mercaptopurine delayed release (DR6MP) / Teva - LARVOL DELTA

Derivation and Internal Validation of a Clinical Prediction Tool to Predict Nonalcoholic Fatty Liver Disease in Patients With Crohn’s Disease. (PubMed, Inflamm Bowel Dis) - "CPN-CD outperforms HSI in detecting NAFLD in patients with CD. Future directions include external validation, outcome validation, and testing generalizability to patients with ulcerative colitis."

Clinical • Journal • Crohn's disease • Gastroenterology • Hepatology • Immunology • Inflammatory Bowel Disease • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Ulcerative Colitis

Hyper-CVAD Plus Ofatumumab as Frontline Therapy for Adults with CD20 Positive Acute Lymphoblastic Leukemia (SOHO 2019) - "Ofatumumab targets a unique small-loop epitope on CD20 was found to have better in vitro efficacy than rituximab.Objective Addition of ofatumumab to Hyper-CVAD may increase response rates, the likelihood of minimal residual disease (MRD) eradication and improve survival.Design Single-arm phase II study with a median follow-up of 44 months (range 4-91).Setting Patients were treated and followed at the University of Texas MD Anderson Cancer Center.Patients Adult patients (older >18 years) with newly diagnosed untreated or minimally treated (≤1 cycle) Philadelphia chromosome (Ph)-negative CD20+ B-cell ALL were eligible.Interventions Patients received 8 alternating cycles of Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) and methotrexate/cytarabine...Patients then received maintenance (6-mercaptopurine, vincristine, methotrexate and prednisone) on cycles 1-5, 8-17 and 20-30 and late intensifications on cycles 6-7 and 18-19...The 3-year CR..."

Clinical

Genetic Polymorphisms of TPMT and NUDT15 Genes and Thiopurine Treatment-Related Toxicity in Adult Patients with Acute Lymphoblastic Leukemia in Russia (SOHO 2019) - P=N/A; "Context 6-mercaptopurine is the main component of therapy for ALL...Patients with above-described polymorphisms of TPMT and NUDT15 genes had significantly higher incidence of resistant disease and toxicity in the RALL-2016 protocol than patients with WT. But we don’t know whether this is due to deficient 6-MP metabolism, which requires further study."

Clinical

Progress in the Management of Older Adults with Acute Lymphoblastic Leukemia (SOHO 2019) - "The addition of blinatumomab may also allow for the use of less chemotherapy and lower doses of inotuzumab, thereby leading to less treatment-related morbidity and mortality.In a phase II study, 64 patients (age 60 to 81) with newly diagnosed Philadelphia-negative ALL were treated with inotuzumab and mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) +/- blinatumomab...By multivariate analysis, age and the combination of inotuzumab with mini-HCVD with or without blinatumomab were identified as independent prognostic factors for survival.The initial results of the SWOG 1318 study, a phase 2 trial of blinatumomab followed by POMP (prednisone, vincristine, methotrexate, 6-mercaptopurine) maintenance in elderly patients with newly diagnosed Philadelphia-negative ALL, reported a CR rate of 66% (among them 92% with negative MRD), a 1-year survival rate of 65% and a..."

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

[VIRTUAL] DNA-THIOGUANINE CONCENTRATION AND RELAPSE RISK IN CHILDREN AND YOUNG ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA: AN IPD META-ANALYSIS (SIOP 2020) - "Background and Aims Methotrexate/6-mercaptopurine maintenance therapy improves acute lymphoblastic leukemia (ALL) outcome. If also excluding the United Kingdom cohort, in which samples were taken non-randomly in selected patients, the HRa for the EOI MRD-positive patients was 0.82 (95% CI 0.68–0.99; p=0.044) per 100 fmol/μg increase in wmDNA-TG. Conclusions The importance of DNA-TG as a biomarker for maintenance therapy intensity calls for novel strategies to increase DNA-TG, although its clinical value may vary by protocol backbone."

