IMPORTANCE Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule with efficacy in children with relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL).OBJECTIVE To evaluate event-free survival in children with high-risk first-relapse B-ALL after a third consolidation course with blinatumomab vs consolidation chemotherapy before allogeneic hematopoietic stem cell transplant. DESIGN, SETTING, AND PARTICIPANTSIn this randomized phase 3 clinical trial, patients were enrolled November 2015 to July 2019 (data cutoff, July 17, 2019). Investigators at 47 centers in 13 countries enrolled children older than 28 days and younger than 18 years with high-risk first-relapse B-ALL in morphologic complete remission (M1 marrow, <5% blasts) or with M2 marrow (blasts Ն5% and <25%) at randomization. INTERVENTION Patients were randomized to receive 1 cycle of blinatumomab (n = 54; 15 μg/m 2 /d for 4 weeks, continuous intravenous infusion) or chemotherapy (n = 54) for the third consolidation. MAIN OUTCOMES AND MEASURESThe primary end point was event-free survival (events: relapse, death, second malignancy, or failure to achieve complete remission). The key secondary efficacy end point was overall survival. Other secondary end points included minimal residual disease remission and incidence of adverse events.RESULTS A total of 108 patients were randomized (median age, 5.0 years [interquartile range {IQR}, 4.0-10.5]; 51.9% girls; 97.2% M1 marrow) and all patients were included in the analysis. Enrollment was terminated early for benefit of blinatumomab in accordance with a prespecified stopping rule. After a median of 22.4 months of follow-up (IQR, 8.1-34.2), the incidence of events in the blinatumomab vs consolidation chemotherapy groups was 31% vs 57% (log-rank P < .001; hazard ratio [HR], 0.33 [95% CI, 0.18-0.61]). Deaths occurred in 8 patients (14.8%) in the blinatumomab group and 16 (29.6%) in the consolidation chemotherapy group. The overall survival HR was 0.43 (95% CI, 0.18-1.01). Minimal residual disease remission was observed in more patients in the blinatumomab vs consolidation chemotherapy group (90% [44/49] vs 54% [26/48]; difference, 35.6% [95% CI, 15.6%-52.5%]). No fatal adverse events were reported. In the blinatumomab vs consolidation chemotherapy group, the incidence of serious adverse events was 24.1% vs 43.1%, respectively, and the incidence of adverse events greater than or equal to grade 3 was 57.4% vs 82.4%. Adverse events leading to treatment discontinuation were reported in 2 patients in the blinatumomab group.CONCLUSIONS AND RELEVANCE Among children with high-risk first-relapse B-ALL, treatment with 1 cycle of blinatumomab compared with standard intensive multidrug chemotherapy before allogeneic hematopoietic stem cell transplant resulted in an improved event-free survival at a median of 22.4 months of follow-up.

Dual-energy x-ray bone densitometry was used to study the lumbar vertebral bone mass in 218 healthy children (134 girls and 84 boys) aged 1-19 years. Vertebral bone mass increased with weight, age, and pubertal Tanner stage. Results of multiple regression analyses showed that Tanner stage and weight were the best predictive indicators of bone mass and bone mineral density. The influences of age, sex, race, physical activity, and diet were not significant when Tanner stage and weight were controlled. Two tables of predictive intervals for lumbar vertebral bone mineral density in healthy children (one based on Tanner stage and weight; the other, on age and weight) are presented. With normative data now available for use with this precise technique, clinicians can better detect abnormal bone mineral density in children and evaluate changes in mineralization over time.

