Comparison of efficacy and safety between simultaneous integrated boost intensity-modulated radiotherapy and standard-dose intensity-modulated radiotherapy in locally advanced esophageal squamous cell carcinoma: a retrospective study

Objective This study aimed to evaluate the efficacy and safety of simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT) versus standard-dose intensity-modulated radiotherapy (SD-IMRT) in the treatment of locally advanced esophageal squamous cell carcinoma. Methods From July 2003 to March 2014, 1748 patients in a single center who received definitive chemoradiotherapy were included in the analysis. A total of 109 patients who underwent SIB-IMRT and fulfilled all inclusion and exclusion criteria were identified as the study group. A total of 266 patients who underwent SD-IMRT (60 Gy/30 fractions, 2 Gy/fraction, 1 time/day, 5 times/week) during the same period were selected as the control group. Propensity score matching (PSM) was used to balance the baseline characteristics. Survival status, treatment failure mode, and the occurrence of adverse events were compared between the two groups. Results There were more women and more cervical and upper thoracic cancers (P = 0.038, < 0.001, respectively) in the SIB-IMRT group before case matching. The median progression-free survival (PFS) in the SD-IMRT and SIB-IMRT groups was 22 and 19 months, respectively, and the median overall survival duration was 24 and 22 months, respectively, with χ2 = 0.244 and P = 0.621. After PSM of 1:1, 138 patients entered the final analysis (69 cases from each group). The median PFS of the SD-IMRT group and the SIB-IMRT group was 13 and 18 months, respectively, with χ2 = 8.776 and P = 0.003. The 1‑, 3‑, and 5‑year overall survival rates were 66.7, 21.7, and 8.7% and 65.2, 36.2, and 27.3%, respectively, and the median overall survival duration was 16 and 22 months, respectively, with χ2 = 5.362 and P = 0.021. Treatment failure mode: 5‑year local regional recurrence rates of SD-IMRT and SIB-IMRT were 50.7 and 36.2%, respectively, with χ2 = 2.949 and P = 0.086. The 5‑year distant metastasis rates of the two groups were 36.2 and 24.6%, respectively, with χ2 = 2.190 and P = 0.139. Adverse events: 3 patients experienced grade 4–5 toxicity (2.2%), including one case of grade 4 radiation esophagitis and two cases of grade 5 radiation pneumonitis, all in the SD-IMRT group; 14 patients experienced grade 3 adverse events (10.1%), primarily including radiation esophagitis, radiation pneumonitis, and hematological toxicity. Conclusion The technique of SIB-IMRT was safe and reliable compared with SD-IMRT. In addition, SIB-IMRT had locoregional control advantages and potential survival benefits.

Promising Immunotherapy in Metastatic Testicular Sex Cord Stromal Tumours After First-Line Chemotherapy

BackgroundTesticular sex cord stromal tumours (TSCSTs) are rare, with few studies focusing on the metastatic TSCST prognosis. The value of treatments, including radical orchiectomy (RO) and retroperitoneal lymph node dissection (RPLND), in preventing metastasis is controversial. Additionally, metastatic TSCSTs are resistant to chemotherapy. We aimed to assess the effectiveness and safety of immunotherapy in metastatic TSCSTs after first-line chemotherapy.MethodsWe retrospectively screened patients with testicular tumours undergoing testis surgery between January 2005 and January 2019. Patients with TSCSTs who had undergone testis-sparing surgery (TSS) or RO were identified. The malignant type was defined as metastasis confirmed by pathology. Treatment responses, progression-free survival (PFS), overall survival (OS) and safety were analysed.ResultsAmong the 494 testicular tumour patients who received TSS or RO, 11 (2.2%) patients with histologically proven TSCSTs were identified. At the last follow-up, 7 patients survived without tumours, and 4 patients developed metastasis and received first-line cisplatin-based chemotherapy, with 1 of them achieving an objective response. Their PFS times were 1.5, 2.2, 9.0, and 17.0 months, respectively. Two patients received immune checkpoint inhibitors (ICIs) after developing chemotherapy resistance and achieved a partial response up to the last follow-up; one of them experienced Grade 1 adverse events, and the other experienced Grade 2 adverse events during immunotherapy. The median OS time of the 4 patients with metastatic TSCSTs was 32 months.ConclusionsTSCSTs are rare, and most are benign with a good prognosis. ICIs represent a promising option for improving clinical outcomes in metastatic TSCSTs.

