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•Compared with other cell sources, TRCB transplant results in improved disease-free survival and relapse risk in pediatric AML/MDS.•Compared with other cell sources, cord-transplant cures with less chronic GvHD and particularly improves GvHD-free, relapse-free survival. more...

Aims and methodsFaecal calprotectin (FCP) measurement is used especially to investigate for inflammatory bowel disease (IBD). To assess the utility of sampling endoscopically normal large bowel among patients first presenting with elevated FCP, this study identified 115 such patients out of 652 patients with elevated FCP from approximately 6000 primary care tests processed over 15 months.Results23 cohort patients showed histologically abnormal large bowel biopsies. Only four cases demonstrated acute inflammation and two such patients only showed scattered cryptitis and did not develop IBD. A third patient demonstrated similar histology but, following repeat colonoscopy, her elevated FCP was attributed to small intestinal inflammation. Only the fourth patient’s large bowel biopsies showed features suggesting Crohn’s disease, but this represented an IBD detection rate out of 115 sets of large bowel biopsies of 0.9%.ConclusionsSampling of endoscopically normal large bowel among patients first presenting with elevated FCP is not clinically justified. more...

Chimeric antigen receptor (CAR) T cells targeting CD19 or CD22 have shown remarkable activity in B cell acute lymphoblastic leukemia (B-ALL). The major cause of treatment failure is antigen downregulation or loss. Dual antigen targeting could potentially prevent this, but the clinical safety and efficacy of CAR T cells targeting both CD19 and CD22 remain unclear. We conducted a phase 1 trial in pediatric and young adult patients with relapsed or refractory B-ALL (n= 15) to test AUTO3, autologous transduced T cells expressing both anti-CD19 and anti-CD22 CARs (AMELIA trial, EUDRA CT 2016-004680-39). The primary endpoints were the incidence of grade 3–5 toxicity in the dose-limiting toxicity period and the frequency of dose-limiting toxicities. Secondary endpoints included the rate of morphological remission (complete response or complete response with incomplete bone marrow recovery) with minimal residual disease-negative response, as well as the frequency and severity of adverse events, expansion and persistence of AUTO3, duration of B cell aplasia, and overall and event-free survival. The study endpoints were met. AUTO3 showed a favorable safety profile, with no dose-limiting toxicities or cases of AUTO3-related severe cytokine release syndrome or neurotoxicity reported. At 1 month after treatment the remission rate (that is, complete response or complete response with incomplete bone marrow recovery) was 86% (13 of 15 patients). The 1 year overall and event-free survival rates were 60% and 32%, respectively. Relapses were probably due to limited long-term AUTO3 persistence. Strategies to improve CAR T cell persistence are needed to fully realize the potential of dual targeting CAR T cell therapy in B-ALL. more...

Our understanding of the perturbation of normal cellular differentiation hierarchies to create tumor-propagating stem cell populations is incomplete. In human acute myeloid leukemia (AML), current models suggest transformation creates leukemic stem cell (LSC) populations arrested at a progenitor-like stage expressing cell surface CD34. We show that in ∼25% of AML, with a distinct genetic mutation pattern where >98% of cells are CD34−, there are multiple, nonhierarchically arranged CD34+ and CD34− LSC populations. Within CD34− and CD34+ LSC–containing populations, LSC frequencies are similar; there are shared clonal structures and near-identical transcriptional signatures. CD34− LSCs have disordered global transcription profiles, but these profiles are enriched for transcriptional signatures of normal CD34− mature granulocyte–macrophage precursors, downstream of progenitors. But unlike mature precursors, LSCs express multiple normal stem cell transcriptional regulators previously implicated in LSC function. This suggests a new refined model of the relationship between LSCs and normal hemopoiesis in which the nature of genetic/epigenetic changes determines the disordered transcriptional program, resulting in LSC differentiation arrest at stages that are most like either progenitor or precursor stages of hemopoiesis. more...

