P444
Inflammatory arthritis induced by the use of checkpoint inhibitors for immunotherapy of cancer
Noha Abdel-Wahab1,2, Jean H. Tayar1, Adi Diab1, Sang T. Kim1, Huifang Lu1, Maria E. Suarez-Almazor1
1
The University of Texas MD Anderson Cancer Center, Houston, TX, USA;
2Assiut University Hospitals, Faculty of Medicine, Assiut, Egypt
Correspondence:Maria E. Suarez-Almazor ([email protected]) Journal for ImmunoTherapy of Cancer2017,5(Suppl 2):P444
Background
Checkpoint inhibitors (CPI) have revolutionized cancer treatment with remarkable survival benefits in multiple cancer patients. Yet, their use can be hampered by frequent immune-related adverse events
(irAEs), affecting any organ, with signs and symptoms usually seen in inflammatory and autoimmune diseases. There is paucity of data on CPI induced arthritis, primarily from case reports or small series. Methods
Patients developed arthritis while using CPI were identified from the Rheumatology Clinic at UT MD Anderson Cancer Center. We diagnosed arthritis if patients developed joint swelling after receiving any FDA ap- proved CPI, after ruling out other potential underlying causes or path- ologies. Here we report 13 pts. Cancer types included melanoma (n=5), non-small cell lung cancer (n=4), renal cell carcinoma (n=2), acute mye- loid leukemia, and cancer colon (1 each). CPI included nivolumab (n=8), pembrolizumab (n=3), and ipilimumab and atezolizumab (1 each). Results
Patients age ranged from 47-74 years and 62% were male. CPI induced arthritis was the sole irAE in eight pts (62%), and was associated with other irAEs including sicca symptoms (xerostomia, dry eyes), colitis, pancreatitis, or dermatitis in the remaining five (38%). Overall, median time to onset of arthritis after the initiation of CPI was 6 (range 1 to 15) months. When occurred with other irAEs, arthritis always manifested up to 4 months after the first occurring irAE despite sufficient immunosup- pressant treatment (infliximab and/or high dose steroid) and symptoms control, with the exception of one patient with sicca symptoms. Initial symptoms varied widely between small and large joints of upper and lower extremities. Over time, symmetrical polyarthritis resembling rheumatoid arthritis, predominantly involving small joints of the hands and wrists, along with larger joints was reported in six patients. Two had oligoarthritis resembling seronegative spondyloarthropathy with axial pain and enthesopathy. Four had asymmetrical inflammatory poly- arthritis, and one had oligoarthritis. Rheumatoid factor and/or anti- citrullinated peptide antibodies were positive in two patients, and anti- nuclear antibodies in two others. Eleven patients were treated with ste- roids, six were controlled, while five needed additional biological agents (4 tocilizumab, 1 infliximab) to achieve appropriate steroid taper (< 7.5 mg). One patient improved with intra-articular steroid injection, and one received tocilizumab as first line.
Conclusions
Our data suggest that arthritis is a late occurring irAE that may be due to a different immunopathology. A multi-institutional collabora- tive work including tissue analysis is needed to enhance our under- standing of the pathogenesis and design optiomal therapy without dampening antitumor immunity.
P445
Clinical features of immune checkpoint inhibitor-induced inflammatory arthritis differ in those treated with combination versus single agent therapy
Laura Cappelli, Clifton Bingham, Julie Brahmer, Patrick Forde, Dung Le, Evan Lipson, Jarushka Naidoo, Lei Zhang, Ami Shah
Johns Hopkins, Baltimore, MD, USA
Correspondence:Laura Cappelli ([email protected]) Journal for ImmunoTherapy of Cancer2017,5(Suppl 2):P445 Background
Multi-system immune-related adverse events (iRAE) can occur as a re- sult of immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4, with variations depending on tumor type and agent used. Inflammatory arthritis (IA) has been increasingly recognized as an iRAE that may occur as a result of anti-PD-1/PD-L1/CTLA-4 therapy used in the treatment of malignancy [1, 2]. We evaluated associations between ICI regimen and clinical presentation of IA in a single institution.
Methods
Patients referred to rheumatology for suspected ICI-induced IA, were identified January 2013- July 2017. Patients were included if they de- veloped de novo IA during or after ICI therapy and had no history of pre-existing autoimmune disease. Patients were included for the sin- gle agent group if they were on a PD-1 or PD-L1 inhibitor without CTLA-4 inhibition. Those in the combination group were treated with PD-1 and CTLA-4 inhibition. Clinical, demographic and laboratory data were obtained from the medical records.
