Characterization of Mycophenolate Mofetil Gastrointestinal Toxicity and Risk Factors for Severe Disease and Poor Prognosis

Lay Summary Authors performed a chart review to identify cases of mycophenolate mofetil gastrointestinal toxicity at our institution. In this cohort, friability was associated with severe disease; and nausea and erythema were associated with poor prognosis.

Discontinuation Due to Toxicity Limits Treatment Duration of BTK Inhibitors in Non-Hodgkin Lymphoma

Background: Although clinical trial data exist describing the adverse effects of Bruton's tyrosine kinase inhibitors (BTKi)s, the patient experience outside clinical trials, including differences among agents is less well-described. We evaluated the selection criteria, efficacy and toxicities related to the use of BTKi at our site. Methods: A retrospective patient chart review was used to collect data from patients treated with one or more BTKi. Demographics, prior therapies, duration of treatment, response to treatment, and incidence and severity of pre-determined toxicities of interest were collected for each patient. Descriptive statistics for each variable were reported. Association between variables of interest and the study cohort were examined using ANOVA for categorical variables and Pearson correlation coefficient for continuous variables. Survival and duration of treatment were estimated using the Kaplan-Meier method according to first novel agent. Survival analysis for each novel agent was conducted using Cox proportional hazards models and log-rank tests. Results: One hundred forty patients were included in this study, including 94 patients with CLL, 24 with MCL, and 22 with other NHL subtypes. One hundred thirteen patients received ibrutinib, while 17 patients received acalabrutinib (n=16) or zanubrutinib (n=1), which were combined in the statistical analysis. Of patients receiving ibrutinib, 69% reported at least one toxicity event during the duration of their treatment. Across all patients who received ibrutinib, 35 individuals did not report a toxicity, 48 individuals reported one toxicity, and 30 individuals reported two or more toxicities. Among the 78 patients who experienced at least one toxicity, 41 (52.5%) discontinued the medication due to these adverse effects, most commonly cytopenias (n=9), diarrhea (n=8), and fatigue (n=9). 57% of patients who reported diarrhea, 36% of patients who reported cytopenias, and 33% of patients who reported fatigue discontinued therapy due to that reported AE. In total, 60/113 patients receiving ibrutinib discontinued therapy, including 40 (66%) due to toxicity and 14 (23.3%) due to disease progression. The remaining patients discontinued therapy due to voluntary choice of new therapy or due to personal decision to stop treatment. Patients remained on ibrutinib therapy for a median duration of 40 months. 53% of patients taking zanabrutinib or acalabrutinib reported at least 1 toxicity, but only 11.7% of patients discontinued therapy for any reason. All patients who discontinued zanubrutinib/acalabrutinib therapy did so due to toxicity, with no patients ceasing therapy due to disease progression. Because only 2 of 17 patients discontinued zanubrutinib/acalabrutinib treatment, a raw median duration of treatment was calculated to be 5 months. 12.4% of patients taking ibrutinib experienced a gastrointestinal toxicity, whereas 5.9% of patients taking acalabrutinib/zanubrutinib experienced a gastrointestinal toxicity (Table 1). Additionally, 8% of individuals taking ibrutinib reported a musculoskeletal toxicity, while no acalabrutinib/zanubrutinib patients reported a musculoskeletal toxicity. There were no statistically significant differences in frequency of toxicities encountered, possibly due to study size. Other toxicities common to all analyzed BTK inhibitors included hematological, cardiovascular, and constitutional adverse effects with no significant difference between agents. Conclusions: We identified that >1/3 of individuals taking BTK inhibitors are stopping therapy prematurely due to toxicity related outcomes rather than due to disease progression. Our findings suggest that proactive identification and management of adverse effects could prolong therapy duration and provide better outcomes for patients. Strategies to personalize therapy selection to limit therapy discontinuation due to toxicity are needed as additional targeted agents are developed. Figure 1 Figure 1. Disclosures Valla: BeiGene: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

