ALBERT

Description: BACKGROUND The Hedgehog (Hh) signaling pathway, which plays an important role during embryogenesis, can be reactivated in a wide range of cancers. Vismodegib, a selective hedgehog pathway inhibitor, demonstrated antitumor activity in medulloblastoma and basal-cell carcinoma (BCC) patients and has been approved by the FDA and EMA for the treatment of BCC. Preclinical data indicate that Hh pathway can also be activated in lymphoid malignancies and that its inhibition has antitumor activity (Dierks et al, Nature Med 2007; Singh et al, Leukemia 2012; Decker et al, Blood 2012). METHODS We conducted a phase II trial testing vismodegib in patients with relapsed/refractory lymphoma and CLL. Vismodegib was given orally at the dose of 150mg/day until disease progression or unacceptable toxicities for a maximum of one year. The primary objective was to evaluate the efficacy of vismodegib as measured by the best overall response rate (ORR) during the treatment period. RESULTS Between February 2013 and January 2014, 31 patients were recruited including diffuse large B-cell lymphoma (DLBCL, N=12), indolent lymphoma (iNHL, N=6), primary CNS lymphoma (PCNSL, N=10) and chronic lymphocytic leukemia (CLL, N=3). Patient characteristics are summarized in Table 1. We found that Hh signaling pathway (measured by IHC and/or PCR based on the expression of SHH, PTCH 1 and 2, SMO, GLI 1, 2 and 3, and ABCG2) was frequently activated at baseline in lymphoma patients. PK analysis demonstrated bioavailability of vismodegib in blood and CSF (median concentration at day 28 = 13398 [6970-20700] and 323 [99-717]ng/L, respectively). Nevertheless, none of the patients responded to vismodegib therapy, except for one. This patient had an iNHL (grade 3a follicular lymphoma). He experienced a partial remission after 2 cycles that lasted for 4.8 months. Interestingly, this patient had the strongest expression of GLI (1, 2 and 3) by PCR compared to all the other patients tested. All patients discontinued treatment prematurely (Table 1), mostly due to disease progression (90.3%). Adverse events (AE) and serious AEs (SAE) related to vismodegib were observed in 51.6 and 12.9% of the patients, respectively. SAEs related to vismodegib were diarrhea, vomiting, lung infection, hypoglycemia, pulmonary embolism, and skin rash (1 patient each). CONCLUSIONS Despite frequent Hh pathway activation, treatment with vismodegib did not show significant clinical efficacy in patients with lymphoma or CLL. This study was supported by Roche. Table 1. DLBCL iNHL PCNSL CLL Patients (N) 12 6 10 3 Median age (years) 74 74.5 65 74 Median number of prior therapies (min-max) 3 [1-6] 2.5 [1-4] 2 [1-3] 3 [1-4] Median duration of treatment (months) 1.7 1.8 1.2 1.9 Best overall response (CR/uCR/PR) 0% 16.7% (N=1*) 0% 0% Median PFS (months) 1.7 2.2 1.2 3 Median OS (months) 5.4 21.3 16.4 19.4 (*) Duration of response = 4.8 months Disclosures Off Label Use: Vismodegib in lymphoid malignancies. Haioun:Roche: Honoraria. Thieblemont:St. Louis Hospital, Paris, France: Employment. Casasnovas:Roche: Consultancy, Research Funding; Takeda: Consultancy; Gilead: Consultancy. Morschhauser:Genentech Inc./Roche: Other: Advisory boards. Salles:Roche: Honoraria, Research Funding.

Description: Background: Mantle cell lymphoma (MCL), an aggressive B-cell non-Hodgkin lymphoma, remains incurable with standard therapies. The highly selective, potent Bruton tyrosine kinase (BTK) inhibitor acalabrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data showing a high rate of durable responses and a favorable safety profile (Lancet 2017;391:659-667). Here, we present long-term follow-up in these patients. Methods: Eligible patients were aged ≥18 years, had confirmed MCL, Eastern Cooperative Oncology Group performance status ≤2, and had relapsed and/or were refractory to 1-5 prior therapies. Exclusion criteria included prior BTK or BCL-2 inhibitor exposure and concomitant warfarin or equivalent vitamin K antagonists. Oral acalabrutinib 100 mg twice daily was administered until progressive disease or unacceptable toxicity. Response was assessed by investigators based on the Lugano classification (J Clin Oncol 2014;32:3059-3068).Analysis of minimal residual disease using next-generation sequencing (10-6) is ongoing for a subset of patients with available samples and will be presented upon completion. Results: A total of 124 patients were treated; 80% were men, and median age was 68 years (range, 42-90 years) with 65% aged ≥65 years. At baseline, 93% of patients had Eastern Cooperative Oncology Group performance status ≤1, 8% had bulky lymph nodes ≥10 cm, 72% had extranodal involvement, and 44%/17% had intermediate-/high-risk simplified MCL International Prognostic Index scores. The median number of prior therapies was 2 (range, 1-5); 24% were refractory to the most recent prior treatment. As of February 12, 2018, median time on study was 26.3 months (range, 0.3-35.1 months), and 40% of patients remain on treatment. Median relative dose intensity (ratio of actual to planned cumulative dose during drug exposure period) was 99% (range, 27%-100%). Investigator-assessed overall response rate was 81% (95% CI: 73%, 87%), with 43% (95% CI: 34%, 52%) achieving complete response (Table). Overall response rates were consistent across prespecified subgroups of tumor bulk, presence of refractory disease and number/type of prior treatment. Median duration of response was 25.7 months (95% CI: 17.5 months, not reached). Median progression-free survival (PFS) was 19.5 months (95% CI: 16.5 months, 27.7; Figure). Median overall survival (OS) was not reached; the estimated 24-month OS rate was 72% (95% CI: 64%, 80%). The most frequent adverse events (AEs; ≥20%) were primarily Grade 1/2 and included headache (38%), diarrhea (36%), fatigue (28%), cough (22%) and myalgia (21%). Grade 3/4 AEs (≥5%) included anemia (10%), neutropenia (10%) and pneumonia (6%). There were 13 patients (10%) with 16 cardiac events, including 4 Grade 3/4 events (3%) in 1 patient each (acute coronary syndrome, acute myocardial infarction, cardiorespiratory arrest, coronary artery disease). Four patients had hypertension events (3%); 1 event was Grade 3. The most common bleeding events were contusion (13%) and petechiae (9%); all bleeding events were Grade 1/2 except for 3 Grade 3 events (gastrointestinal hemorrhage, hematuria, hematoma). Grade 3/4 infections occurred in 15% of patients and none were Grade 5; there was one case of cytomegalovirus viremia and one case of pneumocystis jiroveci pneumonia (both Grade 2). Treatment discontinuation was primarily due to progressive disease (n=54; 44%) and AEs (n=10; 8%).Twelve AEs led to discontinuation in 10 patients; all of these AEs occurred in only 1 patient each.There were 43 deaths (35%), most commonly from progressive disease (n=29; 23%) or AEs (n=6; 5%). Deaths due to AEs included bilateral pulmonary embolism, critical aortic stenosis, myelodysplastic syndrome, pneumonia, suicide, and non-small cell lung cancer; none were considered to be related to acalabrutinib. Conclusion: Response to acalabrutinib remained consistent during long-term (〉24-month) follow-up, including high response rates, median PFS of 19.5 months, and a median OS that has not yet been reached, confirming efficacy in patients with relapsed/refractory MCL. The AE profile was largely similar to earlier reporting, with limited additional safety events observed with an additional year of follow-up. Disclosures Wang: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Research Funding; MoreHealth: Consultancy; Acerta Pharma: Honoraria, Research Funding; Kite Pharma: Research Funding; Novartis: Research Funding. Rule:Celltrion: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees. Zinzani:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: 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; Astra Zeneca: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau. Casasnovas:MSD: Honoraria; Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Gilead Sciences: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Smith:Genentech: Research Funding; Portola: Research Funding; Pharmacyclics: Research Funding; Merck Sharpe Dohme and Corp: Consultancy, Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding. Morschhauser:BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Panizo:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; Roche: Consultancy, Speakers Bureau. Davies:Janssen: Consultancy, Honoraria; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; ADC Therapeutics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding. Jacobsen:Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Merck: Consultancy. Kater:Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Acerta/AZ: Research Funding; Genentech: Honoraria, Research Funding. Robak:Gilead: Consultancy; Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. Dua:Acerta Pharma: Employment. Frigault:AstraZeneca: Employment, Equity Ownership. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Nguyen:Acerta Pharma: Employment. Patel:Acerta Pharma: Employment, Equity Ownership. Yin:Acerta Pharma: Employment. Jurczak:European Medicines Agency: Consultancy; Astra Zeneca/Acerta: Consultancy, Research Funding; Sandoz-Novartis: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Afimed: Research Funding; Bayer: Research Funding; Beigene: Research Funding; Celgene: Research Funding; Epizyme: Research Funding; Nordic Nanovector: Research Funding; Merck: Research Funding; Morphosys: Research Funding; Pharmacyclics: Research Funding; Servier: Research Funding; Roche: Research Funding; TG Therapeutics: Research Funding.

