Molecular Features of Primary Central Nervous System Lymphoma in a Large Tissue Microarray

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 348-348 ◽  
Author(s):  
Diego Villa ◽  
Graham W Slack ◽  
Muntadhar Al-Moosawi ◽  
Susana Ben-Neriah ◽  
Tamara Shenkier ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Protein Expression ◽  
Supportive Care ◽  
Research Funding ◽  
Performance Status ◽  
Central Nervous System Lymphoma ◽  
Cell Of Origin ◽  
Molecular Features

Abstract Background The pathogenesis of primary central nervous system lymphoma (PCNSL) remains poorly understood. The objective of this study was to evaluate the distribution and prognostic impact of a broad range of molecular attributes in a large tissue microarray (TMA) from immunocompetent patients with PCNSL. Methods Patients with PCNSL diagnosed during 1998 - 2010 were identified using the BC Cancer Lymphoid Cancer clinical and pathology databases. Archival formalin-fixed, paraffin-embedded diagnostic biopsy tissue was retrieved, and TMAs were constructed. Immunohistochemistry (IHC) for CD10, BCL6, MUM-1, GCET1, FOXP1, and LMO2 protein expression was used to assign cell of origin (COO) by three different algorithms. IHC for MYC, BCL2, PDL-1, and HLA class II protein expression was also performed. In situ hybridization for Epstein-Barr virus-encoded RNA (EBER) was performed. Fluorescent in-situ hybridization (FISH) was performed for MYC, BCL2, BCL6, PDL1/2 (9p24.1), and CIITA (16p13) rearrangements. Results A total of 115 patients with PCNSL with DLBCL histology were included in the final analysis: 59% male, 70% age >60 years, 77% performance status >1. Primary treatment modalities included high-dose methotrexate (HDMTX) based regimens in 52 (45%) patients, whole brain radiotherapy (WBRT) alone in 40 (35%) patients, and best supportive care in 23 (20%) patients. Among the 52 HDMTX-treated patients, 18 also received WBRT (pre-planned combined modality therapy or inability to tolerate HDMTX), and 11 also received rituximab. Failure of IHC/FISH occurred in 0-21% of individual assays, largely due to insufficient tissue material. The majority of patients had a non-GCB COO phenotype as determined by the Hans (76%), Choi (86%), and Tally (99%) algorithms. MYC protein expression was positive (≥40%) in 37/93 (40%) patients, BCL2 (≥50%) in 68/91 (75%) [124 antibody] and 87/111 (78%) [E17 antibody] patients, and dual MYC/BCL2 in 30/88 (35%) [124 antibody] and 32/92 (35%) [E17 antibody] patients. PDL-1 protein expression was positive (≥1%) in 31/107 (29%) patients. HLA class II antigen expression was positive (≥10%) in 75/112 (67%) patients, with staining restricted to cytoplasm (70%) or cell membrane (30%). EBER was positive (any staining) in 8/108 (7%) patients. Chromosomal rearrangements by FISH were very uncommon for MYC 1/93 (1%), BCL2 1/110 (1%), PDL1/2 1/101 (1%), and CIITA 3/105 (3%). There were no dual rearrangements involving MYC and BCL2, although the only patient with a MYC rearrangement also had a concurrent BCL6 rearrangement. In contrast, BCL6 rearrangements were present in 33/108 (31%) patients, while BCL6 protein expression was positive in 86/111 (77%) patients. With a median follow-up of 8 years (range 8 months - 16 years) in living patients, the 5-year PFS and OS estimates were 11% and 24%, respectively. In univariate analysis, elevated LDH, treatment with WBRT alone or supportive care, and the presence of BCL6 rearrangements (HR 1.73 [95% CI 1.12, 2.66], p=0.011) were significantly associated with worse PFS. Age >60, poor performance status, and treatment with WBRT alone or supportive care were significantly associated with worse OS, and a trend observed with the presence of BCL6 rearrangements (HR 1.46 [95% CI 0.95, 2.27], p=0.085). All other clinical and pathologic variables were not associated with PFS or OS. In the 52 patients treated with HDMTX-based regimens, the presence of a BCL6 rearrangement was the only variable associated with a worse PFS (HR 2.50 [95% CI 1.25 - 5.01], p=0.007), and no variables were associated with OS. Discussion and Conclusions This large TMA study shows that prominent molecular features of PCNSL are different from those of systemic DLBCL. There was a high TMA failure rate reflecting the limitations of brain biopsies, which are often stereotactic needle biopsies, small surgical samples, or obtained after a course of corticosteroids. Consistent with other reports, the majority of cases had a non-GCB phenotype by IHC algorithms, but cell of origin did not impact PFS or OS. MYC, BCL2, and PDL-1 protein expression were common but their corresponding gene rearrangements were extremely uncommon suggesting alternate mechanisms driving expression. BCL6 rearrangements were frequent and were the only factor associated with a poor prognosis in the overall cohort and in the subgroup of patients treated with HDTMX-based regimens. Disclosures Connors: Janssen: Research Funding; Genentech: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Merck: Research Funding; Bristol Myers-Squibb: Research Funding; Bayer Healthcare: Research Funding; F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding; Lilly: Research Funding; Seattle Genetics: Honoraria, Research Funding; Takeda: Research Funding; Amgen: Research Funding; Cephalon: Research Funding. Sehn:TG Therapeutics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Merck: Consultancy, Honoraria. Scott:Celgene: Consultancy, Honoraria; Janssen: Research Funding; Roche: Research Funding; NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding. Steidl:Juno Therapeutics: Consultancy; Bristol-Myers Squibb: Research Funding; Tioma: Research Funding; Seattle Genetics: Consultancy; Nanostring: Patents & Royalties: patent holding; Roche: Consultancy. Gascoyne:NanoString: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies.

