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Blood ◽  
2021 ◽  
Tanya Siddiqi ◽  
Jacob D Soumerai ◽  
Kathleen A Dorritie ◽  
Deborah M. Stephens ◽  
Peter A Riedell ◽  

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50×106 or 100×106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2‒11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100×106 CAR+ T cells.

Liver Cancer ◽  
2021 ◽  
pp. 1-13
Kennedy Yao Yi Ng ◽  
Sze Huey Tan ◽  
Jack Jie En Tan ◽  
Desiree Shu Hui Tay ◽  
Ailica Wan Xin Lee ◽  

<b><i>Introduction:</i></b> Development of immune-related adverse events (irAEs) has been associated with enhanced efficacy with the use of immune checkpoint inhibitors (ICIs). It remains unknown whether such an association exists in advanced hepatocellular carcinoma (aHCC). This study aims to evaluate the association between irAEs and ICI efficacy in patients with aHCC. <b><i>Methods:</i></b> We performed a retrospective cohort study on patients with aHCC who received at least one dose of an ICI between May 2015 and November 2019 at the National Cancer Centre Singapore. The primary study objectives were to compare the overall survival (OS) and progression-free survival (PFS) between patients with and without irAEs. Complementary multivariable landmark analyses were performed at the 6-week and 12-week landmarks. Data cutoff was December 31, 2020. <b><i>Results:</i></b> One hundred and sixty-eight patients were included. Median age was 69 years, 85.7% were male, 57.7% had hepatitis B infection, 60.7% had ECOG 0, and 78.0% had Child-Pugh A liver cirrhosis. 82.7% received ICI monotherapy, while 17.3% received ICI in combination. Development and severity of irAE were correlated with survival. The median PFS for grade ≥3 irAE versus grades 1–2 irAE versus no irAE was 8.5 versus 3.6 versus 1.3 mths (<i>p</i> &#x3c; 0.001). The median OS for grade ≥3 irAE versus grades 1–2 irAE versus no irAE was 26.9 versus 14.0 versus 4.6 mths (<i>p</i> &#x3c; 0.001). Patients with ≥2 irAEs had a significantly longer OS on multivariable analysis (adjusted hazard ratio [aHR]0.35, <i>p</i> &#x3c; 0.001). The presence of grade ≥3 irAEs was associated with a significantly longer OS on the multivariable analysis at the 6-week landmark (aHR0.34, <i>p</i> = 0.030) and 12-week landmark (aHR0.28, <i>p</i> = 0.011). The use of systemic corticosteroids in patients with irAE was associated with a trend toward a longer OS (20.7 vs. 14.3 mths, <i>p</i> = 0.064). <b><i>Conclusion:</i></b> Our study suggests that the presence of all-grade irAEs may be a potential prognostic biomarker in patients with aHCC treated with ICI. Patients with more severe irAEs and multisystem involvement have better prognosis. The prompt use of systemic corticosteroids to treat patients with irAEs is key to ensure the best long-term outcomes for these patients.

Medicina ◽  
2021 ◽  
Vol 57 (11) ◽  
pp. 1151
Shinsuke Suzuki ◽  
Satoshi Toyoma ◽  
Yohei Kawasaki ◽  
Koh Koizumi ◽  
Nobuko Iikawa ◽  

Background and Objectives: In recent years, the effectiveness of chemotherapy after immune checkpoint inhibitor administration has attracted attention in various cancers, including head and neck cancers. However, individual assessments of the administered chemotherapy regimens are insufficient. This study aimed to evaluate the efficacy and safety of chemotherapy after immune checkpoint inhibitor administration in recurrent metastatic head and neck cancer by focusing on a single regimen. Materials and Methods: We retrospectively reviewed clinical and radiological data from the medical records of 18 patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who received systemic chemotherapy with weekly cetuximab and paclitaxel (Cmab + PTX) after progression following immune checkpoint inhibitor (ICI) therapy. The objective response rate (ORR) and disease control rate (DCR) were assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method. Adverse events (AEs) were recorded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: In all patients, the ORR, DCR, median PFS, and median OS were 44.4%, 72.2%, 3.8 months, and 9.6 months, respectively. Regarding AEs, three patients developed grade 3 neutropenia. Grade 3 anemia, paronychia, asthenia, and peripheral neuropathy were observed in one patient each. There were no treatment-related deaths. Conclusions: Cmab + PTX was shown to maintain high efficacy and acceptable safety for R/M HNSCC that progressed after ICI therapy. Further research is needed to establish optimal treatment sequences and drug combinations for recurrent R/M HNSCC.

Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1968
Diego Kauffmann-Guerrero ◽  
Julian Taugner ◽  
Chukwuka Eze ◽  
Lukas Käsmann ◽  
Minglun Li ◽  

Background: Maintenance treatment with immune-checkpoint inhibition (ICI) has been shown to significantly improve patient prognosis after chemoradiotherapy (CRT) for inoperable stage III NSCLC. This survival advantage may be achieved at the expense of an increased probability for symptomatic pneumonitis as CRT as well as ICI treatment is associated with the risk of treatment-related pulmonary toxicity. Methods: We screened a prospective chemoradioimmunotherapy (CRT-IO) cohort consisting of 38 patients and identified patients with therapy-related grade 3 pneumonitis. All patients were treated with intravenous high dose corticosteroids and closely monitored by CT-scans and extended longitudinal lung function tests. We analyzed lung function parameters and CT morphological features to characterize patients’ outcome. Results: Six (16%) patients treated with CRT-IO developed grade 3 pneumonitis one to six months after completion CRT. In the CT imaging, pneumonitis was characterized by diffuse ground glass capacities and in part pulmonary consolidations within and outside the planning target volume. Onset of pneumonitis was accompanied by a reduction in diffusion capacity in all cases. The mean decline of diffusion capacity was 25.8% [6–53%]. Under treatment with corticosteroids, all patients recovered regarding symptoms and changes in CT morphology. In five out of six patients, diffusion capacity improved to at least 80% of the baseline [80–96%]. One patient showed a significant increase of diffusion capacity after treatment (from 32% to 53%) but reached only 62% of the initial value. Conclusions: Pneumonitis is a severe complication of CRT-IO. High-resolution CT imaging and extended lung function testing proved to be a suitable approach in detecting and monitoring of CRT-IO associated pneumonitis.

2021 ◽  
Vol 38 ◽  
pp. 100884
Zoe Laing-Aiken ◽  
Sara Ooi ◽  
Gaithri Mylvaganam ◽  
Huan Xie ◽  
Joanne Ludlow ◽  

Partha Sarathi Roy ◽  
Gaurav Kumar ◽  
Sreya Mallik ◽  
Satya Sadhan Sarangi ◽  
Bhargab Jyoti Saikia ◽  

Abstract Background Squamous cell carcinoma of the esophagus ranks as the most common cause of cancer incidence and mortality in males and the second most common in females. Surgery alone is associated with poor long-term survival. Neoadjuvant chemoradiation and perioperative chemotherapy without radiation have been tried to improve survival rates. Methods We retrospectively evaluated the neoadjuvant chemotherapy in forty-eight patients with non-metastatic, non-cervical squamous cell carcinoma of the esophagus with a docetaxel-based three-drug regimen to improve complete pathological response rates. Results The median age of presentation was 52 years, with male preponderance. All the patients received three cycles of docetaxel-cisplatin-fluorouracil-based chemotherapy. A complete pathological response to neoadjuvant chemotherapy was seen in 8 patients (17%). Rates of grade 3 hematological toxicities were seen in 12% of patients, with no observed grade 4 toxicity. The most common non-hematological toxicity was grade 3 alopecia (seen in 40%) and grade 2 nausea/vomiting in 8% of patients. At a median follow-up of 26.5 months, 2-year survival for the patients receiving chemotherapy and surgery is 66%. Conclusions Preoperative chemotherapy with a taxane-based triple-drug regimen is a reasonable approach in squamous cell carcinoma of the esophagus, associated with improvement in complete pathological response rates, increases complete resection rates, with manageable toxicity.

