Transient Hepatotoxicity Research Articles

P1033 The decrease of 6-TGN concentrations during pregnancy is not associated with an increase in fecal calprotectin in female patients with IBD on thiopurine-treatment

Abstract Background Thiopurines, such as azathioprine (AZA), mercaptopurine (MP) and thioguanine (TG), are commonly used to maintain disease remission in inflammatory bowel disease (IBD). AZA and MP are metabolized to form the active 6-thioguanine nucleotides (6-TGN) and the 6-methylmercaptopurine ribonucleotides (6-MMPR), associated with intolerable adverse drug reactions. Previous studies report a shift in thiopurine metabolism during pregnancy, characterized by a decrease in 6-TGN and an increase in 6-MMPR levels 1,2. The influence of these changes on clinical outcomes remains unclear. This study aims to explore the association of changes in 6-TGN and 6-MMPR levels during pregnancy with disease activity and toxicity markers in women with IBD. Methods A retrospective cohort study was conducted recruiting patients with IBD from six Dutch medical centers. Adult women who were pregnant between 2017 and 2022, using thiopurines for IBD, and with at least one thiopurine metabolite measurement during pregnancy were included. Linear mixed effects models assessed 6-TGN and 6-MMPR levels during pregnancy (categorized to half trimesters) and within 6 months postpartum, compared to preconceptional levels, adjusting for dosage and repeated measurements. The influence of percentual changes in 6-TGN and 6-MMPR on disease activity (calprotectin >250μg/g), hepatotoxicity (alanine aminotransferase (ALT) >2xULN) and myelotoxicity (leukocytes <4.0x109/L) were analyzed, adjusting for dosage and trimester. Results A total of 87 women with 100 pregnancies were included, of whom 64.4% were diagnosed with Crohn’s disease and 32.2% with ulcerative colitis. An adverse pregnancy outcome occurred in 13 pregnancies (13%), with rates comparable to the healthy Dutch population. Subtherapeutic levels of 6-TGN were measured in 32 pregnancies (32%). There were no instances of leukopenia; transient hepatotoxicity occurred thrice (3%). There was active disease in 30 pregnancies, corresponding to 37 metabolite measurements. Analysis showed a significant reduction in 6-TGN levels in the second trimester (Figure 1), with non-significant increases in 6-MMPR. Though disease activity coincided with subtherapeutic 6-TGN-levels 21 times (56.8%), the reduction in 6-TGN was not associated with changes in calprotectin (Estimated marginal mean difference (EMM) =5.435, p=0.104), ALT (EMM=-0.025, p=0.858) or leukocytes (EMM=0.068, p=0.536, Table 1). Conclusion Our study results indicate that despite that 6-TGN levels decrease and 6-MMP may increase during pregnancy, these fluctuations do not seem to associate with markers of disease activity, hepatotoxicity and myelotoxicity. Larger, prospective studies are needed to re-evaluate the postulated need for thiopurine monitoring in the third trimester.

Fosfomycin-induced liver injury: A case report and literature review

Background:Fosfomycin is an antibiotic often used to treat urinary tract infections (UTIs) with only rare transient hepatotoxicity. We present a case of fosfomycin-induced liver injury and describe the histopathologic findings on biopsy.Methods:A 64-year-old female patient with no prior liver disease or risk factors was started on fosfomycin as prophylaxis for recurrent UTIs. Within a week of her first dose, she presented with fatigue, jaundice, and mixed liver enzyme elevation. Clinical workup for acute liver injury was unremarkable, and biopsy showed panacinar and portal necroinflammation with predominantly lymphocytic infiltrate and cholestasis, with no evidence of cirrhosis. This was thought to be likely related to fosfomycin exposure. Although liver enzymes trended down, bilirubin initially remained elevated. However, within 3 months the patient achieved clinical and biochemical recovery.Results:Only two other reports of fosfomycin-induced liver injury requiring biopsy were found. Both developed acute cholestatic hepatitis within days of exposure, and subsequent biopsy similarly showed lymphocytic necroinflammation. Although one patient initially developed acute liver failure, both recovered fully within a few months.Conclusion:Overall, these cases suggest potentially an idiosyncratic or immune-mediated liver toxicity of Fosfomycin, which is typically self-limited but may take months to fully resolve. Liver biopsy may be useful in confirming the diagnosis.

