Allogeneic stem-cell transplantation is an important curative strategy in acute myeloid leukaemia (AML) consequent upon the development of a graft-versus-leukaemia (GVL) effect. Disease relapse is the major cause of transplant failure and novel therapeutic strategies are required in patients with measurable residual disease (MRD) post-transplant. Recognizing that full donor T cell chimerism serves as a biomarker of GVL and that mixed donor T cell chimerism reflects the presence of bi-directional tolerance, we report the first prospective correlation of the impact of post-transplant T cell chimerism and MRD in patients allografted for AML/MDS. Methods: 186 patients from FIGARO, a prospective randomized trial of reduced intensity conditioning regimens in AML/MDS, were alive and relapse free, at the first MRD timepoint and provided post-transplant bone marrow samples for flow cytometric MRD monitoring (day+42, month+3/+6/+9/+12) and peripheral blood samples for T cell chimerism analysis (3-monthly during the first year). Results were not available to clinicians. Flow cytometric MRD incorporating an unsupervised immunophenotypic analysis approach was used on 778 sequential samples. The prognostic significance of post-transplant MRD from each sampling timepoint was assessed by landmark analysis. Results: 29 (15.6%) patients were MRD+ at one or more timepoints in the first year after transplant. The presence of post-transplant MRD was associated with reduced OS (HR:2.19, p=0.0026) and RFS (HR:5.36, p<0.0001), when analyzed as a time varying Cox variable. We, and others, have shown that pre-transplant MRD status is an important determinant of post-transplant survival. We therefore performed a multivariate analysis of factors that may determine the prognoses of patients with pre-transplant MRD+ disease. This demonstrated that the presence of detectable post-transplant MRD was the only independent determinant of RFS in this group of patients (HR 9.05 (95%CI:1.70-48.2), p=0.0099), even when adjusted for cytogenetics, FLT3-ITD and GVHD. The highest frequency of post-transplant MRD positivity occurred at day+42/month+3. The 2yr OS of day+42 MRD+ patients (n=13/158) was 30.8% (95%CI 9.5-55.4) compared to 67.1% (95%CI 58.5-74.2) in MRD negative patients (p<0.001); and 2yr CIR in day+42 MRD+ patients was 92.3% (95% CI:35.8-99.4) versus 22.8%% (95%CI:16.3-29.9) when MRD negative (p<0.001). Day+42 MRD was associated with more rapid relapse kinetics (median RFS of 2 months) compared to when MRD was first detected at later timepoints. Next, we examined the impact of T-cell chimerism, and post-transplant MRD on outcomes. In patients with mixed-donor T-cell chimerism (MDTC) at month+3 or +6, the presence of post-transplant MRD (preceding or at time of first MDTC) was associated with decreased OS (p=0.001) and RFS. Specifically, 2yr RFS in MRD+ patients was 23.1% (95%CI:5.6-47.5), compared to 63.6% (95%CI:44.9-77.5) in patients who were MRD negative (p=0.004) (Figure). In contrast, in 48 patients with full donor T-cell chimerism (FDTC) at months 3 and 6, only 5 patients were MRD+ post-transplant and their outcomes were equivalent to patients who were MRD negative (FDTC/MRD negative 2yr RFS: 80.9% (95% CI:65.3-90.0)). Downregulation of HLA class II molecules on AML blasts after transplant may result in immune evasion from GVL: we examined whether this had an additional impact on outcome in post-transplant MRD+ patients. Both RFS and OS were significantly lower in MRD+ patients when MRD+ blasts had down-regulated HLA-DR expression. In MRD+ patients, 2yr OS was 20.0% (95%CI:3.1-47.5) in those with HLA-DR down-regulation, versus 57.9% (95%CI 33.2-76.3) in those without (p=0.001). Conclusion We demonstrate that dynamic assessment of post-transplant MRD is an important predictor of outcome in patients allografted for AML/MDS, with additional prognostic value to pre-transplant MRD assessment. Post-transplant MRD and T-cell chimerism results are most informative when combined, underlining the importance of a GVL effect in AML/MDS. This suggests post-transplant strategies which result in FDTC may improve outcomes in patients allografted for AML/MDS. Our data also supports the clinical relevance of monitoring for leukemic immune escape as HLA-DR down-regulation identifies a post-transplant MRD positive subgroup at risk of almost inevitable relapse. Figure 1 Figure 1. Disclosures Loke: Novartis: Other: Travel; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Daichi Sankyo: Other: Travel. Protheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Dillon: Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Jazz: Other: Education events; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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. Figure 1 Figure 1. Disclosures Loke: Novartis: Other: Travel; Janssen: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Daichi Sankyo: Other: Travel. Knapper: 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.

Background Early data suggest that patients undergoing salvage chemotherapy for relapsed or refractory (R/R) acute myeloid leukaemia (AML) have poor outcomes if infected with SARS-CoV-2, and nosocomial transmission has been a major problem worldwide. Gilteritinib is effective in R/R FLT3 mutated AML, is significantly less immunosuppressive and does not require hospital admission, however at the start of the pandemic this was not yet approved for routine use in all countries. In the United Kingdom, the National Health Service (NHS) made gilteritinib available as an emergency measure from late April 2020 to patients aged >16y with R/R FLT3 mutated AML, with the aim of reducing both mortality and healthcare resource use. We report a health-system-wide real world data collection for toxicity and patient outcomes across 27 NHS Hospitals. Methods Each patient was registered on a central NHS database, with clinicians certifying that their patient met the above criteria. Anonymised data were retrospectively collected by treating physicians. Gilteritinib dose, duration and toxicity information was requested for the first 4 cycles of therapy. Response definitions were as per European Leukaemia Network (ELN) guidelines. A total of 81 patients have been registered on the scheme, with outcomes reported here for those with follow-up information at a data cut on 1st August 2021. Results Fifty patients were included with a median age of 59y (range 19 - 77) and 50% male. The majority (83%) had an ECOG performance status of 0-1. AML was secondary to a previous haematological disorder in 12%, therapy-related in 4% and de novo in the remaining 84%. The disease was refractory to the last therapy in 38%. Most patients had previously received 1 (65%) or 2 (33%) lines of therapy, including intensive chemotherapy in a majority (86%). A FLT3 inhibitor had previously been administered to 45% and 35% were post allogeneic transplant. The FLT3 mutation was an internal tandem duplication (ITD) in 80% and tyrosine kinase domain (TKD) mutation in 22%. NPM1 mutations were detected in 34%. Next-generation sequencing results were available for 94% of patients, with mutations in IDH1 or IDH2 in 12.5%, ASXL1 in 2%, RUNX1 in 21% and no TP53 mutations. Patients spent a median 3.5 days in hospital in cycle 1, 0 days in cycles 2 and 3 and 1 day in cycle 4. In cycles 1, 2, 3 and 4, the median number of days of grade 4 neutropenia was 18, 7, 7.5, and 6.5 respectively, and the grade 4 thrombocytopenia was 2, 7, 0.5 and 0.5. The composite complete remission (CR) / CR with incomplete haematological recovery (CRi) rate was 27%. MRD data is being collected. The best response was morphological leukaemia free state (MLFS) in 4%, partial remission (PR) in 25% and refractory disease in 38%. The rate of combined CR/CRi did not differ in those with previous exposure to FLT3 inhibitors (23% vs 32%, p=0.6) or with past allogeneic transplant (29% vs 27%, p=0.3). There were no CR/CRi in patients with adverse cytogenetic risk. Median follow-up was 10.5 months (95%CI 7.3 - 12.3) with median overall survival (OS) 6.7 months (95%CI 4.5 - not reached). Mortality at day 30 was 0% and day 60 was 14%. 12-month overall survival was 38%. Patients who achieved a CR/CRi had a 12-month OS of 83%, and for PR this was 35%. Survival did not differ in those with previous FLT3 inhibitor exposure (HR 1.0, p>0.9) or allogeneic transplant (HR 0.63, p=0.3). Seven patients (14%) so far have been bridged with gilteritinib to allogeneic transplant. Conclusion Our data demonstrate that gilteritinib is well tolerated and clinically active in adults with relapsed FLT3 mutated AML. Importantly, during the COVID-19 pandemic, its availability has permitted the great majority of treatment to be delivered as an outpatient with significant resource saving at a time of critically constrained inpatient resources. Patients who achieve CR/CRi have good short-term outcomes and are able to proceed to a potentially curative allogeneic stem cell transplant. Figure 1 Figure 1. Disclosures Belsham: Celgene: Other: meeting attendance; Abbvie: Other: meeting attendance. Byrne: Incyte: Honoraria. Khan: Abbvie: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Jazz: Honoraria; Gilead: Honoraria; Novartis: Honoraria. Khwaja: Pfizer: 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; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: 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. Latif: Kite: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda UK: Speakers Bureau. Loke: Amgen: Honoraria; Daichi Sankyo: Other: Travel Support; Janssen: Honoraria; Novartis: Other: Travel Support; Pfizer: Honoraria. Munisamy: Jazz Pharmaceuticals: Speakers Bureau; Roche: Speakers Bureau. Murthy: Abbvie: Other: support to attend educational conferences.. Smith: Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; ARIAD: Honoraria. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. 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; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events.