Description: Abstract 101 Background: Treatment of primary CNS lymphoma (PCNSL) is based on high-dose methotrexate (HD-MTX) containing chemotherapy (CT) followed by brain radiotherapy (RT). Initial CT allowed 30% to 63% of complete response (CR) in recent large series. After CT, consolidation RT can increase the CR rate up to 80%. Despite this high rate of response after initial treatment, the outcome of patients remained poor. The impact of the quality of response on outcome is not well known as well as the outcome of PR patients who converted to CR after RT. We assessed these questions in patients with newly diagnosed PCNSL treated with HD-MTX-containing CT followed by RT in the prospective LNHCP93 GELA study. Methods: 99 patients were treated in this prospective phase II study between 1995 and 2002. Patients younger than 61 years received C5R protocol (Blay et al. Blood 1995), Patients aged 61-70 years received reduced doses of C5R protocol and patients older than 70 years received a specific schedule with MTX, vepeside and cyclophosphamide. After CT, brain RT was planned: 20 Gy whole brain and a 36 Gy boost to the tumor bed. Responses after CT and after RT were evaluated by MacDonald criteria. Evaluation of response was made at time of the beginning of RT, 21-35 days after the last course of CT, and one month after the end of RT. Results: Median age of the 99 PCNSL patients was 63 years (range, 20-82), 51% were male, 51% had performance status 〉1, and 58% had involvement of deep structures of brain. Forty-five patients were younger than 61 years, 36 were aged 61-70 years and 18 older than 70 years. After a median follow-up 83 months, median overall survival (OS) and progression-free survival (PFS) were 33 and 20 months, respectively. Seventeen patients (17%) died of acute toxicity during CT; 3 patients (3%) did not receive RT; 8 patients (8%) progressed or had stable disease after CT and 3 patients (3%) had no available data. Thus, 68 patients were assessable for this exploratory study with thirty-six patients (36%) in PR and 32 patients (32%) in CR after CT. Sixteen of PR patients converted to CR after RT (44% of PR patients after CT). Median OS of patients in CR and PR after CT was 80 and 34 months with a 5-year OS probability of 65% and 29%, respectively (p=0.02). Median PFS of patients in CR and PR after CT was 60 and 21 months with a 5-year PFS probability of 56% and 17%, respectively (p=0.03). In univariate and multivariate analysis, age and response were the two prognostic factors for OS but not performance status, number of tumors at diagnosis, site of tumor (involvement of deep structures). Only response to CT was predictive of PFS in multivariate analysis but not age, performance status, number of tumors, site of tumor at diagnosis. 5-year OS was 65% for CR patients before RT compared to 31% and 28% for PR patients who converted to CR after RT and for patients not in CR after RT, respectively (p=0.06). The 5-year PFS probability was 56% for CR patients before RT compared to 13% and 20% for patients who converted to CR after RT and those not in CR after RT, respectively (p=0.09). Conclusion: Despite the inherent bias of response analysis as a prognostic factor, this analysis of a prospective study of PCNSL patients showed that only patients achieving CR after CT may experience long term survival. This study also showed that PR patients who converted to CR after RT had a poor outcome, similar to patients that did not reach a CR after chemoradiotherapy. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Data from the Phase II GALEN study suggest that chemo-free induction and maintenance with obinutuzumab (G), a glycoengineered type II anti-CD20 antibody, plus lenalidomide (LEN) may have favorable activity and tolerable safety in patients (pts) with relapsed/refractory (R/R) FL (Morschhauser et al. Hematol Oncol 2017). The combination of G and the anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab (atezo), which has a complementary mode of action to anti-CD20 antibodies, has shown activity in R/R FL (Palomba et al. Hematol Oncol 2017). Atezo-G-LEN has the potential to enhance anti-tumor immune response in R/R FL. Interim data from a Phase Ib/II study (NCT02631577) assessing the safety and efficacy of induction and maintenance with atezo-G-LEN in pts with R/R FL are reported. Methods: This is an ongoing, open-label, multicenter study of pts with R/R FL (excluding grade [Gr] 3b) who have received ≥1 prior anti-CD20 antibody-containing chemo-immunotherapy regimen. The study comprises an initial 3+3 dose-escalation phase (to determine the recommended Phase II dose [RP2D] of LEN for the triplet regimen) followed by an expansion phase (RP2D of LEN). Pts receive induction treatment with six 28-day cycles of: G 1000mg IV on day (D) 1, D8, and D15 of Cycle (C) 1 and D1 of C2-6; atezo 840mg IV on D1 and D15 of C2-6; and LEN 15mg or 20mg (dose escalation), or at the RP2D (expansion), PO on D1-21 of C1-6. Pts with a complete response (CR), partial response, or stable disease at the end of induction (EOI) receive 24 months of maintenance with G 1000mg on D1 every 2 months, atezo 840mg on D1 and D2 monthly, and LEN 10mg on D1-21 monthly (months 1-12). Primary endpoints are dose-limiting toxicities (DLTs) during C2, safety/tolerability, and CR (PET-CT) rate by Independent Review Committee (IRC) at EOI (modified Lugano 2014 criteria) in the LEN 20mg (RP2D) expansion cohort. Data cut-off was February 28, 2018. Results: At the time of interim analysis (IA), 29 pts were enrolled and treated (LEN 15mg, n=4; LEN 20mg, n=25). Three pts were receiving induction treatment, 5 had discontinued during induction (death due to progressive disease [PD], n=3; PD, n=1; withdrawal of consent, n=1), 21 had completed induction, and 20 were still receiving maintenance. Baseline characteristics at study entry were: median age, 62 years (range 38-79); male, 52%; Ann Arbor Stage III-IV, 86%; FLIPI high risk (≥3), 28%; bulky disease (≥7cm), 21%; ≥2 prior lines of therapy, 52%; refractory to last treatment line, 48%; and pts with early progression (within 24 months) on first-line treatment (POD24), 31%. No DLTs were reported during C2 at either LEN dose during dose escalation; therefore, LEN 20mg was selected as the RP2D for expansion. Median dose intensity for all 3 study drugs was 95-100% during induction and 100% during maintenance. Twenty-eight pts (97%) had ≥1 adverse event (AE): 18 (62%) Gr ≥3 AEs; 9 (31%) serious AEs; 2 (7%) AEs leading to discontinuation of any study drug (Gr 2 pneumonitis and Gr 2 myalgia secondary to myositis, both leading to discontinuation of atezo); 3 (10%) AEs leading to LEN dose reduction; and 22 (75%) AEs requiring interruption of any treatment (including LEN dose reduction, missed doses or dose delays); no Gr 5 AEs were reported. Common AEs (all-Gr and Gr ≥3) are shown in Table 1. The most common Gr ≥3 AEs were hematologic toxicities (neutropenia [35%], thrombocytopenia [17%], and anemia [10%]) and infections (10%). The most common AEs of special interest (≥4 pts) were infusion-related reactions (35%), dyspnea (21%), hyperthyroidism (17%), hypothyroidism (14%), and pyrexia (17%); all events were mild or moderate, except one case of dyspnea (Gr 3). One second primary malignancy (meningioma) was reported. Among 20 efficacy-evaluable pts, the PET-CT CR rate at EOI was 80% by IRC and 85% by investigator (modified Lugano 2014 criteria) (Table 2). All pts receiving maintenance had durable clinical responses (Figure). Conclusions: At this IA, the overall safety profile observed for the chemo-free triplet regimen atezo-G-LEN is consistent with the known AE profiles for the individual drugs, with acceptable safety and tolerability. Response rates at EOI with atezo-G-LEN compare favorably with those reported for currently available treatments for R/R FL, with preliminary evidence of durable activity. Disclosures Salles: Amgen: Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; BMS: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Acerta: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Gilead: Honoraria, Other: Advisory Board. Ghosh:PCYC: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; F. Hoffman-La Roche Ltd: Research Funding; Spectrum: Consultancy; Forty seven Inc: Research Funding; Abbvie: Consultancy, Speakers Bureau; Juno: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Consultancy, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy. Lossos:Affimed: Research Funding. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Mehta:Incyte: Research Funding; Kite: Consultancy, Speakers Bureau; Spectrum: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Merck: Research Funding; Epizyme: Research Funding; Gilead: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Casasnovas:Celgene: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Abajo:F. Hoffman-La Roche Ltd: Employment, Other: Ownership interests PLC. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Chitra:Genentech/Roche: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Morschhauser:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background DCDS4501A (DCDS), an anti-CD79b monoclonal antibody (Ab), is conjugated to the anti-mitotic agent MMAE. We previously determined a recommended Phase II dose (RP2D) of 2.4 mg/kg every 21 days (q21d), and clinical activity in R/R B-cell NHL at doses ≥ 1.8 mg/kg (Palanca-Wessels et al. ASH 2012). Here we update results from patients (pts) treated at 1.8 mg/kg and from the 2.4 mg/kg expansion cohort. Methods We evaluated ongoing safety, tolerability, pharmacokinetics (PK) and activity of DCDS with or without rituximab (RTX) at 375 mg/m2 q21d in pts with R/R DLBCL and indolent (i)NHL. Results Sixty pts were treated with DCDS (6 at 1.8 mg/kg, 45 at 2.4 mg/kg) and DCDS+RTX (9, DCDS at 2.4 mg/kg). Median age 68 yrs (range 20-86); 82% ECOG PS100-fold lower than acMMAE with an average Cycle 1 value of 5-9 ng/mL at the 2.4 mg/kg ADC dose level. Moderate accumulation of acMMAE and total Ab on the q21d dosing schedule was observed with no accumulation of free MMAE. Overall objective responses were observed in 27/51 (53%) DCDS and 7/9 (78%) DCDS+RTX pts. Objective (OR) and complete responses (CR) by histology were as follows: The median PFS for DLBCL patients treated with DCDS or DCDS + RTX was 149 days. The median PFS for iNHL patients treated with DCDS or DCDS + RTX was 241 days. Conclusions DCDS and DCDS+RTX were generally well-tolerated. Neutropenia and PN were the principal toxicities. PN was reversible in some patients with dose delays and reductions. Encouraging anti-tumor activity was observed in heavily pretreated pts with R/R NHL. Updated results from this Phase I study will be presented. An ongoing randomized Phase II study of DCDS+RTX versus a CD22-directed ADC (DCDT2980S) with the same linker-cytotoxic agent in patients with R/R DLBCL and follicular lymphoma will further assess the efficacy of DCDS in the treatment of NHL. Additional studies of DCDS combined with immunochemotherapy are being planned. Disclosures: Palanca-Wessels: Genentech, inc.: Research Funding. Off Label Use: anti-CD79b Antibody-Drug Conjugate in r/r B-cell NHL. Salles:Genentech, inc.: Consultancy. Czuczman:Genentech, inc.: Consultancy, Honoraria. Flinn:Genentech, inc.: Research Funding. Sehn:Genentech, inc.: Consultancy, Honoraria, Research Funding. Tilly:Genentech, inc.: Honoraria. Advani:Genentech, inc.: Research Funding. Casasnovas:Genentech, inc.: Research Funding. Press:Genentech, inc.: Consultancy, Research Funding. Yalamanchili:Genentech, inc.: Employment. Kahn:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Chai:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Morschhauser:Genentech, inc.: Honoraria, Research Funding.

Description: Key Points Baseline metabolic tumor volume is a strong prognostic factor in early-stage HL. Baseline metabolic tumor volume affects the early response to treatment and, combined with early PET, improves risk stratification.