SiRNA-mediated reduction of a circulating protein in swine using lipid nanoparticles

Genetic manipulation of animal models is a fundamental research tool in biology and medicine but is challenging in large animals. In rodents, models can be readily developed by knocking out genes in embryonic stem cells or by knocking down genes through invivo delivery of nucleic acids. Swine are a preferred animal model for studying the cardiovascular and immune systems, but there are limited strategies for genetic manipulation. Lipid nanoparticles (LNPs) efficiently deliver small interfering RNA (siRNA) to knock down circulating proteins, but swine are sensitive to LNP-induced complement activation-related pseudoallergy (CARPA). We hypothesized that appropriately administering optimized siRNA-LNPs could knock down circulating levels of plasminogen, a blood protein synthesized in the liver. siRNA-LNPs against plasminogen (siPLG) reduced plasma plasminogen protein and hepatic plasminogen mRNA levels to below 5% of baseline values. Functional assays showed that reducing plasminogen levels modulated systemic blood coagulation. Clinical signs of CARPA were not observed, and occasional mild and transient hepatotoxicity was present in siPLG-treated animals at 5h post-infusion, which returned to baseline by 7days. These findings advance siRNA-LNPs in swine models, enabling genetic engineering of blood and hepatic proteins, which can likely expand to proteins in other tissues in the future.

Hepatotoxicity from high-dose methotrexate in primary central nervous system lymphoma.

High-dose methotrexate (HDMTX) is a mainstay of primary central nervous system lymphoma (PCNSL) treatment. Transient hepatotoxicity from HDMTX has been characterized in pediatric patients but not in adults. We sought to characterize hepatotoxicity in adult PCNSL patients undergoing HDMTX treatment. Retrospective study of 65 PCNSL patients treated at the University of Virginia from 02/01/2002 to 04/01/2020 was performed. Hepatotoxicity was defined using National Cancer Institute Common Toxicity Criteria (CTC) for adverse events, fifth version. High-grade hepatotoxicity was defined as a bilirubin or aminotransferase CTC grade of 3 or 4. Relationships between clinical factors and hepatotoxicity were assessed with logistic regression. Most patients (90.8%) had a rise of at least one aminotransferase CTC grade during HDMTX treatment. 46.2% had high-grade hepatotoxicity based on aminotransferase CTC grade. No patients developed high-grade bilirubin CTC grades during chemotherapy. Liver enzyme test values decreased to low CTC grade or normal in 93.8% of patients after the conclusion of HDMTX treatment without treatment regimen changes. Prior ALT elevation (P = .0120) was a statistically significant predictor of high-grade hepatotoxicity during treatment. Prior history of hypertension was associated with increased risk of toxic serum methotrexate levels during any cycle (P = .0036). Hepatotoxicity develops in the majority of HDMTX-treated PCNSL patients. Transaminase values decreased to low or normal CTC grades in almost all patients after treatment, without modification of MTX dosage. Prior ALT elevation may predict patients' increased hepatotoxicity risk, and hypertension history may be a risk factor for delayed MTX excretion.

Brincidofovir: A Novel Agent for the Treatment of Smallpox.

This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox. A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms Tembexa, brincidofovir, CMX001, smallpox treatment, and variola treatment. Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir. Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo. Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.

Dose- and time-dependent manners of moxifloxacin induced liver injury by targeted metabolomics study.

Moxifloxacin is the most widely prescribed antibiotics due to its excellent oral bioavailability and broad-spectrum antibacterial effect. Despite of its popularity, the rare and severe liver injury induced by moxifloxacin is a big concern that cannot be ignored in clinical practice. However, the early warning and related metabolic disturbances of moxifloxacin induced hepatoxicity were rarely reported. In this study, the dose- and time-dependent manners of moxifloxacin induced liver injury were investigated by a targeted metabolomics method. In dose-dependent experiment, three different dosages of moxifloxacin were administered to the rats, including 36 mg kg−1 d−1, 72 mg kg−1 d−1, and 108 mg kg−1 d−1. In time-dependent experiment, moxifloxacin was orally administered to the rats for 3, 7 or 14 consecutive days. Pathological analysis showed that moxifloxacin caused obvious transient hepatotoxicity, with the most serious liver injury occurred in the 7 days continuous administration group. The transient liver injury can be automatically restored over time. Serum levels of liver function related biochemical indicators, including ALT, AST, TBIL, alkaline phosphatase, superoxide dismutase, and malondialdehyde, were also measured for the evaluation of liver injury. However, these indicators can hardly be used for the early warning of hepatotoxicity caused by moxifloxacin due to their limited sensitivity and significant hysteresis. Targeted metabolomics study demonstrated that serum concentrations of fatty acyl carnitines, fatty acids and dehydroepiandrosterone can change dynamically with the severity of moxifloxacin related liver injury. The elevated serum levels of fatty acyl carnitine, fatty acid and dehydroepiandrosterone were promising in predicting the hepatotoxicity induced by moxifloxacin.

High Response Rate and Corticosteroid Sparing with Arsenic Trioxide-Based First-Line Therapy in Chronic Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Chronic graft-versus-host disease (cGVHD) occurs in 20% to 50% of recipients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Corticosteroids (CS) remain the first-line therapy but have suboptimal efficacy and carry a risk of long-term side effects. New agents with a better safety profile and higher efficacy are urgently needed. This study aimed to evaluate the efficacy and safety of a first-line combination of arsenic trioxide (ATO) and CS in adult patients with cGVHD requiring systemic therapy after first allo-HSCT for a hematologic disease. In this prospective national multicenter single-arm open-label Phase II study conducted in 5 university hospital centers in France, ATO was started within 10 days of CS at 1 mg/kg/day. Patients received 11 infusions per cycle of 28 days at a dose of .15 mg/kg per infusion. According to the clinical response and depending on the clinician's opinion, patients received 1 or 2 cycles of treatment. Cycles were separated by an 8- to 11-week interval from the first infusion of ATO. Patients were evaluated at 6 weeks, 14 weeks, 6 months, 9 months, and 12 months after the first ATO infusion, using the Chronic GVHD Activity Assessment Form A. The primary endpoint was preliminary efficacy based on the overall response rate (ORR; complete response [CR] or partial response [PR]) at 6 months. Response rates were estimated with 2-sided 95% exact confidence intervals (CIs). Twenty-one patients entered the study and received at least 1 ATO infusion (1 incomplete cycle for 1 patient, 1 complete cycle for 11 patients, and 2 complete cycles for 9). Six patients continued ongoing cyclosporine A (CsA) treatment after inclusion, and 4 other patients resumed CsA treatment during the study. The ORR at 6 months was 75.0% (95% CI, 50.9% to 91.3%), with CR in 35% and PR in 40%. Failure-free survival was 90.0% (95% CI, 65.6% to 97.4%) at 6 months and 65.0% (95% CI, 40.3% to 81.5%) at 12 months. The progression-free survival rate was 95.0% (95% CI, 69.5% to 99.3%) at 6 months and 83.8% (95% CI, 57.7% to 94.5%) at 12 months. The mean CS dose was decreased by 74.6 ± 32.7% from baseline to the 6-month visit and by 91.0 ± 14.6% from baseline to the 12-month visit. CS was definitively stopped in 30.0% of patients at the 6-month visit and in 47.4% at the 12-month visit. Two patients died, at 7 months and 12 months after the first ATO infusion from causes unrelated to ATO. One patient withdrew because of transient hepatotoxicity. The first-line combination of ATO and CS was associated with a high clinical response rate and rapid CS sparing in cGVHD after previous allo-HSCT.

