In a Plenary Paper, Young et al describe impressive favorable outcomes of emicizumab prophylaxis in children with hemophilia A and factor VIII inhibitors, reporting a 99% reduction in annualized bleeding, with 77% of patients having no treated bleeding events.

Adults and children with high-risk CRLF2-rearranged acute lymphoblastic leukemia (ALL) respond poorly to current cytotoxic chemotherapy and suffer unacceptably high rates of relapse, supporting the need to use alternative therapies. CRLF2 encodes the thymic stromal lymphopoietin (TSLP) receptor, which activates cell signaling in normal lymphocytes on binding its ligand, TSLP. We hypothesized that aberrant cell signaling occurs in CRLF2-rearranged ALL and can be targeted by signal transduction inhibitors of this pathway. In a large number of primary CRLF2-rearranged ALL samples, we observed increased basal levels of pJAK2, pSTAT5, and pS6. We thus characterized the biochemical sequelae of CRLF2

Introduction Emicizumab - a bispecific humanized monoclonal antibody given subcutaneously - bridges FIXa and FX to restore the function of missing FVIIIa. It is approved for routine prophylaxis in people with hemophilia A (PwHA) with inhibitors of all ages. Previous data from the HAVEN 2 study of emicizumab in pediatric PwHA with inhibitors <12 years (data cut-off May 8, 2017) showed once-weekly (QW) dosing provided effective bleed control and was well tolerated (Young et al. Blood 2017). We present the primary analysis of the study, including analyses of the bi-weekly (Q2W) and monthly (Q4W) dosing regimens. Methods HAVEN 2 (NCT02795767) enrolled PwHA with inhibitors aged <12 years (or 12-17 years if <40kg) previously treated with episodic or prophylactic bypassing agents (BPAs) to receive emicizumab prophylaxis for ≥52 weeks. A loading dose of 3mg/kg emicizumab was given QW for 4 weeks followed by a maintenance dose of 1.5mg/kg QW, 3mg/kg Q2W or 6mg/kg Q4W (cumulative dose identical for all regimens). Efficacy analyses included annualized bleed rates (ABRs) for all bleed endpoints and an intra-individual comparison with ABR on prior BPAs from a prospective non-interventional study (NIS; NCT02476942). Safety assessments included records of adverse events (AEs), serious AEs (SAEs), AEs of interest and immunogenicity. Pharmacokinetics (PK) across dosing regimens was also analyzed. Results Eighty-eight patients were enrolled (n=68 QW; n=10 Q2W; n=10 Q4W), 18 of whom were aged ≤2 years old. At clinical cut-off (April 30, 2018), the median (range) emicizumab exposure for each cohort was 57.2 (17.1-92.1), 20.1 (18.1-24.1), and 18.1 (8.1-24.1) weeks, respectively; 59 patients in the QW cohort completed 52 weeks on study; 3 patients discontinued due to switching to commercial emicizumab (n=2 QW) or lack of efficacy (n=1 Q4W). In the QW, Q2W, and Q4W cohorts, the ABR in treated patients aged <12 years was 0.3 (95% confidence interval [CI]: 0.17-0.50), 0.2 (0.03-1.72), and 2.2 (0.69-6.81) for treated bleeds, respectively. Zero treated bleeds were reported in 50/65 (76.9%), 9/10 (90.0%), and 6/10 (60.0%) patients, respectively. Across cohorts, all patients experienced ≤3 treated bleeds (Table 1). Overall, 30 treated bleeds were reported (n=22 QW; n=1 Q2W; n=7 Q4W): 19 occurring in a joint (n=12 QW; n=1 Q2W; n=6 Q4W), 4 in a muscle (n=3 QW; n=1 Q4W), and 7 classified as 'other' (n=7 QW). The majority (25/30; 83.3%) of treated bleeds were traumatic and 5/30 (16.7%) were spontaneous. An intra-individual comparison of 18 patients <12 years old in the QW cohort who had participated in the NIS (15 and 3 on prior prophylactic and episodic BPAs, respectively) showed a 99% (95% CI: 97.7-99.4) reduced risk of treated bleeds with emicizumab compared with prior BPAs (Figure 1). Emicizumab was safe and well tolerated. No thromboembolic or thrombotic microangiopathy events or deaths occurred. The most common AEs are listed in Table 2. Seventeen patients experienced 21 SAEs. Four patients tested positive for anti-drug antibodies (ADA), two of whom had ADA with neutralizing potential based on reduced emicizumab levels; one discontinued emicizumab treatment and the other had no bleeds as of the clinical cut-off date. Mean steady-state trough concentrations of emicizumab were maintained at therapeutic levels across all regimens (Figure 2). Trough plasma concentrations increased with loading doses until Week 5, then were maintained at approximately 50, 45-50 and 38μg/mL with QW, Q2W and Q4W dosing, respectively. As of the data cut-off, 21 minor surgical procedures had been carried out, 14 (66.7%) of which were central venous access device (CVAD) removals. Conclusions To our knowledge, HAVEN 2 is the largest prospective study in pediatric PwHA with inhibitors to date, and demonstrates that emicizumab prophylaxis is well tolerated and can prevent or substantially reduce bleeds in this population. Meaningful efficacy and PK were maintained with less frequent dosing, with no new safety signals, suggesting the potential for reduced treatment burden in the pediatric population. Additionally, the large number of CVAD removals suggests that prophylactic emicizumab may offer a new and effective standard of care for hemophilia that is also more convenient and less invasive, and may offer the potential for flexible treatment regimens based on patient needs. Disclosures Young: Genentech/Roche: Consultancy, Honoraria, Research Funding; Novo Nordisk: Honoraria; Shire: Honoraria. Liesner:Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Roche: Research Funding; Sobi: Speakers Bureau. Sidonio:Uniqure: Honoraria; CSL Behring: Honoraria; Shire: Honoraria, Research Funding; Genentech/Roche: Honoraria, Research Funding; Kedrion/Grifols: Research Funding; Bioverativ: Honoraria, Research Funding; Biomarin: Honoraria; Novo Nordisk: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jimenez-Yuste:NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sobi: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; CSL Behring: Consultancy; Octapharma: Consultancy, Research Funding; Grifols: Consultancy, Research Funding. Mahlangu:Alnylam: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Biomarin: Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Research Funding; Chugai: Consultancy; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Sanofi: Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Kruse-Jarres:Grifols: Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Wang:Terumo BCT: Other: CPC Clinical Research; Novo Nordisk: Consultancy; Bayer, Novo Nordisk, Octapharma, Genentech, HEMA Biologics, Shire, CSL Behring: Honoraria; Bayer, Bioverative, Novo Nordisk, Octapharma, Shire, Genentech, Biomarain, Pfizer, CSL Behring, HEMA Biologics, Daiichi Sankyo: Research Funding; Bayer: Consultancy; CSL Behring: Consultancy. Chang:Genentech: Employment, Equity Ownership. Uguen:F.Hoffmann-LaRoche: Employment. Doral:Genentech: Employment. Schmitt:F. Hoffmann-La Roche: Employment, Equity Ownership. Levy:Genentech/Roche: Employment, Equity Ownership. Shima:F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Mancuso:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biotest: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kedrion: Consultancy; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Sarit Assouline and Won Seog Kim contributed equally. Introduction: Follicular lymphoma (FL) is considered an indolent yet incurable disease characterized by recurrent relapses: disease-free intervals shorten, and refractoriness increases with each relapse. Patients (pts) with FL who have received at least two prior systemic therapies typically have a poor prognosis. This is particularly true for those who have progression of disease within 24 months of front-line treatment (POD24), or are refractory to multiple agent classes; such patients are left with limited treatment options. Mosunetuzumab is a full-length, fully humanized immunoglobulin G1 CD20/CD3 bispecific antibody that redirects T cells to engage and eliminate malignant B cells. GO29781 (NCT02500407) is an ongoing open-label, multicenter, Phase I/Ib, dose-escalation and expansion study evaluating the safety, efficacy and pharmacokinetics of mosunetuzumab in pts with relapsed/refractory (R/R) B-cell lymphoma. Here, we present updated clinical data from pts with R/R FL treated with mosunetuzumab after at least two prior systemic therapies. Methods: Data are presented from Group B, in which pts received intravenous mosunetuzumab monotherapy as step-up doses in Cycle 1 on Days 1 and 8 and the target dose administered on Day 15. Mosunetuzumab was given on Day 1 of each subsequent 21-day cycle for 8 cycles in pts with a complete response (CR), and up to 17 cycles in those with a partial response (PR) or stable disease (SD). Results: As of January 21, 2020, 62 pts with FL (with at least two prior systemic therapies), received mosunetuzumab at dose levels between 0.4/1.0/2.8mg and 1/2/13.5mg (Cycle 1 Day 1/8/15 dose levels). The median age was 59 (range 27-85) years, and median number of prior therapies was 3 (range 2-11). Thirty-three pts (53%) were refractory to both a prior anti-CD20 antibody and an alkylating agent (double refractory), 30 (48%) had POD24, and four (6%) had received prior chimeric antigen receptor T-cell (CAR-T) therapy. The overall response rate (ORR) was 68% (42/62), with 31 pts (50%) achieving CR (Figure). Consistent CR rates were observed in high-risk pt populations, including those with double refractory disease (18/33 [55%]), POD24 (16/30 [53%]), PI3Ki refractory (7/9 [78%]), and those who received prior CAR-T therapy (2/4 [50%]). With a median time on study of 14.4 months, 26 pts (62% of all responders; including 74% of pts who achieved CR) remained in remission at the data cut-off. The median duration of response (DOR) was 20.4 months (95% CI: 11.7 months, upper limit not reached) for all 42 responders. The median PFS was 11.8 months (95% CI: 7.3-21.9 months). Adverse events (AEs) were reported in 60 pts (97%); serious adverse events (SAE) were reported in 22 pts (35%). The most frequently reported (&gt;10% of pts) grade (Gr) 3 or higher AEs included hypophosphatemia (23%; transient and clinically asymptomatic) and neutropenia (21%; with a low rate of febrile neutropenia [2%]). Overall, 14 pts (23%) experienced CRS; in four pts, CRS was classified as a SAE. CRS events were reversible, mostly of Gr 1 or 2 (Gr 1, n=11; Gr 2, n=2; Gr 3, n=1; Lee, et al. Blood 2014), and predominantly occurred during Cycle 1. No patient required tocilizumab, intensive care unit admission or use of vasopressors for CRS management. Neurologic AEs (NAEs; defined by any AEs reported as Preferred Terms in SOC Nervous System Disorders and SOC Psychiatric Disorders) were observed in 28 pts (45%); all were Gr 1 (n=18) or 2 (n=10). The most commonly reported NAEs were headache (24%), insomnia (15%) and dizziness (11%). No Gr ≥3 NAEs or serious NAEs were reported. Conclusions: Fixed-duration mosunetuzumab monotherapy results in high response rates and durable disease control with a tolerable safety profile in heavily pretreated patients with FL, including known high-risk subgroups. Updated pharmacodynamics and biomarker data will be presented at the meeting. Disclosures Assouline: BeiGene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; Pfizer: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Kim:Mundipharma: Research Funding; Donga: Research Funding; Kyowa Kirn: Research Funding; Celltrion: Research Funding; JJ: Research Funding; Pfizer: Research Funding; F. Hoffmann-La Roche: Research Funding. Sehn:Genentech, Inc.: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; Verastem Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. Cheah:Celgene, F. Hoffmann-La Roche, Abbvie, MSD: Research Funding; Celgene, F. Hoffmann-La Roche, MSD, Janssen, Gilead, Ascentage Pharma, Acerta, Loxo Oncology, TG therapeutics: Honoraria. Nastoupil:Karus Therapeutics: Research Funding; Gilead/KITE: Honoraria; TG Therapeutics: Honoraria, Research Funding; Merck: Research Funding; Novartis: Honoraria, Research Funding; Gamida Cell: Honoraria; Bayer: Honoraria; Pfizer: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding. Shadman:Fred Hutchinson / University of Washington: Current Employment; Abbvie, Genentech, Inc., AstraZeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Mophosys and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Inc., Abbvie, TG therapeutics, Beigene, AstraZeneca, Sunesis: Research Funding. Yoon:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Kyowahako Kirin: Research Funding; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding. Matasar:Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Teva: Consultancy; Rocket Medical: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Juno Therapeutics: Consultancy; Takeda: Consultancy, Honoraria; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck: Consultancy; Bayer: Consultancy, Honoraria, Research Funding. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Denovo: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Gregory:Janssen: Consultancy; F. Hoffmann-La Roche, Genentech, Inc., MSD, AbbVie, BeiGene, AstraZeneca, Celgene, BMS: Research Funding; F. Hoffmann-La Roche, Novartis, AbbVie: Speakers Bureau; F. Hoffmann-La Roche, Novartis, Sandoz, Gilead, AbbVie, MSD: Honoraria; F. Hoffmann-La Roche, Novartis, Sandoz, Gilead: Membership on an entity's Board of Directors or advisory committees. Bartlett:BMS/Celgene: Research Funding; Merck: Research Funding; Kite, a Gilead Company: Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed Therapeutics: Research Funding; Autolus: Research Funding; Acerta: Consultancy; Roche/Genentech: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BTG: Consultancy; ADC Therapeutics: Consultancy; Forty Seven: Research Funding. Wei:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Doral:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Yin:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Negricea:F. Hoffmann-La Roche: Current Employment. Li:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Penuel:Genentech, Inc./ F. Hoffmann-La Roche: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Huang:F. Hoffmann-La Roche: Current Employment. Budde:AstraZeneca: Speakers Bureau; Merck, Amgen, AstraZeneca, Mustang Therapeutics: Research Funding; F. Hoffmann-La Roche, Kite Pharma: Consultancy. OffLabel Disclosure: Mosunetuzumab (RG7828) is a full-length, fully humanized immunoglobulin G1 (IgG1) bispecific antibody targeting both CD3 (on the surface of T cells) and CD20 (on the surface of B cells). Mosunetuzumab redirects T cells to engage and eliminate malignant B cells. Mosunetuzumab is an investigational agent.

Background 131I-metaiodobenzylguanidine (131I-MIBG) is a targeted radiopharmaceutical with significant activity in high-risk relapsed and chemotherapy-refractory neuroblastoma. Our primary aim was to determine if there are differences in response rates to 131I-MIBG between patients with relapsed and treatment-refractory neuroblastoma. Methods This was a retrospective cohort analysis of 218 patients with refractory or relapsed neuroblastoma treated with 131I-MIBG at UCSF between 1996 and 2014. Results were obtained by chart review and database abstraction. Baseline characteristics and response rates between relapsed patients and refractory patients were compared using Fisher exact and Wilcoxon rank sum tests, and differences in overall survival (OS) were compared using the log-rank test. Results The response rate (complete and partial response) to 131I-MIBG-based therapies for all patients was 27%. There was no difference in response rates between relapsed and refractory patients. However, after 131I-MIBG, 24% of relapsed patients had progressive disease compared to only 9% of refractory patients, and 39% of relapsed patients had stable disease compared to 59% of refractory patients (p = 0.02). Among all patients, the 24-month OS was 47.0% (95% CI 39.9%–53.9%). The 24-month OS for refractory patients was significantly higher at 65.3% (95% CI 51.8%–75.9%), compared to 38.7% (95% CI 30.4%–46.8%) for relapsed patients (p < 0.001). Conclusions Although there was no significant difference in overall response rates to 131I-MIBG between patients with relapsed vs. refractory neuroblastoma, patients with prior relapse had higher rates of progressive disease and had lower 2-year overall survival after 131I-MIBG compared to patients with refractory disease.