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60th Annual Meeting of the American-Society-of-Hematology (ASH) -- DEC 01-04, 2018 -- San Diego, CA Jurczak, Wojciech/0000-0003-1879-8084; Johnson, Peter/0000-0003-2306-4974; ZINZANI, PIER LUIGI/0000-0002-2112-2651; Leppa, Sirpa/0000-0002-8265-511X WOS: 000468868300004 PubMed: 30901302 PURPOSE Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL. PATIENTS AND METHODS Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. RESULTS A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%). CONCLUSION The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted. (C) 2019 by American Society of Clinical Oncology Amer Soc Hematol Janssen Global Services; Memorial Sloan Kettering Cancer Center Support Grant [P30 CA008748] Supported by Janssen Global Services, which also provided writing and editorial support, and by Memorial Sloan Kettering Cancer Center Support Grant No. P30 CA008748 (A.Y.).

Purpose Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-α and -δ isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade ≥3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma. Despite the curative aim of the treatment, about 30% of the patients have a primary refractory disease or experience a relapse, and unfortunately usually succumb to the lymphoma. Today, the most frequently used tool to evaluate the risk of progression and death is the International Prognostic Index, which considers clinical factors, such as age and stage. This risk score does not acknowledge biological risk factors such as factors in the blood circulation (from here on called circulating factors). Some cell surface proteins can be detected in blood in soluble form, such as soluble CD163 (sCD163), PD-1 (sPD-1), and PD-L1 (sPD-L1). New prognostic tools are needed that would also assist by targeting more intensive treatment for high-risk patients and less intensive treatment for patients with favorable prognosis. The aim of this study was to evaluate circulating factors in patients with DLBCL and their association with survival. The study was based on a prospective cohort of 139 young patients with high-risk DLBCL treated in a Nordic NLG-LBC-05 trial. Blood samples, tumor tissue, and clinical data were available from the patients. We calculated the lymphocyte-to-monocyte ratio (LMR) prior to treatment. We measured levels of soluble forms of cell surface proteins CD163, PD-1, and PD-L1 in the serum of the patients at different time points during the treatment. Methods included ELISA, TRIFMA, immunohistochemistry, and gene expression analysis. In patients with DLBCL, low lymphocyte count, high monocyte count, and low LMR have been shown to be adverse prognostic factors in usually heterogeneous patient cohorts. We confirmed low LMR to predict poor outcome in our cohort of young high-risk patients. Furthermore, we observed that LMR does not, at least directly, reflect the lymphocyte or monocyte count in the tumor microenvironment. CD163 is a scavenger receptor expressed almost exclusively on macrophages and monocytes. We observed that high pretreatment soluble CD163 (sCD163) levels predict poor outcome. Furthermore, the sCD163 levels declined significantly during therapy, suggesting that sCD163 could be used as a disease response biomarker. sCD163 levels correlated with the proportion of CD163+ macrophages and the CD163 gene expression levels, indicating that sCD163 is likely shed, at least partly, from the surface of the macrophages. PD-1 and its ligand PD-L1 are important in the immune defense. We observed that high pretreatment soluble PD-1 (sPD-1) levels were associated with unfavorable survival. The pretreatment sPD-1 levels correlated with tumor tissue PDCD1 gene