End of life in haematology: quality of life predictors - retrospective cohort study.

OBJECTIVES: Haematology patients are more likely to receive high intensity care near end of life (EOL) than patients with solid malignancy. Previous authors have suggested indicators of quality EOL for haematology patients, based on a solid oncology model. We conducted a retrospective chart review with the objectives of (1) determining our performance on these quality EOL indicators, (2) describing the timing of level of intervention (LOI) discussion and palliative care (PC) consultation prior to death and (3) evaluating whether goals of therapy (GOT), PC consultation and earlier LOI discussion are predictors of quality EOL. METHODS: We identified patients who died from haematological malignancies between April 2014 and March 2016 (n=319) at four participating McGill University hospitals and performed retrospective chart reviews. RESULTS: We found that 17% of patients were administered chemotherapy less than 14 days prior to death, 20% of patients were admitted to intensive care, 14% were intubated and 5% were resuscitated less than 30 days prior to death, 18% of patients received blood transfusion less than 7 days prior to death and 67% of patients died in an acute care setting. LOI discussion and PC consultation occurred a median of 22 days (IQR 7-103) and 9 days (IQR 3-19) before death. Patients with non-curative GOT, PC consultation or discussed LOI were significantly less likely to have high intensity EOL outcomes. CONCLUSIONS: In this study, we demonstrate that LOI discussions, PC consults and physician established GOT are associated with quality EOL outcomes for patients with haematological malignancies.

Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma.

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.

Antimony trioxide-induced apoptosis is dependent on SEK1/JNK signaling.

Very little is known concerning the toxicity of antimony, despite its commercial use as a flame retardant and medical use as a treatment for parasitic infections. Our previous studies show that antimony trioxide (Sb(2)O(3)) induces growth inhibition in patient-derived acute promyelocytic leukemia (APL) cell lines, a disease in which a related metal, arsenic trioxide (As(2)O(3)), is used clinically. However, signaling pathways initiated by Sb(2)O(3) treatment remain undefined. Here, we show that Sb(2)O(3) treatment of APL cells is associated with increased apoptosis as well as differentiation markers. Sb(2)O(3)-induced reactive oxygen species (ROS) correlated with increased apoptosis. In addition, when we decreased the buffering capacity of the cell by depleting glutathione, ROS production and apoptosis was enhanced. Arsenic-resistant APL cells with increased glutathione levels exhibited increased cross-resistance to Sb(2)O(3). Based on studies implicating c-jun kinase (JNK) in the mediation of the response to As(2)O(3), we investigated the role for JNK in Sb(2)O(3)-induced apoptosis. Sb(2)O(3) activates JNK and its downstream target, AP-1. In fibroblasts with a genetic deletion in SEK1, an upstream regulator of JNK, Sb(2)O(3)-induced growth inhibition as well as JNK activation was decreased. These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure.

JNK activation is a mediator of arsenic trioxide-induced apoptosis in acute promyelocytic leukemia cells.

Arsenic trioxide induces c-jun N-terminal kinase (JNK) activation and apoptosis in acute promyelocytic leukemia (APL), where it has major clinical activity, but whether JNK is necessary to induce apoptosis is unknown. To clarify this necessity, we established 2 arsenic trioxide (As(2)O(3))-resistant subclones of the APL cell line, NB4. Both resistant lines showed little activation of JNK1 following treatment with As(2)O(3), even at doses sufficient to elicit robust activation in NB4 cells. One mechanism of resistance in these cells is up-regulated glutathione (GSH) content, and GSH depletion by l-buthionine-[S,R]-sulfoximine (BSO) restores JNK activation and As(2)O(3) sensitivity. This correlation between JNK activation and apoptosis led us to test whether inhibition of JNK would protect cells from As(2)O(3)-induced apoptosis. SEK1(-/-) mouse embryo fibroblasts (MEFs) showed diminished JNK activation following As(2)O(3) treatment and were protected from As(2)O(3)-induced but not doxorubicin-induced apoptosis. Furthermore, treatment of arsenic trioxide-sensitive APL cells with the JNK inhibitor, dicumarol, significantly increased growth and survival in response to As(2)O(3) but did not protect cells from doxorubicin. Together, these data support an essential role for JNK signaling in the induction of growth inhibition and apoptosis by As(2)O(3) and suggest that activating JNK may provide a therapeutic advantage in the treatment of cancers that do not respond to arsenic alone.

Arsenic trioxide: mechanisms of action.

The chimeric protein encoded by the PML-RAR alpha gene that is pathognomonic of acute promyelocytic leukemia (APL) causes the arrest of myeloid cell development at the promyelocyte stage, leading to an accumulation of abnormal promyelocytes in the bone marrow. Differentiation therapy with all-trans retinoic acid (ATRA) is used routinely in patients with APL, but ATRA is not the only agent in clinical use that promotes differentiation of the abnormal clone. Arsenic trioxide (ATO) has been shown to cause degradation of PML-RAR alpha, promoting differentiation. APL cells are extremely sensitive to ATO, which has shown good clinical activity at low doses in patients with relapsed APL. However, degradation of PML-RAR alpha may not be wholly responsible for the great sensitivity of APL cells to ATO, which also acts through the intracellular environment to influence apoptosis, differentiation, growth arrest, and angiogenesis. ATO can act at several points in mitochondrially induced apoptosis, including degradation of peroxides and interaction with glutathione (GSH)-related enzymes. Subclones that are resistant to ATO have been used to demonstrate that sensitivity can be restored by reducing the cellular GSH content. GSH can be reduced using agents such as buthionine sulfoximine (BSO) and ascorbic acid. The key factors that determine the ATO sensitivity of cells and control ATO-induced apoptosis have not yet been defined. It has been proposed that ATO acts through activation of Jun N-terminal kinase (JNK), activator protein-1, and inhibition of dual-specificity phosphatases, and evidence is accumulating that JNK activation is an important event in arsenic-induced apoptosis. Further research is required to determine the exact pathways through which the cytotoxic actions of ATO are mediated.