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Background: Adalimumab, a biological treatment targeting tumour necrosis factor α, might be useful in sciatica. This paper describes the challenges faced when developing a new treatment pathway for a randomised controlled trial of adalimumab for people with sciatica, as well as the reasons why the trial discussed was stopped early. Methods: A pragmatic, parallel group, randomised controlled trial with blinded (masked) participants, clinicians, outcome assessment and statistical analysis was conducted in six UK sites. Participants were identified and recruited from general practices, musculoskeletal services and outpatient physiotherapy clinics. They were adults with persistent symptoms of sciatica of 1 to 6 months’ duration with moderate to high level of disability. Eligibility was assessed by research physiotherapists according to clinical criteria, and participants were randomised to receive two doses of adalimumab (80 mg then 40 mg 2 weeks later) or saline placebo subcutaneous injections in the posterior lateral thigh. Both groups were referred for a course of physiotherapy. Outcomes were measured at baseline, 6-week, 6-month and 12-month follow-up. The main outcome measure was disability measured using the Oswestry Disability Index. The planned sample size was 332, with the first 50 in an internal pilot phase. Results: The internal pilot phase was discontinued after 10 months from opening owing to low recruitment (two of the six sites active, eight participants recruited). There were several challenges: contractual delays; one site did not complete contract negotiations, and two sites signed contracts shortly before trial closure; site withdrawal owing to patient safety concerns; difficulties obtaining excess treatment costs; and in the two sites that did recruit, recruitment was slower than planned because of operational issues and low uptake by potential participants. Conclusions: Improved patient care requires robust clinical research within contexts in which treatments can realistically be provided. Step changes in treatment, such as the introduction of biologic treatments for severe sciatica, raise complex issues that can delay trial initiation and retard recruitment. Additional preparatory work might be required before testing novel treatments. A randomised controlled trial of tumour necrosis factor-α blockade is still needed to determine its cost-effectiveness in severe sciatica.

Purpose Minimal residual disease (MRD) and genetic abnormalities are important risk factors for outcome in acute lymphoblastic leukemia. Current risk algorithms dichotomize MRD data and do not assimilate genetics when assigning MRD risk, which reduces predictive accuracy. The aim of our study was to exploit the full power of MRD by examining it as a continuous variable and to integrate it with genetics. Patients and Methods We used a population-based cohort of 3,113 patients who were treated in UKALL2003, with a median follow-up of 7 years. MRD was evaluated by polymerase chain reaction analysis of Ig/TCR gene rearrangements, and patients were assigned to a genetic subtype on the basis of immunophenotype, cytogenetics, and fluorescence in situ hybridization. To examine response kinetics at the end of induction, we log-transformed the absolute MRD value and examined its distribution across subgroups. Results MRD was log normally distributed at the end of induction. MRD distributions of patients with distinct genetic subtypes were different (P < .001). Patients with good-risk cytogenetics demonstrated the fastest disease clearance, whereas patients with high-risk genetics and T-cell acute lymphoblastic leukemia responded more slowly. The risk of relapse was correlated with MRD kinetics, and each log reduction in disease level reduced the risk by 20% (hazard ratio, 0.80; 95% CI, 0.77 to 0.83; P < .001). Although the risk of relapse was directly proportional to the MRD level within each genetic risk group, absolute relapse rate that was associated with a specific MRD value or category varied significantly by genetic subtype. Integration of genetic subtype–specific MRD values allowed more refined risk group stratification. Conclusion A single threshold for assigning patients to an MRD risk group does not reflect the response kinetics of the different genetic subtypes. Future risk algorithms should integrate genetics with MRD to accurately identify patients with the lowest and highest risk of relapse.

PTEN gene inactivation by mutation or deletion is common in pediatric T-cell acute lymphoblastic leukemia (T-ALL), but the impact on outcome is unclear, particularly in patients with NOTCH1/FBXW7 mutations. We screened samples from 145 patients treated on the MRC UKALL2003 trial for PTEN mutations using heteroduplex analysis and gene deletions using single nucleotide polymorphism arrays, and related genotype to response to therapy and long-term outcome. PTEN loss-of-function mutations/gene deletions were detected in 22% (PTEN(ABN)). Quantification of mutant level indicated that 67% of mutated cases harbored more than one mutant, with up to four mutants detected, consistent with the presence of multiple leukemic sub-clones. Overall, 41% of PTEN(ABN) cases were considered to have biallelic abnormalities (mutation and/or deletion) with complete loss of PTEN in a proportion of cells. In addition, 9% of cases had N- or K-RAS mutations. Neither PTEN nor RAS genotype significantly impacted on response to therapy or long-term outcome, irrespective of mutant level, and there was no evidence that they changed the highly favorable outcome of patients with double NOTCH1/FBXW7 mutations. These results indicate that, for pediatric patients treated according to current protocols, routine screening for PTEN or RAS abnormalities at diagnosis is not warranted to further refine risk stratification.

Background: Health-related quality of life (HRQoL) from diagnosis until end of treatment for children\ud with Acute Lymphoblastic Leukaemia (ALL) was investigated, examining effects of age, gender, risk\ud stratified treatment regimen (A,B,C) and therapy intensity (1 vs 2 ‘delayed intensifications’: DI).\ud \ud Method: \ud In a multi-centre prospective study, parents reported their child’s generic and disease specific\ud HRQoL and their own care-giving burden at five time-points. From 1428 eligible patients, 874\ud parents completed questionnaires at least once during treatment.\ud \ud Results:\ud At each time-point, generic HRQoL was significantly lower than equivalent norm scores for healthy\ud children. HRQoL decreased significantly at the start of treatment, before recovering gradually (but\ud remained below pre-treatment levels). Parents reported that older children worried more about side effects and their appearance but showed less procedural anxiety than younger children. Concern for appearance was greater among girls than boys. Compared to regimen B (i.e.additional doxorubicin\ud during induction and additional cyclophosphamide and cytarabine during consolidation\ud chemotherapy), patients receiving regimen A had fewer problems with pain and nausea. There were\ud no statistically significant differences in HRQoL by number of DI blocks received.\ud \ud Interpretation: HRQoL is compromised at all stages of treatment, and is partly dependent on age.\ud The findings increase understanding of the impact of therapy on children’s HRQoL and parental caregiving burden, and will contribute to the design of future trials.

Background: Health-related quality of life (HRQoL) from diagnosis until end of treatment for children with Acute Lymphoblastic Leukaemia (ALL) was investigated, examining effects of age, gender, risk stratified treatment regimen (A,B,C) and therapy intensity (1 vs 2 ‘delayed intensifications’: DI). Method: In a multi-centre prospective study, parents reported their child’s generic and disease specific HRQoL and their own care-giving burden at five time-points. From 1428 eligible patients, 874 parents completed questionnaires at least once during treatment. Results: At each time-point, generic HRQoL was significantly lower than equivalent norm scores for healthy children. HRQoL decreased significantly at the start of treatment, before recovering gradually (but remained below pre-treatment levels). Parents reported that older children worried more about side effects and their appearance but showed less procedural anxiety than younger children. Concern for appearance was greater among girls than boys. Compared to regimen B (i.e.additional doxorubicin during induction and additional cyclophosphamide and cytarabine during consolidation chemotherapy), patients receiving regimen A had fewer problems with pain and nausea. There were no statistically significant differences in HRQoL by number of DI blocks received. Interpretation: HRQoL is compromised at all stages of treatment, and is partly dependent on age. The findings increase understanding of the impact of therapy on children’s HRQoL and parental care-giving burden, and will contribute to the design of future trials.