Late-breaking abstract • Retrospective data • Acute Lymphocytic Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics

[VIRTUAL] First Results of an Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Therapy Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with Acute Lymphoblastic Leukemia (INITIAL-1 trial) (ASH 2020) - P2 | "No previous ALL-specific treatment, with the exception of corticosteroids and/or single dose vincristine and/or up to 3 doses of cyclophosphamide (cycloph.) plus standard prephase treatment are allowed. The 1st induction cycle consists of inotuzumab ozogamicin (InO) 0.8 mg/m2 on day1 and 0.5 mg/m2 on days 8 and 15 together with dexamethasone 10 mg/m2 (days 7-8, days 14-17) and 1 intrathecal injection of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dexa)...Patients achieving a complete remission are offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/AraC/cycloph./Dexa) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-mercaptopurine/MTX... Replacement of conventional induction chemotherapy by InO is feasible, results in promising remission rates, and may reduce the risk of early morbidity and lethality, particular in older patients..."

Clinical • P2 data • Acute Lymphocytic Leukemia • Hematological Disorders • Hematological Malignancies • Hepatology • Leukemia • Leukopenia • Oncology • T Acute Lymphoblastic Leukemia • Thrombocytopenia • Transplantation • CD20

Addition of Lomustine in the Treatment of Elderly Patients with Acute Myeloblastic Leukemia Improves Survival with Acceptably Increased Infectious Toxicity. a Filo Study (ASH 2017) - P3; "with or without lomustine 80 mg D1) and 6 mini-reinductions (idarubicin 8 mg/m² D1 IV, cytarabine 50 mg/m²/12h D1-D5 with or without lomustine 40 mg D1), followed by a 6-months oral maintenance with 6-mercaptopurine and methotrexate.In this trial, lomustine significantly improved the rate of complete remission after 1 cycle (75% vs 85% p= 0.01) as well as event-free survival (47% [39 – 54] vs 29% [22 – 37; p= 0.02]). We therefore keep recommending its association with standard chemotherapy in AML elderly patients, yet propose to abandon the consolidation phase because of increased toxicity."

Clinical • Acute Myelogenous Leukemia • Biosimilar • Immunology

Individualized 6-Mercaptopurine Increments in Consolidation Treatment of Childhood Acute Lymphoblastic Leukemia: A NOPHO ALL2008 Randomized Controlled Trial (ASH 2017) - P3; "In this randomized controlled trial on children with non-high risk ALL, we tested the hypothesis that individualized, toxicity-titrated 6-mercaptopurine (6-MP) increments during consolidation therapy with high-dose methotrexate were superior to the standard fixed-dose 6-MP regimen. Despite 6-MP dose intensifications in 58% of patients in the experimental arm and a strong association between dose increments and DNA-TGN levels, as well as a non-significant improvement in MRD at end of consolidation, we found no survival benefit from individualized 6-MP increments compared to standard therapy."

Clinical • Acute Lymphocytic Leukemia • Biosimilar • Venous Thromboembolism

Hyper-CVAD Plus Ofatumumab As Frontline Therapy in CD20+ Acute Lymphoblastic Leukemia: Updated Results of a Phase II Trial (ASH 2017) - P2; "...Ofatumumab (O) is a type I human antibody that binds to a distinct CD20 epitope compared to rituximab, and induces more potent antibody-dependent and complement mediated cytotoxicity in vitro...Patients (pts) received intensive therapy with 4 cycles (cy) of HCVAD [odd cy 1, 3, 5, 7 comprised of fractionated cyclophosphamide, vincristine (VCR), doxorubicin, dexamethasone] alternating with 4 cy of methotrexate-cytarabine (MTX-ara-C, even cy 2, 4, 6, 8)...Pts received POMP maintenance (6-mercaptopurine, MTX, VCR, prednisone) for nearly 30 months (mo), and intensification with MTX-PEGylated asparaginase on mo 6 and 18 and with O-HCVAD on mo 7 and 19... O-HCVAD is safe, highly effective, and produces durable responses in adults with Ph- CD20+ ALL.nClinical trial registration information: NCT01363128"

