thioguanine / Generic mfg. - LARVOL DELTA

Thiopurine pharmacogenomic landscape in India: TPMT and NUDT15 allele frequencies (ASH 2025) - "Thiopurines—such as azathioprine, mercaptopurine, and thioguanine—are commonly used in hematology as immunosuppressants and chemotherapeutic agents. We also identified rare, potentially deleterious TPMT variants that are absent or underrepresented in global reference datasets, underscoring the value of population-specific pharmacogenomic profiling. Our findings support pre-treatment NUDT15 genotyping (and TPMT where indicated) with genotype-informed dose adjustment and early monitoring to reduce myelosuppression-related treatment interruptions."

Biomarker • NUDT15

Effect and mechanism of allopurinol in ALL maintenance therapy: Reducing hepatotoxicity and improving myelosuppression effect via TPMT inhibition and increased DNA-thioguanine levels (ASH 2025) - "Introduction: 6-Mercaptopurine (6-MP) based-maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL). In conclusion, intensifying 6-MP dosing does not achieve adequate myelosuppression effect, but primarily increases the risk of hepatotoxicity by experiencing skewed metabolism. Low-dose 6-MP combined with allopurinol, rather than intensifying 6-MP dose, could be an alternative strategy for better efficacy and lower risk of hepatotoxicity."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Hepatology • Leukemia • NUDT15

Identifying patients with indolent Acute Myeloid Leukemia: Long term survivors after best supportive care only, results from the pethema registry (ASH 2025) - P=N/A | "BSCincluded transfusions and other supportive measures, with or without oral cytoreductive agents (e.g.,hydroxyurea, melphalan, mercaptopurine or thioguanine). Approximately 8% of elderly AML patients treated exclusively with BSC show unexpectedly long survival,consistent with an indolent clinical course, reflecting that in the absence of more efficacious therapeuticregimens, some patients could benefit from less invasive approaches. Easily measurable clinicalparameters such as bone marrow blasts, platelet count, and serum albumin may help identify thesepatients. Further prospective and molecular studies are warranted to validate these findings andelucidate the biological underpinnings of iAML."

Clinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • FLT3 • NPM1

Thioguanine and decitabine can overcome hypomethylating agent resistance in patients with advanced myeloid malignancies (ASH 2025) - "Background : Despite active therapies such as hypomethylating agents (HMA) and venetoclax advancedmyeloid malignancies, outcomes in relapsed/refractory (R/R) disease or secondary acute myeloidleukemia (AML) remain poor. 6TG/DEC is a clinically active regimen in high-risk and R/R AML with a 30% ORR andfavorable survival outcomes compared to historical controls. Single-cell proteomic data reveal immune-modulatory mechanisms that may underlie therapeutic response, offering a novel lens into resistancebiology. Taken together, this combination remains a viable therapeutic option for elderly and unfitpatients with high-risk and R/R AML who cannot tolerate intensive chemotherapy."

Clinical • Metastases • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • B2M • CD36 • SCARB1

Impact of noncoding tandem repeat sequence on TPMT function and thiopurine metabolism in children with ALL (ASH 2025) - "Of these, 369 cases also had 6-MP metabolites quantified using liquid chromatography-mass spectrometry, including for thioguanine nucleotides (TGNs) and methylmercaptopurine nucleotides(MMPNs)...Studying whole genome sequencing in large reference populations and ALL patients, we havedemonstrated that the TPMT-VNTR impacts TPMT transcription and enzymatic function in addition tocoding variants in this gene. This work highlights the importance of noncoding variants in modulatingdrug efficacy and toxicity in hematological malignancies."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Infectious Disease • Leukemia • TPMT

A semi-focused multi-state variant of the mapping approach to surface hopping. (PubMed, J Chem Phys) - "A key distinguishing aspect of our approach is that only a selected subset of electronic states, identified through an appropriate clustering procedure, is initially populated. Test simulations of the ultrafast photodynamics of three molecular systems (spiropyran, thioguanine, and azobenzene) show that SMASH gives results closely matching those of decoherence-corrected fewest-switches surface hopping, while eliminating the need for the ad hoc decoherence correction."

Journal • Metabolic Dysfunction-Associated Steatohepatitis

Development and Validation of a Sensitive LC-MS/MS Method for Determination of Deoxythioguanosine in Human DNA and its Application in Thiopurine-Treated Inflammatory Bowel Disease Patients. (PubMed, J Chromatogr Sci) - "Nucleoside diphosphate-linked moiety X-type motif 15 variant carriers (*2, *3, *5, *6) showed significantly higher DNA-TG/dose and DNA-TG/erythrocyte thioguanine nucleotides ratios than wild-type patients (P = 0.0023, P = 0.0001). In summary, this method was simple and stable to detect dTG in DNA, which may act as a promising biomarker predicting the toxicity and efficacy in patients treated with thiopurine."

