No abstract

Stem cell transplant (SCT) outcomes in high-risk (HR) and relapsed/refractory (R/R) paediatric acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) have been poor historically. Cord blood allows T-cell replete transplant (TRCB), enabling enhanced graft-versus-leukaemia. We collected data from 367 consecutive patients undergoing TRCB (112 patients) or other cell source (255 patients) SCT for paediatric AML/MDS in the UK and Ireland between January 2014 and December 2021. Data was collected about patient's demographics, disease and its treatment including previous transplant, measurable residual disease (MRD) status at transplant, HLA-match, relapse, death, graft versus host disease (GvHD) and transplant-related mortality (TRM). Univariable and multivariable analyses were undertaken. There was a higher incidence of poor prognosis features in the TRCB cohort: 51.4% patients were MRD positive at transplant, 46.4% had refractory disease and 21.4% had relapsed after a previous SCT, compared with 26.1%, 8.6% and 5.1% respectively in the comparator group (all p <0.001). Within the TRCB cohort, Event Free Survival (EFS) was 64.1%, 50% in MRD positive patients and 79% in MRD negative (p= 0.009). To allow for the imbalance in baseline characteristics, a multivariable analysis was performed: the TRCB cohort had significantly improved EFS (0.57[0.35-0.91], p=0.019), time to relapse (0.46[0.26-0.81), p=0.008), and reduced chronic GVHD (HR 0.28 [95% CI 0.11-0.70]; p=0.007), with some evidence of improved Overall Survival (OS) (0.65[0.39-1.07], p = 0.088). The effect appeared similar regardless of MRD status, (interaction p-value= 0.29). CB transplant without serotherapy may be the optimal transplant option for children with myeloid malignancy.

Risk factors for severe SARS-Cov-2 infection course are poorly described in children following hematopoietic cell transplantation (HCT). In this international study, we analyzed factors associated with a severe course (intensive care unit (ICU) admission and/or mortality) in post-HCT children. Eighty-nine children (58% male; median age 9 years (min-max 1–18)) who received an allogeneic (85; 96%) or an autologous (4; 4%) HCT were reported from 28 centers (18 countries). Median time from HCT to SARS-Cov-2 infection was 7 months (min-max 0–181). The most common clinical manifestations included fever (37; 42%) and cough (26; 29%); 37 (42%) were asymptomatic. Nine (10%) children following allo-HCT required ICU care. Seven children (8%) following allo-HCT, died at a median of 22 days after SARS-Cov-2 diagnosis. In a univariate analysis, the probability of a severe disease course was higher in allo-HCT children with chronic GVHD, non-malignant disease, immune suppressive treatment (specifically, mycophenolate), moderate immunodeficiency score, low Lansky score, fever, cough, coinfection, pulmonary radiological findings, and high C-reactive protein. In conclusion, SARS-Cov-2 infection in children following HCT was frequently asymptomatic. Despite this, 10% needed ICU admission and 8% died in our cohort. Certain HCT, underlying disease, and SARS-Cov-2 related factors were associated with a severe disease course.

