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Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A.; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S.; Rahma, Osama E.; Suarez-Almazor, Maria E.; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35"“3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95"“5.66), P =.054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P =.53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
SCOPUS:85175548637
ISSN: 2162-4011
CID: 5616442

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S; Rahma, Osama E; Suarez-Almazor, Maria E; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
PMCID:10732692
PMID: 38126033
ISSN: 2162-402x
CID: 5626492

Safety and Effectiveness of Immune Checkpoint Inhibitors Combination versus Single Agent Therapy in Patients with Pre-existing Autoimmune Diseases [Meeting Abstract]

Reid, P; Sandigursky, S; Lopez-Olivo, M A; Song, J; Safa, H; Cytryn, S; Buni, M; Pavlick, A; Krogsgaard, M; Abu-Shawer, O; Altan, M; Weber, J; Suarez-Almazor, M; Diab, A; Abdel-Wahab, N
Background/Purpose: Treatment with a combination of immune checkpoint inhibitors (ICI) has promising outcomes in many tumor types but carries higher adverse event risk than ICI monotherapy. Also, patients with pre-existing autoimmune disease (AID) have largely been excluded from ICI clinical trials due to concern for pre-existing AID flare or immune-related adverse events (irAEs). This is the first study to analyze safety and effectiveness of ICI combination versus monotherapy for this at-risk population.
Method(s): We conducted a multi-center retrospective study in patients with pre-existing AIDs receiving ICIs (i.e., antiprogrammed cell death protein 1 (PD-1) single-agent (monotherapy) or ICI combination). Primary endpoints included the time to occurrence of any-type ICI AE (irAE or AID flare), time to irAEs and time to AID flares in the presence of the competing risk of death with progression free survival (PFS, time to progression or death) and overall survival (OS) as secondary endpoints. We used Fine-Gray models and Cox regression models to investigate the factors associated with these endpoints.
Result(s): 133 patients with pre-existing AID who received ICIs were identified: 69 (52%) monotherapy and 64 (48%) combination (Table 1). About half the patients had melanoma (44%) and 25% had lung cancer. Rheumatic (34%) or dermatologic (22%) pre-existing AIDs were the most common. Most patients (95%) had controlled autoimmune disease at ICI start. Six of 7 patients with active AID at baseline experienced some AE. Patients receiving baseline DMARD(s) were more likely to experience an AE (95%CI 1.079-2.996, p=0.024). The cumulative incidence of irAEs was higher for ICI combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.28, 95%CI 1.36-3.84), adjusting for age at malignancy, but there was no significant difference between rate of high-grade toxicity for patients treated with ICI combination versus monotherapy (See Figure 1). On subgroup analysis for patients with melanoma or lung cancer, the cumulative incidence of irAEs or AID flares were not statistically different between treatment groups. PFS was longer (but not statistically significant) for combination therapy for any tumor type compared to single agent (median 12.3mo, 95%CI 5.0-23.2 versus 7.3mo, 95%CI 5.2-11.3, p=0.116). Similar trend was noted for PFS for melanoma (median 23.2mo combination vs. 14.0mo monotherapy, p=0.4237), while the opposite relation was noted for lung cancer subgroup (4.4mo combination vs. 7.1mo monotherapy, p=0.2933).
Conclusion(s): Efficacy of ICI combination versus monotherapy was not statistically significant and so still remains unclear in this patient population, but there was no significant difference in rates of high-grade toxicity between the two cohorts. Our data supports the notion that patients with pre-existing AIDs should not be indiscriminately precluded from getting ICI combination. Our results provide guidance for future prospective clinical trials studying combination therapy for subgroups of this at-risk population. No statistically significant difference appreciated in high grade adverse events between patients with pre-existing autoimmune disease treated with ICI combination versus monotherapy. Grading determined by the Common Terminology Criteria for Adverse Events rubric with grade 3 or higher considered "high grade."
EMBASE:639967125
ISSN: 2326-5205
CID: 5512972

Risk of Toxicity After Initiating Immune Checkpoint Inhibitor Treatment in Patients With Rheumatoid Arthritis

Efuni, Elizaveta; Cytryn, Samuel; Boland, Patrick; Niewold, Timothy B; Pavlick, Anna; Weber, Jeffrey; Sandigursky, Sabina
INTRODUCTION/BACKGROUND:Immune checkpoint inhibitors (ICIs) are increasingly used to treat advanced cancer. Rheumatoid arthritis (RA) is associated with an increased risk of malignancies; however, patients with RA have been excluded from ICI trials. In this study, we evaluated risk of toxicity after initiation of ICI treatment in RA patients. METHODS:We conducted a single-institution, medical records review analysis to assess the incidence of immune-related adverse events (irAEs) and autoimmune disease (AID) flares among patients with AIDs treated with ICIs from 2011 to 2018. A subgroup analysis for RA patients was performed with frequencies of irAEs and AID flares reported. RESULTS:Twenty-two patients with RA who were treated with ICI for malignancy were identified. At the time of ICI initiation, 86% had inactive RA disease activity. Immune-related adverse events occurred in 7 (32%) of patients, with 2 (9%) developing grade 3 (i.e., severe) irAEs. Immune checkpoint inhibitors were temporarily discontinued because of irAEs in 5 patients (23%), and permanently in 1 patient. Rheumatoid arthritis flares occurred in 12 patients (55%). Of those, 10 (83%) received oral corticosteroids with an adequate treatment response. CONCLUSIONS:Our analysis suggests that irAEs following ICI treatment are not increased among RA patients compared with other cancer patients. Heightened RA disease activity during ICI treatment is common, but most adverse events are manageable with oral corticosteroids, and few require permanent ICI discontinuation. A close collaboration between the oncologist and rheumatologist is advisable when considering ICIs in patients with RA.
PMID: 31977647
ISSN: 1536-7355
CID: 4273562