Sustainable Efficacy and Safety Results from Lummicar Study 1: A Phase 1/2 Study of Fully Human B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Chinese Subjects with Relapsed and/or Refractory Multiple Myeloma

Background: CT053 is a fully human autologous chimeric antigen receptor (CAR) T-cell therapy comprising a B-cell maturation antigen (BCMA)-specific single-chain variable fragment (25C2). A clinical trial of CT053 is ongoing in LUMMICAR STUDY 1 (NCT03975907) for patients with relapsed and refractory multiple myeloma (RRMM) in China. The pivotal Phase 2 of LUMMICAR STUDY 1 is actively enrolling patients. Here, we report clinical data from Phase 1 with 12 months of follow-up. Methods: Subjects with RRMM who had received ≥3 prior therapies, including at least one proteasome inhibitor and one immunomodulatory drug were enrolled in Phase 1 study. Adverse events (AEs) were graded according to CTCAE, v5.0; Cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). Response was assessed per IMWG 2016 criteria. Minimal residual disease (MRD) was tested by next-generation flow cytometry on bone marrow aspirates by the EuroFlow assay with a minimum sensitivity of 1 in 10⁵ nucleated cells or higher, and CAR copies in the subject peripheral blood were monitored by quantitative real-time polymerase chain reaction (qPCR). Results: Fourteen subjects with a median age of 54 years (range 34-62) received CT053 infusion. Three subjects received 1.0×10 8 CAR+ T cells and eleven subjects received 1.5×10 8 CAR+ T cells. As of July 8, 2021, 14 subjects with a median follow-up of 13.6 months since infusion. Of the 14 subjects, 11 (78.6%) had received autologous stem cell transplantation, 2 (14.2%) had extramedullary disease at baseline, 2 (14.3%) had ISS stage III, and 5 (35.7%) had high-risk cytogenetics. The median prior therapies was 6 (range 3-7) and no subject received bridging therapy. The most common AEs were expected hematological toxicities. All subjects (100%) experienced ≥ grade 3 neutropenia, 91.7% experienced ≥ grade 3 thrombocytopenia, and most recovered to ≤ grade 2 within 2 weeks. No dose limiting toxicity or treatment-related death was reported. Additionally, no ≥ grade 3 CRS or neurotoxicity was observed, 92.9% subjects (13/14) experienced grade 1 or 2 CRS (9 grade 1, 4 grade 2). CRS occurred at a median of 6 days (range 2-12) post-infusion with a median duration of 7 days. No severe infections were reported except one case of grade 3 lung infection. A 100% overall response rate was achieved in 14 subjects, with 11 stringent complete responses (sCR, 78.6%), 2 very good partial responses (VGPR), and 1 partial response, with a ≥VGPR rate of 92.9%. Four subjects achieved sCR at week 52. As of July 8, 2021, 12 subjects with at least 12 months of efficacy assessment were still in the study, and the 12-month progression-free survival (PFS) rate was 85.7%. With a median follow-up of 13.6 months, the median duration of response and the median PFS had not been reached. All 11 subjects with sCR were MRD-negative, and 9 subjects reached sustained CR/sCR for more than 12 months (Figure 1). Three subjects had disease progressed including two subjects with extramedullary disease progressed at week 16. Interestingly, the CR/sCR rate for the subjects without extramedullary disease is 91.7% (11/12). The 1-year PFS rate for subjects without extramedullary disease reached 100%。 CT053 cells expanded and persisted well. No immunogenicity was detected. Conclusion: These results demonstrate that CT053 CAR T cells at a dose of 1.0-1.5×10 8 cells achieve a deep and durable response, including a high MRD-negative sCR rate, with an acceptable safety profile in subjects with heavily pretreated RRMM. Figure 1 Figure 1. Disclosures Li: CARsgen: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Xiao: CARsgen Therapeutics Corp: Current Employment. Wang: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Tang: CARsgen Therapeutics Corp: Current Employment.

