Image texture analysis (radiomics) uses radiographic images to quantify characteristics that may identify tumour heterogeneity and associated patient outcomes. Using fluoro-deoxy-glucose positron emission tomography/computed tomography (FDG-PET/CT)-derived data, including quantitative metrics, image texture analysis and other clinical risk factors, we aimed to develop a prognostic model that predicts survival in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) from GOYA (NCT01287741). Image texture features and clinical risk factors were combined into a random forest model and compared with the international prognostic index (IPI) for DLBCL based on progression-free survival (PFS) and overall survival (OS) predictions. Baseline FDG-PET scans were available for 1263 patients, 832 patients of these were cell-of-origin (COO)-evaluable. Patients were stratified by IPI or radiomics features plus clinical risk factors into low-, intermediate- and high-risk groups. The random forest model with COO subgroups identified a clearer high-risk population (45% 2-year PFS [95% confidence interval (CI) 40%-52%]; 65% 2-year OS [95% CI 59%-71%]) than the IPI (58% 2-year PFS [95% CI 50%-67%]; 69% 2-year OS [95% CI 62%-77%]). This study confirms that standard clinical risk factors can be combined with PET-derived image texture features to provide an improved prognostic model predicting survival in untreated DLBCL.

• Publikační typ
• časopisecké články MeSH

Fc γ receptor IIB (FcγRIIB) is an inhibitory molecule capable of reducing antibody immunotherapy efficacy. We hypothesized its expression could confer resistance in patients with diffuse large B-cell lymphoma (DLBCL) treated with anti-CD20 monoclonal antibody (mAb) chemoimmunotherapy, with outcomes varying depending on mAb (rituximab [R]/obinutuzumab [G]) because of different mechanisms of action. We evaluated correlates between FCGR2B messenger RNA and/or FcγRIIB protein expression and outcomes in 3 de novo DLBCL discovery cohorts treated with R plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) reported by Arthur, Schmitz, and Reddy, and R-CHOP/G-CHOP-treated patients in the GOYA trial (NCT01287741). In the discovery cohorts, higher FCGR2B expression was associated with significantly shorter progression-free survival (PFS; Arthur: hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.01-1.19; P = .0360; Schmitz: HR, 1.13; 95% CI, 1.02-1.26; P = .0243). Similar results were observed in GOYA with R-CHOP (HR, 1.26; 95% CI, 1.00-1.58; P = .0455), but not G-CHOP (HR, 0.91; 95% CI, 0.69-1.20; P = .50). A nonsignificant trend that high FCGR2B expression favored G-CHOP over R-CHOP was observed (HR, 0.67; 95% CI, 0.44-1.02; P = .0622); however, low FCGR2B expression favored R-CHOP (HR, 1.58; 95% CI, 1.00-2.50; P = .0503). In Arthur and GOYA, FCGR2B expression was associated with tumor FcγRIIB expression; correlating with shorter PFS for R-CHOP (HR, 2.17; 95% CI, 1.04-4.50; P = .0378), but not G-CHOP (HR, 1.37; 95% CI, 0.66-2.87; P = .3997). This effect was independent of established prognostic biomarkers. High FcγRIIB/FCGR2B expression has prognostic value in R-treated patients with DLBCL and may confer differential responsiveness to R-CHOP/G-CHOP.

• MeSH
• cyklofosfamid terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   genetika   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie * terapeutické užití   MeSH
• receptory IgG genetika   MeSH
• rituximab terapeutické užití   MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Single-nucleotide polymorphisms (SNPs) have been shown to influence Fcγ receptor (FcγR) affinity and activity, but their effect on treatment response is unclear. We assessed their importance in the efficacy of obinutuzumab or rituximab combined with chemotherapy in untreated advanced follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) in the GALLIUM (www.clinicaltrials.gov #NCT01332968) and GOYA (#NCT01287741) trials, respectively. Genomic DNA was extracted from patients enrolled in GALLIUM (n = 1202) and GOYA (n = 1418). Key germline SNPs, FCGR2A R131H (rs1801274), FCGR3A F158V (rs396991), and FCGR2B I232T (rs1050501), were genotyped and assessed for their impact on investigator-assessed progression-free survival (PFS). In both cohorts there was no prognostic effect of FCGR2A or FCGR3A. In FL, FCGR2B was associated with favorable PFS in univariate and multivariate analyses comparing I232T with I232I, with a more modest association for rituximab-treated (univariate: hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.54-1.14; P = .21) vs obinutuzumab-treated patients (HR, 0.56; 95% CI, 0.34-0.91; P = .02). Comparing T232T with I232I, an association was found for obinutuzumab (univariate: HR, 2.76; 95% CI, 1.02-7.5; P = .0459). Neither observation retained significance after multiple-test adjustment. FCGR2B was associated with poorer PFS in multivariate analyses comparing T232T with I232I in rituximab- but not obinutuzumab-treated patients with DLBCL (HR, 4.40; 95% CI, 1.71-11.32; P = .002; multiple-test-adjusted P = .03); however, this genotype was rare (n = 13). This study shows that FcγR genotype is not associated with response to rituximab/obinutuzumab plus chemotherapy in treatment-naive patients with advanced FL or DLBCL.

• MeSH
• folikulární lymfom * farmakoterapie   MeSH
• humanizované monoklonální protilátky MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nukleotidy terapeutické užití   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• receptory IgG * genetika   MeSH
• rituximab terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.

• MeSH
• cyklofosfamid terapeutické užití   MeSH
• difúzní velkobuněčný B-lymfom * diagnóza   farmakoterapie   genetika   MeSH
• doxorubicin terapeutické užití   MeSH
• lidé MeSH
• mutace MeSH
• prednison terapeutické užití   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie MeSH
• protoonkogenní proteiny c-bcl-2 genetika   MeSH
• protoonkogenní proteiny c-myc * genetika   MeSH
• rituximab terapeutické užití   MeSH
• vinkristin terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for diffuse large B cell lymphoma (DLBCL). Obinutuzumab (G), a glycoengineered, type II anti-CD20 monoclonal antibody, has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. We present the final analysis results of the Phase III GOYA study (NCT01287741), which compared the efficacy and safety of G-CHOP versus R-CHOP in patients with previously untreated DLBCL. METHODS: Patients aged ≥ 18 years with previously untreated advanced DLBCL were randomly assigned to receive eight 21-day cycles of R or G, plus six or eight cycles of CHOP. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, other time-to-event endpoints, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory endpoint. RESULTS: A total of 1418 patients were randomized, with 1414 included in this final analysis (G-CHOP, N = 704; R-CHOP, N = 710). Five-year PFS rates were 63.8% and 62.6% for G-CHOP and R-CHOP, respectively (stratified hazard ratio 0.94, 95% CI 0.78-1.12; p = 0.48). The results of the secondary efficacy endpoints did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3-5 (75.1% vs 65.8%), serious (44.4% vs 38.4%), and fatal (6.1% vs 4.4%) adverse events (AEs) were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7%) versus the R-CHOP arm (4.9%). CONCLUSIONS: The final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. The results of the secondary endpoints were consistent with the primary endpoint. Further exploratory analyses and investigation of biomarkers are ongoing.

• MeSH
• cyklofosfamid aplikace a dávkování   škodlivé účinky   MeSH
• difúzní velkobuněčný B-lymfom farmakoterapie   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• doxorubicin aplikace a dávkování   škodlivé účinky   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• prednison aplikace a dávkování   škodlivé účinky   MeSH
• protokoly antitumorózní kombinované chemoterapie aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• rituximab aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• vinkristin aplikace a dávkování   škodlivé účinky   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

PURPOSE: Natural killer (NK) cells are key effector cells for anti-CD20 monoclonal antibodies (mAb), such as obinutuzumab and rituximab. We assessed whether low pretreatment NK-cell count (NKCC) in peripheral blood or tumor tissue was associated with worse outcome in patients receiving antibody-based therapy. PATIENTS AND METHODS: Baseline peripheral blood NKCC was assessed by flow cytometry (CD3-CD56+ and/or CD16+ cells) in 1,064 of 1,202 patients with follicular lymphoma treated with obinutuzumab or rituximab plus chemotherapy in the phase III GALLIUM trial (NCT01332968) and 1,287 of 1,418 patients with diffuse large B-cell lymphoma (DLBCL) treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP or R-CHOP) in the phase III GOYA trial (NCT01287741). The prognostic value of tumor NK-cell gene expression, as assessed by whole-transcriptome gene expression using TruSeq RNA sequencing, was also analyzed. The association of baseline variables, such as treatment arm, was evaluated using multivariate Cox regression models using a stepwise approach. RESULTS: In this exploratory analysis, low baseline peripheral blood NKCC was associated with shorter progression-free survival (PFS) in both follicular lymphoma [hazard ratio (HR), 1.48; 95% confidence interval (CI), 1.02-2.14; P = 0.04] and DLBCL (HR, 1.36; 95% CI, 1.01-1.83; P = 0.04), and overall survival in follicular lymphoma (HR, 2.20; 95% CI, 1.26-3.86; P = 0.0058). Low tumor NK-cell gene expression was associated with shorter PFS in G-CHOP-treated patients with DLBCL (HR, 1.95; 95% CI, 1.22-3.15; P < 0.01). CONCLUSIONS: These findings indicate that the number of NK cells in peripheral blood may affect the outcome of patients with B-cell non-Hodgkin lymphoma receiving anti-CD20-based immunochemotherapy.

• MeSH
• buňky NK imunologie   patologie   MeSH
• cyklofosfamid aplikace a dávkování   MeSH
• difúzní velkobuněčný B-lymfom krev   farmakoterapie   imunologie   patologie   MeSH
• doxorubicin aplikace a dávkování   MeSH
• folikulární lymfom krev   farmakoterapie   imunologie   patologie   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• imunoterapie MeSH
• lidé MeSH
• míra přežití MeSH
• prednison aplikace a dávkování   MeSH
• prognóza MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• rituximab aplikace a dávkování   MeSH
• senioři MeSH
• vinkristin aplikace a dávkování   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS-International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; P = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; P = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; P = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.

• MeSH
• difúzní velkobuněčný B-lymfom farmakoterapie   genetika   patologie   MeSH
• dospělí MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru diagnóza   epidemiologie   genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mutace * MeSH
• nádorové biomarkery genetika   MeSH
• nádory centrálního nervového systému farmakoterapie   genetika   sekundární   MeSH
• následné studie MeSH
• prediktivní hodnota testů MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   MeSH
• protoonkogenní proteiny c-bcl-2 genetika   MeSH
• protoonkogenní proteiny c-myc genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH