Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas

INTRODUCTION: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity. MATERIALS AND METHODS: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment. RESULTS: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care. CONCLUSION: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management

RTS,S/AS01E immunization increases antibody responses to vaccine-unrelated Plasmodium falciparum antigens associated with protection against clinical malaria in African children:a case-control study

BACKGROUND: Vaccination and naturally acquired immunity against microbial pathogens may have complex interactions that influence disease outcomes. To date, only vaccine-specific immune responses have routinely been investigated in malaria vaccine trials conducted in endemic areas. We hypothesized that RTS,S/A01E immunization affects acquisition of antibodies to Plasmodium falciparum antigens not included in the vaccine and that such responses have an impact on overall malaria protective immunity. METHODS: We evaluated IgM and IgG responses to 38 P. falciparum proteins putatively involved in naturally acquired immunity to malaria in 195 young children participating in a case-control study nested within the African phase 3 clinical trial of RTS,S/AS01E (MAL055 NCT00866619) in two sites of different transmission intensity (Kintampo high and Manhiça moderate/low). We measured antibody levels by quantitative suspension array technology and applied regression models, multimarker analysis, and machine learning techniques to analyze factors affecting their levels and correlates of protection. RESULTS: RTS,S/AS01E immunization decreased antibody responses to parasite antigens considered as markers of exposure (MSP142, AMA1) and levels correlated with risk of clinical malaria over 1-year follow-up. In addition, we show for the first time that RTS,S vaccination increased IgG levels to a specific group of pre-erythrocytic and blood-stage antigens (MSP5, MSP1 block 2, RH4.2, EBA140, and SSP2/TRAP) which levels correlated with protection against clinical malaria (odds ratio [95% confidence interval] 0.53 [0.3-0.93], p = 0.03, for MSP1; 0.52 [0.26-0.98], p = 0.05, for SSP2) in multivariable logistic regression analyses. CONCLUSIONS: Increased antibody responses to specific P. falciparum antigens in subjects immunized with this partially efficacious vaccine upon natural infection may contribute to overall protective immunity against malaria. Inclusion of such antigens in multivalent constructs could result in more efficacious second-generation multistage vaccines

The prevalence and correlates of secondary traumatic stress among alcohol and other drug workers in Australia

Introduction and Aims: The high prevalence of trauma exposure and post-traumatic stress disorder (PTSD) among clients of alcohol and other drug (AOD) services is well documented. Less is known, however, about the impact this has on workers who assess and treat such clients. The aim of this study was to examine the prevalence and correlates of secondary traumatic stress (STS) among AOD workers in Australia. Design and Methods: An anonymous web-based survey was undertaken and completed by 412 Australian AOD workers. The questionnaire assessed current levels of trauma training, extent of exposure to clients with a history of trauma history, AOD workers' own history of trauma exposure and PTSD, and current STS. Analyses compared individuals who currently met criteria for experiencing STS with those who did not. Results: Despite the high volume of traumatised clients accessing AOD services, less than two-thirds of AOD workers reported having ever received trauma training. The prevalence rate of STS was 19.9% and was independently predicted by a higher traumatised client workload, fewer hours of clinical supervision, and stress and anxiety levels of the worker. Discussion and Conclusions: The findings highlight the importance of providing adequate trauma training and clinical supervision to AOD workers in order to maintain their health and welfare and ensure optimal treatment to clients with PTSD. [Ewer PL, Teesson M, Sannibale C, Roche A, Mills KL. The prevalence and correlates of secondary traumatic stress among alcohol and other drug workers in Australia

Integrated exposure-based therapy for co-occurring post traumatic stress disorder (PTSD) and substance dependence: Predictors of change in PTSD symptom severity

This paper examines factors associated with change in PTSD symptom severity among individuals randomised to receive an integrated exposure-based psychotherapy for PTSD and substance dependence–Concurrent Treatment of PTSD and Substance Use Disorders Using Prolonged Exposure (COPE). Outcomes examined include change in PTSD symptom severity as measured by the Clinician Administered PTSD Scale (CAPS), and the reliability and clinical significance of change in PTSD symptom severity. Factors examined include patient baseline characteristics, treatment characteristics, and events over follow-up. The mean difference in CAPS score was 38.24 (SE 4.81). Approximately half (49.1%) demonstrated a reliable and clinically significant improvement in PTSD symptom severity. No one was classified as having demonstrated clinically significant worsening of symptoms. Three independent predictors of reductions in PTSD symptom severity were identified: baseline PTSD symptom severity (β 0.77, SE 0.23, p = 0.001), number of traumas experienced prior to baseline (β -0.30, SE 0.15, p = 0.049), and number of sessions attended (β 2.05, SE 0.87, p = 0.024). The present study provides further evidence regarding the safety of the COPE treatment and factors associated with improvement in PTSD symptom severity. The identification of only a small number of predictors of the outcome points to the broad applicability of the COPE treatment to PTSD and substance use disorder (SUD) patients

Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials

Background: We conducted a systematic review and meta-analysis to clarify the risk of early and late cardiotoxicity of anthracycline agents in patients treated for breast or ovarian cancer, lymphoma, myeloma or sarcoma.Methods: Randomized controlled trials were sought using comprehensive searches of electronic databases in June 2008. Reference lists of retrieved articles were also scanned for additional articles. Outcomes investigated were early or late clinical and sub-clinical cardiotoxicity. Trial quality was assessed, and data were pooled through meta-analysis where appropriate.Results: Fifty-five published RCTs were included; the majority were on women with advanced breast cancer. A significantly greater risk of clinical cardiotoxicity was found with anthracycline compared with non-anthracycline regimens (OR 5.43 95% confidence interval: 2.34, 12.62), anthracycline versus mitoxantrone (OR 2.88 95% confidence interval: 1.29, 6.44), and bolus versus continuous anthracycline infusions (OR 4.13 95% confidence interval: 1.75, 9.72). Risk of clinical cardiotoxicity was significantly lower with epirubicin versus doxorubicin (OR 0.39 95% confidence interval: 0.20, 0.78), liposomal versus non-liposomal doxorubicin (OR 0.18 95% confidence interval: 0.08, 0.38) and with a concomitant cardioprotective agent (OR 0.21 95% confidence interval: 0.13, 0.33). No statistical heterogeneity was found for these pooled analyses. A similar pattern of results were found for subclinical cardiotoxicity; with risk significantly greater with anthracycline containing regimens and bolus administration; and significantly lower risk with epirubicin, liposomal doxorubicin versus doxorubicin but not epirubicin, and with concomitant use of a cardioprotective agent. Low to moderate statistical heterogeneity was found for two of the five pooled analyses, perhaps due to the different criteria used for reduction in Left Ventricular Ejection Fraction. Meta-analyses of any cardiotoxicity (clinical and subclinical) showed moderate to high statistical heterogeneity for four of five pooled analyses; criteria for any cardiotoxic event differed between studies. Nonetheless the pattern of results was similar to those for clinical or subclinical cardiotoxicity described above.Conclusions: Evidence is not sufficiently robust to support clear evidence-based recommendations on different anthracycline treatment regimens, or for routine use of cardiac protective agents or liposomal formulations. There is a need to improve cardiac monitoring in oncology trials.<br/