Survival after childhood acute lymphoblastic leukemia (ALL) has increased over the last 40 years with an overall survival above 90%. Survivors may experience neurological late effects secondary to chemotherapy and radiotherapy. This observational retrospective study evaluated the cumulative incidence of neurological late effects among 890 childhood ALL survivors treated in EORTC CLG trials (58741, 58831/2 and 58881) between 1971 and 1998. Median follow-up was 19 years and interquartile range of the follow-up was 15–22 years. At 20 years from the end of treatment, approximately 66% of patients from the 58741 trial (accrual time: 1971–1978) and approximately 15% from the more recent trials had cognitive disturbance grade 1 or higher. Cumulative incidences at 20 years from treatment end of seizures, stroke and leukoencephalopathy were respectively 45%, 16% and 62% in study 58741, 13%, 2% and 5% in study 58831/2, and 8%, 2% and 3% in study 58881. Patients who were 10–17 years of age at diagnosis had a higher incidence of stroke and leukoencephalopathy as compared to those less than 6 years of age. Noteworthy, all neurological late effects continued to occur beyond 5 years after end of treatment. This retrospective study highlights the frequency of neurological late effects in survivors of childhood ALL. With the increase of the overall survival of ALL patients, the role and potential benefit of longitudinal neurological screening should be evaluated in further studies as these neurological late effects become an important public health challenge. This study is part of the larger EORTC CLG 58 Late Adverse Effects (LAE) study (ClinicalTrials.gov Identifier NCT01298388, date of registration February 16, 2011).

PURPOSE:Survivors of childhood cancer can suffer from long-term sequelae or decline in quality of life (QoL), for which careful and standardized selection of outcome measures become more important. This study aims to assess different QoL-related outcomes using three distinct questionnaires in an international study, identify the priorities of childhood ALL survivors via the administered questionnaires, and investigate potential interrelationships among QoL domains across the questionnaires. METHODS:Childhood ALL survivors treated according to the EORTC CLG treatment protocols 58741, 58831/2, and 58881 were recruited in Belgium and France and answered self-report QoL questionnaires, including the Short-Form Health Survey 12 (SF12), the Quality-of-Life Systemic Inventory (QLSI), and the Impact of Cancer for Childhood Cancer Survivors (IOC-CS). To explore which scales overlapped or were novel, Pearson correlations were used to explore associations. In addition, based on the QLSI, we checked whether each of the top priorities of childhood ALL survivors were covered by the SF12 or IOC-CS, by mapping their scales quantitatively and qualitatively. RESULTS:QoL data for 186 survivors were provided. Priority areas, as assessed by the QLSI, were vitality, physical abilities, memory, overall physical health, sleep, interaction with friends, love life. Love life was an important source of happiness (for 42%), and for some reported as the domain they were unhappiest in (13%). Quantitative mapping shows moderate correlations between the SF12 scales and IOC-CS scales: life challenges, body and health, thinking and memory, and socializing. Qualitative mapping highlighted additional important domains, specifically family, romantic and friendship relationships, and sleep and memory. CONCLUSIONS:Our findings suggest that the measures complement each other, but are less valuable in isolation for ALL survivors. Using a cancer survivorship measure, combined with some additional items covering priorities might provide a more holistic picture.

OBJECTIVE:The objective of this study is to evaluate the socio-economic outcomes of survivors of childhood acute lymphoblastic leukaemia (ALL).METHODS:Childhood ALL adult survivors, enrolled in EORTC trials between 1971 and 1998 in France and Belgium, were invited to fill out a questionnaire with information about their socio-economic situation (living with a partner, having a university degree, having a job, working part time and history of having a paid job). The outcomes were compared with two matched control populations.RESULTS:Among 1418 eligible patients, 507 (35.8%) participated, including 39 (8%) and 61 (12%) patients who received a haematopoietic stem cell transplantation (HSCT) and a cranial radiotherapy (CRT), respectively. The median time to follow-up was 20 years, and median age was 25 years. Survivors showed a socio-economic level at least as good as controls. HCST and CRT were associated with a higher probability of not obtaining a bachelor degree (respectively OR = 3.49, 95% CI: 1.46-8.35 and OR = 2.31, 95% CI: 1.04-5.15), HSCT was associated with unemployment (OR = 2.89, 95% CI: 1.09-7.65) and having a relapse was associated with a higher probability of not having a partner (OR = 1.88, 95% CI: 1.01-3.51) adjusting for confounders.CONCLUSION:Childhood ALL survivors showed a high level of socio-economic participation. HCST and CRT were associated with poorer functioning.

