ABSTRACT
Background: Venetoclax (Ven) in combination with hypomethylating agents, such as azacitidine (Aza) and low dose cytarabine (LDAC) has been shown to be effective therapy in acute myeloid leukaemia (AML) and has become standard of care for newly-diagnosed patients unfit for intensive chemotherapy (DiNardo et al., 2020;Wei et al., 2019;Pollyea et al., 2020). Efficacy has also been shown in the relapsed/refractory (R/R) setting in more limited data sets (Báez-Gutiérrez et al., 2021;Pollyea et al., 2020, Stahl et al., 2020;DiNardo et al., 2019). Ven combination therapy has become widely used in newly-diagnosed patients in the UK since its approval during the COVID-19 pandemic as an alternative to intensive chemotherapy and subsequently for patients unfit for intensive therapy. Aims: We describe the characteristics and outcomes of patients with AML or high risk myelodysplastic syndrome (HRMDS) receiving Ven combinations in frontline and R/R settings to provide real-world insight into their use in UK clinical practice. Methods: A retrospective analysis was performed of all patients with AML or HR-MDS who received Ven combination therapy at University College London Hospital between April 2020 and September 2021. Patient demographics, treatment history and bone marrow results were obtained from electronic health care and laboratory records. Disease stratification and response assessments were made as per European LeukemiaNet (ELN) criteria (Döhner et al., 2017). Results: At the time of analysis, 95 patients received Ven combinations (61 as frontline treatment and 34 for R/R AML), with a median follow up of 14 months. The majority of patients in both groups had adverse risk ELN classification (70.5% of frontline patients, 64.7% of R/R) and received Ven-Aza (100% frontline and 91.1% R/R) (Table 1). The median ages were 72 and 59 years respectively. The incidence of composite CR/CRi was 70.5% in the frontline setting, with median duration of response (DoR) of 8.3 months and overall survival (OS) of 7.1 months. In R/R AML, the CR/CRi rate was 64.7%, median DoR 10.5 months and median OS 9.8 months. Four out of the 43 patients who achieved CR/CRi (9.3%) following frontline treatment and 9 of the 22 R/R (40.9%) patients proceeded to allogeneic stem cell transplant (alloSCT) post induction. The median survival for all patients who underwent alloSCT is not reached in this analysis. The highest CR/CRi rates were observed in intermediate risk patients (90.9% in frontline treatment, 71.4% in R/R), with lower rates in both favourable (80% and 66.7%) and adverse risk patients (65.1% and 59.1% respectively). The presence of NPM1 and IDH1/2 mutations were associated with high CR/CRi rates in both the frontline (85.7% and 84.6% respectively) and R/R groups (100% and 81.8%), with below average response rates seen in TP53 mutated AML (62% in frontline, 40% in R/R). Notable responses were seen in patients with RUNX1 mutations in both settings (77.8% frontline, 66.6% R/R). Summary/Conclusion: Our data describes real world effectiveness for venetoclax combinations as both frontline and salvage therapy in UK clinical practice, similar to that seen in clinical trials. This further contributes to our understanding of these therapies, in particular their use as a viable treatment option in R/R patients and as a bridge to alloSCT, and highlights the importance of further characterisation of genetic predictors of response to inform treatment decisions in real-world practice.
