We recently published a case series of typically commensal Neisseria spp. disease among eculizumab recipients.1 Eculizumab is a terminal complement inhibitor indicated for treatment of paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and certain patients with generalized myasthenia gravis or neuromyelitis optica spectrum disorder.2 Due to complement inhibition, many different Neisseria spp. can cause invasive disease in eculizumab recipients1,3,4 and eculizumab recipients are at an estimated 2000-fold increased risk of meningococcal disease (caused by Neisseria meningitidis).

Proteasome inhibitors (PIs) have emerged as an important treatment strategy for multiple myeloma (MM). Currently, there are three FDA-approved PIs including bortezomib, carfilzomib, and ixazomib.1-3 Bortezomib, the first PI that was approved, is currently indicated for the treatment of patients with multiple myeloma and mantle cell lymphoma.1 Carfilzomib and ixazomib are indicated for the treatment of relapsed/refractory myeloma.2, 3 Although PIs are generally well tolerated, common toxicities specific to the class include thrombocytopenia, hepatotoxicity, and other toxicities as described in the US prescribing information.1-3 Recently, several published case reports have described thrombotic microangiopathy (TMA) among patients receiving bortezomib and ixazomib (Table 1). Thrombotic microangiopathy represents a clinical spectrum of diseases related to microvascular thrombi, including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), characterized by systemic or intra-renal thrombi, hematologic abnormalities, and related organ dysfunction.4 Many causes of TMA have been described including A Disintegrin and Metalloprotease with a Thrombospondin type 1 motif member 13 (ADAMTS13) deficiency, Shiga toxin producing bacterial infections, complement-mediated (also known as atypical HUS), and drug-induced TMA.4, 5 Drug- induced TMA is a rare but serious outcome that we estimate to occur at a rate of approximately one case per million population per year.5, 6 Notably, TMA is an identified risk with carfilzomib, and this safety finding was added to carfilzomib's prescribing information in 2015.3 We evaluated postmarketing adverse event reports from the FDA Adverse Event Reporting System (FAERS) and published in the literature. This was to investigate a potential association between PI exposure, specifically bortezomib and ixazomib, and TMA to determine if the prescribing information should be updated similar to carfilzomib, as a therapeutic class effect. We report our findings for bortezomib-associated and ixazomib-associated TMA as well as the regulatory actions taken by the FDA. We identified 27 unique cases of TMA from FAERS (n = 24) and the literature (n = 3) associated with bortezomib (n = 21) and ixazomib (n = 6) use (Table 1). A case with histologic findings of TMA or laboratory evidence of TMA (eg, thrombocytopenia and evidence of schistocytes on blood smear) was considered a confirmed case of TMA (Table S1). We applied the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment to our cases and determined causality as certain in one case, probable in four cases, and possible in the remaining 22 cases. The median time to event onset of TMA from the first dose of bortezomib or ixazomib was 34 and 78 days, respectively, among the cases that reported this information. Notably, this is consistent with the time to onset for TMA observed with carfilzomib.7 As is expected for non-immune mediated, drug-induced TMA, 10 cases reported normal ADAMTS-13 levels.5 Twenty three of the cases reported use of the PI for the treatment of multiple myeloma. The median case age was 57 years and the cases were evenly distributed among males and females. Although TMA is rare, it has a risk for fatality often manifesting clinically as end-organ damage involving the kidney, related to endothelial injury.4 Most patients with TMA require hospitalization and many require long-term treatment with renal replacement therapy. All cases in our case series reported serious outcomes including hospitalization (n = 18) and death (n = 2). Both fatal cases occurred in the setting of TMA among the ixazomib cases. Renal injury was the most common serious clinical manifestation of TMA (n = 23) and led to renal replacement therapy in 10 cases, including two cases that required long-term dialysis. We assessed the cases for the presence of concomitant medications and comorbidities as potential confounding factors. Overall, we determined the drug-event causality as certain in one case and as probable in four cases without apparent contributory factors. The remaining 22 cases were confounded by relevant comorbidities, concomitant medications, or did not report this information. Underlying malignancy is considered a risk factor for TMA. However, MM is a rare underlying cause of TMA and usually occurs at the initial presentation, prior to treatment, or at disease recurrence.8 Other suggested mechanisms for TMA in MM include systemic chemotherapy and hematopoietic stem cell transplantation (HSCT)-induced endothelial injury.4, 8 Although MM was reported as the underlying malignancy for our certain and probable cases, all patients improved clinically with PI therapy discontinuation and other supportive