scholarly journals XPO1 Inhibition By Selinexor Synergizes with BCR Inhibition, Blocks Tumor Growth and Prolongs Survival in a Bioluminescent Animal Model of Primary Central Nervous System Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 463-463 ◽  
Author(s):  
Marta Crespo ◽  
Julia Carabia ◽  
Isabel Jiménez ◽  
Sabela Bobillo ◽  
Pau Abrisqueta ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cells ◽  
Tumor Growth ◽  
Cell Lines ◽  
Research Funding ◽  
Central Nervous System Lymphoma ◽  
Cell Of Origin ◽  
Cerebral Parenchyma ◽  
Time Point

Abstract Primary central nervous system lymphoma (PCNSL) is a very aggressive non-Hodgkin lymphoma localized in the cerebral parenchyma, eyes, leptomeninges or spinal cord in the absence of systemic involvement. Approximately 95% of PCNSL are classified as diffuse large B-cell lymphoma (DLBCL), being most of them more closely related to activated B-cell type (ABC-DLBCL). PCNSL is associated with poor prognosis, particularly because of the difficulty for drugs to cross the blood brain barrier. High dose methotrexate is the most effective treatment, but relapse is very common and salvage therapies are scarce. Therefore, the development of effective drugs with ability to penetrate the CNS is highly needed. Selinexor (KTP-330) is a Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO-1 protein. This inactivation induces anti-tumor effects by forcing nuclear retention and activation of tumor suppressor proteins. Selinexor has shown excellent brain penetration, exhibits promising results in pre-clinical models of glioblastoma and can inhibit both BCR and NF-kB signaling in malignant B-cells. Therefore, in order to provide a pre-clinical rationale for the use of selinexor for patients with PCNSL, we tested the role of XPO-1 inhibition in PCNSL using intracerebral xenograft murine models. We then determined the inhibitory concentration 50 (IC50) in 4 ABC and 5 GCB DLBCL cell lines. Cell survival and proliferation were tested 96 hours after incubation with selinexor. Analysis showed that the DLBCL cell lines have equivalent sensitivity to selinexor, regardless cell of origin (COO). In detail, survival assessed by AnnexinV-PI exclusion showed that mean ID50 for ABC cell lines was 4.98 µM +/- 3.6 and 6.3 µM +/- 3.8 for GCB (p=0.9). Proliferation assessed by MTS was also blocked by selinexor (mean ID50 for ABC-DLBCL was 1.35 µM +/- 0.7 vs. 16.16 µM +/- 11.17 for GCB-DLBCL (p=0.41)). Since SINE compounds have been shown to inhibit BCR signaling, we next tested the potential synergy between ibrutinib and selinexor. All three ABC-DLBCL cell lines tested were sensitive to ibrutinib and in two of them the combination with selinexor was strongly synergic. In contrast, none of the 3 GCB-DLBCL cell lines analyzed were sensitive to up to 100 µM single agent ibrutinib; interestingly, however, treatment with selinexor sensitized SUDHL4 cells to ibrutinib and the combination index values indicated strong synergism between the two drugs. Finally, we established an orthotopic xenograft model of PCNSL by stereotactic injection of the OCI-Ly10 (ABC) cell line stably transfected with firefly luciferase into the cerebral parenchyma of nude athymic mice. This allows the non-invasive longitudinal quantification of intracerebral tumor growth (bioluminescence detection, IVIS¨ Spectrum). Eleven days after the injection of cells all animals had developed detectable tumors confined to the CNS. Tumor size was measured and animals were randomly distributed into drug or vehicle experimental group (vehicle: n=8, mean radiance= 1.33á107 p/sec/cm2/sr ± 0.68á107; treatment: n=9, mean radiance=2.99á107 p/sec/cm2/sr ± 2.3á107). At this time point mice were treated with 5mg/kg of selinexor or vehicle via oral gavage three times a week. Treatment with selinexor significantly increased mice survival, with a median survival of 48 days in the treatment group compared to 34 days in the vehicle group (p< 0.0001; figure 1A). Mice in the treatment group showed a significantly slower increase in bioluminescence signal (two-way ANOVA: p< 0.0001; figure 1B). Specific time-point analysis showed that differences were significant as soon as 8 days after treatment. At final point, histopathological analysis showed diffuse infiltration in meninges and cerebral parenquima of highly proliferative CD20-positive B-cells (virtually 100% Ki-67-positive malignant B cells) In conclusion, selinexor inhibits proliferation and survival of DLBCL cell lines, regardless of the cell of origin and it can synergize with ibrutinib. Moreover, treatment of mice with CNS confined ABC-DLBCL with selinexor significantly reduces tumor growth and increases survival. Therefore, our results provide pre-clinical evidence for the development of selinexor as new therapeutic option for PCNSL or DLBCL with CNS involvement. Figure 1 Figure 1. Disclosures Bosch: Hoffman La Roche: Consultancy, Honoraria, Research Funding; Millennium: Research Funding.

International Primary Central Nervous System Lymphoma Collaborative Group (IPCG) Study on Low-Grade Primary Central Nervous System Lymphoma in Immunocompetent Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3343-3343
Author(s):  
Agnieszka Korfel ◽  
Kristoph Jahnke ◽  
Brian P. O’Neill ◽  
Jean-Yves Blay ◽  
Lauren Abrey ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Tumor Resection ◽  
Central Nervous System Lymphoma ◽  
Collaborative Group ◽  
Low Grade ◽  
Term Outcome ◽  
Long Term Outcome

Abstract Low-grade primary central nervous system lymphoma is a very rare subtype of primary central nervous system lymphoma (PCNSL), for which almost no data is currently available. The purpose of this retrospective study was to characterize the clinical presentation, course and outcome of patients with low-grade PCNSL. Forty patients (18 male, 22 female) from 18 cancer centers in five countries were identified with a median age of 58 (range, 19–78) years and a median Eastern Cooperative Oncology Group (ECOG) performance status of 1 (range, 0–4). The mean time to diagnosis was 14.8 months (range, 0.25–84). Thirty-two patients (80%) had a B-cell and eight a T-cell lymphoma. Thirty-seven patients (92.5%) showed involvement of a cerebral hemisphere or deeper brain structures, while two evidenced only leptomeningeal involvement, and one patient had spinal cord disease. Treatment was performed in 39 patients: chemotherapy and radiotherapy in 15 (38%), radiotherapy alone in 12 (30%), chemotherapy alone in 10 (25%), and tumor resection alone in two. The median progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OAS) were 61.5 (range, 0–204), 130 (range, 1–204), and 79 (range, 1–204) months, respectively. An age ≥60 years was associated with a shorter PFS (P = .009), DSS (P = .015) and OAS (P = .001) in multivariate analysis. Low-grade PCNSL differ from the high-grade subtype in pathological, clinical and radiological features. In this study, the long-term outcome was better as compared to the results obtained in PCNSL in general with age ≥60 years adversely affecting survival.

scholarly journals Primary Central Nervous System Lymphoma: A Retrospective Study of the Population of Texas and Florida with an Emphasis on Survival Outcomes on Hispanics Vs Non-Hispanics

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1443-1443
Author(s):  
Kana Tai Lucero ◽  
Lakene Raissa Djoufack Djoumessi ◽  
Joel E Michalek ◽  
Qianqian Liu ◽  
Adolfo Enrique Diaz Duque
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Retrospective Study ◽  
Research Funding ◽  
Central Nervous System Lymphoma ◽  
Survival Outcomes ◽  
P Value ◽  
Poverty Index ◽  
Significant Difference ◽  
The U.S

