Zucca, Emanuele

ABSTRACT The characteristics at diagnosis and clinical course of primary extranodal follicular lymphoma (EFL) have not been extensively described. The International Extranodal Lymphoma Study Group (IELSG) conducted an international retrospective survey aimed to describe the clinical features at diagnosis and the outcomes of FL cases with a clinically dominant extranodal component. The dataset included 605 pathologically reviewed cases from 19 different countries, and their outcomes were compared to those of nodal follicular lymphomas. The two most common presentation sites for EFL were the skin ( n = 334) and the gastrointestinal tract ( n = 72), with 22 cases having primary duodenal localization. These subsets exhibited unique features at diagnosis and significantly different overall survival (OS) patterns. After a median follow‐up of 5.5 years, primary cutaneous lymphomas showed a superior outcome [10‐year OS: 89% (95% CI, 83%–93%)], while primary gastrointestinal lymphomas had an intermediate outcome [10‐year OS: 79% (95% CI, 59%–90%)]. Among the gastrointestinal lymphomas, primary duodenal lymphomas tended toward the best outcome [10‐year OS: 95% (95% CI, 69%–99%)]. Other primary extranodal sites had inferior outcomes [10‐year OS: 59% (95% CI, 48%–68%)], similar to primary nodal lymphomas [10‐year OS: 57% (95% CI, 49%–64%)]. These findings support the identification of specific primary FL localizations as distinct entities with particular clinical and biological characteristics.

Abstract Extranodal marginal zone lymphoma (EMZL) has a very indolent course, and the validation of surrogate markers could accelerate novel therapies. Although prognostic markers do exist, no surrogate markers have been validated in EMZL. We hypothesized that time to complete response within 24 months (TTCR24) and complete response (CR) at 24 months (CR24) could be valid surrogate markers of progression-free survival (PFS). The International Extranodal Lymphoma Study Group 19 phase 3 trial showed the advantage of double therapy (rituximab + chlorambucil) over single therapy (rituximab or chlorambucil) on PFS. We used 2 recently published single-trial approaches to assess whether TTCR24 and CR24 were good surrogate markers of 8-year PFS (8y-PFS). Among the 401 patients, 264 (66%) reached a CR in the first 24 months, of which 222 (84%) remained in CR at month 24. The cumulative incidence of CR over time was significantly higher in patients under double therapy (hazard ratio, 1.75; P < .001). The double therapy arm was associated with a higher CR24 rate, a shorter TTCR24, and a longer 8y-PFS. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% confidence interval [CI], 0.27-1.87). CR24 was also a strong surrogate marker because it mediated 90% (95% CI, 0.51-2.22) of the treatment effect on PFS and its natural indirect effect was significant throughout the follow-up. We found that TTCR24 predicted 95% and that CR24 mediated 90% of the treatment effect on long-term PFS. Therefore, TTCR24 and CR24 could be used in clinical trials as informative and valid early indicators of treatment effect on PFS. This trial was registered at www.clinicaltrials.gov as #NCT00210353.

AbstractExtranodal marginal zone lymphoma (EMZL) is a heterogeneous disease with a subset of patients exhibiting a more aggressive course. We previously reported that EMZL with multiple mucosal sites (MMS) at diagnosis is characterized by shorter survival. To better recognize patients with different patterns of progression‐free survival (PFS) we developed and validated a new prognostic index primarily based on patient's disease characteristics. We derived the “Revised mucosa‐associated lymphoid tissue International Prognostic Index” (Revised MALT‐IPI) in a large data set (n = 397) by identifying candidate variables that showed highest prognostic association with PFS. The revised MALT‐IPI was validated in two independent cohorts, from the University of Iowa/Mayo Clinic (n = 297) and from IELSG‐19 study (n = 400). A stepwise Cox regression analysis yielded a model including four independent predictors of shorter PFS. Revised MALT‐IPI has scores ranging from 0 to 5, calculated as a sum of one point for each of the following‐ age >60 years, elevated LDH, and stage III–IV; and two points for MMS. In the training cohort, the Revised MALT‐IPI defined four risk groups: low risk (score 0, reference group), low‐medium risk (score 1, HR = 1.85, p = .008), medium‐high risk (score 2, HR = 3.84, p < .0001), and high risk (score 3+, HR = 8.48, p < .0001). Performance of the Revised MALT‐IPI was similar in external validation cohorts. Revised MALT‐IPI is a new index centered on disease characteristics that provides robust risk‐stratification identifying a group of patients characterized by earlier progression of disease. Revised MALT‐IPI can allow a more disease‐adjusted management of patients with EMZL in clinical trials and practice.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Abstract Since the publication of the Revised European-American Classification of Lymphoid Neoplasms in 1994, subsequent updates of the classification of lymphoid neoplasms have been generated through iterative international efforts to achieve broad consensus among hematopathologists, geneticists, molecular scientists, and clinicians. Significant progress has recently been made in the characterization of malignancies of the immune system, with many new insights provided by genomic studies. They have led to this proposal. We have followed the same process that was successfully used for the third and fourth editions of the World Health Organization Classification of Hematologic Neoplasms. The definition, recommended studies, and criteria for the diagnosis of many entities have been extensively refined. Some categories considered provisional have now been upgraded to definite entities. Terminology for some diseases has been revised to adapt nomenclature to the current knowledge of their biology, but these modifications have been restricted to well-justified situations. Major findings from recent genomic studies have impacted the conceptual framework and diagnostic criteria for many disease entities. These changes will have an impact on optimal clinical management. The conclusions of this work are summarized in this report as the proposed International Consensus Classification of mature lymphoid, histiocytic, and dendritic cell tumors.

