Pharmacokinetics, pharmacodynamics, efficacy, and safety of ravulizumab in pediatric paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease of uncontrolled terminal complement activation leading to intravascular hemolysis, thrombotic events, increased morbidity and mortality. This phase 3, open-label, single-arm multicenter study (NCT03406507) evaluated ravulizumab treatment in eculizumab-naive or -experienced pediatric patients (aged <18 years) with PNH over a 26-week primary evaluation period (PEP) and 4-year extension period (EP). Patients included in the study received weight based intravenous ravulizumab dosing. Primary endpoints were pharmacokinetic and pharmacodynamic parameters to confirm complement component 5 (C5) inhibition by ravulizumab; secondary endpoints assessed the efficacy (including percentage change in lactate dehydrogenase levels over time) and safety of ravulizumab. Thirteen patients, 5 (38.5%) eculizumab-naive and 8 (61.5%) experienced, were enrolled. Ravulizumab Ctrough levels were above the pharmacokinetic threshold of 175 µg/mL in the PEP and EP except in one patient. At the end of the study, pre-and post-infusion mean ± standard deviation serum ravulizumab concentrations were 610.50 ± 201.53 µg/mL and 518.29 ± 109.67 µg/mL for eculizumab-naive and -experienced patients, respectively. After the first ravulizumab infusion, serum free C5 concentrations were <0.5 µg/mL in both cohorts until the end of the study (0.061 ± 0.021 µg/mL and 0.061 ± 0.018 µg/mL for eculizumab-naive and -experienced patients, respectively). Compared with baseline, ravulizumab improved and maintained efficacy outcomes in both groups. Ravulizumab had an acceptable safety profile with no new safety signals identified, and provided immediate, complete, and sustained terminal complement inhibition, translating to clinical benefit for pediatric patients with PNH.

Genomic imbalances analysis provides new insight into prognostic factors in adult and pediatric T-ALL.

Given the poor outcome of refractory and relapsing T-ALL, identifying prognostic markers is still challenging. Using SNP-array analysis, we provide a comprehensive analysis of genomic imbalances in a cohort of 317 newly-diagnosed T-ALL patients including 135 children and 182 adults with respect to clinical and biological features and outcomes. SNP-array results identified at least one somatic genomic imbalance in virtually all T-ALL patients (~96%). Del(9)(p21) (~70%) and UPD(9)p21)/CDKN2A/B (~28%) were the most frequent genomic imbalances. Unexpectedly del(13q14)/RB1/DLEU1 (~14%) was the second more frequent CNV followed by del(6)(q15)/CASP8AP2 (~11%), del(1)(p33)/SIL-TAL1 (~11%), del(12)(p13)ETV6/CDKN1B (~9%), del(18)(p11)/PTPN2 (~9%), del(1)(p36)/RPL22 (~9%), and del(17)(q11)/NF1/SUZ12 (~8%). SNP-array also revealed distinct profiles of genomic imbalances according to age, immunophenotype, and oncogenetic subgroups. In particular, adult T-ALL patients demonstrated a significantly higher incidence of del(1)(p36)/RPL22, and del(13)(q14)/RB1/DLEU1, and lower incidence of del(9)(p21) and UPD(9p21)/CDKN2A/B. We determined a threshold of 15 genomic imbalances to stratify patients into high- and low-risk groups of relapse. Survival analysis also revealed the poor outcome, despite the low number of affected cases, conferred by the presence of chromothripsis (n=6, ~2%), del(16)(p13)/CREBBP (n=15, ~5%) as well as the newly identified recurrent gain at 6q27 involving MLLT4 (n=10, ~3%). Genomic complexity, del(16)(p13)/CREBBP and gain at 6q27 involving MLLT4 maintained their significance in multivariate analysis for survival outcome. Our study thus demonstrated that whole genome analysis of imbalances provides new insights to refine risk stratification in T-ALL.

A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95%CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatmentrelated mortality (TRM) of 9.0% (95%CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95%CI: 65.7-82.4) and 66.4% (95%CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT >6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with three or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced yet still substantial relapse incidence. By integrating genetic information with clinical and hematological features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit novel therapeutic agents and post-transplant strategies.

Educational outcomes in siblings of childhood leukemia survivors: Factors associated with school difficulties and comparison with general population.

