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PURPOSE A previous study by the International Berlin-Frankfurt-Münster Study Group (I-BFM-SG) on childhood KMT2A-rearranged ( KMT2A-r) AML demonstrated the prognostic value of the fusion partner. This I-BFM-SG study investigated the value of flow cytometry-based measurable residual disease (flow-MRD) and evaluated the benefit of allogeneic stem-cell transplantation (allo-SCT) in first complete remission (CR1) in this disease. METHODS A total of 1,130 children with KMT2A-r AML, diagnosed between January 2005 and December 2016, were assigned to high-risk (n = 402; 35.6%) or non–high-risk (n = 728; 64.4%) fusion partner-based groups. Flow-MRD levels at both end of induction 1 (EOI1) and 2 (EOI2) were available for 456 patients and were considered negative (RESULTS The high-risk group had inferior EFS (30.3% high risk v 54.0% non-high risk; P < .0001), CIR (59.7% v 35.2%; P < .0001), and OS (49.2% v 70.5%; P < .0001). EOI2 MRD negativity was associated with superior EFS (n = 413; 47.6% MRD negativity v n = 43; 16.3% MRD positivity; P < .0001) and OS (n = 413; 66.0% v n = 43; 27.9%; P < .0001), and showed a trend toward lower CIR (n = 392; 46.1% v n = 26; 65.4%; P = .016). Similar results were obtained for patients with EOI2 MRD negativity within both risk groups, except that within the non–high-risk group, CIR was comparable with that of patients with EOI2 MRD positivity. Allo-SCT in CR1 only reduced CIR (hazard ratio, 0.5 [95% CI, 0.4 to 0.8]; P = .00096) within the high-risk group but did not improve OS. In multivariable analyses, EOI2 MRD positivity and high-risk group were independently associated with inferior EFS, CIR, and OS. CONCLUSION EOI2 flow-MRD is an independent prognostic factor and should be included as risk stratification factor in childhood KMT2A-r AML. Treatment approaches other than allo-SCT in CR1 are needed to improve prognosis.

As treatments for second relapsed and refractory first relapsed paediatric AML transition from purely palliative to more commonly curative in nature, comparative data is necessary for evaluating the effectiveness of emerging treatment options. Furthermore, little is known about predictors of prognosis following third-line therapy. From 2004 until 2019, 277 of the 869 patients enrolled in NOPHO-DB SHIP consortium trials experienced a first relapse and, of these patients, 98 experienced refractory first relapse and 59 a second relapse. Data on patient and disease characteristics within this cohort of 157 patients was analysed to determine probability of overall survival (pOS) and to identify factors influencing survival. Data on early treatment response and complete remission were not available. One and 5-year pOS were 22 ± 3% and 14 ± 3%, respectively. There was no statistically significant difference in survival between refractory first relapsed and second relapsed AML. Factors influencing prognosis included: late relapse, type of third-line treatment, FLT3 mutational status, and original treatment protocol. These data provide a baseline for evaluating the effectiveness of emerging therapies for the treatment of children with refractory first relapsed and second relapsed paediatric AML and evidence that select patients receiving third-line therapy can be cured.

Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between 2000-2021. Median time from diagnosis to relapse was 6.8 (range 1.1 - 45.5) months. Three-year event-free (EFS) and overall survival (OS) were 20.9±5.3% and 22.1±5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (HR 0.28), duration of first complete remission (CR1) (HR 0.31 for > 12 months) and attainment of remission after relapse (HR 4.03). Patients who achieved CR prior to HSCT, had an improved OS and EFS of 56.0±11.8% and 50.5±11.9% respectively, compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0±9.5%). Treatment failure after HSCT was predominantly due to disease recurrence (52%) followed by treatment related mortality (10%). The prognosis of r/r ML-DS remains dismal even in the current treatment period and serve as a reference point for current prognostication and future interventional studies. Clinical trials aimed at improving the survival of patients with r/r ML-DS are needed.

Mucormycosis has emerged as an increasingly important cause of morbidity and mortality in immunocompromised patients, but contemporary data in children are lacking. We conducted a nationwide multicentre study to investigate the characteristics of mucormycosis in children with haematological malignancies. The cohort included 39 children with mucormycosis: 25 of 1136 children (incidence 2·2%) with acute leukaemias prospectively enrolled in a centralized clinical registry in 2004-2017, and an additional 14 children with haematological malignancies identified by retrospective search of the databases of seven paediatric haematology centres. Ninety-two percent of mucormycosis cases occurred in patients with acute leukaemias. Mucormycosis was significantly associated with high-risk acute lymphoblastic leukaemia (OR 3·75; 95% CI 1·51-9·37; P = 0·004) and with increasing age (OR 3·58; 95% CI 1·24-9·77; P = 0·01). Fifteen patients (38%) died of mucormycosis. Rhinocerebral pattern was independently associated with improved 12-week survival (OR 9·43; 95% CI 1·47-60·66; P = 0·02) and relapsed underlying malignancy was associated with increased 12-week mortality (OR 6·42; 95% CI, 1·01-40·94; P = 0·05). In patients receiving frontline therapy for their malignancy (n = 24), one-year cumulative mucormycosis-related mortality was 21 ± 8% and five-year overall survival was 70 ± 8%. This largest paediatric population-based study of mucormycosis demonstrates that children receiving frontline therapy for their haematological malignancy are often salvageable.

