The prognostic role of the transcription factor SOX11 in mantle cell lymphoma (MCL) is controversial. We investigated prognostic markers in a population-based cohort of 186 MCL cases. Seventeen patients (9%) did not require any therapy within the first 2 years after diagnosis and were retrospectively defined as having an indolent disease. As expected, indolent MCL had less frequent B symptoms and extensive nodal involvement and 88% of these cases expressed SOX11.In our cohort 13 cases (7.5%) lacked nuclear SOX11 at diagnosis. SOX11 ؊ MCL had a higher frequency of lymphocytosis, elevated level of lactate dehydrogenase (LDH), and p53 positivity. The overall survival in the whole cohort, excluding 37 patients receiving autologous stem cell transplantation, was 3.1 year and in patients with indolent or nonindolent disease, 5.9 and 2.8 years, respectively (P ‫؍‬ .004). SOX11 ؊ cases had a shorter overall survival, compared with SOX11 ؉ cases, 1.5 and 3.2 years, respectively (P ‫؍‬ .014). In multivariate analysis of overall survival, age > 65 (P ‫؍‬ .001), Eastern Cooperative Oncology Group score > 2 (P ‫؍‬ .022), elevated LDH level (P ‫؍‬ .001), and p53 expression (P ‫؍‬ .001) remained significant, and SOX11 lost significance. We conclude that most indolent MCLs are SOX11 ؉ and that SOX11 cannot be used for predicting an indolent disease course. (Blood. 2012;119(18): 4215-4223)

The cannabinoid receptors are upregulated in many types of cancers, including mantle cell lymphoma (MCL) and have been suggested to constitute novel therapeutic targets. The expression pattern of the key members of the endocannabinoid system was analyzed in a well-characterized MCL patient cohort and correlated to biological features. 107 tumor tissues were analyzed for the mRNA levels of cannabinoid receptors 1 and 2 (CNR1 and CNR2) and the two main enzymes regulating the endocannabinoid anandamide levels in tissue: NAPEPLD and FAAH (participating in synthesis and degradation, respectively). NAPEPLD, CNR1 and CNR2 were overexpressed while FAAH expression was reduced in MCL compared to non-malignant B-cells. Both low CNR1 and high FAAH levels correlated with lymphocytosis (p=0.016 and p=0.022, respectively) and with leukocytosis (p=0.0018 and p=0.047). Weak to moderate CNR1 levels were a feature of SOX11 negative MCL (p=0.006). Both high CNR2 and high FAAH levels correlated to anemia (p=0.0006 and p=0.038, respectively). In conclusion, the relative expression of the anandamide synthesizing and metabolizing enzymes in MCL is heavily perturbed. This finding, together with high expression of cannabinoid receptors, could favor enhanced anandamide signaling and suggest that targeting the endocannabinoid system might be considered as part of lymphoma therapy.

1592 Introduction: Mantle cell lymphoma (MCL) constitutes 3–10% of non-Hodgkin lymphomas and affects predominantly middle-aged to elderly men. The median survival is 3–5 years and seems to improve with new therapeutic regimens. The MCL International Prognostic Index (MIPI) has been proven useful for predicting survival in MCL patients included in clinical trials, but its value in unselected population based MCL cohorts is less well known. Biological markers are increasingly used for prognostication of MCL patients, especially for defining indolent cases. Material and Methods: All 186 patients diagnosed with MCL, confirmed by IHC for cyclinD1 and/or by FISH for t(11;14), between January 1998 and June 2010 in the Stockholm region, were included in a retrospective analysis. Clinical data from patient files, diagnostic biopsies and flow cytometry data were reviewed. Last follow-up was in May 2011. The prognostic value of the following variables, evaluated at the time of diagnosis, were analyzed: age, sex, Ann Arbor stage, ECOG, B-symptoms, Hb, LDH, albumin, lymphocytosis, leukocytosis, splenomegaly, nodal, extranodal and bone marrow involvement, blastoid morphology, expression of CD23, light chain, Ki 67, p53 and nuclear SOX11. Results: The median age at diagnosis was 68.8 years (range 36.2 – 89.9); 67.4 in males and 72.1 in females, respectively. The male: female ratio was 2. Thirty patients had a known malignancy of other type before the MCL diagnosis and 12 acquired a cancer later. In 13 patients the other malignancy was the cause of death. Median overall survival (OS) time was 43 months in the whole cohort and 38 months, when excluding 39 patients receiving ASCT as part of first-line therapy. No statistically significant difference in OS was seen with respect to whether the lymphoma was diagnosed before or after 2005. In the non-transplanted patients (n=149), univariate analysis showed the following clinical variables to be negatively correlated to overall survival: age >65 years, B-symptoms, splenomegaly, ECOG >2, low albumin, and high LDH. The median survival was not reached in the low risk MIPI group, and was 79 and 34 months, in the middle and high risk MIPI group, respectively. Blastoid morphology and p53 positivity (>20%), were negatively correlated to overall survival (both with p<0.0001), as was increasing tumor cell proliferation (measured as a continous variable or using the cut-offs >50%, both with with p<0.0001), but not with cut-off >30% (p=0.061), while SOX11 positivity was related to a prolonged survival (p=0.015). Multivariate analyses showed that age >65 (HR 6.1, p<0,002), ECOG >2 (HR 63, p<0.001), high LD (HR 3.7, p< 0.001), and p53 positivity (HR 5.6, p< 0.0001) remained significant. Clinically indolent MCL, defined as in retrospect not requiring treatment within two years from diagnosis, was seen in 17 patients. In two of these patients the proliferation was >30%, in one >50%, two had a p53 expression >20% and two were SOX11 negative. Therapy was never required in 9 of these initially indolent patients and only one had an autologous transplantion later in the disease course. The median OS was 72 months for the 17 indolent MCL compared with 34 months in patients requiring treatment earlier in their disease (p=0.003). The follow-up time did not differ significantly between the two groups. Conclusions: Compared to data from published clinical trials of advanced MCL, our population-based cohort of 186 cyclin D1 positive MCL patients were diagnosed at an older age, which may contribute to a shorter overall survival. Certain well-established prognostic variables seem to loose significance outside study populations. In the group of 147 non-transplanted patients multivariate analysis showed that only age, ECOG, LDH and p53 positivity were independently associated with overall survival. Leukocytosis as a variable of MIPI had no impact. Neither SOX11, CD23 or other biological markers applied at the time of diagnosis could predict for clinically indolent disease. Disclosures: No relevant conflicts of interest to declare.

Background There is a consensus that younger patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens including high-dose cytarabine, rituximab and high-dose chemotherapy with stem cell support, but the optimization of treatment for elderly or unfit patients, as well as patients with localized or indolent disease, remains a challenge. Methods Our study is based on data from the Swedish and Danish Lymphoma Registries from the period of 2000-2011, in Sweden supplemented by review of patients´ records. The Lymphoma Registries comprise >95% of all diagnosed lymphoma patients in Sweden and Denmark. Results 1389 patients were diagnosed with MCL, confirmed by positive cyclin-D1 and CD5 staining, in Sweden and Denmark between 2000 and 2011. In this population based cohort, we could confirm the prognostic impact of MIPI, but in addition, male sex was associated with inferior overall survival (OS) in multivariate analysis (HR 1.4, p<0.001). Treatment with the Nordic MCL2 regimen (n=324) was associated with superior outcome compared to the majority of other regimens (3-year OS: 80%). In patients >65 years, chlorambucil (n=132) was superior to CVP (n=35) (HR 1.8, p=0.003), when adjusted for MIPI and rituximab, but there was no significant difference between CHOP (n=311) and CHOP+Cytarabine (n=84). Rituximab (HR 1.5, p<0.001) and autologous stem cell transplantation (HR 1.9, p<0.001 ) per se were both associated with prolonged OS in multivariate analysis. Forty-three (3.1%) patients with stage I-II disease received radiotherapy as primary treatment with curative intent showing an estimated 3-year OS of 93%. A small proportion, 29 patients (2.1%), were followed without treatment. Estimated 3-year OS for this group of patients was 79%. Conclusion By a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice. Disclosures: No relevant conflicts of interest to declare.