Journal • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease • NUDT15

Allopurinol increases DNA-thioguanine nucleotides during maintenance therapy in pediatric acute lymphoblastic leukemia. (PubMed, Haematologica) - "Not available."

Journal • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

An optimized LC-ESI-MS/MS assay for erythrocyte 6-TG and 6-MMPD: Addressing critical methodological considerations for thiopurine metabolite monitoring. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "The erythrocyte-based active metabolites 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotides (6-MMPN) serve as biomarkers reflecting systemic drug exposure and predicting both therapeutic efficacy and adverse reactions...Selectivity, carry-over, intra- and inter-batch accuracy and precision, reproducibility, recovery, matrix effect, and stability all complied with the acceptance criteria outlined in the US Food and Drug Administration (FDA) Bioanalytical Method Validation Guidance (2018). The validated method was successfully employed to quantify 6-TG and 6-MMPD in samples obtained from 20 patients with IBD or ALL."

Journal • Acute Lymphocytic Leukemia • Gastroenterology • Gastrointestinal Disorder • Hematological Malignancies • Immunology • Inflammatory Bowel Disease • Leukemia • Oncology

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between TPMT/NUDT15 and thiopurines. (PubMed, Eur J Hum Genet) - "The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM.DPWG classifies genotyping for TPMT and NUDT15 "essential" before thiopurine initiation."

Biomarker • Journal • CNS Disorders • Depression • Hematological Malignancies • Leukemia • Oncology • Psychiatry • NUDT15

Direct evidence of singlet molecular oxygen [O2 (1Δg)] production from UVA excited 6-thioguanine. (PubMed, Photochem Photobiol) - "These compounds presented kt values of 1.5 × 107 L mol-1 s-1 and 1.1 × 107 L mol-1 s-1, respectively. Through the comparison of these values with the ones obtained for 2'-deoxyguanosine (dGuo) and its oxidation product 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), we aim to provide new insights into the 6-TGua-containing DNA (DNA-6-TGua) reactivity towards 1O2 in a biological context."

Journal • Non-melanoma Skin Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Skin Cancer

LC-MS/MS quantification of 6-methylthio-2'-deoxyguanosine and 6-thio-2'-deoxyguanosine in genomic DNA with enzymatically synthesized isotope-labelled internal standards. (PubMed, Anal Bioanal Chem) - "The thiopurines 6-mercaptopurine and 6-thioguanine (TG) are analogs of guanine and are used in the treatment of hematological malignancies and immune-mediated inflammatory diseases. dMeTG could also be detected in patient samples, although in low amounts and primarily in samples with high DNA-TG levels. The developed method for the quantitation of dMeTG and dTG can be used in further studies to investigate the role of DNA-MeTG in the mechanism of action of thiopurines, including its antileukemic efficacy and effects on acquired mutations."

Journal • Tumor mutational burden • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • TMB

Detection of In Vivo Mutation in the Hprt and Pig-a Genes of Rat Lymphocytes. (PubMed, Methods Mol Biol) - "The identification and selective expansion of mutant lymphocytes is based upon the phenotypic properties of Hprt- and Pig-a-deficient cells, i.e., resistance to the purine analog, 6-thioguanine, or to the bacterial toxin, proaerolysin. Expanded mutants can be further analyzed by sequencing cDNA from the target transcripts for identification of small sequence alterations and by multiplex PCR analysis of genomic DNA for the detection of deletions."

Journal • Preclinical • Oncology

Influence of xanthine oxidase and inosine monophosphate dehydrogenase polymorphisms on 6-mercaptopurine treatment response in pediatric acute lymphoblastic leukemia. (PubMed, Sci Rep) - "Excessive 6-thioguanine (6-TGN) levels worsen neutropenia, while elevated 6-methylmercaptopurine (6-MMP) levels contribute to hepatotoxicity. In contrast, two variants in the IMPDH1 gene, rs2228075 and rs2278294, are correlated with more frequent neutropenia. These findings highlight novel genetic variants influencing 6-MP metabolism and toxicity in paediatric ALL patients."

Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Pediatrics • ITPA

Allopurinol Add-on 6-Mercaptopurine Strategy Improves Efficacy and Reduces Toxicity in Pediatric Patients With Acute Lymphoblastic Leukemia. (PubMed, Clin Pharmacol Ther) - "Metabolite levels (6-thioguanine nucleotides (6-TGNs), methyl mercaptopurine nucleotides (6-MMPN), DNA-thioguanine (DNA-TG)), thiopurine methyltransferase (TPMT) activity were measured pre- and post-combination. LOESS regression estimates indicated significant fluctuations in WBC, ANC, and 6-MP/allopurinol dosage ratios following 3 months of combination therapy (P  1 m2, when co-administered with allopurinol (50 mg/m2/day)."

Journal • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology • Pediatrics

Delayed Intensification Including Venetoclax and Bortezomib Prolongs Survival in Very High Risk Acute Lymphoblastic Leukaemia (ASH 2023) - "Primary ALL blasts extracted by density centrifugation, were seeded on immortalized human bone marrow stromal cells and treated with a 14-drug panel: prednisolone; vincristine (VCR), daunorubicin; asparaginase (ASNase), bortezomib (BZM), venetoclax (VEN), panobinostat (PNB), mitoxantrone, cyclophosphamide, cytarabine, selinexor, dasatinib, 6-thioguanine and idarubicin. In conclusion, drug response profiling identifies alternative combination therapies for VHR ALL. Our pilot study provides proof-of-concept of effectiveness and tolerability of inclusion of VEN and BZM in the post-induction treatment of patients with poor-response disease."

Acute Lymphocytic Leukemia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Septic Shock • Targeted Protein Degradation • ABL1 • IKZF1 • KMT2A • TCF3

Systematic Literature Review of Incidence and Management of Non-HCT-Related Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) (ASH 2023) - "One study reported outcomes for 206 children who received supportive care for VOD/SOS during 6-thioguanine therapy for ALL; only three pts had acute hepatic failure and all pts recovered from VOD/SOS. Non-HCT VOD/SOS occurs in diverse disease areas, including hematologic and solid tumor cancers. A lack of consensus regarding VOD/SOS diagnosis in the non-HCT setting may lead to underdiagnosis; therefore, clinicians should be vigilant for VOD/SOS even in non-HCT pts. Though defibrotide is approved for post-HCT VOD/SOS, there is no approved therapy for non-HCT VOD/SOS; future trials should focus on diagnosis and treatment outside the HCT setting, which represents a significant unmet need."

Review • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Hepatology • Infectious Disease • Liver Failure • Nephrology • Otorhinolaryngology • Solid Tumor • Wilms Tumor

The Role of Small Nucleolar RNAs As Putative Biomarkers of Chemoresistance in Pediatric Acute Lymphoblastic Leukemia (ASH 2023) - "05 and absolute log2FC>1) in the high-resistance group for one or multiple drugs: amsacrine (ams, n = 10), etoposide (eto, n = 10), tioguanine (thio, n = 8) and mitoxantrone (mito, n = 1). Importantly, our analysis indicates that the differential expression of snoRNAs in the resistance groups cannot be solely attributed to host gene expression, implying that targeting pathways involving host genes might not be the most effective approach. Rather than concentrating on pathways involving host genes, our results suggest that understanding the mechanisms of action of snoRNAs could provide promising avenues for developing novel therapeutic targets to enhance drug response in pediatric ALL."

Biomarker • Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • SNHG1

Multinational Retrospective Analysis of Bridging Therapy Prior to Chimeric Antigen Receptor T Cells for Relapsed/Refractory Acute Lymphoblastic Leukemia in Children and Young Adults (ASH 2023) - "Bridging therapies were defined as high-intensity if at least one chemotherapeutic agent of the following was given: cyclophosphamide/ifosfamide, etoposide, anthracyclines or other agents with high toxicity potential (intravenous methotrexate, platinum-based antineoplastic drugs, thiotepa, high-dose cytarabine, fludarabine). Low-intensity bridging therapies comprised the administration of steroids, vincristine, low-dose cytarabine, PEG-asparaginase/Erwinia asparaginase and oral maintenance therapy (mercaptopurine, thioguanine, oral methotrexate, hydroxyurea)... In this retrospective cohort data, a high-intensity bridging therapy has not improved the outcome of CAR T cell therapy in terms of overall and disease-free survival. Yet high-intensity bridging therapy has caused more mucositis, bacterial adverse events and worsened the performance status. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow..."