Abstract 496 UKALL 2003 is an ongoing randomised controlled trial investigating treatment modification according to Minimal Residual Disease (MRD) status at the end of induction and week 11 in children and young adults (up to age 25 years) with ALL. Whilst the randomisation testing the benefit of intensification for an MRD defined high risk group remains open, a treatment reduction randomisation for MRD low risk patients closed in August 2009 after recruiting the target number of patients. Over 2600 patients have so far been enrolled into the trial and we have observed a significant improvement in 5 year event-free (EFS) compared with its predecessor, ALL 97/99, (EFS 87 vs 80%, p Patients in the trial are initially stratified by NCI risk, blast karyotype, and morphological marrow response at day 8/15 of induction for allocation to one of 3 treatment regimens, escalating in intensity (A, B, C). NCI standard risk (SR) patients receive a 3 drug induction (Regimen A) whilst high risk (HR) patients receive 4 drugs including daunorubicin (Regimen B). Patients with a slow early response at day 8 (NCI HR) or day 15 (NCI SR) of induction and patients with poor risk cytogenetics are transferred to Regimen C. Patients without poor risk cytogenetics and who have a rapid early response are eligible for the MRD randomisations. MRD was measured using Real Time Quantitative PCR with a sensitivity of 10−4. Five hundred and twenty-one patients who were either MRD negative at day 29 of induction or positive < 10−4 at day 29 but negative by week 11 entered a randomisation comparing two courses of delayed intensification (standard arm, n = 261) with one (treatment reduction arm, n = 260). Of these patients, 342 (65%) were NCI SR and 179 (35%) NCI HR. With follow-up to October 2009 (median 2 years 9 months), there is no difference in 5 year EFS for patients in the standard (94%) or reduced treatment arms (96%). As shown in table 1, the number of patients with relapse is similar in both arms but there was a non-significant excess of deaths in remission, serious adverse events and grade 3/4 toxicity in recipients of 2 DIs. 7/10 relapses have involved the CNS. The 3 CR deaths in the 2 DI arm were due to gram negative sepsis (DI1), pulmonary haemorrhage (DI2) and RSV pneumonitis (Maintenance, Down). There have been no relapses or CR deaths among 23 MRD low risk patients in the 16 – 25 age group. Table 1 1DI 2DI Statistics for 2DI Obs/N Obs/N Odds ratio(95% CI) 2p Any event 6/260 7/261 1.19 (0.40–3.53) 0.76 Relapse 6/260 4/261 0.69 (0.20–2.38) 0.57 Remission death 0/260 3/261 7.40 (0.77–71.14) 0.08 Grade 3/4 toxicity 177 (68%) 191 (71%) 0.2 SAEs 64 (25%) 77 (29.5%) 0.2 This randomised study provides evidence that treatment can be reduced for around 40% of children and young adults who show rapid clearance of MRD by the end of induction. These patients have an excellent outcome with < 5% risk of relapse on a treatment protocol that does not include cranial radiotherapy or high dose methotrexate and gives minimal exposure to anthracyclines and alkylating agents. Future trials should test the feasibility of further reductions in treatment for this group of patients. Disclosures: No relevant conflicts of interest to declare.

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

Cytotoxic T lymphocytes (CTL) are important for the recognition and lysis of virally infected cells, but their effectiveness can be limited by viral immune evasion mechanisms. We investigated the immunophenotype and function of human CD8+ T cells raised in response to herpes simplex virus (HSV). The expanded population contained cells of an activated and mature phenotype, as determined by the expressions of CD25, CD45RO, CD57, CD95 and HLA-DR. Cultured cells also expressed CD45RA. These cells lysed autologous and allogeneic HSV-infected lymphoblastoid cell line (LCL) targets via a non-major histocompatibility complex (MHC) restricted recognition pathway. Inhibition assays showed the mechanism of cytotoxicity to be calcium-dependent, granule exocytosis pathway, rather than the internal disintegration pathway. Cold target competition assays indicated that a common CTL population contributed to the recognition of autologous and allogeneic-infected targets. These effectors showed recognition of infected targets which was distinct from that of K562 cells. Non-MHC restricted lysis-associated molecule 2B4 (CD244) was upregulated on culturing and made a significant contribution to lysis of FcγR-bearing targets in a redirected killing assay. These findings suggest that CTL can recognize virally infected cells through a combination of non-MHC restricted mechanisms and may result in more efficient lysis than classical CD8+ T cells.

Hematopoietic chimerism was analyzed in serial bone marrow samples taken from 28 children following T-cell depleted unrelated donor bone marrow transplants (UD BMT) for acute lymphoblastic leukemia (ALL). Chimeric status was determined by polymerase chain reaction (PCR) of simple tandem repeat (STR) sequences (maximal sensitivity, 0.1%). At least two serial samples were examined in 23 patients. Of these, two had evidence of complete donor engraftment at all times and eight showed stable low level mixed chimerism (MC) (1% recipient hematopoiesis). All 10 of these patients remain in remission with a minimum follow-up of 24 months. By contrast, 13 patients demonstrated a progressive return of recipient hematopoiesis. Five of these relapsed (4 to 9 months post BMT), one died of cytomegalovirus pneumonitis and seven remain in remission with a minimum follow-up of 24 months. Five children were excluded from serial analysis as two serial samples were not collected before either relapse (3) or graft rejection (2). We conclude that as with sibling transplants, ex vivo T depleted UD BMT in children with ALL is associated with a high incidence of MC. Stable donor engraftment and low level MC always correlated with continued remission. However, detection of a progressive return of recipient cells did not universally correlate with relapse, but highlighted those patients at greatest risk. Serial chimerism analysis by PCR of STRs provides a rapid and simple screening technique for the detection of relapse and the identification of patients with progressive MC who might benefit from detailed molecular analysis for minimal residual disease following matched volunteer UD BMT for childhood ALL.

Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein–Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0–28) days without vaccination compared to 56 (range: 0–221) days with vaccination (P=0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.Leukemia advance online publication, 10 March 2017; doi:10.1038/leu.2017.39

L-asparaginase is an integral component of therapy for acute lymphoblastic leukemia. However, asparaginase-related complications, including the development of hypersensitivity reactions, can limit its use in individual patients. Of considerable concern in the setting of clinical allergy is the development of neutralizing antibodies and associated asparaginase inactivity. Also problematic in the use of asparaginase is the potential for the development of silent inactivation, with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction. Here we present guidelines for the identification and management of clinical hypersensitivity and silent inactivation with Escherichia coli- and Erwinia chrysanthemi- derived asparaginase preparations. These guidelines were developed by a consensus panel of experts following a review of the available published data. We provide a consensus of expert opinions on the role of serum asparaginase level assessment, indications for switching asparaginase preparation, and monitoring after change in asparaginase preparation.

Purpose We sought to determine whether cranial radiotherapy (CRT) is necessary to prevent relapse in any subgroup of children with acute lymphoblastic leukemia (ALL). Patients and Methods We obtained aggregate data on relapse and survival outcomes for 16,623 patients age 1 to 18 years old with newly diagnosed ALL treated between 1996 and 2007 by 10 cooperative study groups from around the world. The proportion of patients eligible for prophylactic CRT varied from 0% to 33% by trial and was not related to the proportion eligible for allogeneic stem-cell transplantation in first complete remission. Using a random effects model, with CRT as a dichotomous covariate, we performed a single-arm meta-analysis to compare event-free survival and cumulative incidence of isolated or any CNS relapse and isolated bone marrow relapse in high-risk subgroups of patients who either did or did not receive CRT. Results Although there was significant heterogeneity in all outcome end points according to trial, CRT was associated with a reduced risk of relapse only in the small subgroup of patients with overt CNS disease at diagnosis, who had a significantly lower risk of isolated CNS relapse (4% with CRT v 17% without CRT; P = .02) and a trend toward lower risk of any CNS relapse (7% with CRT v 17% without CRT; P = .09). However, this group had a relatively high rate of events regardless of whether or not they received CRT (32% [95% CI, 26% to 39%] v 34% [95% CI, 19% to 54%]; P = .8). Conclusion CRT does not have an impact on the risk of relapse in children with ALL treated on contemporary protocols.