P2 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Biosimilar • Immunology

A Phase II Study of Pegylated Asparaginase, Cyclophosphamide, Rituximab, and Dasatinib Added to the UCSF 8707 (Linker 4-drug) Regimen with Liposomal Cytarabine CNS Prophylaxis for Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL): University of California Hematologic Malignancies Consortium Study (UCHMC) 1401 (ASH 2018) - P2; "...Treatment consisted of induction Course 1A (C1A): daunorubicin 60 mg/m2 IV d1-3, vincristine (VCR) 1.4 mg/m2 (2 mg if age >50 yrs) IV day 1,8,15,22, prednisone 60 mg/m2 orally (PO) d1-28, peg-asp 2,000 IU/m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d15, cyclophosphamide 750 mg/m2 IV d1,15 (or 500 mg/m2 IV q12h d15,16 if d14 marrow M2 or M3). ALL pts in CR/CRi and LBL pts in CR or PR proceeded to post-remission Course 1B (C1B): methotrexate (MTX) 220 mg/m2 IV bolus then 60 mg/m2/hr CIV for 36 hrs d1,15 with leucovorin rescue, 6-mercaptopurine (6-MP) 60 mg/m2 PO d1-7, 15-21, peg-asp 2,000 IU/ m2 (cap 3,750 IU; 1,000 IU/m2 if age >50 yrs) IV d16. Course 1C (C1C) consisted of cytarabine 2,000 mg/m2 IV d1-4 and etoposide 500 mg/m2 IV d1-4...EFS, RFS, and OS are favorable with follow up and accrual ongoing (NCT02043587). Strategies to limit peg asp toxicity are needed."

Clinical • P2 data • Acute Lymphocytic Leukemia • Biosimilar • Cardiovascular • Dyslipidemia • Hematological Disorders • Hematological Malignancies • Immunology • Indolent Lymphoma • Leukemia • Lymphoma • Oncology • Pancreatitis • Venous Thromboembolism

Results of SWOG 1318: A Phase 2 Trial of Blinatumomab Followed By Pomp (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) Maintenance in Elderly Patients with Newly Diagnosed Philadelphia Chromosome Negative B-Cell Acute Lymphoblastic Leukemia (ASH 2018) - "Three pts received hydroxyurea or steroids prior to treatment initiation. Conclusion s: Blinatumomab was well tolerated and effective in the treatment of newly diagnosed elderly patients with Ph negative B-lineage ALL. Further follow up will determine the durability of these responses."

Clinical • P2 data • Acute Lymphocytic Leukemia • Biosimilar • Brain Cancer • Hypertension • Immunology • Neutropenia • Oncology

[VIRTUAL] Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932. (ASCO 2020) - P3 | "LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8...LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose)... AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Research Funding: U.S. National Institutes of Health,..."

Clinical • Allergy • Developmental Disorders • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Mucositis • Oncology • ETV6

GERIATRIC ASSESSMENT-BASED TREATMENT OF ELDERLY PHILADELPHIA-NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS. RESULTS OF THE GIMEMA LAL1104 PROTOCOL (EHA 2019) - "Treatment was more intensive for fit and intermediate pts: including daunorubicine 25 mg/m2 on days 1-3, 22-24 and vincristine 1.4 mg/m2 days 1, 8, 15, 22 in induction, and methotrexate (MTX) 1 g/m2 and cytarabine 1.5 g/m2 as consolidation, autologous transplantation (auto-SCT) in fit pts followed by maintenance with MTX, 6-mercaptopurine (6-MP) and vincristine; frail pts received vinblastine 5 mg/m2 on days 1, 8, 15, 22 as induction, and MTX and 6-MP as maintenance. Importantly, the geriatric assessment proved effective in reducing early fatal side effects in unfit pts and abolished the differences in terms of OS, with a survival rate of 26% at 4-ys for the fit pts. Enrollment in clinical trials designed specifically for elderly Ph- ALL, including new drugs and a geriatric assessment, will likely improve further the survival rates of these difficult to treat pts."

Clinical • Acute Lymphocytic Leukemia • Gene Therapies • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Oncology • Pain • Respiratory Diseases • Transplantation

Adam Cheifetz, MD, on Managing Severe Ulcerative Colitis (HMP Global) - "Dr Cheifetz...spoke about the treatment options available for patients with severe ulcerative colitis, from medical management to surgery at the recent Interdisciplinary Autoimmune Summit."

Video

Bruce E. Sands, MD: The Return of Small Molecule Treatments for IBD (HCPLive) - "In an interview with HCPLive, Bruce E. Sands, MD...explained the value in using small molecule treatments for both ulcerative colitis and Crohn's disease....While these treatments have been historically effective, Sands said he expects future research to focus once again on this class of medicine to develop new treatments for patients who may not respond to biologics."

Interview • Video

Blinatumomab, Inotuzumab Ozogamicin, and Combination Chemotherapy as Frontline Therapy in Treating Patients With B Acute Lymphoblastic Leukemia (clinicaltrials.gov) - P2; N=80; Recruiting; Sponsor: M.D. Anderson Cancer Center; N=60 ➔ 80

Clinical • Enrollment change • Acute Lymphocytic Leukemia • B Acute Lymphoblastic Leukemia • Hematological Malignancies • Leukemia • Lymphoma • Oncology

Adenylosuccinate lyase is oncogenic in colorectal cancer by causing mitochondrial dysfunction and independent activation of NRF2 and mTOR-MYC-axis. (PubMed, Theranostics) - "Transfected cell lines or patient-derived organoids (PDO) were treated with 5-fluorouracil (5-FU) and 6-mercaptopurine (6-MP) and drug response was correlated with ADSL expression levels. Our results suggest that ADSL is a novel oncogene in CRC, modulating mitochondrial function, metabolism and oxidative stress, thus promoting cell cycle progression, proliferation and migration. Our results also suggest that ADSL is a predictive biomarker of response to 6-mercaptopurine in the pre-clinical setting."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Metabolic Disorders • Oncology • Solid Tumor • KEAP1 • MYC

Aqueous-Organic Solvent Derived Recombinant Spider Silk Gels as Depots for Drugs. (PubMed, Angew Chem Int Ed Engl) - "The presence of the organic co-solvent further enabled the incorporation of hydrophobic drugs as exemplary shown for 6-mercaptopurine. The developed gels showed shear-thinning behaviour and could be easily injected to serve e.g. as drug depots and could even be 3D printed to serve as scaffolds for biofabrication. With this new processing route, the formulation of water-insoluble drugs in spider silk-based depots is possible, circumventing common pharmaceutical solubility issues."

Journal

[VIRTUAL] METHOTREXATE FOR THE INDUCTION OF REMISSION IN ULCERATIVE COLITIS (CDDW 2021) - "An additional head-to-head randomised controlled study (n = 34) compared oral methotrexate (15 mg/week) to 6-mercaptopurine (1.5 mg/kg/day) and 5-aminosalicylic acid (3 g/day)... Methotrexate demonstrated no benefit over placebo or active comparators for the induction of steroid-free remission. Future research is ongoing to explore the utility of combination therapy with monoclonal antibody biologic therapy for the treatment of active ulcerative colitis."

Clinical • Developmental Disorders • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammatory Bowel Disease • Ulcerative Colitis

[VIRTUAL] CHARACTERIZING THE ROLE OF NR4A1 IN THE REGULATION OF INTESTINAL SMOOTH MUSCLE CELL PHENOTYPE AND FUNCTION (CDDW 2021) - "NR4A1 activation was induced by selective agonists, cytosporone B (Csn-B) and 6-mercaptopurine (6-MP)... Our suggest that NR4A1 is a regulator of intestinal SMC proliferation, bioenergetics, and phenotype. Its induction by mitogens may contribute to a negative feedback loop to control smooth muscle growth. These data support targeting NR4A1 to treat excessive smooth muscle hypertrophy/hyperplasia that contributes to tissue remodelling observed in fibrostenotic CD."

Crohn's disease • Fibrosis • Gastroenterology • Immunology • Inflammatory Bowel Disease • NR4A1

Dynamics of leucocyte DNA thioguanine nucleotide levels during maintenance therapy of childhood acute lymphoblastic leukemia. (PubMed, Cancer Chemother Pharmacol) - "Fluctuations in DNA-TG are predominantly caused by corresponding fluctuations in DNA-TG, thus DNA-TG measures recent TGN incorporation in these short-lived cells. Measurement of DNA-TG at 2-4 weeks intervals provides a reliable profile of DNA-TG levels."

Clinical • Journal • Acute Lymphocytic Leukemia • Gene Therapies • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] Management of Older Patients with Acute Lymphocytic Leukemia — Novel Treatment Strategies (SOHO 2020) - "Inotuzumab ozogamicin with mini-hyper-CVD (i.e., a lower intensity version of the hyper-CVAD regimen without anthracycline), with or without blinatumomab, is one such strategy and appears to be promising in the elderly population.10 Among 64 patients treated with this regimen, the median age was 68 years (range, 60–81 years) and 42% of patients were ≥ 70 years of age)...The SWOG 1318 study evaluated the chemotherapy-free induction and consolidation with blinatumomab (total of 4–5 cycles) followed by POMP maintenance (prednisone, vincristine, methotrexate, and 6-mercaptopurine).12 Thirty-one patients with a median age of 73 years (range 66–84) were treated...Preclinical studies have demonstrated activity of the BH3-mimetics in B-cell and T-cell ALL cell lines.13, 14, 15 Preliminary results of the combination of venetoclax with low-intensity chemotherapy in newly diagnosed older patients unfit for intensive chemotherapy are promising with objective response and MRD..."

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

Boron carbon oxyphosphide heterostructured nanodots with phosphate tunable emission for switchable dual detection channels of 6-mercaptopurine assay. (PubMed, Talanta) - "Furthermore, the presence of ClO anion efficaciously sparks the release of the 6-MP molecule from the 6-MP/BCPO complexes, thereby a rapid photo-switch of the BCPO for the 6-MP has been developed. Thus, this study can not only guide the further rational design of the BCPO probe, but also inspire the in-depth application of the BCPO and other nanomaterial-based probes."

Journal

Withdrawal of Combination Immunotherapy in Paediatric Inflammatory Bowel Disease - An International Survey of Practice. (PubMed, J Pediatr Gastroenterol Nutr) - "Most PG's favour initial withdrawal of immunomodulator (usually thiopurines) rather than biologic therapy in the step-down process, usually after 6-12 months based on sustained clinical remission. This survey precedes an in-depth, multicentre study of clinical outcomes of withdrawal of co-immunosuppression in PIBD."

Journal • Crohn's disease • Gastroenterology • Gastrointestinal Disorder • Immune Modulation • Immunology • Inflammation • Inflammatory Bowel Disease • Pediatrics • Ulcerative Colitis

Thioguanine restoration through type I photosensitization-superoxide oxidation-glutathione reduction cycles. (PubMed, Phys Chem Chem Phys) - "UVA-induced deleterious effect of thiopurine prodrugs including azathioprine, 6-mercaptopurine and 6-thioguanine (6-TG) increases the risk of cancer development due to the incorporation of 6-TG in patients' DNA. (2) In the absence of GSH, 6-TG thiyl radicals undergo oxygen addition and sulfur dioxide removal to form carbon radicals (C6) which further convert to thioether by reacting with 6-TG molecules. These findings help explain not only thiol-regulation in a biological system but chemoprevention of cancer."

Journal • Oncology