Abstract Introduction Primary central nervous system lymphoma (PCNSL) is a devastating subtype of extranodal non-Hodgkin's lymphoma (NHL) that accounts for ~4% of newly diagnosed central nervous system (CNS) tumors. (NeuroOncol PMID: 21915121) The age-adjusted incidence of PCNSL in the U.S. has increased since the 1970s. (ACS PMID: 19273630) despite advances in the treatment of lymphoma, and clinical outcomes remain poor with an estimated 5- year survival for immunocompetent patients at 30%. (NCBIPMID:31424729) Trends in outcomes of PCNSL have been reported, but sub-analyses for minorities like Hispanics (HI), have not been widely studied. Understanding ethnic disparities on outcomes and patterns of care in PCNSL are crucial given the rapid growth of HI in the U.S. This study aims to examine the demographics, treatment patterns, and survival outcomes of PCNSL in HI compared to Non-Hispanics (NH) in Texas (TX) and Florida (FL). Methods This is a retrospective study of a cohort of patients diagnosed with lymphoma (Hodgkin and Non-Hodgkin) from the TX Cancer Registry (TCR) and the FL Cancer Data System (FCDS) from 2006-2017. Patients with PCNSL were identified by the International Classification of Diseases for Oncology Third Edition (ICD-O-3) code list. Standard demographic variables collected include gender, ethnicity, dates at diagnosis and death, primary payer at diagnosis, type of treatment and poverty index (PI). The significance of variation in the distribution of categorical outcomes with ethnicity (HI and NH) was assessed with Fisher's Exact tests or Pearson's Chi-square tests as appropriate; age was assessed with T-tests or Wilcoxon tests as appropriate. Survival distributions were described with Kaplan-Meier curves and significance of variation in median survival with ethnicity was assessed with log rank testing. All statistical testing was two-sided with a significance level of 5%. Results The study included 1969 patients (TX: n=297 HI, n= 708 NH; FL: n=149 HI, n=415 NH). PCNSL was diagnosed at younger median age in HI (TX: 59,FL:59) compared to NH (TX: 62, FL:63),with a significant difference noted within each state (TX: p= 0.005; FL: p=0.007). HI in TX were identified primarily as Mexican, Spanish or NOS/Hispanic. There was a significant predominance of overall males (M) in TX (p=0.009). There was a non-significant predominance of M in FL. Regarding poverty index (PI), there were more HI (TX:51% and FL: 35%) in the 20-100% bracket than NH (TX: 25%; FL: 22%). Conversely there were more NH in all other PI in TX and FL. Government sponsored insurance was the most common insurance in all subgroups. This reached a significant predominance in HI (54%) and NH (54%) in TX (p&lt;0.001). There was no significant difference in insurance types between HI and NH in FL(p=0.772). Regarding chemotherapy there was a trend to either use multiple agents [(TX: 34% in HI vs 32% in NH; p=0.68); (FL: 33% in HI vs 67% in NH; p=0.042)] or to not offer chemotherapy at all [(TX: 26% in HI vs 29% in NH; p= 0.68); (FL: 44% in HI vs 33% in NH; p=0.042)] with significant differences noted in FL only. (Table 1) The median survival (MS) for HI and NH in TX was similar in years (y) at 0.8 while the MS time in FL for HI vs NH was higher (1.3 vs 0.6 respectfully) Thus, the MS for HI in FL was higher compared to NH in FL and HI and NH in both TX and FL. (Table 2) The survival probability for HI was shorter at 2 and 5 years compared to NH in TX with a non-significant overall survival (OS) probability (p-value=0.19) seen in Figure 1. Significantly, the survival probability of HI in FL at 2, 5 and 10 years was higher compared to NH with an OS probability (p-value=0.0063) seen in Figure 2. Conclusion This retrospective study showed a statistically significant difference in OS probabilities at all years between HI and NH in FL with PCNSL. The OS probability also remained higher in HI in FL compared to both HI and NH in TX. In addition, the study demonstrated a longer MS in HI in FL compared to not only HI in TX, but also both NH in TX and FL. Sociodemographic differences like gender and insurance types were noted between HI in TX and FL. HI origin groups are also a subject of interest. The primary HI origin group in TX were Mexican and not otherwise specified (NOS). This data was missing for FL HI. Future studies should be conducted to uncover any further disparities between these two HI populations to explore the impact of access to care and disease biology on PCNSL survival outcomes. Figure 1 Figure 1. Disclosures Diaz Duque: Incyte: Consultancy; Morphosys: Speakers Bureau; Astra Zeneca: Research Funding; Hutchinson Pharmaceuticals: Research Funding; Epizyme: Consultancy; ADCT: Consultancy.

Del(6)(q22) and BCL6 Rearrangements in Primary Central Nervous System Lymphoma (PCNSL) Are Indicators of an Aggressive Clinical Course.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1557-1557
Author(s):  
Francois M. Cady ◽  
Mark E. Law ◽  
Caterina Giannini ◽  
Alyx B. Porter ◽  
Brian P. O’Neill ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
In Situ Hybridization ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Thin Sections ◽  
Ebv Infection ◽  
Partner Gene ◽  
Immunocompetent Patients

Abstract Purpose: Despite therapeutic advancements, biological markers that predict the natural history of primary central nervous system lymphoma (PCNSL) are lacking and age and performance status are the only consistently identified independent prognostic variables. BCL6 rearrangements and deletion of the tumor suppressor gene R-PTP-κ (PTPRK) at 6q22 are thought to be common genetic abnormalities in PCNSL but their prognostic significance is unknown. The aim of this study is to determine the prevalence and survival impact of del(6)(q22), BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements and prevalence of Epstein-Barr virus (EBV) infection in PCNSL affecting immunocompetent patients. Patients and methods: Seventy-six specimens from 76 HIV-negative, immunocompetent patients with PCNSL newly diagnosed and treated at Mayo Clinic between 1985 and 2006 were studied. Interphase fluorescence in-situ hybridization (FISH) was performed using two-color break apart probes (BAP) for BCL6 and MYC, a two-color dual-fusion probe for IGH-BCL6, and a two-color probe for del(6)(q22) on thin sections of paraffin-embedded tumor samples. Two-color IGH BAP FISH probes were also used to confirm IGH rearrangements in cases showing extra IGH signals without fusion using the IGH-BCL6 probe. In situ hybridization was performed using probes that recognize EBV-encoded RNA (EBER) on paraffin-embedded tumor samples. Survival data were analyzed for patients diagnosed after 1997 (n=53), corresponding to the change to high dose methotrexate as the standard of care. Survival was calculated from the date of tissue diagnosis to date of death or last contact. Survival curves were estimated using the Kaplan-Meier method. The log-rank test was used to compare survival across groups. Two-tailed p-values &lt;0.05 were considered statistically significant. Clinical information for the 1985–2006 and 1997–2006 groups was comparable, including median age (67 years (y) vs 68 y), age range (26–87 y for both groups), percentage of deaths (67 vs 64) and median follow up for survivors (588 d vs 395 d). Results: Thirty-four (45%) cases showed del(6)(q22), 6 of which alsocontained a BCL6 rearrangement. Seventeen (22%) cases had a BCL6 rearrangement. Translocations involving IGH and an unknown partner gene (n=2) and MYC and an unknown partner gene (n=2) were also identified. All cases were EBER negative. Of the 53 patients diagnosed after 1997, 23 lacked del(6)(q22) or BCL6 rearrangement and had a median overall survival (MS) of 731 days (d). The 17 patients with an isolated del(6)(q22) had a MS of 90 d and the 13 patients with a BCL6 rearrangement had a MS of 442 d (p=0.0016). Conclusions: Del(6)(q22) and BCL6 rearrangements are common in PCNSL (45% and 22% of cases, respectively) and are associated with decreased survival, particularly del(6)(q22) seemingly independent of patient age and treatment time trends. IGH translocations were less frequent than in systemic diffuse large B-cell lymphoma (13% vs 51%), suggesting a distinct pathogenesis. MYC translocations and EBV infection are rare in PCNSL affecting immunocompetent patients.