(Abstracted from Hum Reprod 2022;37:44–53) Childhood acute lymphoblastic leukemia (ALL) has an expected cure rate of greater than 90%, reflecting a vast improvement in diagnosis and treatment over the last 40 years. Fertility impairment is among the chief concerns of long-term survivors because of possible damage to reproductive organs or hormonal balance stemming from treatment.

Improved treatment landscape has led to better outcomes for paediatric acute lymphoblastic leukemia (ALL) survivors. As the number of survivors increase, we need to elucidate the long‐term quality of life (QoL) and domains of complaints in these patients. Furthermore, the main priorities of these patients need to be clarified. We assessed long‐term QoL outcomes of survivors of childhood ALL compared to matched population controls.

Background: due to increasing survival rates in childhood acute lymphoblastic leukemia (ALL), the number of survivors has been expanding. A significant proportion of these survivors can experience long-term emotional and psychosocial problems. However, the exact risk factors remain inconclusive. We investigated potential risk factors for decreased daily life quality and life challenges in long-term childhood ALL survivors enrolled between 1971 and 1998 in EORTC studies. Methods: self-report questionnaires were collected from 186 survivors (109 females; mean age at diagnosis 5.62 years, range 0.2–14.7; median time since diagnosis of 20.5 years (12.9–41.6)), including the Short-Form Health Survey (SF-12) and Impact of Cancer-Childhood Survivors (IOC-CS). Multivariable linear regression models were used to assess the impact of gender, age at diagnosis, relapse/second neoplasm, National Cancer Institute (NCI) risk group and cranial radiotherapy on 2 subscales of the SF-12 (physical and mental health) and five subscales of the IOC-CS (life challenges, body and health, personal growth, thinking and memory problems and socializing). Results: mental component scores of SF-12 were not significantly associated with any risk factor. Physical component scores were lower in relapsed, irradiated and NCI high-risk patients. Regarding IOC-CS negative impact subscales, life challenges was more negatively impacted by cancer in female, younger (i.e., <6 years) and relapsed patients. Regarding the positive impact scales, personal growth was more positively impacted in relapsed patients, whereas body and health, and socializing, were less positively impacted in these patients, compared to non-relapsed patients. Socializing was more positively impacted in older patients (>6 years). Conclusions: this study demonstrates that long-term outcomes can be both adverse and positive, depending on the patient’s demographic and clinical characteristics. Younger, female, and relapsed patients might encounter more life challenges years after their disease, while physical challenges could occur more often in relapsed and high-risk patients. Finally, the positive effect on socializing in the older patients sheds new light on the importance of peer interactions for this subgroup. Specific individual challenges thus need specialized support for specific subgroups.

STUDY QUESTIONWhat are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors?SUMMARY ANSWERWe observed similar fertility outcomes in both male and female childhood ALL survivors compared with the general population, with the exception of a higher proportion of miscarriages among partners of male survivors.WHAT IS KNOWN ALREADYSurvival after childhood ALL is currently >90% and fertility impairments are among the main concerns of the long-term survivors. Few studies have focused on the fertility issues within this selected population and the existing data are difficult to interpret due to the different treatment regimens received by the patients, the small sample sizes and the unavailability of control data in many studies.STUDY DESIGN, SIZE, DURATIONChildhood ALL patients enrolled in European Organisation for Research and Treatment of Cancer (EORTC) studies between 1971 and 1998 in France and Belgium, <18 years old at diagnosis and alive and ≥18 years at follow-up were eligible. Among 1418 eligible survivors, 507 (35.8%) participated (277 females, 230 males). Controls from the general population matched one to one by age, province, level of urbanization and sex could be identified for 503 survivors.PARTICIPANTS/MATERIALS, SETTING, METHODSSurvivors and controls were invited to fill out a questionnaire including information about their menstrual cycles (for females), intention to have children, having children, use of medical help to become pregnant and occurrence of negative pregnancy outcomes (birth defect, miscarriage, medical abortion or stillbirth). The results were analysed separately for females and males. The association between age at diagnosis and fertility outcomes, adjusted by age at follow-up, study and country were investigated using logistic regression.MAIN RESULTS AND THE ROLE OF CHANCEThe median time since diagnosis was 20.1 years and the median age at follow-up was 25 years. There were 144 survivors (97 females, 47 males) who wanted to have children. Among these, craniospinal radiotheraphy (CRT) and haematopoietic stem cell transplantation (HSCT) were administered to 18% and 4%, respectively. Of these who tried to have children, 75% of females and 69% of males succeeded, compared with 72% and 61% of the controls, respectively. These differences were not statistically significant (P = 0.73 for females and P = 0.50 for males). Overall, fertility outcomes were comparable between survivors and controls, except that a higher proportion of miscarriages occurred in partners of male survivors (28.1% versus 5.9%, P = 0.021). Among female survivors, an older age at diagnosis (10-17 years) was associated with a greater risk of pregnancy problems (adjusted OR 5.61, P = 0.046).LIMITATIONS, REASONS FOR CAUTIONThe interpretation of the incidence of miscarriage among the partners of male survivors is limited by the lack of data regarding the males' partners and by a possibly higher tendency to recall and disclose fertility issues among male survivors compared with male controls.WIDER IMPLICATIONS OF THE FINDINGSFertility outcomes were similar in childhood ALL survivors and controls, and the low proportion of patients treated with CRT or HSCT might explain this. Further studies should confirm the higher proportion of miscarriages in partners of male survivors.STUDY FUNDING/COMPETING INTEREST(S)This publication was supported by donations from the Fonds Cancer (FOCA) from Belgium and the KU Leuven from Belgium. G.R. has been awarded a fellowship by the EORTC Cancer Research Fund (ECRF). C.P. has been awarded a fellowship by Fonds Cancer (FOCA) from Belgium and the Kinderkankerfonds from Belgium (a non-profit childhood cancer foundation under Belgian law). No competing interests were declared.TRIAL REGISTRATION NUMBERNCT01298388 (clinicaltrials.gov).

Aim: To evaluate the prognostic significance of initial central nervous system (CNS) involvement of children with acute lymphoblastic leukemia (ALL) enrolled in the EORTC 58951 trial. Patients and methods: From 1998 to 2008, 1930 ALL patients were included in the randomized EORTC 58951 trial. Overall treatment intensity was adjusted according to known prognostic factors including the level of minimal residual disease after induction treatment. CNS-directed therapy comprised four to 11 courses of i.v. methotrexate (5 g/m(2)), and 10 to 19 intrathecal chemotherapy injections, depending on risk group and CNS status. Cranial irradiation was omitted for all patients. Results: The overall 8-year event-free survival (EFS) and overall survival (OS) rates were 81.3% and 88.1%, respectively. In the CNS-1, TPL+, CNS-2, and CNS-3 groups, the 8-year EFS rates were 82.1%, 77.1%, 78.3%, and 57.4%, respectively. Multivariable analysis indicated that initial CNS-3 status, but not CNS-2 or TLP+, was an independent adverse predictor of outcome. The 8-year incidence of isolated CNS relapse was 1.7% and of isolated or combined CNS relapse it was 3.7%. NCI high-risk group, male sex, CNS-2 and CNS-3 status were independent predictors for a higher incidence of any CNS relapse. Conclusions: CNS-3 status remains associated with poor prognosis and requires intensification of both systemic and CNS-directed therapy. (C) 2021 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

