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This work's objective was to evaluate the safety of isavuconazole (ISA) as a treatment or prophylaxis for invasive fungal infections (IFIs) in immunocompromised children. IFI was reported as proven or probable according to international definitions. Therapeutic drug monitoring was performed using mass tandem spectrometry to quantify trough plasma concentrations. Targeted ISA levels were 2–4 mg/L, as reported in adult series. Nine patients received ISA as a curative treatment, and six received ISA as prophylaxis. IFIs were proven in four cases and probable in five. The median ISA trough plasma concentration in curative use was 3.19 mg/L [0.88;5.00], and it was 2.94 mg/L [2.77;3.29] in the prophylactic use. The median durations of treatment were 81 days [15;276] and 95 days [15;253], respectively. Three patients had elevated aspartate aminotransferase and alanine aminotransferase, and three patients had elevated creatinine serum. The IFI response was satisfactory in all cases at day 90. No side effects were reported. No patients developed an IFI. Our data underline the safety of an ISA 100 mg dosing regimen in children of <30 kg, which we recommend in this fragile population. We suggest that ISA plasma levels are monitored 10 days after ISA initiation and then every two weeks, alongside guided therapeutic drug monitoring (TDM) administration. [ABSTRACT FROM AUTHOR]

Abstract Background Gemtuzumab ozogamicin (GO) is a cytotoxic anti-CD33 monoclonal antibody that has given promising preliminary results in adult myeloid CD33+ AML. We conducted a retrospective multicenter study of 12 children treated with GO on a compassionate basis (median age 5.5 y). Three patients (2 MDS/AML, 1 JMML) were refractory to first-line treatment, 8 patients with de novo AML were in refractory first relapse, and one patient with de novo AML was in 2nd relapse after stem cell transplantation (SCT). CD33 expression exceeded 20% in all cases. Methods GO was administered alone, at a unit dose of 3–9 mg/m2, once (3 patients), twice (3 patients), three (5 patients) or five times (1 patient). Mean follow-up was 128 days (8–585 d). Results There were three complete responses (25%) leading to further curative treatment (SCT). Treatment failed in the other nine patients, and only one patient was alive at the end of follow-up. NCI-CTC grade III/IV adverse events comprised hematological toxicity (n = 12), hypertransaminasemia (n = 2), allergy and hyperbilirubinemia (1 case each). There was only one major adverse event (grade IV allergy). No case of sinusoidal obstruction syndrome occurred. Conclusion These results warrant a prospective trial of GO in a larger population of children with AML.

Keywords: acute lymphoblastic leukaemia; childhood leukaemia; immunotherapy EN acute lymphoblastic leukaemia childhood leukaemia immunotherapy e53 e56 4 07/01/20 20200701 NES 200701 Paediatric patients with refractory or relapsed (r/r) B-cell acute lymphoblastic leukaemia (BALL) are facing therapeutic challenges, considering their poor five year disease-free survival.[[1]] Immunotherapy could improve their survival and reduce adverse events. Lymphocyte subpopulations were studied in four patients: B-cell aplasia post InO was documented as soon as day 8 of cycle 1 and as late as day 16 after the last injection (Table SII). Loss of I CD19 i was also described with blinatumomab or CAR-T cell therapy.[[8]] InO can be effective and safe in r/r I CD22 i -positive B-ALL paediatric patients. [Extracted from the article]

Differentiation syndrome is a potentially life-threatening complication developing in 2-5-30% of patients with newly diagnosed APL receiving ATRA. Nine patients (42-9%) underwent differentiation syndrome prophylaxis (dexamethasone), and four (19%) developed true differentiation syndrome. All patients achieved cytological remission during induction therapy with a median of 34 [28;60] days and molecular remission with a median of 8 [4-26] weeks. Combined ATRA/ATO therapy for paediatric patients with SR APL was well tolerated without any severe short-term toxicity. [Extracted from the article]

The article focuses on the impact of the multikinase inhibitor Midostaurin in children experiencing relapsed acute leukaemia despite past tretaments. It talks about the relapse of acute leukaemia being common in children along with diseases like myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL).