2021 ◽  
Hejing Bao ◽  
LingZhen Ma ◽  
Xiaoli Lin ◽  
Boshen Zhang ◽  
Juan Zhang ◽  

Abstract Objectives Primary pulmonary lymphoepithelioma-like carcinoma (PPLELC) is a rare subtype of primary non-small cell lung cancer (NSCLC), and the first-line therapy for metastatic PPLELC patients remains controversial. The purpose of this study was to investigate the efficacy and safety of immune checkpoint inhibitors(ICIs) combined with chemotherapy(CT) compared with traditional chemotherapy in these patients. Methods A total of 168 patients with metastatic PPLELC came from six grade A hospitals from August 2018 to August 2020 were selected. 17 patients were enrolled in the ICI group and received 200mg of Pembrolizumab plus albumin paclitaxel and carboplatin every 3 weeks. 34 patients with chemotherapy alone were assigned to the CT group and received albumin-paclitaxel combined with carboplatin every 3 weeks. Results As of June 1, 2021, the median PFS was 14.9 months for ICI group and 6.4 months for CT group [Hazard Ratio (HR), 0.29; 95% confidence interval (CI), 0.15-0.55; P < 0.05]. ORR was 64.7% in ICI group and 35.3% in CT group [HR, 0.65; 95%CI, 0.39-0.90; P=0.047]. The median OS of ICI group was not reached, while that of CT group was 13 months. In the ICI group, there were 8 cases (47.1%) of grade 3 treatment-related adverse reactions and 5 cases (29.4%) of grade 4 treatment-related adverse reactions. In the CT group, there were 9 cases (26.5%) of grade 3 treatment-related adverse reactions and 8 cases (23.5%) grade 4 treatment-related adverse reactions. FBXW7 mutation were negatively and TP53 mutation, MRE11A p.V198S mutation, PTEN p.T319FS mutation were positively correlated with the efficacy of immunotherapy. Conclusions In patients with metastatic PPLELC, the efficacy of immune checkpoint inhibitors combined with chemotherapy was significantly better than that of chemotherapy alone, and adverse reactions were acceptable.

2021 ◽  
Vol 11 ◽  
You-Meng Sun ◽  
Wei Li ◽  
Zhi-Yu Chen ◽  
Ying Wang

BackgroundImmune checkpoint inhibitors (ICIs) have dramatically altered the treatment landscape for patients with melanoma. However, their use also generates unique immune-related adverse effects (irAEs). We performed a systematic review and network meta‐analysis to compare the risk of pneumonitis associated with ICIs for patients with advanced or metastatic melanoma.MethodsPhase II/III randomized clinical trials (RCTs) with ICIs were identified through comprehensive searches of multiple databases. An NMA was conducted to compare the risk of pneumonitis associated with ICIs and all‐grade (grade 1‐5) and high‐grade (grade 3‐5) immune‐related pneumonitis (IRP) were estimated by odds ratios (ORs).ResultsA total of 10 randomized clinical trials involving 5,335 patients were enrolled in this study. Conventional chemotherapy was associated with a lower risk of grade 1–5 IRP compared with ICIs monotherapy (OR, 0.14, 95% CI, 0.03 to 0.73) and dual ICIs combination (OR, 0.03, 95% CI, 0.00 to 0.19). In addition, dual ICIs combination showed a noticeably higher risk than ICI monotherapy (OR, 4.45, 95% CI, 2.14 to 9.25) of grade 1–5 IRP. No significant difference in grade 1–5 IRP was observed between cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors. As to grade 3‐5 IRP, no statistically significant difference was found among different ICIs-based regimens.ConclusionThese findings revealed that ICIs could increase the risk of all-grade pneumonitis for patients with advanced melanoma, compared with conventional chemotherapy. Dual ICIs combination could further increase the risk of all-grade pneumonitis than ICIs monotherapy. There was no significant difference in the risk of pneumonia between CTLA-4 and PD-1 inhibitors.