Asparaginase (ASNase) is an important anti-leukaemic drug in the treatment of childhood acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL). A substantial proportion of patients develop hypersensitivity reactions with anti-ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), and characterised by inactivation and rapid clearance of ASNase. We report results of a prospective, real-time therapeutic drug monitoring of pegylated Escherichia coli (PEG-)ASNase and Erwinia ASNase in children treated for ALL and NHL in Belgium. Erwinia ASNase was given as second-line after hypersensitivity to PEG-ASNase. In total, 286 children were enrolled in the PEG-ASNase cohort. Allergy was seen in 11·2% and SI in 5·2% of patients. Of the 42 patients treated with Erwinia ASNase, 7·1% experienced allergy and 2·4% SI. The median trough PEG-ASNase activity was high in all patients without hypersensitivity. After Erwinia administration significantly more day 3 samples had activities <100 IU/l (62·5% vs. 10% at day 2 (D2)). The median D2 activity was significantly higher for intramuscular (IM; 347 IU/l) than for intravenous Erwinia administrations (159 IU/l). This prospective, multicentre study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Treatment with Erwinia ASNase warrants close monitoring and optimally adherence to a 2-day interval of IM administrations.

Background:Asparaginase (ASNase) is an important anti‐leukemic drug in the treatment of childhood acute lymphoblastic leukemia (ALL) and non‐Hodgkin lymphoma (NHL). Depletion of asparagine by ASNase results in selective apoptosis of lymphoblasts which depend on an external source of asparagine for their cell growth. A substantial proportion of patients develops anti‐ASNase neutralising antibodies, resulting in allergic reactions or silent inactivation (SI), characterized by rapid clearance and inactivation of ASNase.Aims:Prospective, real‐time therapeutic drug monitoring of peg‐ASNase (Oncaspar®) and Erwinia ASNase (Erwinase®) in children treated for ALL and NHL in Belgium.Methods:Patients (1‐18y) with newly diagnosed ALL and precursor B‐ or T‐lymphoblastic NHL from 8 Belgian pediatric hemato‐oncology centres were enrolled between 01/2013 and 11/2017. All patients were treated according to the treatment guidelines of the EORTC‐CLG 58081 study. ASNase activity was quantified using the AHA test (described by Lanvers et al., 2002) using a SpectraMax M3 spectrophotometer (Molecular Devices). ASNase activity >100U/L was considered to be sufficient for complete depletion of asparagine. Erwinia ASNase was given as second line after allergic reaction or silent inactivation to Peg‐ASNase. One dose of Peg‐ASNase 2,500IU/m2 was replaced by 6 doses of 20,000U/m2 Erwinia ASNase in 2 weeks.Results:In total, 286 children (118 girls and 168 boys) with newly diagnosed ALL (n = 260) and NHL (n = 26) were enrolled in the prospective real‐time ASNase monitoring programme.Clinical allergic reactions were seen in 33 (11.5%), and silent inactivation in 14 (4.9%) patients treated with peg‐ASNase. Most allergies were CTCAE 4.03 grade 2‐3 and occurred after the second or third administration. SI was mainly seen after the second administration and in maintenance therapy. Patients were more at risk for hypersensitivity reactions after an ASNase‐free period. Forty‐two of them were switched to Erwinia ASNase. Three patients (7.1%) experienced a clinical allergic reaction, and 1 (2.4%) a silent inactivation on Erwinia ASNase.Median ASNase activity after the first peg‐ASNase was 1254U/L (range:704‐2027U/L) one hour after administration (peak), 921U/L (147–1727U/L) at day 7 (D7) and 574U/L (<5–1807U/L) at day 14 (D14). After the second administration in induction, patients reached higher median activity levels 2091U/L (<5–5208U/L) (peak), 1181U/L (<5–2107U/L) at D7 and 666U/L (<5–1151U/L) at D14. After peg‐ASNase in re‐induction, median ASNase activity was 1916U/L (<5–13255U/L) (peak), 1358U/L (<5–5621U/L) at D7 and 802U/L (<5–3346U/L) at D14.Median Erwinia ASNase activity 2 days after administration (D2) was 321U/L (14–1195U/L) and 76U/L (<5–529U/L) at day 3 (D3), with significantly more D3‐samples <100U/L (62.5% vs 10%, P = <0,001). According to the route of administration, median activity at D2 was significantly higher for intramuscularly (IM) Erwinia administrations (358U/L, [19–1195U/L]) than for intravenous (IV) administrations (159U/L, [14–1097U/L]). 61.5% IV‐treated patients and 90.5% IM‐treated patients achieved an activity above 100U/L in ≥75% of the D2 samples.Summary/Conclusion:This prospective nation‐wide, multi‐center study shows that monitoring of ASNase activity during treatment of children with ALL and NHL is feasible and informative. Allergy and SI occurred after both peg‐ASNase and Erwinia ASNase administration.Treatment with Erwinia ASNase warrants close monitoring of activity levels and optimally, adherence to a two‐day interval of IM administrations.

