Zucca, Emanuele

INTRODUCTION: EMZL is a heterogeneous disease with variable risk for relapse and progression. Based on age ≥70 years, stage III-IV and elevated LDH, Thieblemont et al (Blood. 2017) developed the MALT-IPI to identify high-risk patients. In this index, disease characteristics (stage and LDH) account for 66% while a disease nonspecific characteristic (age) for 33% of the index score. We reported (Am J Hematol. 2019) that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival and increased incidence of higher grade transformation. To better recognize disease-attributable high-risk patients, we developed a new EMZL prognosis score chiefly based on patient's disease characteristics. METHODS: The revised (R)-MALT-IPI was developed using a retrospective data set of 405 EMZL patients treated at the University of Miami (UM) from 1995 to 2017. Cox proportional hazards regression analysis was conducted to evaluate the effect of the potential prognostic variables on progression-free survival (PFS) and overall survival (OS) and to develop the new index R-MALTI-IPI based on PFS. Model validation was performed in two independent cohorts of EMZL patients from the University of Iowa/Mayo Clinic Molecular Epidemiology Resource (MER) database (n=297) and the IELSG-19 study (n=400) used for the development of MALT-IPI. Performance of various prognostic indices was compared using AIC statistics, and concordance c-statistics by Harrell (CH) and by Gonen and Heller (CGH). RESULTS: Among the candidate variables tested in univariable analysis, the following were statistically significant predictors of shorter PFS: age >60, age ≥70, anemia (Hb<12g/dL), stage III-IV, ECOG PS ≥2, elevated serum LDH, number of extranodal sites >1, number of nodal sites >4, and presence of MMS at diagnosis, defined as EMZL with ≥2 different extranodal sites excluding spleen and bone marrow. A stepwise Cox regression analysis yielded a multivariable model with four independent predictors of shorter PFS: age >60 (HR=1.53, p=0.010), elevated LDH (HR=1.73, p=0.004), stage III-IV (HR=2.03, p=0.0003) and presence of MMS (HR=2.78, p<0.0001). Based on this, a new index R-MALT-IPI was developed with scores ranging from 0 to 5, calculated as a sum of 1 point for age >60, elevated LDH, stage III-IV, and 2 points for MMS. The R-MALT-IPI defined 4 risk groups: low-risk (score 0 (35%), reference group), low-medium risk (score 1 (39%), HR=1.91, p=0.005), medium-high risk (score 2 (13%), HR=3.77, p<0.0001), and high-risk (score 3+ (13%), HR=8.54, p<0.0001). When compared with MALT-IPI, R-MALT-IPI better stratifies and separates high risk patients (26%) into medium-high risk and high-risk patients with a median PFS of 5.8 years (2.9-9.1) and 1.8 years (1.3-2.6) respectively, compared to 2.6 years (1.8-4.7) in the high-risk MALT-IPI patients (16.8%). The R-MALT-IPI index also distinguished patients with different OS. For validation, we analyzed R-MALT-IPI index performance in independent Iowa/Mayo Clinic MER and IELSG-19 cohorts. Both R-MALT-IPI and MALT-IPI were useful in distinguishing PFS and OS in all the cohorts. In the UM training cohort, the concordance c-statistics' values for the two indices were similar: for PFS, CH=0.6893 and CGH=0.6611 for R-MALT-IPI, and CH=0.6551 and CGH=0.6367 for MALT-IPI; for OS, CH=0.7017 and CGH=0.6813 for R-MALT-IPI, and CH=0.7029 and CGH=0.67715 for MALT-IPI. In the validation cohorts, the concordance c-statistics' values for the two indices were also similar, but slightly lower than in the UM cohort for PFS. When comparing medium-high to high-risk R-MALT-IPI groups, there was a reduction of 4 years in median PFS in the UM cohort, and reduction in median EFS of 5.6 years in the MER cohort, an important difference between these risk groups identified by the R-MALT-IPI index. CONCLUSIONS: R-MALT-IPI is a new index for EMZL centered principally on disease characteristics. Overall, there is a similar prediction of PFS (EFS) by R-MALT-IPI and MALT-IPI indexes; however, R-MALT-IPI better recognizes a high-risk group accounting for 13% of EMZL patients with short median PFS and thus obviates the waiting period needed to recognize patients with shorter EFS24. Collaborative studies addressing best treatment approach for these high-risk EMZL patients are eagerly needed. Disclosures Alderuccio: Agios: Other: Immediate family member; Foundation Medicine: Other: Immediate family member; OncLive: Consultancy; Targeted Oncology: Honoraria; Puma Biotechnology: Other: Immediate family member; Inovio Pharmaceuticals: Other: Immediate family member. Thieblemont:Cellectis: Membership on an entity's Board of Directors or advisory committees; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria. Cerhan:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding. Zucca:Kite, A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; AstraZenaca: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Merck: Research Funding; Celltrion