Giuseppe Gritti
@asst-pg23.it
Consultant hematologist, Hematology and BMT Unit, Department of Hematology and Oncology
ASST Papa Giovanni XXIII
RESEARCH, TEACHING, or OTHER INTERESTS
Hematology, Oncology
Scopus Publications
Scopus Publications
Giuseppe Gritti, Silvia Ferrari, Federico Lussana, Anna Maria Barbui, Francesco Landi, Monica Rondi, Alessandro Putelli, Francesco Ballardini, Giulia Quaresmini, Muriel Paganessi,et al.
Springer Science and Business Media LLC
Giuseppe Gritti, Anton Belousov, James Relf, Mark Dixon, Maneesh Tandon, and Krishna Komanduri
American Society of Hematology
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that can occur due to high-level immune activation. CRS can be triggered non-speci fi cally by T-cell engaging therapies administered to treat hematologic malignancies. 1-3 Clinical manifestations vary, from fever to more severe symptoms requiring hospitalization. 2 Although CRS severity is in fl uenced by disease status and underlying histology, prediction of CRS risk is currently not possible. 4 Identi fi cation of high-grade CRS risk factors is critical to inform decisions on patient management when administering T-cell engaging therapies. 5 Glo
Sam Yuen, Tycel J. Phillips, Rajat Bannerji, Paula Marlton, Giuseppe Gritti, John F. Seymour, Anna Johnston, Christopher Arthur, Anna Dodero, Sunil Sharma,et al.
Wiley
AbstractThe Phase 2 portion of this study evaluated safety and efficacy of polatuzumab vedotin 1.8 mg/kg and venetoclax 800 mg, plus fixed‐dose obinutuzumab 1000 mg or rituximab 375 mg/m2 in patients with relapsed/refractory (R/R) follicular lymphoma (FL) or diffuse large B‐cell lymphoma (DLBCL), respectively. Patients with complete response (CR) or partial response (PR)/stable disease (FL) or CR/PR (DLBCL) at end of induction (EOI; six 21‐day cycles) received post‐induction therapy with venetoclax and obinutuzumab or rituximab, respectively. Primary endpoint was CR rate at EOI. Safety‐evaluable populations included 74 patients (FL cohort; median age 64 years; progression of disease within 24 months on first‐line treatment, 25.7%; FL International Prognostic Index 3–5, 54.1%; ≥2 previous therapies, 74.3%) and 57 patients (DLBCL cohort; median age 65 years; International Prognostic Index 3–5, 54.4%; ≥2 previous therapies, 77.2%). The most common non‐hematologic adverse events (mostly Grades 1–2) in the FL and DLBCL cohorts were diarrhea (55.4% and 47.4%, respectively) and nausea (47.3% and 36.8%); neutropenia was the most common Grades 3–4 toxicity (39.2% and 52.6%). Efficacy‐evaluable populations included patients treated at the recommended Phase 2 dose (FL, n = 49; DLBCL, n = 48). CR rates at EOI were 59.2% (FL) and 31.3% (DLBCL); median progression‐free survival was 22.8 months (95% confidence interval [CI], 14.5—not evaluable) and 4.6 months (95% CI, 3.6–8.1), respectively. Polatuzumab vedotin plus venetoclax and obinutuzumab/rituximab had acceptable safety in patients with R/R FL or DLBCL, with promising response rates in R/R FL, including high‐risk patients.
A. Pinto, M. Caltagirone, M. Battista, G. C. Gazzoli, C. Patti, E. Pennese, S. De Lorenzo, V. Pavone, M. Merli, A. Chiarenza,et al.