expression levels and the proportion of PD-1+ T-lymphocytes, suggesting that the T-lymphocytes are likely the main source of sPD-1. sPD-1 and soluble PD-L1 levels declined significantly during therapy, indicating that they could be used as disease response biomarkers. As a summary, we showed LMR, sCD163, and sPD-1 to have prognostic impact on survival in young high-risk patients with DLBCL. Still, future research is needed to further study the role of sCD163 and sPD-1 in DLBCL, and moreover to study sCD163 and sPD-1 as possible tools in treatment selection. Diffuusi suurisoluinen B-solulymfooma (DLBCL) on aggressiivinen imukudossyöpä. Huolimatta hoidon parantavasta tavoitteesta, noin kolmanneksella potilaista tauti ei reagoi hoidolle tai uusiutuu, jolloin potilas yleensä lopulta menehtyy. Yleisin lymfooman uusiutumisen ja kuoleman riskiä arvioiva työkalu on International Prognostic Index, joka huomioi kliinisiä tekijöitä, kuten ikä ja lymfooman levinneisyys. Tämä työkalu ei kuitenkaan huomioi biologisia riskitekijöitä, kuten esimerkiksi veressä kiertäviä proteiineja. Onkin tarve uusille DLBCL:n uusiutumisriskiä arvioiville työkaluille, joiden avulla voitaisiin kohdentaa tehokkaampaa hoitoa korkean riskin potilaille ja toisaalta kevyempää hoitoa paremman ennusteen potilaille. Tämän tutkimuksen tavoitteena oli määrittää verenkierrossa olevia tekijöitä DLBCL:aa sairastavilla potilailla sekä tutkia näiden tekijöiden vaikutusta ennusteeseen. Tutkimus pohjautui 139 nuoren korkean riskin DLBCL-potilaan aineistoon. Potilaista oli saatavilla verinäytteitä, kasvainkudosta sekä kliiniset tiedot. Laskimme hoitoa edeltävän lymfosyytti-monosyytti-suhteen (LMR) verestä. Määritimme valikoitujen solun pinnan proteiinien (CD163, PD-1 ja PD-L1) liukoisten muotojen tasoja potilaiden verinäytteistä hoidon eri vaiheissa. Aiemmin heterogeenisissä DLBCL-potilasaineistoissa on osoitettu matalan lymfosyyttimäärän, korkean monosyyttimäärän ja matalan LMR:n yhdistyvän huonoon ennusteeseen. Tuloksemme vahvistivat matalan LMR:n liittyvän huonoon ennusteeseen nuorilla korkean riskin DLBCL-potilailla. Lisäksi havaitsimme, että LMR ei ainakaan suoraan heijasta kasvaimen mikroympäristön lymfosyytti- ja monosyyttimäärää. CD163 on lähinnä makrofagien ja monosyyttien pinnalla oleva proteiini. Havaitsimme korkean, hoitoa edeltävän liukoisen CD163-tason ennustavan potilaiden huonoa selviytymistä. Hoidon myötä liukoisen CD163:n tasot laskivat merkittävästi, minkä perusteella liukoista CD163:a voisi käyttää apuna lymfooman hoitovastetta arvioitaessa. Hoitoa edeltävä liukoisen CD163:n taso oli yhteydessä sekä kasvainkudoksen CD163-positiivisten makrofagien määriin, että CD163:n geeniekspressiotasoihin viitaten siihen, että liukoinen CD163 on peräisin, ainakin osittain, sen irtoamisesta kasvainkudoksen makrofagien pinnalta. PD-1 ja PD-L1 ovat tärkeitä tekijöitä immuunipuolustuksessa. Havaitsimme hoitoa edeltävän korkean liukoisen PD-1:n tason liittyvän potilaiden huonoon ennusteeseen. Hoitoa edeltävä liukoisen PD-1:n taso oli yhteydessä kasvainkudoksen PD-1-proteiinia koodaavan geenin ekspressiotasoihin ja kasvainkudoksen PD-1-positiivisten lymfosyyttien määriin. Tämä viittaa siihen, että kasvainkudoksen lymfosyytit ovat todennäköisesti pääasiallinen liukoisen PD-1:n lähde. Havaitsimme lisäksi liukoisen PD-1:n ja PD-L1:n tasojen laskevan merkittävästi hoidon myötä, mikä viittaisi siihen, että niitä voisi käyttää apuna lymfooman hoitovastetta arvioitaessa. Osoitimme siis, että LMR, liukoinen CD163 ja liukoinen PD-1 vaikuttavat ennusteeseen nuorilla korkean riskin DLBCL-potilailla. Jatkossa tarvitaan lisää tutkimusta liukoisen CD163:n ja PD-1:en tehtävästä DLBCL:ssa sekä niiden mahdollisesta hyödyntämisestä hoidon valinnassa.