Immunotherapy toxicity in patients over 65 years.

12027 Background: Cancer patients increasingly present an advanced age at diagnosis; 50% of the new cases are over 65 years old, being underrepresented in clinical trials. The safety of immunotherapy has not been adequately evaluated in the subgroup of elderly patient. In this population, with more comorbidities, adverse events may be less well tolerated and have more serious consequences. Methods: A retrospective observational study was developed, including all patients treated with immunotherapy at our center between January 2015 to February 2020. Of the total (279 patients), the analysis was performed with the 105 patients ≥65 years of age who had received at least one cycle (in routine clinical practice or within an unblinded clinical trial). All clinical and radiological data of the patients were collected. Results: From the total, the majority had a lung carcinoma or melanoma, treated with nivolumab or pembrolizumab either in first or second line. 63% had died at the time of the analysis. The frequency of toxicities: digestive (15%), pneumonitis (12%) and endocrine (9%). We divided the population into 65-75 years (76 patients) or > 75 years (29 patients), analyzing the frequency of toxicity and deaths secondary to it. Those > 75 years had more digestive toxicity (25% vs 11%), but less pneumonitis (3% vs 15%). There were 7 deaths (6%) related to treatment: 2 patients with ipilimumab-nivolumab (28%), 2 nivolumab (28%), 2 pembrolizumab (28%), and 1 ipilimumab (16%). 5 patients were > 75 years old (median 78 years) presenting a higher mortality rate in relation to toxicity (4% vs 20%, p 0.02) and a worse median survival (29 vs 23 months). The fatal toxicities were: 3 neurological (2 meningoencephalitis and 1 acute diffuse axonal denervation), 2 hepatic, 1 hemophagocytic syndrome and 1 myocarditis. Conclusions: The most frequent toxicity was digestive, but those that led to death were neurological, hepatic, hematological and cardiac. In our series, neurological and cardiac adverse events accounted for 57% of immunotherapy deaths in older patients. Our data warn that patients over 75 years have a higher risk of death from immune-mediated events. In addition, these would be mainly neurological and cardiac, which represents a diagnostic and treatment challenge for oncologists.[Table: see text]

Toxicity, risk factors and management of cisplatin-induced toxicity: A prospective study

Background and propose Cisplatin is a cytotoxic drug that triggers several toxicities. However, nephrotoxicity and ototoxicity remain major clinical limitations. The aim of our study was to evaluate the incidence of chemotherapy toxicity induced by cisplatin and to analyze the influence of risk factors in the Tunisian population. Methods We performed a prospective descriptive study in a period of four months. Patients were eligible if they had pathologically confirmed malignancies and treated with cisplatin-regimen chemotherapy. Nephrotoxicity and digestive toxicity were graded according to the World Health Organization toxicity scale and ototoxicity was scored clinically according to the Common Terminology Criteria for Adverse Events (CTCAE). Multivariate logistic regression analysis was performed to evaluate the influence of clinical variables on cisplatin-induced toxicity. Results A total of 150 patients were included. Forty-four percent of patients developed cisplatin-regimen toxicity: 15% developed cisplatin-induced nephrotoxicity, 9% cisplatin-induced ototoxicity and 27% digestive toxicity. In the multivariate analysis, age >65 years (OR= 6.129, p = 0.010), metastatic cancer (OR = 0.171, p = 0.007) and cumulative dose (OR= 1.004 mg/m2; p = 0.042) were strong predisposing factors for CDDP-induced nephrotoxicity. The cumulative dose was an independent prognostic indicator for digestive toxicity (OR = 0.997, p = 0.002). Conclusion In our study, age >65 years and metastatic cancer were risk factors for cisplatin-induced nephrotoxicities. We also found the correlation between cumulative dose and nephrotoxicity or digestive toxicity.

High Incidence of HHV-6 Infection Associated with Bendamustine, Cytarabine, Etoposide and Melphalan (BeEAM) Conditioning Regimen: Results of a Monocentric and Retrospective Study

