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Background: In patients with ALL, inability to receive L-asparaginase therapy due to hypersensitivity is associated with higher relapse risk (Gupta S, et al. J Clin Oncol. 2020). JZP458 is a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform to produce a reliable supply of enzyme with minimal immunologic cross-reactivity to E. coli-derived asparaginases. It has an amino acid sequence identical to that of native Erwinia asparaginase and its activity on asparagine is comparable based on in vitro measurements. This report includes initial analyses from the phase 2/3 open-label, multicenter, confirmatory pharmacokinetic (PK) and safety study (NCT04145531) of JZP458 in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E. coli-derived asparaginase.
Method(s): For eligible patients, each remaining course of long-acting E. coli-derived asparaginase was substituted by six doses of intramuscular (IM) JZP458 on a Monday/Wednesday/Friday (M/W/F) schedule. The primary efficacy endpoint of the trial was evaluated by the proportion of patients with the last 72-hr (primary endpoint) and last 48-hr (key secondary endpoint) nadir serum asparaginase activity (NSAA) level >=0.1 IU/mL during the first treatment course. Cohort 1a started with 25 mg/m ² IM JZP458 (M/W/F) and Cohort 1b explored a higher dose of 37.5 mg/m ² IM M/W/F. A preliminary population pharmacokinetic (PPK) model using Cohort 1a and 1b data predicted that a regimen of 25 mg/m ² (M/W) and 50 mg/m ² (F) would be optimal to support M/W/F dosing and Cohort 1c was initiated using this regimen.
Result(s): This initial report (data cutoff of Jan 11, 2021) provides data from 102 study patients enrolled in Cohort 1a (n=33, 51.5% male), 1b (n=53, out of 87 patients enrolled, 62.3% male), and 1c (n=16, out of 52 patients enrolled, 50.0 % male). The median (range) number of courses received in Cohorts 1a, 1b, and 1c as of the data cutoff was 4 (1, 14), 3 (1, 12), and 1 (1, 2), respectively, and 53% of patients were ongoing in treatment. The mean serum asparaginase activity (SAA) levels (95% confidence intervals [CIs]) for evaluable patients in Cohorts 1a, 1b, and 1c at 48 hrs were 0.4489 IU/mL (0.3720, 0.5258), 0.8376 IU/mL (0.6813, 0.9939), and 0.5085 IU/mL (0.3261, 0.6908); and at 72 hrs were 0.1543 IU/mL (0.1162, 0.1924), 0.3000IU/mL (0.2269, 0.3730), and 0.3579 IU/mL (0.2184, 0.4974). The proportion of patients achieving NSAA >=0.1 IU/mL at 48 and 72 hr time points are presented in Table 1. PPK modeling and simulation analysis suggested that JZP458 given IM as 25 mg/m ² on M/W and 50 mg/m ² on F was expected to achieve NSAA levels >=0.1 IU/mL in 99.8% of patients (95% CI: 99.6%, 100%) at 48 hours and 97.3% of patients (95% CI: 96.5%, 98.0%) at 72 hours. Grade 3 or higher treatment-emergent adverse events, regardless of causality, occurred in 73/102 (72%) patients. Adverse drug reactions (ADRs) are shown in Table 2. These ADRs are consistent with the safety profile observed with other asparaginases.
Conclusion(s): The JZP458 IM dosing regimen of 25 mg/m ² M and W, and 50 mg/m ² F demonstrates a positive benefit:risk profile, achieving SAA levels >=0.1 IU/mL in >90% of patients studied at both 48- and 72-hrs and a safety profile that is consistent with what has been observed in published literature on asparaginases. [Formula presented] Disclosures: Maese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Aoki: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zanette: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Agarwal: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Jazz Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Choi: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Servier Pharmaceuticals: Consultancy; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.
