A Summary of the Rare Reports of Osteonecrosis of the Jaw Associated With Tumor Necrosis-α Inhibitors in the United States Food and Drug Administration's Adverse Event Reporting System Database.

PURPOSE: Recent case reports highlight an association between osteonecrosis of the jaw (ONJ) and antitumor necrosis factor (anti-TNF) medications. Our study reviewed and described reports of anti-TNF associated ONJ reported to the United States of America's Food and Drug Administration Adverse Event Reporting System to explore this potential adverse drug reaction further. METHODS: Using the Food and Drug Administration Adverse Event Reporting System database, we identified reported cases of ONJ between 2010 and 2021. Cases were included in our study if they reported any prior or concomitant anti-TNF medication use. Additionally, only adults (age 18+) and reports from health-care professionals were included. Cases lacking subject age or gender were excluded. After duplicates were removed, a dataset was created and demographics were described including age, gender, and indication for use. Naranjo scoring was conducted to assess adverse drug reaction probability. Subject demographics were then separately described for cases without reported denosumab or bisphosphonate therapy history and compared to those with reported history or concomitant denosumab or bisphosphonate therapy. RESULTS: Over twenty thousand cases of ONJ were reported. Forty-four potential cases (0.22%) of anti-TNF medication-associated ONJ were identified and reviewed. Of these, female gender comprised 77.3% (35 cases) and there was an average age of 61.3 years ± 13.7 years. Twenty cases (45.5%) had no prior/concomitant bisphosphonate or denosumab therapy. Of these, 55% (11 cases) were female and the average age was 54.5 ± 17.3 years. Rheumatoid arthritis was the most frequent indication for use (5 cases, 25%) followed by inflammatory bowel disease (IBD) and psoriatic arthritis (4 cases each, 20%) in this cohort. CONCLUSIONS: Twenty potential cases of anti-TNF-associated ONJ without prior or concomitant medications known to be associated with ONJ were identified and described. Interestingly, male gender was more frequent and subjects were younger in these cases compared to those with prior/concomitant bisphosphonates or denosumab therapy. Naranjo scoring indicated a probable interaction for three cases. Further studies are needed to clarify the association of ONJ and anti-TNF therapy, including investigating potential mechanisms and reporting future cases with sufficient detail to assess possible confounding factors.

Medication-induced osteonecrosis of the jaw: a review of cases from the Food and Drug Administration Adverse Event Reporting System (FAERS).

BACKGROUND: Osteonecrosis of the jaw (ONJ) is a rare but serious adverse drug reaction (ADR) commonly associated with bisphosphonate and denosumab therapy. Prior research utilized an online, public FDA Adverse Event Reporting System (FAERS) Database to explore this ADR. This data identified and described several novel medications associated with ONJ. Our study aims to build upon the prior findings, reporting trends of medication induced ONJ over time and identifying newly described medications. METHODS: We searched the FAERS database for all reported cases of medication related osteonecrosis of the jaw (MRONJ) from 2010 to 2021. Cases lacking patient age or gender were excluded. Only adults (18 +) and reports from Healthcare Professions were included. Duplicate cases were removed. The top 20 medications were identified and described for April 2010-December 2014 and April 2015-January 2021. RESULTS: Nineteen thousand six hundred sixty-eight cases of ONJ were reported to the FAERS database from 2010-2021. 8,908 cases met inclusion criteria. 3,132 cases were from 2010-2014 and 5,776 cases from 2015-2021. Within the cases from 2010-2014, 64.7% were female and 35.3% were male, and the average age was 66.1 ± 11.1 years. Between 2015-2021, 64.3% were female and 35.7% were male, and the average age was 69.2 ± 11.5 years. Review of the 2010-2014 data identified several medications and drug classes associated with ONJ not previously described. They include lenalidomide, corticosteroids (prednisolone and dexamethasone), docetaxel and paclitaxel, letrozole, methotrexate, imatinib, and teriparatide. Novel drugs and classes described between 2015-2021 include palbociclib, pomalidomide, radium 223, nivolumab, and cabozantinib. DISCUSSION: While stricter inclusion criteria and removal of duplicate cases led to fewer overall identified cases of MRONJ when compared to prior research, our data represents a more reliable analysis of MRONJ reports to the FAERS database. Denosumab was the most frequently reported medication associated with ONJ. While unable to imply incidence rates from our data due to the nature of the FAERS database, our findings provide further description of the various medications associated with ONJ and elucidate patient demographics associated with the ADR. Additionally, our study identifies cases of several newly described drugs and drug classes that have not been previously described in literature.

Primary Central Nervous System Lymphoma With Systemic Recurrence.

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin's lymphoma confined to the brain, leptomeninges, spinal cord, or eyes without systemic involvement. Nearly half of patients with PCNSL who achieve complete remission, relapse within five years. The majority of patients who relapse have a local recurrence. Systemic relapse, however, is much rarer. Here, we report a rare case of a 70-year-old male diagnosed with PCNSL who relapsed systemically nearly 1.5 years after achieving complete remission. His treatment consisted of chemoimmunotherapy and targeted therapy followed by an autologous transplant. Currently, there is no standard of care for systemic relapse of PCNSL. This multiagent treatment modality may be one such option for salvage therapy.

The Role of Navitoclax in Myelofibrosis.

Primary myelofibrosis (PMF) is the most aggressive type of chronic myeloproliferative neoplasm, characterized by a disarray of hematopoietic stem cells and bone marrow fibrosis. The estimated incidence is 1.5 per 100,000 individuals per year with a median survival of less than six years. This statistic can vary by risk category, primarily based on clinical and cytogenetic features. Death can result from many causes, including leukemic transformation, cachexia, vascular events, and infection. Currently, allogeneic hematopoietic cell transplant is the only curative method for those at high risk. Unfortunately, only about 10% are eligible for this therapy. JAK2 kinase inhibitors are commonly used for high-risk patients with symptomatic splenomegaly or systemic symptoms from PMF. In clinical trials, the major endpoint is a reduction of spleen size by 35%. Secondary endpoints have included amelioration of symptomatic PMF and overall survival, which can be difficult to determine because of frequent co-morbid conditions. Current Food and Drug Administration (FDA)-approved JAK2 inhibitors have not shown increased survival or reduced risk of leukemic transformation. In relapsed or refractory disease, there is currently no standard of care. In this paper, we discuss the role of a new anti-apoptotic B cell leukemia 2 (Bcl-2) inhibitor, Navitoclax, for the treatment of myelofibrosis. The clinical data thus far for Navitoclax, especially in synergistic combination with traditional JAK2 inhibitors, have been promising for those with a refractory or relapsing disease on prior therapies. Following the encouraging results of phase II trials, ongoing phase III trials will primarily evaluate splenic size reduction versus the standard of care and evaluate secondary endpoints such as symptom reduction and overall survival. These studies may establish a new standard of care for refractory or relapsed myelofibrosis.