Description: Introduction: AITL, one of the most common peripheral T-cell Lymphoma portends a poor prognosis. AITL is characterized by neoplastic T cells with a follicular helper immunophenotype, frequent mutations in epigenetic regulators TET2, IDH2, DNMT3A and in RHOA, and a prominent tumor microenvironment that could contribute to lymphomagenesis. Aiming to target this microenvironment and given the promising activity of lenalinomide (Len) in a relapsed setting (PMID: 23731832), we postulated that AITL patients (pts) might benefit from a treatment with Len combined with a classical CHOP regimen. This multicenter, open label, phase 2 trial (NCT01553786) investigates this treatment in previously untreated elderly pts. Patients and methods: Patients older than 59 years were treated with 8 cycles of Len + CHOP 21 (Len 25 mg/day (d), d1 to 14) and received intrathecal methotrexate prophylaxis. Thromboprophylaxis with low molecular weight heparin was mandatory. PET CTs at diagnosis and at the end of treatment were centrally reviewed. The primary objective was to evaluate the complete metabolic response rate according to the Lugano 2014 Classification. Secondary endpoints were safety, progression-free (PFS) and overall survival (OS). Mutations in TET2, IDH2, DNMT3A, RHOA, CD28, PLCG1, STAT3 and STAT5B were analyzed by deep sequencing (1000X) using DNA extracted from formalin-fixed paraffin-embedded tumor samples by PGM technology and were correlated to clinical parameters. Results: Between November 2011 and March 2017, 80 pts were enrolled, and 78 were evaluable. Central pathology review confirmed the diagnosis of AITL in 72 cases (92%). Median age was 69 (59-80), 52 % were female, 68% had a performance status of 0 to 1, 94% an Ann Arbor stage ≥III, 82% IPI≥3. Forty-five patients (58 %) completed the 8 planned cycles (mean number of cycles delivered, 5.9). Of the 624 planned treatment cycles, 458 (72 %) were completed. Treatment was stopped in 8 pts because of progressive disease, and in 15 because of adverse events. Toxicity was within the range expected of R-CHOP therapy with 70% grade 4 neutropenia and 31 % thrombocytopenia. Deep vein thrombosis occurred in 8 pts. Four secondary primary malignancies were reported. Five patients died from toxicity (4 from infection). Len dose reductions or interruptions were applied in 37 (5%) and 59 (9%) cycles, respectively, related to toxic effects. The median dose of Len per patient was 2275 mg (IQR 95-2825)-i.e. 81% of the planned dose of 2800 mg. Doxorubicin and cyclophosphamide were administrated at 98% and 97% of the planned dose. Complete metabolic response was observed in 34 patients (43.6%) (90%CI = [34.0%; 53.5%]), partial metabolic response in 3 (3.8%), no metabolic response in 2 (2.6%) and progressive metabolic disease in 16 (20.5%), the other being not evaluated because of progression (N=20) or death (N=3). With a median follow-up duration of 31.5 months (95%CI = [23.0; 43.7]) at the time of the cut-off, 2-year PFS is 42.3% (95%CI = [30.9%; 53.2%]) and 2-year OS is 60.1% (95%CI = [47.4%; 70.7%]). IPI was strongly associated with the survival (figure 1A). Mutational status was successfully determined in 64 pts with confirmed AITL diagnosis. TET2 mutations were detected in 49 cases (77%), with 28 (43%) pts bearing ≥2 TET2 mutations. RHOAG17V mutations in 34 pts (53%), DNMT3A mutations in 20 (31%) pts, including 6 with the DNMT3AR882X variant and IDH2 mutations in 14 (22%). CD28, PLCCG1 and STAT mutations were detected in less than 10% of pts (figure 1B). TET2 mutations correlated to age〉65 years (p=0.006) and IPI 3-5 (p=0.007). Interestingly, DNMT3A mutations were associated with a decreased response rate (p=0.003), a shorter PFS (p=0.04) and a trend toward a shorter OS (0.08). It is noteworthy that none of the 6 pts with the DNMT3AR882X mutant had response, suggesting that the resistance to anthracycline reported in DNMT3AR882X mutated acute myeloid leukemia (PMID: 27841873) could also occur in DNMT3AR882X mutated AITL. No correlation between other detected mutations and outcome was observed (table 1C). Conclusion A combination of 25 mg of Len for 14 days with CHOP cycles gives acceptable toxicity in AITL elderly pts. However, response rate and outcome appear similar to previous studies. We also confirmed in a prospective study the frequency of mutations in epigenetic regulators and RHOA in AITL and clarified their prognostic impact. Figure Figure. Disclosures Bachy: Gilead Sciences: Honoraria; Sandoz: Consultancy; Janssen: Honoraria; Roche: Research Funding; Takeda: Research Funding; Amgen: Honoraria; Celgene: Consultancy. Cartron:Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria. Casasnovas:Merck: Honoraria; Takeda: Honoraria; Roche: Honoraria; Gilead Sciences: Research Funding; Roche: Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; MSD: Consultancy; merck: Consultancy; takeda: Consultancy; Roche: Consultancy; Janssen: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; MSD: Honoraria. Tilly:Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees. Gaulard:Celgene: Research Funding; Roche: Honoraria; Takeda: Consultancy, Honoraria, Research Funding. Haioun:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sciences: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Description: Temsirolimus has shown clinical activity in heavily pretreated patients with mantle cell lymphoma (MCL) leading to evaluate tolerability and efficacy of combinations regimens. The T3 trial is a multicenter, Phase IB, dose escalation study (3+3) of Temsirolimus administered in combination with three chemotherapy regimens in relapse or refractory (R/R) mantle cell lymphoma (MCL) patients. The primary objective was to determine the maximum tolerated dose (MTD). DLT was assessed during the first two cycles. Study design: Temsirolimus was added for 6 cycles to R-CHOP (R-CHOP-T) administered every 3 weeks or to or R-FC (R-FC-T) and R plus high dose cytarabine and dexamethasone (R-DHA-T) administered every 4 weeks. Temsirolimus was administered IV at day 2, 8 and 15. Three dose levels of Temsirolimus was tested: 15 mg, 25 mg (starting dose) and 50 mg. Patients were treated with one of these 3 chemotherapy regimens according to the choice of local investigator and no randomization was performed. LYSARC was the sponsor and the trial was conducted with a financial support of Pfizer Results: forty-one patients (R-CHOP-T n=10; R-FC-T n=14 and R-DHA-T, n=17)were enrolled. At time of inclusion, median age of patients was 68y (56-79), 32 patients were male, median time from last therapy to inclusion was 23,1m (2-143), MIPI score was low in 8, intermediate in 13 and high in 19 cases (missing=1). Previous lines of treatment included autologous stem cell transplantation in 18 patients. Among patients treated in the R-CHOP-T arm, all patients (n=4) presented grade 3 toxicities at the 25mg dose level. At the 15mg dose level (n=6), one DLT occurs (Thrombopenia). Consequently, the maximum tolerated dose (MTD) of Temsirolimus in the R-CHOP-T was 15 mg. Among patients of the R-FC-T arm (n=14) and R-DHA-T, the recommended dose of Temsirolimus has not been found because of toxicities that occurred at all Temsirolimus doses (25 and 15mg). Hematologic grade 3/4 toxicities were the most frequent, mainly thrombocytopenia (n=28). In term of efficacy, ORR (CR/CRu/PR) during treatment period was 40% for R-CHOP-T including 2 patients who reached CR, 35,7% for R-FC-T including 3 patients who reached CR and 47,1% for R-DHA-T including 6 patients who reached CR. For all patients, mFU is 30.5 m (23-39). The mPFS and mOS according to treatment arms and for all patients (n=41) are as followed: 15,1m and not reached for R-CHOP-T (n= 10); 8.6m and 17.8 m for R-FC-T (n=14) ; 11.9m and 24.2m for R-DHA-T (n=17). In conclusion, the recommended dose of Temsirolimus for R-CHOP-T is 15mg D1,8,15. We are not able to recommend a dose of Temisrolimus for both R-DHA-T and R-FC-T. Hematologic toxicity was the main concern in all arms. A good efficacy in term of response rates PFS and OS was observed in all arms suggesting that Temsirolimus-based chemotherapy regimen should be further investigated in prospective trials but dose of Temsirolimus should be carefully investigated. Disclosures Cartron: Roche: Consultancy, Honoraria; Celgene: Honoraria; Gilead: Honoraria; Jansen: Honoraria. Thieblemont:Roche: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Haioun:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Hermine:AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Research Funding; Alexion: Research Funding.