interventions. This is not the expected outcome for TMA due to uncontrolled malignancy, and favors drug-induced TMA. A causal association is further supported by a positive rechallenge with respect to bortezomib re-initiation in one of the cases. The most frequently reported confounding factors among the remaining possible cases included prior HSCT (n = 7), possible infection (n = 4), and underlying hypertension (n = 3). Although the mechanism by which PI-induced TMA could occur is unknown, dysregulation of the vascular endothelial growth factor (VEGF) signal pathway is a proposed mechanism.9, 10 The PIs affect VEGF signaling through the NF-κB pathway; blocking the ubiquitination of IκB leads to decreased NF-κB activity and reduced VEGF production. Vascular endothelial growth factor is produced by podocytes within the kidney, and maintains microvasculature integrity via paracrine signaling through VEGF receptors found on glomerular capillary endothelial cells.9, 10 In animal models, antagonism of VEGF receptor signaling by genetic or pharmacologic manipulation is associated with TMA, including impaired endothelial cell proliferation and capillary formation with subsequent loss of glomerular and mesangial cells.9, 10 To our knowledge, this is the largest published case series describing TMA with bortezomib and ixazomib. These cases are characterized by serious clinical outcomes including death in some instances. Although our analysis is limited by the quality of spontaneous adverse event reporting and other limitations inherent to spontaneous reporting systems (eg, under-reporting, reporting biases), the strong temporal association and biologic plausibility provide evidence supportive of a drug-event causal association between the drugs, bortezomib and ixazomib, and the event, TMA. Additionally, the known association of TMA with carfilzomib suggests this may be a class effect related to proteasome inhibition.3 The US prescribing information for bortezomib and ixazomib was recently updated to include the risk of TMA under warnings and precautions, with recommendations to discontinue PI therapy for suspected TMA.1, 2 This revision of the prescribing information is intended to increase clinicians' awareness of the risk for TMA with bortezomib and ixazomib, and to mitigate the risk for serious outcomes by improving the likelihood of early therapeutic interventions. The authors report no conflict of interest. Table S1 Case Definition for Thrombotic Microangiopathy (TMA) Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single-arm, multicenter Study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% [95% confidence interval (CI), 35.1-53.2], with complete responses in 12%. Median response duration was 7.6 months (95% CI, 6.3-not estimable). Grade 3-4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Chronic myeloid leukemia (CML) is characterized by the presence of the Philadelphia chromosome (Ph+) producing a constitutively active tyrosine kinase, BCR-ABL1.1 BCR-ABL1 tyrosine kinase inhibitors (TKIs) are the mainstay treatment for patients with CML. Currently, there are five BCR-ABL1 TKIs approved by the U.S. Food and Drug Administration (FDA), including imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, most of which have indications beyond CML. Thyroid dysfunction, specifically hypothyroidism and hyperthyroidism, is a well-known adverse event observed with many TKIs.2 Among the BCR-ABL TKIs, hypothyroidism, hyperthyroidism, and thyroiditis were identified in clinical trials with dasatinib and nilotinib, whereas a distinct risk of hypothyroidism in thyroidectomy patients on levothyroxine was identified with imatinib in the postmarket setting. The latter was observed in studies conducted by DeGroot and colleagues, in which thyroidectomized patients receiving imatinib required increased thyroid hormone replacement, while patients with intact thyroid glands receiving imatinib remained euthyroid.3 The FDA approved prescribing information for imatinib with this risk in 2008. We evaluated postmarketing adverse event reports from the FDA Adverse Event Reporting System (FAERS) and published in the literature from the product approval date through September 10, 2019, to investigate an association between BCR-ABL1 TKI exposure and thyroid dysfunction as a potential class effect. A confirmed case of thyroid dysfunction was supported by laboratory evidence or initiation of thyroid treatment. An unconfirmed case of thyroid dysfunction did not provide this level of evidence. We further characterized the cases as new-onset or worsening thyroid dysfunction as indicated by modification of thyroid medication regimen or worsening thyroid function tests. The severity of thyroid dysfunction was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.4 We identified 326 unique cases of thyroid dysfunction from FAERS (n = 239) and the literature (n = 87) associated with imatinib (n = 112), dasatinib (n = 41), nilotinib (n = 126), bosutinib (n = 8), and ponatinib (n = 39) use. We applied the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) causality assessment and determined causality as probable in five and possible in all others. Descriptive characteristics of the cases are summarized in Table 1. Overall, 74% (240/326) described hypothyroidism, 