Background: Acute myeloid leukemia (AML) is an aggressive malignancy and is the most common and second most common form of acute leukemia in adults and children, respectively. The combination of the highly selective BCL-2 inhibitor venetoclax and the hypomethylating agent azacitidine was shown to be safe and effective in clinical trials (DiNardo et al. Blood. 2019;133:7-17; DiNardo et al. N Engl J Med. 2020;383:617-629) and is approved by the United States Food and Drug Administration and European Medicines Agency for the treatment of patients with AML who are not eligible to receive intensive chemotherapy. Following allogeneic stem cell transplantation (alloSCT), most patients do not receive antileukemic therapy; however, an unmet need remains as disease relapse and graft-versus-host disease (GvHD) commonly occur posttransplant. In addition to the antileukemic effect of venetoclax shown in clinical studies, preclinical studies suggest venetoclax may mitigate the risk of GvHD. VIALE-T is a Phase 3, randomized, open-label trial in progress (NCT04161885) evaluating the safety and efficacy of venetoclax in combination with azacitidine versus best supportive care (BSC) as maintenance therapy following alloSCT in patients with AML. Aims: N/A Methods: This Phase 3 study consists of 2 parts (Figure). Key inclusion criteria include diagnosis of AML; plans to receive alloSCT or have received alloSCT within the past 30 days; bone marrow blasts <10% before pretransplant conditioning and <5% posttransplant; have received myeloablative, or reduced intensity, or nonmyeloablative pretransplant conditioning protocols. Grafts are allowed from various sources (bone marrow, peripheral blood stem cells, cord blood cells). Patients must be ≥18 years old for Part 1 and ≥12 years old for Part 2. Additionally, patients must meet key laboratory values for absolute neutrophil count (Part 1, ≥1500/µL; Part 2, ≥1000/µL), platelet count (Part 1, ≥80,000/µL; Part 2, ≥50,000/µL), bilirubin ≤3 times the upper limit of normal, and creatinine clearance >30 mL/min. Patients who have received venetoclax and had no history of disease progression while receiving venetoclax are eligible. Part 1 evaluates dose levels of venetoclax combined with azacitidine to determine the recommended Phase 3 dose (RP3D), which will be confirmed in approximately 12 additional patients enrolled in the Safety Expansion Cohort. Part 2 will be a randomized, open-label evaluation of the RP3D of venetoclax combined with azacitidine and BSC versus BSC only in adults and children aged 12 years or older. All venetoclax-treated patients will receive antibiotic prophylaxis during Cycle 1. The primary endpoint for Part 1 is the frequency of dose-limiting toxicities. The primary endpoint for Part 2 is relapse-free survival as assessed by an independent review committee. Key secondary endpoints for Part 2 include overall survival, GvHD-free relapse-free survival, and the rate of patients without higher grade GvHD at 90 days after randomization. Enrollment into the Safety Expansion Cohort will be completed in 2021. Part 2 will enroll approximately 400 patients across approximately 175 participating study sites in 17 countries, with recruitment beginning in 2022. Results: N/A Image:Summary/Conclusion: N/A
Over the last two decades, umbilical cord blood (UCB) has become an established alternative donor source for paediatric haematopoietic transplantation (HSCT) (Ballen et al, 2013). UK national trends and outcomes in UCB transplantation (UCBT) have never been comprehensively appraised in adults. We therefore analysed the demographic data and outcomes in patients aged ≥18 years undergoing UCBT in 22 UK National Health Service (NHS) transplant centres from 2000-2012. Between 1998 and 2012, 526 UCBT were performed in the UK and reported to Eurocord (http://eurocord.org/home.html), of which 183 were in adult patients (aged ≥18 years). Patients enrolled on the national clinical trials (EUDRACT registrations; RIC 2004-003845-41 and MAC 2009-011818-21) (n = 29) were recorded in these numbers but excluded from further analysis. Expanded and experimental UCBT were also excluded. Data were obtained from Eurocord database and supplementary questionnaires. Statistical analyses were performed using spss Statistics 21 (IBM Corporation, Armonk, NY, USA) and R 3·0·2 (https://www.r-project.org) with P < 0·05 considered significant. Engraftment, graft-versus-host disease (GvHD), relapse and transplant-related mortality (TRM) were assessed using cumulative incidence with competing risk (relapse for TRM; death for other outcomes). Overall survival (OS) was analysed using Kaplan–Meier (univariate) and Cox Proportional Hazards (multivariate). Variables with P < 0·1 or known to be clinically significant were included in multivariate analysis, using a backward approach keeping variables with P < 0·05. Between 2000 and 2012, 183 UCBT in patients ≥ 18 years were registered in the UK, accounting for 3·2% of the 5694 unrelated donor allogeneic HSCT reported to the British Society of Blood and Marrow Transplantation (BSBMT) registry for this period (personal communication Keiren Kirkland, BSBMT Registry, London). Internationally, the UK-based cohort comprised 5·7% of the European/Eurocord activity of 3210 UCBT undertaken in patients ≥18 years. In the UK, the first adult single unit UCBT (sUCBT) was performed in 2000 and first double unit UCBT (dUCBT) in 2005. This contrasts with France, Spain and Italy, where the first UCBTs in adults were performed in 1996–1997 (single) and 2002 (double). The characteristics of the 154 UCBT patients available for analysis are summarized in Table 1. Most patients (74%) received dUCBT and the remainder non-expanded sUCBT. Engraftment of neutrophils to >0·5 × 109/l occurred at a median of 22 days (range 3–52), 21 days (range 9–50) for sUCBT and 23 days (range 3–52) for dUCBT (P = 0·26). Platelet recovery to >20 × 109/l occurred at a median of 40 days (range 1–174), 36 days (range 18–103) for sUCBT and 42 days (range 1–174) for dUCBT (P = 0·046). The incidence of grade II–IV acute GvHD was 29% (95% CI 22–36%) and chronic GvHD at 1 year was 28% (95% CI 20–36%). In patients treated for malignant disease (n = 148), cumulative incidence of relapse was 12% [95% confidence interval (95% CI) 7–17%] at 100 days and 25% (95% CI 19–33%) at 1 year, with TRM 22% (95% CI 16–29%) at 100 days and 31% (95% CI 24–39%) at 1 year. OS at 1 year was 50% (95% CI 42–58%) and 40% (95% CI 32–49%) at 3 years, with a median survival of 3·7 years (range 0·3–8·1) for survivors. Survival outcomes are summarized in Fig 1. In univariate analysis, OS was strongly related to stage of disease, with a 53% 4-year OS (95% CI 41–69%) for early [first complete remission; chronic phase chronic myeloid leukaemia (CML)], 44% (95% CI 29–66%) for intermediate (second or later complete remission; accelerated CML) and 20% (95% CI 12–35%) for advanced (non-remission; blastic CML; myelodysplatic syndrome; myeloma) (P < 0·0001). Use of T-depleting serotherapy (anti-thymocyte globulin or alemtuzumab) in the conditioning regimen impacted negatively on OS (23% vs. 43% at 4 years, P = 0·004), but there was no significant impact of gender, age, diagnosis, intensity of conditioning, dUCBT or sUCBT, total nucleated cell (TNC) or CD34+ dose, human leucocyte antigen (HLA) or ABO matching, cytomegalovirus (CMV) serostatus, granulocyte colony-stimulating factor or year of UCBT (2000–2008 vs. 2009–2012). In multivariate analysis, advanced disease [Hazard ratio (HR) 4·1 (95% CI 2·2–7·6), P < 0·0001] and use of serotherapy [HR 1·9 (95% CI 1·2–3·0), P = 0·004] were associated with inferior OS. In subgroup analysis for acute leukaemia (n = 90), the relationship between OS and disease status was even stronger (P < 0·0001); 56% for early disease, 38% for intermediate and 0% for advanced disease at 4 years. There was no significant difference in outcome between acute myeloid leukaemia (n = 63) and acute lymphoblastic leukaemia (n = 27). Again, use of serotherapy was associated with inferior survival (23% vs. 49% at 4 years, P = 0·004). In multivariate analysis, advanced disease (HR 5·0 (95% CI 2·4–13·1), P < 0·0001), use of serotherapy (HR 3·4 (95%CI 1·7–6·7), P = 0·0006) and older recipient age (HR 1·03 per year (95% CI 1·00–1·06), P = 0·02) were associated with inferior OS. However, UCBT with two or more HLA-mismatches between the recipient and cord blood unit(s) [CBU(s)] were associated with improved survival [HR 0·4 (95% CI 0·2–0·8), P = 0·01]. Despite the relatively slow uptake of UCBT in the UK, the survival data in this analysis provides reassurance of similar long-term outcomes compared to those achieved