Background Osteonecrosis is a major cause of acute and long-lasting complications of acute lymphoblastic leukemia (ALL) therapy in children. Our study aimed to evaluate the prevalence, characteristics, risk factors, and outcome of osteonecrosis in children with ALL. Procedure The cohort included 559 children aged 1-20 years diagnosed with ALL between 2003 and 2018 at two tertiary medical centers in Israel and enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. Symptomatic osteonecrosis was prospectively captured as an adverse event. Results Osteonecrosis occurred in 51 patients (9.1%). Ninety-four percent of the events were graded as moderate or severe (grades 3-4, Ponte di Legno Toxicity Working Group classification) and multiple bone involvement was common. Full resolution of osteonecrosis was documented in only 16% of the children (median follow-up 4.2 years). Stepwise logistic regression identified five risk factors for osteonecrosis, with a high predictive value (AUC = 0.88): older ageat ALL diagnosis, high-risk ALL group, T-cell immunophenotype, female gender, and a novel risk factor: bone pain at the time of leukemia diagnosis. In addition, osteonecrosis was less common among children of Arab ethnicity. Thrombophilia and an elevated age-adjusted body mass index were not confirmed as risk factors for osteonecrosis. Conclusion Due to the low rates of osteonecrosis resolution and its debilitating long-term impact, the identification of patients at high risk for osteonecrosis is important for their inclusion in further studies evaluating potential therapeutic adjustments.

Background: Mucormycosis is a life-threatening infection with a tendency for angioinvasion that may lead to progressive dissemination. Disseminated mucormycosis, defined as the involvement of two or more non-contiguous sites, is rare in children, and data concerning its management and outcome are scarce. The aim of this study was to assess the contemporary management strategies and outcomes of disseminated mucormycosis in the pediatric population. Methods: We conducted a retrospective search in six large tertiary medical centers for all cases of disseminated mucormycosis that occurred between 2009–2020 in patients aged 1–20 years. Results: Twelve cases were identified. Underlying conditions included hematological malignancies (n = 10), solid tumor (post-autologous hematopoietic stem cell transplantations, n = 1), and solid organ (liver) transplantation (n = 1). In all cases, amphotericin B formulations were administered as first-line therapy, in eight cases, they were also administered in combination with an echinocandin or triazole. Seven patients underwent surgical debridement procedures. The six-week mortality was 58%. Among the patients diagnosed between 2009–2015, one of the six survived, and of those diagnosed between 2016–2020, four of the six were salvaged. Conclusions: Disseminated mucormycosis is a life-threatening and often fatal disease, and improved diagnostic and therapeutic strategies are needed. Nevertheless, in this population-based study, five patients (42%) were salvaged through combined liposomal amphotericin/triazole treatment and extensive surgical interventions.

Venous thromboembolism (VTE) is a serious complication of acute lymphoblastic leukemia (ALL) therapy. The aim of this population-based study was to evaluate the rate, risk factors, and long-term sequelae of VTE in children treated for ALL. The cohort included 1191 children aged 1&ndash, 19 years diagnosed with ALL between 2003&ndash, 2018, prospectively enrolled in two consecutive protocols: ALL-IC BFM 2002 and AIEOP-BFM ALL 2009. VTEs occurred in 89 patients (7.5%). Long-term sequelae were uncommon. By univariate analysis, we identified four significant risk factors for VTEs: Severe hypertriglyceridemia (p = 0.005), inherited thrombophilia (p &lt, 0.001), age &gt, 10 years (p = 0.015), and high-risk ALL group (p = 0.039). In addition, the incidence of VTE was significantly higher in patients enrolled in AIEOP-BFM ALL 2009 than in those enrolled in ALL-IC BFM 2002 (p = 0.001). Severe VTE occurred in 24 children (2%), all of whom had at least one risk factor. Elevated triglyceride levels at diagnosis did not predict hypertriglyceridemia during therapy. In a multivariate analysis of 388 children, severe hypertriglyceridemia and inherited thrombophilia were independent risk factors for VTE. Routine evaluation for these risk factors in children treated for ALL may help identify candidates for intervention.

Background Immunocompromised children are at high risk of rapid deterioration and of developing life-threatening pulmonary infections. Etiologies in this setting are diverse, including those that are infectious and noninfectious, and many etiologies may coexist. Accurate diagnosis is required for the rational use of medications. Fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) can identify infectious causes in this population. Objectives The aims of this study were to evaluate diagnostic rate, safety, and changes in treatment following FOB with BAL, when applied with advanced laboratory diagnostic techniques. Patients and methods We reviewed the records of children who underwent FOB with BAL during the period spanning from 2006 to 2014 in the Hematology-Oncology Department. BAL samples were processed in microbiology, virology, cytology, and molecular laboratories. Results Antimicrobials were initiated in 91 of 117 children. BAL yielded an infectious etiology in 55 episodes. Management was altered in 74 patients following a positive (40/55) or a negative (30/54) result (4 patients had missing data). No severe complications associated with the procedures occurred. Conclusions Most immunocompromised patients with pulmonary manifestations are treated empirically with multiple medications. Evaluation FOB/BAL is a useful diagnostic tool, and seems to have changed the course of therapy in more than half of patients, by initiation or cessation of treatment. FOB/BAL is a safe diagnostic tool for the evaluation of pulmonary manifestations in this setting.