20% (67/326) hyperthyroidism, and 6% (19/326) did not specify the type of thyroid dysfunction. Among 122 cases that reported sufficient clinical information to assess baseline thyroid function, new-onset and worsening thyroid dysfunction occurred in 83% (n = 101) and 17% (n = 21) of cases, respectively. Half of the cases reported a time to onset, which varied widely. Among these cases, 54% (88/162) of thyroid dysfunction occurred within the first nine months of BCR-ABL1 TKI initiation. This may reflect gradual progression of drug-induced thyroid toxicity. Alternatively, inadequate monitoring requirements for thyroid function tests may have limited earlier detection of thyroid dysfunction.5 All forms of thyroid disorders may be associated with significant morbidity and mortality if unsuspected and untreated.6 Among cases that reported severity grading information, 83% (156/189) were CTCAE grade 2 thyroid dysfunction. Most cases required intervention with thyroid replacement or antithyroid therapy, and patients were able to continue BCR-ABL1 TKI therapy at the same or reduced dose. One fatal case of hyperthyroidism reported with imatinib therapy occurred in a patient with pre-existing hyperthyroidism, but the report was missing sufficient detail to adequately assess the cause. Clinical management of thyroid dysfunction depends on severity; however, as observed in our case series, cases of low severity tolerated continuing BCR-ABL1 TKI therapy with appropriate management, such as levothyroxine supplementation or anti-thyroid directed therapy. We assessed any contributory role between BCR-ABL1 TKIs and thyroid dysfunction by considering competing causes, temporality, existence of positive rechallenge and dechallenge, and potential biologic mechanisms of toxicity. All cases had a compatible temporal relationship and a suspected biologic mechanism. Cases deemed probable included one positive rechallenge case with imatinib and those cases without known confounding factors. Most cases were deemed to have possible causality due to missing data, presence of potential confounding, or a history of thyroid dysfunction. All cases that did not report thyroidectomy were presumed to have an intact thyroid. It is noteworthy that four cases of worsening thyroid dysfunction resulted in increased levothyroxine requirements after imatinib initiation in patients with pre-existing hypothyroidism and an intact thyroid. This supports an imatinib-induced exacerbation of hypothyroidism in patients with an intact thyroid. The exact mechanism underlying BCR-ABL1 TKI-induced thyroid dysfunction is not fully understood; however, multiple mechanisms have been proposed for TKIs. Thyroid angiogenesis is regulated by vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor (PDGFR) signaling.7 Although the BCR-ABL1 TKIs are selective for BCR-ABL1, they also exemplify variable affinity for other tyrosine kinases, including PDGFR and VEGFR. Imatinib, dasatinib, and nilotinib are selective for PDGFR with no VEGFR activity. Ponatinib selectively inhibits PDGFR and VEGFR, whereas bosutinib does not inhibit signaling through either of these receptors.8 Inhibition of VEGFR and PDGFR dysregulates thyroid angiogenesis, which may result in an ischemic thyroiditis followed by hyperthyroidism or gradual thyroid destruction followed by hypothyroidism.7 Other proposed mechanisms included thyroid peroxidase activity inhibition, iodine uptake inhibition, autoimmune thyroiditis, irreversible thyroid destruction, thyroid hormone plasma membrane transport inhibition, and increased clearance of thyroid hormones through enzyme induction. We observed different forms of thyroid dysfunction (ie, hypothyroidism, hyperthyroidism, autoimmune thyroiditis) in our case series and recognize the variable spectrum of activity of BCR-ABL1 TKIs.7 Therefore, consistent with the literature, we believe that more than one mechanism is likely involved with BCR-ABL1 TKI-induced thyroid dysfunction. To our knowledge, this is the largest published case series describing thyroid dysfunction with the BCR-ABL1 TKIs. All members of the BCR-ABL1 TKI class have had cases of thyroid dysfunction reporting an association between drug exposure and thyroid dysfunction. Although our analysis is limited by the quality of FAERS data and other limitations inherent to spontaneous reporting systems (eg, under-reporting, reporting biases), the temporal association, biologic plausibility, and positive rechallenge data provide evidence supportive of a drug-event causal association between the BCR-ABL1 TKIs and thyroid dysfunction. The U.S. prescribing information for imatinib, bosutinib, and ponatinib was recently updated to include the risk of hypothyroidism and hyperthyroidism under Adverse Reactions. This revision of the prescribing information is intended to increase clinicians' awareness of the risk for thyroid dysfunction with BCR-ABL1 TKIs and to mitigate the risk for serious outcomes by improving monitoring and early therapeutic interventions. Given that dasatinib and nilotinib are labeled for hypothyroidism and hyperthyroidism under Adverse Reactions, this labeling revision of the remaining BCR-ABL1 TKIs will harmonize the prescribing information among the BCR-ABL1 TKIs regarding this safety issue. The authors report no conflict of interest.

