Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition

Background Compared to conventional chemotherapy, Immune checkpoint inhibitors (ICI) are known to have a distinct toxicity profile commonly identified as immune-related adverse events (irAEs). These irAEs that are believed to be related to immune dysregulations triggered by ICI can be serious and lead to treatment interruptions and in severe cases, precipitate permanent discontinuation. Isolated neutropenia secondary to ICI has been rarely documented in the literature and needs further description. We report a case of pembrolizumab related severe isolated neutropenia in a patient with metastatic non-small cell lung cancer. We were also able to obtain serial blood and plasma-based biomarkers for this patient during treatment and during neutropenia to understand trends that may correlate with the irAE. In addition we summarize important findings from other studies reporting on ICI related neutropenia. Case presentation A 74 years old Caucasian male treated with single-agent pembrolizumab for metastatic non-small cell lung cancer presented with fevers, chills, and an isolated neutrophil count (ANC) of 0 2 weeks after the fourth dose. In addition to antibiotics, due to the strong suspicion of this neutropenia being immune-mediated, he was started on 1 mg/kg of steroids and also received filgrastim to accelerate neutrophil recovery. Serial trends in C-reactive protein and certain other inflammatory cytokines demonstrated a corresponding rise at the time of neutropenia. Post recovery, his pembrolizumab was kept on hold. Eight weeks later he had a second episode of neutropenia which was again managed similar to the first episode. Despite permanent discontinuation of ICI after the first neutropenia, his disease showed an ongoing complete metabolic response on imaging. Our literature review reveals that hematological toxicities constitute < 1% irAEs with isolated neutropenia roughly accounting for one-fourth of the hematological irAEs. Based on the handful of ICI related neutropenia cases reported to date, we identified nivolumab to be the most common offender. The median number of ICI cycles administered before presenting with neutropenia was three, and the median time to recovery was approximately two weeks. All of these neutropenic episodes were ≥ grade 3 and led to permanent ICI discontinuation. Using immunosuppressive therapies in conjunction with granulocyte-colony stimulating factor was the most common strategy described to have favorable results. Conclusion Neutropenia as an isolated irAE secondary to ICI is rare but represents a severe toxicity that needs early recognition and can often result in treatment discontinuations. Careful monitoring of these patients with the prompt initiation of immunosuppressive and supportive measures to promote rapid recovery as well as prevent and treat infectious complications should be part of the management algorithms. Serial monitoring of blood and plasma-based biomarkers from more extensive studies may help in identifying patients at risk for irAEs and thus guide patient selection for ICI

Peptide and Peptide-Like Modulators of 20S Proteasome Enzymatic Activity in Cancer Cells

The involvement of the ubiquitin–proteasome pathway in the degradation of critical intracellular regulatory proteins suggested a few years ago the potential use of proteasome inhibitors as novel therapeutic agents being applicable in many different disease indications, and in particular for cancer therapy. This article reviews recent salient medicinal chemistry achievements in the design, synthesis, and biological characterization of both synthetic and natural peptide-like proteasome inhibitors, updating recent reviews on this class of agents. As shown herein, different compound classes are capable of modulating the subunit-specific proteolytic activities of the 20S proteasome in ways not previously possible, and one of them, bortezomib, has provided proof-of-concept for this therapeutic approach in cancer clinical settings

Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking

The potential of the diverse chemistries present in natural products (NP) for biotechnology and medicine remains untapped because NP databases are not searchable with raw data and the NP community has no way to share data other than in published papers. Although mass spectrometry techniques are well-suited to high-throughput characterization of natural products, there is a pressing need for an infrastructure to enable sharing and curation of data. We present Global Natural Products Social molecular networking (GNPS, http://gnps.ucsd.edu), an open-access knowledge base for community wide organization and sharing of raw, processed or identified tandem mass (MS/MS) spectrometry data. In GNPS crowdsourced curation of freely available community-wide reference MS libraries will underpin improved annotations. Data-driven social-networking should facilitate identification of spectra and foster collaborations. We also introduce the concept of ‘living data’ through continuous reanalysis of deposited data

Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors among Patients Aged 80 Years or Older with Cancer: A Multicenter International Cohort Study

Importance: Geriatric (aged 6580 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. Objective: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged 6580 years) with cancer. Design, Setting, and Participants: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. Main Outcomes and Measures: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. Results: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged &lt;85 vs 6585 years). Among all 928 patients, 383 (41.3%) experienced 651 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P =.008). Conclusions and Relevance: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age