Background: Because of the disruption of BCNU (Carmustine) in France during several months, and based on the results reported by Visani and colleagues (Visaniet al, Blood 2011) Bendamustine has been used in combination with Etoposide, Cytarabine and Melphalan (BeEAM) in a new high dose conditioning regimen before autologous transplant in relapsed/refractory (R/R) lymphoma patients. We report our experience on the safety and efficacy of BeEAM compared to the classical BEAM regimen. Patients and methods: Ninety consecutive pts (BEAM = 60, BeEAM = 30) with R/R lymphoma were enrolled between December 2013 and September 2015 (BEAM from December 2013 to January 2015 and BeEAM from February to September 2015) in this retrospective study. Pts in complete or partial response after salvage therapy received high dose conditioning with Bendamustine (d-8 and d-7), Cytarabine (400 mg/m2 continuous infusion from d-6 to d-3), Etoposide (200 mg/m2 continuous infusion from d-6 to d-3) and Melphalan (200 mg/m2 d-2) followed by ASCT on d0. Bendamustine was given at 200 mg/m2/d for the first 4pts then 100 mg/m2/d for the 4 subsequentpts and finally at 120 mg/m2/d for the remaining pts (22 pts). Among the BEAM group, 68% had Non-Hodgkin's Lymphoma (NHL) and 32% Hodgkin's Lymphoma (HL) compared to 87% and 13% respectively in the BeEAM group (p = 0,014). HHV-6 detection was performed by PCR for symptomatic pts (fever, rash or prolonged cytopenia). Patients were housed in single bedrooms with air filtration and received the same supportive care. Results: Median age was 50 (18-66) and 56 (20-67) in the BEAM and BeEAM groups respectively and median of previous chemotherapy regimens was 2 (1-5). Fifty two out of 90 patients were male (37/60 in the BEAM group and 15/30 in the BeEAM group). Pts were in CR (46, 7% Vs 56, 7%) or PR (53, 3% Vs 43, 3%) at time of transplant. There was no difference in terms of hematologic recovery (median = 11 days (range: 7-22)), blood and platelets transfusion, mucositis toxicity. There was no statistical difference in the incidence of acute renal failure when comparing the two groups. However, there was a very striking difference when considering the highest dose of Bendamustine when compared as well to the two others doses of Bendamustine (p < 0.00001) as to the BEAM group (p=0.005). Additionally, we also observed a high incidence of symptomatic HHV-6 infections (53.3% vs 8.3%, p < 0.00001), digestive toxicity (36.6% vs 15%, p = 0.03) and a longer hospitalization duration (25 days (range: 18-59) vs 21 days (range: 18-32), p = 0.001) for patients in the BeEAM group overall. With a median follow up of 18.3 and 9.7 months for BEAM and BeEAM respectively, overall survival (93% vs 86%), transplant related mortality (0% vs 3%) and event free survival (83% vs 78%) were comparable. Conclusion: Overall, BeEAM regimen was associated with longer duration of hospitalization, higher rate of digestive toxicity and increased risk of symptomatic HHV-6 infection as compared to the BEAM regimen. In addition, higher doses of Bendamustine (200mg/m2/d for two consecutive days) were associated with unacceptable high rate of acute renal toxicity. With a still short follow-up, the absence of benefit on disease control together with higher short term toxicity does not allow to recommend the use of BeAM instead of classical BEAM. Should it be used, we suggest that pts should be carefully monitored for renal toxicity and for HHV-6 infection in case of symptoms. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Pharmacokinetic (PK) and tolerance profiles of oral tegafur/uracil (UFT) given as three versus two daily intakes

12013 Background: This phase II randomized bioequivalence cross-over study compared the tolerance and PK profiles of oral UFT (tegafur-uracil) given as 3 daily intakes (tid, usual schedule) to that obtained with 2 daily intakes (bid). Methods: Twenty-one metastatic colorectal cancer patients were enrolled (16 men, 5 women ; mean age 64, extremes 42–79 ; ECOG PS ≤ 1). Tegafur-uracil (300 mg/m2/d) and leucovorin (90 mg/d) were given for 2 consecutive four-week cycles separated by one rest week. Patients were randomized for receiving 1st cycle either tid (arm A, 12 patients) or bid (arm B, 9 patients). For each schedule, PK was evaluated at steady state, over 24 h. Plasma concentrations of tegafur, uracil and fluorouracil (FU) were analyzed by HPLC. Results: Analysis of tolerance (digestive toxicity mainly, OMS grade) showed a tendency (p = 0.08) for a greater toxicity with the bid schedule (29% grade 2, 14% grade 3) relative to tid (24% grade 2 only). Although daily doses were similar, FU and uracil AUC0–24h were respectively 1.8 and 2.0-fold higher for bid as compared to tid (95% CI were 1.5–2.1 and 1.6–2.6, respectively, p < 0.0001). For tegafur, the 1.2-fold difference was of borderline significance (p = 0.057). The greater the FU AUC0–24h, the higher the toxicity intensity (p = 0.044). Analysis of systemic exposure with respect to daily time revealed that FU (p < 0.01) and uracil (p < 0.03) AUC corresponding to the morning intake were significantly higher than those corresponding to the afternoon or evening intakes, with AUC ratio as high as 1.6 for FU and 2.9 for uracil. Such a circadian influence was not observed for tegafur. Conclusions: To reach bioequivalence, bid tegafur-uracil administration will require lower doses than those given tid. The circadian variability observed for FU and uracil PK concords with that previously reported for dihydropyrimidine deshydrogenase activity. No significant financial relationships to disclose.