Abstract
Background. Lymphoplasmacytic lymphoma (LPL) is a low-grade B-cell neoplasm exhibiting a spectrum of B-cell differentiation ranging from small lymphocytes to plasma cells. In the majority of cases LPL is associated with an immunoglobulin M (IgM) paraprotein in the serum, corresponding to the clinico-pathologic entity of Waldenström's Macroglobulinemia (WM). In a minority of patients with LPL the paraprotein is absent or is of IgG or IgA isotype. These cases are very rare and their relationship with WM still unclear.
Aim of the study. The aim of this study was to analyze clinical and biological features, treatment characteristics and outcome of patients with LPL not associated with an IgM paraprotein and to compare these cases with a control group of WM patients.
Patients and methods. The study was conducted within the Rete Ematologica Lombarda (REL) and approved by the Ethic Committee of the six participating centers. Clinical characteristics, treatment and outcome of patients were retrieved from clinical archives. MYD88 and CXCR4 mutation status were evaluated by means of allele-specific PCR for MYD88 (L265P) and Sanger sequencing respectively. Five patients from the coordinating center were studied also with next-generation sequencing. DNA was extracted from bone marrow total mononuclear cells (n=20), bone marrow biopsy (n=8), lymph node (n=6), spleen (n=3) or extranodal sites (n=3).
Results. We identified 45 cases of LPL not associated with a serum IgM paraprotein for whom clinical data were available. Twenty-nine patients out of 45 (64%) had a serum IgG (n= 22) or IgA (n=7) paraprotein, whereas serum immunofixation was negative in 16 cases (36%). Patients characteristics are reported in Table 1. Forty samples from 36 patients were available for molecular analyses. MYD88 and CXCR4 mutation status before treatment were evaluable in 34 and 35 cases respectively. Six patients of 34 (18%) were found to harbor the MYD88 L265P and one the S219C mutation. Five patients of 35 (14%) had a CXCR4 and three of them were MYD88-wild type. The median follow-up of LPL patients was 40.1 months (range 0.5-207). Thirty-five patients (78%) were treated after a median time of 2.5 months from diagnosis (range: 0-49). Immunochemotherapy represented the first line therapy in 25 of 35 patients (71%). Chemotherapy consisted of alkylating-containing regimens in 12/35 patients (34%), CHOP or CHOP-like regimens in 11 (31%), bendamustine in 9 (26%), fludarabine-based regimens in 2 (6%), other treatment in 1 patient (3%). Fifteen of 35 patients (43%) progressed after treatment. Progression-free survival (PFS) after first-line treatment was 55% at 5 years. Overall survival (OS) was 81% at 5 years.
As compared with 142 WM controls with a median follow-up of 44.9 months (0-180), LPL patients were more frequently females (58% versus 39%, P=0.038), had more frequently lymphadenopathies (56% versus 15%, P<0.001), spleen enlargement (22% versus 8%, P=0.015) or extranodal involvement (20% versus 8%, P=0.05), while bone marrow infiltration was less common (84% versus 99%, P<0.001). The prevalence of the MYD88 (L265P) mutation was significantly lower in LPL as compared with WM patients (18% versus 91%, P<0.001) while the prevalence of CXCR4 mutations was similar in the two groups (14% versus 17%, P=0.794). A higher proportion of LPL patients were treated as compared to the control group (78% versus 50%, P=0.001). LPL received more frequently anthracycline-containing regimens (31% versus 4%, P<0.001) and less frequently alkylating-containing regimens (34% versus 65%, P=0.004) than WM patients. The use of bendamustine-containing regimens was not significantly different between the two groups (17% versus 26%, P=0.308). As compared with WM, LPL patients had a similar PFS (P=0.26) (Figure 1) and OS (P=0.62) (Figure 2).
Conclusions. LPL not associated with an IgM monoclonal protein displays distinctive clinical and biological characteristics, in particular a higher prevalence of extramedullary disease and a lower rate of MYD88 mutations as compared to WM. The outcome of patients with LPL is similar to WM in terms of progression-free and overall survival.
Varettoni: Jannsen: Consultancy, Other: travel expenses. Tedeschi: Janssen: Consultancy, Other: travel expenses; AbbVie: Consultancy; Gilead: Consultancy, Other: travel expenses. Arcaini: Sandoz: Consultancy; Gilead: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees.
