ABSTRACT
Background: Nucleoside analog (NAs) drugs are used for the treatment of a variety of diseases, such as cancers and viral infections. After phosphorylation of viral and host kinases, NA drugs compete with the corresponding naturally occurring nucleotide during DNA replication of the infected cell. After incorporation, they can lead to mutations, or chain termination. However, because of their mechanism of action, NA are also potentially mutagenic to the genome of physiologically normal cells. Indeed, we have shown that treatment with the antiviral NA ganciclovir (GCV) after stem cell transplantation induces an increased mutation burden in the hematopoietic stem and progenitor cells (HSPCs) of pediatric leukemia patients. Using mutational signature analysis, we provided evidence that GCV-induced mutagenesis contributes to development of relapses and second malignancies in pediatric patients by inducing driver mutations. Over 30 NA drugs have been approved for clinical use and millions of people receive antiviral treatment worldwide to treat viral infections, including COVID-19. However, the mutagenicity in normal cells and potential carcinogenicity is unclear. Aims: Here, we aimed to systematically assess the mutational consequences of antiviral NAs in human HSPCs and identify underlying mechanisms. Methods: By combining in vitro treatment of umbilical cord blood-derived HSPCs with whole-genome sequencing (WGS) analyses, we provide a compendium of mutational consequences of antiviral NAs in a relevant human tissue (i.e., toxicity to the hematopoietic system is often dose-limiting). We treated HSPCs with IC40-60 concentration of the assessed compound followed by clonal expansions to obtain sufficient DNA for WGS. Using established bioinformatic pipelines, we catalogued the somatic mutations and mutational signatures in these cells. Results: At time of writing, 5 out of 7 tested antiviral NAs induce an enhanced mutation burden in exposed HSPCs. For some of this antiviral NAs we were able to identify unique unreported mutational signatures. Of note, the thymidine analog brivudine showed the highest increase in single base substitutions, which were characterized by a T>C signature, depleted for flanking cytosines. Furthermore, like GCV, we also observed a signature characterized by C>ApA substitution after treatment with the penciclovir, a molecule nearly identical to GCV. Currently we are working on machine learning approach to identify relevant mutation characteristics and modes of action as well as to screen cancer genome databases for mutational signature occurrence. Summary/Conclusion: Many compounds of the NA class currently prescribed for the treatment of viral infections are mutagenic to healthy cells. This calls for more thorough screening of these drugs, incorporation of information on mutagenicity to healthy cells in drug safety guidelines and patient surveillance over time.
ABSTRACT
Background: Vaso-occlusive crises (VOC) are the most common acute complication of sickle cell disease (SCD). Crizanlizumab, an anti-P-selectin monoclonal antibody, is an FDA-approved disease-modifying therapy (DMT) for SCD patients (pts) aged ≥16 yrs to reduce the frequency of VOC. To better understand its use and impact, the National Alliance for Sickle Cell Centers (NASCC) conducted a retrospective study of pts prescribed crizanlizumab from 11/2019-6/30/2021. NASCC is a non-profit organization formed to support SCD centers in delivering quality comprehensive care by setting and adopting specific standards and advocating for improved health outcomes in SCD. This study describes the largest real-world cohort of pts treated with crizanlizumab. Methods: This is a two-part study. Part 1 was to evaluate NASCC center crizanlizumab practice and to summarize data on insurance approval and the frequency of drug discontinuation. Part 2 includes pt level data to evaluate reasons for discontinuation and acute care utilization pre and post therapy. Acute care use includes day hospital/infusion, emergency department visits, and hospitalizations for VOC (excluding COVID-19). The index date for each pt is defined as the 1st crizanlizumab infusion date. Chart review (electronic health records) was used to identify all acute care visits 12 months pre-index and ≤12 months post index. Acute care data will be analyzed in aggregate. Evaluation of center-specific use of crizanlizumab, time to initial site level formulary approval and drug discontinuation were analyzed. Pt level data collection is ongoing to include sufficient time post index date. VOC characteristics will be summarized using medians, median differences (pre/post treatment), and 95% confidence intervals. Additional evaluation of effectiveness of crizanlizumab will include analysis based on number of doses received, pre-treatment VOC burden, concomitant hydroxyurea (HU) use and genotype. Results: Data includes pts prescribed crizanlizumab at 11 NASCC centers. Site- formulary approvals to use crizanlizumab varied from 12/2019-12/2020. As a result, the 1st pt to receive treatment at each site varied from 1/15/2020-1/20/2021. Mean time from site-level approval to first infusion was 77 days (range: 0-394). Over 50% of sites received insurance