Tigecycline-Induced Clinical Jaundice: A Case Report and Review of the Literature

Tigecycline gained large popularity due to its efficacy against multi-drug-resistant organisms. Tigecycline has a good safety profile, and its most encountered side effects are nausea, vomiting and diarrhea. However, tigecycline has been associated with a mild and transient hepatotoxicity. Extreme hyperbilirubinemia and jaundice are rare side effects of tigecycline that have not been reported in clinical trials.

A critical review of ozanimod for the treatment of adults with moderately to severely active ulcerative colitis

Introduction: Ozanimod is a sphingosine-1-phosphate (S1P) modulator that inhibits lymphocyte trafficking from lymph nodes to the circulation. It is approved by the U.S. Food and Drug Administration (FDA) for treatment of relapsing multiple sclerosis and most recently for the management of moderate-severe ulcerative colitis (UC). Areas covered: Here we review the status of drugs approved for moderate-severe UC, the unmet needs in the management of UC, proposed mechanisms of action of S1P modulators, clinical data regarding ozanimod in UC and emerging S1P modulators being evaluated in inflammatory bowel disease. Expert opinion: Ozanimod is superior to placebo in inducing and maintaining clinical and endoscopic remission in UC. Adverse events include transient asymptomatic bradycardia and first-degree atrioventricular blocks, transient asymptomatic hepatotoxicity, macular edema in patients with pre-existing risk factors, and increased risk of nasopharyngitis. Ozanimod is contraindicated in patients with clinically significant cardiovascular diseases, type II second- or third-degree atrioventricular blocks, and females of child-bearing age not using contraception. Ozanimod is the first S1P modulator to be approved for UC, offering a new therapeutic class option for patients. It has the advantages of being convenient with a once daily oral administration, non-immunogenic, and overall safe when used in patients without contraindications.

Use of a Clostridioides difficile Murine Immunization and Challenge Model to Evaluate Single and Combination Vaccine Adjuvants Consisting of Alum and NKT Cell-Activating Ligands.

Adjuvant combinations may enhance or broaden the expression of immune responses to vaccine antigens. Information on whether established Alum type adjuvants can be combined with experimental CD1d ligand adjuvants is currently lacking. In this study, we used a murine Clostridioides difficile immunization and challenge model to evaluate Alum (Alhydrogel™), α-galactosylceramide (α-GC), and one of its analogs 7DW8-5 singly and in combination as vaccine adjuvants. We observed that the Alum/α-GC combination caused modest enhancement of vaccine antigen-specific IgG1 and IgG2b responses, and a broadening to include IgG2c that did not significantly impact overall protection. Similar observations were made using the Alum/7DW8-5 combination. Examination of the impact of adjuvants on NKT cells revealed expansion of invariant NKT (iNKT) cells with modest expansion of their iNKTfh subset and little effect on diverse NKT (dNKT) cells. Side effects of the adjuvants was determined and revealed transient hepatotoxicity when Alum/α-GC was used in combination but not singly. In summary these results showed that the Alum/α-GC or the Alum/7DW8-5 combination could exert distinct effects on the NKT cell compartment and on isotype switch to produce Th1-driven IgG subclasses in addition to Alum/Th2-driven subclasses. While Alum alone was efficacious in stimulating IgG-mediated protection, and α-GC offered no apparent additional benefit in the C. difficile challenge model, the work herein reveals immune response features that could be optimized and harnessed in other vaccine contexts.

TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy.

Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.

Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL)

The best strategy for incorporating imatinib in front-line treatment of Ph+ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph+ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P = .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic efficacy.