A Prospective Observational Study on the Efficacy and Safety of Infliximab-Biosimilar (CT-P13) in Patients With Takayasu Arteritis (TAKASIM)

Objectives: Infliximab (IFX) is widely used in patients with refractory Takayasu arteritis (TAK). Recently, the IFX-biosimilar CT-P13 has been introduced for the treatment of inflammatory diseases. The aim of this study was to assess the efficacy and safety of CT-P13 in patients with refractory TAK.Methods: In this prospective, open-label, single-center trial, TAK patients either already on treatment with IFX-originator (switch group) or never treated with IFX (naïve group) received CT-P13 for 52 weeks. The primary outcomes of the study were: (i) number of patients with active disease at month 6; (ii) incidence of treatment-emergent adverse events at month 12. Disease activity was assessed at month 6 and month 12 by clinical evaluation (ITAS-2020, ITAS-ESR, and ITAS-CRP scores) and imaging assessment [magnetic resonance angiography (MRA) and (18F)-FDG-PET].Results: 23 patients were recruited (21 switch, 2 naïve). At baseline, 7 patients (32%) were classified as active. At month 6, one patient voluntarily dropped out and 7 patients were still active (30%), including one patient started on a different bDMARD at month 2 due to poor disease control. Mean daily dose of prednisone equivalent was significantly lower than baseline (4.2 ± 1.9 mg vs. 4.8 ± 2.1 mg, p = 0.009). At month 12, another patient was excluded because of pregnancy desire. Five patients were classified as active (24%), including two patients started on a different bDMARD at month 2 and month 6. Mean daily dose of prednisone equivalent was significantly lower than baseline (3.3 ± 2.6, p = 0.034). No patient experienced side effects during CT-P13 infusion. Overall, one patient experienced grade 1 adverse event and 9 patients experienced grade 2 adverse events. In no case hospitalization was required. CT-P13 retention rate was 90.9% at month 6 and 90.4% at month 12.Conclusion: In this study, the use of IFX-biosimilar CT-P13 in patients with refractory TAK showed satisfying efficacy and safety profile.

Radiotherapy dose–volume parameters predict facial lymphedema after concurrent chemoradiation for nasopharyngeal carcinoma

Background To investigate risk factors for developing radiation-associated facial lymphedema (FL) in nasopharyngeal carcinoma (NPC) patients after concurrent chemoradiation (CCRT). Methods Clinical data from 87 patients who underwent definitive CCRT for NPC in 2010–2018 was retrospectively evaluated. FL severity was graded using MD Anderson Cancer Center head and neck lymphedema rating scale. Logistic regression analysis was used to examine the factors associated with the presence of moderate/severe FL (grade ≥ 2). Results At a median follow-up of 34 months (range, 18–96), 26/87 (29.9%) patients experienced grade ≥ 2 FL. A majority (84.6%) was experienced grade ≥ 2 FL 3–6 months after CCRT. Mean dose to the level IV, level I-VII neck node and N stage were significantly correlated with grade ≥ 2 FL at univariate analysis. At multivariate analysis, mean dose of level IV neck node (hazard ratio [HR], 1.238; 95% confidence interval [CI] = 1.084–1.414; p = 0.002) and level I-VII neck node (HR, 1.384; 95% CI = 1.121–1.708; p = 0.003) were independent predictors. Receiver Operating Characteristics (ROC) curve analysis showed that cut-off value of mean level IV neck node dose was 58.7 Gy (area under the curve [AUC] = 0.726; 95% CI = 0.614–0.839, p = 0.001) and mean level I-VII neck node dose was 58.6 Gy (AUC = 0.720; 95% CI = 0.614–0.826, p = 0.001) for grade ≥ 2 FL. Conclusions Keeping mean dose to the level IV and level I-VII below 58.7 Gy and 58.6 Gy may reduce the likelihood of moderate/severe FL after CCRT for NPC.