Wiley
SummaryURBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab‐based immuno‐chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID‐19 emergency declaration in Italy. It is currently ongoing for follow‐up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll‐out phases and prevalence of SARS‐CoV‐2 variants. Outcomes of interest of the present sub‐analysis included SARS‐CoV‐2 infection rates and COVID‐19‐related hospitalizations/deaths. At data cut‐off, 86 (28.8%) and 213 patients (71.2%) were treated before and during/after the COVID‐19 outbreak respectively; 294 (98.3%) completed the induction, 31 (10.4%) completed maintenance and 170 (56.9%) were still on maintenance. Overall, 245 patients (81.9%) received at least one SARS‐CoV‐2 vaccine dose: 13.5%, 31.4% and 55.1% received one, two and three doses respectively. We observed a substantial decrease in COVID‐19‐related mortality rates in pre‐ versus post‐vaccination phases, along with a reduction in COVID‐19‐related outcomes due to the shift from alpha/delta to omicron variant predominance. No differences emerged between patients given maintenance or not, although the schedule was modified in 65% of cases. To our knowledge, URBAN represents the largest dataset of COVID‐19‐related outcomes in FL patients extensively exposed to obinutuzumab. ClinicalTrials.gov identifier: NCT04034056.
Pier Luigi Zinzani, Armando Santoro, Giuseppe Gritti, Pauline Brice, Paul M. Barr, John Kuruvilla, David Cunningham, Justin Kline, Nathalie A. Johnson, Neha Mehta-Shah,et al.
American Society of Hematology
Abstract Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) have poor responses to salvage therapy. Nivolumab and brentuximab vedotin (BV) showed promising early efficacy in patients with R/R PMBL in the phase 1/2 open-label, multicenter CheckMate 436 study; we report safety and efficacy findings from the 3-year follow-up. Patients who were eligible were aged ≥15 years with R/R PMBL previously treated with either high-dose chemotherapy plus autologous hematopoietic cell transplantation (HCT) or ≥2 prior multiagent chemotherapies, and had Eastern Cooperative Oncology Group performance status scores of 0 to 1 and CD30 expression of ≥1%. Patients were treated with nivolumab 240 mg and BV 1.8 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points included complete response rate, duration of response, progression-free survival (PFS), and overall survival (OS). Safety was monitored throughout. At final database lock (30 March 2022), 29 patients had received nivolumab plus BV; median follow-up was 39.6 months. Investigator-assessed ORR was 73.3%; median time to response was 1.3 months (range, 1.1-4.8). Median PFS was 26.0 months; median OS was not reached. PFS and OS rates at 24 months were 55.5% (95% confidence interval [CI], 32.0-73.8) and 75.5% (95% CI, 55.4-87.5), respectively. The most frequently occurring grade 3/4 treatment-related adverse event was neutropenia. Consolidative HCT was received by 12 patients, with a 100-day complete response rate of 100.0%. This 3-year follow-up showed long-term efficacy for nivolumab plus BV in R/R PMBL, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT02581631.
Emmanuel Bachy, Kerry J. Savage, Huiqiang Huang, Yok-Lam Kwong, Giuseppe Gritti, Qingyuan Zhang, Anna Marina Liberati, Junning Cao, Haiyan Yang, Siguo Hao,et al.
American Society of Hematology
Abstract Patients with relapsed/refractory (R/R) mature T- and natural killer (NK)–cell neoplasms lack effective treatments after failure of standard therapies. This phase 2 study evaluated the efficacy and safety of the programmed cell death protein 1 inhibitor tislelizumab in these patients. Seventy-seven patients were treated with 200 mg tislelizumab every 3 weeks. Twenty-two patients with extranodal NK-/T-cell lymphomas were enrolled in cohort 1; 44 patients with peripheral T-cell lymphoma (PTCL) were enrolled in cohort 2 (21 patients had PTCL not otherwise specified, 11 patients had angioimmunoblastic T-cell lymphoma, and 12 patients had anaplastic large-cell lymphoma). Cohort 3 comprised 11 patients with cutaneous T-cell lymphoma, of which 8 patients had mycosis fungoides (MF) and 3 had Sézary syndrome. Of the 77 patients, 76.6% had advanced-stage disease, 51.9% had refractory disease, and 49.4% received ≥3 prior systemic regimens. Promising efficacy was observed in cohort 3 (median follow-up [FU], 16.6 months; overall response rate [ORR], 45.5%; complete response [CR], 9.1%; median duration of response [DOR], 11.3 months; median progression-free survival, 16.8 months; median overall survival, not reached). Modest efficacy was observed in cohort 1 (median FU, 8.4 months; ORR, 31.8%; CR, 18.2%; median DOR, not reached) and cohort 2 (median FU, 9.3 months; ORR, 20.5%; CR, 9.1%; median DOR, 8.2 months). Most treatment-related adverse events were grade 1 or 2, and the safety profile was consistent with the known safety profile of tislelizumab. In conclusion, tislelizumab was well tolerated, achieving modest efficacy in R/R mature T- and NK-cell neoplasms, with some long-lasting remissions. This trial was registered at www.clinicaltrials.gov as #NCT03493451.
