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Objective. To study risk factors, etiology, clinical signs and treatment outcomes of invasive aspergillosis (IA) and mucormycosis combination (IAM) in children. Materials and Methods. A retrospective review of Saint-Petersburg register (1998–2021) of patients with IA was done and children with IAM were included. EORTC/MSGERG 2019 criteria were used for diagnosing and treatment results evaluation of invasive mycosis. We presented a clinical case of IAM in a child with acute lymphoblastic leukemia relapse. Results. A total of 12 children with IAM were included. They accounted 8% of all pediatric patients with invasive aspergillosis (n = 152). IAM was diagnosed in children with hematological malignancies and solid tumors from 4 to 16 years (median age – 11.5 years), mostly in girls (83%). Main risk factors of IAM were prolonged lymphopenia (75%, median 22 days) and neutropenia (67%, median 30 days) due to chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. The predominant etiological agents of IA were Aspergillus niger (33%), A. nidulans (33%) and A. fumigatus (17%), of mucormycosis – Lichtheimia corymbifera (50%) and Rhizomucor spp. (50%). Based on EORTC/MSGERG 2019 criteria, «proven» mucormycosis was diagnosed in 83% of patients, «probable» – in 17%. «Probable» IA was found in 100% of patients. The most common clinical sites of IAM were the lungs (75%) and paranasal sinuses (43%), multifocal involvement was revealed in 33% of patients. Mucormycosis developed during antifungal therapy of IA in 83% of patients. Antifungal therapy of mucormycosis received 75% of patients (amphotericin B lipid complex – 89%, posaconazole – 78%, caspofungin – 33%), combined antifungal therapy – 33%, surgery – 50%; combination of surgical and antifungal treatment was used in 42% of patients. The overall 12-week survival was 77.8%. The use of combined surgical and antifungal treatment significantly improved the survival of children with IAM (p = 0.023). Conclusions. Mucormycosis was diagnosed in 8% of children with IA. IAM developed mostly in patients with hematological malignancies (83%), prolonged lymphopenia (75%) and neutropenia (67%) against the background of chemotherapy, systemic corticosteroids and/or immunosuppressive therapy, as well as HSCT. In 83% of patients mucormycosis was diagnosed during antifungal therapy for IA. The development of IAM increased overall 12-week mortality (50%). The combination of antifungal therapy with surgical treatment significantly improved prognosis of IAM (p = 0.023).

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Mast cell leukemia (MCL) is a very rare form of aggressive systemic mastocytosis accounting for < 1% of all mastocytosis. Mastocytosis is a broad term used for a group of clonal disorders characterized by accumulation of mast cells in the skin with or without extracutaneous involvement. The clinical spectrum of the disease varies from only cutaneous lesions to highly aggressive systemic involvement such as MCL. Mastocytosis can present from birth to adulthood. In children, mastocytosis is usually benign, and there is a good chance of spontaneous regression at puberty, unlike adult-onset disease, which is generally systemic and more severe. Individuals with systemic mastocytosis may be at risk of developing hematologic malignancies. MCL diagnosis requires the presence of SM criteria with additional features including leukemic infiltration of bone marrow and/or blood by at least 20% high-grade MC as well as the infiltration of extracutaneous organs by neoplastic MC. Genetic aberrations, mainly the KIT D816V mutation, play a crucial role in the pathogenesis of mastocytosis and are detected in most patients. To date, there is no approved standard therapy. For MCL, few options are available for treatment and because of the rarity of the disease very few clinical trials address the question. Even if SM occurs occasionally, all children with mastocytosis require planned follow-up over time. We present an overview of literature on MCL and a rare case of MCL diagnosed in a 4-year-old girl who had had cutaneous mastocytosis since early childhood. A bone marrow examination revealed MCL. She ultimately died despite chemotherapy. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Acute lymphoblastic leukemia (ALL) in infants (less than 1 year old) is a unique tumor with distinct biological features and poor outcome even when modern treatment schemes are used. Rearrangementsof MLL-gene, located in 11q23 region, are detected in approximately 75-80% of infants with ALL and lead to treatment resistance and high relapse rate. Nevertheless patients with germline MLL also demonstrate inferior outcome compared to ALL in older children. Thus additional risk factors implementation is one of the crucial points in infant ALL management. Minimal residual disease (MRD) measurement by multicolor flow cytometry (FCM) or various PCR technics is a well-standardized method of treatment response evaluation in childhood ALL, although in infants MRD data is not so widely applied. The aim of the study was to evaluate the relapse prediction feasibility in infant ALL by FCM MRD assessment during remission induction of MLL-Baby protocol. Methods. Totally 89 infants aged from 5 days to 11 months were enrolled in the present study. In 23 cases (25.8%) MLL gene was germline (MLL-g group), 33 patients (37.1%) had MLL-AF4 fusion while in remaining 33 cases (37.1%) other types of MLL-rearrangements were found. All patients were diagnosed as B-cell precursor ALL and all were treated by well established in Russia and Belarus MLL-Baby protocol, which is specially designed for infant ALL management. MRD was measured by 6-10-color FCM in bone marrow (BM) samples obtained at day 15 and at the end of remission induction (day 36). The availability of samples at at least one of these time-points was the only criteria for study group completion. In 43 patients with known types of MLL-rearrangements MRD was also assessed by fusion gene transcript (FGT) detection in RQ-PCR after first consolidation or first high risk block (for intermediate risk and high risk groups respectively). Relapse risk was investigated by cumulative incidence of relapse (CIR) estimation. Median of follow-up was 3 years 10 months. Results. Finally at day 15 MRD was studied in 71 cases. 17 patients (23.9%) were tested MRD-negative while remaining ones displayed various levels of MRD-positivity: 8 cases (11.3%) - from 0.01% to 0.1%; 14 (19.7%) - from 0.1% to 1%; 22 (31.0%) - from 1% to 10%; 10 (14.1%) - more than 10%. Proportion of MRD-positivity was lower in MLL-g group compared to MLL-rearranged (MLL-r) patients (58.8% and 81.5% respectively, p=0.06). Prognostic impact of day 15 MRD differed due to MLL-status. In MLL-r group significant differences between MRD(+) and MRD(-) patients were observed (n=10, CIR 0.28(0.18) and n=37, CIR 0.67(0.08) respectively, p=0.025). At the same time in MLL-g group these outcome differences were not significant (n=7, CIR 0 and n=9, CIR 0.22(0.14) correspondingly, p=0.197). Interestingly, in patients carrying MLL-AF4 fusion, known to be one of the most adverse types of MLL-rearrangements, day 15 MRD-negativity predicted low relapse incidence (n=5, CIR 0 and n=16, CIR 0.68(0.12) respectively, p=0.045). Thus day 15 MRD-negativity allows to detect low-risk MLL-r infants but it is not applicable in MLL-g group. It was previously shown that any detectable level of FGT after first consolidation or first high risk block predicts very poor outcome in MLL-r cases (G. Tsaur et al, ASH-2011). In current series RQ-PCR data in patients, FCM MRD(+) at day 15, distinguished groups of intermediate and very high relapse risk (n=17, CIR 0.51(0.13) and n=18, CIR 0.84(0.09) respectively, p=0.017). At day 36 FCM MRD was assessed in 82 infants. Among them 35 (42.7%) were tested negative while remaining 47 (57.3%) were MRD(+) at various levels. Prognostic value of day 36 FCM MRD data in MLL-r group was not significant: MRD(+) patients (n=23) had CIR of 0.71(0.08) while in MRD(-) cases (n=33) CIR was 0.49(0.12), p=0.153. Conversely, in MLL-g group low end-induction MRD (less than 0.1%) lead to excellent outcome compared to patients with higher MRD (n=14, CIR 0 and n=7, CIR 0.22(0.20) respectively, p=0.010). Conclusions. Thus FCM MRD data could distinguish infants with low risk of ALL relapse, but in MLL-r and MLL-g groups different time-points are prognosticaly significant. In MLL-g patients tandem application of FCM at early time-point and RQ-PCR later could help to define groups with low, intermediate and high relapse risk. MRD data could be added to MLL-Baby protocol risk group stratification, which is currently based on type of MLL-rearrangement. Disclosures No relevant conflicts of interest to declare.