Introduction: IMIDs are a cornerstone of multiple myeloma treatment and have a recently expanded role in the treatment of selected lymphomas. However, the safety of chemotherapeutic regimens containing IMIDs in patients with a history of solid organ transplantation (SOT) is uncertain. Recently, several published case reports have described SOT rejection (SOTr) among patients taking IMIDs. Methods: To investigate a potential association between IMID exposure and SOTr, we evaluated postmarketing adverse event reports submitted to the FDA Adverse Event Reporting System (FAERS) and published in the literature. We descriptively characterized the clinical outcomes and severity of SOTr and utilized the World Health Organization-Uppsala Monitoring (WHO-UMC) scale to assess drug causality. Results: We identified 22 cases of SOTr associated with the use of lenalidomide (n=16), pomalidomide (n=3), or thalidomide (n=3) from FAERS and the literature. After IMID initiation, the median time to onset of SOTr was 39 days (range 3-70 days) with 89% of cases occurring by 60 days. Notably, SOTr occurred within 2 weeks of lenalidomide and pomalidomide administration in 5 cases, including 2 patients with a distant history of SOT (lenalidomide, n=1; pomalidomide, n=1). The most commonly affected organs were the kidney (n=13) and heart (n=10), with 3 of these cases involving rejection of both organs. In 12 cases, rejection was confirmed with biopsy findings of acute T-cell mediated rejection. Notably, 6 of these 12 cases provided baseline biopsy findings prior to IMID initiation that indicated stable organ function and showed no signs of rejection. All cases were complicated by serious outcomes including 7 deaths described as related to graft rejection. Other serious clinical manifestations included surgical excision of the original transplanted organ (n=2), requirement of a second transplant (n=3), and dialysis (n=4), including 2 cases that required long-term renal replacement therapy. We determined the causality as probable (no confounding factor identified) in 6 cases and possible (confounding factor identified) in the remaining 16 cases. The most frequently reported confounding factor was concomitant change of the baseline immunosuppressive regimen with the initiation of the IMID (n=7). Notably, 5 of the 7 cases with fatal outcome had immunosuppression reduced at IMID therapy initiation, including 2 cases with a distant history of SOT and stable graft function. Conclusion: To our knowledge, this is the largest case series describing SOTr with the IMIDs. These cases are characterized by serious events including death and reduced long-term survival of the graft. Although this analysis is limited by the quality of spontaneous adverse event reporting, the strong temporal relationship and the histologic findings of T-cell mediated rejection provide reasonable evidence of a contributory role of IMIDs to SOTr. This risk is plausible because IMIDs induce T-cell proliferation, enhance interleukin-2 and interferon-gamma production, and inhibit regulatory T-cell function. Increased surveillance for early signs of acute rejection is warranted for SOT recipients receiving IMID therapy. The US prescribing information is currently being revised to reflect the risk of SOTr across all IMIDs. Disclosures No relevant conflicts of interest to declare.

The U.S. Food and Drug Administration (FDA) has approved several vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, including lenvatinib, for thyroid and renal malignancies. Inhibition of the VEGFR signaling pathway impairs angiogenesis and can disrupt wound healing. The objective of this work was to evaluate wound healing complications as a potential safety risk for patients treated with lenvatinib. We searched the FDA Adverse Event Reporting System (FAERS) database for postmarketing reports of wound healing complications with lenvatinib between 13 February 2015 (FDA approval date) and 15 February 2017. The search identified nine FAERS cases of lenvatinib-associated wound healing complications that were not previously reported in the medical literature. Seven cases involved postoperative wound healing complications, such as impaired healing or wound dehiscence. In our case series, the reported time to identification of delayed wound healing from tissue injury or surgery varied over a wide range (4-58 days). The time of initial lenvatinib exposure relative to the tissue injury was also highly varied in our series, which may have influenced the development and detection of impaired healing. FAERS case-level evidence suggests that lenvatinib may have contributed to wound healing complications based on temporality and biologic plausibility. Healthcare professionals should be aware of this safety risk to facilitate prompt recognition and risk mitigation.