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INTRODUCTION Children with Down Syndrome (DS) and B-lymphoblastic leukemia (B-ALL) are at an increased risk of both relapse and treatment-related mortality, compared to those without DS. On COG study AALL1731 for de novo B-ALL, patients with DS and higher risk features (DS-High) are non-randomly treated with a regimen replacing intensive elements of conventional chemotherapy with three 28-day cycles of blinatumomab, with the combined goals of reducing toxicity and enhancing anti-leukemic efficacy. The DS-High group includes all NCI high risk (HR) patients; NCI standard risk (SR) patients with end-induction minimal residual disease positivity (>0.01%), unfavorable cytogenetics, CNS3 status, steroid pre-treatment, neutral cytogenetics with CNS2 status, or testicular disease. Neurotoxicity is a known risk of blinatumomab, with an incidence of 4% in block 1 and 1% in block 2 among pediatric patients with relapsed ALL (Brown et al, JAMA 2021). However, the specific risk in patients with DS has not been described to date. Here, we provide an early report of increased seizure incidence associated with blinatumomab in older DS-High patients enrolled on AALL1731 to date. METHODS We reviewed seizure incidence among patients with DS enrolled on AALL1731 from June 2019 to June 2021 who had proceeded to receive blinatumomab. Blinatumomab was administered at a dose of 15 mcg/m ²/day, using dexamethasone pre-medication in cycle 1. Infusions were interrupted for seizures, with resumption at 5 mcg/m ²/d permitted following full resolution for grade 1-3 seizures. RESULTS Among DS NCI HR patients, 8 of 47 (17%) had a seizure during blinatumomab infusion (Table 1). All 8 seizures occurred in patients over 10 years old. Six of the 8 seizures occurred in the first cycle of blinatumomab, most in the first 3 days of the infusion. Four had concomitant fever or cytokine release syndrome. Seizures were grade 2 (n=2) or grade 3 (n=6), and all resolved with full neurologic recovery. Of the 8 patients, 5 elected to resume blinatumomab; no further seizures occurred in these patients. There was no indication of increased seizure risk among NCI SR DS-High patients (1 seizure among 11 patients), or among DS or non-DS patients receiving blinatumomab on other study strata (0 of 7 DS SR-Avg; 1 of 146 non-DS SR-Avg; and 2 of 120 non-DS SR-High). CONCLUSIONS The incidence of seizures associated with blinatumomab in DS-ALL patients older than 10 years appears higher than previously reported in children without DS. The majority of seizures occurred within the first 3 days, all fully resolved with no sequelae, and no patient who resumed blinatumomab infusion at a lower rate experienced further seizures. Seizure prophylaxis may be advisable in DS patients while receiving blinatumomab, particularly those >10 years of age. Further follow-up and a larger sample size are needed to confirm incidence and identify risk factors predisposing DS patients to neurologic toxicity. [Formula presented] Disclosures: Li: Novartis Canada: Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder; Servier Pharmaceuticals: Consultancy. OffLabel Disclosure: This trial includes the use of blinatumomab in combination with chemotherapy for treatment of de novo B-lymphoblastic leukemia.