BACKGROUND: To investigate the educational outcomes of siblings of childhood leukemia survivors, explore determinants of school difficulties, and compare the rates of repeating grades between siblings and the general population. METHODS: A cross-sectional study of childhood leukemia survivors' siblings recruited through the Leucémies de l'Enfant et de l'Adolescent cohort, a French long-term follow-up program, was conducted, and education-related data were obtained via self-report questionnaires. Adjusted logistic regression models were used to identify variables associated with school difficulties and time since diagnosis. Rates of repeating a grade in middle school were compared between siblings and the general population of the same generation. RESULTS: A total of 564 siblings with a mean time from diagnosis of 14.1 ± 6.4 years were included, among whom 139 (24.6%) repeated a grade, at an average of 6.4 ± 4.5 years after diagnosis. In multivariate analysis, the risk factors for repeating a grade were older siblings (odds ratio [OR] 2.3, p = 0.006), family financial difficulties (OR 2.8, p = 0.008), and history of repetition in survivors (OR, 2.5, p = 0.001). Sibling hematopoietic stem cell donors were at greater risk of repeating a grade long-term after diagnosis (p = 0.018). Overall, siblings did not have a higher risk of educational delays at the end of middle school than the general population. CONCLUSION: Although the results are reassuring, socioeconomic and cancer-related factors may have an impact on siblings' schooling long after diagnosis. Paying attention to siblings contributes to identifying the most vulnerable families, allowing more attention and appropriate resources to avoid long-term repercussions. Additionally, supportive and targeted interventions can be developed to improve the organization of education and the health care system.

Patient-Level Meta-analysis of Clofarabine in Acute Lymphoblastic Leukemia.

INTRODUCTION: Clofarabine monotherapy at a dose of 52 mg/m2 per day was approved in the USA in 2004 for the treatment of relapsed or refractory acute lymphoblastic leukemia (R/R ALL) in patients aged 1-21 years after at least two prior regimens. To address a post-marketing requirement for additional evidence of the clinical benefit of clofarabine in its approved indication, a meta-analysis of patient-level data was conducted. METHODS: A systematic literature review was conducted, using the Dr.Evidence software platform, DOC Search, and Embase, to identify clinical trials with patients with R/R ALL who received clofarabine monotherapy at 52 mg/m2. The primary endpoint was complete remission (CR). Secondary endpoints were overall remission (OR, defined by CR or CR with either incomplete platelet recovery or incomplete neutrophil and platelet recovery), duration of response, overall survival (OS), and safety. RESULTS: A total of 754 patients in 12 clinical studies were analyzed including 682 patients with R/R ALL treated with clofarabine monotherapy at 52 mg/m2; of them, 374 were aged < 22 years (pediatric population). Rates of CR and OR were 16% (95% confidence interval [CI] 7, 26) and 28% (95% CI 20, 37), respectively, in the pediatric population and 12% (95% CI 5, 21) and 21% (95% CI 13, 31) in the overall population. Median OS (evaluable in three studies in pediatric patients) was 3.7 months (95% CI 0.1, 31.4), reaching 10.1 months (95% CI 0.3, 68.9) for those achieving OR. Sensitivity analyses supported these findings. The most frequent grade 3-4 adverse events were liver abnormalities, anemia, diarrhea, and febrile neutropenia. CONCLUSION: In this meta-analysis, CR duration and median OS in pediatric patients with R/R ALL appeared to be slightly longer than in the phase II study. No new safety signals were identified. Results support the use of clofarabine monotherapy in its approved indication.

INSPIRED Symposium Part 2: Prevention and Management of Relapse Following Chimeric Antigen Receptor T Cell Therapy for B Cell Acute Lymphoblastic Leukemia.

Although CD19-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) for relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) has been transformative in inducing and sustaining remission, relapse rates remain unacceptably high, with approximately 50% of children and young adults experiencing relapse within the first year postinfusion. Emerging strategies to extend the durability of remission involve the use of prognostic biomarkers to identify those at high risk of relapse or incorporate strategies aimed to enhancing functional CAR T cell persistence. Nonetheless, with antigen loss/down-regulation or evolution to lineage switch as major mechanisms of relapse, optimizing single antigen targeting alone is insufficient. Here, with a focus on relapse prevention strategies, including postinfusion surveillance and treatment approaches being explored to optimize post-CAR-T management (eg, combinatorial antigen targeting strategies, preemptive hematopoietic cell transplantation), we review the current state of the art in the prevention and management of post CAR-T relapse. We highlight the advancements in the field and identify gaps in the literature to guide future research in optimizing the prevention and management of post-CAR-T relapse in children and young adults with B-ALL.