Introduction KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) is a heterogeneous genetic subgroup with a frequency of about 25% in children with AML. At the 62 nd ASH annual meeting last year, we reported on the differences in outcome of various KMT2A subgroups based on translocation partner and the significance of minimal residual disease (MRD) status during and after induction as a follow-up study of Balgobind et al., Blood 2009. The impact of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) and the presence of additional cytogenetic aberrations (ACAs) on prognosis have not yet been described for our cohort. Methods Data on allo-HSCT in CR1 and the presence of ACAs of 1256 KMT2A-r de novo pediatric AML patients from 15 AML study groups affiliated with the I-BFM Study Group, diagnosed between 2005 and 2016, were retrospectively collected and studied. Karyotypes were reviewed and classified by two of the authors (RW&CH). Based on translocation partners, patients were classified to the KMT2A high-risk subgroup (6q27, 10p11.2, 10p12, 4q21, and 19p13.3) or non-high-risk subgroup (9p22, 19p13, 19p13.1, 1q21, Xq24, 17q21, 1p32, and 17q12). These two categories have been used to estimate a Cox model. Patients with unknown translocation partners were excluded from these analyses (n=126). Flow cytometry MRD levels at the end of induction course 1 (EOI1) and 2 (EOI2) Results Of 1256 pediatric patients with KMT2A-r AML, data on HSCT in CR1 and ACAs were available for 1186 (94.4%) and 1204 patients (95.9%), respectively; 211 (17.8%) patients received HSCT in CR1 and ACAs were present in 601 (49.9%) patients. Compared with the KMT2A non-high-risk subgroup, patients in the KMT2A high-risk subgroup underwent HSCT in CR1 more often (23.8% vs 15.0%; P < .001). ACAs were borderline significantly more common in the KMT2A high-risk subgroup (54.1% vs 46.4%; P = .015). Univariate analysis of the probability of DFS (Table 1) showed that the KMT2A high-risk subgroup (HR 2.1; 95% CI, 1.7-2.5), age ≥10 years (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 1.5; 95% CI, 1.1-1.9) were associated with DFS. HSCT in CR1 was a borderline significant prognostic factor (HR 0.7; 95% CI, 0.6-0.9). In a multivariate analysis for DFS (n=515) (Table 1), the KMT2A high-risk subgroup (HR 2.0; 95% CI, 1.6-2.6), MRD ≥0.1 at EOI1 (HR 1.7; 95% CI, 1.2-2.3), and HSCT in CR1 (HR 0.6; 95% CI, 0.4-0.9) were associated with DFS. Univariate analysis of the probability of OS (Table 1) showed that the KMT2A high-risk subgroup (HR 1.8; 95% CI, 1.5-2.2), age ≥10 years (HR 1.6; 95% CI 1.3-2.0), WBC ≥100 x10 9/L (HR 1.4; 95% CI, 1.1-1.7), the presence of ACAs (HR 1.4; 95% CI, 1.2-1.7), and MRD ≥0.1 at EOI1 (HR 2.1; 95% CI, 1.6-2.7) were associated with OS. HSCT in CR1 was not associated with OS. The effect of HSCT in CR1 was not significantly different between the KMT2A high-risk and non-high-risk subgroups. In a multivariate analysis for OS (n=557) (Table 1), the KMT2A high-risk subgroup (HR 1.9; 95% CI, 1.4-2.5), age ≥10 years (HR 1.5; 95% CI, 1.1-1.9), the presence of ACAs (HR 1.6; 95% CI, 1.2-2.1), and MRD positivity at EOI1 (HR 1.9; 95% CI, 1.4-2.5) were associated with OS. Conclusions In this cohort of KMT2A-r pediatric AML patients, the presence of ACAs at diagnosis was independently associated with inferior OS, but not with DFS. This may be due to the exclusion of refractory patients in DFS analysis, who were significantly more common in the group of patients with ACAs. Analysis has yet to be performed to distinguish karyotype complexity. In addition, allo-HSCT in CR1 was an independent predictor of improved DFS, but was not a prognostic factor for OS. Figure 1 Figure 1. Disclosures Abrahamsson: wedish Children´s Cancer Foundation. Research grants and 50% senior research position for clinical research on pediatric leukemia: Research Funding. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau.

To study the prognostic relevance of rare genetic aberrations in acute myeloid leukemia (AML), such as t(16;21), international collaboration is required. Two different types of t(16;21) translocations can be distinguished: t(16;21)(p11;q22), resulting in the FUS-ERG fusion gene; and t(16;21)(q24;q22), resulting in RUNX1-core binding factor (CBFA2T3). We collected data on clinical and biological characteristics of 54 pediatric AML cases with t(16;21) rearrangements from 14 international collaborative study groups participating in the international Berlin-Frankfurt-Münster (I-BFM) AML study group. The AML-BFM cohort diagnosed between 1997 and 2013 was used as a reference cohort. RUNX1-CBFA2T3 (n = 23) had significantly lower median white blood cell count (12.5 × 109/L, P = .03) compared with the reference cohort. FUS-ERG rearranged AML (n = 31) had no predominant French-American-British (FAB) type, whereas 76% of RUNX1-CBFA2T3 had an M1/M2 FAB type (M1, M2), significantly different from the reference cohort (P = .004). Four-year event-free survival (EFS) of patients with FUS-ERG was 7% (standard error [SE] = 5%), significantly lower compared with the reference cohort (51%, SE = 1%, P < .001). Four-year EFS of RUNX1-CBFA2T3 was 77% (SE = 8%, P = .06), significantly higher compared with the reference cohort. Cumulative incidence of relapse was 74% (SE = 8%) in FUS-ERG, 0% (SE = 0%) in RUNX1-CBFA2T3, compared with 32% (SE = 1%) in the reference cohort (P < .001). Multivariate analysis identified both FUS-ERG and RUNX1-CBFA2T3 as independent risk factors with hazard ratios of 1.9 (P < .0001) and 0.3 (P = .025), respectively. These results describe 2 clinically relevant distinct subtypes of pediatric AML. Similarly to other core-binding factor AMLs, patients with RUNX1-CBFA2T3 rearranged AML may benefit from stratification in the standard risk treatment, whereas patients with FUS-ERG rearranged AML should be considered high-risk.