Comparative Oncology Evaluation of Intravenous Recombinant Oncolytic Vesicular Stomatitis Virus Therapy in Spontaneous Canine Cancer.

Clinical translation of intravenous therapies to treat disseminated or metastatic cancer is imperative. Comparative oncology, the evaluation of novel cancer therapies in animals with spontaneous cancer, can be utilized to inform and accelerate clinical translation. Preclinical murine studies demonstrate that single-shot systemic therapy with a vesicular stomatitis virus (VSV)-IFNβ-NIS, a novel recombinant oncolytic VSV, can induce curative remission in tumor-bearing mice. Clinical translation of VSV-IFNβ-NIS therapy is dependent on comprehensive assessment of clinical toxicities, virus shedding, pharmacokinetics, and efficacy in clinically relevant models. Dogs spontaneously develop cancer with comparable etiology, clinical progression, and response to therapy as human malignancies. A comparative oncology study was carried out to investigate feasibility and tolerability of intravenous oncolytic VSV-IFNβ-NIS therapy in pet dogs with spontaneous cancer. Nine dogs with various malignancies were treated with a single intravenous dose of VSV-IFNβ-NIS. Two dogs with high-grade peripheral T-cell lymphoma had rapid but transient remission of disseminated disease and transient hepatotoxicity that resolved spontaneously. There was no shedding of infectious virus. Correlative pharmacokinetic studies revealed elevated levels of VSV RNA in blood in dogs with measurable disease remission. This is the first evaluation of intravenous oncolytic virus therapy for spontaneous canine cancer, demonstrating that VSV-IFNβ-NIS is well-tolerated and safe in dogs with advanced or metastatic disease. This approach has informed clinical translation, including dose and target indication selection, leading to a clinical investigation of intravenous VSV-IFNβ-NIS therapy, and provided preliminary evidence of clinical efficacy and potential biomarkers that correlate with therapeutic response. Mol Cancer Ther; 17(1); 316-26. ©2017 AACR.

Safety and Efficacy of Doxorubicin Drug-Eluting Embolic Chemoembolization of Hepatocellular Carcinoma Supplied by Extrahepatic Collateral Arteries

PurposeTo assess safety and efficacy of doxorubicin drug-eluting embolic (DEE) transarterial chemoembolization of hepatocellular carcinoma (HCC) by extrahepatic collateral arteries. Materials and MethodsRecords of 177 patients with HCC who underwent 338 consecutive DEE chemoembolization procedures from 2011 to 2014 were retrospectively reviewed. A subgroup of 16 patients (13 men, 3 women, median age 66 y) underwent 24 procedures for 17 HCCs via extrahepatic arteries and was included in the study. Median tumor size was 3.1 cm (range, 1.0–10.3 cm). Extrahepatic collaterals included right inferior phrenic (19 procedures; 12 patients), adrenal (4 procedures; 3 patients), and cystic arteries (2 procedures; 2 patients). Radiographic response was assessed by Modified Response Evaluation Criteria in Solid Tumors criteria. Complications were defined by National Cancer Institute Common Terminology Criteria for Adverse Events. ResultsDEE chemoembolization achieved stable disease in 6 (35.3%), partial response in 6 (35.3%), and complete response in 4 (23.5%) HCCs. Disease progression was ultimately observed in 8 tumors (47.1%), with mean time to progression of 8.3 months after chemoembolization (range, 2–13 mo). Three minor and 5 major complications occurred in 8 patients; 2 minor complications were rash in vascular distribution after right inferior phrenic artery DEE chemoembolization. The 5 major complications were transient hepatotoxicity that resolved within 4–80 days; 1 was accompanied by pleural effusion requiring hospitalization. A mean 13.4 months after DEE chemoembolization, 67% of transplant candidates proceeded to liver transplant. ConclusionsDEE transarterial chemoembolization via extrahepatic collaterals was effective and facilitated bridging to transplant. It was generally well tolerated; transient hepatotoxicity was the most common major complication.