SummaryWe investigated the long‐term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high‐risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n = 92) versus CRT (standard arm, n = 84) in the non‐inferiority EORTC 58832 study (1983–1989). Median follow‐up was 20 years (range 4–32 years). The 25‐year disease‐free survival rate (±SE) was 67·4 ± 4·9% without CRT and 70·2 ± 5·0% with CRT. The 25‐year incidence of isolated (6·5 ± 2·6% vs. 4·8 ± 2·3%) and any CNS relapse {8·7 ± 2·9% vs. 11·9 ± 3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28–1·79]; test of non‐inferiority: P = 0·01} was not increased without CRT. The 25‐year SN incidence in CR1 was 7·9 ± 4·6% vs. 11·0 ± 4·2%. The 25‐year event‐free and overall survival rates were quite similar in both arms [59·5 ± 6·3% vs. 60·5 ± 5·9%, HR 0·94 (95% CI 0·57–1·52), and 78·1 ± 4·3% vs. 78·5 ± 4·5%, HR 1·00 (95% CI 0·53–1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.

Background:PIM1 is an oncogenic kinase that recently emerged as an interesting novel therapeutic target for the treatment of T‐cell acute lymphoblastic leukemia and lymphoma (T‐ALL/T‐LBL). Indeed, aberrant levels of PIM1 have been identified in primary T‐ALL/T‐LBLs with T‐cell receptor driven PIM1 translocations or activating mutations targeting IL7R/JAK/STAT signaling. However, based on these cell‐intrinsic mechanisms, the absolute number of T‐ALL/T‐LBL patients that might benefit from PIM inhibition remains limited.Aims:Besides intrinsic molecular genetic defects, non‐cell autonomous mechanisms might also be able to drive therapeutically relevant aberrant signaling in T‐ALL/T‐LBL. Indeed, recent work revealed that interleukin‐7 (IL7) induced JAK/STAT signaling could be targeted by JAK inhibitors, irrespective of the cell‐intrinsic IL7R/JAK/STAT mutational status of the T‐ALL/T‐LBL patient sample. With this in mind, we here aimed to study the potential mechanisms as well as the therapeutic relevance of cytokine induced PIM1 activation in human T‐ALL/T‐LBL.Methods:We performed ex vivo stimulation experiments on patient derived xenograft cells from T‐ALL and T‐LBL samples using a panel of cytokines. Phospho‐STAT5 levels were analyzed by flow cytometry and PIM1 levels were determined by qPCR and western blot analysis. T‐ALL or T‐LBL patients samples that showed cytokine induced PIM1 activation were subsequently used for preclinical in vivo evaluation of the PIM inhibitor PIM447 in immunocompromised mice both as monotherapy as well as in combination with glucocorticoids.Results:Here, we show that specific hematopoietic cytokines, such as interleukin‐3 (IL3), IL7, stem cell factor (SCF) and FLT3 ligand, are able to induce PIM1 expression in specific primary T‐ALL and T‐LBL patient samples. As expected, this induction capacity is based on the pattern of cytokine receptor expression (IL3R, IL7R, KIT or FLT3) on the leukemic blasts and is therefore linked to the mature stage of the respective leukemic T‐ALL/T‐LBL sample. Indeed, IL7 mediated effects were observed in a broad panel of T‐ALL/T‐LBLs, whereas IL3, SCF and FLT3LG driven effects on PIM1 induction were more restricted to immature T‐ALLs.Interestingly, we subsequently used patient derived xenografts to show that cytokine induced PIM1 activation renders T‐ALL/T‐LBL cells susceptible to in vivo treatment with PIM447, a PIM inhibitor that is currently in clinical trials for the treatment of acute myeloid leukemia. Of note, these in vivo anti‐leukemic effects upon PIM inhibition were also observed for primary T‐ALL/T‐LBL patient samples that initially displayed low PIM1 levels at diagnosis. In line with this notion, paired analysis of diagnostic and xenografted material from these T‐ALL/T‐LBL samples revealed a profound increase in PIM1 expression upon xenotransplantation. Finally, we also confirmed that in cytokine induced T‐ALL/T‐LBL samples, PIM447 treatment displays a strong synergy with glucocorticoids.Summary/Conclusion:In conclusion, we show that non‐cell autonomous mechanisms can cause aberrant PIM1 activation in primary T‐ALL/T‐LBL through IL3, IL7, SCF or FLT3LG stimulation. We show that cytokine induced PIM1 activation renders leukemic blasts susceptible for in vivo PIM inhibition with synergistic anti‐leukemic effects observed for the combination with glucocorticoids. Therefore, our results suggest that the patient population that might benefit from combined PIM/glucocorticoid inhibition therapy extends beyond T‐ALL/T‐LBL samples that display cell‐intrinsic PIM1 activation.