A significant proportion of children with T-cell acute lymphoblastic leukemia (T-ALL) continue to fail therapy. Consequently, characterization of the cells that proliferate to maintain the disease should provide valuable information on the most relevant therapeutic targets. We have used in vitro suspension culture (SC) and nonobese diabetic–severe combined immune deficient (NOD/SCID) mouse assays to phenotypically characterize and purify T-ALL progenitor cells. Cells from 13 pediatric cases were maintained in vitro for at least 4 weeks and expanded in 8 cases. To characterize the progenitors, cells were sorted for expression of CD34 and CD4 or CD7 and the subfractions were evaluated in vitro and in vivo. The majority of cells capable of long-term proliferation in vitro were derived from the CD34+/CD4− and CD34+/CD7− subfractions. Moreover, the CD34+/CD4− or CD7− cells were the only subfractions capable of NOD/SCID engraftment. These T-ALL cells successfully repopulated secondary and tertiary recipients with equivalent levels of engraftment, demonstrating self-renewal ability. The immunophenotype and genotype of the original leukemia cells were preserved with serial passage in the NOD/SCID mice. These data demonstrate the long-term repopulating ability of the CD34+/CD4− and CD34+/CD7− subfractions in T-ALL and suggest that a cell with a more primitive phenotype was the target for leukemic transformation in these cases. more...

A significant proportion of children with T-cell acute lymphoblastic leukemia (T-ALL) continue to fail therapy. Consequently, characterization of the cells that proliferate to maintain the disease should provide valuable information on the most relevant therapeutic targets. We have used in vitro suspension culture (SC) and nonobese diabetic–severe combined immune deficient (NOD/SCID) mouse assays to phenotypically characterize and purify T-ALL progenitor cells. Cells from 13 pediatric cases were maintained in vitro for at least 4 weeks and expanded in 8 cases. To characterize the progenitors, cells were sorted for expression of CD34 and CD4 or CD7 and the subfractions were evaluated in vitro and in vivo. The majority of cells capable of long-term proliferation in vitro were derived from the CD34+/CD4−and CD34+/CD7−subfractions. Moreover, the CD34+/CD4−or CD7−cells were the only subfractions capable of NOD/SCID engraftment. These T-ALL cells successfully repopulated secondary and tertiary recipients with equivalent levels of engraftment, demonstrating self-renewal ability. The immunophenotype and genotype of the original leukemia cells were preserved with serial passage in the NOD/SCID mice. These data demonstrate the long-term repopulating ability of the CD34+/CD4−and CD34+/CD7−subfractions in T-ALL and suggest that a cell with a more primitive phenotype was the target for leukemic transformation in these cases. more...

Introduction

Dillon: Abbvie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Forty Seven, Inc.: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau. Amrolia:UCLB: Patents & Royalties. Baruchel:Bellicum: Consultancy; Servier: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. more...

Response to induction therapy is a powerful prognostic indicator in acute myeloid leukemia (AML). Measurable/minimal residual disease (MRD) assays are being increasingly incorporated into response assessment; however, their value as a surrogate for long-term outcome remains unclear because of assay limitations and the effect of post remission therapies. This is particularly the case for the molecularly heterogeneous NPM1wild type standard risk patients for whom treatment decisions, including predicting the benefit of allogeneic stem cell transplantation (SCT), are particularly challenging. We investigated the effect on outcome of MRD status compared to other response criteria after each cycle of induction for NPM1wild type (wt) standard risk patients and other risk groups in a cohort of younger AML patients. more...

Off Label Use: Off Label Use: Gemtuzumab Ozogamicin, an antibody-drug conjugate used to treat AML. Russell:Therakos: Other: shares.

On behalf of the UK NCRI AML Working Group

No relevant conflicts of interest to declare.

