Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome in MZL and identifies a high-risk population. This trial was registered at www.clinicaltrials.gov as #NCT02904577.

Waldenstrom Macroglobulinemia is a rare lymphoproliferative disorder with distinctive clinical features.Diagnostic and prognostic characterisation in WM significantly changed with the discovery of two molecular markers: MYD88 and CXCR4. Mutational status of these latter influences both clinical presentation and prognosis and demonstrated therapeutic implications.Treatment choice in Waldenstrom disease is strictly guided by patients age and characteristics, specific goals of therapy, the necessity for rapid disease control, the risk of treatment-related neuropathy, disease features, the risk of immunosuppression or secondary malignancies and potential for future autologous stem cell transplantation.The therapeutic landscape has expanded during the last years and the approval of ibrutinib, the first drug approved for Waldenstrom Macroglobulinemia, represents a significant step forward for a better management of the disease.

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In ibrutinib era it is still unclear whether age, CIRS and ECOG-PS retain their predictive role on treatment vulnerability. In this 712 CLL patients series treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia, resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions may affect drug management. We confirmed the role of CIRS>6 as a predictor of a poorer progression and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDR), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A-inhibitors with ibrutinib. In our series, these factors had no impact, though CYP3A4 inhibitors use correlated at Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes and importantly neutropenia emerged as a relevant tool influencing patients vulnerability. Although CIRS>6 retained a significant impact on PFS and EFS its value should be confirmed by prospective studies.

Lymphoplasmacytic lymphoma (LPL) is usually associated with a serum IgM paraprotein, corresponding to Waldenström's Macroglobulinemia (WM). Cases presenting with IgG or IgA, or without a monoclonal protein are extremely rare. We analyzed clinical characteristics, frontline treatment, and the outcome of 45 patients with non‐IgM LPL, and compared them with a control group of WM patients. The median age was similar, with significantly higher prevalence of females in non‐IgM LPL, than in WM patients (60% vs 39%, P = .016). Patients with non‐IgM LPL more frequently presented with lymphadenopathies (53% vs 15%, P < .001), splenomegaly (22% vs 8%, P = .015) or extranodal involvement (20% vs 8%, P = .05). In non‐IgM LPL a serum monoclonal protein and bone marrow infiltration were less common than in WM patients (69% and 84% of cases respectively, P < .001 for both comparisons). The MYD88 (L265P) mutation was found in 8/19 patients using allele‐specific polymerase chain reaction. A CXCR4 mutation was found in 4/17 cases using Sanger. In 16 patients we performed targeted next‐generation sequencing of genes MYD88, CXCR4, ARID1‐A, KMT2D, NOTCH2, TP53, PRDM1, CD79B, TRAF3, MYBBP1A, TNFAIP3. Seven patients (44%) had a MYD88 mutation (S219C in one), four (25%) a CXCR4 mutation, three (19%) a KMT2D mutation, one (6%) a TP53 mutation and one (6%) a TRAF3 mutation. With a median follow‐up of 55.7 months, 36 non‐IgM LPL patients (80%) were treated. Non‐IgM LPL patients received more frequently anthracycline‐containing regimens, as compared with WM patients, who mainly received alkylating‐based therapies. Five‐year overall survival (OS) was 84%, similar to that of WM patients.

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