Durable Responses and Low Toxicity After Fast Off-Rate CD19 Chimeric Antigen Receptor-T Therapy in Adults With Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 ( NCT02935257 ) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4-84.4) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.

A Real-World Observation of Eltrombopag and Recombinant Human Thrombopoietin (rhTPO) in Lymphoma Patients With Chemotherapy Induced Thrombocytopenia

This real-world, observational study aimed to assess and compare the clinical efficacy and safety of eltrombopag with recombinant human thrombopoietin (rhTPO) in the treatment of chemotherapy induced thrombocytopenia (CIT) in patients with lymphoma. One hundred and fifty-three patients who experienced grade 3 or 4 thrombocytopenia after chemotherapy for lymphoma were enrolled, 51 of which were treated with eltrombopag, 50 with rhTPO, and 52 patients with no drug treatment were served as the control group. The lowest platelet level and mean platelet counts at Day 5, Day 7, and Day 10 were significantly higher in both the eltrombopag group (P=.041,.003,.000,.000) and rhTPO group (P=.005,.005,.000,.000) than the control, but there was no difference between treatment with eltrombopag and rhTPO. Similarly, days required for the recovery of platelet counts to ≥50×109/L and ≥75×109/L were not different between the two treatment groups but significantly higher than the control group (P &lt;.05). Rates of bleeding and platelet transfusion were all significantly reduced in patients treated with eltrombopag (P=.031,.032) or rhTPO (P=.017,.009) when compared to the control. Treatment-related adverse events (AEs) were reported in 7 (13.7%) and 6 (12.0%) patients in the eltrombopag and rhTPO groups, respectively, all being mild and transient in nature. In conclusion, both eltrombopag and rhTPO were effective and safe in the treatment of thrombocytopenia after chemotherapy for lymphoma.

The Efficacy of Prophylactic Intravenous Granisetron in Preventing Post Anaesthesia Shivering in Gynaecological Patients Undergoing Surgery Under General Anaesthesia

Post-anaesthetic shivering is one of the commonest complications during emergence from general anaesthesia with the rate of occurrence between 5 to 65%. It increases oxygen consumption and carbon dioxide production resulting in delayed recovery from anaesthesia and other adverse events. Granisetron is one of the drugs used to prevent post-anaesthetic shivering. This prospective, double-blind and randomised control study compared the efficacy of prophylaxis IV granisetron at 2 mg and 3 mg doses in preventing post-anaesthetic shivering. There were 104 patients, ASA I and II scheduled for elective open gynaecological surgery recruited and randomised into 2 groups: Group A and B, receiving 2 and 3 mg of IV granisetron, resepectively. Intravenous anaesthetic drugs were administered and tracheal intubation was facilitated by muscle paralysis. Patients’ baseline and periodic tympanic core temperatures were measured perioperatively. The incidence and severity of shivering were assessed postoperatively using Wrench Scoring Classification whereby Group A and B had 8.3% and 16.7% of incidence, respectively, in which they were not statistically significant (p = 0.199). All patients from both groups who shivered experienced Grade 1 shivering except for one patient who registered a Grade 2 in Group B. None of our patients had Grade 3 or 4 shivering postoperatively. No one experienced nausea or vomiting in the recovery area. Prophylactic IV granisetron of 2 mg and 3 mg were equally effective in reducing the incidence and severity of post-anaesthetic shivering in gynaecological patients undergoing surgery under general anaesthesia with no unpleasant side effects.

Impact of Anatomical Variations during Intensity Modulated Radiotherapy on Target Volumes, Organs at Risk, and Dose Volume Histograms in Locally Advanced Head and Neck Cancers – A Prospective Interventional Study from Hyderabad, Telangana

