CD22 CAR T-cell associated hematologic toxicities, endothelial activation and relationship to neurotoxicity.

BACKGROUND: Hematologic toxicities, including coagulopathy, endothelial activation, and cytopenias, with CD19-targeted chimeric antigen receptor (CAR) T-cell therapies correlate with cytokine release syndrome (CRS) and neurotoxicity severity, but little is known about the extended toxicity profiles of CAR T-cells targeting alternative antigens. This report characterizes hematologic toxicities seen following CD22 CAR T-cells and their relationship to CRS and neurotoxicity. METHODS: We retrospectively characterized hematologic toxicities associated with CRS seen on a phase 1 study of anti-CD22 CAR T-cells for children and young adults with relapsed/refractory CD22+ hematologic malignancies. Additional analyses included correlation of hematologic toxicities with neurotoxicity and exploring effects of hemophagocytic lymphohistiocytosis-like toxicities (HLH) on bone marrow recovery and cytopenias. Coagulopathy was defined as evidence of bleeding or abnormal coagulation parameters. Hematologic toxicities were graded by Common Terminology Criteria for Adverse Events V.4.0. RESULTS: Across 53 patients receiving CD22 CAR T-cells who experienced CRS, 43 (81.1%) patients achieved complete remission. Eighteen (34.0%) patients experienced coagulopathy, of whom 16 had clinical manifestations of mild bleeding (typically mucosal bleeding) which generally subsided following CRS resolution. Three had manifestations of thrombotic microangiopathy. Patients with coagulopathy had higher peak ferritin, D-dimer, prothrombin time, international normalized ratio (INR), lactate dehydrogenase (LDH), tissue factor, prothrombin fragment F1+2 and soluble vascular cell adhesion molecule-1 (s-VCAM-1). Despite a relatively higher incidence of HLH-like toxicities and endothelial activation, overall neurotoxicity was generally less severe than reported with CD19 CAR T-cells, prompting additional analysis to explore CD22 expression in the central nervous system (CNS). Single-cell analysis revealed that in contrast to CD19 expression, CD22 is not on oligodendrocyte precursor cells or on neurovascular cells but is seen on mature oligodendrocytes. Lastly, among those attaining CR, grade 3-4 neutropenia and thrombocytopenia were seen in 65% of patients at D28. CONCLUSION: With rising incidence of CD19 negative relapse, CD22 CAR T-cells are increasingly important for the treatment of B-cell malignancies. In characterizing hematologic toxicities on CD22 CAR T-cells, we demonstrate that despite endothelial activation, coagulopathy, and cytopenias, neurotoxicity was relatively mild and that CD22 and CD19 expression in the CNS differed, providing one potential hypothesis for divergent neurotoxicity profiles. Systematic characterization of on-target off-tumor toxicities of novel CAR T-cell constructs will be vital as new antigens are targeted. TRIAL REGISTRATION NUMBER: NCT02315612.

A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies.

BACKGROUND: Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. MATERIALS AND METHODS: This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. RESULTS: Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11 years (range 3-21 years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). CONCLUSION: Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. IMPLICATIONS FOR PRACTICE: Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.

Impact of Patient-Directed Cytology Results Correspondence Program on Follow-Up of High-Grade Pap Tests.

OBJECTIVE: Proper follow-up of high-grade (HG) Pap tests is critical to the prevention of cervical cancer. This study evaluated the impact of a patient-directed cytology results correspondence program on follow-up of HG Pap tests among at-risk women aged 21 to 69 in Ontario. METHODS: A cohort study with a historical control was used to investigate the impact of a result letter on adherence to follow-up after an HG Pap test. Analyses were conducted on an intention-to-treat basis. The intervention group was defined as women with an HG Pap test in 2014-2016, and the control group included women with an HG Pap test in 2010-2012. Follow-up was defined as a colposcopy or related treatments within 6 months of an HG Pap test. Factors that could influence adherence to follow-up were included as covariates in a multivariable logistic regression model (Canadian Task Force Classification II-2). RESULTS: The study population comprised 7088 women in the intervention group and 6887 women in the non-intervention group. The follow-up rate in the intervention group was 86.2% compared with 81.0% in the non-intervention group. Controlling for covariates, women in the intervention group were more likely to have a follow-up (adjusted odds ratio 1.5; 95% confidence interval 1.3-1.6). Other significant factors included being registered to a family physician and the physician's gender. CONCLUSIONS: A patient-directed correspondence program that provides Pap test results directly to the woman may reduce loss to follow-up for an HG abnormality, with an increased likelihood that these women will seek and complete a colposcopy and related treatment.

Systematic Evaluation of Neurotoxicity in Children and Young Adults Undergoing CD22 Chimeric Antigen Receptor T-Cell Therapy.

Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.

Women's Behaviors Toward Mammogram and Pap Test: Opportunities to Increase Cervical Cancer Screening Participation Rates among Older Women.

OBJECTIVES: Screening rates for cervical cancer remain moderate among women over 50 years of age. Because cervical and breast screening interventions can be linked, evaluating screening factors relating to both is important. This study evaluates factors associated with breast and cervical screening participation in women aged 52 to 69. METHODS: A cross-sectional study was used to describe characteristics associated with screening behaviors of 1,173,456 eligible women in Ontario, Canada. Overdue for screening was defined as more than 2.5 years from last mammogram or more than 3.5 years from last Pap test. Factors that might influence uptake of mammogram or Pap test were included as covariates in a multivariable multinomial logistic regression model. RESULTS: Overall, 52.4% of eligible women were up-to-date for both, 21.3% were overdue for both, 14.4% were overdue for Pap test but were up-to-date with mammogram, and 11.9% were overdue for mammogram but were up-to-date with Pap test. There was an opposite effect of age on likelihood of being overdue for Pap test only versus mammogram only. Women aged 67 to 69 compared with those 52 to 54 were more likely to be overdue for Pap test only (adjusted odds ratio, 2.3; 95% confidence interval, 2.3-2.4) and less likely to be overdue for mammogram only (adjusted odds ratio, 0.5; 95% confidence interval, 0.5-0.6). A greater proportion of women rostered to a female physician versus a male physician were up-to-date for both (63.7% vs. 51.5%). CONCLUSIONS: Comparing screening patterns may provide physician- and patient-directed strategies to increase cervical screening participation by recruiting women who are overdue for Pap test but undergoing breast cancer screening.

Strategic analytics: towards fully embedding evidence in healthcare decision-making.

Cancer Care Ontario (CCO) has implemented multiple information technology solutions and collected health-system data to support its programs. There is now an opportunity to leverage these data and perform advanced end-to-end analytics that inform decisions around improving health-system performance. In 2014, CCO engaged in an extensive assessment of its current data capacity and capability, with the intent to drive increased use of data for evidence-based decision-making. The breadth and volume of data at CCO uniquely places the organization to contribute to not only system-wide operational reporting, but more advanced modelling of current and future state system management and planning. In 2012, CCO established a strategic analytics practice to assist the agency's programs contextualize and inform key business decisions and to provide support through innovative predictive analytics solutions. This paper describes the organizational structure, services and supporting operations that have enabled progress to date, and discusses the next steps towards the vision of embedding evidence fully into healthcare decision-making.