01), with both therapeutic and subtherapeutic TGNs independent predictors on multivariate analysis. Among 370 semesters, there was no difference in outcomes between combination therapy and monotherapy (P = 0.42), nor when combination semesters were stratified by therapeutic versus subtherapeutic TGN (P = 0.56). In semester 1 only, a significantly higher remission rate was observed with therapeutic compared with subtherapeutic TGN (76% vs 33%, P = 0.02). CONCLUSIONS: Combination therapy dosed with an optimized thiopurine was superior to infliximab monotherapy for induction of response, durability of response, and clinical outcomes in the first 6 months following induction. Thereafter, combination therapy yielded no clinical advantage, supporting consideration of thiopurine withdrawal on a case-by-case basis.

Extremely low dose of 6-mercaptopurine in a Chinese child with acute lymphoblastic leukaemia and multiple pharmacogenetic mutations.

WHAT IS KNOWN AND OBJECTIVES: Thiopurines are cornerstone drugs in the treatment of acute lymphoblastic leukaemia (ALL), but their use can be complicated by the incidence of life-threatening leucopenia. CASE DESCRIPTION: We describe a case of a 6-year-old Chinese boy with B-ALL receiving extremely low dose of 6-mercaptopurine (only 4% of recommended dose) during the ALL maintenance therapy phase. WHAT IS NEW AND CONCLUSION: Complex pharmacogenetic tests and TDM should be recommended in children with complicated ALL to highlight the large individual variability in the responses to 6-MP exposure and the associated adverse effects.

Adolescent and young adult acute lymphoblastic leukemia. Final results of the phase II pediatric-like GIMEMA LAL-1308 trial.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) represent a unique patient population with specific characteristics and needs. Growing evidences suggest that pediatric-inspired approaches improve the outcome in AYA. These results prompted the design of a pediatric AIEOP-BFM ALL 2000-based regimen - the GIMEMA LAL-1308 protocol - for newly diagnosed AYA (range 18-35 years) with Philadelphia negative (Ph-) ALL. The protocol included minimal residual disease (MRD) analysis at two different time-points (TP), that is, at the end of induction IA and consolidation IB, and a modulation in post-consolidation intensity according to MRD. Seventy-six patients were eligible between September 2010 and October 2014. The regimen was well tolerated, with 2.7% induction deaths and no deaths in the post-consolidation phase. The complete response (CR) rate was 92%; the 48-month overall survival (OS) and disease-free survival (DFS) were 60.3% and 60.4%. Both OS and DFS were significantly better in T-ALL than B-ALL. A molecular MRD <10-3 at TP1 was associated with a significantly better OS and DFS (77% vs 39% and 71.9% vs 34.4%, respectively);similar results were documented at TP2 (OS and DFS 74.5% vs 30.6% and 71.5% vs 25.7%, respectively). The LAL-1308 results were compared to those from similar historic AYA populations undergoing the two previous GIMEMA LAL-2000 and LAL-0904 protocols. Both OS and DFS improved significantly compared to the two previous protocols. These results indicate that this pediatric-inspired and MRD-oriented protocol is feasible and effective for Ph- AYA ALL patients, and underline the prognostic value of MRD determinations at specific TPs.