Lack of progress in curing AML is likely, in part, to be due to the genetic and functional heterogeneity of AML. ~13 Tier 1 mutations occur per patient sample arrayed in 2-5 clones (CGARN, N Engl J Med, 2013). Not all AML cell populations may be equally chemosensitive; for example, leukemia-propagating leukemic stem cells (LSC) are more chemoresistant. (Ishikawa et al., Nat Biotechnol, 2007). Additionally, the impact of genetic heterogeneity on LSC function is unclear. more...

The majority of acute myeloid leukaemia (AML) patients are older than 60 years but little progress has been made in improving their poor outcome. Recent studies have used analysis of pre-treatment risk factors to identify patient subgroups most likely to tolerate and respond to more intensive treatment approaches. There are as yet no data on whether treatment effectiveness measured by the level of residual disease has independent prognostic value in determining the duration of response for older patients achieving a remission. Here we report the largest prospective series of immunophenotypic residual disease monitoring in older adult AML.We prospectively and sequentially assessed the utility of residual disease (MRD) monitoring by multiparameter flow cytometry in older AML or high risk myelodysplastic (MDS) patients (excluding APL) receiving intensive treatment as part of the ongoing MRC AML16 trial for adults over 60 years. Patients were randomised to 2 or 3 courses of either daunorubicin/cytarabine or daunorubicin/clofarabine with or without mylotarg for the first course. Samples from consented patients (treated from 2006 to 2009) were processed by reference laboratories using an identical 4 colour antibody panel and standard operating procedure. Leukemic aberrant phenotypes (LAPs) were defined in pretreatment bone marrow and/or blood samples and then quantified using selected panel antibody combinations in post chemotherapy cycle bone marrow samples. MRD was reported as positive if detected above the LAP sensitivity threshold.As previously shown for younger AML patients, immunophenotypic MRD monitoring was applicable to the majority of AML/high risk MDS patients over 60 years treated intensively. At least one LAP was identified in >90% of 224 analysed patients (median age 66, range 57–77) in whom an adequate pretreatment sample was received. Selected LAP sensitivity thresholds ranged from 0.05% to 0.2% as determined by analysis of control bone marrows. Most of patients in whom suitable LAPs could not be identified had AML M5. Aberrant CD7 expression in patients pretreatment (n=49) was associated with a poorer outcome (2 year OS of 11% (CD7+) v 40% (CD7-), HR adjusted for baseline characteristics 2.22 (1.33-3.70), p=0.002).170 patients in remission were evaluable for MRD after cycle 1 (C1). 90/170 patients (58%) were MRD positive (MRD+) of whom 12% were high risk MDS (10-20% blasts) pretreatment v 11% of MRD negative (MRD-) patients. 2 year cumulative incidence of relapse was 88% (median RFS 8 months) for C1 MRD+ patients v 45% (18 months) for C1 MRD- patients. Adjusted analysis (allowing for age, sex, WBC, cytogenetics, secondary disease, performance status) shows MRD+ after course 1 is highly prognostic for relapse; HR 4.08 (2.05-8.10) p<0.0001.Post cycle 2 (C2) 57/147 patients (39%) were MRD+ with a 2 year cumulative incidence of relapse of 78% (median RFS 8 months) v 66% (13 months) for C2 MRD- (adjusted HR for relapse 2.36 (1.33-4.20) p=0.003). Only 30 patients were evaluable after 3 cycles of chemotherapy. MRD positivity at this time point was again prognostic from adjusted analysis of relapse but with wide confidence intervals due to small numbers: HR 83.58 (1.91-3654.09) p=0.003.These results suggest that flow cytometric analysis of residual disease in AML patients >60 treated intensively, particularly after course 1, may be useful in predicting the duration of remission, thus informing risk assessment for further treatment. Further data are needed to determine whether available treatment options can improve outcome of older AML patients with MRD positive disease.This research was funded by a grant from Cancer Research UK.No relevant conflicts of interest to declare. more...

Abstract 2714

Abstract 91

No relevant conflicts of interest to declare.