Brigitte Nelken

Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections, and an increased leukemia risk. Multiple genetic defects that underlie SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. In this study, we report 4 independent pedigrees with heterozygous variants in LCP1. Variants c.740-1G>T and c.740-20_744del produced the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree produced p.S170L, and variant c.806T>C in the fourth pedigree produced p.L269P. Affected individuals suffered from neutropenia, poor or complete lack of response to granulocyte colony–stimulating factor (G-CSF) treatment, and variable degrees of lymphopenia, hypogammaglobulinemia, and monocytopenia. Patients with A247_E254del and p.L269P presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, 2 individuals developed acute leukemia. G-CSF nonresponsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function effect, both the A247_E254del and S170L variants increased F-actin bundling and the formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways that control mitosis in multilineage and lymphoid-primed HSPC subsets. We concluded that activating LCP1 variants cause a new hematopoietic disorder with autosomal dominant inheritance. Depending on the consequences of the LCP1 variants in terms of protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, hypogammaglobulinemia, monocytopenia, and defective cytokinesis.

Children with relapsed acute leukemia have a poor prognosis; current relapse treatments are toxic, and novel treatments are needed. The anti‐CD38 antibody isatuximab is approved for relapsed‐refractory multiple myeloma in adults. We present results of the ISAKIDS study (NCT03860844) investigating isatuximab in children with relapsed‐refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). This Phase 2, single‐arm, multicenter, open‐label study enrolled children aged 28 days to −4 sensitivity threshold for ALL and 10 ⁻³ sensitivity threshold for AML. One event of fatal cytokine release syndrome was reported in a patient with a high baseline white blood cell count, leading to trial adaptation. The toxicity of isatuximab with chemotherapy was otherwise manageable. Despite initial evidence of efficacy of isatuximab combined with intensive chemotherapy, CR/CRi rates did not meet stringent prespecified criteria to proceed to ISAKIDS Stage 2 (≥60% [T‐ALL] and ≥70% [B‐ALL and AML]).

Background: Acyclovir treatment is an efficient prophylaxis to prevent varicella‐zoster virus (VZV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT).Aims: This single center retrospective study tried to determine if the lymphocytes immunophenotyping could help to determine the duration of prophylaxis, and evaluated complications, and associated risk factors for VZV infection.Methods and Results: Eighty‐four children underwent an allogeneic HSCT, in which 77 received an acyclovir prophylaxis. Twenty‐one of the 77 had a VZV infection with an incidence rate of 1.30 per 100 patients‐months (exact 95% CI, 0.81 to 2.01). Among these 21 patients with VZV infection, 16 had an infection after withdrawing acyclovir prophylaxis within a median of 49 days (range, 11 days–5.8 months). Thirty‐five percent of the VZV infected patients were hospitalized, 9% had a visceral dissemination, and 9% had postherpetic neuralgia. In multivariate analysis, higher VZV infection rate was associated with conditioning regimen with total body irradiation, immunoglobulin substitution, and antithymocyte globulin. The incidence of VZV infection increased significantly when patients had a CD4+ lymphocytes count below 23% (cHR 3.28 [95% CI, 1.09–9.81]; p = 0.03) or a CD4⁺/CD8⁺ ratio less than 0.9 (cHR 3.13 [95% CI, 1.04–9.36]; p = 0.04) at the time of stopping acyclovir prophylaxis.Conclusion: After cessation of acyclovir prophylaxis, VZV reactivation can occur and be responsible for morbidity after allogeneic HSCT. This study suggests that the proportion of CD4+ lymphocytes and the CD4⁺/CD8⁺ ratio can inform decisions about the duration of acyclovir prophylaxis after allogeneic HSCT to prevent VZV reactivation.

Purpose:We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment.Patients and Methods:Fifteen patients (aged 1–<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients.Results:The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission.Conclusions:Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.

Within the International Registry of Childhood Chronic Myeloid Leukemia (CML), we identified 18 patients less than 18 years old at diagnosis of CML who were in the chronic phase and exhibiting a sustained deep molecular response (DMR) to imatinib defined as BCR-ABL1/ABL1 < 0.01% (MR⁴) for at least two years followed by discontinuation of imatinib. Before discontinuation, the median duration of imatinib was 73.2 months (range, 32–109) and the median duration of MR⁴ was 46.2 months (range, 23.9–98.6). Seven patients experienced loss of major molecular response (MMR) 4.1 months (range, 1.9–6.4) after stopping and so restarted imatinib. The median molecular follow-up after discontinuation was 51 months (range, 6–100) for the nine patients without molecular relapse. The molecular free remission rate was 61% (95% CI, 38–83%), 56% (95% CI, 33–79%) and 56% (95% CI, 33–79%) at 6, 12 and 36 months, respectively. Six of the seven children who experienced molecular relapse after discontinuation regained DMR (median, 4.7 months; range, 2.5–18) after restarting imatinib. No withdrawal syndrome was observed. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment and DMR durations before discontinuation had no influence on treatment free remission. These data suggest that imatinib can be safely discontinued in children with sustained MR⁴ for at least two years.

Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Patients and Methods: Fifteen patients (aged 1–<18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase I study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics of nilotinib in pediatric patients. Results: The area under the concentration–time curve at steady state was slightly lower in pediatric patients versus adults (14,751.4 vs. 17,102.9 ng/h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 [90% confidence interval (CI), 0.70–1.06]. Body surface area–adjusted systemic clearance was slightly higher in pediatric versus adult patients (GMR, 1.30; 90% CI, 1.04–1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and three with Ph+ ALL achieved complete remission. Conclusions: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a pharmacokinetics and safety profile comparable with the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.