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. Recent clinical trials based on immunotherapies targeting the PD-1/PD-L1 pathway have shown striking durable responses in a subset of patients with solid cancers. The Programmed death 1 (PD-1) protein is a key immune checkpoint inhibitor expressed by activated T cells. Its ligand, PD-L1, was reported highly expressed by tumor cells in some diffuse large B-cell lymphomas (DLBCL) of non-Germinal Center phenotype. We recently reported on the French multicenter GOELAMS075 trial that pre-treatment soluble PD-L1 (sPD-L1) in plasma was elevated in DLBCL patients compared to controls, and that elevated sPD-L1 was associated with inferior overall survival (OS), independent of the International Prognostic Index (IPI) and other clinical factors (Rossille et al., Leukemia 2014). Here, we replicate and extend these findings in two independent studies from Australia and the US. Methods. The protein expression of sPD-L1 was evaluated using a commercial ELISA kit. The French discovery cohort consisted of 288 adults with newly diagnosed aggressive DLBCL, age 18 to 60 years, and treated with R-CHOP or high dose chemotherapy plus rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379); there were also 60 controls. The Australian study consisted of 51 DLBCL patients age 18 to 71 years, all stages, treated with R-CHOP14, along with 57 controls. The US study was an observational cohort from the Iowa/Mayo Lymphoma SPORE and consisted of 225 DLBCLs, age 19 to 92 years, all stages, treated with immunochemotherapy, along with 98 controls. Plasma samples were collected pre-treatment using EDTA tubes for the Australian and the US cohorts, BDª P100 tubes for the French cohort. sPD-L1 expression was measured in Rennes, France (French & US samples) and in Brisbane, Australia (Australian samples).The Kaplan-Meier method and Cox regression were used to model the association of sPD-L1 with OS. The 95th percentile of the sPD-L1 levels in each matched control group was used as the cutoff point to define elevated sPD-L1 levels. Results. Replicating the French findings, sPD-L1 levels were significantly higher for DLBCL patients compared to controls in both the US (P

Description: Key Points IgM+ FL B cells display a stronger BCR response than their GC B-cell counterpart despite significant BCR-related phosphatase activity. M2 macrophages trigger DC-SIGN–dependent cell adhesion and BCR activation in IgM+ FL B cells with a highly mannosylated BCR.

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.