Author(s): Milani, Gloria; Matthijssens, Filip; Van Loocke, Wouter; Durinck, Kaat; Roels, Juliette; Peirs, Sofie; Thenoz, Morgan; Pieters, Tim; Reunes, Lindy; Lintermans, Beatrice; Vandamme, Niels; Lammens, Tim; Van Roy, Nadine; Van Nieuwerburgh, Filip; Deforce, Dieter; Schwab, Claire; Raimondi, Susana; Dalla Pozza, Luciano; Carroll, Andrew J; De Moerloose, Barbara; Benoit, Yves; Goossens, Steven; Berx, Geert; Harrison, Christine J; Basso, Giuseppe; Cave, Helene; Sutton, Rosemary; Asnafi, Vahid; Meijerink, Jules; Mullighan, Charles; Loh, Mignon; Van Vlierberghe, Pieter

Differential impact of drugs on the outcome of ETV6-RUNX1 positive childhood B-cell precursor acute lymphoblastic leukaemia: results of the EORTC CLG 58881 and 58951 trials

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. With dramatic improvements in survival observed since the 70's, it progressively became evident that the long-term survivors faced late morbidity, late mortality and psychosocial troubles. In 2010, the EORTC developed the retrospective 58LAE study in order to evaluate the long-term outcome of the 2621 eligible childhood ALL survivors enrolled between 1971 and 1998. The first sub-project project showed that ETV6-RUNX1 positive patients had better long-term outcome and had specific sensitivities to treatments. The second sub-project showed that omission of cranial radiotherapy did not increase the risk of relapse and was associated with a higher incidence of second neoplasms and late toxicities in medium and high-risk patients, without central nervous system (CNS) involvement. The third subproject identified hematopoietic stem cell transplantation, cranial radiotherapy and having a relapse as risk factors for worse socio-economic outcome. Finally, the fertility status of the survivors was also evaluated. The 58LAE project has raised several challenges when translated into the "real-life" setting, which include the difficulties of following childhood cancer survivors throughout their transition to adult life; the statistical analysis of a cohort of patients treated in multiple clinical trials and along different years; the need for combining different approaches to gather sufficient quality patient data; and the challenge of overcoming the healthcare administrative and regulatory obstacles. New ways of addressing survivorship studies are needed to address these challenges.

Background