CAR T-Cell Therapy • Retrospective data • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Mucositis • Oncology

Mapping Chemo-Resistance Profiles of Pediatric Acute Leukemia through Integration of Ex-Vivo Drug Screens with Molecular Data (ASH 2023) - "Similarly, relapse free survival was significantly lower for patients with ex-vivo resistance to cytarabine, dexamethasone, doxorubicin, prednisolone and thioguanine (p < 0.05). We show molecular evidence for differentiating low- and high-resistant types based on diagnostic gene expression and DNA methylation profiles, suggesting contribution of certain molecular signatures to drug response. Our data integrating molecular data with drug response profiles may help identifying such changes of importance in drug resistance mechanisms."

Preclinical • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Pediatrics

Pooled overexpression screening identifies PIPPI as a novel microprotein involved in the ER stress response. (PubMed, Nucleic Acids Res) - "As a proof-of-concept, we performed a phenotypic screen to identify sORFs protecting cells from treatment with the nucleotide analogue 6-thioguanine...PIPPI overexpression protects, while PIPPI knockdown sensitizes cells to ER stress. Besides providing mechanistic insights into a new microprotein, this study highlights the power of using pooled overexpression screens to identify functional microproteins."

Journal

Treatment Intensification Does Not Improve Outcome for Children with Myeloid Leukemia of Down Syndrome (ML-DS) Who Are MRD-Positive after Induction Therapy: A Report from the Children's Oncology Group (ASH 2024) - "All patients received the same first course of induction therapy (Induction I) : daunorubicin, cytarabine, 6-thioguanine (DAT)...Patients with EOI-1 MRD >0.05% were classified as High Risk (HR, Arm B) and had their subsequent treatment intensified to a level consistent with that of pediatric non-DS AML (Induction II : mitoxantrone/high-dose cytarabine; Intensification I : cytarabine/etoposide; Intensification II : high-dose cytarabine/asparaginase) with the aim of reducing the number of relapse events...Overall, results of AAML1531 demonstrate that stratification of treatment intensity according to flow cytometric EOI-1 MRD did not did not improve outcomes for patients with ML-DS. Alternative approaches such as mutational profiling of ML-DS blasts should be evaluated with regard to prognostication, risk stratification and identification of targets for novel agents to improve the overall outcome for this disease."

Clinical • Minimal residual disease • Developmental Disorders • Febrile Neutropenia • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukemia • Neutropenia • Oncology • Pediatrics • Septic Shock

Allopurinol Add-on Treatment - Promising Approach to Opitimize Maintenance Therapy for Acute Lymphoblastic Leukemia in Children (ASH 2024) - P2 | "These patients have high erythrocyte levels of methylated mercaptopurine metabolites (e-MeMP) associated with liver toxicity, including transaminitis and hypoglycemia, and low erythrocyte levels of thioguanine nucleotides (e-TGN), the key intermediate metabolites mediating the antileukemic effect...Conclusions Addition of allopurinol to standard MT with 6MP and methotrexate leads to substantially increased DNA-TG levels. DNA-TG/e-TGN ratio was unchanged indicating that DNA incorporation of TGN was not significantly affected during allopurinol treatment. The 46 % rise in DNA-TG, together with our previously published data with higher proportion of ANC levels within target, lower ALT and no increase in SAE, indicate that addition of allopurinol could be an effective strategy to optimize ALL MT."

Clinical • Acute Lymphocytic Leukemia • Hematological Malignancies • Hypoglycemia • Leukemia • Oncology • Pediatrics

Budget Impact of Azathioprine Metabolite Monitoring in Crohn's Disease in Algeria (ISPOR-EU 2025) - "This study aimed to assess the budget impact of introducing systematic monitoring of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP) to enable treatment personalization and cost containment. A budget impact analysis was conducted over a 5-year horizon (2025-2029) from the public payer's perspective. Implementing metabolite monitoring in Crohn's disease management could optimize care and reduce costs in Algeria. This personalized approach offers both clinical and economic value, supporting its inclusion in national treatment guidelines."

HEOR • Crohn's disease • Gastroenterology • Immunology • Inflammatory Bowel Disease

Investigation of 6-thioguanine as a strategy to overcome methotrexate resistance in a mouse model of leptomeningeal carcinomatosis. (PubMed, J Neurooncol) - "Sequential 6-TG administration capitalizes on salvage pathway activation in MTX-resistant LC and may represent a promising therapeutic strategy to overcome MTX resistance."

Journal • Preclinical • Brain Cancer • Breast Cancer • Oncology • Solid Tumor • BCL2 • DHFR