Jenny Firkins

What Does the Boxed Warning Tell Us? Safe Practice of Using Ferumoxytol as an MRI Contrast Agent

BACKGROUND AND PURPOSE: Despite the label change and the FDAs boxed warning added to the Feraheme (ferumoxytol) label in March 2015, radiologists have shown increasing interest in using ferumoxytol as an MR imaging contrast agent as a supplement or alternative to gadolinium. The goals of this study were to provide information regarding ferumoxytol safety as an imaging agent in a single center and to assess how the Feraheme label change may affect this potential, currently off-label indication. MATERIALS AND METHODS: This retrospective study evaluated the overall frequency of ferumoxytol-related adverse events when used for CNS MR imaging. Patients with various CNS pathologies were enrolled in institutional review board–approved imaging studies. Ferumoxytol was administered as multiple rapid bolus injections. The risk of adverse events was correlated with demographic data/medical history. RESULTS: The safety of 671 ferumoxytol-enhanced MR studies in 331 patients was analyzed. No anaphylactic, life-threatening, or fatal (grade 4 or 5) adverse events were recorded. The overall proportion of ferumoxytol-related grade 1–3 adverse events was 10.6% (8.6% occurring within 48 hours), including hypertension (2.38%), nausea (1.64%), diarrhea (1.04%), and headache (1.04%). History of 1 or 2 allergies was associated with an increased risk of adverse events (14.61% versus 7.51% [no history]; P = .007). CONCLUSIONS: The frequency of mild ferumoxytol-related adverse events was comparable with literature results, and no serious adverse event was recorded. Although the recommendations in the boxed warning should be followed, serious adverse events appear to be rare, and with proper precautions, ferumoxytol may be a valuable MR imaging agent.

Quantitative comparison of delayed ferumoxytol T1 enhancement with immediate gadoteridol enhancement in high grade gliomas

Delayed ferumoxytol enhancement on T1‐weighted images appears visually similar to gadoteridol enhancement. The purpose of this study was to quantitatively compare ferumoxytol T1 enhancement to gadoteridol enhancement with an objective, semi‐automated method.

Combination immunotherapy as a non-chemotherapy alternative for refractory or recurrent CNS lymphoma

Primary central nervous system lymphoma (PCNSL) is an extemely rare, CD20þ non-germinal center B cell lymphoma (diffuse large cell type) in a bed of T-cell rich tumor microenvironment. The prognostic or predictive significance of the T-cell infiltration in the tumor microenvironment is unclear, but provides an attractive therapeutic opportunity. Traditionally, high dose methotrexate (HD-MTX)-based regimens are considered as the standard of care in first-line therapy. Most centers include rituximab, an anti-CD20 antibody, in their regimens based on multiple retrospective studies and a randomized phase II trial [1]. The role of rituximab was recently challenged by the preliminary results of a prospective phase III trial that indicates no improvement in progression-free survival with the addition of rituximab for PCNSL. Rituximab is expected to continue to be a part of many first-line regimens until long-term follow up data including overall survival is available [2]. Although excellent responses have been reported with HD-MTX-based regimens, most patients relapse within the first two years [3–5]. In the absence of large randomized phase III trials, the optimum therapy for cases that are refractory or have relapsed after HD-MTX is not well defined; patients are generally re-challenged with HD-MTX-based regimens and receive whole brain radiotherapy (WBRT) or their combination, followed by myeloablative therapy and stem cell transplant. However, these therapies are associated with a high incidence of treatment-related toxicities and prognosis continues to be poor [6–8]. HD-MTX-based regimens require hospitalization for up to a week and are quite challenging for many patients, especially those with poor performance status, impaired renal function, or the inability to tolerate the aggressive hydration and alkalization necessary to safely administer HD-MTX. Similarly, WBRT is associated with significant neurocognitive dysfunction [9]. Safer and more effective alternatives are essential to improve outcomes and quality of life in this aggressive brain tumor. PD-L1 overexpression has been described in nongerminal center B-cell-like type of diffuse large B-cell lymphoma (DLBCL), suggesting that anti-PD-1/PD-L1 approaches may be beneficial in these types of tumors [10]. Since CNS lymphoma is a type of non-germinal center non-Hodgkin lymphoma and is also known to overexpress PD-L1 and -L2 receptors, there is significant interest in evaluating this approach in this aggressive tumor type [11]. Very limited low level evidence in the form of small retrospective studies demonstrate promising efficacy in recurrent/refractory CNS lymphoma with the off-label use of a PD-1 inhibitor as monotherapy [12]. Combining a check point inhibitor with an anti-CD20 antibody allows the simultaneous targeting of both CD20 malignant cells as well as T cells in the tumor microenvironment. Blocking PD-1 could enhance the antitumor activity of T cells that could be further enhanced by inducing antibody-dependent cellular cytotoxicity using an anti-CD20 antibody. Thus, this combination may result in the activation of both the innate and adaptive immune systems and in enhanced clinical response [13]. The combination of pembrolizumab and rituximab has been shown to be well tolerated with no additional autoimmune or treatment-related serious adverse events [14]. Between December 2015 and December 2017, six patients with relapsed or progressive CNS lymphoma were treated at our institution with the combination of off-label PD-1 inhibitor (five patients received pembrolizumab while one received nivolumab) and rituximab, an anti-CD20 monoclonal antibody. Their medical records were reviewed retrospectively after institutional review board approval. Images were reviewed and the response was assessed by a neuroradiologist. Three had systemic lymphoma with isolated CNS recurrences, the other three

Combined Iron Oxide Nanoparticle Ferumoxytol and Gadolinium Contrast Enhanced MRI Defines Glioblastoma Pseudo-progression

BACKGROUND Noninvasively differentiating therapy-induced pseudoprogression from recurrent disease in patients with glioblastoma is prospectively difficult due to the current lack of a biologically specific imaging metric. Ferumoxytol iron oxide nanoparticle MRI contrast characterizes innate immunity mediated neuroinflammation; therefore, we hypothesized that combined ferumoxytol and gadolinium enhanced MRI could serve as a biomarker of glioblastoma pseudoprogression. METHODS In this institutional review board-approved, retrospective study, we analyzed ferumoxytol and gadolinium contrast enhanced T1-weighted 3T MRI in 45 patients with glioblastoma over multiple clinical timepoints. Isocitrate dehydrogenase 1 (IDH-1) mutational status was characterized by exome sequencing. Sum of products diameter measurements were calculated according to Response Assessment in Neuro-Oncology criteria from both gadolinium and ferumoxytol enhanced sequences. Enhancement mismatch was calculated as the natural log of the ferumoxytol to gadolinium sum of products diameter ratio. Analysis of variance and Students t-test assessed differences in mismatch ratios. P-value <0.05 indicated statistical significance. RESULTS With the development of pseudoprogression we observed a significantly elevated mismatch ratio compared with disease recurrence (P < 0.01) within IDH-1 wild type patients. Patients with IDH-1 mutation demonstrated significantly reduced mismatch ratio with the development of pseudoprogression compared with disease recurrence (P < 0.01). Receiver operator curve analysis demonstrated 100% sensitivity and specificity for the use of mismatch ratios as a diagnostic biomarker of pseudoprogression. CONCLUSION Our study suggests that ferumoxytol to gadolinium contrast mismatch ratios are an MRI biomarker for the diagnosis of pseudoprogression in patients with glioblastoma. This may be due to the unique characterization of therapy-induced neuroinflammation.