Description: Introduction Angioimmunoblastic T-cell lymphomas (AITL) are frequently associated with immune system activation such as hypergammaglobulinemia, positive direct antiglobulin test, anti-smooth muscle antibodies and clinical autoimmunity. Autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) have been reported, but to date, there is no specific study focusing on autoimmune cytopenia (AIC) in AITL. We sought to determine the clinical characteristics, evolution and response to treatment of AITL presenting with autoimmune cytopenia, including ITP, AIHA, auto-immune neutropenia (AIN) and pure red cell aplasia (PRCA) in a large cohort of patients from the multicentric T-cell lymphoma consortium (TENOMIC). Patients and methods We conducted a retrospective, multicenter study of patients diagnosed with AITL between 2001 and 2015 and presenting with at least one AIC (i.e. AHAI and/or ITP and/or AIN and/or PRCA, defined according to the international criteria). Patients were retrospectively selected from a cohort of 293 patients with AITL from a multicentric T-cell lymphoma consortium (TENOMIC). Medical charts were collected using a standardized from. Patients with AIC were matched for age and sex to control patients (5/1 ratio) diagnosed with AITL without AIC from the cohort. Results 28 patients were included, with a mean age of 63 years (range 39 - 83), and 50% were females. There were 41 AIC (AIHA, n=21 (including 5 cold agglutinin diseases), ITP, n=12, PRCA, n=7, AIN, n=1). Among them, 17 patients had only one AIC, 7 had both ITP and AIHA (Evan's syndrome) and 4 had PCRA associated with another AIC. One hundred and thirty six control patients were included (mean age 64 years (range 35 - 84), 49% female). Clinical characteristics of AITL at diagnosis showed more stage IV disease in AIC patients versus control patients (86% vs 66%, P= 0.0442), as well as more bone marrow (71% vs 34%, P=0.0005) and splenic (61% vs 19%, P〈 0.0001) involvement. Immune activation markers such as anti-smooth muscle antibodies (71% vs 0.9%, P〈 0.0001), gammaglobulins titers (27 g/l vs 18 g/l, P= 0.0019), and EBV replication (89% vs 61%, P= 0.0232), were significantly increased in AIC patients versus control patients. AIC were mainly concomitant with AITL diagnosis (83%). Only 2 patients had AIC before AITL diagnosis (2 and 8 months), and 4 patients developed AIC during the disease course (median 14 months (8 - 114)). Mean hemoglobin level at AIHA and PRCA diagnosis were 7.1 g/dl and 5.3 g/dl, and red blood cell transfusions were required in 52% and 86% of patients, respectively. Mean platelet count was 35 x 109/L at ITP diagnosis, and 42% of patients had bleeding manifestations, although no life threatening bleeding manifestation was observed. First line treatments of AIC included corticosteroids (88%), chemotherapy for AITL (71%), intravenous immunoglobulin (27%), or other treatments (12%), and were effective in all patients except for two patients who presented with refractory ITP. Ten patients had a relapse of AIC (5 ITP, 4 AIHA, 3 PRCA) with a median time to relapse of 4 months (1 - 18)). All AIC relapses were associated with AITL relapse. Only 3 patients had active AIC while AITL was considered in remission, including one patient who developed ITP after autologous stem cell transplantation. Sixty-four percent versus 66% of patients experienced AITL relapse in AIC and control group, respectively (P=1). Median overall survival (OS) and median progression free survival (PFS) were 77 and 12 months in the AIC group, and 41 and 12 months in the control group, respectively (P=ns). Conclusion In summary, AITL associated with AIC had more advanced disease with increased immune activation compared to our control group, although it did not impact OS and PFS. AIC were mainly inaugural and responded well to chemotherapy. Interestingly, all AIC relapses were associated with AITL relapse. These findings are of interest for management of AITL patients presenting with AIC. Disclosures Casasnovas: Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; ROCHE: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Leblond:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Michel:Amgen: Honoraria; Novartis: Honoraria. Dupuis:janssen: Honoraria; ABBVIE: Membership on an entity's Board of Directors or advisory committees.

Description: In spite of the tremendous progresses of therapeutic approaches in the past decades, the prognosis of AML remains very poor. Developing new biological tools for disease monitoring is therefore a constant challenge, to adapt therapeutic protocols as early as possible. It has been suggested (Leuk Res,1992) that a morphologically assessed rate of decrease of medullary blasts during induction could be a prognostic indicator. Increasing sophistication of flow cytometry (FC) has considerably improved the sensitivity of this technique, allowing for a precise and reliable detection of low blast percentages (