using adult unrelated donors and with international reports of alternative donor transplantation (Marks et al, 2014; Rodrigues et al, 2014). As expected, there was a strong relationship between disease stage and survival, especially in acute leukaemia. The negative effect of T-cell depletion in the conditioning regimen is potentially explained by poor immune reconstitution and its consequences (Chiesa et al, 2012). Other factors did not appear to have a significant impact in this UK cohort. Significantly, survival and engraftment outcomes following dUCBT were not superior to sUCBT, concurring with recent data in the paediatric and young adult population (Wagner et al, 2014). However, use of dUCBT extends access to larger patients for whom no sufficient single CBU is available. Larger analyses have confirmed HLA match, CD34+/TNC dose and CMV status to be strongly related to outcome (Rocha & Gluckman, 2009), but these factors were not significant in this UK sample, possibly due to cohort size or degree of allele matching. In conclusion, the UK experience of UCBT in adults to date shows encouraging results and comparable long-term outcomes with international data. Prospective comparator studies are warranted against haploidentical and other HLA-mismatched bone marrow SCT (Ruggeri et al, 2015). In the meantime, updated national guidelines (Hough et al, 2016), NHS policy and other strategic initiatives (NHS Blood and Transfusion, 2014; NHS England, 2015), along with publication of prospective national trial data, will provide future direction for UCBT in the UK. JAS, RD, AR, BES, DIM & VR designed the study, with support from GC (BSBMT) and EG (Eurocord). JAS, DIM, REH, AP, CC, MP, NR, AC, PM, BES, VR made significant patient data contributions on behalf of their transplant programmes. All authors critically reviewed and approved the final manuscript. We would also like to acknowledge the patient data contributions made by the following as transplant programme directors and/or treating physicians (in alphabetical order): J Apperley, H Campbell, R Clark, C Crawley, M Collin, M Gilleece, A Hunter, M Kazmi, M Koh, S Mackinnon, G McQuaker, A Peniket, P Shankara, E Tholouli and K Wilson.
The use of antihuman T-lymphocyte immunoglobulin in the setting of transplantation from an HLA-matched related donor is still much debated. Acute and chronic graft-versus-host disease are the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. The aim of this study was to evaluate the effect of antihuman T-lymphocyte immunoglobulin in a large cohort of patients with myelofibrosis (n=287). The cumulative incidences of grade II-IV acute graft-versus-host disease among patients who were or were not given antihuman T-lymphocyte immunoglobulin were 26% and 41%, respectively. The corresponding incidences of chronic graft-versus-host disease were 52% and 55%, respectively. Non-adjusted overall survival, disease-free survival and non-relapse mortality rates were 55% versus 53%, 49% versus 45%, and 32% versus 31%, respectively, among the patients who were or were not given antihuman T-lymphocyte immunoglobulin. An adjusted model confirmed that the risk of acute graft-versus-host disease was lower following antihuman T-lymphocyte immunoglobulin (hazard ratio, 0.54; P=0.010) while it did not decrease the risk of chronic graft-versus-host disease. The hazard ratios for overall survival and non-relapse mortality were 0.66 and 0.64, with P-values of 0.05 and 0.09, respectively. Antihuman T-lymphocyte immunoglobulin did not influence disease-free survival, graft-versus-host disease, relapse-free survival or relapse risk. In conclusion, in the setting of matched related transplantation in myelofibrosis patients, this study demonstrates that antihuman T-lymphocyte immunoglobulin decreases the risk of acute graft-versus-host disease without increasing the risk of relapse.
<p>A hypothetical example of an updated DTP for Cohorts 7 to 9 in the Viola trial with the final recommended MTD. This is based on observing DLT outcomes of 0/3 DLT at Dose 0, 1/3 DLT at Dose 1 and 0/3 DLT at Dose 1 for Cohorts 1 to 3 respectively (pathway 5 in Table 2), followed by 1/3 DLT at Dose 2, 0/3 DLT at Dose 1 and 2/2 DLT at Dose 2 for Cohorts 4 to 6 respectively (pathway 19 in Supplementary Table S3).</p>
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