Down syndrome and leukemia: from basic mechanisms to clinical advances.

Children with Down syndrome (DS, trisomy 21) are at a significantly higher risk of developing acute leukemia compared to the overall population. Many studies investigating the link between trisomy 21 and leukemia initiation and progression have been conducted over the last two decades. Despite improved treatment regimens and significant progress in iden - tifying genes on chromosome 21 and the mechanisms by which they drive leukemogenesis, there is still much that is unknown. A focused group of scientists and clinicians with expertise in leukemia and DS met in October 2022 at the Jérôme Lejeune Foundation in Paris, France for the 1st International Symposium on Down Syndrome and Leukemia. This meeting was held to discuss the most recent advances in treatment regimens and the biology underlying the initiation, progression, and relapse of acute lymphoblastic leukemia and acute myeloid leukemia in children with DS. This review provides a summary of what is known in the field, challenges in the management of DS patients with leukemia, and key questions in the field.

TREC mediated oncogenesis in human immature T lymphoid malignancies preferentially involves ZFP36L2.

The reintegration of excised signal joints resulting from human V(D)J recombination was described as a potent source of genomic instability in human lymphoid cancers. However, such molecular events have not been recurrently reported in clinical patient lymphoma/leukemia samples. Using a specifically designed NGS-capture pipeline, we here demonstrated the reintegration of T-cell receptor excision circles (TRECs) in 20/1533 (1.3%) patients with T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Remarkably, the reintegration of TREC recurrently targeted the tumor suppressor gene, ZFP36L2, in 17/20 samples. Thus, our data identified a new and hardly detectable mechanism of gene deregulation in lymphoid cancers providing new insights in human oncogenesis.

Impact of childhood leukemia on siblings: their long-term perception of family functioning and its relationship with their psychosocial characteristics using structural equation modeling.

PURPOSE: In the context of pediatric cancer, siblings' adaptation and needs have been previously investigated; however, research on the long-term consequences on siblings, especially on their family environment, is scarce. We aimed to (1) assess the family functioning (FF) perceived by siblings of childhood leukemia survivors long after diagnosis and (2) explore characteristics likely associated and investigate associations with psycho-behavioral and social factors. METHODS: Childhood leukemia survivors' siblings older than 11 years were recruited through the LEA cohort, a French long-term follow-up program, and completed the family assessment device (FAD). Logistic regression analysis was used to determine factors likely associated with unhealthy functioning in families as perceived by siblings. Structural equation modeling (SEM) was used to examine relationships that predict siblings' perception of FF. RESULTS: We included 605 siblings (mean follow-up time from diagnosis 14.1 ± 6.8 years), of whom 175 (28.9%) perceived unhealthy functioning. SEM showed that older siblings were more likely to perceive problematic functioning (ß = 0.095, p = 0.014). Sex and leukemia burden had indirect effects on FF through mediators. Family financial situation at diagnosis was not associated with the risk of reporting unhealthy functioning. CONCLUSIONS: Our study contributed to identifying siblings at risk of facing family issues and reinforced the need to provide more consideration and suitable resources to avoid late consequences. Often considered as the "forgotten children", future research should focus on developing targeted interventions to facilitate family communication and improve siblings' social support. IMPLICATIONS FOR CANCER SURVIVORS: Overall, results regarding FF perceived by siblings are reassuring and provide new enlightening elements that allow for better support to all families.

The Development of New Agents for Post-Hematopoietic Stem Cell Transplantation Non-Infectious Complications in Children.

Hematopoietic stem cell transplantation (HSCT) is often the only curative treatment option for patients suffering from various types of malignant diseases and some non-cancerous conditions. Nevertheless, it is associated with a high risk of complications leading to transplant-related mortality and long-term morbidity. An increasing number of therapeutic and prevention strategies have been developed over the last few years to tackle the complications arising in patients receiving an HSCT. These strategies have been mainly carried out in adults and some are now being translated into children. In this manuscript, we review the recent advancements in the development and implementation of treatment options for post-HSCT non-infectious complications in pediatric patients with leukemia and other non-malignant conditions, with a special attention on the new agents available within clinical trials. We focused on the following conditions: graft failure, prevention of relapse and early interventions after detection of minimal residual disease positivity following HSCT in acute lymphoblastic and myeloid leukemia, chronic graft versus host disease, non-infectious pulmonary complications, and complications of endothelial origin.

Symptomatic osteonecrosis in French survivors of childhood and adolescent leukemia: a clinical and MRI study of LEA cohort.

Osteonecrosis (ON) is a known complication of acute leukemia (AL) management, affecting 1%-10% of young patients and resulting in long-term morbidity. Widespread access to MRI over the past decade has allowed earlier detection and more accurate assessment. This study investigated clinical and MRI features of the 129 (2.5%) patients with symptomatic ON retrospectively recruited from the French LEA (Leucémies de l'Enfant et de l'Adolescent, or child and adolescent leukemias) cohort (n = 4,973). We analyzed data concerning ON risk factors, multifocal involvement, severe lesions detected by MRI, and patient quality of life (QoL). ON patients tended to be >10 years old at the time of AL diagnosis (odds ratio [OR]: 22.46; p < 10-6), female (OR: 1.8; p = 0.002), or treated for relapse (OR: 1.81; p = 0.041). They more frequently suffered from other sequelae (p < 10-6). Most necroses involved weight-bearing joints, and they were multifocal in 69% of cases. Double-blinded review of MRIs for 39 patients identified severe lesions in 14, usually in the hips. QoL of adolescents and adults was poor and permanently impacted after onset of ON. In conclusion, age >10 at time of AL diagnosis, female sex, and relapse occurrence were risk factors for multifocal ON; MRI revealed severe ON in a third of the patients considered; and ON was associated with persistently poor QoL affecting multiple domains. Future studies should include prospective data addressing ON management and seek to identify genetic markers for targeted screening enabling early ON detection and treatment.

Ovarian Function and Spontaneous Pregnancy After Hematopoietic Stem Cell Transplantation for Leukemia Before Puberty: An L.E.A. Cohort Study.

Ovarian function impairment and infertility are among the most frequent late effects after hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate ovarian function, occurrence of premature ovarian insufficiency (POI), and spontaneous pregnancy in a large cohort of adult survivor women who had undergone HSCT for leukemia before puberty. We conducted a retrospective observational study in women from the national cohort L.E.A., the long-term French follow-up program after childhood leukemia. The median follow-up duration was 18 years (14.2-23.3) after HSCT. Among 178 women, 106 (60%) needed pubertal induction with hormone substitution treatment, whereas 72 (40%) had spontaneous menarche. After spontaneous menarche, 33 (46%) developed POI, mostly within 5 years of HSCT. Older age at time of HSCT and cryopreservation of ovarian tissue appeared as significant risk factors for POI. More than 65% of patients who underwent HSCT before the age of 4.8 years had spontaneous menarche, and almost 50% didn't have POI at last evaluation, whereas more than 85% with HSCT after the age of 10.9 years didn't have spontaneous menarche and needed induction of puberty with hormone replacement therapy. Twenty-two women (12%) had at least one spontaneous pregnancy, with 17 live-births, 14 miscarriages, 4 legal abortions, and 2 therapeutic abortions. These results add supplementary data to better counsel patients and their families on the chances of ovarian residual function and pregnancy after HSCT, as well as on the potential interest of fertility preservation.

Harnessing the MYB-dependent TAL1 5'super-enhancer for targeted therapy in T-ALL.

The acquisition of genetic abnormalities engendering oncogene dysregulation underpins cancer development. Certain proto-oncogenes possess several dysregulation mechanisms, yet how each mechanism impacts clinical outcome is unclear. Using T-cell acute lymphoblastic leukemia (T-ALL) as an example, we show that patients harboring 5'super-enhancer (5'SE) mutations of the TAL1 oncogene identifies a specific patient subgroup with poor prognosis irrespective of the level of oncogene dysregulation. Remarkably, the MYB dependent oncogenic 5'SE can be targeted using Mebendazole to induce MYB protein degradation and T-ALL cell death. Of note Mebendazole treatment demonstrated efficacy in vivo in T-ALL preclinical models. Our work provides proof of concept that within a specific oncogene driven cancer, the mechanism of oncogene dysregulation rather than the oncogene itself can identify clinically distinct patient subgroups and pave the way for future super-enhancer targeting therapy.