Durvalumab consolidation therapy in a patient with stage IIIB unresectable NSCLC harboring a MET exon 14 splice site alteration

Cytryn, Samuel; Ferreira, Virginia; Boland, Patrick; Chachoua, Abraham; Sabari, Joshua
BACKGROUND:Recent literature has identified significant benefit of consolidation durvalumab following chemoradiotherapy in patients with unresectable non-small cell lung cancer (NSCLC). However, immunotherapy has demonstrated modest benefit in patients harboring oncogene driver mutations. While standard of care in metastatic oncogenic driven tumors is targeted tyrosine kinase inhibitors (TKIs), there is little data to guide treatment for patients who present with earlier stage unresectable disease, receiving chemoradiotherapy and have both high PD-L1 expression as well as concomitant actionable driver mutations. CLINICAL PRESENTATION/METHODS:We report a patient who presented with stage IIIB lung adenocarcinoma with high PD-L1 expression (80%) for which she received definitive concurrent chemoradiotherapy with consolidation durvalumab. The patient quickly progressed and was found to harbor a MET exon 14 splice site alteration for which she received crizotinib and had a good response. DISCUSSION/CONCLUSIONS:This case highlights the possibility that patients with non-metastatic, unresectable NSCLC with high PD-L1 expression and a concomitant driver mutation may benefit from targeted tyrosine kinase inhibitors rather than immune checkpoint inhibitor therapy.
PMID: 34091214
ISSN: 1872-8332
CID: 4899452

Common Germline Mutations in a Patient With Multiple Primary Lung Cancers [Case Report]

Cytryn, Samuel; Moreira, Andre; Chachoua, Abraham; Sabari, Joshua
PMID: 32127285
ISSN: 1938-0690
CID: 4339692

Outcomes in patients with aggressive B-cell non-Hodgkin lymphoma after intensive frontline treatment failure

Ayers, Emily C; Li, Shaoying; Medeiros, L Jeffrey; Bond, David A; Maddocks, Kami J; Torka, Pallawi; Mier Hicks, Angel; Curry, Madeira; Wagner-Johnston, Nina D; Karmali, Reem; Behdad, Amir; Fakhri, Bita; Kahl, Brad S; Churnetski, Michael C; Cohen, Jonathon B; Reddy, Nishitha M; Modi, Dipenkumar; Ramchandren, Radhakrishnan; Howlett, Christina; Leslie, Lori A; Cytryn, Samuel; Diefenbach, Catherine S; Faramand, Rawan; Chavez, Julio C; Olszewski, Adam J; Liu, Yang; Barta, Stefan K; Mukhija, Dhruvika; Hill, Brian T; Ma, Helen; Amengual, Jennifer E; Nathan, Sunita; Assouline, Sarit E; Orellana-Noia, Victor M; Portell, Craig A; Chandar, Ashwin; David, Kevin A; Giri, Anshu; Hess, Brian T; Landsburg, Daniel J
BACKGROUND:Salvage immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation is the standard-of-care second-line treatment for patients with relapsed/refractory diffuse large B-cell lymphoma after first-line R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Outcomes after receipt of second-line immunochemotherapy in patients with aggressive B-cell lymphomas who relapse or are refractory to intensive first-line immunochemotherapy regimens (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [R-EPOCH], rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine [R-HyperCVAD], rituximab, cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and cytarabine [R-CODOX-M/IVAC]) remain unknown. METHODS:Outcomes of patients with non-Burkitt, aggressive B-cell lymphomas and relapsed/refractory disease after first-line treatment with intensive immunochemotherapy regimens who received platinum-based second-line immunochemotherapy were reviewed retrospectively. Analyses were performed to determine progression-free survival (PFS) and overall survival (OS) from the time of receipt of second-line immunochemotherapy. RESULTS:In total, 195 patients from 19 academic centers were included in the study. The overall response rate to second-line immunochemotherapy was 44%, with a median PFS of 3 months and a median OS of 8 months. Patients with early treatment failure (primary refractory or relapse <12 months from completion of first-line therapy) experienced inferior median PFS (2.8 vs 23 months; P < .001) and OS (6 months vs not reached; P < .001) compared with patients with late treatment failure. Although the 17% of patients with early failure who achieved a complete response to second-line immunochemotherapy experienced prolonged survival, this outcome could not be predicted by clinicopathologic features at the start of second-line immunochemotherapy. CONCLUSIONS:Patients with early treatment failure after intensive first-line immunochemotherapy experience poor outcomes after receiving standard second-line immunochemotherapy. The use of standard-of-care or experimental therapies currently available in the third-line setting and beyond should be investigated in the second-line setting for these patients.
PMID: 31568564
ISSN: 1097-0142
CID: 4165282

Toxicities of single agent and combination immune checkpoint inhibitors in patients with autoimmune diseases. [Meeting Abstract]

Cytryn, Samuel; Efuni, Elizaveta; Sandigursky, Sabina
ISI:000487345800542
ISSN: 0732-183x
CID: 4645582

Risk of Immunotherapy Related Toxicity in Patients with Rheumatoid Arthritis [Meeting Abstract]

Efuni, Elizaveta; Cytryn, Samuel; Boland, Patrick; Sandigursky, Sabina
ISI:000507466902197
ISSN: 2326-5191
CID: 4645592