Primary Central System Lymphoma Research Articles

160P - Molecular profiling and prognostic significance of TP53 mutations in diffuse large b cell lymphoma: Identifying a high-risk subgroup

BackgroundDiffuse large B-cell lymphoma (DLBCL) is heterogenous morphologically, clinically and genetically. Although half of patients could be cured by frontline R-CHOP, approximately 10%-15% are refractory or relapse within the 1st year. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. MethodsTargeted sequencing was performed on baseline samples of 105 DLBCL patients. After a median follow-up of 67 months, 63 (60.0%) patients had refractory or relapsed disease. All patients received R-CHOP(-like) regimen as the first-line treatment. After excluding double-hit and primary central system lymphoma, 81 patients with measurable disease before initial treatment and followed over 1 year were included for survival analysis. Patients who received less than a partial remission in the first-line setting or those relapsed within the first 12 months since the initiation of the treatment were defined as having primary refractory. ResultsCollectively, we identified 1162 mutations spanning 103 genes from this cohort. The most commonly seen mutations included PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (41.7% vs 7.4%, p=0.002). For those with TP53 disruptive mutations, primary refractory is also more common (22.9% vs. 0%, p=0.006). Interestingly, BCL-2 somatic hypermutation (SHM) was only seen in patients without primary refractory disease (p=0.014). The International prognostic index (IPI) score and other clinical characteristics were comparable between the 2 groups. Furthermore, TP53 mutations were correlated with shorter PFS (p=0.001) and OS (p=0.049). Next, we investigated mutation landscape in patients with WT TP53 (n=58) and found that patients harboring MYD88 L265P had significantly inferior PFS than those with WT or non-265P (p=0.046). ConclusionsWe revealed that patients with TP53 mutation are more likely to have primary refractory to standard R-CHOP. This study also showed the prognostic potential of MYD88 L265P in those with WT TP53 and indicated that distinct subgroups could be identified by TP53 and MYD88 L265P mutations. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Efficacy and Toxicity of Treatments for Primary Central System Lymphoma: Review of the Recent Literature

Primary Central Nervous system lymphoma (PCNSL) is an uncommon type of central nervous system lymphoma, most commonly presenting as hemiparesis and headache. Currently, there is a wide range of treatments for PCNSL, consisting of various permutations between chemotherapy, radiation and autologous stem cell transplant (ASCT). Although the backbone of PCNSL treatment consists of High-dose Methotrexate (HD-MTX), the role of combination versus single agent chemotherapy, combined modality (chemotherapy + radiation) versus chemotherapy or radiation alone, and the use of consolidative ASCT are contested. Surgery does not have a role in the treatment of PCNSL although stereotactic biopsies tend to help with symptomatic relief. Radiation monotherapy is generally reserved for patients with contraindications to chemotherapy or as a palliative measure. Combined chemotherapy and radiation treatment has been shown to have a great efficacy, although its increased neurotoxicity compared to chemotherapy alone is a major drawback. A growing body of research is focused on comparing the efficacy of various chemotherapeutic regimens. Currently, the MATRix regimen comprising of HD-MTX(3.5g/m2)-cytarabine/rituximab/thiotepa is widely used. The additional survival benefit of ASCT is contested although its role in the treatment of refractory or relapsed PCNSL is generally agreed upon. Finally, intrathecal HD-MTX has been shown to have added survival benefit when added to the standard therapies. Further retrospective and prospective studies are required to compare the efficacy and toxicity of various treatment options, with a focus on different chemotherapeutic agents and ASCT.

Diffusion-Weighted Imaging for Predicting and Monitoring Primary Central Nervous System Lymphoma Treatment Response.

Whether ADC value predicts the therapy response and outcomes of primary central system lymphoma remains controversial. This study assessed the minimum ADC correlated with treatment response in patients with primary central nervous system lymphoma undergoing methotrexate-based chemotherapy. Thirty-five patients with primary central nervous system lymphoma underwent conventional MR imaging and DWI before chemotherapy and after 1 and 5 cycles of chemotherapy. Treatment response was determined according to the International PCNSL Collaborative Group criteria and was classified as a complete response, partial response, or progressive disease. Pretreatment minimum ADC, minimum ADC after 1 cycle, minimum ADC after 5 cycles, and change in minimum ADC were compared among the different response groups. The Pearson correlation test was calculated between these ADC parameters and tumor response. The pretreatment minimum ADC of the progressive disease group was lower than that of the complete response and partial response groups, but there was no significant difference among them. The minimum ADC after 1 cycle and minimum ADC after 5 cycles were statistically significantly higher than the pretreatment minimum ADC. A comparison among groups showed that minimum ADC after 1 cycle, minimum ADC after 5 cycles, minimum ADC change, and the percentage of minimum ADC change were all significantly different among the 3 groups. A significant positive correlation was observed between the percentage of minimum ADC after 1 cycle of chemotherapy and the size reduction percentage after 5 cycles of chemotherapy. The minimum ADC change and the percentage of minimum ADC change performed better in the differentiation of the final treatment response, specifically in complete response and partial response from progressive disease. The minimum ADC after 1 cycle and minimum ADC changes were better correlated with the treatment response than the pretreatment minimum ADC. Minimum ADC after early therapy may potentially to be used to predict and monitor the response of primary central nervous system lymphoma to chemotherapy.

Non-enhancing primary CNS lymphoma

Primary central system lymphomas (PCNSL) are highly proliferative tumors that require aggressive treatment, e.g. using high-dose methotrexate-based chemotherapy. Early histological diagnosis is crucial for proper management of PCNSL. Histological diagnosis is obtained through stereotactic biopsy which is usually performed upon demonstration of the typical hallmarks of PCNSL on MRI. This includes large, preferentially periventricular, homogenously contrast-enhancing lesions [1]. Although the MRI presentation of PCNSL is relatively uniform regarding the appearance as homogenously contrast-enhancing lesion(s), the MRI presentation of PCNSL may very rarely be atypical [2, 3] and may lead to significant delay in diagnosis and therapy initiation in such patients. We here present a patient with the rare case of a PCNSL without contrastenhancement. An 81-year-old patient presented with a 5-week history of rapidly progressive dementia. On examination, he was disoriented and showed psychomotor slowing and gait difficulty. The Mini Mental state examination (MMSE) revealed 16/30 points. He was HIV negative and all serological and biochemical tests were normal. The CSF examination showed just a slight increase in protein content (556 mg/l), no pleocytosis and no atypical cells. The MRI of the brain taken without prior steroid treatment revealed diffuse white matter changes involving both hemispheres. No pathological contrast-enhancement could be detected (Fig. 1). A diagnosis of gliomatosis cerebri was initially suspected. A biopsy was taken from the right frontal lobe. Histological examination revealed a diffuse large cell lymphoma (non-Hodgkin’s lymphoma of germinal B cell origin; Fig. 2). The present case highlights the fact that, in very rare cases, PCNSL may present as a non-enhancing lesion. Non-enhancing presentation was found in 1% of patients in a large series of immunocompetent patients [1] and is just one form of atypical MRI presentation of PCNSL. Another atypical form is the presentation with a central nonenhancing necrosis; this is found in 6–17% of immunocompetent PCNSL patients [1]. PCNSL without contrast uptake are usually caused by angiotropic large cell lymphoma or intravascular lymphomatosis [4]. In contrast, the present case did not show a particular angiotropic pattern but had the typical pattern of a diffuse large cell lymphoma with some perivascular accentuation (Fig. 2c). Unusual non-enhancing presentation may lead to substantial prolongation of definitive diagnosis and start of therapy. This underlines that PCNSL without contrast-enhancement has to be kept in the differential diagnosis of diffuse white matter disorders. Also, it further supports the importance of histologic verification before the onset of therapy. Since histological diagnosis of PCNSL may be greatly hampered by the use of lympholytic steroids prior to biopsy, it M. L. Lachenmayer and E. Blasius contributed equally.

Treatment patterns and prognosis in patients with human immunodeficiency virus and primary central system lymphoma

The incidence of human immunodeficiency virus (HIV)-associated primary central nervous system lymphoma (PCNSL) has decreased in the era of highly active anti-retroviral therapy, but PCNSL continues to be a prominent AIDS-defining illness. Using surveillance epidemiology and end results, cancer registry data linked with Medicare, we identified PCNSL cases diagnosed from 1994 to 2002. The effects of comorbidity, year of diagnosis, and sociodemographic characteristics on the odds of receiving treatment were assessed. One hundred and eighty-four patients with both HIV and PCNSL were identified. Forty-six per cent were treated with radiation therapy (RT) alone, 10% received RT and chemotherapy, 4% received chemotherapy alone, and 40% received no treatment. No time trends in treatment patterns were observed, and no sociodemographic factors were associated with receipt of treatment. Median survival was 2 months. Age did not impact survival. Survival was improved for patients diagnosed with PCNSL after 1996 (p = 0.028). Despite improved treatment for both diseases over the past decade, survival remains dismal in this cohort of Medicare/Medicaid beneficiaries with HIV-related PCNSL. These results may not apply to the general HIV population.