Introduction Outcome of KMT2A-rearranged (KMT2A-r) pediatric AML (pAML) is in general poor with a 5-year probability of event-free survival (5y-pEFS) and overall survival (5y-pOS) of 44% and 56%, respectively (Balgobind et al., 2009). However, over the past decades, the heterogeneity of KMT2A-r pAML has emerged, showing differences in outcome between subgroups based on translocation partners. The predictive value of MRD in KMT2A-r pAML is undefined. This retrospective study aimed to confirm the outcome of pediatric KMT2A subgroups (Balgobind et al., 2009) in a more recent era and to study the significance of MRD status during and after induction. Methods Outcome and MRD data of 1257 KMT2A-rde novo pAML patients from 15 AML groups affiliated with the I-BFM-AML study group, diagnosed between 2005 and 2016 were retrospectively collected. Patients were assigned to KMT2A subgroups, or to the KMT2A-other group in case of unknown translocation partner. Flow cytometry MRD levels Results The 1257 patients were assigned to 13 KMT2A subgroups, or the KMT2A-other group. Two novel subgroups were identified: t(X;11)(q24;q23) (n=21, 2%) and t(1;11)(p32;q23) (n=12, 1%). The median age was 2.5 years (range, 0-18.9). The median WBC was 21.4 x 109/L (range, 0.2-727). Overall complete remission rate was 91%. The 5y-pEFS was 46% [SE, 2%] and the 5y-pOS was 62% [SE, 2%]. Differences across subgroups in 5y-pEFS (Figure 1) ranged from 24% [SE, 5%] to 76% [SE, 9%], and in 5y-pOS from 25% [SE, 13%] to 92% [SE, 8%] (both p The subgroups t(10;11)(p12;q23) (HR 1.7, p100 x 10^9/L (HR 1.3, p=.006), and age >10y (HR 1.3, p=.005) were revealed as independent predictors of poor EFS. These factors also predicted OS. MRD data after induction course one were available for n=635 (MRD-positivity (range, 0.1-94) n=126, 20%) and after course two for n=527 (MRD-positivity (range, 0.1-88) n=51, 10%). In the four KMT2A poor-risk subgroups, MRD-positivity was not significantly more common after induction course one (p=.0232) or two (p=.066), compared with the other subgroups. MRD-positivity was associated with inferior 5y-pDFS after both induction course one (36% [SE, 4%] vs 48% [SE, 2%]; p=.002) and course two (28% [SE, 6%] vs 49% [SE, 2%]; p10y (HR 1.5, p=.002) were revealed as independent predictors of poor DFS. Within the group of patients with MRD-negativity after induction course two, the subgroups t(10;11)(p12;q23) and t(10;11)(p11.2;q23) were independent predictors of poor EFS (5y-pEFS 35%, HR 1.7, p=.003 and 5y-pEFS 18%, HR 2.7, p=.004, respectively). Conclusion Outcome for KMT2A-r pAML patients has improved slightly, but similar subgroups were identified as poor risk (Balgobind et al., 2009), including t(10;11)(p12;q23), t(10;11)(p11.2;q23) and t(6;11)(q27;q23). In our study, t(4;11)(q21;q23) was poor risk as well. These subgroups should be considered for high-risk pAML therapy protocols. The favorable risk of t(1;11)(q21;q23) could not be confirmed in our cohort. MRD status is highly predictive of outcome within KMT2A subgroups. In MRD-negative patients after induction course two, both t(10;11) KMT2A subgroups were associated with poor outcome. Disclosures Guest: Syndax Pharmaceuticals: Consultancy. Locatelli:Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceeutical: Speakers Bureau. Rubnitz:AbbVie Inc.: Research Funding. Kaspers:Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months; AbbVie: Ended employment in the past 24 months.

ABL-class fusions other than BCR-ABL1 characterize around 2-3% of precursor B-cell acute lymphoblastic leukemia. Case series indicated that patients suffering from these subtypes have a dismal outcome and may benefit from the introduction of tyrosine kinase inhibitors. We analyzed clinical characteristics and outcome of 46 ABL-class fusion positive cases other than BCR-ABL1 treated according to AIEOP-BFM (Associazione Italiana di Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Munster) ALL 2000 and 2009 protocols; 13 of them received a tyrosine kinase inhibitor (TKI) during different phases of treatment. ABL-class fusion positive cases had a poor early treatment response: minimal residual disease levels of ≥5×10-4 were observed in 71.4% of patients after induction treatment and in 51.2% after consolidation phase. For the entire cohort of 46 cases, the 5-year probability of event-free survival was 49.1+8.9% and that of overall survival 69.6+7.8%; the cumulative incidence of relapse was 25.6+8.2% and treatment-related mortality (TRM) 20.8+6.8%. One out of 13 cases with TKI added to chemotherapy relapsed while eight of 33 cases without TKI treatment suffered from relapse, including six in 17 patients who had not received hematopoietic stem cell transplantation. Stem cell transplantation seems to be effective in preventing relapses (only three relapses in 25 patients), but was associated with a very high TRM (6 patients). These data indicate a major need for an early identification of ABL-class fusion positive acute lymphoblastic leukemia cases and to establish a properly designed, controlled study aimed at investigating the use of TKI, the appropriate chemotherapy backbone and the role of hematopoietic stem cell transplantation. (Registered at: clinicaltrials.gov identifier: NTC00430118, NCT00613457, NCT01117441).

BACKGROUND Therapy outcomes for childhood acute lymphoblastic leukemia (ALL) had substantially improved in the last decades, but variability across racial and ethnic groups was identified in some clinical studies. In this study, we aimed to investigate whether such a difference in outcome is found in the diverse ethnicities in Israel as well. METHODS A retrospective study was conducted among 1154 patients (855 Jews, 195 Muslims, 52 Bedouins, 26 Druze, and 26 others) aged 1 to 21 years, who were diagnosed with ALL between 1989 and 2011 and were treated according to the same Berlin-Frankfurt-Muenster-based Israel National Study protocols. RESULTS Bedouins had a higher incidence of t(1;19) (16% vs 3% for non-Bedouins) and a lower incidence of high-hyperdiploidy (10% vs 25% for non-Bedouins) (P = 0.01). Five-year event-free survival (EFS) and overall survival (OS) were poorer for the Bedouins (60.3% ± 7.2% and 63.1% ± 7.2%, respectively) compared with the Jews, Muslims, and Druze (80.4% ± 1.4%, 77.3% ± 3.2%, and 84% ± 7.3%, respectively, for EFS [P = 0.02], and 86.3% ± 1.2%, 82.3% ± 2.9%, and 88.3% ± 6.4%, respectively, for OS [P = 0.002]). Adherence to intensive chemotherapy was similar between the Muslims and the Bedouins. CONCLUSIONS Our findings suggest that the Bedouins, a highly inbred ethnic Arab people, may be considered a higher risk group that may need more intensive chemotherapy and/or supportive care in order to improve their outcome.

This study investigated the prevalence of inherited thrombophilia, risk of venous thromboembolism (VTE) and benefit of low molecular weight heparin prophylaxis in 476 Israeli children with acute lymphoblastic leukaemia (ALL) treated between 2004 and 2016. Thrombophilia was found in 15·5%. Arab children had a higher prevalence of F5 R506Q (factor V Leiden) than Jewish children (19·4% vs. 2·9%, P < 0·01). Patients with thrombophilia had higher VTE rates VTE (26·5% vs. 5·6%, P < 0·001). None of the thrombophilic children given prophylaxis had severe VTE. Routine evaluation for inherited thrombophilia followed by thromboprophylaxis when findings are positive may benefit at-risk patients with ALL.

ABL-class fusions other than BCR-ABL1 (or Ph+) are found in 2-3% of precursor B-cell acute lymphoblastic leukemia (pB-ALL) in children and adolescents. Occasional reports suggest that this rare ALL subtype has a poor prognosis and patients can benefit from treatment with tyrosine kinase inhibitors (TKIs). Aim of this retrospective study is to investigate the presenting features, treatment response and outcome in ABL-class fusion positive cases identified within large cohorts of patients treated in AIEOP-BFM ALL trials. This retrospective survey of ABL-class fusion positive pB-ALL other than Ph+ ALL was performed in patients aged 1-17 years at the diagnosis, treated from October 2000 to August 2018 according to the AIEOP-BFM (Associazione-Italiana- di- Ematologia-Oncologia Pediatrica-Berlin-Frankfurt-Münster) ALL 2000 and 2009 protocols in Austria, Australia, Czech Republic, Germany, Israel, Italy and Switzerland. While ABL-class fusions screening was not required by protocols, it was performed in some patients, according to centers' policies, usually after poor early treatment response. Overall, 46 ABL-class fusion positive cases with ABL1 fusions (N=15), ABL2 fusions (N=5), CSF1R fusions (N=3) and PDGFRB rearrangements (N=23) were identified. Compared with other pB-ALL children and adolescents, the ABL-class fusion positive cases presented with higher proportions of patients aged 10 years or older (52.2 vs. 22.2, P< .0001), hyperleukocytosis (WBC ≥100x109/l, 41.3 vs. 6.3, P< .0001), or poor minimal residual disease (MRD) response (>5x10-4 levels were observed in 65.2% vs. 18%, P< .0001 of patients after induction treatment phase IA and in 45.7% vs. 4.8%, P< .0001 after consolidation phase IB). For the entire cohort of 46 cases, the 5-year probability of event-free survival (EFS) was 49.1+8.9% and that of overall survival (OS) 69.6+7.8%; the cumulative incidence of relapse (CI) was 25.6+8.2% and treatment-related mortality 20.8+6.8%. Although not prescribed by the protocols, 13 patients received a TKI during different phases of treatment (TKI group), by choice of treating physicians, generally due to poor early treatment response. Eight TKI patients with high MRD levels at the end of induction phase IA received the TKI during consolidation phase IB, and six of them achieved either a low positive or negative MRD level at the end of consolidation phase IB. Nine of the 13 patients treated with TKIs underwent hematopoietic stem cell transplantation (HSCT) and only 1/9 (TKI+HSCT) relapsed. Thirty-three cases did not receive any TKI (no-TKI group) and eight of them relapsed; 6/17 patients treated with chemotherapy only, versus only 2/16 who underwent HSCT. Overall, 25 patients underwent HSCT, and of them 3 relapsed and 6 died of treatment-related complications. In patients with a WBC higher or lower than 100x109/L, the 5-year EFS was 36.8+12.7% vs. 59.9+11.6%, respectively (P= .21), and the 5-year OS was significantly lower in patients with a high WBC (48.8+12.9% vs. 87.4+6.8%, P= .036). This difference was more pronounced in the no-TKI group with a 5-year EFS 27.8+13.6% vs 61.8+12.7%, (P= .07), and an OS of 36.7+14.6% vs 94.4+5.4%, respectively (P= .0015). Presenting features, treatment response and outcome in this cohort of ABL-class fusion positive patients are markedly similar to those of patients with Ph+ ALL included in the EsPhALL studies. Our results suggest that TKIs and HSCT may be beneficial in reducing the risk of relapse. Thus there is an urgent need for large international cooperative controlled studies to investigate the impact of TKI, in combination with an appropriate chemotherapy backbone and the role of HSCT. To this purpose, an early identification of patients with ABL-class fusion positive acute lymphoblastic leukemia will be necessary. Disclosures Izraeli: sightdx: Consultancy; novartis: Honoraria; prime oncology: Speakers Bureau. Locatelli:Miltenyi: Honoraria; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees. White:BMS: Honoraria, Research Funding; AMGEN: Honoraria, Speakers Bureau. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria.

BACKGROUND Immunocompromised patients are at increased risk for severe respiratory syncytial virus (RSV) infection. Palivizumab is approved for prevention of RSV in specific populations but not for treatment. Few studies demonstrated the safety and successful treatment with intravenous (IV) palivizumab. We describe our experience with IV palivizumab treatment for RSV in a pediatric hematology-oncology department during an outbreak. METHODS During a short period of renovations, oncology patients were placed in a general pediatric ward. After a case of severe fatal RSV pneumonia in a 2-year-old male patient with acute myeloid leukemia, all patients were actively screened twice weekly regardless of symptoms. Respiratory samples were tested for RSV using rapid immunochromatography detection, immunofluorescence, or reverse transcriptase polymerase chain reaction. A single dose of palivizumab (15 mg/kg) was given to children below 3 years of age who tested positive for RSV. RESULTS Over a 6-week period, 12 patients tested positive for RSV. Seven patients were treated with palivizumab. Five patients had respiratory symptoms, and 2 were asymptomatic. No adverse events were attributed to IV palivizumab treatment. Early-treated patients had no complications attributed to RSV. CONCLUSIONS Containment of RSV outbreak in high-risk children is difficult. Screening with reverse transcriptase polymerase chain reaction and the early use of IV palivizumab is safe and may prevent complications of RSV infection among these patients.

Nontuberculous mycobacteria may cause central venous catheter-associated bacteremia. Between March 2011 and October 2013, 6 cases of Mycobacterium phocaicum bacteremia were found in the pediatric hematology-oncology department. All patients recovered. No positive blood culture was documented after removal of the central venous catheter. All 4 patients with pulsed field gel electrophoresis had the same pattern, different from the water sample, suggesting a common water source.

Mucormycosis has emerged as an increasingly important infection in patients with hematological malignancies, and is associated with considerable morbidity and mortality. However, contemporary data concerning epidemiology and outcome in children is lacking. Here we report a nationwide multicenter study of mucormycosis among children with hematological malignancies. Between the years 2004-2017, 1136 Israeli children aged ≤18 years with acute leukemias (acute lymphoblastic leukemia (ALL)-941; acute myeloid leukemia (AML)-195) were prospectively enrolled on a centralized clinical registry. Fungal infections, including mucormycosis, were prospectively and retrospectively captured. In addition, all 7 pediatric hematology centers were required to search hospital medical records, microbiology databases, and pathology information systems for cases of mucormycosis. Following central revision, 39 cases of mucormycosis were identified. Patient characteristics: Median age at mucor diagnosis: 13.5 years. Underlying diseases: ALL-27, AML-9, other-3. In 24 patients mucormycosis occurred during frontline therapy of their disease, and in 15 patients at relapse. Known risk factors included stem cell transplantation (SCT)-13 (33%), severe neutropenia-33 (85%) and corticosteroids-26 (67%). Among 20 patients on frontline ALL therapy, mucormycosis was diagnosed during induction in 13 cases, reinduction-6 cases, consolidation-1 case. Twenty-five patients with mucormycosis were enrolled on the national acute leukemia registry (not included: other malignancies, non-Israeli patients, relapsed leukemia with primary diagnosis preceding registry initiation, secondary AML). An analysis of registry cases demonstrated that the incidence of mucormycosis did not significantly increase during the study period. There was no seasonal clustering. Mucormycosis was significantly more common among patients ≥10 years old (4% vs 1%, p=0.004). Among patients on frontline treatment, mucormycosis was significantly more common in high-risk (HR) ALL patients (6%) than in non-HR (1%) or AML (1%) patients (p=0.001). Mucormycosis: Patterns of infection included sinusitis/sino-orbital-16 (41%), rhinocerebral-8 (21%), pulmonary-3 (8%), mandibular -4 (10%), gastrointestinal-1, cutaneous-1, otomastoiditis-1, disseminated-6 (15%). The majority (46%) were caused by Rhizopus spp. EORTC criteria: proven-30, probable-7, possible-2 (pathognomonic radiological findings and molecular diagnosis). Treatment: Nineteen patients were treated with amphotericin B formulations only and 19 received combined antifungal treatment. Nine patients received step-down treatment with posaconazole/ isavuconazole. In addition, 33 patients underwent surgical interventions, 26 underwent 2 procedures or more (range 2-14). Median time from presentation to antifungal treatment-3 days. Outcome: Twenty-one patients died, 15 of mucormycosis, 3 of other toxicities, 3 of leukemia. Factors significantly associated with mortality from mucormycosis were preceding SCT (p=0.01), less than 2 surgical interventions (p=0.0003) and relapsed disease (p=0.006). Eight-year OS of the whole cohort, those on frontline therapy and relapsed patients was 42% (±21%), 70%(±13%), 13%(±66%), respectively. Eight-year cumulative incidence of death from mucormycosis (CIDM) in those subgroups was 40%(±8), 21%(±8), 67% (±13), respectively. To our knowledge, this is the largest population-based study of mucormycosis in children with hematological malignancies. Our study demonstrates that mucormycosis is an age-dependent toxicity, significantly more common in patients ≥10 years of age. A striking finding was the high incidence of mucormycosis among patients on frontline high-risk ALL therapy, a fact which may reflect the increasing intensity of childhood ALL treatment. In a cohort of 24 patients who developed mucormycosis on frontline therapy, including 2 patients with AML and 13 with HR-ALL, 8y-OS was 70% and 8y-CIDM was 21%.The majority of patients in this cohort were salvageable through control of underlying disease, rapid instigation of antifungal treatment, and surgical debridement procedures, albeit in some cases at a price of mutilation and long-term sequelae. Future research should focus on the complex interactions between fungi and host, and on developing novel therapeutic strategies. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Objective: To determine the prevalence and relationship between apnea and gastroesophageal reflux (GER) among infants with apparent life-threatening events. Methods: We evaluated 67 infants of ages up to 6 months who had an idiopathic apparent life-threatening event as determined by polysomnography and pH monitoring. Results: No reflux (pH Conclusions: Episodes of apnea were seldom associated with GER. However, in those instances when apnea and reflux were associated, the predominant sequence of events was obstructive apnea and to a lesser extent mixed apnea followed by reflux. (J Pediatr 2000;137:321-6)

