Ruxolitinib for pediatric patients with treatment-naïve and steroid-refractory acute graft-versus-host disease (REACH4).

In REACH4 (NCT03491215), a phase 1/2, open-label, single-arm, multicenter study, the pharmacokinetics (PK), efficacy, and safety of ruxolitinib were evaluated in treatment-naïve and steroid-refractory pediatric patients with grade II-IV acute graft-versus-host disease (aGVHD; n=45). Ruxolitinib dosing was based on age and targeted the exposure in adults receiving 10 mg twice daily; group 1 (≥12 to <18 years) received 10 mg twice daily and preliminary starting doses for groups 2 (≥6 to <12 years) and 3 (≥2 to <6 years) were 5 mg twice daily and 4 mg/m2 twice daily, respectively. Phase 1 primary objective was to assess ruxolitinib PK parameters and define an age-appropriate recommended phase 2 dose (RP2D) for patients <12 years of age. Phase 2 primary objective was to measure the activity of ruxolitinib as assessed by overall response rate (ORR) at day 28; the key secondary objective was to assess the durable ORR at day 56. Ruxolitinib exposure was comparable across age groups; starting doses were confirmed as the RP2D. The median duration of ruxolitinib exposure was 3.8 months (range 0.3-11.2). ORR in all patients was 84.4% (90% confidence interval [CI], 72.8-92.5) at day 28, with a durable ORR at day 56 of 66.7% (90% CI, 53.4-78.2); high response rates were observed across age groups and in both treatment-naïve and steroid-refractory subgroups. Adverse events were consistent with those expected in ruxolitinib-treated patients with aGvHD (anemia, decreased neutrophil and leukocyte count). In pediatric patients with aGvHD, ruxolitinib showed clinically meaningful efficacy with no new safety signals.

[Treatment of high-risk leukaemia: allograft and immunotherapy]. / Traitement des leucémies à haut risque : allogreffe et immunothérapie.

Leukaemia results from a malignant proliferation of cells in the bone marrow. The prognosis is defined by the disease's biological characteristics. Treatment is based on chemotherapy. In cases of high-risk leukaemia, an allograft may be proposed. The arrival of targeted therapies and immunotherapy has revolutionised the prognosis of the disease. The challenge of the next few years will be to define the place of these therapies.

Prevalence of the reversed halo sign in neutropenic patients compared with non-neutropenic patients: Data from a single-centre study involving 27 patients with pulmonary mucormycosis (2003-2016).

Pulmonary mucormycosis (PM) is a life-threatening infection and the diagnosis can be challenging. The objective was to retrospectively explore the value of the RHS in our cohort of 27 patients with mucormycosis and its relation to neutropenia. This was a retrospective study including all patients with a diagnosis of probable or proven invasive PM according to the 2008 EORTC/MSG criteria between September 2003 to April 2016. Fisher's exact test and Mann-Whitney test, with a P-value statistically significant under .05 (P<.05), were used to compare neutropenic and non-neutropenic groups. 27 patients were eligible. The RHS could be identified in 78% of cases in the neutropenic group, and was less common in the non-neutropenic group (31%) (P<.05). Reticulations inside ground-glass opacity in case of RHS were present in 13 out of 15 patients (87%). Mucorales DNA detection by PCR on serum provided, a median time to the first PCR-positive sample of 3 days (-33 to +60 days) before diagnosis was confirmed. Six patients had IPA co-infection. In conclusion, RHS is more frequent in case of PM in neutropenic patients compare to non-neutropenic patients. Its presence in immunocompromised patients should be sufficient to promptly start Mucorales-active antifungal treatment, while its absence especially in non-neutropenic cases should not be sufficient to exclude the diagnosis.

Hematopoietic stem cell transplantation for acute lymphoblastic leukemia: why do adolescents and young adults outcomes differ from those of children? A retrospective study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC).

PURPOSE: In the acute lymphoblastic leukemia (ALL) landscape, adolescents and young adults (AYA) often present high-risk diseases and increased chemotherapy-related toxicity. Studies analyzing the outcomes of AYA after hematopoietic stem cell transplantation (HSCT) are scarce. Our study aimed to compare the outcomes of children and AYA with ALL after HSCT and to determine the factors influencing potential differences. METHOD: 891 patients, from the SFGM-TC registry, aged between 1 and 25 years who received HSCT between 2005 and 2012 were included. The outcomes of AYA were compared to the ones of their younger counterparts. RESULTS: Five-year OS and GRFS were lower in AYA: 53.1% versus 64% and 36% versus 47% (p = 0.0012 and p = 0.007, respectively). WhileCIR was similar in both groups, 5 year-treatment related mortality was higher in AYA: 19% versus 13% (p = 0.04). The lower GRFS in AYA was mainly explained by a higher chronic graft versus host disease (cGvHD) incidence: 32% versus 19% (p < 0.001). Use of peripheral blood stem cells and use of anti-thymoglobulin appeared to be the main factors impacting cGvHD occurrence in AYA. CONCLUSION: AYA have worse outcomes than children after HSCT for ALL because of a greater risk of TRM due to cGvHD. HSCT practices should be questioned in this population.

Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation.

Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation.