Getting the Most Out of the Evidence for Transfusion Medicine and Lessons from the COVID-19 Pandemic

Evidence-based medicine (EBM) has been described by Sackett et al. as ‘the integration of best research evidence with clinical expertise and patient values'. This chapter discusses core elements of EBM with particular reference to clinical research in transfusion medicine, and provides a practical approach to searching for evidence and critical appraisal, with some considerations of different study designs. It also includes a review of how the evidence base for transfusion medicine was collated in response to the COVID-19 pandemic. One important component of EBM is the critical appraisal of the evidence generated from a study. One important aspect of clinical trial appraisal concerns the understanding of chance variation and sample-size calculation. Appraising the evidence base for transfusion medicine is one part of improving practice;another is the effective dissemination of the evidence to clinicians. © 2022 John Wiley and Sons Ltd.

Low Incidence of COVID-19 Infection in Patients with Acute Myeloid Leukemia Undergoing Reduced Intensity/Venetoclax Based Treatment: Initial Results of the PACE Prospective Clinical Study from the UK Trials Acceleration Program

The impact of Coronavirus disease 2019 (COVID-19) on outcomes in patients with cancer remains unclear. Acute Myeloid Leukemia (AML)/high-risk myelodysplasia (MDS) are common hematological malignancies resulting in profound immunosuppression, which is exacerbated by intensive and less-intensive chemotherapy. Importantly, venetoclax based regimens have been increasingly used during the pandemic as a strategy to reduce patient hospitalization however, there is little information concerning the impact of such regimens on COVID-19 infection rates. We therefore opened a prospective clinical study (PACE), at the start of the current pandemic in April 2020 to characterize the risk of COVID-19 infection in patients with AML/MDS-EB2 receiving intensive or non-intensive treatment, including patients treated with venetoclax-based regimens. The primary aim was to determine the incidence of COVID-19 in patients with AML /MDS-EB2 including both, prior to study entry and during treatment until 4 weeks after the last cycle of treatment. Secondary aims were to: characterize the presentation of COVID-19;define the severity and type of both non-COVID-19 and COVID-19 infections;and undertake an exploratory analysis to quantify the incidence of COVID-19 infection in patients receiving (less-intensive) venetoclax based regimens. All analysis conducted to date has been descriptive. 211/230 recruited patients had full treatment histories available, of whom 116 patients received intensive chemotherapy and 95 low intensity regimens. 48 patients received a venetoclax-based regimen. The median age of the non-intensive treatment arm was 72 years;(range 19.1-86.5) and of the intensive arm was 59 years (range 16.1-76.1). There were more cases of secondary AML and relapsed disease in the non-intensive arm as compared to the intensive arm. 25/226 evaluable patients tested positive for COVID-19 as defined by positive SARS-CoV2 PCR test, 10 with a prior diagnosis at study entry and 15 tested positive during the study. The incidence of COVID-19 infection for patients with AML/MDS-EB2 was 11.1% (90%CI: 7.8%-15.1%) (Table). A lower proportion of patients (n=6/91 6.6%) undergoing non-intensive treatment suffered COVID-19 as compared to those undergoing more intensive chemotherapy regimens (n=19/116, 16.4%). Specifically, only 3/48 (6.3%) patients undergoing a venetoclax regimen were infected with SARS-CoV2. The most common presenting symptoms of COVID-19 in this study, regardless of the intensity of chemotherapy, was fever and cough with 6/25 patients asymptomatic. The risk of death at 30 days following study entry in patients who had prior COVID-19 infection or who contracted COVID-19 during this period was 13.6%, compared to 3.9% in the overall cohort without COVID-19 infection. There was a lower incidence of non-COVID-19 related infections in patients receiving venetoclax-based regimens, n=43 infections in 24 (50.0%) of patients;with 313 infections in 94 (81%) of intensively treated patients. The overall occurrence of non-COVID-19 infection in the non-intensive arm was 87 infections in 50 (54.9%) patients. Our multi-center study provides real-world estimates for the incidence and presentation of COVID-19 infection in a cohort of patients with AML/MDS-EB2, and indicates a higher risk of death at 30 days in patients with prior COVID-19 infection prior to, or during treatment. Venetoclax based, and other non-intensive, regimens, increasingly implemented during the pandemic, to minimize patient exposure and reduce usage of hospital beds, appeared to be associated with a low incidence of COVID-19. Further follow-up will be required to understand the long-term impact of this strategy. Analysis of immune responses to COVID-19 infection and vaccination is on-going. Acknowledgments: This study was funded by Cure Leukaemia under the Trials Acceleration Program (TAP), and grants from BMS and Blood Cancer UK. [Formula presented] Disclosures: Loke: Novartis: Other: Travel;Janssen: Honoraria;Amgen: Honoraria;Pfizer: Honoraria;Daichi Sankyo: Other: Travel. K apper: Pfizer: Consultancy, Speakers Bureau;Astellas: Ended employment in the past 24 months, Speakers Bureau;Jazz: Consultancy, Speakers Bureau;Novartis: Consultancy, Research Funding, Speakers Bureau. Khan: Abbvie: Honoraria;Astellas: Honoraria;Takeda: Honoraria;Jazz: Honoraria;Gilead: Honoraria;Novartis: Honoraria. Dillon: Amgen: Other: Research support (paid to institution);Astellas: Consultancy, Other: Educational Events, Speakers Bureau;Menarini: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau;Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events;Jazz: Other: Education events;Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events;Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Culligan: AbbVie Ltd: Honoraria, Speakers Bureau;Celgene Ltd: Honoraria, Speakers Bureau;Gilead: Honoraria, Speakers Bureau;Jazz Pharma: Honoraria, Speakers Bureau;Takeda UK Ltd: Honoraria, Speakers Bureau. McMullin: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial support, Research Funding;Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AOP Orphan: Research Funding, Speakers Bureau. Murthy: Abbvie: Other: support to attend educational conferences. Craddock: Novartis Pharmaceuticals: Other: Advisory Board;Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

