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Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic stem-cell transplantation; not all patients have a response to standard glucocorticoid treatment. In a phase 2 trial, ruxolitinib, a selective Janus kinase (JAK1 and JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory acute GVHD.We conducted a multicenter, randomized, open-label, phase 3 trial comparing the efficacy and safety of oral ruxolitinib (10 mg twice daily) with the investigator's choice of therapy from a list of nine commonly used options (control) in patients 12 years of age or older who had glucocorticoid-refractory acute GVHD after allogeneic stem-cell transplantation. The primary end point was overall response (complete response or partial response) at day 28. The key secondary end point was durable overall response at day 56.A total of 309 patients underwent randomization; 154 patients were assigned to the ruxolitinib group and 155 to the control group. Overall response at day 28 was higher in the ruxolitinib group than in the control group (62% [96 patients] vs. 39% [61]; odds ratio, 2.64; 95% confidence interval [CI], 1.65 to 4.22; P0.001). Durable overall response at day 56 was higher in the ruxolitinib group than in the control group (40% [61 patients] vs. 22% [34]; odds ratio, 2.38; 95% CI, 1.43 to 3.94; P0.001). The estimated cumulative incidence of loss of response at 6 months was 10% in the ruxolitinib group and 39% in the control group. The median failure-free survival was considerably longer with ruxolitinib than with control (5.0 months vs. 1.0 month; hazard ratio for relapse or progression of hematologic disease, non-relapse-related death, or addition of new systemic therapy for acute GVHD, 0.46; 95% CI, 0.35 to 0.60). The median overall survival was 11.1 months in the ruxolitinib group and 6.5 months in the control group (hazard ratio for death, 0.83; 95% CI, 0.60 to 1.15). The most common adverse events up to day 28 were thrombocytopenia (in 50 of 152 patients [33%] in the ruxolitinib group and 27 of 150 [18%] in the control group), anemia (in 46 [30%] and 42 [28%], respectively), and cytomegalovirus infection (in 39 [26%] and 31 [21%]).Ruxolitinib therapy led to significant improvements in efficacy outcomes, with a higher incidence of thrombocytopenia, the most frequent toxic effect, than that observed with control therapy. (Funded by Novartis; REACH2 ClinicalTrials.gov number, NCT02913261.).

e22504 Background: Pediatric/YA pts with r/r B-NHL are rare and have heterogenous, aggressive histology and poor prognosis. We report early results for tisagenlecleucel (anti-CD19 CAR-T cell therapy) in pediatric/YA pts with r/r B-NHL. Methods: BIANCA (NCT03610724) is a phase 2, single-arm, global, open-label trial of tisagenlecleucel in pediatric/YA pts with CD19+ r/r B-NHL. Pts must have confirmed mature B-NHL r/r to ≥1 prior lines of therapy and no active CNS involvement. Primary endpoint is ORR. Secondary outcomes include DOR, EFS, safety and pharmacokinetics. Results: As of Nov 4, 2019, 8 pts were enrolled, of whom 4 had large B-cell lymphoma (LBCL), 3 Burkitt lymphoma (BL), and 1 gray zone lymphoma (GZL) (Table). Five pts had ≥2 lines of prior therapy. Suitable apheresis product was harvested in all 8 pts. Five pts were infused and 3 were pending infusion at data cut off. Product was successfully manufactured within specifications for all infused pts. Median time from enrollment to infusion was 33 days (range 30-67). All 5 pts have ≥28 days follow up; 2 pts have ≥3 months follow up (median [range] 85 days [69-97]). All 8 pts received bridging chemotherapy (including 1 pt who also had surgery and 1 who also had radiotherapy). Tisagenlecleucel dose range was 0.3-1.1 × 108 CAR+ viable T cells (weight-based: 0.9-1.7 × 106 CAR+ viable T cells/kg). Cmax (range: Cmax= 8520-14,200 copies/µg; time to Cmax= 2-21 days; n = 4) was within range of expansion observed in pediatric/YA acute lymphoblastic leukemia and adult diffuse LBCL. All 5 pts had CRS; no grade ≥3 CRS was recorded. Three pts had neurologic events, including 2 grade 3/4 events. One pt died due to disease progression. Conclusions: Pediatric/YA pts with r/r B-NHL (including BL) were successfully infused with tisagenlecleucel in the BIANCA trial with a manageable safety profile. Apheresis/manufacturing were feasible in this cohort of rapidly progressing disorders. Tisagenlecleucel was shown to expand in vivo. BIANCA provides the first systematic data on CAR-T cell therapy in highly aggressive, pediatric/YA B-NHL. Planned enrollment is 35 pts (26 infused and evaluable). Clinical trial information: NCT03610724. [Table: see text]