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Background Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer and while curable in the majority of cases, 15%-20% of children will relapse with only 50% surviving long-term. Treatment failures arise from the outgrowth of pre-existing or acquired sub-clones that are genetically or epigenetically primed to resist treatment. In addition, the bone marrow microenvironment is known to provide a protective niche. We performed the first mapping of the human B-cell ALL (B-ALL) immune bone marrow (BM) microenvironment at single cell resolution at diagnosis, remission and relapse (Witkowski, 2020). We uncovered a striking rewiring of the myeloid compartment during B-ALL progression with significant over-representation of a leukemia-associated monocyte subpopulation expressing high levels of the Macrophage Colony Stimulating Factor Receptor (M-CSFR/CSF1R). Using both peripheral blood (PB) complete blood count analysis and RNA-seq data, we demonstrated that high monocyte abundance at B-ALL diagnosis is predictive of inferior pediatric and adult overall survival in two large independent clinical cohorts. To determine the association of non-classical monocyte abundance in BM and PB with risk of relapse, we examined a cohort of clinical samples from children enrolled on Children's Oncology Group (COG) protocols. Methods Using an unmatched case-control design, we established a preliminary cohort of PB and BM samples collected at diagnosis from 24 B-ALL patients with eventual relapse and 24 patients in long-term remission. Four remission samples from an NYU Langone cohort were used to validate the expansion of this population in the presence of B-ALL. We applied a customized flow cytometry based assay to identify CD115-expressing human monocyte subsets: classical (CD45 ⁺CD56 ^-CD14 ⁺CD16 ^-), non-classical (CD45 ⁺CD56 ^-CD14 ^-CD16 ⁺), as well as B-cells (CD19, CD22, CD10) and T/NK cells (CD3, CD56). We then performed univariate and multivariable analysis of outcome (relapse versus long-term remission) compared to monocyte subset abundance, adjusting for potential confounding factors (age, gender, CNS status, NCI risk, genetic subtype, WBC at diagnosis, and end of induction minimal residual disease). Results We observed a significantly higher percentage of non-classical monocytes in the diagnostic BM from the COG cohort when compared to remission samples (COG diagnostic B-ALL BM non-classical percentage mean 52.19% vs NYU B-ALL remission BM non-classical percentage mean 1.775%, P = 0.0001). We also observed a strong correlation between the percentage of non-classical monocytes in the PB when compared to their matched BM specimens (r = 0.6, P = 0.0001). Multivariable analysis revealed a significant association between PB non-classical monocyte percentage at diagnosis and patient outcome (remission cohort non-classical monocyte percentage [mean, range]: 52.4%, 33.3-68.1%, n = 24, relapse cohort non-classical monocyte percentage: 65.9%, 56.4-84.7%, n = 24, P = 0.021). Similarly, a strong trend was observed in the BM, although it did not reach statistical significance. Flow cytometric analysis confirmed CD115 (M-CSFR/CSF1R) expression in this non-classical monocyte population, thereby validating a novel target for intervention. Conclusions These findings validate the presence of a unique monocyte subpopulation associated with childhood B-ALL and suggests that assessing this population in PB at diagnosis may be of prognostic significance. The availability of small molecule inhibitors and monoclonal antibodies targeting CSF1R-expressing monocytes may offer a novel approach to treating B-ALL. [Formula presented] Disclosures: Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Teachey: Sobi: Consultancy; NeoImmune Tech: Research Funding; Janssen: Consultancy; BEAM Therapeutics: Consultancy, Research Funding. Aifantis: AstraZeneca: Research Funding; Foresite (FL2020-010) LLC: Consultancy.
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Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal. The primary goal of T-ALL/T-LL treatment is to prevent relapse. In the phase 3 Children's Oncology Group (COG) clinical trial AALL1231 (NCT02112916), children, adolescents and young adults (age 1-30 years) with T-ALL and T-LL were treated with a modified augmented BFM (aBFM) backbone that used dexamethasone as the only corticosteroid and included two (rather than one) doses of pegaspargase during induction and delayed intensification. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphology, minimal residual disease (MRD) performed by multiparameter flow cytometry at a central reference laboratory) at end of induction and consolidation (T-ALL), and radiographic response for T-LL. Pts were randomized 1:1 to receive/not receive bortezomib during induction and delayed intensification (1.3mg/m ² x 4 doses per block). VHR T-ALL pts were defined as having day 29 M3 marrow (>25% blasts) or end of consolidation (EOC) MRD >0.1%. 10-15% of T-ALL pts were predicted to be VHR based on COG AALL0434. Pts with induction failure (M3 marrow by morphology) or EOC MRD >0.1% were expected to have 4-yr event-free survival (EFS) of ~66+/-16%. Following consolidation, VHR pts received 3 BFM-based intensification blocks in lieu of interim maintenance (IM). Detectable MRD following the intensification blocks was considered an event and these pts were removed from protocol therapy. VHR ALL pts who had undetectable MRD continued protocol therapy, received delayed intensification, an IM phase with Capizzi escalating methotrexate plus pegaspargase, and maintenance. A secondary aim of AALL1231 was to compare survival in VHR T-ALL pts with EOC MRD >= 0.1% but undetectable MRD after intensification of chemotherapy with those who continued to have detectable MRD and were eligible for other treatment strategies, including hematopoietic stem cell transplant (HSCT). This study also analyzed outcomes for pts with M3 marrow at the end of induction.
Result(s): AALL1231 accrued 847 pts (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure. The 3-year EFS for the bortezomib randomization for the SR and IR groups has been reported previously (Teachey, et. al ASH 2020). Because only 2 of 209 T-LL pts were VHR; this report focuses on the outcomes of the 5.2% (32/615) of T-ALL pts who were VHR. In total, 25 VHR T-ALL pts were EOC MRD >0.1%, and 18 of these had MRD sent at the end of HR intensification. Of the 8 pts who became MRD undetectable and continued protocol therapy, only 2 survived (3-year overall survival [OS] 25+15.3%). In contrast, 10 pts who had detectable MRD were taken off protocol and underwent HSCT. Of these 10, only one relapsed (3-year OS 90+12.7%). The 3-year OS for the 10 pts who were M3 at Day 29 was 60.0+/-17.0%. As there were not enough pts to assess the impact of EOC MRD on pts who were M3 at Day 29, we assessed the impact of EOC MRD on outcomes in M2 (5-25% blasts at Day 29; n = 24) and M3 pts, which defines induction failure in other cooperative groups. M2+M3 T-ALL who were EOC MRD <0.1% (n = 15) had 3-year OS of 86.7+/-10.0% vs 45.5+/-15.0% for those with EOC MRD >0.1% (n = 12) pts.
Conclusion(s): T-ALL pts treated on AALL1231 who are EOC MRD >=0.1% with undetectable MRD after 3 BFM-based intensification blocks had a very poor outcome when treated with standard cytotoxic chemotherapy. In contrast, while patient numbers are small, those pts that remained MRD-positive after 3 intensification blocks and underwent HSCT had an excellent outcome. These data not only impact the recommended treatment for T-ALL pts who are induction and consolidation failures, but also support the importance of the graft-versus-leukemia (GVL) effect in refractory T-ALL. Disclosures: Hayashi: Magenta Therapeutics: Consultancy. August: Jazz: Membership on an entity's Board of Directors or advisory committees. Hermiston: Sobi: Consultancy; Novartis: Consultancy. Bollard: Cabeletta Bio: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio and Mana Therapeutics: Other: member and cofounder; SOBI: Other: DSMB. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Teachey: BEAM Therapeutics: Consultancy, Research Funding; NeoImmune Tech: Research Funding; Sobi: Consultancy; Janssen: Consultancy.
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Background and Aims: Standard treatment for B-ALL first relapse begins with reinduction chemotherapy. Predictors of severe toxicity and poor efficacy would identify patients for whom alternative approaches could be prioritized.
Method(s): Patients aged 1-30 years received reinduction with vincristine, dexamethasone, pegaspargase, mitoxantrone and intrathecal chemotherapy (UKALLR3 mitoxantrone arm), followed by risk stratification and randomization to chemotherapy vs. blinatumomab. We reviewed reinduction response [morphologic and flow minimal residual disease (MRD)] and adverse events (AEs) by age (<12 vs 12-17 vs 18+ years), sex, site of relapse [marrow vs extramedullary (EM)] and duration of first remission (<18 months vs. 18-36 months vs >36 months). Pearson's chi-squared test or Fisher's exact test was used to evaluate associations. P values are two-sided and a p value <0.05 was considered statistically significant.
Result(s): Of 662 patients starting reinduction, 24 (4%) died during reinduction (22 AEs; 2 disease progression). Death was associated only with shorter first remission duration (p=0.006). Of those surviving, 44 (7%) had treatment failure (M3 marrow and/or persistent CNS disease) and 67 (11%) had non-fatal severe AEs (grade 4 febrile neutropenia, infection, sepsis or mucositis). Treatment failure was associated with site of relapse (marrow greater than EM, p=0.029) and shorter first remission duration (p<0.001). Severe AEs were associated only with older age (p=0.014). Of patients without death or treatment failure, 272 (46%) were MRD-positive (>=0.01%); MRD-positivity was associated with older age (p=0.038) and marrow relapse (p<0.001).