Gastrointestinal and genitourinary toxicity profiles of metformin versus placebo in men with prostate cancer receiving prostate radiotherapy: interim toxicity results of a double-blinded, multicenter, phase II randomized controlled trial

Androgen deprivation therapy (ADT) used for prostate cancer (PCa) management is associated with metabolic and anthropometric toxicity. Metformin given concurrent to ADT is hypothesized to counteract these changes. This planned interim analysis reports the gastrointestinal and genitourinary toxicity profiles of PCa patients receiving ADT and prostate/pelvic radiotherapy plus metformin versus placebo as part of a phase 2 randomized controlled trial. Men with intermediate or high-risk PCa were randomized 1:1 to metformin versus placebo. Both groups were given ADT for 18–36 months with minimum 2-month neoadjuvant phase prior to radiotherapy. Acute gastrointestinal and genitourinary toxicities were quantified using CTCAE v4.0. Differences in ≥ grade 2 toxicities by treatment were assessed by chi-squared test. 83 patients were enrolled with 44 patients randomized to placebo and 39 randomized to metformin. There were no significant differences at any time point in ≥ grade 2 gastrointestinal toxicities or overall gastrointestinal toxicity. Overall ≥ grade 2 gastrointestinal toxicity was low prior to radiotherapy (7.9% (placebo) vs. 3.1% (metformin), p = 0.39) and at the end of radiotherapy (2.8% (placebo) vs 3.1% (metformin), p = 0.64). There were no differences in overall ≥ grade 2 genitourinary toxicity between treatment arms (19.0% (placebo) vs. 9.4% (metformin), p = 0.30). Metformin added to radiotherapy and ADT did not increase rates of ≥ grade 2 gastrointestinal or genitourinary toxicity and is generally safe and well-tolerated.

Bullet for periodontal disease in future: Chemically modified tetracyclines

Chronic periodontitis is nowadays popularly regarded as Dysbiosis, [1] which causes destruction of tissues rich in collagen like periodontal ligament, alveolar bone and gingival connective tissue. The oral biofilm comprises many periodontal pathogens better regarded as ‘triggers’ in causing chronic periodontitis. Since, not everyone will be affected in the same manner due to periodontal pathogens. Some might not elicit a host response while, the others might have exaggerated response. So, host modulation therapy came into existence to counteract the exaggerated host response. The chemically modified tetracyclines (CMTs) have emerged to inhibit the inflammatory response or to reduce the collagenolytic activity of host. Though a derivative of tetracyclines, it still lacks an antimicrobial action and hence, can be used for periodontitis for longer duration with no adverse effects of gastrointestinal toxicity which parent tetracyclines have.

Microbiota-Host-Irinotecan Axis: A New Insight Toward Irinotecan Chemotherapy

Irinotecan (CPT11) and its active metabolite ethyl-10-hydroxy-camptothecin (SN38) are broad-spectrum cytotoxic anticancer agents. Both cause cell death in rapidly dividing cells (e.g., cancer cells, epithelial cells, hematopoietic cells) and commensal bacteria. Therefore, CPT11 can induce a series of toxic side-effects, of which the most conspicuous is gastrointestinal toxicity (nausea, vomiting, diarrhea). Studies have shown that the gut microbiota modulates the host response to chemotherapeutic drugs. Targeting the gut microbiota influences the efficacy and toxicity of CPT11 chemotherapy through three key mechanisms: microbial ecocline, catalysis of microbial enzymes, and immunoregulation. This review summarizes and explores how the gut microbiota participates in CPT11 metabolism and mediates host immune dynamics to affect the toxicity and efficacy of CPT11 chemotherapy, thus introducing a new concept that is called “microbiota-host-irinotecan axis”. Also, we emphasize the utilization of bacterial β-glucuronidase-specific inhibitor, dietary interventions, probiotics and strain-engineered interventions as emergent microbiota-targeting strategies for the purpose of improving CPT11 chemotherapy efficiency and alleviating toxicity.