Abstract A recent systematic review reported that trials involving patients with marginal zone lymphoma (MZL) show marked heterogeneity both in the choice and definitions of primary and secondary endpoints, thus hampering comparability between trials. The main objective of this study was to reach consensus, through a Delphi process, on the definitions of four time‐to‐event endpoints in MZL trials, by surveying clinicians and methodologists involved in the conduct of clinical trials including patients with MZL. We polled a panel of leading international experts involved in MZL trials by means of self‐administered sequential questionnaires in 2021. Of these 105 experts, 62 responded to the Round 1 questionnaire regarding the definitions of progression‐free survival (PFS), event‐free survival (EFS), time‐to‐failure (TTF), and time‐to‐next‐treatment (TTNT). Afterward, we therefore focused the Round 2 and 3 questionnaires among principal investigators, coinvestigators, and trial methodologists. Consensus was reached when there was a >80% agreement on all potential events (11 choices) of each endpoint. Participants in our survey reached consensus on three of the four time‐to‐event endpoints definitions. Consensus was reached on the definitions of PFS and TTNT after Round 1, of TTF after Round 2, and was not reached for EFS after Round 3. The disagreement concerned the event “treatment discontinuation” in EFS definition. The main interest of our study was to elicit investigator's interest in the importance of consistently defining endpoints in MZL trials and to highlight that composite endpoints should not be encouraged. Fifteen years after the last consensus statement on time‐to‐event endpoints definitions issued in Lugano (2007), both the review of literature and survey of international investigators agree on the inconsistency of endpoints definitions used within the MZL community. Hopefully, revised standardized definitions of endpoints shall be provided at the upcoming International Conference on Malignant Lymphoma in 2023.

AbstractMost patients with chronic lymphocytic leukemia (CLL) are diagnosed with early-stage disease and managed with active surveillance. The individual course of patients with early-stage CLL is heterogeneous, and their probability of needing treatment is hardly anticipated at diagnosis. We aimed at developing an international prognostic score to predict time to first treatment (TTFT) in patients with CLL with early, asymptomatic disease (International Prognostic Score for Early-stage CLL [IPS-E]). Individual patient data from 11 international cohorts of patients with early-stage CLL (n = 4933) were analyzed to build and validate the prognostic score. Three covariates were consistently and independently correlated with TTFT: unmutated immunoglobulin heavy variable gene (IGHV), absolute lymphocyte count higher than 15 × 109/L, and presence of palpable lymph nodes. The IPS-E was the sum of the covariates (1 point each), and separated low-risk (score 0), intermediate-risk (score 1), and high-risk (score 2-3) patients showing a distinct TTFT. The score accuracy was validated in 9 cohorts staged by the Binet system and 1 cohort staged by the Rai system. The C-index was 0.74 in the training series and 0.70 in the aggregate of validation series. By meta-analysis of the training and validation cohorts, the 5-year cumulative risk for treatment start was 8.4%, 28.4%, and 61.2% among low-risk, intermediate-risk, and high-risk patients, respectively. The IPS-E is a simple and robust prognostic model that predicts the likelihood of treatment requirement in patients with early-stage CLL. The IPS-E can be useful in clinical management and in the design of early intervention clinical trials.