Oral Toxicities Associated with Immune Checkpoint Inhibitors: Meta-Analyses of Clinical Trials

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment; however, their oral toxicity profile is not well elucidated. This review aimed to investigate the prevalence of oral toxicities including xerostomia, mucositis/stomatitis, dysgeusia, dysphagia, oral/oropharyngeal pain, oral infections, angular cheilitis, osteonecrosis, osteomyelitis, and oral mucosal reactions with ICIs. A review protocol was registered with PROSPERO (ID: CRD42023391674). A systematic search of ClinicalTrials.gov was conducted as of April 10, 2022. Studies were selected, assessed, and data extracted using PRISMA guidelines. Oral toxicity data were extracted from study arms using a single immunotherapy drug. Meta-analyses were conducted to summarize prevalence of oral toxicities using random-effects models. Of 750 screened records, 95 trials were included in the meta-analysis with published results. Time between study completion and first publication on ClinicalTrials.gov was 1 to 146 months (mean = 20.3, SD = 18.4). Weighted pooled prevalence was 5% (95% CI: 4-6%) for xerostomia, 3% (95% CI: 3-4%) for mucositis/stomatitis, 3% (95% CI: 2-3%) for dysgeusia, 2% (95% CI: 1-2%) for dysphagia, 3% (95% CI: 2-4%) for oropharyngeal/oral pain, 2% (95% CI: 1-3%) for oral candidiasis, and 2% (95% CI: 0-4%) for angular cheilitis. Subgroup differences based on ICI drugs were minimal. No trials reported lichenoid or pemphigoid mucosal reactions. Meta-analysis results revealed low prevalence of oral toxicities with ICIs; however, data reporting was limited and inconsistent. Limitations of study dataset reveal a significant need for systematic collection of oral morbidity data as well as improved consistency and compliance of reporting results on ClinicalTrials.gov

Altered T-cell subset repertoire affects treatment outcome of patients with myelofibrosis

Phenotypic characterization of T cells in myelofibrosis (MF) is intriguing owing to increased inflammation, markedly elevated pro-inflammatory cytokines, and altered distribution of T-cell subsets. Constitutive activation of Janus kinase-2 (JAK2) in the majority of MF patients contributes to the expression of the programmed cell death protein-1 (PD1) and T-cell exhaustion. We wondered whether T-cell activation affects treatment outcome of patients with MF and sought to determine whether the JAK1/2 inhibitor ruxolitinib affects the activation of T-cell subsets. T cells from 47 MF patients were analyzed and the percent of either helper (CD4+) or cytotoxic (CD8+) naive, central memory, effector memory, or effector T cells; and fractions of PD1-expressing cells in each subset were assessed. An increased number of T cells coexpressing CD4/PD1 and CD8/PD1 in MF compared to healthy controls (n=28) was found, and the T cells were significantly skewed toward an effector phenotype in both CD4+ and CD8+ subsets, consistent with a shift from a quiescent to an activated state. Over the course of ruxolitinib treatment, the distribution of aberrant T-cell subsets significantly reversed towards resting cell phenotypes. CD4+ and CD8+ subsets at baseline correlated with monocyte and platelet counts, and their PD1-positive fractions correlated with leukocyte counts and spleen size. Low numbers of PD1+/CD4+ and PD1+/CD8+ cells were associated with complete resolution of palpable splenomegaly and improved survival rate, suggesting that low levels of exhausted T cells confer a favorable response to ruxolitinib treatment

The performance of human papillomavirus high-risk DNA testing in the screening and diagnostic settings.

