Citations

Abstract Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 “don't eat me” signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

Abstract Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically <6 months. However, data in patients that develop SCNS following primary therapy that contains a rituximab-based-regimen as well as the impact of more intensified treatment for SCNS are limited. Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS. Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy's and St. Thomas' Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records. Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87%) patients and 112 (40%) had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27%) or without upfront CNS prophylaxis (N=205, 73%) (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15%). In multivariable analysis, performance status >1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, P<0.01]). The 2yr post-SCNS survival for patients treated with HDMTX and/or platinum-based regimens (N=163) was 29% (95% CI 22-37). For patients with isolated parenchymal SCNS, single modality treatment with radiotherapy resulted in 2-yr OS of 19% (95% CI 8-35). For the subgroup of 49 patients treated with HDMTX- and/or platinum-based regimens for isolated SCNS after 1st line DLBCL treatment and with performance status 0 or 1, the 2yr post-SCNS survival was 46% (95% CI 31-59). Overall, 9% of the patients received HDT with ASCT as part of salvage therapy at the time of SCNS. Amongst 36 SCNS patients without systemic involvement and in CR following intensive treatment (HDMTX and/or platinum-based treatments), 11 patients consolidated with HDT had similar outcomes to 25 patients treated without consolidating HDT (P=0.9, Fig 1) Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status >1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS. Disclosures El-Galaly: Roche: Consultancy, Other: travel funding. Cheah:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Speaker's Bureau. Kansara:Celgene: Honoraria. Connors:Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.

PURPOSE Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger. PATIENTS AND METHODS We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score–weighted (PSW) analysis were performed. RESULTS Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2). CONCLUSION In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.