Summary:with lethal organ dysfunction in the renal, pulmonary and cardiac systems. 5-8A hypercoaguable state has been demonstrated to occur A hypercoaguable state has been shown to follow highdose chemotherapy for bone marrow transplantation in many patients following bone marrow transplantation (BMT). 6,7,[9][10][11][12][13][14][15][16] Specifically, the natural anticoagulants (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S cor-(antithrombin-III (AT-III), protein C and protein S) have been reported to be decreased in BMT patients, while prorelate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dyscoagulants (fibrinogen and factor VIII) were increased. The resulting imbalance between procoagulants and the natfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% urally occurring anticoagulants has been implicated in the development of VOD. and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every Fibrinolytics (tissue plasminogen activator, tPA) and anticoagulants (heparin) in addition to fluid restriction, 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-diuretics, and supportive care have been used to treat VOD. 1,4,[17][18][19][20][21][22] The use of tPA and heparin in this patient 5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platpopulation has been reported to have a high risk of bleeding and low response rate. 21elet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction Low levels of AT-III have correlated with the development of organ dysfunction during BMT in previously pubof severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatenlished reports. 6,7,9,16 In addition, VOD or other single organ dysfunction has been associated with progression to fatal ing organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control multiorgan failure. 5-8 Based on these reports, we hypothesized that correction of the AT-III deficit with AT-III congroup receiving the same preparative regimen (P ‫؍‬ 0.047 and P ‫؍‬ 0.034, respectively). Significant centrate might prevent progression to lethal organ dysfunction. Patients who developed organ dysfunction following improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationhigh-dose chemotherapy for BMT and who also had low AT-III activity levels were treated with AT-III concentrate. ship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.This paper reports the outcome of our AT-III-treated patients compared to historical control patients treated at Keywords: bone marrow transplantation; antithrombin III; veno-occlusive disease; orga...

To evaluate long-term durability of blinatumomab, a BiTE â (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosomeepositive (Phþ) B-cell precursor acute lymphoblastic leukaemia (ALL). M e t h o d s : I n t h i s fi n a l a n a l y s i s o f a n o p e n -l a b e l , s i n g l e -a r m , p h a s e 2 , multicentre ALCANTARA study (NCT02000427), adults (age !18 years) with Phþ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment.

We report a 3-month-old infant in whom Sweet's syndrome was a presenting manifestation of pediatric human immunodeficiency virus infection. Although rare in children, Sweet's syndrome may be associated with certain infections and malignancies. The diagnosis of Sweet's syndrome in a child should always prompt a thorough evaluation to assess for an associated systemic disease.

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Adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (ALL) have a poor prognosis. Blinatumomab is a bispecific T-cell engager (BiTE) immuno-oncology therapy with dual specificity for CD19 and CD3 that redirects patients' CD3-positive cytotoxic T cells to lyse malignant and normal B cells. We conducted an open-label, phase 1b/2 study to determine the safety, pharmacokinetics, efficacy and recommended dose of blinatumomab in Japanese adults with R/R B-precursor ALL. Patients received 9 μg/day blinatumomab during week 1 and 28 μg/ day during weeks 2-4, with a 2-week treatment-free interval (6-week cycle); patients received 28 μg/day blinatumomab in subsequent cycles. Primary endpoints were the incidence of dose-limiting toxicities (DLT) in phase 1b and complete remission (CR)/ CR with partial hematologic recovery (CRh) within the first two cycles in phase 2. A total of 26 patients enrolled and 25 (96%) reported grade ≥3 adverse events (mostly cytopenias). There were no DLT. CR/CRh within two cycles was achieved by 4 of 5 patients (80%) in phase 1b and 8 of 21 patients (38%) in phase 2. Among patients with evaluable minimal residual disease, 4 (100%) in phase 1b and 3 (38%) in phase 2 had a complete MRD response. Median RFS for 8 patients who achieved CR/CRh in phase 2 was 5 (95% CI: 3.5-6.4) months; median OS was not estimable. There were no significant associations between maximum cytokine levels or percentage of specific cell types during cycle 1 and response. Consistent with global studies, blinatumomab appeared to be safe and efficacious in Japanese adults with R/R ALL. K E Y W O R D S acute lymphoblastic leukemia, blinatumomab, clinical study, Japan, phase 1b, refractory, relapsed | 1315 KIYOI et al.

