Long-term neurotoxicity among childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC Children Leukemia Group studies.

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).

Gonadal development and function after immature testicular tissue banking as part of high-risk gonadotoxic treatment.

BACKGROUND: Experimental fertility preservation programs have been started to safeguard the future fertility of prepubertal and pubertal males requiring high-risk gonadotoxic treatment protocols. However, long-term follow-up studies evaluating the effects on their gonadal development and function related to the testicular biopsy procedure are rather limited. DESIGN: This two-center follow-up study (between 2002 and 2020) evaluated the gonadal development and function of a cohort of 59 prepubertal and pubertal males who have been offered immature testicular tissue banking (TTB) prior to conventional high-risk chemo- and/or radiotherapy (HR-C/R) or conditioning therapy before hematopoietic stem cell transplantation (CT-HSCT). The aim is to investigate the long-term impact of the testicular biopsy procedure and the high-risk gonadotoxic treatment. Testicular growth and the reproductive hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), and inhibin B (INHB) were analyzed after treatment completion, and compared between males accepting TTB and those refusing TTB (control) as well as between HR-C/R and CT-HSCT treatment protocols. RESULTS: Of the 59 prepubertal and pubertal males included, 25 were treated by HR-C/R and 34 required CT-HSCT. TTB was accepted for 39 males and refused for 20 males. Most patients were prepubertal at diagnosis (85%), at TTB (79%), and at treatment completion (76%), and pubertal or postpubertal at their last follow-up visit (66%). After 5.0 (1.0-13.0) years post treatment, most patients show normal testicular volumes (83%) and normal LH (89%), FSH (87%), T (87%), and INHB (79%) serum levels. The testicular biopsy procedure did not have an effect on testicular growth, LH, FSH, T, and INHB. Significantly more small postpubertal testicular volumes (p = .0278) and low INHB serum levels (p = .0130) were recorded after CT-HSCT, especially after myeloablative conditioning. CONCLUSION: The clinical follow-up data demonstrate no effect related to the biopsy procedure, but a substantial risk for impaired gonadal development after high-risk gonadotoxic treatment, in particular myeloablative CT-HSCT. Longer follow-up studies with a larger study population are needed to confirm these preliminary findings.

Blinatumomab Added to Chemotherapy in Infant Lymphoblastic Leukemia.

BACKGROUND: KMT2A-rearranged acute lymphoblastic leukemia (ALL) in infants is an aggressive disease with 3-year event-free survival below 40%. Most relapses occur during treatment, with two thirds occurring within 1 year and 90% within 2 years after diagnosis. Outcomes have not improved in recent decades despite intensification of chemotherapy. METHODS: We studied the safety and efficacy of blinatumomab, a bispecific T-cell engager molecule targeting CD19, in infants with KMT2A-rearranged ALL. Thirty patients younger than 1 year of age with newly diagnosed KMT2A-rearranged ALL were given the chemotherapy used in the Interfant-06 trial with the addition of one postinduction course of blinatumomab (15 µg per square meter of body-surface area per day; 28-day continuous infusion). The primary end point was clinically relevant toxic effects, defined as any toxic effect that was possibly or definitely attributable to blinatumomab and resulted in permanent discontinuation of blinatumomab or death. Minimal residual disease (MRD) was measured by polymerase chain reaction. Data on adverse events were collected. Outcome data were compared with historical control data from the Interfant-06 trial. RESULTS: The median follow-up was 26.3 months (range, 3.9 to 48.2). All 30 patients received the full course of blinatumomab. No toxic effects meeting the definition of the primary end point occurred. Ten serious adverse events were reported (fever [4 events], infection [4], hypertension [1], and vomiting [1]). The toxic-effects profile was consistent with that reported in older patients. A total of 28 patients (93%) either were MRD-negative (16 patients) or had low levels of MRD (<5×10-4 [i.e., <5 leukemic cells per 10,000 normal cells], 12 patients) after the blinatumomab infusion. All the patients who continued chemotherapy became MRD-negative during further treatment. Two-year disease-free survival was 81.6% in our study (95% confidence interval [CI], 60.8 to 92.0), as compared with 49.4% (95% CI, 42.5 to 56.0) in the Interfant-06 trial; the corresponding values for overall survival were 93.3% (95% CI, 75.9 to 98.3) and 65.8% (95% CI, 58.9 to 71.8). CONCLUSIONS: Blinatumomab added to Interfant-06 chemotherapy appeared to be safe and had a high level of efficacy in infants with newly diagnosed KMT2A-rearranged ALL as compared with historical controls from the Interfant-06 trial. (Funded by the Princess Máxima Center Foundation and others; EudraCT number, 2016-004674-17.).

The prognostic value of IKZF1plus in B-cell progenitor acute lymphoblastic leukemia: Results from the EORTC 58951 trial.

BACKGROUND: IKZF1 gene deletion is an indicator of poor prognosis in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The AEIOP/BFM group proposed that the prognostic strength of IKZF1 deletion could be remarkably improved by taking into account additional genetic deletions and reported that among patients with an IKZF1 deletion those with deletions in CDKN2A/2B, PAX5, or PAR1 in the absence of ERG deletion, grouped as IKZF1plus , had the worst outcome. PROCEDURE: Between 1998 and 2008, 1636 patients under 18 years of age with previously untreated BCP-ALL were registered in the EORTC 58951 trial. Those with multiplex ligation-dependent probe amplification data were included in this analysis. Unadjusted and adjusted Cox model was used to investigate the additional prognostic value of IKZF1plus . RESULTS: Among 1200 patients included in the analysis, 1039 (87%) had no IKZF1 deletion (IKZF1WT ), 87 (7%) had an IKZF1 deletion but not IKZF1plus (IKZF1del ) and 74 (6%) had IKZF1plus . In the unadjusted analysis, both patients with IKZF1del (hazard ratio [HR] = 2.10, 95% confidence interval [CI]: 1.34-3.31) and IKZF1plus (HR = 3.07, 95% CI: 2.01-4.67) had a shorter event-free survival compared with IKZF1WT . However, although the IKZF1plus status was associated with patients' characteristics indicating poor prognosis, the difference between IKZF1plus and IKZF1del was not statistically significant (HR = 1.46, 95% CI: 0.83-2.57, p = .19). The results of the adjusted analysis were similar to the unadjusted analysis. CONCLUSIONS: In patients with BCP-ALL from the EORTC 58951 trial, the improvement of the prognostic importance of IKZF1 by considering IKZF1plus was not statistically significant.

European standard clinical practice - Key issues for the medical care of individuals with familial leukemia.

Although hematologic malignancies (HM) are no longer considered exclusively sporadic, additional awareness of familial cases has yet to be created. Individuals carrying a (likely) pathogenic germline variant (e.g., in ETV6, GATA2, SAMD9, SAMD9L, or RUNX1) are at an increased risk for developing HM. Given the clinical and psychological impact associated with the diagnosis of a genetic predisposition to HM, it is of utmost importance to provide high-quality, standardized patient care. To address these issues and harmonize care across Europe, the Familial Leukemia Subnetwork within the ERN PaedCan has been assigned to draft an European Standard Clinical Practice (ESCP) document reflecting current best practices for pediatric patients and (healthy) relatives with (suspected) familial leukemia. The group was supported by members of the German network for rare diseases MyPred, of the Host Genome Working Group of SIOPE, and of the COST action LEGEND. The ESCP on familial leukemia is proposed by an interdisciplinary team of experts including hematologists, oncologists, and human geneticists. It is intended to provide general recommendations in areas where disease-specific recommendations do not yet exist. Here, we describe key issues for the medical care of familial leukemia that shall pave the way for a future consensus guideline: (i) identification of individuals with or suggestive of familial leukemia, (ii) genetic analysis and variant interpretation, (iii) genetic counseling and patient education, and (iv) surveillance and (psychological) support. To address the question on how to proceed with individuals suggestive of or at risk of familial leukemia, we developed an algorithm covering four different, partially linked clinical scenarios, and additionally a decision tree to guide clinicians in their considerations regarding familial leukemia in minors with HM. Our recommendations cover, not only patients but also relatives that both should have access to adequate medical care. We illustrate the importance of natural history studies and the need for respective registries for future evidence-based recommendations that shall be updated as new evidence-based standards are established.

Somatic genetic alterations predict hematological progression in GATA2 deficiency.

Germline GATA2 mutations predispose to myeloid malignancies resulting from the progressive acquisition of additional somatic mutations. Here we describe clinical and biological features of 78 GATA2-deficient patients. Hematopoietic stem and progenitor cell phenotypic characterization revealed an exhaustion of myeloid progenitors. Somatic mutations in STAG2, ASXL1 and SETBP1 genes along with cytogenetic abnormalities (monosomy 7, trisomy 8, der(1;7)) occurred frequently in patients with GATA2 germline mutations. Patients were classified into three hematopoietic spectra based on bone marrow cytomorphology. No somatic additional mutations were detected in patients with normal bone marrow (spectrum 0), whereas clonal hematopoiesis mediated by STAG2 mutations was frequent in those with a hypocellular and/or myelodysplastic bone marrow without excess blasts (spectrum 1). Finally, SETBP1, RAS pathway and RUNX1 mutations were predominantly associated with leukemic transformation stage (spectrum 2), highlighting their implications in the transformation process. Specific somatic alterations, potentially providing distinct selective advantages to affected cells, are therefore associated with the clinical/hematological evolution of GATA2 syndrome. Our study not only suggests that somatic genetic profiling will help clinicians in their management of patients, but will also clarify the mechanism of leukemogenesis in the context of germline GATA2 mutations.

Socio-economic outcomes among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: Results of the 58LAE study.

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.

Quality of life of long-term childhood acute lymphoblastic leukemia survivors: Comparison with healthy controls.

OBJECTIVE: 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. METHODS: QoL data were collected from survivors recruited in France and Belgium between 2012 and 2017, including the Short Form Health Survey (SF-12) and the Quality of Life Systemic Inventory (QLSI). The Wilcoxon test was used to compare SF-12 scale scores between survivors and matched population controls. For the QLSI, comparisons were mainly descriptive. RESULTS: One hundred and eighty-six survivors (mean age: 27.6 years; range: 18.1-52.8) at follow-up completed QoL measures, amongst whom 180 were matched to controls. Overall, survivors had higher QoL on all SF12 scale scores, indicating that they had better functioning compared to controls. Statistically significant differences on the SF12 were observed for Vitality, Social Functioning, Role Limitations due to Emotional Problems and Mental Health scales. QLSI outcomes suggested that survivors were happier than controls with Couple and Social Relations. Controls were unhappiest compared to survivors with Money, Love life, Self-esteem, Nutrition and Paid Work. CONCLUSIONS: Our findings suggest that survivors of childhood ALL have better QoL outcomes on some domains compared to the general population, specifically around social and emotional functioning, and that they tend to prioritize their relationships more. Interventions for improving QoL outcomes, might build on existing positive experiences with family, friends and partners.

Immunoglobulin Heavy Chain High-Throughput Sequencing in Pediatric B-Precursor Acute Lymphoblastic Leukemia: Is the Clonality of the Disease at Diagnosis Related to Its Prognosis?

High-throughput sequencing (HTS) of the immunoglobulin heavy chain (IgH) locus is a recent very efficient technique to monitor minimal residual disease of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It also reveals the sequences of clonal rearrangements, therefore, the multiclonal structure, of BCP-ALL. In this study, we performed IgH HTS on the diagnostic bone marrow of 105 children treated between 2004 and 2008 in Belgium for BCP-ALL in the European Organization for Research and Treatment of Cancer (EORTC)-58951 clinical trial. Patients were included irrespectively of their outcome. We described the patterns of clonal complexity at diagnosis and investigated its association with patients' characteristics. Two indicators of clonal complexity were used, namely, the number of foster clones, described as clones with similar D-N2-J rearrangements but other V-rearrangement and N1-joining, and the maximum across all foster clones of the number of evolved clones from one foster clone. The maximum number of evolved clones was significantly higher in patients with t(12;21)/ETV6:RUNX1. A lower number of foster clones was associated with a higher risk group after prephase and t(12;21)/ETV6:RUNX1 genetic type. This study observes that clonal complexity as accessed by IgH HTS is linked to prognostic factors in childhood BCP-ALL, suggesting that it may be a useful diagnostic tool for BCP-ALL status and prognosis.

Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. OBJECTIVE: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. METHODS: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. RESULTS: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P < .001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P < .001). Genetic subgroups did not differ in 2-year OS (P = .1) and EFS (P = .073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5 × 10e3/µL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. CONCLUSION: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.

Fertility status among long-term childhood acute lymphoblastic leukaemia survivors enrolled between 1971 and 1998 in EORTC CLG studies: results of the 58 Late Adverse Effects study.

STUDY QUESTION: What are the fertility outcomes of male and female childhood acute lymphoblastic leukaemia (ALL) long-term survivors? SUMMARY ANSWER: We 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 ALREADY: Survival 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, DURATION: Childhood 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, METHODS: Survivors 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 CHANCE: The 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 CAUTION: The 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 FINDINGS: Fertility 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 NUMBER: NCT01298388 (clinicaltrials.gov).

Serum calprotectin (S100A8/A9): a promising biomarker in diagnosis and follow-up in different subgroups of juvenile idiopathic arthritis.

INTRODUCTION: In the management of juvenile idiopathic arthritis (JIA), there is a lack of diagnostic and prognostic biomarkers. This study assesses the use of serum calprotectin (sCal) as a marker to monitor disease activity, and as a classification and prognosis tool of response to treatment or risk of flares in patients with JIA. METHODS: Eighty-one patients with JIA from the CAP48 multicentric cohort were included in this study, as well as 11 non-paediatric healthy controls. An ELISA method was used to quantify sCal with a commercial kit. RESULTS: Patients with an active disease compared with healthy controls and with patients with inactive disease showed an eightfold and a twofold increased level of sCal, respectively. sCal was found to be correlated with the C-reactive protein (CRP) and even more strongly with the erythrocyte sedimentation rate. Evolution of DAS28 scores correlated well with evolution of sCal, as opposed to evolution of CRP. With regard to CRP, sCal could differentiate forms with active oligoarthritis from polyarthritis and systemic forms. However, sCal brought an added value compared with the CRP as a prognosis marker. Indeed, patients with active disease and reaching minimal disease activity (according to Juvenile Arthritis Disease Activity Score) at 6 months following the test had higher sCal levels, while patients with inactive disease had higher sCal levels if a flare was observed up to 3-9 months following the test. CONCLUSIONS: This study confirms the potential uses of sCal as a biomarker in the diagnosis and follow-up of JIA.

Retrospective study of diffuse intrinsic pontine glioma in the Belgian population: a 25 year experience.

INTRODUCTION: Diffuse intrinsic pontine glioma is a rare disease with a high mortality. Our primary aim was to determine the incidence of this disease in Belgium. Secondly, we wanted to compare the treatment approach of Belgian pediatric oncology centres, to investigate possibilities for improvement. METHODS: We retrospectively collected and analysed data on DIPG-patients diagnosed between 1994 and 2018 and recorded in the Belgian Cancer Registry. We included patients ≤ 18 years who were followed in one of the eight Belgian pediatric oncology centres. RESULTS: We included 100 patients. Files were complete in 87 patients. We observed an increase in diagnoses with an incidence of 3.1 per 1,000,000 persons (aged 0-≤ 18) per year over the last 5 years compared to an overall incidence of 1.8. Biopsy was performed at diagnosis in 51.7% of patients. In one fifth this was study-related. Mutation analysis was known in eight patients, of which six showed the H3 K27M-mutation. 58.8% of patients received chemotherapy, without a significant survival benefit. 12.6% of patients were included in a clinical trial. Biopsy rate and the use of chemotherapy differed widely between centres. Mean OS and PFS were 10.49 and 4.87 months respectively. We observed an improved survival over time. CONCLUSIONS: Over the past 25 years, we observed an increase of new DIPG-diagnoses. Outcome in our cohort is comparable with literature findings. We demonstrate an important heterogeneity in treatment approach between different centres and limited inclusion in clinical trials. Therefore, collaboration between centres and inclusion of patients in clinical trials is much needed.

Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease.

Human inborn errors of IFN-γ underlie mycobacterial disease, due to insufficient IFN-γ production by lymphoid cells, impaired myeloid cell responses to this cytokine, or both. We report four patients from two unrelated kindreds with intermittent monocytosis and mycobacterial disease, including bacillus Calmette-Guérin-osis and disseminated tuberculosis, and without any known inborn error of IFN-γ. The patients are homozygous for ZNFX1 variants (p.S959* and p.E1606Rfs*10) predicted to be loss of function (pLOF). There are no subjects homozygous for pLOF variants in public databases. ZNFX1 is a conserved and broadly expressed helicase, but its biology remains largely unknown. It is thought to act as a viral double-stranded RNA sensor in mice, but these patients do not suffer from severe viral illnesses. We analyze its subcellular localization upon overexpression in A549 and HeLa cell lines and upon stimulation of THP1 and fibroblastic cell lines. We find that this cytoplasmic protein can be recruited to or even induce stress granules. The endogenous ZNFX1 protein in cell lines of the patient homozygous for the p.E1606Rfs*10 variant is truncated, whereas ZNFX1 expression is abolished in cell lines from the patients with the p.S959* variant. Lymphocyte subsets are present at normal frequencies in these patients and produce IFN-γ normally. The hematopoietic and nonhematopoietic cells of the patients tested respond normally to IFN-γ. Our results indicate that human ZNFX1 is associated with stress granules and essential for both monocyte homeostasis and protective immunity to mycobacteria.

Clinical Implications of Minimal Residual Disease Detection in Infants With KMT2A-Rearranged Acute Lymphoblastic Leukemia Treated on the Interfant-06 Protocol.

PURPOSE: Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of KMT2A gene rearrangements and poor outcome. We evaluated the value of minimal residual disease (MRD) in infants with KMT2A-rearranged ALL treated within the Interfant-06 protocol, which compared lymphoid-style consolidation (protocol IB) versus myeloid-style consolidation (araC, daunorubicin, etoposide/mitoxantrone, araC, etoposide). MATERIALS AND METHODS: MRD was measured in 249 infants by DNA-based polymerase chain reaction of rearranged KMT2A, immunoglobulin, and/or T-cell receptor genes, at the end of induction (EOI) and end of consolidation (EOC). MRD results were classified as negative, intermediate (< 5 × 10-4), and high (≥ 5 × 10-4). RESULTS: EOI MRD levels predicted outcome with 6-year disease-free survival (DFS) of 60.2% (95% CI, 43.2 to 73.6), 45.0% (95% CI, 28.3 to 53.1), and 33.8% (95% CI, 23.8 to 44.1) for infants with negative, intermediate, and high EOI MRD levels, respectively (P = .0039). EOC MRD levels were also predictive of outcome, with 6-year DFS of 68.2% (95% CI, 55.2 to 78.1), 40.1% (95% CI, 28.1 to 51.9), and 11.9% (95% CI, 2.6 to 29.1) for infants with negative, intermediate, and high EOC MRD levels, respectively (P < .0001). Analysis of EOI MRD according to the type of consolidation treatment showed that infants treated with lymphoid-style consolidation had 6-year DFS of 78.2% (95% CI, 51.4 to 91.3), 47.2% (95% CI, 33.0 to 60.1), and 23.2% (95% CI, 12.1 to 36.4) for negative, intermediate, and high MRD levels, respectively (P < .0001), while for myeloid-style-treated patients the corresponding figures were 45.0% (95% CI, 23.9 to 64.1), 41.3% (95% CI, 23.2 to 58.5), and 45.9% (95% CI, 29.4 to 60.9). CONCLUSION: This study provides support for the idea that induction therapy selects patients for subsequent therapy; infants with high EOI MRD may benefit from AML-like consolidation (DFS 45.9% v 23.2%), whereas patients with low EOI MRD may benefit from ALL-like consolidation (DFS 78.2% v 45.0%). Patients with positive EOC MRD had dismal outcomes. These findings will be used for treatment interventions in the next Interfant protocol.