BACKGROUND Intensity modulated radiation therapy (IMRT) has become the standard treatment in head & neck cancer (HNC). Anatomic changes during IMRT can have impact on dose coverage and organs at risk (OAR) doses. These changes can be compensated by modifying the plan during treatment. The purpose of this study is to evaluate the impact of anatomical variations during IMRT on target volumes, OAR and dose volume histogram (DVH) in locally advanced HNC patients. METHODS Twenty-four HNC patients undergoing definitive chemoradiotherapy were planned with initial plan. Repeated computerised tomography (CT) scans were performed at 2nd week (repeat CT1) and 4th week (repeat CT2). Previous plan was transferred to new CT for dosimetric analysis. Patient received remaining fractions with adaptive plan if needed based on triggers (1. more than 5 % deviation in OAR doses 2. If PTV dose did not conform to ICRU83). Plan 1 was generated by replanning on repeat CT and plan 2 was by superimposition of previous plan. DVH of both plans were compared for volumetric and dosimetric parameters in patients who required re-planning. RESULTS Fifty-eight percent of patients required adaptive plan. Seventy-one percent required re-plan at the end of 4th week and 28.5 % at 2nd week. Parotid glands and gross tumour volume (GTV) node reduction were significant in patients who required re-plan compared to patients who did not require re-plan. Patients with significant GTV node reduction experienced grade III/IV mucositis. Patients with significant GTV node and parotid glands reduction experienced grade III/IV dermatitis. CONCLUSIONS More than half of HNC patients required re-planning. Most of them required replanning at 4th week. GTV node and parotid glands reduction can predict the requirement of re-plan, risk of grade III/IV dermatitis. GTV node reduction can predict the risk of grade III/IV mucositis. KEYWORDS IMRT, Adaptive Radiotherapy, Anatomical Variations in Head and Neck Cancer, Implementation of Adaptive Plan

Nivolumab/pembrolizumab in Child-Pugh grade B/C patients with advanced HCC.

e16184 Background: Hepatic derangement commonly accompanies advanced HCC (aHCC) and limits the use of systemic therapies. We aimed to evaluate the use of single agent anti-PD-1 nivolumab or pembrolizumab in Child-Pugh (CP) grade B or C patients with aHCC. Methods: Consecutive aHCC patients with CP grade B (CPB) or C (CPC) liver function who received single agent nivolumab or pembrolizumab were analysed. Objective response rate (ORR), time-to-progression (TTP), overall survival (OS), and treatment-related adverse events (TRAEs) were assessed. Results: Between May 2015 and June 2020, 61 patients were included. The median age was 60 (range 28-82). 81% and 4.8% had hepatitis-B and hepatitis-C related HCCs respectively. 72.1% (n = 44) were of CPB and 27.9% (n = 17) were of CPC. Amongst CPB patients, 19 (31.1% of all patients) had CP score 7 (CP7) and 25 (41.0% of all patients) had CP score 8 or 9. The median follow-up was 2.3 months. The ORR of CPB and CPC patients were 6.8% and 0% respectively (p = 0.553). The TTP of CPB and CPC patients were 2.1 months (95% C.I. 1.4-2.8) and 1.4 months (95% C.I. 0.6-2.1) respectively (p = 0.204). CPB patients had significantly better OS than CPC patients (3.1 months (95% C.I. 1.4-4.7), vs. 1.7 months (95% C.I. 1.0-2.4), p = 0.041). Compared to CP score ≥8 (CP≥8) patients, CP7 patients had significantly better OS (median OS CP7 6.7 months (95% C.I. 4.0-9.3), vs. CP≥8 1.8 months (1.2-2.4), p = 0.002). Patients with diuretic-refractory ascites had significantly worse OS compared to those without (1.7 months (95% C.I. 1.0-2.5) vs. 3.7 months (95% C.I. 0.1-7.3), p = 0.004). Portal vein (PV) thrombosis was also significantly associated with inferior survival, with median OS of patients with any PV thrombosis being 1.8 months (95% C.I. 1.0-2.5), compared to 5.3 months (95% C.I. 2.4-8.1) of those without (p = 0.004). The median number of doses given was 3 (range 1-34). Median treatment duration was 5.0 weeks (range 0-77). Overall, 25.4% of patients experienced TRAEs and 4.8% experienced grade ≥3 TRAEs. The most common TRAEs were skin-related (13.1%) and constitutional symptoms (6.6%). Conclusions: Nivolumab/pembrolizumab had acceptable safety in CPB/C patients with aHCC. CP7, absence of diuretic-refractory ascites and lack of PV thrombosis were associated with better survival.