A. Stathis, F. Hitz, S. Schär, U. Novak, N. Fischer, U. Mey, G. Gritti, T. Zander, N. Lang, A. Cairoli,et al.
Wiley
N. Mehta‐Shah, E. D. Jacobsen, P. L. Zinzani, J. Zain, M. Mead, C. Casulo, G. Gritti, L. Pinter‐Brown, K. Izutsu, S. Waters,et al.
Wiley
Elisabeth A. Lasater, Dhara N. Amin, Rajat Bannerji, Raghuveer Singh Mali, Kathy Barrett, Ryan N. Rys, Jason Oeh, Eva Lin, Tim Sterne‐Weiler, Ellen Rei Ingalla,et al.
Wiley
AbstractThe treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge. Here, we identify the pro‐survival BCL‐2 protein family member MCL‐1 as a resistance factor for the BCL‐2 inhibitor venetoclax in non‐Hodgkin lymphoma (NHL) cell lines and primary NHL samples. Mechanistically, we show that the antibody‐drug conjugate polatuzumab vedotin promotes MCL‐1 degradation via the ubiquitin/proteasome system. This targeted MCL‐1 antagonism, when combined with venetoclax and the anti‐CD20 antibodies obinutuzumab or rituximab, results in tumor regressions in preclinical NHL models, which are sustained even off‐treatment. In a Phase Ib clinical trial (NCT02611323) of heavily pre‐treated patients with relapsed or refractory NHL, 25/33 (76%) patients with follicular lymphoma and 5/17 (29%) patients with diffuse large B‐cell lymphoma achieved complete or partial responses with an acceptable safety profile when treated with the recommended Phase II dose of polatuzumab vedotin in combination with venetoclax and an anti‐CD20 antibody.
Leo I. Gordon, Reem Karmali, Jason B. Kaplan, Rakesh Popat, Howard A. Burris, Silvia Ferrari, Sumit Madan, Manish R. Patel, Giuseppe Gritti, Dima El-Sharkawi,et al.
Impact Journals, LLC
We report an updated analysis from a phase I study of the spleen tyrosine kinase (SYK) and FMS-like tyrosine kinase 3 inhibitor mivavotinib, presenting data for the overall cohort of lymphoma patients, and the subgroup of patients with diffuse large B-cell lymphoma (DLBCL; including an expanded cohort not included in the initial report). Patients with relapsed/refractory lymphoma for which no standard treatment was available received mivavotinib 60–120 mg once daily in 28-day cycles until disease progression/unacceptable toxicity. A total of 124 patients with lymphoma, including 89 with DLBCL, were enrolled. Overall response rates (ORR) in response-evaluable patients were 45% (43/95) and 38% (26/69), respectively. Median duration of response was 28.1 months overall and not reached in DLBCL responders. In subgroups with DLBCL of germinal center B-cell (GCB) and non-GCB origin, ORR was 28% (11/40) and 58% (7/12), respectively. Median progression free survival was 2.0 and 1.6 months in the lymphoma and DLBCL cohorts, respectively. Grade ≥3 treatment-emergent adverse events occurred in 96% of all lymphoma patients, many of which were limited to asymptomatic laboratory abnormalities; the most common were increased amylase (29%), neutropenia (27%), and hypophosphatemia (26%). These findings support SYK as a potential therapeutic target for the treatment of patients with B-cell lymphomas, including DLBCL. Trial registration: ClinicalTrials.gov number: NCT02000934.
Alejandro Martín García-Sancho, Monica Bellei, Miriam López-Parra, Giuseppe Gritti, María Cortés, Silvana Novelli, Carlos Panizo, Luigi Petrucci, Antonio Gutiérrez, Ivan Dlouhy,et al.
Ferrata Storti Foundation (Haematologica)
Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare lymphoid malignancies that mostly have poor prognoses with currently available treatments. Upfront consolidation with autologous stem cell transplantation (ASCT) is frequently carried out, but its efficacy has never been investigated in randomized trials. We designed a multicenter, international, retrospective study with the main objective of comparing progression-free survival and overall survival of patients with PTCL who underwent ASCT in complete remission (CR) after first-line chemotherapy with a control group who did not undergo ASCT. From the initial population of 286 registered patients, 174 patients with PTCL other than anaplastic large cell lymphoma, ALK-positive, deemed fit for ASCT at the time of diagnosis, and who were in CR or uncertain CR after induction therapy (CR1) were included in our analysis. one hundred and three patients underwent ASCT, whereas 71 did not, in most cases (n=53) because the physician decided against it. With a median follow-up of 65.5 months, progression-free survival was significantly better in the transplanted patients than in the non-transplanted group: 63% versus 48% at 5 years (P=0.042). Overall survival was significantly longer for ASCT patients in the subgroup with advanced stage at diagnosis (5-year overall survival: 70% vs. 50%, P=0.028). In the multivariate analysis, first-line ASCT was associated with significantly prolonged progression-free survival (HR=0.57, 95% CI: 0.35-0.93) and overall survival (HR=0.57, 95% CI: 0.33-0.99). In conclusion, our study supports the use of ASCT as a consolidation strategy for patients with PTCL in CR1. These results should be confirmed in a prospective randomized study.
Yeman B. Hagos, Ayse U. Akarca, Alan Ramsay, Riccardo L. Rossi, Sabine Pomplun, Victoria Ngai, Alessia Moioli, Andrea Gianatti, Christopher Mcnamara, Alessandro Rambaldi,et al.
Wiley
AbstractThe spatial architecture of the lymphoid tissue in follicular lymphoma (FL) presents unique challenges to studying its immune microenvironment. We investigated the spatial interplay of T cells, macrophages, myeloid cells and natural killer T cells using multispectral immunofluorescence images of diagnostic biopsies of 32 patients. A deep learning‐based image analysis pipeline was tailored to the needs of follicular lymphoma spatial histology research, enabling the identification of different immune cells within and outside neoplastic follicles. We analyzed the density and spatial co‐localization of immune cells in the inter‐follicular and intra‐follicular regions of follicular lymphoma. Low inter‐follicular density of CD8+FOXP3+ cells and co‐localization of CD8+FOXP3+ with CD4+CD8+ cells were significantly associated with relapse (p = 0.0057 and p = 0.0019, respectively) and shorter time to progression after first‐line treatment (Logrank p = 0.0097 and log‐rank p = 0.0093, respectively). A low inter‐follicular density of CD8+FOXP3+ cells is associated with increased risk of relapse independent of follicular lymphoma international prognostic index (FLIPI) (p = 0.038, Hazard ratio (HR) = 0.42 [0.19, 0.95], but not independent of co‐localization of CD8+FOXP3+ with CD4+CD8+ cells (p = 0.43). Co‐localization of CD8+FOXP3+ with CD4+CD8+ cells is predictors of time to relapse independent of the FLIPI score and density of CD8+FOXP3+ cells (p = 0.027, HR = 0.0019 [7.19 × 10−6, 0.49], This suggests a potential role of inter‐follicular CD8+FOXP3+ and CD4+CD8+ cells in the disease progression of FL, warranting further validation on larger patient cohorts.
Paul M. Maciocia, Patrycja A. Wawrzyniecka, Nicola C. Maciocia, Amy Burley, Thaneswari Karpanasamy, Sam Devereaux, Malika Hoekx, David O’Connor, Theresa Leon, Tanya Rapoz-D’Silva,et al.
American Society of Hematology
Abstract T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in >70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.
Olga Minenkova, Daniela Santapaola, Ferdinando Maria Milazzo, Anna Maria Anastasi, Gianfranco Battistuzzi, Caterina Chiapparino, Antonio Rosi, Giuseppe Gritti, Gianmaria Borleri, Alessandro Rambaldi,et al.
Elsevier BV
Ferdinando Bonfiglio, Alessio Bruscaggin, Francesca Guidetti, Lodovico Terzi di Bergamo, Martin Faderl, Valeria Spina, Adalgisa Condoluci, Luisella Bonomini, Gabriela Forestieri, Ricardo Koch,et al.
American Society of Hematology
Abstract Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments.
Luca Ceriani, Lisa Milan, Luciano Cascione, Giuseppe Gritti, Federico Dalmasso, Fabiana Esposito, Maria Cristina Pirosa, Sämi Schär, Andrea Bruno, Stephan Dirnhofer,et al.
Wiley
AbstractFunctional parameters from positron emission tomography (PET) seem promising biomarkers in various lymphoma subtypes. This study investigated the prognostic value of PET radiomics in diffuse large B‐cell lymphoma (DLBCL) patients treated with R‐CHOP given either every 14 (testing set) or 21 days (validation set). Using the PyRadiomics Python package, 107 radiomics features were extracted from baseline PET scans of 133 patients enrolled in the Swiss Group for Clinical Cancer Research 38/07 prospective clinical trial (SAKK 38/07) [ClinicalTrial.gov identifier: NCT00544219]. The international prognostic indices, the main clinical parameters and standard PET metrics, together with 52 radiomics uncorrelated features (selected using the Spearman correlation test) were included in a least absolute shrinkage and selection operator (LASSO) Cox regression to assess their impact on progression‐free (PFS), cause‐specific (CSS), and overall survival (OS). A linear combination of the resulting parameters generated a prognostic radiomics score (RS) whose area under the curve (AUC) was calculated by receiver operating characteristic analysis. The RS efficacy was validated in an independent cohort of 107 DLBCL patients. LASSO Cox regression identified four radiomics features predicting PFS in SAKK 38/07. The derived RS showed a significant capability to foresee PFS in both testing (AUC, 0.709; p < 0.001) and validation (AUC, 0.706; p < 0.001) sets. RS was significantly associated also with CSS and OS in testing (CSS: AUC, 0.721; p < 0.001; OS: AUC, 0.740; p < 0.001) and validation (CSS: AUC, 0.763; p < 0.0001; OS: AUC, 0.703; p = 0.004) sets. The RS allowed risk classification of patients with significantly different PFS, CSS, and OS in both cohorts showing better predictive accuracy respect to clinical international indices. PET‐derived radiomics may improve the prediction of outcome in DLBCL patients.
P. A. Wawrzyniecka, L. Ibrahim, G. Gritti, M. A. Pule, and P. M. Maciocia
Springer Science and Business Media LLC
Yeman Brhane Hagos, Ayse U Akarca, Alan Ramsay, Riccardo L Rossi, Sabine Pomplun, Alessia Moioli, Andrea Gianatti, Christopher Mcnamara, Alessandro Rambaldi, Sergio A. Quezada,et al.
Springer Nature Switzerland
Francesco Perrone, Maria Carmela Piccirillo, Paolo Antonio Ascierto, Carlo Salvarani, Roberto Parrella, Anna Maria Marata, Patrizia Popoli, Laurenzia Ferraris, Massimiliano M. Marrocco-Trischitta, Diego Ripamonti,et al.
Springer Science and Business Media LLC
Francesco Perrone , Maria Carmela Piccirillo, Paolo Antonio Ascierto, Carlo Salvarani, Roberto Parrella, Anna Maria Marata, Patrizia Popoli, Laurenzia Ferraris, Massimiliano M. Marrocco‐Trischitta, Diego Ripamonti, Francesca Binda, Paolo Bonfanti, Nicola Squillace, Francesco Castelli, Maria Lorenza Muiesan, Miriam Lichtner, Carlo Calzetti, Nicola Duccio Salerno, Luigi Atripaldi, Marco Cascella, Massimo Costantini, Giovanni Dolci, Nicola Cosimo Facciolongo, Fiorentino Fraganza, Marco Massari, Vincenzo Montesarchio, Cristina Mussini, Emanuele Alberto Negri, Gerardo Botti, Claudia Cardone, Piera Gargiulo, Adriano Gravina, Clorinda Schettino, Laura Arenare, Paolo Chiodini and Ciro Gallo on behalf of the TOCIVID‐19 investigators, Italy
Giuseppe Gritti, Federico Raimondi, Barbara Bottazzi, Diego Ripamonti, Ivano Riva, Francesco Landi, Leonardo Alborghetti, Marco Frigeni, Marianna Damiani, Caterina Micò,et al.
Springer Science and Business Media LLC
Giuseppe Gritti, Federico Raimondi, Barbara Bottazzi, Diego Ripamonti, Ivano Riva, Francesco Landi, Leonardo Alborghetti, Marco Frigeni, Marianna Damiani, Caterina Micò,et al.
Springer Science and Business Media LLC
G. Apolone, A. Ardizzoni, A. Biondi, A. Bortolami, C. Cardone, C.M. Ciniselli, P. Conte, C. Crippa, F. de Braud, M. Duca,et al.
Elsevier BV
Marianna Damiani, Lucia Gandini, Francesco Landi, Gianmaria Borleri, Fabrizio Fabretti, Giuseppe Gritti, and Ivano Riva
Elsevier BV
Philippe Armand, Ann Janssens, Giuseppe Gritti, John Radford, John Timmerman, Antonio Pinto, Santiago Mercadal Vilchez, Peter Johnson, David Cunningham, John P. Leonard,et al.
American Society of Hematology
Abstract Nivolumab, an anti–programmed death-1 (PD-1) monoclonal antibody, showed promising activity in relapsed or refractory (R/R) follicular lymphoma (FL) in a phase 1 study. We conducted a phase 2 trial to further evaluate its efficacy and safety in patients with R/R FL and to explore biomarkers of response. Patients with R/R FL and at least 2 prior lines of therapy, each containing a CD20 antibody or an alkylating agent, were treated with nivolumab 3 mg/kg every 2 weeks. The primary end point was objective response rate (ORR) assessed by an independent radiologic review committee. Biomarker analyses included gene expression profiling and multiplex immunofluorescence studies of pretreatment tumor samples. A total of 92 patients were treated. After a minimum follow-up of 12 months, ORR was 4% (4 of 92 patients). Median progression-free survival (PFS) was 2.2 months (95% confidence interval [CI], 1.9-3.6 months). Median duration of response was 11 months (95% CI, 8-14 months). Exploratory analyses suggested that responders had significantly higher proportion of CD3+ T cells in the tumor microenvironment than nonresponders, but no significant differences in PD-1 or programmed death-ligand 1 expression were observed. High expression of a set of tumor-associated macrophage genes was associated with reduced PFS (hazard ratio, 3.28; 95% CI, 1.76-6.11; P = .001). The safety profile was consistent with previous reports of nivolumab. In conclusion, nivolumab monotherapy was associated with very limited activity in patients with R/R FL. Better understanding of the immune biology of this disease may facilitate the development of effective checkpoint-based strategies. This trial was registered at www.clinicaltrials.gov as #NCT02038946.
Federico Lussana, Giuseppe Gritti, and Alessandro Rambaldi
American Society of Clinical Oncology (ASCO)
The outcome of B-cell precursor acute lymphoblastic leukemia (ALL) is different in children and adults, with overall survival (OS) rates at 5 years ranging from 90% to 45%. Significant needs also remain unmet in patients with B-cell non-Hodgkin lymphoma (NHL), with rates of refractory disease up to 20% according to histology in the rituximab era. In both ALL and NHL, many patients fail not only front-line but also salvage treatments, including allogeneic hematopoietic stem cell transplantation (alloHSCT). The therapeutic scenario for these patients with relapsed/refractory (R/R) disease is evolving, and immunotherapy is at the forefront. It took many years to move from the first to the current generation of bispecific antibodies that are changing the therapeutic landscape of acute leukemias and lymphomas. Today the ability to produce recombinant antibodies allows the generation of bispecific antibodies with defined pharmacological properties (Fig 1). Herein, we have reviewed the clinical development of antibodies designed to redirect the cytotoxic potential of nonantigen-specific T cells on specific antigens, such as CD19 and CD20 expressed on the cell surface of precursor and mature B lymphocytes.