Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849 ), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
Summary Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded‐access study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109/l) and patients without splenomegaly – populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low‐platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low‐platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non‐haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50–100 × 109/l. (ClinicalTrials.gov identifier NCT01493414).
Tisagenlecleucel demonstrated high rates of durable responses in adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in the JULIET trial. Most patients (92%) received bridging therapies to control disease after study entry and before tisagenlecleucel infusion. Here, we examine the efficacy and safety of tisagenlecleucel in the subset of 7 patients who achieved complete response (CR) after bridging therapy and before tisagenlecleucel infusion. Tisagenlecleucel rapidly expanded in all 7 patients, and the transgene levels were measurable for up to 2 years after infusion. After infusion, all 7 patients were still in CR at the month 3 evaluation, and 5 of 7 patients remained progression-free >12 months. Adverse events were similar to the overall JULIET population. Cytokine release syndrome (CRS) was reported in 4 of 7 patients (grade 2 = 2 and grade 3 = 2 using the Penn grading scale), and 1 patient experienced grade 1 neurotoxicity. No patient required tocilizumab or steroids for CRS management. These data provide preliminary evidence of tisagenlecleucel efficacy in patients with r/r DLBCL without detectable disease after bridging or salvage therapies and warrant further investigation of tisagenlecleucel as consolidative therapy in future trials. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
Background: Tisagenlecleucel, an anti-CD19 chimeric antigen receptor (CAR)-T cell therapy, has demonstrated durable responses and a manageable safety profile in adult patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). We report the correlation of pre- and post-infusion factors and biomarkers with efficacy in tisagenlecleucel-treated pts with r/r DLBCL. Methods: Results from JULIET, a global, single-arm, pivotal, phase 2 trial of tisagenlecleucel in adult pts with r/r DLBCL, were analyzed to identify baseline disease and pt characteristics and serum biomarkers that may correlate with efficacy. The relationships between markers such as lactate dehydrogenase (LDH), baseline tumor volume (TV, within 30 days prior to infusion) using positron emission tomography/computed tomography, pre-treatment C-reactive protein (CRP) and thrombocytopenia, as well as cytokine release syndrome (CRS; Penn scale)/neurological events (NE; CTCAE v4.03) severity, and month 3 response (complete or partial response [CR, PR]), progression-free survival (PFS), and overall survival (OS) were assessed. Results: As of December 11, 2018, 115 pts were infused with tisagenlecleucel and evaluable for efficacy. Baseline TV did not correlate with month 3 response; we then examined additional pre-treatment candidate factors. Median LDH levels at enrollment, pre-lymphodepleting chemotherapy (LDC), and pre-infusion were higher in nonresponders (NRs) compared with pts achieving CR/PR. 15/16 pts with pre-infusion grade 3/4 thrombocytopenia (<50 x 109/L) were NRs. Pre-infusion CRP levels did not associate with month 3 response. Univariate and multivariate logistic regression analyses showed that high pre-infusion LDH levels (defined as higher than 2-fold the upper limit of normal [ULN]) were independently associated with NRs. Compared with pts with normal levels of LDH at pre-infusion, pts with LDH 1-2-fold above the ULN and >2-fold above the ULN had poorer PFS and OS (Figure 1). Similar separations of PFS and OS were observed with LDH levels at enrollment and pre-LDC. Pts with pre-infusion platelet levels <50 x 109/L also had significantly worse PFS and OS compared with pts with platelet levels ≥50 x 109/L. Pre-infusion high TV, high CRP, high ferritin, and low serum albumin associated with worse OS, but not PFS. Additional analyses including factors at enrollment and pre-LDC will be presented. Post-infusion, correlations between severe (grade 3/4) CRS/NE and efficacy were examined. All 13 pts with severe NE were NRs. 9/17 pts with grade 3 CRS and all 9 pts with grade 4 CRS were also NRs. In addition, pts with severe CRS had worse PFS and OS compared with pts with grade 0-2 CRS. Similarly, pts with severe NE had worse PFS and OS compared with pts with grade 0-2 NE. High pre-infusion LDH and pre-infusion grade 3/4 thrombocytopenia and severe NE were independently associated with poorer PFS in Cox regression analyses. Severe CRS did not correlate with PFS in a multivariate Cox model. Pts with severe CRS who were also NRs had higher median baseline TV compared with other pts. Notably, the highest levels of serum biomarkers (eg, ferritin, IL4, IL8, IL10), highest LDH, and lowest platelet counts within 1 month post-infusion were observed in pts with severe CRS who were also NRs, compared with pts with severe CRS who achieved CR/PR and pts with grade 0-2 CRS. Analyses of the impact of tocilizumab and steroids usage are ongoing. Conclusions: Multivariate analyses identified that high levels of pre-infusion LDH, a known marker of tumor burden, metabolic activity, and disease aggressiveness, was associated with NRs at month 3 as well as worse PFS and OS. Grade 3/4 thrombocytopenia at pre-infusion and grade 3/4 NE were also associated with poor efficacy outcomes. Furthermore, the highest serum biomarker profiles post-infusion appeared to associate with pts with severe CRS who were also NRs. Overall, these analyses suggest that a subset of pts with aggressive disease at infusion and/or pts with severe CRS/NE had poorer outcomes in the JULIET trial. These analyses may reinforce the rationale for current and future directions of using CAR-T cell therapy in an earlier line of therapy (during less aggressive/less advanced disease), optimizing pt care, and developing interventions to prevent severe CRS and/or NE. Clinical trial information: NCT02445248. Disclosures Westin: Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; 47 Inc: Research Funding; Juno: Other: Advisory Board; MorphoSys: Other: Advisory Board; Unum: Research Funding; Janssen: Other: Advisory Board, Research Funding; Kite: Other: Advisory Board, Research Funding. Tam:Roche: Honoraria; AbbVie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria; Novartis: Honoraria. Jaeger:Novartis, Roche, Sandoz: Consultancy; Celgene, Roche, Janssen, Gilead, Novartis, MSD, AbbVie, Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen, AbbVie, Celgene, Eisai, Gilead, Janssen, Novartis, Roche, Takeda Millennium, MSD, BMS, Sanofi: Honoraria; AbbVie, Celgene, Gilead, Novartis, Roche, Takeda Millennium: Research Funding. McGuirk:Bellicum Pharmaceuticals: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board. Waller:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Other: Travel expenses, Research Funding; Cerus Corporation: Other: Stock, Patents & Royalties; Chimerix: Other: Stock; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Amgen: Consultancy; Kalytera: Consultancy. Jaglowski:Juno: Consultancy, Other: advisory board; Unum Therapeutics Inc.: Research Funding; Kite: Consultancy, Other: advisory board, Research Funding; Novartis: Consultancy, Other: advisory board, Research Funding. Bishop:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Andreadis:Celgene: Research Funding; Juno: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Employment; Kite: Consultancy; Gilead: Consultancy; Jazz Pharmaceuticals: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; Roche: Equity Ownership. Foley:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Fleury:Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; AstraZeneca: Consultancy. Ho:Janssen: Other: Trial Investigator meeting travel costs; Celgene: Other: Trial Investigator meeting travel costs; La Jolla: Other: Trial Investigator meeting travel costs; Novartis: Other: Trial Investigator meeting travel costs. Mielke:EBMT/EHA: Other: Travel support; IACH: Other: Travel support; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; DGHO: Other: Travel support; Bellicum: Consultancy, Honoraria, Other: Travel (via institution); ISCT: Other: Travel support. Teshima:Novartis: Honoraria, Research Funding. Schuster:AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination CAR-T and PD-1 Inhibitors, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Nordic Nanovector: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding. Bachanova:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Incyte: Research Funding; GT Biopharma: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; Celgene: Research Funding. Maziarz:Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Incyte: Consultancy, Honoraria; Celgene/Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Izutsu:Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria; Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy. Kersten:Bristol Myers Squibb: Other: Travel grants, honorarium, or advisory boards; Gilead: Other: Travel grants, honorarium, or advisory boards; Roche: Consultancy, Research Funding, Travel grants, honorarium, or advisory boards; Amgen: Other: Travel grants, honorarium, or advisory boards; Novartis: Consultancy, Other: Travel grants, honorarium, or advisory boards; Roche: Other: Travel grants, honorarium, or advisory boards; Celgene: Other: Travel grants, honorarium, or advisory boards; Kite: Consultancy, Other: Travel grants, honorarium, or advisory boards; Janssen/Cilag: Other: Travel grants, honorarium, or advisory boards; MSD: Other: Travel grants, honorarium, or advisory boards; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Wagner-Johnston:Bayer: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees. Corradini:Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Celgene: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Janssen: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Daiichi Sankyo: Honoraria. Han:Novartis: Employment. Tiwari:Novartis: Employment. Agoulnik:Novartis: Employment. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Bubuteishvili Pacaud:Novartis: Employment. Salles:Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events; BMS: Honoraria; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Epizyme: Consultancy, Honoraria.
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