ABSTRACT
Patients with haematological malignancies, such as acute leukaemia (AL) and high-risk MDS (HRMDS), have significantly increased mortality and morbidity from COVID-19 but vaccine efficacy in these patients remains to be fully established. To date, seroconversion rates following SARS-CoV-2 vaccination in patients with AL and HR-MDS have been reported in small numbers within large retrospective studies, with most not receiving active treatment We characterised the serological responses of patients with AL and HR-MDS who are receiving anti-cancer therapy and were vaccinated within the UK vaccination and programme, receiving two doses of either BNT162b2 or ChAdOx1nCoV-19. Fifty-five patients (35 AML [64%], 14 ALL [25%], 6 HRMDS [11%]), underwent serological testing for anti-S antibody levels after receiving 2 SARS-CoV-2 vaccine doses (71% BNT162b2, 16% ChAdOx1nCoV-19, 13%unknown), between December 2020 and July 2021, Table 1. Serological testing was performed per clinical practice using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay (seropositive results being 0.8 U/ml and upper limit >2500 U/ml). The median age was 53 (range 18-76) and 53 patients (96%) were receiving SACT. Serological testing for anti-N antibodies performed on 48 patients (87%) identified 11 (20%) seropositive patients, indicative of previous natural infection. Fifty (91%) were seropositive for anti-S antibodies after two doses (median 43 days [range 4-133] post dose), of these, 33 (60%) were tested following dose 1 (median 36 days [range 24-86]). 76% were seropositive after dose 1, with median antibody titres 7.88 U/ml (IQR 0.7-2.37). This rose to 91% following dose 2, with median 333 U/ml (IQR 27.5-1821). Higher rates of seropositivity are observed in AML/HR-MDS patients (95%) compared to ALL (79%). Patients with AML/HR-MDS also showed a significant increased seropositivity (95%) and titres following dose 2 (median 352 U/ml [IQR 89.95-2116], p = 0.0003), compared to patients with ALL who showed no increase (median 8.395 [IQR 2.335-669.3]). To precisely define seroconversion rates, we excluded patients with anti-N antibodies (indicative of previous SARSCoV-2 infection). SARS-CoV-2 naïve patients with AML/ HR-MDS had higher seroconversion rates and median anti-S antibody titres compared to ALL (median 291 U/ml [IQR 87.03-1771] vs. 5.06 U/ml [1.69-175.6], p = 0.005) and also showed significant increases in titres between post dose 1 and 2 dose titres, not seen in ALL. Patients with previous SARS-CoV-2 infection (anti-N positive) had higher antibody titres, following vaccination in AML/MDS (median 2500 U/ ml [IQR 141-2500]) compared to ALL (median 1541 U/ml [IQR 574.5-2500]), although not statistically significant. There was no significant difference in anti-S antibody response to vaccination in patients treated with intensive or non-intensive AML therapy but significantly reduced anti-S antibody titres were present in patients who received venetoclax-based regimens compared to other therapies ( n = 20, median 158.5 U/ml [IQR 34.85-873] vs. n = 19 median 796 U/ml [IQR 132-2500] p = 0.04). Patients with AML and HR-MDS on SACT are able to generate robust serological responses to SARS-CoV-2 infection but this is not the case for all patients following vaccination. Understanding impact of disease subtypes and therapy on vaccine response is pertinent, as decisions on modifying or delaying treatment in the context of either SARS-CoV-2 infection or vaccination require a clear evidence base. (Table Presented).
ABSTRACT
Safety reporting in traditional clinical trials is often accomplished through investigator's independent identification of events meeting Adverse Event reporting criteria. In some study settings, such as observational or standard of care-based research, the subjectivity in this reporting approach can result in gaps or inconsistencies in safety data, limiting the ability to confidently confirm both presence and absence of key events. The Emmes contract research organization has adopted a new approach for clinical research studies to improve upon the traditional, passive, non-specific collection of adverse events with a more targeted solicitation of study-specific Events of Special Interest. Events of Special Interests may be derived from the drug labels, package inserts, or known disease indications, and ensure consistency and uniformity in safety data collection across sites and similar studies. Events of Special Interest reporting aims to target specific events and avoids over or under reporting by sites. Events of Special Interests also reduce the burden of site reporting of irrelevant events, the need to determine if an event is or is not reportable, such as in a sick patient population, and finally supports efficient data and safety monitoring in alignment with the Food and Drug Administration Investigational New Drug Application Safety reporting guidance. The Emmes contract research organization has adopted this approach to ensure comprehensive data collection in support of improved labeling for marketed products in pediatric and adolescent populations. It has proven most effective in observational or standard of care studies, particularly those with sick and/or inpatient populations. Safety event data are bolstered with site required confirmation of occurrence in an unequivocal No or Yes manner, along with the addition of severity, causality, and association assessments by the clinician/ subject matter expert. Events of Special Interests are study-defined events, aiding study staff or programmatic searches of health records in the identification and ion of event data. Events of Special Interests also allow researchers to more accurately tabulate event frequency and rates, as well as assist sponsors in identifying site reporting imbalances. Clinical research is constantly evolving, driven by the need to optimize data collection and reduce time, effort, and cost, which is particularly important for trials being implemented during the COVID-19 pandemic. The traditional methods used to collect safety data require a high level of effort to collect, review by numerous subject matter experts, and can often result in the collection of large amounts of data that are irrelevant to research objectives. This utilization of safety reporting and analysis to include Events of Special Interests has been shown to significantly reduce the level of effort to collect, subject matter expert review, MedDRA code, and tabulate safety data. By improving data collection consistency and uniformity, utilization of Events of Special Interest reporting has improved the overall process of safety event reporting in our clinical research, increasing the efficacy of study data utilized to inform regulatory authorities.