scholarly journals NQPC-06 FUNCTIONAL OUTCOMES OF INITIAL TREATMENTS FOR PATIENTS WITH PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA ASSESSED BY ADL AND NEUROCOGNITIVE FUNCTION

2019 ◽  
Vol 1 (Supplement_2) ◽  
pp. ii30-ii30
Author(s):  
Mikiko Taku ◽  
Keiichi Kobayashi ◽  
Yuki Yamagishi ◽  
Kuniaki Saito ◽  
Daisuke Shimada ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Induction Therapy ◽  
Social Adjustment ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Central Nervous System Lymphoma ◽  
Neurocognitive Function ◽  
Remission Induction ◽  
High Dose

Abstract BACKGROUNDS Primary central nervous system lymphoma (PCNSL) frequently causes severe damage of activities of daily living (ADL) and neurocognitive function (NCF) due to extensive brain infiltration, necessitating their appropriate assessment and measures even in clinical practice. Since few studies have focused on the changes in the level of ADL and NCF in the course of PCNSL treatment, we retrospectively analyzed the effect of initial treatment of PCNSL in view of ADL and NCF. METHODS Among 55 patients (13 male/9 female) with newly-diagnosed PCNSL treated in our institution from January 2014 to June 2019, 22 were evaluated with both ADL and NCF. Remission induction therapies consisted of high-dose methotrexate alone (two patients), R-MPV (rituximab, methotrexate, procarbazine, and vincristine)(17 patients), and R-MPV+radiaotherapy (three patients), according to the patients’ conditions. Rehabilitation staffs intervened from the beginning, providing specific exercises and periodically evaluating scores of Karnofsky Performance Status (KPS) and Mini Mental State Examination (MMSE). RESULTS Mean age was 68.4 yo (range 34 to 85). After induction therapies, there were 11 complete responses (CRs), eight partial responses (PRs), and three progressive diseases (PDs). Both KPS and MMSE scores improved after induction therapy, from median 70 (40–90) to 80 (50–90), and from 24 (0–30) to 27(0–30), respectively. Among three patients who underwent RT, MMSE declined in two (one CR/one PR). CONCLUSIONS Case-adjusted induction therapies resulted in significant radiographical responses, and the longitudinal evaluation of ADL and NCF by rehabilitation staffs could validate their maintenance or improvement over time through effective treatments and early rehabilitation intervention. However, three was difficulty in assessing patients with higher brain dysfunction such as aphasia and social adjustment disorder. Further study is needed to include more patients and to explore more appropriate evaluation batteries and timings during and after completion of induction therapy for PCNSL.

scholarly journals Non-Diffuse Large B-Cell Primary Central Nervous System Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4208-4208
Author(s):  
Sangeetha Gandhi ◽  
Grzegorz S. Nowakowski ◽  
Thomas M. Habermann ◽  
Kay M. Ristow ◽  
Patrick Johnston
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Cell Lymphoma ◽  
Performance Status ◽  
Central Nervous System Lymphoma ◽  
Cns Lymphoma ◽  
Ecog Performance Status ◽  
Kaplan Meier ◽  
Large B Cell

Abstract Background: The majority of subjects with a diagnosis of primary central nervous system lymphoma (PCSNL) have diffuse large B-cell lymphoma (DLBCL) as their histology. However, there are a sub-set of PCSNL patients who present with other histologies. This retrospective study was conducted to evaluate histological morphology, risk factors and clinical course in subjects with non-diffuse large B-cell primary CNS lymphoma. Methods: We used the Mayo Clinic Lymphoma Database to search for patients with PCSNL during the time period from January 1995 to June 2018. One hundred and fifty nine patients met the criteria and underwent record review. One hundred and nine patients were excluded as they had PCSNL with DLBCL histology (N=47, 43%), secondary central nervous system lymphoma (N=56, 51%) and post-transplant lymphoproliferative disorders (PTLD) with DLBCL morphology (N=6, 5%). We identified fifty patients with PCSNL Non-DLBCL histology, by evaluating the biopsy reports. We abstracted clinical data and outcomes for these groups through medical chart review. Kaplan-Meier analysis was used to estimate survival. Results: The mean age of the study population was 70 ± 11.3 years and 66% were male. Of the 50 patients, the most common histology was low grade CNS lymphoma (N=14, 28%) while Hodgkin's lymphoma (N= 1, 2%), Burkitt's lymphoma (N= 1, 2%) and histiocytic lymphoma (N= 1, 2%) were the least common. The frequencies of other PCSNL Non-DLBCL histology are demonstrated in Table1. Most patients showed good ECOG performance status of 0-2 and four patients had ECOG performance status of grade 3 (N=4, 8%). Six of the patients were immunocompromised (N=6, 12%), PPD positive tuberculosis; corticosteroids and PTLD with DLBCL histology were the causes for the immunocompromised state. The location of the CNS lymphoma included brain (N=24, 50%); spinal cord (N=9, 18%); orbits (N=5, 10%); deep structures which included brainstem, cerebellum, cerebellopontine angle and cauda equina (N=5, 10%); leptomeninges (N=4, 8%) and neural involvement which included sciatic, peroneal and facial nerve (N=3, 6%). CSF examination revealed increased protein levels (N=10, 20%), malignant cells (N=11, 22%), negative cytology (N=14, 28%) and unknown or not done (N=15, 30%). Most patients presented with neurological symptoms such as seizures, peripheral neuropathy (numbness/weakness/tingling), headache, confusion & cognitive disturbances (memory changes), gait disturbances (difficulty with balance/ataxia), visual disturbances (blurry vision) and paraplegia, but none of them presented with B-cell symptoms such as fever, night sweats and weight loss. Treatment modalities included chemotherapy, radiation and surgery. Fourteen patients underwent radiation therapy (N=14, 28%); three of the patients had undergone surgery of which the patient with peripheral T-cell lymphoma had undergone a complete excision, the patient with marginal zone lymphoma had undergone debulking with subtotal craniotomy and the patient with MALT lymphoma had undergone resection with gamma knife. Table 2 demonstrates the various chemotherapy drugs used and the distribution of frequency of biopsy, radiation and surgical treatment in the different pathology of PCSNL Non-DLBCL. The median overall survival period using Kaplan-Meier analysis showed that Burkitt's Lymphoma had the least median time survival of less than a month and PTLD had the highest median survival of 146.25 months (p=0.0017). Table 3 shows the median survival time for all the different pathology's of PCSNL Non-DLBCL. Conclusion: This retrospective study reinforces the critical need for a histologic diagnosis when a patient is diagnosed with PCNSL. PCSNL is considered to be DLBCL but there are other histology's that could potentially be PCSNL and the treatment should be tailored to the individual patient's histology. Disclosures No relevant conflicts of interest to declare.

scholarly journals Real-World Outcomes of Older Patients with Primary Central Nervous System Lymphoma (PCNSL): Methotrexate Dose Intensity and Combination with Cytarabine Correlate with Response and Survival

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 572-572
Author(s):  
Nicolas Martinez-Calle ◽  
Edward Poynton ◽  
Alia Alchawaf ◽  
Shireen Kassam ◽  
Matthew Horan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Central Nervous System ◽  
Nervous System ◽  
Median Time ◽  
Real World ◽  
Research Funding ◽  
Single Agent ◽  
Dose Intensity ◽  
Central Nervous System Lymphoma ◽  
Support Research