OBJECTIVE: We sought to evaluate the performance of the human papillomavirus high-risk DNA test in patients 30 years and older. MATERIALS AND METHODS: Screening (n=835) and diagnosis (n=518) groups were defined based on prior Papanicolaou smear results as part of a clinical trial for cervical cancer detection. We compared the Hybrid Capture II (HCII) test result with the worst histologic report. We used cervical intraepithelial neoplasia (CIN) 2/3 or worse as the reference of disease. We calculated sensitivities, specificities, positive and negative likelihood ratios (LR+ and LR-), receiver operating characteristic (ROC) curves, and areas under the ROC curves for the HCII test. We also considered alternative strategies, including Papanicolaou smear, a combination of Papanicolaou smear and the HCII test, a sequence of Papanicolaou smear followed by the HCII test, and a sequence of the HCII test followed by Papanicolaou smear. RESULTS: For the screening group, the sensitivity was 0.69 and the specificity was 0.93; the area under the ROC curve was 0.81. The LR+ and LR- were 10.24 and 0.34, respectively. For the diagnosis group, the sensitivity was 0.88 and the specificity was 0.78; the area under the ROC curve was 0.83. The LR+ and LR- were 4.06 and 0.14, respectively. Sequential testing showed little or no improvement over the combination testing. CONCLUSIONS: The HCII test in the screening group had a greater LR+ for the detection of CIN 2/3 or worse. HCII testing may be an additional screening tool for cervical cancer in women 30 years and older

Impact of Type of Induction Therapy on Outcomes in Older Adults With AML After Allogeneic Stem Cell Transplantation

Although venetoclax-based lower-intensity regimens have greatly improved outcomes for older adults with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy, the optimal induction for older patients with newly diagnosed AML who are suitable candidates for hematopoietic stem cell transplant (HSCT) is controversial. We retrospectively analyzed the post HSCT outcomes of 127 patients ≥60 years of age who received induction therapy at our institution with intensive chemotherapy (IC; n = 44), lower-intensity therapy (LIT) without venetoclax (n = 29), or LIT with venetoclax (n = 54) and who underwent allogeneic HSCT in the first remission. The 2-year relapse-free survival (RFS) was 60% with LIT with venetoclax vs 54% with IC, and 41% with LIT without venetoclax; the 2-year overall survival (OS) was 72% LIT with venetoclax vs 58% with IC, and 41% with LIT without venetoclax. The benefit of LIT with venetoclax induction was greatest in patients with adverse-risk AML (2-year OS: 74%, 46%, and 29%, respectively). Induction with LIT, with or without venetoclax, was associated with the lowest rate of nonrelapse mortality (NRM) (2-year NRM: 17% vs 27% with IC; P = .04). Using multivariate analysis, the type of induction therapy did not significantly affect any of the post HSCT outcomes evaluated; hematopoietic cell transplantation-specific comorbidity index was the only factor that independently predicted RFS and OS. LIT plus venetoclax followed by HSCT is a feasible treatment strategy in older, fit, HSCT-eligible patients with newly diagnosed AML and may be particularly beneficial for those with adverse-risk disease

Challenges and Opportunities Associated With the MD Anderson IMPACT2 Randomized Study in Precision Oncology

We investigated the challenges of conducting IMPACT2, an ongoing randomized study that evaluates molecular testing and targeted therapy (ClinicalTrials.gov: NCT02152254). Patients with metastatic cancer underwent tumor profiling and were randomized between the two arms when eligibility criteria were met (Part A). In Part B, patients who declined randomization could choose the study arm. In Part A, 69 (21.8%) of 317 patients were randomized; 78.2% were not randomized because of non-targetable alterations (39.8%), unavailability of clinical trial (21.8%), other reasons (12.6%), or availability of US Food and Drug Administration (FDA)-approved drugs for the indication (4.1%). In Part B, 32 (20.4%) of 157 patients were offered randomization; 16 accepted and 16 selected their treatment arm; 79.0% were not randomized (patient\u27s/physician\u27s choice, 29.3%; treatment selection prior to genomic reports, 16.6%; worsening performance status/death, 12.7%; unavailability of clinical trials, 6.4%; other, 6.4%; non-targetable alterations, 5.7%; or availability of FDA-approved drugs for the indication, 1.9%). In conclusion, although randomized controlled trials have been considered the gold standard for drug development, the execution of randomized trials in precision oncology in the advanced metastatic setting is complicated. We encountered various challenges conducting the IMPACT2 study, a large precision oncology trial in patients with diverse solid tumor types. The adaptive design of IMPACT2 enables patient randomization despite the continual FDA approval of targeted therapies, the evolving tumor biomarker landscape, and the plethora of investigational drugs. Outcomes for randomized patients are awaited