Background: Prognostic scoring systems for allogeneic stem cell transplantation (HSCT) are of clinical value when determining a leukemic patient's suitability for this curative, but risky, procedure. Several such scores have been developed over the years for HSCT from sibling or unrelated donors, but no predictive score has been developed specifically for umbilical cord blood transplantation (UCBT). Although individual parameters have been identified to be associated with UCBT outcomes in acute leukemia (AL) patients, integrative tools for risk evaluation in this setting are lacking. We sought to develop a prediction model for overall survival (OS) (primary objective) and leukemia free survival (LFS) (secondary objective) at 2 years following UCBT in acute leukemia patients. Methods: A retrospective, international registry-based study, of 3140 acute leukemia patients who underwent UCBT from 2004 through 2014. Inclusion criteria were patients with AL receiving single or double cord blood units transplantation. Median follow up was 30 months. The dataset was geographically split into a derivation (65%) and validation set (35%). A Random Survival Forest was utilized to identify predictive factors. Top predictors were introduced into a Cox regression model, and a risk score was constructed according to each variable's hazard. Results: The median age at UCBT was 21.9 years. The 2 years OS rate was 47.7% (95% CI: 45.8-49.6). After identifying the top predictive variables, the UCBT risk score (Table 1) was constructed using 9 variables (disease status, diagnosis, cryopreserved cell dose, age, center experience, recipient cytomegalovirus sero-status, degree of HLA mismatch, previous autograft and anti thymocyte globulin administration). Over the derivation and validation datasets, a higher score was associated with decreasing probabilities for 2 years OS and LFS, ranging over the validation set from 0.72 (0.64-0.8, 95% CI) and 0.68 (0.6-0.76, 95% CI) to 0.13 (0.06-0.27, 95% CI) and 0.14 (0.07-0.28, 95% CI), respectively (Figure 1). An increasing score was also associated with increasing hazard of the predictive outcomes (Table 2). The score's discrimination (AUC) over the validation set for 2 years OS and LFS was 68.26 (64.25-72.27, 95% CI) and 66.95 (62.88-71.02, 95% CI), respectively. Calibration was excellent. Conclusion: We have developed the first integrative score for prediction of overall survival and leukemia free survival in acute leukemia patients undergoing a UCBT. The score is simple and stratifies patients into distinct risk groups. Table 1 The UCBT Risk Score Table 1. The UCBT Risk Score Table 2 Association between the UCBT risk score and 2 years OS and LFS over the validation dataset Table 2. Association between the UCBT risk score and 2 years OS and LFS over the validation dataset Figure 1 Overall survival stratified by the UCBT risk score over the validation data set Figure 1. Overall survival stratified by the UCBT risk score over the validation data set Disclosures Bader: Servier: Consultancy, Honoraria; Neovii Biotech: Research Funding; Riemser: Research Funding; Medac: Consultancy, Research Funding; Novartis: Consultancy, Honoraria.

Severe congenital neutropenia (SCN) is a heterogeneous group of disorders characterized by defective production and viability of neutrophil granulocytes and predisposition to life-threatening bacterial infections. Currently, OMIM lists five defined monogenic SCN: SCN1 ELANE, SCN2 GFI1, SCN3 HAX1, SCN4 G6PC3. Here, we describe a novel SCN subtype (SCN6) caused by recessively-inherited loss-of-function mutations in the gene encoding the granulocyte colony-stimulating receptor (CSF3R). We have identified four affected children in two distinct families. Family A had a homozygous missense mutation in close proximity of the highly conserved WSXWS motif (c.922T, p.Arg308Cys) and family B had two compound heterozygous small deletions provoking frameshift mutations (p.Gly316fs and p.Gly415fs). Mutated G-CSFR p.Arg308Cys protein was characterized by perturbed N-glycosylation and aberrant localization to cell surface. G-CSF induced phosphorylation of STAT3 and STAT5 was greatly diminished. In contrast to other SCN subtypes, all patients had morphological evidence of full myeloid cell maturation in bone marrow. However, none of the patients responded to granulocyte colony-stimulating growth factor (GCSF) treatment in vivo, confirming aberrant GCSF-receptor dependent signaling. Our studies highlight the genetic and morphological variability of SCN and provide evidence both for functional importance and redundancy of G-CSFR-mediated signaling in human granulopoiesis. Disclosures: No relevant conflicts of interest to declare.