Abstract INTRODUCTION Primary central nervous system lymphoma (PCNSL) in patients (pts) over 65 years old have poorer outcome compared to younger cohorts, as comorbidities, baseline performance status and susceptibility to iatrogenic toxicity impede adequate drug delivery (Kasenda et al, Ann Oncol, 2015). Balancing toxicity against treatment benefits remains a challenge in this age group. Recent trials have attempted to rationalize treatment aiming for reduced toxicity whilst maintaining CNS penetration. Efficacy of additional agents, such as oral alkylators (Fritsch et al, Leukemia 2017) has also been demonstrated. Most clinical trial cohorts underrepresent elderly pts and thus analysis of real-world outcomes and therapeutic practice is warranted. METHODS Consecutively diagnosed pts between 01/10/12 and 01/10/17, ≥65 years old in 14 tertiary UK centres were analysed retrospectively. Radiological exclusion of systemic disease and histological diagnosis were mandatory. Pts receiving any form of 1st line treatment including palliative (whole-brain radiotherapy [WBRT]/oral chemotherapy), best supportive care (BSC) or clinical trial were included. Diagnostic and referral pathways were audited. Baseline patient characteristics and treatment received was recorded in order to document current UK practice. Pts. were stratified into 4 treatment groups: single agent MTX; MTX with oral alkylator; high-intensity HI-MTX (MTX/AraC and MATRix) or palliative intent treatment (WBRT/oral alkylator/BSC). The study primary outcome was overall response rate (ORR) after induction. Secondary outcomes were PFS and OS. Additional variables were MTX clearance and the relative dose intensity (RDI) of MTX normalised with a reference of 14mg/m2. UV/MVA for ORR and Cox-regression for PFS and OS were used for identification of baseline predictors of response and survival. RESULTS 244 pts were included in the analysis with median age 71yrs (range 65-91) and 123 (50%) male. LDH (Elevated:104, 42%) and ECOG performance score (PS) (3-4: 87, 36%) were the only prognostic markers recorded. Median time from presenting scan to treatment was 33 days (IQR 22-48). Demographic characteristics are summarised in table 1. 80% of pts (n=192) received MTX based chemotherapy. 68% of pts >70yr and 50% >75yr received >1 cycle of MTX. MTX median cumulative dose delivered was 10.6 g/m2 (range 1.5-21), median number of cycles was 4 (range 1-6). Dose reductions of MTX occurred in 53/176 pts. (30%). Median time to MTX clearance was 3 days (range 1-18) and median RDI was 0.75 (range 0.11-1.5). TRM for MTX treated pts was 7.2%. 112 pts received rituximab (46%; 11% pre-2015 vs. 64% post-2015). 73 pts. (38%) received <2 cycles of treatment, reasons for dropout were progression (49/73), chemotherapy-related adverse events (13/73) and unknown (11/66); median OS for these pts was 4.1 months. 66 pts received consolidation (15 WBRT, 36 ASCT and 13 oral alkylator) with a median age of 69 (range 65-84). Median OS in this group was 64 months. ORR after induction was 63%. HI-MTX (HR 3.4; CI 95% 1.5 - 7.6; p=0.003) was independently associated with superior ORR compared to HD-MTX alone (Table 1). Median follow up for survival was 25 months. 2-yr PFS and OS were both 39%, median OS after progression was 80 days. MTX RDI (HR 0.18; p<0.001) was the only independent covariate for PFS. Treatment allocation to HI-MTX (HR 0.47; p=0.02), MTX RDI (HR 0.23; p=0.001) and complete response following induction (HR 0.29; p=0.001) were covariates for OS. 52 pts (21%) received upfront palliative treatment and compared to MTX cohort, were older (median 76y vs. 70y), had a poorer PS (ECOG 3-4: 62% vs. 28%) and higher incidence of impaired renal function (GFR < 60ml/min: 15% vs. 5%). CONCLUSION MTX can be delivered to the majority of pts >70 years with manageable TRM rates. Notably, early treatment discontinuation was relatively frequent with outcomes in this group comparable to palliative care. By contrast, pts who completed >3 cycles of HI-MTX and underwent consolidation experienced comparable outcomes to younger trial cohorts. MTX combination chemotherapy and MTX dose intensity were the strongest predictors of survival whilst rituximab was not a covariate for response or survival despite an increase in its use. Maximising cumulative MTX dose, particularly within more intensive protocols, may translate into improved ORR and survival in older pts with PCNSL. Table. Table. Disclosures Kassam: AbbVie: Equity Ownership. Culligan:Merck Sharp & Dohme (MSD): Honoraria; Celgene: Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences; JAZZ: Honoraria; Abbvie: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Pfizer: Honoraria. McKay:Epizyme: Consultancy, Honoraria. Eyre:Roche: Consultancy; Janssen: Consultancy, Other: travel support; Gilead: Consultancy, Other: travel support; Abbvie: Consultancy, Other: travel support; Celgene: Other: travel support. Osborne:Roche: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Servier: Consultancy; MSD: Consultancy; Celgene: Consultancy; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Other: Travel to conference. Yallop:Servier: Other: Travel funding; Pfizer: Consultancy. Fox:Janssen: Consultancy, Other: Personal fees and non-financial support, Speakers Bureau; AbbVie: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Celgene: Consultancy, Other: Travel support, Speakers Bureau; Sunesis: Consultancy; Roche: Consultancy, Other: Travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel support, Research Funding, Speakers Bureau. Cwynarski:Roche: Consultancy, Other: Conferences/Travel support, Speakers Bureau; Autolus: Consultancy; Kite: Consultancy; Gilead: Consultancy, Other: Conferences/Travel support, Speakers Bureau; Janssen: Other: Conferences/Travel support.

scholarly journals Ifosphamide and Carboplatin Based (R-DeVIC) Salvage Therapy in Patients with Relapsed/Refractory PCNSL - a Multicentre Retrospective Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1705-1705
Author(s):  
Hans-Guido Holl ◽  
Elisabeth Schorb ◽  
Jürgen Finke ◽  
Nikolaos Vassiliadis ◽  
Benjamin Kasenda ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Research Funding ◽  
Progressive Disease ◽  
Response Rate ◽  
Brain Mri ◽  
Central Nervous System Lymphoma ◽  
Common Adverse Event ◽  
High Dose ◽  
Eligibility Criteria

Abstract Background Primary central nervous system lymphoma (PCNSL) is rare and aggressive Non-Hodgkin lymphoma of the central nervous system (CNS).High-dose methotrexate (HD-MTX) based chemotherapy is standard first-line treatment in newly diagnosed disease. Although remissions can be achieved in most patients, at least a third relapses and therapeutic options in relapsed/refractory PCNSL (r/r PCNSL) are still limited. Aim of this study was to investigate efficacy and safety in of the R-DeVIC protocol consisting of: rituximab, ifosfamide, dexamethason, carboplatin and etoposide. Methods This was a retrospective study based on routinely collected health data from two sites in Germany (Stuttgart and Freiburg). Patient eligibility criteria were: r/r PCNSL confirmed by local pathology treated with at least one prior therapy. The R-DeVIC protocol was applied according to the following schedule: Rituximab 375 mg/m2/d (d0), dexamethasone 40 mg/d (d1-3), etoposide 100 mg/m2/d (d1-3), ifosfamide 1500 mg/m2/d (d1-3), carboplatin 300 mg/m2/ (d1) and repeated after 21 days. Feasibility endpoints included: toxicity, dose density, and treatment related death. Efficacy endpoints included: response as evaluated on brain MRI, progression free survival (PFS) and overall survival (OS). We used descriptive statistics for summarizing patient characteristics and outcomes; including the Kaplan-Meier estimator to plot time-to-event endpoints. Results We identified 19 eligible patients with r/r PCNSL being treated with R-DeVIC between 2010 and 2018. All patients received prior HD-MTX based chemotherapy (58% (11/19) treated with R-MTX/AraC/Thiotepa, 11% (2/19) treated with R-MTX/AraC and 26% (5/19) treated with R-MTX). All, but 2 patients received R-DeVIC at first progression after 1stline treatment. In 52% (10/19), treatment was discontinued after the first cycle. In 3 patients R-DeVIC was discontinued due to severe infections or renal injury and in 2 patients due to ifosfamide induced neuro-toxicity, as well as progressive disease in 2 patients. 2 patients already achieved complete remission and in one case reasons for discontinuance were not recorded. A 2ndcycle was administered in 47% (9/19) and 3 patients received a 3rdcycles of R-DeVIC. Observed overall response rate after R-DeVIC was 79% (15/19): Five patients with complete and 10 with partial remission, respectively. Three (26%) patients had progressive disease and one patient achieved disease stabilization. Neutropenic fever requiring intravenous antibiotic treatment was the most common adverse event (21% of administered cycles), followed by neurological disturbances, mainly associated with ifosfamide. After a median follow-up of 5 months, 6- month and 12 -month PFS were both 47% (95% CI 24-67); 6 month and 12-month was OS 59% (95% CI 32-78). Conclusions R-DeVIC is a feasible therapeutic salvage option in r/r PCNSL associated with a response rate of 79%. However, substantial toxicity was also observed leading to discontinuation of treatment in about a quarter of patients. Further data will be presented at the meeting. Disclosures Finke: Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding. Illerhaus:Riemser: Consultancy, Honoraria.

Successful Use of Rituximab To Treat Central Nervous System Lymphoma in a Patient with B-Cell Post-Transplant Lymphoproliferative Disorder (PTLD).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4788-4788
Author(s):  
Shirley A. Riggs ◽  
Charles Van Buren ◽  
Barry Kahan
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
B Cell ◽  
Vasogenic Edema ◽  
Performance Status ◽  
Central Nervous System Lymphoma ◽  
Brain Biopsy ◽  
Perioperative Period ◽  
Vascular Involvement ◽  
Cerebral Disease

Abstract A 27 year old male with end-stage renal failure secondary to IgA nephropathy received a living related renal transplant in 10/2002, complicated by severe cellular and humoral rejection. Immunosuppression included steroids, OKT3, cyclosporine A, rapamycin, thymoglobulin, antithymocyte globulin, and plasmapheresis. He developed multiple complications including severe pancytopenia, pleural effusions, Pseudomonas sepsis, and Vancomycin resistant enterococcus cystitis. Transplant nephrectomy was required 2/2003 for intractable rejection with blood clots in the urine, revealing large nodules of monomorphous B-cell PTLD throughout the renal parenchyma, along with type 2 acute cellular rejection. The B-cells were CD20 positive, and in situ hybridization for EBER was positive in the majority of the cells. PTLD staging was negative in other sites including brain and bone marrow. All immunosuppression was discontinued shortly following the nephrectomy, and he was placed on acyclovir for 3 months until he developed progressive cytopenias. In 8/2003 he underwent open brain biopsy following 2 grand mal seizures and an MRI showing multiple bilateral nonenhancing cortical and subcortical lesions up to several centimeters, with enhancing right temporal and parietal lesions with surrounding vasogenic edema and regional mass effect. Right temporal lobe biospy showed extensive high grade monomorphous B-cell PTLD with necrosis and vascular involvement. Lymphoma staging including lumbar puncture was otherwise negative and LDH was normal. He received a brief course of steroids and valacyclovir in the perioperative period. His performance status remained extremely poor, on hemodialysis, and thus he was not considered a good candidate for systemic chemotherapy, brain radiotherapy, or intrathecal chemotherapy. We elected to give a total of 8 courses of rituximab at 375 mg/m2 intravenously weekly. Although systemic rituximab does not generally penetrate the central nervous system very well, it was presumed that the blood brain barrier in this patient was broken down due to extensive lymphomatous cerebral disease. By 9/2003 there was improvement in the brain parenchymal lesions, and since 11/2003 there has been complete stabilization of residual involuted nonenhancing lesions. He remains in complete clinical remission, off rituximab for 22 months. This excellent response suggests that systemic rituximab can be an effective treatment in selected cases of PTLD in which extensive brain disease is present.

Sign in / Sign up

Export Citation Format

Share Document