Results
Tumor types for included patients were melanoma, non-small cell lung cancer, small cell lung cancer, colon cancer, Hodgkin or cutaneous lymph- oma, renal cell carcinoma, endometrial carcinoma, duodenal carcinoma, merkel cell carcinoma, basal cell carcinoma, or squamous cell carcinoma. The group treated with combination CTLA-4/PD-1 inhibition was signifi- cantly younger than the monotherapy group; those in the combination group were also more likely to be male and to have melanoma (Table 1). Combination therapy was associated with higher levels of C-reactive pro- tein (4 mg/dl vs. 0.7 mg/dL) and a higher likelihood of having a large joint affected first in the arthritis course (table 1). All instances of reactive arthritis-like presentation (arthritis + sterile urethritis, conjunctivitis) were in the combination therapy group. Patients who received PD-1/PD-L1 monotherapy were more likely to have IA as their first IRAE. No patients had CCP antibodies; two patients were positive for rheumatoid factor. Conclusions
This study illustrates the diversity in clinical phenotypes of patients with ICI-induced IA. Differences in presentation may be explained by the regimen used to treat a patient’s malignancy. Understanding the diversity of clinical presentations will help oncologists identify and treat this increasingly important iRAE.
References
1. Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017; 761):43-50.
2. Calabrese C, Kirchner E, Kontzias K, et al. Rheumatic immune-related ad- verse events of checkpoint therapy for cancer: case series of a new nosological entity. RMD open 2017;3(1):e000412.
P446
Immunosuppression use and clinical outcomes in patients with immune checkpoint inhibitor -induced inflammatory arthritis Laura Cappelli, Clifton Bingham, Julie Brahmer, Patrick Forde, Dung Le, Evan Lipson, Jarushka Naidoo, Lei Zheng, Ami Shah
Johns Hopkins, Baltimore, MD, USA
Correspondence:Laura Cappelli ([email protected]) Journal for ImmunoTherapy of Cancer2017,5(Suppl 2):P446 Background
Inflammatory arthritis (IA) resulting from immune checkpoint in- hibitors (ICIs) is an increasingly recognized immune-related ad- verse event. The requirement for immunosuppression to treat IA, including TNF-inhibitors (TNF-I), has been documented in previ- ous case series [1, 2]. How often immunosuppression is required to treat ICI-induced IA is unclear. The consequences of long- term immunosuppression on tumor response from ICIs is also uncertain.
Methods
Patients treated at Johns Hopkins Rheumatology for IA due to ICIs were included if they received anti-CTLA-4, anti-PD-1, and/or anti-PD- L1 therapy and developed IA during or after therapy. Patients with pre-existing autoimmune disease were excluded. Patients were man- aged by rheumatology and oncology based on preliminary recom- mendations for ICI-induced IA treatment [3].
Results
Included patients (n=32) had melanoma, non-small cell lung can- cer (NSCLC), small cell lung cancer, colon cancer, Hodgkin or cu- taneous lymphoma, renal cell carcinoma, endometrial carcinoma, duodenal carcinoma, merkel cell carcinoma, basal cell carcinoma, or squamous cell carcinoma. Of these patients, 20 (63%) had a partial or complete tumor response to ICIs clinically or by RECIST criteria. Twenty six (81.3%) required corticosteroids for manage- ment of their IA. Eleven patients (34.3%) required additional im- munosuppression. TNF-Is were used in 7 patients (tumor types: melanoma n=6, RCC n=1). Methotrexate or leflunomide was used in 4 patients (tumor types: NSCLC, small cell lung cancer, duo- denal carcinoma, endometrial carcinoma). Duration of TNF-I use ranged from 2-16 months. Four patients treated with TNF-I, all with melanoma, had complete response by RECIST criteria or no evidence of disease at ICI start. None of these patients had tumor progression while on TNF-I (duration: 3-16 months). Of the pa- tients treated with methotrexate or leflunomide, 3 had a complete or partial response to ICIs, and none had tumor pro- gression during 2-12 months of IA management.
Conclusions
In a cohort of patients with ICI-induced IA, the majority of patients required corticosteroids to control IA symptoms. In this series, TNF- inhibitors and other forms of non-corticosteroid immunosuppression did not affect tumor response in those who had an initial response to ICIs for malignancy.
References
1. Cappelli LC, Gutierrez AK, Baer AN, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab. Ann Rheum Dis 2017;76(1):43-50.
2. Calabrese C, Kirchner E, Kontzias K, et al. Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity. RMD open 2017;3(1):e000412.
3. Naidoo J, Cappelli LC, Forde PM, et al. Inflammatory Arthritis: A Newly Recognized Adverse Event of Immune Checkpoint Blockade. Oncologist 2017;22(6):627-30.
Table 1 (abstract P445).See text for description
P447
Infliximab associated with faster symptom resolution compared to corticosteroids alone for management of immune related enterocolitis
Daniel H Johnson1, Chrystia Zobniw2, Van A Trinh2, Roland Bassett2, Junsheng Ma2, Jamie Anderson2, Jennifer Davis2, Jocelyn Joseph2,
Marc Uemura2, Cassian Yee2, Rodabe Amaria2, Sapna Patel2,
Hussein Tawbi2, Isabella Glitza2, Michael A Davies2, Michael Wong2, Scott Woodman2, Patrick Hwu2, Wen-Jen Hwu2, Yinghong Wang2, Adi Diab2
1University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2
UT-MD Anderson Cancer Center, Houston, TX, USA
Correspondence:Daniel H Johnson ([email protected]); Adi Diab Journal for ImmunoTherapy of Cancer2017,5(Suppl 2):P447
Background
Immune-related enterocolitis (irEC) is the most common serious compli- cation from checkpoint inhibitors (CPIs) that can lead to bowel perfor- ation, sepsis, and death. The current front-line treatment for irEC is high-dose corticosteroids (CS). However, prolonged high-dose CS ther- apy has significant toxicities and side effects, and prolonged therapy may reduce CPI anti-tumor activity. Early addition of TNF-alpha inhibi- tors such as infliximab may expedite symptom resolution and shorten CS duration. The only prospective trial evaluating infliximab with CS versus CS alone for irEC (NCT02763761) has recently been terminated. Thus we conducted a retrospective study to evaluate symptom reso- lution in patients with irEC treated with infliximab + CS versus CS alone. Methods
The medical records of patients with irEC between January 1, 2012 and June 30, 2017 were reviewed under an institution review board- approved protocol. Patient demographics, CPI regimen (aCTLA-4, aPD- 1/L-1, alone or in combination), colitis grade, colitis treatment, treatment-related toxicities, time to symptom resolution, and CS dur- ation were collected. The primary-endpoint was time to symptom reso- lution for irEC (times to diarrhea resolution and to initiation of steroid titration) for patients managed with versus without infliximab. Duration of CS and rate of CS-associated toxicities were secondary-endpoints. Categorical and continuous variables were assessed between groups by Fisher's exact test and Kruskal-Wallis test (or two-sample t-test). Results
Among 75 patients with irEC, 39 (52%) received CS alone and 36 (48%) received infliximab within a median of 8 days after CS initi- ation. Patient characteristics (age, comorbidities, cancer type, im- munotherapy regimen, and initial steroid dose), were similar between the two arms. The incidence of grade 3+ colitis was higher in the infliximab + CS arm (86.1% vs. 34.2%,p<0.001). Despite this, times to diarrhea resolution (median 3 vs. 9 days,p<0.001) and to steroid titration (median 4 vs. 13 days, p<0.001) were shorter in pa- tients treated with infliximab + CS versus CS alone. Rates of CS- associated toxicities (39% vs. 54%;p= 0.249) and total steroid dur- ation (median 35 days vs. 51 days;p= 0.241) were numerically lower in the infliximab-treated patients (Table 1).
Conclusions
To our knowledge this is the first study to compare time to symptom resolution for irEC with infliximab + CS versus CS alone. Despite higher incidence of grade 3+ colitis, infliximab treatment was associ- ated with a statistically significant shorter time to symptom reso- lution without additional toxicities. The data suggest that early introduction of infliximab should be considered for patients with irEC until definitive prospective clinical trials.
P448
Incidence of thyroid test function abnormalities in patients receiving immune-checkpoint inhibitors for cancer treatment Nisha Patel, Anais Oury, Gregory Daniels, Lyudmila Bazhenova, Sandip Patel
University of California San Diego, La Jolla, CA, USA
Correspondence:Nisha Patel ([email protected]) Journal for ImmunoTherapy of Cancer2017,5(Suppl 2):P448 Background
With the advent of immune-checkpoint inhibitor (ICI) therapy (anti- CTLA-4, anti-PD-1), immune related adverse events (irAE) such as thy- roid function test abnormalities (TFTA) are common with a reported incidence range of 2-15% depending upon the ICI utilized [1,2]. The aim of this study was to describe the incidence of TFTAs retrospect- ively in patients who received ICI therapy.