RBC-Enhance: A Randomized Pilot Feasibility Trial of Red Cell Transfusion Thresholds in Myelodysplastic Syndromes

Background Red blood cell (RBC) transfusion dependence (TD) and anemia are associated with inferior quality of life (QOL) and survival in myelodysplastic syndromes (MDS). As part of a research programme to identify the optimal transfusion hemoglobin (Hb) threshold that translates into significantly improved QOL, we conducted a pilot randomized study of two transfusion algorithms (liberal versus restrictive) to determine the feasibility of a larger study. This trial was aligned with the REDDS study (ISRCTN26088319, Stanworth et al., BJH 2019) and followed the same pre-defined statistical analysis plan. Methods The study was undertaken at 3 cancer centers (NCT02099669). We included patients with MDS, CMML, low blast AML (20-30%) or myeloproliferative neoplasms who were TD (> 1 RBC/8 weeks x 16 weeks). Patients on disease modifying therapy for > 6 months were permitted only if they had remained stably RBC-TD with a life expectancy of > 3 months. Central randomization was to one of two RBC transfusion strategies over a 12-week period: 1. Restrictive strategy to maintain Hb between 85 and 105g/L. To achieve this, 2 RBC units were transfused when Hb < 85 g/L 2. Liberal strategy to maintain Hb between 110 and 120 g/L. To achieve this, 2 RBC units were transfused when Hb < 105 g/L and 1 unit for Hb 105-110 g/L. The first 4 weeks were considered a run-in period to achieve the target Hb. The primary outcomes of this feasibility study were 1. The percentage compliance of Hb being within or above the target range of the assigned transfusion threshold (after the 4 week run-in). Feasibility was set at 70%. 2. Achievement of at least a 15 g/L difference between the mean pre-transfusion Hb of the liberal and restrictive strategy groups. Secondary outcomes included changes and differences in QOL scores, rates of transfusion reactions and alloimmunizations, overall blood utilization and visit numbers and impact on serum ferritin. The primary analysis was intention to treat. The study was closed early due to COVID-19, with 28 patients randomized of planned 30. Results 30 patients were enrolled over 5 years and 28 patients randomized (n=15, liberal;n=13 restrictive). Median age was 74 (range 58-84), 26/28 had MDS or CMML and there were no significant imbalances in baseline disease and patient characteristics although patients in the restrictive group tended to have lower risk disease (IPSS-R very low + low 69% versus 53% liberal). Compared with the restrictive arm, liberal arm patients had more complete blood counts, were transfused more RBC units (only during the 4-week run-in) and were transfused at shorter intervals (Table 1). There were no differences in adverse events. Over the 12 weeks, the mean Hb value was 90 ± 4 g/L (restrictive) versus 101 ± 4 g/L (liberal), (p <0.0001, Figure 1). The pretransfusion difference was 11.8 g/L (95% CI 9.4-14.3) with mean pre-transfusion Hb values of 98.6 (± 10.6) g/L and 86.7 (± 8.6) in the liberal and restrictive arms respectively. Percentage compliance of pre-transfusion Hb falling within or above the target Hb range was 48% for restrictive patients but only 14% for liberal patients. Adherence with QOL completion (minimum of 4 serial) was 93%. While sample sizes are small and comparisons exploratory, the area under the curve for several serial quality of life scores was numerically higher and the curve more stable for the liberal arm (EQ5D (figure 2), EORTC cognitive and emotional functioning). Similarly, a higher % of patients in the liberal arm achieved pre-defined clinically meaningful increases in several symptom and function domains (emotional, social, fatigue, dyspnea, financial problems). Discussion Whilst our study results did not meet our feasibility endpoints, this small randomized trial in MDS patients demonstrated clinically important differences in mean Hb achievable with different transfusion thresholds. Poor rates of compliance with Hb targets were clearly identified for patients in the liberal arm, suggesting a need to understand the barriers to protocol adherence in this rm prior to embarking on larger trials. Compared with the REDDS trial, we did not document a significant excess of RBC transfusions needed (post run-in period) to maintain the higher Hb threshold. Similar to REDDS, we did observe some signals of improved QOL with a liberal transfusion strategy. A formal analysis of pooled results with REDDS study patients is planned. (Funding, CCSRI grant QOLL-14 and MOSPI Fund 2014). [Formula presented] Disclosures: Buckstein: Novartis: Honoraria;Astex: Honoraria;Celgene: Honoraria;Celgene: Research Funding;Takeda: Research Funding. Prica: seattle genetics: Honoraria;Gilead: Honoraria;astra zeneca: Honoraria. Leber: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees;Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees;Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees;Lundbeck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda/Palladin: Honoraria, Membership on an entity's Board of Directors or advisory committees;Treadwell: Honoraria, Membership on an entity's Board of Directors or advisory committees. Chodirker: Hoffman Laroche: Honoraria. Lin: Novartis: Research Funding;Pfizer: Honoraria. Callum: Octapharma: Research Funding;Canadian Blood Services: Research Funding.