Helathcare: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Grant. Lossos:NIH: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Janssen Scientific: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 880 Pulmonary marginal zone lymphoma is a distinct subgroup of B-cell non-Hodgkin's lymphomas originating from the bronchial-associated lymphoid tissue (BALT) and characterized by an indolent clinical course. Here we present the data of the IELSG-28 study of the International Extranodal Lymphoma Study Group (IELSG) on primary pulmonary lymphoma patients. Clinical records and histological material of 186 patients diagnosed with pulmonary marginal zone lymphoma from December 1986 to June 2009 were collected. The pathology was reviewed centrally and the diagnosis was confirmed in 180 (96%) patients. The median age at diagnosis was 62 (30 – 88). The majority of the patients (149/180) had localized disease at diagnosis with a good performance status (0–1) and low prognostic index (IPI 0–2). Eighty-one patients (45%) received local treatment, including surgery (74%) or radiotherapy (4%). Ninety-nine patients with advanced stage disease or incomplete surgical resection received an additional systemic treatment. Most of these patients (66; 66%) received an alkylating containing regimen, 22 (22%) patients were treated with an anthracycline containing regimen and 29 (29%) received the anti-CD20 monoclonal antibody in combination with chemotherapy. With a median follow up of 67 (range 1–256) months, 47/180 patients (26%) experienced disease progression. (median time to progression 30 months, range 0–109). Progression free survival analysis showed a trend in favour of patients treated with immuno-chemotherapy versus those receiving chemotherapy alone (HR 0.53–95%CI: 0.21, 1.33), while no difference in terms of OS and PFS was observed between patients receiving systemic anthracycline or alkylating containing regimens. In twenty five cases a specific PCR-assay was carried out for detecting the presence of Achromobacter (Alcaligenes) xylosoxidans. The presence of Achromobacter was detected in 50% of patients. Our results confirm that local therapy (surgery or radiotherapy) is the treatment of choice for patients with localized disease. Chemotherapy has to be considered in case of relapse, incomplete surgical excision or advanced disease. In this setting, alkylating containing regimens plus rituximab is the most effective option. Further studies are ongoing to confirm the relevance of infection/colonization with Achromobacter (Alcaligenes) xylosoxidans for pathogenesis of BALT lymphoma. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Isolated brain parenchyma relapse as initial site of relapse is a rare complication of NHL and carries a poor prognosis. Few large series focus on treatment characteristics and outcomes of isolated brain parenchyma relapse of NHL. Methods: The IPCG conducted a retrospective review of patient and treatment characteristics and outcomes of this complication. Following initial diagnosis and treatment of NHL (1980–2004), cases with brain parenchyma relapse as initial relapse site, with no evidence of lymphoma elsewhere in the body at the time of brain relapse, were eligible. Cases with brain, spine or leptomeningeal involvement at NHL diagnosis were not eligible. Results: 113 cases were assembled from 13 investigators in 8 countries. Preliminary data summaries are: 94 (83%) cases had diffuse large B-cell NHL, 5 (4%) follicular lymphoma, 3 (3%) Burkitt’s lymphoma, other NHL subtypes (11) . Median age at NHL diagnosis was 61yrs (16–85 yrs). 55% were male. Median ECOG at NHL diagnosis was 1. Median time from NHL diagnosis to isolated brain relapse was 1.8 yrs (3 months–15.9 yrs). 76 (67%) relapsed in brain less than 3 yrs after NHL diagnosis. Symptoms at brain relapse included mental status changes in 37%, gait/balance disturbance (27%), motor/sensory symptoms (23%). Median ECOG at brain relapse was 2. Parenchyma relapse was documented by brain imaging plus biopsy in 54 (48%), or imaging without biopsy in 58 (52%); not reported (1). 53 (48%) cases had one brain lesion; 56 (50%) had two or more lesions; not reported (4). Site of relapse was cerebral hemispheres in 53 (48%) cases, deep brain structures (brain stem/cerebellum) in 30 (27%), cerebral hemispheres and deep brain structures in 23 (21%); not reported (7). At brain relapse, CSF was positive in 11 (10%) cases, negative in 56 (50%); not reported (46[40%]). Treatment for brain relapse was chemotherapy alone in 52 (46%) cases, WBRT alone in 34 (30%), chemotherapy followed by RT in 26 (23%), and brain surgery alone (1). 78 (69%) cases are deceased. Median survival from brain parenchyma relapse to death was 1.6 yrs (95% CI: 11 months–2.6 yrs). Effect of treatment type at brain relapse on survival, will be reported. Brain lymphoma was the cause of death in 49 (63%) cases; CNS toxicity was the cause in 6 (8%) cases. Conclusion: Though a rare relapse site, prospective studies are needed to improve understanding and outcomes of isolated brain parenchyma relapse of NHL.