Conclusion(s): Patients with early relapse are at higher risk of toxic death and early treatment failure. Older patients are at higher risk of non-fatal severe AEs and MRD positivity. Patients with bone marrow relapse are at higher risk of early treatment failure and MRD positivity. Males and females have similar risks of poor reinduction outcomes

Importance/UNASSIGNED:Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations. Objective/UNASSIGNED:To determine whether focal deletions within the λ variable chain region in chromosome 22q11.22 were associated with patients with B-ALL with IKZF1 alterations with the highest risk of relapse and/or death. Design, Setting, and Participants/UNASSIGNED:This cohort study included 1310 primarily high-risk pediatric patients with B-ALL who were taken from 6 independent clinical cohorts, consisting of 3 multicenter cohorts (AALL0232 [2004-2011], P9906 [2000-2003], and patients with Down syndrome who were pooled from national and international studies) and 3 single-institution cohorts (University of Utah [Salt Lake City], Children's Hospital of Philadelphia [Philadelphia, Pennsylvania], and St. Jude Children's Hospital [Memphis, Tennessee]). Data analysis began in 2011 using patients from the older studies first, and data analysis concluded in 2021. Exposures/UNASSIGNED:Focal 22q11.22 deletions. Main Outcomes and Measures/UNASSIGNED:Event-free and overall survival was investigated. The hypothesis that 22q11.22 deletions stratified the prognostic effect of IKZF1 alterations was formulated while investigating nearby deletions in VRPEB1 in 2 initial cohorts (n = 270). Four additional cohorts were then obtained to further study this association (n = 1040). Results/UNASSIGNED:This study of 1310 patients with B-ALL (717 male [56.1%] and 562 female patients [43.9%]) found that focal 22q11.22 deletions are frequent (518 of 1310 [39.5%]) in B-ALL and inconsistent with physiologic V(D)J recombination. A total of 299 of 1310 patients with B-ALL had IKZF1 alterations. Among patients with IKZF1 alterations, more than half shared concomitant focal 22q11.22 deletions (159 of 299 [53.0%]). Patients with combined IKZF1 alterations and 22q11.22 deletions had worse outcomes compared with patients with IKZF1 alterations and wild-type 22q11.22 alleles in every cohort examined (combined cohorts: 5-year event-free survival rates, 43.3% vs 68.5%; hazard ratio [HR], 2.18; 95% CI, 1.54-3.07; P < .001; 5-year overall survival rates, 66.9% vs 83.9%; HR, 2.05; 95% CI, 1.32-3.21; P = .001). While 22q11.22 deletions were not prognostic in patients with wild-type IKZF1 , concomitant 22q11.22 deletions in patients with IKZF1 alterations stratified outcomes across additional risk groups, including patients who met the IKZF1plus criteria, and maintained independent significance in multivariate analysis for event-free survival (HR, 2.05; 95% CI, 1.27-3.29; P = .003) and overall survival (HR, 1.83; 95% CI, 1.01-3.34; P = .05). Conclusions and Relevance/UNASSIGNED:This cohort study suggests that 22q11.22 deletions identify patients with B-ALL and IKZF1 alterations who have very poor outcomes and may offer a new genetic biomarker to further refine B-ALL risk stratification and treatment strategies.

We conducted the first HLA allele and genome wide association study to identify loci associated with hypersensitivity reactions exclusively to the PEGylated preparation of asparaginase (pegaspargase) in racially diverse cohorts of pediatric leukemia patients: St. Jude Children's Research Hospital's Total XVI (TXVI, n = 598), Children's Oncology Group AALL0232 (n = 2472) and AALL0434 (n = 1189). Germline DNA was genotyped using arrays. Genetic variants not genotyped directly were imputed. HLA alleles were imputed using SNP2HLA or inferred using BWAkit. Analyses between genetic variants and hypersensitivity were performed in each cohort first using cohort-specific covariates and then combined using meta-analyses. Nongenetic risk factors included fewer intrathecal injections (P = 2.7x10^-5 in TXVI) and male sex (P = 0.025 in AALL0232). HLA alleles DQB1*02:02, DRB1*07:01, and DQA1*02:01 had the strongest associations with pegaspargase hypersensitivity (P < 5.0x10^-5 ) in patients with primarily European ancestry (EA), with the three alleles associating in a single haplotype. The top allele HLA-DQB1*02:02 was tagged by HLA-DQB1 rs1694129 in EAs (r² = 0.96) and less so in non-EAs. All single nucleotide polymorphisms associated with pegaspargase hypersensitivity reaching genome-wide significance in EAs were in class II HLA loci, and were partially replicated in non-EAs, as is true for other HLA associations. The rs9958628 variant, in ARHGAP28 (previously linked to immune response in children) had the strongest genetic association (P = 8.9x10^-9 ) in non-EAs. The HLA-DQB1*02:02-DRB1*07:01-DQA1*02:01 associated with hypersensitivity reactions to pegaspargase is the same haplotype associated with reactions to non-PEGylated asparaginase, even though the antigens differ between the two preparations.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. TCF3-PBX1 fusion defines a common molecular subtype of ALL with unique clinical features, but the molecular basis of its inherited susceptibility is unknown. In a genome-wide association study of 1494 ALL cases and 2057 non-ALL controls, we identified a germline risk locus located in an intergenic region between BCL11A and PAPOLG: rs2665658, P = 1.88 × 10-8 for TCF3-PBX1 ALL vs non-ALL, and P = 1.70 × 10-8 for TCF3-PBX1 ALL vs other-ALL. The lead variant was validated in a replication cohort, and conditional analyses pointed to a single causal variant with subtype-specific effect. The risk variant is located in a regulatory DNA element uniquely activated in ALL cells with the TCF3-PBX1 fusion and may distally modulate the transcription of the adjacent gene REL. Our results expand the understanding of subtype-specific ALL susceptibility and highlight plausible interplay between germline variants and somatic genomic abnormalities in ALL pathogenesis.

5-year overall survival rates have surpassed 90% for childhood acute lymphocytic leukaemia, but survivors are at risk for permanent health sequelae. Although event-free survival appropriately represents the outcome for cancers with poor overall survival, this metric is inadequate when cure rates are high but challenged by serious, persistent complications. Accordingly, a group of experts in paediatric haematology-oncology, representative of 17 international acute lymphocytic leukaemia study groups, launched an initiative to construct a measure, designated severe toxicity-free survival (STFS), to quantify the occurrence of physician-prioritised toxicities to be integrated with standard cancer outcome reporting. Five generic inclusion criteria (not present before cancer diagnosis, symptomatic, objectifiable, of unacceptable severity, permanent, or requiring unacceptable treatments) were used to assess 855 health conditions, which resulted in inclusion of 21 severe toxicities. Consensus definitions were reached through a modified Delphi process supplemented by two additional plenary meetings. The 21 severe toxicities include severe adverse health conditions that substantially affect activities of daily living and are refractory to therapy (eg, refractory seizures), are without therapeutic options (eg, blindness), or require substantially invasive treatment (eg, cardiac transplantation). Incorporation of STFS assessment into clinical trials has the potential to improve and diversify treatment strategies, focusing not only on traditional outcome events and overall survival but also the frequencies of the most severe toxicities. The two major aims of this Review were to: prioritise and define unacceptable long-term toxicity for patients with childhood acute lymphocytic leukaemia, and define how these toxicities should be combined into a composite quantity to be integrated with other reported outcomes. Although STFS quantifies the clinically unacceptable health tradeoff for cure using childhood acute lymphocytic leukaemia as a model disease, the prioritised severe toxicities are based on generic considerations of relevance to any other cancer diagnosis and age group.