Methods
A total of 285 patients were reviewed (178 male, 107 female; ages 16-94) of which 218 had no baseline TFTA, 61 had baseline TFTAs, and 6 had history of thyroidectomy and were excluded. Patients re- ceived at least one dose of ipilimumab and/or nivolumab or pembro- lizumab. Post-ICI therapy TFTA was classified according to definitions of thyroid abnormalities when possible [3].
Results
A total of 35% (76/218) patients had new onset TFTAs on ICI therapy. Of note, 70.5% (43/61) had baseline TFTA that were exacerbated by ICI ther- apy. Median time to new onset or exacerbated baseline TFTA were 46 & 33 days respectively. Of note, 65% (20/31) of patients on both ipilimumab and nivolumab had new onset TFTA, compared to 31.3% (15/48) with ipili- mumab, 31.5% (28/89) nivolumab, 26% (13/50) pembrolizumab (Table 1). Conclusions
The incidence of TFTAs with ICI therapy was higher than previously reported. Patients with baseline TFTA and/or receiving ipilimumab and nivolumab combination therapy had a higher incidence of TFTA than one agent ICI therapy. In conclusion, we recommend more fre- quent evaluation of TFT in the first two months, especially in those with baseline TFTA.
References
1. Corsello S, Barnabei A, Marchetti P, et al. Endocrine Side Effects Induced by Immune Checkpoint Inhibitors.J Clin Endocrinol Metab.
2013;98(4):1361-1375.
2. Morganstein D.L, Lai Z, Spain L, et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death recep- tor protein -1 inhibitors in the treatment of melanoma. Clinical Endocrin- ology. 2017;(0) 1-7.
3. Rossi E, Sgambato A, De Chiara G, et al. Thyroid-Induced Toxicity of Check-Point Inhibitors Immunotherapy in the Treatment of Advanced Non-Small Cell Lung Cancer. J Endocrinol Diabetes. 2016; 3 (1):1-10.
Table 1 (abstract P447).See text for description
Table 1 (abstract P448).See text for description
P449
Neurotoxicity in patients with metastatic solid tumors treated with immune checkpoint inhibitors: a single institution retrospective analysis
Bianca Santomasso, Rachna Malani, Aya Haggiagi, Jenessa Holder, Yelena Shames, Samuel Briggs, Margaret Callahan
Memorial Sloan Kettering Cancer Center, New York, NY, USA
Correspondence:Bianca Santomasso ([email protected]); Margaret Callahan
Journal for ImmunoTherapy of Cancer2017,5(Suppl 2):P449 Background
Immune checkpoint inhibitors (ICIs) have dramatically improved survival for patients with melanoma and are playing an increasingly important role in the management of other tumor types. Anti-CTLA4, anti-PD1, and anti-PDL1 antibodies have been approved for multiple tumor types based on their clinical benefit, however they can be as- sociated with a unique set of toxicities termed immune related ad- verse events (irAEs). We aimed to identify the incidence and clinical manifestations of patients who developed neurologic irAEs with ICIs at our institution in order to inform investigation and management guidelines.
Methods
An IRB approved retrospective study involved review of charts and institutional databases at MSKCC. We identified patients who devel- oped neurotoxicity while on at least one of the following ICIs: anti- CTLA4, anti-PD1 or anti-PD-L1 over a 6 year period (1/1/2010-11/16/ 2016).
Results
We identified a total of 3,804 patients who were treated with one or more ICI during the period of review. Neurotoxicity was observed in 81 patients (2.1%) and affected both central and peripheral nervous systems. 31 patients (38.2%) received more than one ICI. Median number of cycles prior to developing toxicity was 3 (1-29). Ten patients had more than one neurotoxicity. The various neurologic phenotypes observed in patients included: sensory neuropathy, en- cephalopathy, headache and aseptic meningitis, myasthenia gravis- like syndrome, myopathy, autonomic neuropathy, radiculopathy, brachial plexitis, mononeuritis multiplex, Guillain-Barre syndrome or chronic inflammatory demyelinating polyneuropathy, paraneoplastic neurologic disorder, and PRES. 43 patients required hospital admis- sion and 2 required ICU level of care. A diagnosis of neurotoxicity was based upon the temporal association with ICIs and appropriate workup including but not limited to neurologic consultation, lumbar puncture, and neuroimaging. Patients were treated with drug holi- day, observation, corticosteroids, plasma exchange and/or IVIG. Conclusions
As ICIs are being used with increased frequency, oncologists and other health care providers should be aware of the varied manifesta- tions of neurotoxicity in order to ensure appropriate diagnosis, work up and treatment. Prompt treatment may relay a benefit in regards to outcome.