Abstract Background: The salivary gland is one of the most common sites of involvement by non-gastric extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). This multicenter, international trial sought to characterize the clinical course, treatment and outcome of patients with salivary gland MALT lymphoma. Methods: Patients were identified from multiple international sites including the Mayo Clinic Lymphoma Database (n=89), three International Extranodal Lymphoma Study Group (IELSG) cohorts (n=138), and the University of Athens (n=21). All patients had biopsy-confirmed MALT lymphoma of the salivary gland by WHO criteria. Clinical characteristics, treatment, and outcomes were obtained from the respective patient databases. Survival probability was estimated using the Kaplan-Meier method and compared between groups with the Wilcoxon or log-rank. The impact of variables on survival was assessed by the Cox proportional hazards model. Results: Patients and clinical features: From 1983 to 2012, 247 patients with MALT lymphoma were included. Clinical characteristics are shown in Table 1. The median age at diagnosis was 59, and the male-to-female ratio was 1:3. The majority of patients (76%) presented with limited stage disease, and the parotid gland was the most common site of involvement (78%). There was a history of antecedent autoimmune disease in 41% of patients, and Sjögren’s disease was the most common (83%). Treatment: Information on initial treatment was available on 242 patients. 137/242 patients (57%) initially received local therapy with either surgery (n=81), radiation (n=26), or both (n=30). Of these, 25 received adjuvant systemic therapy. 90/242 patients (37%) were treated initially with systemic therapy, of whom 54% had localized and 46% had stage IV disease. Rituximab was used alone (n=16) or in combination with chemotherapy (n=26) in 42 of the 90. 15/242 patients (6%) were initially observed. Survival: The median OS for all patients was 18.3 years. PFS following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first line for all patients, or for those with stage I or II disease. On univariate analysis age <60, stage, IPI, normal LDH, the presence of Sjögren’s disease, and treatment with rituximab were associated with improved overall survival. Age <60, low to intermediate IPI and normal LDH were associated with improved PFS. On multivariate analysis, age<60, and IPI were associated with improved OS and PFS and Sjögren’s disease was associated with improved OS. Relapse/progression: The site of progression was known in 51 of 76 patients who progressed. 15 (29%) patients progressed in the same salivary gland or regional nodes; in 16 (21%) recurrence involved the contralateral salivary gland; 20 (31%) had distant progression. Relapse histology was identified in 30. The most common pathology at relapse was MALT (n=28), with one patient progressing to diffuse large B-cell lymphoma. A second patient developed a mantle cell lymphoma. Conclusions: Salivary gland MALT lymphoma commonly presents at an early stage, and has a favorable prognosis with a median OS of 18 years. Surgical or radiation therapy does not appear to have benefit over systemic therapy. Patients with Sjögren’s disease appear to have a better survival. The role of rituximab and optimal first-line therapy should be evaluated further in prospective trials. Table 1: Characteristics of 247 patients with salivary MALT Characteristic N (%) Age, median; range 59; 18-93 Sex, Male: Female 62: 185 (25: 75) Primary site of involvement Parotid 193 (78) Submandibular 12 (5) Other/not specified 42 (17) Extent (unilateral: bilateral) 89:21 Missing data 137 Autoimmune disorder* 101(41) Sjögren’s 84 (33) Rheumatoid arthritis 9 (4) Raynaud’s phenomenon 8 (3) Scleroderma 5 (2) Other 19 (8) Stage IE 147 (59) IIE 42 (17) IV 56 (23) Missing data 2 (1) IPI Score Low (0-1) 126 (51) Low-Intermediate (2) 20 (8) High-intermediate (3) 21 (8) High (4-5) 5 (2) Missing data 75 (31) Elevated LDH 17 (7) ECOG PS 0-1 246 2 1 Extranodal sites 1 58 (23) 2 187 (76) Missing data 2 (1) B symptoms 9 (4) * Percents may not equal 100 as some patients had more than one disorder. Figure One: Overall survival of patients with and without Sjögren’s disease Figure One:. Overall survival of patients with and without Sjögren’s disease Disclosures Nowakowski: Celgene, Morphosis: Consultancy. Zucca:Roche, Mundipharma, Novartis, Jannsen, Celgene: Consultancy, Honoraria, Research Funding.

Purpose Follicular lymphoma (FL) is an indolent cancer, with effective but rarely curative treatment options. As a standard study end point for first-line FL therapy, progression-free survival (PFS) requires extended follow-up (median PFS, > 7 years). To provide patients with earlier access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to formally assess the complete response rate at 30 months (CR30) after initiation of induction therapy as a potential surrogate end point for PFS in first-line FL therapy. Patients and Methods We analyzed individual patient data from 13 randomized multicenter trials of induction and maintenance regimens in first-line FL therapy published after 1990 and with sufficient data to evaluate whether CR30 could predict treatment effects on PFS. Correlation of the CR30 odds ratio with the PFS hazard ratio was evaluated by both linear regression (R2WLS) and bivariate copula (R2Copula) models. Prespecified criteria for surrogacy required either R2WLS or R2Copula ≥ 0.80, with a lower-bound 95% CI > 0.60. Results Data from eight induction and five maintenance randomized trials in 3,837 evaluable patients were analyzed. The prespecified surrogacy threshold was met, with an R2WLS of 0.88 (95% CI, 0.77 to 0.96) and an R2Copula of 0.86 (95% CI, 0.72 to 1.00). Multiple sensitivity and supplemental analyses supported the robustness of the findings. A minimum 11% absolute improvement in CR30 from a 50% control rate predicted a significant treatment effect on PFS (hazard ratio, 0.69). Conclusion This large, prospective, pooled analysis of randomized chemotherapy, immunotherapy, and chemoimmunotherapy trials demonstrates that CR30 is a surrogate end point for PFS in first-line FL treatment trials. Use of this end point may expedite therapeutic development with the intent of bringing novel therapies to this patient population years before PFS results are mature.

Abstract Background. The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. Methods. Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. Results. A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age &lt;60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. Conclusion. Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy. Implications for Practice: Patients with salivary gland extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) have an excellent prognosis, particularly those with associated Sjögren's disease. A wide range of available therapies may provide similar durable rates of disease control and survival. Therefore, an important goal in selection of therapy should be to minimize morbidity from treatment. When determining initial therapy for these patients, practitioners should consider the potential side effects and long-term toxicities of treatment.

Abstract Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow‐up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa‐associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty‐five per cent of the patients were female. The median age at diagnosis was 62 (range 28–88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression‐free survival ( p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long‐term disease‐free survival for patients with localized disease. Systemic treatment, including alkylating‐containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.

Abstract Isolated central nervous system (CNS) relapse involving the brain parenchyma is a rare complication of systemic non-Hodgkin lymphoma. We retrospectively analyzed patient characteristics, management, and outcomes of this complication. After complete response to initial non-Hodgkin lymphoma treatment, patients with isolated CNS relapse with the brain parenchyma as initial relapse site were eligible. Patients with isolated CNS relapse involving only the cerebrospinal fluid were not eligible. Information on 113 patients was assembled from 13 investigators; 94 (83%) had diffuse large B-cell lymphoma. Median time to brain relapse was 1.8 years (range, 0.25-15.9 years). Brain relapse was identified by neuroimaging in all patients; in 54 (48%), diagnostic brain tumor specimen was obtained. Median overall survival from date of brain relapse was 1.6 years (95% confidence interval, 0.9-2.6 years); 26 (23%) have survived 3 years or more. Median time to progression was 1.0 year (95% confidence interval, 0.7-1.7 years). Age less than 60 years (P = .006) at relapse and methotrexate use (P = .008) as front-line treatment for brain relapse were significantly associated with longer survival in a multivariate model. Our results suggest systemic methotrexate is the optimal treatment for isolated CNS relapse involving the brain parenchyma. Long-term survival is possible in some patients.