Background. Gonorrhea is the second most commonly reported notifiable condition in the United States. Infrequently, Neisseria gonorrhoeae can cause disseminated gonococcal infection (DGI). Eculizumab, a monoclonal antibody, inhibits terminal complement activation, which impairs the ability of the immune system to respond effectively to Neisseria infections. This series describes cases of N. gonorrhoeae infection among patients receiving eculizumab. Methods. Pre- and postmarketing safety reports of N. gonorrhoeae infection in patients receiving eculizumab worldwide were obtained from US Food and Drug Administration safety databases and the medical literature, including reports from the start of pivotal clinical trials in 2004 through 31 December 2017. Included patients had at least 1 eculizumab dose within the 3 months prior to N. gonorrhoeae infection. Results. Nine cases of N. gonorrhoeae infection were identified; 8 were classified as disseminated (89%). Of the disseminated cases, 8 patients required hospitalization, 7 had positive blood cultures, and 2 required vasopressor support. One patient required mechanical ventilation. Neisseria gonorrhoeae may have contributed to complications prior to death in 1 patient; however, the fatality was attributed to underlying disease per the reporter. Conclusions. Patients receiving eculizumab may be at higher risk for DGI than the general population. Prescribers are encouraged to educate patients receiving eculizumab on their risk for serious gonococcal infections and perform screening for sexually transmitted diseases (STDs) per the Centers for Disease Control and Prevention STD treatment guidelines or in suspected cases. If antimicrobial prophylaxis is used during eculizumab therapy, prescribers should consider trends in gonococcal antimicrobial susceptibility due to emerging resistance concerns.

BACKGROUND:Non-meningococcal, non-gonococcal Neisseria spp. are typically commensal and rarely cause invasive disease. Eculizumab is a terminal complement inhibitor that increases susceptibility to meningococcal disease, but data on disease caused by typically-commensal Neisseria spp. are lacking. This series describes postmarketing reports of typically-commensal Neisseria spp. disease in patients receiving eculizumab. METHODS:We searched the FDA Adverse Event Reporting System (FAERS) and medical literature for reports of commensal Neisseria spp. disease in patients receiving eculizumab, from eculizumab U.S. approval (2007) through January 31, 2018. RESULTS:We identified seven FAERS reports (including one case also reported in the literature) of non-meningococcal, non-gonococcal Neisseria disease, including N. sicca (mucosa)/subflava (n = 2), N. cinerea (n = 2), N. sicca (mucosa) (n = 1), N. mucosa (n = 1, with concurrent alpha-hemolytic Streptococcus bacteremia), and N. flavescens (subflava) (n = 1). Four cases had sources of patient immunosuppression in addition to eculizumab. Three patients had sepsis (n = 2) or septic shock (n = 1). Five patients were bacteremic. All patients were hospitalized; the infections resolved with antibiotics. CONCLUSIONS:Our search identified seven cases of disease from typically commensal Neisseria spp. in eculizumab recipients. These findings suggest that any Neisseria spp. identified from a normally sterile site in an eculizumab recipient could represent true infection warranting prompt treatment.

Pneumocystis jirovecii pneumonia (PCP) is a serious infection that occurs in immunocompromised individuals, most commonly among HIV-infected patients, hematopoietic stem cell and solid organ transplant recipients receiving immunosuppressants, and patients with hematologic malignancies. The common feature of patients at high risk for PCP is defective T-cell immunity, induced by underlying diseases or immunosuppressive therapy. Prolonged corticosteroid exposure is a frequently identified immunosuppressive associated with PCP risk.1 The clinical presentation of PCP may differ between non-HIV infected patients and HIV-infected patients, with more acute onset of symptoms and significantly higher mortality rates (30%-60%) in non-HIV infected patients compared to those with HIV (10%-20%).2 We report a series of cases of PCP associated with the use of ibrutinib that were submitted to the FDA Adverse Event Reporting System (FAERS). The Division of Pharmacovigilance at the U.S. Food and Drug Administration reviewed postmarketing cases of PCP from FAERS and the published literature among patients treated with ibrutinib for chronic lymphocytic leukemia (CLL), small lymphocytic leukemia, mantle cell lymphoma, and B cell lymphoma. We defined a case of PCP as confirmed if criteria 1, or both 2 and 3 were met: (1) documentation of P. jirovecii in induced sputum by microscopy with appropriate stains or bronchoalveolar lavage fluid by microscopy, or by polymerase chain reaction; (2) new onset of respiratory system findings supported by compatible radiographic findings as follows: chest radiograph or computed tomography demonstrating diffuse bilateral interstitial infiltrates, solitary or multiple nodules, pneumatoceles, blebs and cysts, asymmetric disease, upper lobe localization, or pneumothorax;2 (3) treatment of presumed PCP infection with PCP specific treatment.3 A case was considered unconfirmed if the reporter stated that the case involved PCP, but the report did not provide the results of diagnostic testing required of a confirmed case. We identified 13 FAERS cases of ibrutinib-associated PCP, and five of these cases included statements which fulfilled the confirmed criteria. Using the World Health Organization-Uppsala Monitoring Centre causality assessment scale, we determined the causal association of PCP with ibrutinib for all of the FAERS cases as possible. The time from ibrutinib initiation to PCP diagnosis exhibited a wide range, with a median of 89 days (range of 7–772 days). Overall, the onset of PCP occurred during the first six months of ibrutinib treatment in 7 of 13 (54%) cases, which is consistent with that reported in the literature.4 Seven of 13 cases reported the use of no other immunosuppressive therapy. Table 1 summarizes the characteristics of the FAERS cases. All FAERS cases resulted in clinically significant outcomes with five deaths and eight requiring hospitalization. PCP was reported as the sole cause of death in three cases. In these three cases, the times to death from PCP diagnosis were 8, 12, and 29 days. In the fourth fatal case, the cause of death was multifactorial including septic shock, PCP, and respiratory failure. No cause of death was reported in the fifth case. We assessed the cases for the presence of confounding factors. In addition to the underlying diseases, ten cases had refractory disease indicating prior exposure to other immunosuppressive therapy, and six cases reported the concomitant use of other immunosuppressive agents (refer to Table 1). One case reported no exposure to other immunosuppression prior to ibrutinib treatment, and two cases did not report prior therapy. We identified one published case series, which comprised five cases of PCP that developed among 96 patients with CLL who participated in two single-agent ibrutinib studies at the US National Cancer Institute.4 Four of the five patients received ibrutinib as first-line treatment, which removes the confounding factors of prolonged disease duration and concomitant immunosuppressive therapy.4 The clinical presentations of PCP in these patients were mild, ranging from asymptomatic pulmonary infiltrates to chronic cough. All of these patients resolved their infection with early recognition and trimethoprim/sulfamethoxazole treatment. The close, scheduled monitoring as part of a study protocol, and early detection of PCP in these study patients, may have contributed to improved outcomes compared to the FAERS cases. Biological plausibility for PCP risk with ibrutinib is supported by its irreversible inhibitory effect on interleukin-2–inducible kinase (ITK), the critical role of ITK in T Helper 2 (Th2) T-cells, and the essential role of Th2 cells in PCP immunity.5 Given the serious outcomes in this FAERS cases series, practitioners should be aware of a possible contribution of ibrutinib to the risk of PCP. Mitigating the risk of mortality with PCP infection in non-HIV patients requires an appropriate assessment of the risk for PCP infections based on underlying disease and concomitant or prior medications to include immunosuppressive therapy, institution of appropriate prophylaxis regimen, and early diagnosis and prompt use of effective antibiotics.6 We recommend a careful consideration of the benefits and risks of PCP prophylaxis when patients are exposed to ibrutinib, especially in the context of additional risk factors which can diminish T-cell immunity. The sponsor updated the Warnings and Precautions section of the ibrutinib prescribing information to include the occurrence of PCP in patients treated with ibrutinib and consideration for prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Regina Lee http://orcid.org/0000-0001-7726-2373

e18226Background: Everolimus is a mammalian target of rapamycin (mTOR) kinase inhibitor approved for treatment of several human cancers including renal cell carcinoma, pancreatic neuroendocrine tum...