OP28PRELIMINARY RESULTS OF THE PROSPECTIVE FEASIBILITY CNS GCT-4 CONSORTIUM TRIAL FOR PATIENTS WITH REFRACTORY/RECURRENT CNS GERM CELL TUMORS (GCT)

INTRODUCTION: We present updated findings on the response rate, toxicity and early outcomes of a re-induction regimen of gemcitabine, oxaliplatin and paclitaxel (GemPOx) administered, in responsive patients, prior to myeloablative chemotherapy and autologous hematopoietic cell rescue (HDCx + AuHCR). METHOD: Since December 2004, 14 recurrent or refractory patients (12 MMGCT, 2 germinoma; 12 males; mean age 16.5 years, range 7-34 years) have been treated with up to 4 cycles of gemcitabine (800mg/m2), oxaliplatin (100mg/m2) and paclitaxel (170 mg/m2), administered on one day at 14 days intervals. RESULTS: Of 14 patients, five were treated on a preceding feasibility pilot with 1-3 cycles of GemPOx, and nine have been formally enrolled on an ongoing prospective multi-center trial. Seven patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions and two developed progressive disease (PD) while on GemPOx. Twelve of the 14 patents subsequently underwent HDCx + AuHCR; 6 subsequently received irradiation. Transient hepatotoxicity and pancytopenia were the most prevalent toxicities. Five patients continue alive and disease-free for 9 + , 20 + , 22 + , 26+ and 28+ months since end of therapy. CONCLUSION: GemPOx appears to be an effective re-induction regimen for patients with recurrent CNS MMGCT, with acceptable toxicities. The ongoing multi-center, international trial should confirm this and demonstrate the contribution of GemPOx towards improved survival when followed by HDCx + AuHCR with or without further irradiation, in the setting of minimal residual disease.

Abstract IA18: Clinical validation of PI3Kδ as a therapeutic target in B-cell malignancy

Abstract Idelalisib (ZYDELIG®, GS-1101) is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). We studied idelalisib in 2 registrational trials, one in relapsed chronic lymphocytic leukemia (CLL) and one in refractory, indolent non-Hodgkin lymphoma (iNHL). In the Phase 3 CLL trial (Furman 2014), patients with relapsed disease and multiple co-morbidities precluding the use of chemotherapy were randomized to receive blinded idelalisib 150 mg BID plus rituximab intravenously (at a dose of 375 mg per square meter, followed by 500 mg per square meter every 2 weeks for 4 doses and then every 4 weeks for 3 doses) for a total of 8 infusions or an oral placebo plus rituximab. A total of 220 patients were randomized, with a median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12). Of these, 44% of pts had del17p/TP53 mutation. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). IDELA+R retained robust efficacy across all high-risk subpopulations and achieved 76.5% ORR and PFS HR 0.13 in the highest risk patients who were positive for both 17p deletion and TP53 mutation. The Phase 2 iNHL study (Gopal 2014) enrolled 125 heavily pretreated patients with disease refractory to rituximab and alkylating agents to receive single agent idelalisib 150 mg BID. The median age of the patients was 64 yrs (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). The predominate iNHL subtype was follicular lymphoma (72 patients), followed by small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and Waldenström's macroglobulinemia (10). The overall response rate was 57%. Responses were rapid (median time to a response was 1.9 months) and the median duration of response was 12.5 months. Median progression-free survival was 11 months. Key safety findings across the idelalisib program include an early transient hepatotoxicity characterized by elevations in serum transaminases (≥ Grade 3) occurring in 14% of treated subjects, late onset (≥ Grade 3) severe diarrhea/colitis, also occurring in 14% of subjects, and pneumonitis of any grade, occurring in 3% of subjects. Additional trials of idelalisib in combination with other chemoimmunotherapy are ongoing in both CLL and iNHL, including studies in patients with previously untreated disease. Future development plans include establishing the role of PI3Kδ inhibition in solid tumors and testing the activity of idelalisib against a range of hematologic malignancies. Citation Format: Roger Dansey. Clinical validation of PI3Kδ as a therapeutic target in B-cell malignancy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA18.

Efficient in vivo transfection and safety profile of a CpG-free and codon optimized luciferase plasmid using a cationic lipophosphoramidate in a multiple intravenous administration procedure

As any drug, the success of gene therapy is largely dependent on the vehicle that has to selectively and efficiently deliver therapeutic nucleic acids into targeted cells with minimal side-effects. In the case of chronic diseases that require a life-long treatment, non-viral gene delivery vehicles are less likely to induce an immune response, thereby allowing for repeated administration. Beyond the gene delivery efficiency of a given vector, the nature of nucleic acid constructs also has a central importance in gene therapy protocols.Herein, we investigated the impact of two firefly luciferase encoding plasmids on the transgene expression profile following systemic delivery of lipoplexes in mice, as well as their potential to be safely and efficiently readministered. Whereas pTG11033 plasmid is driven by a strong ubiquitous cytomegalovirus promoter, pGM144 plasmid, which has been designed to avoid inflammation and provide sustained transgene expression in lungs, is CpG-free and is under control of the human elongation factor-1 alpha promoter.Combined to the efficient cationic lipophosphoramidate BSV4, bioluminescence data showed that both plasmids were mostly expressed in the lungs of mice following a primary injection of lipoplexes. However, mice transfected with pGM144 exhibited a higher and more sustained transgene expression than those treated with pTG11033. Repeated administration studies revealed that several injections of lipoplexes could lead to similar transgene expression profiles if an interval of several weeks between subsequent injections was respected. A transient hepatotoxicity and a partial inflammatory response were caused by lipoplex injection, irrespective of the plasmid used.Altogether, these results indicate that repeated systemic administration of lipophosphoramidate-based lipoplexes in mice conducts to an effective lung transfection without serious side effects, and highlight the need to use long-lasting expressing and well tolerated plasmids in order to efficiently renew transgene expression by the successive doses.

70. Safety, Toxicity and Efficacy of Systemic Recombinant VSV Therapy in Pet Dogs With Spontaneous Cancer

Clinical translation of oncolytic therapy to benefit cancer patients is dependent upon extensive evaluation of viral safety, toxicity and therapeutic efficacy in disease bearing animals. Comparative oncology, the study of naturally occurring cancer in animals, allows evaluation of novel cancer therapies in pet dogs that are similar in size, genetic make-up, physiology and exposure to environmental risk factors to humans. We have previously shown single shot systemic therapy with recombinant Vesicular stomatitis virus (VSV) engineered to express Interferon-beta (IFN) and the sodium-iodide symporter (NIS) in tumor bearing mice results in tumor-specific virus replication that can be monitored noninvasively by SPECT/CT imaging using NIS specific radio-tracer, induces tumor remission and confers significant survival benefit. A comparative oncology approach was utilized to investigate safety, clinical toxicities and therapeutic efficacy of systemic VSV therapy in dogs with spontaneous cancer. A pre-clinical rapid dose-escalation study was performed in healthy lab beagles defined a safe systemic dose range. We initiated evaluation of systemic VSV administration in dogs with spontaneous cancer. 8 dogs with various cancers were treated with VSV expressing either human or canine IFN-beta and NIS. We demonstrate that systemic VSV therapy at a dose of 10(10) TCID is well tolerated in dogs with spontaneous disease. We detected transient hepatotoxicity that resolved spontaneously in 2/8 dogs following systemic VSV-IFN-NIS treatment. No infectious virus was detected in urine or buccal swab samples. Monitoring of disease response indicated that 2/2 dogs with T-cell lymphoma had dramatic disease remission following systemic VSV-hIFN-NIS treatment resulting in partial response, though remission was transient and disease eventually relapsed. Virus pharmacokinetics (PK) studies indicate that dogs with robust responses also had highest viral PK in blood, suggesting therapeutic response is PK dependent. A dose optimization protocol was adopted where gradual dose escalation and multi-dosing protocols are being evaluated. Initial findings indicate two-dose systemic VSV-IFN-NIS therapy in a dog with metastatic Osteosarcoma (OSA) is well tolerated, delays viral decay in blood, and has resulted in improved health of the treated dog with no major disease progression to date. RNAseq analysis of tumor biopsies from treated animals reveals changes in tumor gene expression following systemic VSV therapy. Overall the data demonstrate that recombinant VSV can be safely administered systemically in cancer bearing dogs. Our data suggest that therapeutic response is PK dependent, prompting dose optimization studies that will directly inform and support planned clinical studies to evaluate systemic VSV therapy in patients with relapsed or metastatic cancer.

Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen. Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes. The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively. ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.

PRELIMINARY RESULTS OF A PROSPECTIVE FEASIBILITY PILOT STUDY OF "GEMPOX" (GEMCITABINE, OXALIPLATIN, AND PACLITAXEL) IN PEDIATRIC AND ADULT PATIENTS WITH REFRACTORY OR RECURRENT CENTRAL NERVOUS SYSTEM (CNS) GERM CELL TUMORS (GCT): THE INTERNATIONAL CNS GCT CONSORTIUM TRIAL, CNS GCT-4

BACKGROUND: The optimal management of patients with recurrent CNS GCT, especially those with non-germinomatous (mixed malignant) GCT (MMGCT), remains unclear. Preliminary results are presented on the response rate, toxicity and early outcomes of a re-induction regimen of gemcitabine, oxaliplatin and paclitaxel (GEMPOX) administered, in responsive patients, prior to myeloablative chemotherapy and autologous hematopoietic cell rescue (HDCx + AuHCR). METHODS: Since December 2004, 13 recurrent or refractory patients (12 MMGCT, 1 germinoma; 12 males; mean age 16.5 years, range 7-34 years) have been treated with up to 4 cycles of gemcitabine (800 mg/m2), oxaliplatin (100 mg/m2) and paclitaxel (170 mg/m2), administered on one day at 14 days intervals. RESULTS: Of 13 patients, five were treated on a preceding feasibility pilot with 1-3 cycles of GEMPOX, and seven have been formally enrolled on an ongoing prospective multi-center trial. Six patients achieved complete remissions (tumor marker and/or imaging studies), five achieved partial remissions and two developed progressive disease (PD) while on GEMPOX; one patient with PD after 1 cycle had pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma.; the second patient, with pure pineal choriocarcinoma, progressed following the second cycle of GEMPOX. Eleven of the 13 patents subsequently underwent HDCx + AuHCR. Six of them subsequently received irradiation. Transient hepatotoxicity and pancytopenia were the most commonly observed toxicities. Other toxicities included: paclitaxel anaphylaxis (1), transient encephalopathy (1), peripheral neuropathy (1), hyperesthesia (4), mucositis (2) and electrolyte imbalances (3). Four of the 12 patients with MMGCT continue alive and disease-free for 8+ , 10+ , 14+ and 16+ months since discontinuation of all therapy. One patient (with pure yolk sac tumor) relapsed in a loco-regional extra-CNS location (cavernous and ethmoid/sphenoid sinuses) and remains alive with progressive disease on therapy now 12+ months post-HDCx + AuHCR. CONCLUSIONS: GEMPOX appears to be an effective re-induction regimen for patients with recurrent CNS MMGCT, with acceptable toxicities. The ongoing multi-center, international trial should confirm this and demonstrate the contribution of GEMPOX towards improved survival when followed by HDCx + AuHCR with or without further irradiation, in the setting of minimal residual disease. SECONDARY CATEGORY: Pediatrics.