2021 ◽  
Vol 11 ◽  
Qiuji Wu ◽  
Chunmei Zhu ◽  
Shuyuan Zhang ◽  
Yunfeng Zhou ◽  
Yahua Zhong

BackgroundCisplatin-based concurrent chemoradiotherapy is standard of care for locally advanced head and neck cancers (LAHNC). Nedaplatin, lobaplatin and nimotuzumab have shown anti-cancer effect with less gastrointestinal toxicity and nephrotoxicity. However, the profile of hematological toxicities of these agents in combination with radiotherapy has not been fully illustrated.MethodsWe retrospectively collected the clinical data of consecutive LAHNC patients treated by cisplatin-, nedaplatin-, lobaplatin-, and nimotuzumab-based concurrent chemoradiotherapy. Routine blood cell counts were obtained every 4 to 7 days. Hematological toxicities were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.ResultsA total of 181 eligible LAHNC patients were assigned to nimotuzumab group (n = 34), cisplatin group (n = 52), nedaplatin group (n = 62) or lobaplatin group (n = 33). Among the four groups, nimotuzumab group displayed lightest hematological toxicities, followed by cisplatin group, nedaplatin group, and lobaplatin group. Lobaplatin was more likely to produce grade 3/4 leukopenia compared with cisplatin (48.5% vs 25.0%). Compared with cisplatin, nedaplatin and lobaplatin were more likely to cause grade 3/4 thrombocytopenia (nedaplatin 19.4% vs cisplatin 3.8%; lobaplatin 30.3% vs cisplatin 3.8%). Similarly, nimotuzumab group showed highest nadir levels among the four groups, followed by cisplatin, nedaplatin, and lobaplatin group. Moreover, concurrent platinum treatment and induction chemotherapy were risk factors of developing grade 3/4 hematological toxicities.ConclusionNimotuzumab-based concurrent chemoradiotherapy in head and neck cancers produced the lightest hematological toxicities, followed by cisplatin, nedaplatin, and lobaplatin. Patients should be given specific attention during concurrent chemoradiotherapy, particularly in the presence of previous induction chemotherapy.

2021 ◽  
Vol 12 ◽  
Juanfang Liu ◽  
Zhen Li ◽  
Wenguang Zhang ◽  
Huibin Lu ◽  
Zhanguo Sun ◽  

Aim: This study aimed to report the efficacy and safety of trans-arterial chemoembolization (TACE) plus lenvatinib and camrelizumab in patients with advanced hepatocellular carcinoma (HCC).Methods: This retrospective study enrolled 22 patients with advanced HCC from March 2018 to December 2019. All the patients received comprehensive treatment with TACE plus lenvatinib followed by camrelizumab. Overall survival (OS) and progression-free survival (PFS) were calculated and analysed using the Kaplan-Meier method and log-rank test. Treatment response and adverse events (AEs) were also evaluated.Results: The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 68.2 and 100% at the first month and 72.7 and 95.5% at the third month, respectively. The median OS was 24 months (95% CI, 20.323–27.677 months), and the median PFS was 11.4 months (95% CI, 8.846–13.954 months). The majority of treatment-related adverse reactions were mild or moderate, except for 4 that developed to grade 3–4 (3 reactions of grade 3, 1 reaction of grade 4). No deaths or other serious adverse reactions occurred.Conclusion:Trans-arterial chemoembolization plus lenvatinib and camrelizumab shows good results incontrolling tumour progression and prolonging median OS in patients with advanced HCC.

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