Introduction The clinical manifestations of COVID-19 infection in recipients of allogeneic hematopoietic stem cell transplantation (HSCT) have been reported in multiple retrospective cohorts of patients, but there have been no prospective studies to date. Previous studies report that HSCT recipients are at higher risk, with cumulative incidence of death between 17-35%. Although an excessive pro-inflammatory viral response has been documented in the general population, its role in the immune incompetent HSCT setting has not been documented. We present a combined prospective and retrospective national study run through the UK IMPACT trial network to characterize the clinical and immunological features of COVID-19 infection in 96 adult and pediatric recipients of HSCT in the United Kingdom. Methods HSCT recipients of any age and transplanted for any indication, with an RT-PCR-proven COVID-19 infection, were eligible for this study. Patients within 72 hours of COVID-19 diagnosis, who had not received cytokine-targeted treatment, were recruited to a prospective cohort. All other patients were eligible for a retrospective cohort. Prospective patients provided blood samples within 72 hours of COVID-19 diagnosis, and again within 72 hours of clinical deterioration (defined as requirement for oxygen administration) if applicable. Follow-up data were collected on patients 30 and 100 days after COVID-19 diagnosis. Results 100 patients were recruited from 16 sites across the UK between May 2020-June 2021, comprising 12 in a prospective cohort and 88 recruited retrospectively. 96 patients were evaluable, as 4 proved ineligible post-registration. Patients were diagnosed with COVID-19 at a median of 11 months after HSCT. Patient/HSCT characteristics are shown Table 1. The most common symptoms associated with the onset of COVID-19 were fever in 8 prospective (73%) and 35 (41%) retrospective patients, followed by cough in 5 (45%) prospective and 35 (41%) retrospective patients and dyspnea in 4 (36%) prospective and 16 (19%) retrospective patients. 8 (73%) prospective and 40 (47%) retrospective patients were actively immunosuppressed at the time of COVID-19 infection. 16% of the patients had moderate/severe disease at baseline. At day 30 (±2 days) after COVID-19 diagnosis, 2 prospective and 8 retrospective patients continued to demonstrate SARS-CoV-2 positivity on respiratory PCR testing. The median time to viral clearance was 40 (IQR 17-78) days for the prospective and 34 (IQR 15-70) days for the retrospective cohort. Prolonged (more than 14 days) neutropenia was reported in 4 (5%) patients in the retrospective cohort, prolonged thrombocytopenia in 2 (18%) prospective and 11 (13%) retrospective patients. 1 retrospective patient developed secondary hemophagocytic lymphohistiocytosis, and graft rejection was reported in 1 (1%) retrospective patient, within 30 days of COVID-19 diagnosis. In the prospective cohort, 3 (27%) patients died, all by day 30, and all due to COVID-19. In the retrospective cohort, 13 (17%) patients died by day 30, rising to 18 (21%) by day 100, 61% of deaths were attributed to COVID-19. Lower baseline platelets (p=0.013, Mann-Whitney U test), lymphocytes (p=0.012), albumin (p=0.028), and higher baseline CRP (p=0.007), were seen in patients who died following COVID-19 diagnosis. Additionally, exploratory univariate logistic regression of the retrospective cohort found mortality at day 100 to be associated with increased age at diagnosis (OR 1.04, 95% CI 1.01-1.08, p=0.04), and no requirement compared with requirement for invasive ventilation (OR 0.02, 95% CI 0.00-0.16, p=0.001). The 11 prospective patients showed normal levels of interleukin (IL)-2, -4, -10, interferon gamma and tumor necrosis factor alpha at COVID-19 presentation. IL-6 was minimally raised (up to 127 pg/ml, nv<50) in 3/11 pts at presentation. Respiratory deterioration was not associated with detectable cytokine storm. Conclusion Our study confirms a significant mortality rate in patients affected by COVID-19 post HSCT and confirms age as well as requirement for invasive ventilation to be independent risk factors associated with death at day 100. Baseline laboratory data at disease presentation can identify patients at higher risk of COVID-19 related death. In the prospective cohort of our study, pathophysiology of the viral disease did not seem related to cytokine storm-mediated inflammation. Figure 1 Figure 1. Disclosures Protheroe: Jazz Pharmaceuticals: Honoraria; Astellas: Honoraria; Kite Gilead: Honoraria. Peggs: Autolus: Consultancy, Current equity holder in publicly-traded company. Craddock: Novartis Pharmaceuticals: Other: Advisory Board ; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicholson: BMS/Celgene: Consultancy; Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; Pfizer: Consultancy. Amrolia: ADC Therapeutics: Other: Named inventor on a patent which is being transferred to ADCT.; Autolus: Patents & Royalties.

Chimeric antigen receptor (CAR) T-cell therapy is a new, effective treatment for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukaemia (ALL). Tisagenlecleucel achieved a complete remission (CR) rate and minimal residual disease (MRD) negativity of 81% at 3 months in the pivotal study; overall survival (OS) was 76% at 12 months (Maude et al, 2018). Real world data confirmed similar outcomes, with 1-year OS of 77% and event free survival (EFS) of 52% (Pasquini et al, 2020). Relapse can occur in the form of CD19 negative or CD19 positive ALL. The latter is associated with lack of persistence of the CAR T product. B-cell aplasia (BCA) is an indirect measure of CAR T presence. Early (<6 months from infusion) loss of BCA is associated with high relapse risk (Pillai et al, 2019); therefore, allogeneic stem cell transplantation (SCT) is often considered. However, SCT is associated with therapy-related morbidity and mortality and not all patients will find a suitable donor. Therefore, the optimal management of patients with loss of BCA is yet to be defined. In our centre, we administered maintenance therapy to a cohort of children with early loss of BCA. When compared to UK patients undergoing SCT for the same indication, we noted promising early outcomes. We report the findings here. We collected data on children with r/r ALL treated with tisagenlecleucel at Great Ormond Street Hospital (GOSH) from January 2018 to January 2021 who presented loss of BCA without evidence of disease (negative molecular or flow cytometry MRD) within 12 months from infusion. Loss of BCA was defined as peripheral B-cell count ≥0.10 x 10^9/L or bone marrow (BM) CD19+ events ≥0.1%. We compared outcomes of children who received maintenance as per UKALL 2011 protocol at GOSH to those who received SCT for the same indication from all UK paediatric centres. Fourteen patients from GOSH met the inclusion criteria. Four had loss of BCA after 6 months from CAR T infusion, none of them received additional therapy and they are all alive and in CR at a median of 535 days after CAR T infusion (Figure 1, A and B). Ten patients recovered B cells at <6 months: 3 proceeded to SCT, 6 started on maintenance therapy, 1 received other treatment. In 2 cases, maintenance was commenced after a second CAR T infusion. Two patients from the UK cohort met the inclusion criteria for the SCT group. Analysis was performed on 6 children who received maintenance and 5 who had SCT. Baseline characteristics of the 2 groups were similar (male/female ratio, median age at infusion, cytogenetics). Time from infusion to loss of BCA did not differ: the median was 80 days (range 28-168) in children who had maintenance vs 93 days (range 28-150) in those who had SCT. At a median follow up of 511 days (range 222-812), 3/6 children who received maintenance relapsed at median 210 days after infusion and proceeded to further treatment, no patient relapsed post SCT. One child died of disease in the maintenance group 237 days after infusion, 2 children died of transplant related mortality in the SCT group at 222 and 422 days post infusion. OS and EFS did not differ statistically between the 2 groups, as shown in Figure 1 (C and D). We observed that outcome for patients who presented loss of BCA within or at 2 months from infusion was poor regardless of the intervention (maintenance or SCT). Management of patients who experience early loss of BCA after CAR T is challenging and there are little data to support optimal treatment. In our experience, maintenance therapy compared favourably with SCT with similar rate of OS and EFS. Of note, 2/5 patients died of TRM in the SCT group highlighting the toxicity of this approach in such heavily pre-treated patients. On the other hand, maintenance is a well tolerated, low-cost treatment which can be easily delivered on an out-patient basis. Our preliminary data support investigation of this strategy in larger, prospectively-recruited cohorts of patients. Moreover, our preliminary data suggest that the time of loss of BCA is a crucial clinical parameter, as children who developed it within 2 months from infusion had the worst outcome, possibly reflecting prior therapy intensity and its impact on autologous T cells. Figure 1 Figure 1. Disclosures Amrolia: ADC Therapeutics: Other: Named inventor on a patent which is being transferred to ADCT.; Autolus: Patents & Royalties. Ghorashian: UCLB: Patents & Royalties: CARPALL; Novartis: Honoraria.