Candida inconspicua and Candida norvegensis are two closely related species rarely involved in invasive infections. The purpose of this study was to depict the epidemiologic and clinical characteristics of candidemia due to these emerging fluconazole less susceptible species. A retrospective analysis of the epidemiology of C. inconspicua and C. norvegensis during the period 2006-2010 was initiated in six French University hospitals. From this, demographics, clinical, diagnostic and therapeutic data of C. inconspicua or C. norvegensis candidemia were recorded and compared to the observations reported in the literature. C. inconspicua was more frequently isolated compared to C. norvegensis (ratio 2.6) but from the same preferential body sites: mainly digestive (56.4% and 48.37%, respectively, for C. inconspicua and C. norvegensis) and respiratory (26% and 28.2%, respectively). Thirteen cases of candidemia were recorded and five additional cases were found in the literature. Hematogical malignancy was the main underlying disease ( n = 12). Associated factors were the presence of a vascular catheter ( n = 18), broad-spectrum antibiotics ( n = 15), and neutropenia ( n = 14). In 13 cases (72%), prior colonization was noted before the candidemia diagnosis. Combining the results for the two species, Minimal Inhibitory Concentrations (MIC50) of amphotericin B, fluconazole, voriconazole and caspofungin were 0.125, 48, 0.25, and 0.19 mg/l, respectively. These two species must be added to the growing list of emerging Candida species poorly susceptible to fluconazole. [ABSTRACT FROM AUTHOR]

Background: Gemtuzumab ozogamicin (GO) is a cytotoxic anti-CD33 monoclonal antibody that has given promising preliminary results in adult myeloid CD33+ AML. We conducted a retrospective multicenter study of 12 children treated with GO on a compassionate basis (median age 5.5 y). Three patients (2 MDS/AML, 1 JMML) were refractory to first-line treatment, 8 patients with de novo AML were in refractory first relapse, and one patient with de novo AML was in 2nd relapse after stem cell transplantation (SCT). CD33 expression exceeded 20% in all cases. Methods: GO was administered alone, at a unit dose of 3-9 mg/m2, once (3 patients), twice (3 patients), three (5 patients) or five times (1 patient). Mean follow-up was 128 days (8-585 d). Results: There were three complete responses (25%) leading to further curative treatment (SCT). Treatment failed in the other nine patients, and only one patient was alive at the end of follow-up. NCI-CTC grade III/IV adverse events comprised hematological toxicity (n = 12), hypertransaminasemia (n = 2), allergy and hyperbilirubinemia (1 case each). There was only one major adverse event (grade IV allergy). No case of sinusoidal obstruction syndrome occurred. Conclusion: These results warrant a prospective trial of GO in a larger population of children with AML. [ABSTRACT FROM AUTHOR]

We have previously introduced the concept of high proliferative potential-quiescent (HPP-Q) cells to refer to primitive human hematopoietic progenitors, on which transforming growth factor-β1 (TGF-β1) exerts a pleiotropic effect. TGF-β1 confers to these slow-dividing cells a mitogenic receptor[sup low] phenotype and maintains immature properties by preventing differentiation and apoptosis. However, the effect of TGF-β1 on long-term expansion has not yet been clearly demonstrated. Here, we describe the characterization of a human skin keratinocyte subpopulation, highly enriched for primitive epidermal precursors, on the basis of high adhesion capacity (Adh[sup +++]) and low expression of the epidermal growth factor receptor (Adh[sup +++]EGF-R[sup low]). In our standard culture condition without feeder cells, the mean estimated output for cells from an unfractionated population of primary foreskin keratinocytes was 10[sup 7]-10[sup 8], increasing to 10[sup 12]-10[sup 13] in cultures initiated with selected Adh[sup +++]EGF-R[sup low] precursors. Characterization of these cells revealed a hitherto unknown property of TGF-β1: its addition at a very low concentration (10 pg/ml) in long-term cultures induces a very significant additional increase of expansion. In this optimized system, outputs obtained in cultures initiated with Adh[sup +++]EGF-R[sup low] cells repeatedly reached 10[sup 16]-10[sup 17] (∼60 population doublings, ∼4×10[sup 18] keratinocytes produced per clonogenic cell present in the initial population). At the molecular level, this effect is associated with an increase in Smad1, Smad2 and Smad3 phosphorylation and an increase in α6 and β1 integrin expression. No such effect could be observed on mature keratinocytes with low adhesion capacity (Adh[sup -/+]). We finally demonstrated that the progeny of Adh[sup +++]EGF-R[sup low] precursors after long-term expansion is still capable of generating a pluristratified epidermis in a model for skin reconstruction. In conclusion, after further characterizing the phenotype of primitive epidermal precursors, we demonstrated a new function of TGF-β1, which is to promote undifferentiated keratinocyte amplification. [ABSTRACT FROM AUTHOR]

This document provides a summary of a study on the treatment of infants with acute lymphoblastic leukemia (ALL). The study found that very late relapses in infants with a specific genetic mutation (KMT2A-) were rare but had a favorable outcome. All patients achieved a second complete remission after treatment, and those who received a hematopoietic stem cell transplant had promising long-term results. The use of effective first-line therapies, such as blinatumomab, is expected to reduce the overall relapse rate in infants with ALL. The study was conducted in accordance with ethical principles and informed consent was obtained from all legal guardians. [Extracted from the article]

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.) [ABSTRACT FROM AUTHOR]