denials mainly due to “insufficient medical necessity” or “medication not covered by the prescription plan.” Sites were able to successfully appeal denials for 71% of pts (Table 1). Treatment Delivery: Each site gives infusions over 30 minutes and the majority (64%) do not use pre-medication unless pts had reactions. Some sites use diphenhydramine/acetaminophen (3) or normal saline and ketorolac (1). All sites prescribe crizanlizumab to pts of all SCD genotypes. Pts Treated: 297 pts were prescribed crizanlizumab of whom 238 received ≥ 1 infusion. There was variation in number of pts/site (range 6-73, mean 21) due to time to site-level approval, insurance and pt population. Of these 238, 75 pts (32%) discontinued treatment (0-17 pts/site). Sites reported pts perceived lack of improvement or feeling their overall pain was increased, transportation issues and infusion related reactions (IRRs) characterized by pain as some of the reasons for discontinuation. Evaluation of real-world efficacy measured by changes in acute care utilization, including sub-analysis by genotype, pre-treatment VOC burden and concomitant HU use, are pending sample size dependent feasibility. Discussion: This is the first multi-center real-world analysis of crizanlizumab. Findings demonstrate some insurance barriers to therapy. The majority of pts who initiated crizanlizumab have remained on therapy;however, 1/3 of pts had lack of effect or barriers to care. Pt level data will include characteristics related to treatment failure or IRR. Improving the understanding of phenotype-specific response to novel therapies is essential in SCD. Conclusion: Post-approval therapies for rare diseases must undergo real-world evaluation to ensure study results transla e to the community. NASCC uses defined criteria for multidisciplinary care for Alliance inclusion and findings reflect the use of DMT in such centers. This is the first NASCC study of DMT in SCD. Part 2 of the study will give early insights into the effectiveness of crizanlizumab;long term follow-up is needed for a full understanding of its utility in SCD. [Formula presented] Disclosures: Kanter: Fulcrum Therapeutics, Inc.: Consultancy;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees;Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees;Graphite Bio: Consultancy;GuidePoint Global: Honoraria;Fulcrum Tx: Consultancy. Manwani: Novartis: Consultancy. Idowu: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding;Pfizer: Research Funding;Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Forma Therapeutics, Inc.: Research Funding;Ironwood: Research Funding. Treadwell: National Alliance of Sickle Cell Centers: Other: Early Evaluation of the Use of Crizanlizumab in Sickle Cell Disease. Clay: GBT: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria. Little: Hemex Health, Inc.: Patents & Royalties;Biochip Labs: Patents & Royalties. Desai: Global Blood Therapeutics: Honoraria, Research Funding;Novartis: Research Funding, Speakers Bureau;Pfizer: Other: Publication Fee, Research Funding;Forma: Consultancy;Foundation for Sickle Cell Research: Honoraria. Lanzkron: Shire: Research Funding;Pfizer: Current holder of individual stocks in a privately-held company;Bluebird Bio: Consultancy;Teva: Current holder of individual stocks in a privately-held company;Novo Nordisk: Consultancy;GBT: Research Funding;Imara: Research Funding;CSL Behring: Research Funding;Novartis: Research Funding.
ABSTRACT
Background: In Louisiana, deaths related to COVID-19 have disproportionately occurred in Black persons. Granular data are needed to better understand inequities and develop prevention strategies to mitigate further impact on Black communities. Methods: We conducted a retrospective cohort study of patients admitted to an urban safety net hospital in New Orleans, LA with reactive SARS-CoV-2 testing from March 9-31, 2020. Clinical characteristics and outcomes of Black and other racial/ethnic group patients were compared using Wilcoxon rank-sum test and Fisher's exact tests. We examined Day-14 status using an ordinal scale to assess race and outcome. Results: This study included 249 patients. Median age was 59, 44% were male, 86% were age ≥65 years or had ≥1 comorbidity. Overall, 87% were Black, relative to 55% Black patients typically hospitalized at our center. Black patients had longer symptom duration at presentation (6.41 versus 5.88 days, p=0.05), and were more likely to have asthma (p=0.008), but less likely to have dementia (p=0.002). There were no racial differences in initial respiratory status or laboratory values other than higher initial LDH in Black patients. Patient age and initial oxygen requirement, but not race (adjusted proportional odds ratio = 0.92, 95%CI: 0.70-1.20), were associated with worse Day-14 outcomes. Conclusion: Our results demonstrate minor racial differences in comorbidities or disease severity at presentation, and Day-14 outcomes were not different between groups. However, Black patients were disproportionately represented in hospitalizations, suggesting that prevention efforts should include strategies to limit SARS-CoV-2 exposures in Black communities as one step towards reducing racial inequities related to COVID-19. (Table Presented).