Legionnaires' disease is a rare cause of community acquired pneumonia in children and is exceedingly rare in infants and neonates. We describe a case of a 15 years old female, with lymphoblastic leukemia and legionella pneumophila pneumonia. Diagnosis was made by specific culture and polymerase chain reaction method from sputum and bronchoalveolar ravage specimens. Treatment was prolonged because of slow resolution and the fact that she underwent bone marrow transplantation. This emphasizes the importance of considering this rare entity in cases of severe pneumonia, especially in the immunocompromised host.

INTRODUCTION Traditionally in pediatric oncology, biopsies were incisional, with a recent alternative of percutaneous imaging-guided biopsies. In our department, ultrasound (US)-guided core biopsy is the first choice for tissue diagnosis in the pediatric population. We retrospectively reviewed our experience and assessed the accuracy rate, safety, and availability of the procedure. MATERIALS AND METHODS Pediatric US-guided biopsies performed in our hospital between November 2003 and November 2011 were studied. Data collection included demographics, clinical and procedural data, and follow-up. RESULTS A total of 213 biopsies were performed on 191 patients: 40 known oncologic patients and 173 to establish diagnosis. Seventeen biopsies were excluded, as malignancy was not suspected. Sixty-five percent of the patients had a biopsy within a day. A total of 138 biopsies with tumor at the biopsy site were correctly diagnosed and 4 were missed. Fifty-eight patients were negative for tumor. The sensitivity of our ultrasound-guided core biopsy is 97.1%, specificity 100%, and accuracy 97.9%.We found no complication related to sedation, and 2 procedural complications-bleeding from the biopsy site and seeding of tumor cells-were reported. DISCUSSION We find US-guided core biopsy for suspected malignancy in the pediatric population to be highly available, safe, and very accurate, having a potential to become the procedure of choice.

Survival in T cell lymphoblastic lymphoma has improved over the past 30 years, largely due to treatment protocols derived from regimens designed for children with acute lymphoblastic leukemia.To assess the outcome of the NHL-BFM-95 protocol in children and adolescents hospitalized during the period 1999-2006.We conducted a retrospective multi-institutional, non-randomized study of children and adolescents up to age 21 with T cell lymphoma admitted to pediatric departments in six hospitals in Israel, with regard to prevalence, clinical characteristics, pathological characteristics, prognostic factors, overall survival (OS) and event-free survival (EFS). All patients had a minimal follow-up of one year after diagnosis. The study was based on the NHL-BFM-95 protocol.At a median follow-up of 4 years (range 1-9 years), OS and EFS for all patients was 86.5% and 83.8%, respectively. OS was 86.7% and 83.3% for patients with stage III and stage IV, respectively, and EFS was 83.3% and 83.3%, respectively. EFS was 62.5% for Arab patients and 89.7% for Jewish patients (P = 0.014). Patients who did not express CD45 antigen showed superior survival (P = 0.028). Five patients (13.5%) relapsed, four of whom died of their disease. Death as a consequence of therapy toxicity was documented in one patient while on the re-induction protocol (protocol IIA).Our study shows that OS and EFS for all patients was 86.5% and 83.8%, respectively.

Background and aims: Differences in outcome and disease characteristics of childhood acute lymphoblastic leukemia (ALL) among ethnic groups were reported worldwide. We explored such differences among ethnic populations in Israel. Methods: Patient and disease characteristics and outcome were compared retrospectively among Jewish, Muslim, Bedouin, Druze, and Christian populations. Dose intensity and adherence to chemotherapy was measured by comparing dose and duration of treatment between the ethnic groups. Treatment duration was measured in days, from the first day of induction until the beginning of maintenance, compared to the scheduled time table according to the protocol, and expressed as percentage of delay. All data were retrieved from the Israeli National Center of Childhood ALL database after approval of the ethics committees of the participating institutions. Results: Between the years 1984-2011, 1286 patients aged 1-21 years were enrolled into 4 Israeli National Studies (INSs) for childhood ALL. The patients included 963 Jews (75%), 211 Muslims (16%), 54 Bedouins (4%), 28 Druze (2%) and 30 Christians (2%). In the first ALL INS-84 protocol (132 patients) the outcome of Muslims was inferior to that of the Jews in patients with pre-B ALL (10 years event free survival (EFS): 33.3%±13.6 Vs 68.8% ±5.3 (p=0.043)). The other ethnic groups were too small for statistical analysis. In the three subsequent ALL-BFM-based protocols since 1989: ALL-INS 89, 98, and 2003/7 the outcome improved with time for both Jewish and Muslim patients, abrogating the earlier group difference. In the combined latter 3 studies, the Bedouins had a poorer outcome compared to Jews, Muslims, Druze, and Christians with 5-year EFS of 60.3%±7.2%, 80.4%±1.4%, 77.3%±3.2%, 84.0%±7.3%, and 88%+6.8% (p=0.020), respectively. The difference was mainly due to higher relapse rates in high risk (HR) group (5 year cumulative incidence of relapse (CIR) of 85.7%, 30.3%, 29.4% (p=0.003) in the Bedouin, Jew and Muslim respectively) and in T ALL (5 year CIR of 45.8%, 16.9%, 13.9% (p=0.05) respectively). Higher rate of death in remission (DIR) due to infections was observed in the medium risk (MR) group (5 year DIR of 11%, 1.5%, 0.9% (p=0.005) in the Bedouin, Jew and Muslim respectively) and in pre-B ALL (10.9%, 1.3%, 2.1% (p=0.001) respectively). As opposed to the other ethnic groups the current study did not improve outcome of Bedouins. No major differences in clinical and leukemia cell characteristics (age, gender, white blood cell count, phenotype, central nervous system involvement), as well as in early response (day 8 peripheral blood prednisone response, day 15 and 33 bone marrow morphology) and in BFM risk group stratification, could be detected between the Bedouin and the rest. However, the Bedouins had a tendency to higher incidence of t(1;19),and lower incidence of high hyperdiploid karyotype. Adherence to chemotherapy was compared between 27 Bedouins and matched 57 Jews and 43 Muslims, treated with the last ALL-INS 2003/7 protocol. Lower incidence of treatment delay was demonstrated among Jews compared to Bedouins and Muslims (P = 0.01 and 0.03, respectively), but no significant difference was found between Bedouins and Muslims (p=0.46). Conclusion: The ethnic Bedouin group had inferior outcome with higher rate of relapse and death in remission compared to Jew, Muslim and Druze patients with no improvement over the years. Adherence to chemotherapy was similar to that of the Muslims. Other possible factors such as adherence to supportive treatment in a lower socioeconomic group and/or inherited factors associated with susceptibility to different subtypes of leukemia and to a different response to chemotherapy and toxicity might have contributed to the observed differences. Further studies are needed to investigate whether Bedouin ethnicity may serve as a marker for high risk stratification and whether pharmacogenetic data, yet unknown, contribute to their higher infection related toxicity. These data could aid in optimizing anti-leukemic and supportive treatment. Disclosures No relevant conflicts of interest to declare.

Febrile neutropenia (FN) is a common complication among children undergoing chemotherapy for hematologic malignancies. A microbial agent is identified in 15–30% of these episodes. Recently, several studies reported a high incidence (25% -60%) of respiratory viral infections (RVI) in children with FN, using RT- PCR analysis. Implementation of routine RVI workup in children with FN was suggested, in order to minimize the overuse of antibiotics. However, data on the incidence of RVI in children with persistent FN (PFN) is meager. In the setting of PFN, invasive fungal infection (IFI) is a major concern. The incidence of IFI among children with hematologic malignancies varies with clinical settings, although most children who present with PFN do not have IFI eventually. Yet, most international guidelines indicate empiric initiation of antifungal therapy after 4-7 days of FN. Alternatively, a “preemptive” approach using currently available diagnostic modalities (CT and serum specific biomarkers) was suggested in adult patients. In children with PFN, however, this workup resulted only in a modest decline in the antifungal treatment rate. Therefore, there is a growing need to enhance diagnostic resolution, in order to stratify pediatric patients according to their risk for IFI, and minimize the overuse of antifungal drugs, imaging, and invasive procedures. To the best of our knowledge, there are no studies comparing the incidence of RVI to that of IFI in the setting of PFN. Based on previous published data, we hypothesized that RV infection is a significant cause of PFN in children with hematologic malignancies, and that IFI is the cause in a minority of cases. We further aimed to investigate whether detection of RVI, as the cause of PFN in these children, would affect their risk of IFI. For that purpose, we analyzed the clinical charts of children (38oc, for >96 hours and ≤500ANC/µl) and documented PCR results of RV. Patients were considered positive for IFI if they had ‘possible’, ‘probable’ or ‘proven’ infection according to the revised EORTC definition (2008). RVI were detected in nasopharyngeal aspirates using RT-PCR and included: RSV, Influenza A/B, H1N1, Parainfluenza 1/2/3, HMPV, Adenovirus and HHV-6. Additional data included age and gender, specific hematologic malignancy, total number of neutropenia ( A total number of 75 PFN episodes were evaluable, representing 54 patients with ALL (HR n=18; SR n=23), AML (n=6), NHL (n=5) or Hodgkin’s (n=2). Of these, there were 31 episodes with RV-positive infections (41.3%). The most prevalent virus was RSV (29%), followed by Parainfluenza (26%) and Adenovirus (19%).There were 16 possible (21%), 2 probable (2.6%), and 2 proven (2.6%) episodes of IFI. Only in 3 episodes we detected co-infection of IFI (2 possible and 1 probable) and RVI. Multivariate analysis revealed that the total days of neutropenia and antibiotic therapy were independent risk-factors for IFI (p Children with PFN and RVI have a significantly lower risk for IFI. This observation may reduce unnecessary imaging and invasive procedures, antifungal treatment, and hospital expanses. Further studies are needed in order to establish whether RV-status can be implemented in the routine workup algorithm of PFN in children with hematologic malignancies. Disclosures No relevant conflicts of interest to declare.