Acute lymphoblastic leukemia (ALL) in infants is a relatively rare disease with peculiar biological features, high frequency of KMT2A gene rearrangements and grim prognosis. Even with new therapeutic approaches, event-free survival (EFS) in infants with ALL does not exceed 50%. Currently large cooperative studies of infant ALL have been promoted by the Interfant and MLL-Baby networks. Minimal residual disease (MRD) monitoring is considered a strong tool for optimizing management of childhood ALL. In contrast to older children in this age group the prognostic impact of MRD detected by multicolor flow cytometry (MFC) is still unclear. Aim of the present study was to evaluate the prognostic value of MFC MRD measurement during induction in infants with ALL treated with Interfant-99 and Interfant-06 protocols in AIEOP centers in Italy as well as MLL-Baby protocol in Russia and Belarus. Patients and methods. Two independent groups of patients were investigated: study cohort of 139 consecutive infants with newly diagnosed ALL enrolled between September 2003 and April 2016 in Russian and Belorussian centers with MLL-Baby protocol and validation group of 146 ones enrolled in AIEOP centers in Interfant trials during the same period. By availability of MFC MRD data obtained at day 15 and/or end of induction (EOI), 81 and 86 patients of study and validation cohorts respectively were selected for outcome evaluation. In 61 MLL-Baby patients (75.3%) and 61 AIEOP cases (70.9%) different types of KMT2A gene rearrangements were identified. All patients were diagnosed as BCP-ALL, except one with cortical T-ALL. Overall, day 15 samples were studied in 64 MLL-Baby patients and 73 AIEOP cases while EOI samples in 75 and 63 cases respectively. MRD detection was performed in Reference Laboratories in Ekaterinburg, Minsk and Padua according the BFM AIEOP FLOW Network SOP. MRD negativity was defined as <0.01% of all bone marrow nucleated cells. Results. Patients were stratified according to the AIEOP-BFM-ALL day 15 stratification usually used for older children into three risk groups: standard risk (SR: MRD<0.1%), intermediate risk (IR: MRD 0.1% to 10%) and high risk (HR: MRD≥10%). Patients' distribution was similar in both study and validation cohorts: 34.4% and 32.9% in SR, 53.1% and 54.5% in ImR, 12.5% and 12.3% in HR respectively. At EOI significant differences in MRD-positive and MRD-negative patients' distribution was observed in different protocols: 44 (58.7%) and 31 (41.3%) cases respectively for MLL-Baby, but 17 (27.0%) and 46 (73.0%) cases respectively for AIEOP group. It was observed that KMT2A-rearranged cases in both trials have slower MRD response compared to the children with wild type KMT2A. In study cohort the 22 SR patients had a 5-year EFS and cumulative incidence of relapse (CIR) significantly better than other ones, thus we considered two major groups of patients with different outcome: SR with 5-year EFS 67.4%, standard error (SE) 10.2; CIR 23.3%, SE 9.4 and non-SR with 5-year EFS 30.8%, SE 7.2; CIR 52.6%, SE 7.9, (p=0.0039 and p=0.0229, respectively). Difference between these groups was observed also in KMT2A-rearranged cases (n=49) both for 5-year EFS (60.0%, SE 12.7 and 23.2%, SE 7.3, p=0.0160) and in 5-year CIR (33.3%, SE 12.7 and 59.2%, SE 8.8, p=0.0881). Analysis of outcome in validation cohort confirmed these data. In study cohort outcome of children being MRD-negative at EOI (n=31, 5-year EFS 60.8%, SE 8.8 and CIR 29.3%, SE 8.4) was significantly better than that of MRD-positive patients (n=44, 5-year EFS 31.1%, SE 7.1 and CIR 57.6%, SE 7.8 with p=0.0153 and p=0.0267, respectively). Outcome by EOI MFC MRD in the validation cohort is generally in keeping with that of the study cohort. Interestingly, in AIEOP cohort MFC data showed a prognostic impact also in KMT2A-rearranged subgroup. In multivariate analysis with KMT2A-status, each MRD time-point data showed independent impact on the risk of relapse. Conclusion. Our data was obtained by well-harmonized MFC MRD monitoring in a large group of infants with ALL treated in a multicenter setting with two different protocols. In spite of differences in therapy, we observed strong and independent prognostic impact of MFC MRD both at day 15 and at EOI regardless the protocol applied. We can conclude that MFC MRD can be used in combination with KMT2A-status to improve treatment allocation in future protocols. Disclosures Parasole: Servier: Honoraria; Baxalta: Honoraria; Eusapharma: Honoraria. Pieters:jazz farmaceuticals: Consultancy; medac: Consultancy.