Background: Rituximab combined with chemotherapy (R-chemotherapy) is the standard of care first-line treatment for diffuse large B-cell lymphoma (DLBCL). Despite success with R-chemotherapy, 30% to 50% of patients with high-risk DLBCL will relapse, and outcomes are poor among patients who relapse within one year of diagnosis. Given the challenge of successful salvage, novel first-line therapies are needed. Blinatumomab, a bispecific T-cell engager (BiTE®) antibody construct that directs cytotoxic T cells to lyse CD19-expressing B cells, has shown efficacy as salvage therapy in patients with relapsed or refractory DLBCL. This open-label, multicenter, phase 2 study (ClinicalTrials.gov, NCT03023878) assessed the efficacy and safety of blinatumomab after first-line R-chemotherapy for patients with newly diagnosed, high-risk DLBCL. Methods: Patients (≥18 y) had proven high-risk DLBCL (International Prognostic Index [IPI] 3−5 and double/triple hit or double MYC/BCL2 expressor) and Eastern Cooperative Oncology group performance status ≤2. To be eligible for blinatumomab, patients were required to achieve complete metabolic response (CMR), partial metabolic response (PMR), or stable metabolic response by PET/CT after a run-in period with 6 cycles of R-chemotherapy (R-CHOP, R-DA-EPOCH, or R-CHOEP). Blinatumomab was given by continuous intravenous infusion in a single 84-day cycle 1 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 42 days, followed by a 28-day treatment-free interval) and an optional 28-day cycle 2 (9 μg/day for 7 days, 28 μg/day for 7 days, and 112 μg/day for 14 days) for patients without progressive metabolic disease (PMD). The primary endpoint was the incidence and severity of adverse events (AEs). Additional endpoints were objective response rate (ORR [CMR + PMR]) per Lugano criteria, minimal residual disease (MRD) by plasma cell−free circulating tumor DNA, overall survival (OS), and pharmacokinetics (PK). Results: Of 47 patients enrolled, 17 (36%) discontinued R-chemotherapy run-in (protocol criteria, n=6; patient request, n=5; disease progression, n=3; ineligibility, n=1; AE, n=1; death, n=1) and 30 (64%) completed the run-in (2 did not proceed to blinatumomab). Of 28 patients who received blinatumomab, 26 (93%) had high or high-intermediate IPI; 8 (29%) were double/triple hit and 10 (36%) were double protein expressors (Table). In total, 26 (93%) patients completed cycle 1; ten of 11 (91%) patients completed optional cycle 2. Blinatumomab PK were consistent with those in previous studies. After the R-chemotherapy run-in before starting blinatumomab, 24 patients had objective metabolic responses and 4 had no metabolic response (NMR). After blinatumomab treatment, the ORR (within 12 weeks of starting blinatumomab) was 89% (25/28 patients; 95% CI, 72−98; Table). The 4 patients with NMR before blinatumomab had objective responses after blinatumomab treatment. Three patients with objective responses before blinatumomab relapsed after blinatumomab. Twenty-six (93%) patients were still alive with a median follow-up time of 8.6 months; 2 died (disease progression; n=1; infection not related to treatment, n=1). Nine of 13 (69%) patients during the R-chemotherapy run-in were MRD positive, all of whom converted to MRD negative after treatment with blinatumomab. After treatment with blinatumomab, 17 of 18 (94%) patients were MRD negative; the MRD positive patient had PMD. During blinatumomab treatment, 11 (39%) patients had grade ≥3 AEs, and 5 (18%) had grade ≥4 AEs. Two (7%) patients discontinued treatment due to AEs (grade 3 neurotoxicity; grade 4 neutropenia). Consistent with previous blinatumomab reports, neurologic events (NEs) were reported in 17 (61%) patients, including 3 (11%) with grade 3 NEs and 1 (4%) with NEs leading to treatment discontinuation. No patients had grade ≥3 cytokine release syndrome. Other grade ≥3 events of interest included neutropenia and febrile neutropenia (n=4; 14%) and infection (n=3; 11%). Conclusions: In patients with newly diagnosed, high-risk DLBCL, blinatumomab monotherapy after first-line R-chemotherapy led to an 89% ORR, and safety was consistent with that in earlier studies in DLBCL. Thus, blinatumomab is a potential treatment option for patients with newly diagnosed disease. Disclosures Katz: Stemline: Speakers Bureau; Dova: Consultancy. Chu:Celgene: Honoraria; Teva: Consultancy; AstraZeneca: Honoraria; Amgen Inc.: Honoraria; Gilead: Honoraria. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Morley:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees, conference support ; TAKEDA: Other: conference support ; Janssen Pharmaceuticals: Other: speaker fees; ROCHE: Membership on an entity's Board of Directors or advisory committees, Other: conference support; ABBVIE: Other: speaker fees. Chen:Amgen Inc.: Employment, Equity Ownership. Kalabus:Amgen Inc.: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Avilion:Amgen Inc.: Employment, Equity Ownership. González-Barca:Takeda: Honoraria; Kiowa: Consultancy; Celtrion: Consultancy; Janssen: Consultancy, Honoraria; Celgene: Consultancy; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria.