Incidence Of Central Nervous System Relapse Research Articles

Efficacy of central nervous system prophylaxis with stand-alone intrathecal chemotherapy in diffuse large B-cell lymphoma patients treated with anthracycline-based chemotherapy in the rituximab era: a systematic review.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma remains uncommon but catastrophic. The benefit of standalone intrathecal prophylaxis in reducing CNS recurrence is unclear and remains controversial. No systematic review analysing the evidence for stand-alone intrathecal prophylaxis has been performed in the era of anti-CD20 monoclonal antibody therapy. A comprehensive search (01/2002-01/2019) was systematically performed using Ovid MEDLINE®, Ovid EMBASE® and Cochrane. Studies were selected from a total of 804, screened based on predefined inclusion/exclusion criteria, and were critically appraised. Three post hoc analyses (RICOVER-60, RCHOP-14/21, GOYA), one prospective database and 10 retrospective series were included. 7,357 rituximab/obinutuzumab-exposed patients were analysed. The median percentage receiving intrathecal prophylaxis was 11.9%. Cumulative CNS relapse incidence ranged from 1.9% at 6.5 years to 8.4% at 5 years. Median time (of medians) to CNS relapse was 10 months. 73% developed isolated CNS relapses, 24% concurrent CNS/systemic relapse, and 3% post-systemic relapse. Reported CNS relapse sites were: parenchymal (58%), leptomeningeal (27%), and both (12%). Event rates were low resulting in limited power within each study to provide robust univariable/multivariable analysis. Intrathecal prophylaxis was not a univariable or multivariable factor associated with a reduction in CNS relapse in any study. We found no strong evidence for the benefit, or indeed genuine lack of benefit, of stand-alone intrathecal prophylaxis in preventing CNS relapse in diffuse large B-cell lymphoma-treated patients using anthracycline-based immunochemotherapy. Current published study designs limit the strength of such conclusions.

Stand-alone intrathecal central nervous system (CNS) prophylaxis provide unclear benefit in reducing CNS relapse risk in elderly DLBCL patients treated with R-CHOP and is associated increased infection-related toxicity.

Central nervous system (CNS) relapse following R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) occurs in 2-5% of patents with diffuse large B-cell lymphoma (DLBCL). Many patients aged ≥70years are unsuitable for high-dose methotrexate (HDMTX) prophylaxis and therefore often receive stand-alone intrathecal prophylaxis. The CNS international prognostic index (CNS-IPI) is a clinical CNS relapse risk score that has not specifically been validated in elderly patients. The value of CNS prophylaxis in patients aged ≥70years remains uncertain. Data on 690 consecutively R-CHOP-treated DLBCL patients aged ≥70years were collected across 8 UK centres (2009-2018). CNS prophylaxis was administered per physician preference. Median age was 77·2years and median follow-up was 2·8years. CNS-IPI was 1-3 in 60·1%, 4 in 23·8%, 5 in 13·0% and 6 in 3·3%. Renal and/or adrenal (R/A) involvement occurred in 8·8%. Two-year overall CNS relapse incidence was 2·6% and according to CNS-IPI, 1-3:0·8%, 4:3·6%, 5:3·8% and 6:21·8%. Two-year CNS relapse incidence for R/A was 10·0%. When excluding HDMTX (n=31) patients, there remained no change in unadjusted/adjusted CNS relapse for intrathecal prophylaxis effect according to CNS-IPI. CNS-IPI is valid in elderly R-CHOP-treated DLBCL patients, with the highest risk in those with CNS-IPI 6 and R/A involvement. We observed no clear benefit for stand-alone intrathecal prophylaxis but observed an independent increased risk of infection-related admission during R-CHOP when intrathecal prophylaxis was administered.

PF302 CENTRAL NERVOUS SYSTEM RELAPSE IN DIFFUSE LARGE B CELL LYMPHOMA: RISK FACTORS AND ROLE OF INTRATHECAL PROPHYLAXIS

Background:Relapse of diffuse large B cell lymphoma (DLBCL) in the central nervous system (CNS) is a devastating event with dismal prognosis. Several risk factors for CNS recurrence have been reported including parameters of the International Prognostic Index (IPI) and involvement of particular extranodal sites by lymphoma. These have been combined into a risk stratification tool termed CNS‐IPI (Schmitz et al, JCO 2016). The method and efficacy of CNS prophylaxis remain controversial.Aims:We analyzed a large single institution cohort of patients with DLBCL treated in the rituximab era and who were candidates to receive intrathecal (i.t.) prophylaxis with methotrexate according to the guidelines of the Italian Society of Hematology (SIE) of 2006. We analyzed risk factors for CNS recurrence and the possible impact of i.t. prophylaxis on CNS recurrence.Methods:From our patient registry, we identified 684 patients with diffuse large B cell lymphoma diagnosed between 1/2006 and 12/2017. Ten patients (1.5%) with CNS involvement at diagnosis were excluded. Fifty‐six patients (8.3%) aged >80 years were not considered candidates for i.t. CNS prophylaxis. In the final analysis, we included 618 patients who were potential candidates for i.t. prophylaxis when risk factors, according to the SIE guidelines, were present. Prophylaxis consisted in 4 cycles of i.t. methotrexate during the first 4 cycles R‐CHOP and was administered to 177 patients (29%). We investigated the incidence of CNS relapse according to CNS‐IPI, involvement of particular extranodal sites and application of i.t. prophylaxis in a competing‐risk analysis with systemic relapses as competing event.Results:Progression‐free survival at 4 years in 618 patients with DLBCL was 72% (95% C.I., 67–75%). We observed 159 events of disease recurrence, of these 16 involved the CNS. CNS relapse involved the brain parenchyma in 10 patients and leptomeningeal infiltration occurred in 6 patients. CNS relapses were observed in 5/227 patients with a CNS‐IPI score 0–1, in 4/286 patients with a CNS‐IPi score 2–3 and in 7/149 patients with CNS‐IPI score ≥4. Considering systemic relapse as competing risk, a CNS‐IPI score ≥4 was only of borderline significance (p = 0.08). Analyzing for involvement of extranodal sites we found that involvement of testes, peripheral blood and kidney/adrenal glands (the latter sites combined with > 3‐fold elevation of LDH) were associated with high risk of CNS relapse (>20%). As these risk factors were independent, they could be combined into a risk model. Patients with at least one risk factor had a 15.6‐fold (95% C.I, 5.1–48.3) risk of CNS recurrence. This risk was not modified by administration of intrathecal prophylaxis.Summary/Conclusion:Involvement of extranodal sites as testes and peripheral blood that are not included in the CNS‐IPI, in addition to kidney/adrenal glands should be considered high‐risk factors for CNS recurrence. Prophylaxis with i.t. methotrexate appears not to be sufficient to contrast this risk.image

Results of successive EORTC-CLG 58881 and 58951 trials in paediatric T-cell acute lymphoblastic leukaemia (ALL).

Outcomes in childhood T-cell acute lymphoblastic leukaemia (T-ALL) are steadily improving due to intensive therapy. Between 1989 and 2008, 599 children with newly diagnosed T-ALL were enrolled in two successive European Organization for Research and Treatment of Cancer-Children's Leukaemia Group trials (58881 and 58951), both based onthe Berlin-Frankfurt-Munster protocol and without cranial irradiation. In the lattertrial induction chemotherapy was intensified. The most important randomizations were Medac Escherichia coli asparaginase versus Erwinia asparaginase in trial 58881, and dexamethasone (6mg/m2 /day) versus prednisolone (60mg/m2 /day) and prolonged versus conventional asparaginase duration in trial 58951. 8-year event-free survival (EFS) increased from 65·1% to 74·0% in trial 58951. Improvement was most profound for patients with white blood cell (WBC) counts <100×109 /l and "good responders" to prephase. Medac E.coli asparaginase was associated with longer EFS [hazard ratio (HR) 0·54, P=0·0015] and overall survival (HR 0·51, P=0·0018). Induction therapy with dexamethasone did not improve EFS compared to prednisolone. Remarkably, intensification of central nervous system (CNS)-directed therapy in trial 58951 resulted in fewer bone marrow relapses, while the incidence of CNS relapses remained low. In summary, we showed that adequate asparaginase therapy, intensified induction treatment and intensification of CNS-directed chemotherapy can result in an improvement of outcome in T-ALL patients with good prephase response and initial WBC counts <100×109 /l, representing approximately 50% of T-ALL patients.

Prophylaxis with Intrathecal Chemotherapy and High Dose Methotrexate in Patients with Diffuse Large B Cell Lymphoma at High Risk for Central Nervous System Relapse: A Single Centre Experience

Central nervous system involvement (CNS) is a serious and mostly fatal complication of aggressive lymphoma. The incidence of CNS disease in diffuse large B-cell lymphoma (DLBCL) is low (about 5%) and there are not randomised prospective trial which specifically address a decision-making process for CNS prophylaxis. Potentially two methods exist for identifying patients requiring CNS directed treatment. Surveillance lumbar puncture and brain magnetic resonance (MRI) at the time of diagnosis could identify the presence of lymphoma; another method is the identification of patients whose characteristics are indicative of a high risk of CNS disease. Several site-specific risks are described in literature such as testicular, breast, paranasal sinuses, epidural spaces, and intravascular involvement with an incidence of CNS relapse ranging from 15% to 50%. Recently a modified IPI score (CNS IPI) was described to predict risk of CNS relapse.The efficacy of different forms of CNS prophylaxis has never formally been demonstrated. In the RICOVER 60 trial, patients treated with R-CHOP-14 instead of CHOP-14 presented a lower incidence of CNS relapse while intrathecal methotrexate (MTX) has not showed a role in preventing CNS disease for patients treated with combined immunochemotherapy. Recently, combination of intrathecal MTX and high dose MTX infusion after R-CHOP treatment was considered an effective strategy of prevention of CNS relapse.In order to evaluate the efficacy and feasibility of intrathecal MTX administration and high dose MTX after first line chemotherapy, we retrospectively reviewed 27 patients (11 males and 16 females, mean age 61 yrs, range 27-79) with newly diagnosed DLBCL at high risk for CNS relapse, treated from January 2009 to April 2018 at Veneto Institute of Oncology IOV-IRCCS.In our cohort 21 (78%) patients were at advanced stage (III-IV Ann Arbor stage) and 15 (56%) belonged to intermediate-high or high risk IPI categories, two patients presented with orbital localization. Almost all patients received R-CHOP as first line treatments, two patients with paravertebral localization received HyperCVAD as front line approach.For 20 patients CNS-IPI was intermediate or high. In the other cases with low CNS-IPI, disease localization was considered at high risk of CNS relapse (breast, paravertebral, orbit, paranasal sinus). In all patients we performed brain MRI and diagnostic lumbar puncture at diagnosis (all negative at flow cytometry analysis). All 14 patients >65 yrs were evaluated with comprehensive geriatric assessment (CGA) and 8 (57%) were considered fit.Nineteen (19) patients (70%) received at least 3 lumbar punctures with MTX and 24 (89%) two courses of high dose intravenous MTX during first line therapy.At the end of planned first line treatment, 24 (89%) patients obtained a complete remission at PET scan evaluation and 3 patients (11%) presented progressive disease, 2 with CNS involvement and another with peritoneal disease; this last patient had a Double Hit lymphoma with BCL6 and c-MYC rearrangements. Another patient in complete remission after R-CHOP chemotherapy, experienced CNS relapse three year after obtaining complete remission. Among the two patients treated with Hyper CVAD regimen, one is still in complete remission 5 years after the end of treatment; another developed early CNS relapse.All the 3 patient who experienced CNS involvement after R-CHOP, didn't receive prophylaxis because were evaluated frail at CGA. So, at a median follow up of 26.2 months (3.5-100 months) all patients who received the planned treatment at full dose including CNS prophylaxis did not experience central nervous system relapse.In conclusion, CNS prophylaxis including intrathecal MTX administration and high dose MTX infusion after first line chemotherapy is feasible and effective.Larger prospective trials are needed to evaluate the most effective prophylactic therapy and the correct timing of intravenous MTX infusion. DisclosuresNo relevant conflicts of interest to declare.

Central Nervous System Relapse in Patients with Extranodal NK/T-Cell Lymphoma, Nasal Type

Introduction: Extranodal NK/T cell lymphoma (ENKTL), nasal type is an uncommon, unique subset of non-Hodgkin lymphoma. Its clinical outcome has improved significantly with introduction of non-anthracycline based chemotherapy and radiotherapy. Yet little is known about central nervous system (CNS) involvement of ENKTL, nasal type.Methods: A total of 168 patients with ENKTL-nasal type were included in this study. All patients were diagnosed between 2003.1 and 2016.6 in Asan Medical Center, Seoul, Korea. Patients with secondary CNS involvement at diagnosis and patients with aggressive NK-cell leukemia were excluded. CNS involvement was confirmed by pathology or MRI of affected organ. Cox regression analysis was performed to identify possible risk factors for CNS involvement.Results: Out of 168 patients, 109 patients were male and 59 patients were female. Median age at diagnosis was 52 years (range: 16-83). The number of patients with stage I/II disease was 112 (66.7%) and stage III/IV was 56 (33.3%). The number of patients with low, intermediate, high prognostic index of natural killer cell lymphoma (PINK) was 70 (41.7%), 55 (32.7%), 43 (25.6%) each. Thirty (17.8%) out of 168 received anthracycline-based chemotherapy for first line treatment, either CHOP or CHOP-like regimen, and 123 patients (73.2%) had non-anthracycline based chemotherapy. Ninety two patients (54.8%) received sequential radiotherapy or concurrent chemoradiation.During the 63 months of median follow-up, 9 patients (5.4%) developed CNS relapse. Among those 9 patients, 4 had leptomeningeal involvement, 3 had brain parenchymal disease, and the remaining 2 had both leptomeningeal and brain parenchymal involvement.Median time from diagnosis to CNS relapse was 5.0 months (95% confidence interval (CI): 4.6-5.3). Median OS after CNS metastasis was 3.4 months (1.6-5.1). Significant differences in OS were noted between the two groups, with median OS in patients with CNS relapse of 8.9 months (7.8-10.1) and 58 months (19.6-96.4) in patients without CNS relapse. (p<0.001)After univariate analysis, eastern cooperative oncology group (ECOG) performance status≥2 (hazard ratio (HR) 9.7 [95% CI: 1.1-84.3] p=0.039), stage III/IV (HR 5.8 [1.5-23.5], p=0.013), lung or pleural involvement (HR 12.5 [3.3-47.5], p<0.001), peritoneal involvement (HR 46.2 [4.1-521.5], p=0.002), PINK≥2 (HR 6.2 [1.2-32.2], p=0.03) were associated with increased CNS relapse. First-line treatment regimens including etoposide or high-dose methotrexate (MTX) were associated with decreased incidence of CNS relapse. (HR 0.24 [0.06-0.88], p=0.032). Due to the small number of CNS events, multivariate analysis was not available. No association was found with age, sex, serum lactate dehydrogenase level, number of involved extranodal sites, international prognostic index, non-nasal or nasal type and Ki-67 labeling index.Conclusions: Our study demonstrated that CNS relapse or progression in ENKTL-nasal type is rare (5.4%) but its clinical course is poor. CNS event usually occurred in the early course of the disease and we suggest that CNS evaluations should be considered in highly selected patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The risk of central nervous system relapses in patients with peripheral T-cell lymphoma.

We performed a retrospective analysis to identify risk factors and survival outcome for central nervous system (CNS) relapse of peripheral T-cell lymphoma (PTCL) by histologic type. Records of 600 PTCL patients diagnosed between 1999 and 2014 were analyzed including PTCL not otherwise specified (PTCL-NOS, 174 patients), angoimmunoblastic T-cell lymphoma (AITL, 144), ALK+anaplastic large cell lymphoma (ALCL, 74), ALK-ALCL (103), extranodal NK-cell lymphoma (ENKL, 54), or others (51). With a median follow up of 57 months, 13 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 ENKL) experienced CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.5% (95%CI: 0.7–2.8%) and 2.1% (95%CI: 1.1–3.5%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.4% in ALK+ALCL, 2.1% in ALK-ALCL and 3.7% in ENKL. Extranodal involvement >1 site was the only significant factor associated with higher chance of CNS relapse (HR: 4.9, 95%CI: 1.6–15.0, p = 0.005). Patients with ALK+ALCL who had extranodal involvement >1 (N = 19) had very high risk of CNS relapse with one year cumulative incidence of 17% (95%CI: 4%-37%), all occurring within six months after diagnosis. All patients with CNS relapse eventually died (median, 1.5 months; range, 0.1–10.1 months). CNS relapse in patients with PTCL is rare event but the risk varies by subtype. ALK+ALCL patients with extranodal involvement >1 site have a very high risk of early CNS relapse, and thus evaluation of CNS involvement at the time of diagnosis and possible CNS-directed prophylaxis may be considered.

Central Nervous System Involvement in Peripheral T Cell Lymphoma.

Central nervous system (CNS) involvement in peripheral T cell lymphoma (PTCL) is a difficult condition to treat, both as a primary and a secondary disease. Primary CNS lymphoma (PCNSL) in PTCL is very rare, making up only 2% of all PCNSLs. The incidence of CNS relapse is generally 2-6% in all cases of PTCL, but the risk may vary by histologic subtype, and extranodal involvement > 1 has been consistently found to be a risk factor for CNS relapse. Currently, there is no consensus about indications for CNS prophylactic treatment. A high-dose systemic methotrexate-based regimen is the most commonly used treatment, with or without consolidation with high-dose chemotherapy with autologous stem cell transplantation for both primary and secondary CNS involvement. This approach, however, is generally toxic for older patients. New therapeutic approaches against PTCL are therefore needed.

Intrathecal Methotrexate-Induced Necrotizing Myelopathy: A Case Report and Review of Histologic Features.

Central nervous system (CNS) relapse of acute lymphoblastic leukemia (ALL) is associated with a poor prognosis. However, prophylactic measures, including intrathecal (IT) methotrexate, reduce the incidence of CNS relapse in these patients considerably. Unfortunately, IT methotrexate can cause several neurologic complications, including transverse myelopathy; ie, the development of isolated spinal cord dysfunction over hours or days following the IT infusion of methotrexate, but in the absence of a compressive lesion. Transverse myelopathy following IT methotrexate is a well-established clinical phenomenon, but the histologic features have been described only very rarely. We report the autopsy findings from a 31-year-old man with a history of T-cell ALL who received prophylactic IT methotrexate in anticipation of a bone marrow transplant. Microscopic examination showed transverse necrosis of the thoracic cord, with massive infiltration by macrophages and lymphocytes, and perivascular lymphocytic infiltrates. There was cavitary necrosis of cervical and lumbar spinal cord involving the entire gray matter and focal white matter, as well as extensive subpial vacuolar degeneration of the dorsal and lateral columns.

Central nervous system disease in pediatric acute myeloid leukemia.

Central nervous system disease in pediatric acute myeloid leukemia.

Analysis of the role of intratecal liposomal cytarabine in the prophylaxis and treatment of central nervous system lymphomatosis: The Balearic Lymphoma Group experience.

Central nervous system (CNS) lymphomatosis is a fatal complication of aggressive non-Hodgkin lymphoma (NHL). In lymphoblastic or Burkitt lymphoma, without specific CNS prophylaxis the risk of CNS relapse is 20–30%. DLBCL has a lower risk of relapse (around 5%) but several factors increase its incidence. There is no consensus or trials to conclude which is the best CNS prophylaxis. Best results seem to be associated with the use of intravenous (iv) high-dose methotrexate (HDMTX) but with a significant toxicity. Other options are the administration of intrathecal (IT) MTX, cytarabine or liposomal cytarabine (ITLC). Our aim is to analyze the experience of the centers of the Balearic Lymphoma Group (BLG) about the toxicity and efficacy of ITLC in the prophylaxis and therapy of CNS lymphomatosis. We retrospectively reviewed cases from 2005 to 2015 (n = 58) treated with ITLC. Our toxicity results were: 33% headache, 20% neurological deficits, 11% nausea, 9% dizziness, 4% vomiting, 4% fever, 2% transient blindness and 2% photophobia. In the prophylactic cohort (n = 26) with a median follow-up of 55 months (17–81) only 3 CNS relapses (11%) were observed (testicular DLBCL, Burkitt and plasmablastic lymphoma, with a cumulative incidence of 8%, 14% and 20% respectively). In the treatment cohort (n = 32), CSF complete clearance was obtained in 77% cases. Median OS was 6 months (0–16). Death causes were lymphoma progression (19 patients, 79%), treatment toxicity (2 patients) and non-related (3 patients, 12%). Toxicity profile was good especially when concomitant dexamethasone was administered. In the prophylactic cohort the incidence of CNS relapse in DLBCL group was similar to previously reported for HDMTX and much better than IT MTX. A high number of ITLC injections was associated with better rates of CSF clearance, clinical responses, PFS and lower relapses. Survival is still poor in CNS lymphomatosis and new therapeutic approaches are still needed.

Incidence and Outcomes of Central Nervous System Hemophagocytic Lymphohistiocytosis Relapse after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation

Hemophagocytic lymphohistiocytosis (HLH) is an immune regulatory disorder that commonly presents with central nervous system (CNS) involvement. The only cure for genetic HLH is hematopoietic stem cell transplantation (HSCT), typically treated with reduced-intensity conditioning (RIC) regimens. We sought to estimate the incidence of CNS relapse after RIC HSCT, determine risk factors, and evaluate outcomes. We performed a retrospective chart review of 94 consecutive children and young adults with primary HLH who received RIC HSCT. CNS relapse within 1 year after transplantation was diagnosed by review of clinical symptoms, cerebral spinal fluid (CSF), and radiologic findings. Four (4.25%) patients developed symptoms of possible CNS HLH after HSCT and 3 patients were diagnosed. Eight patients underwent screening lumbar puncture because of history of active CNS disease at the onset of the conditioning regimen and 4 had evidence of continued disease. The overall incidence of CNS relapse and continued CNS disease after RIC HSCT was 8%. All patients with CNS disease after HSCT responded to CNS-directed therapy. Whole blood donor chimerism at the time of CNS relapse was low at 1% to 34%, but it remained high at 88% to 100% for patients with continued CNS disease. Overall survival for patients with CNS relapse was 50%, compared with 75% for patients without CNS disease (P = .079). Our data suggest that a low level of donor chimerism or active CNS disease at the time of transplantation increase the risk of CNS HLH after HSCT. Surveillance CSF evaluation after allogeneic RIC HSCT should be considered in patients with risk factors and CNS-directed treatment should be initiated if appropriate.

Prognostic Significance of Cerebrospinal Fluid Lymphoblasts at Initial Presentation with Acute Lymphoblastic Leukemia Attending at Bangabandhu Sheikh Mujib Medical University, Bangladesh

Prognostic Significance of Cerebrospinal Fluid Lymphoblasts at Initial Presentation with Acute Lymphoblastic Leukemia Attending at Bangabandhu Sheikh Mujib Medical University, Bangladesh

Influence of rituximab and central nervous system directed prophylactic therapy on central nervous system relapse in high-risk diffuse large B-cell lymphoma

Background: Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) although rare, can be devastating. Conflicting reports have been published regarding the protective effect of systemic rituximab therapy and likely reduction in incidence of CNS relapse in post-rituximab era. Methods: We retrospectively identified all the DLBCL patients at our institute between 2004 and 2014 who received systemic rituximab-based chemo-therapy at initial presentation. Patients were categorized into two groups, “standard risk” with no risk factors and “high risk” with one or more of the following risk factors, elevated lactate dehydrogenase (LDH) (above the institute normal), international prognostic index (IPI) ≥3, involvement of testis, breast, bone, kidneys, adrenal gland, retroperitoneal lymph nodes, para-meninges, and bone marrow. Descriptive statistics were used to analyze inci-dence of CNS relapse, patient and disease characteristics. Historically reported incidence rates were used for comparison. Results: A total of 122 patients received rituximab-based therapy at the initial diagnosis; 73 patients (60%) qualified for standard risk; 49 patients (40%) met the criteria for “high risk” based on the above definition. Standard risk group received no CNS directed prophylaxis and none of these patients had CNS relapse. Thirty-one of 49 (63%) “high risk” patients received CNS prophylaxis, mainly intrathecal (IT) methotrexate. Five patients (4.0%) developed CNS relapse in the entire study population. Percentage of patients developed CNS relapse in high-risk patients was 10.2% (5/49). Median time to relapse was 8.76 months and median survival after CNS relapse was 9.16 months. Four out of five patients who developed CNS relapse received prophylaxis with IT. Conclusions: CNS relapse continued to be a rare but devas-tating complication in post rituximab era, however our study confirms that majority of the DLBCL patients do not need CNS directed therapy. Current CNS directed therapies are probably inadequate to prevent CNS relapse in high risk DLBCL patients, therefore further research to develop better agents is needed in this area.

Incidence and Risk Factors for Central Nervous System Relapse in Very Elderly Patients over 80 with Diffuse Large B-Cell Lymphoma: A Retrospective Analysis of Two Lysa Studies

Background. The prevalence of diffuse large B-cell lymphoma (DLBCL) in patients aged over 80 years is reported to have tripled compared to patients in their sixties. Treating very elderly patients is particularly challenging given the likelihood of comorbidities and concerns over risks of toxicity. One of the most devastating and rapidly fatal complications in DLBCL is central nervous system (CNS) relapse. Most studies reporting incidence and risk factors of CNS relapse concern DLBCL patients under the age of 80 years, and little is known about CNS recurrence in the very elderly, aged over 80 years. CNS prophylaxis is rarely implemented in this population due to the burden of comorbidities, frequent antiplatelet or anticoagulant treatment along with renal failure and hypoalbuminemia, as well as potential prophylaxis toxicity of IV high dose methotrexate and/or the invasiveness of IT therapy.Aim. We retrospectively evaluated the incidence of CNS relapse, risk factors and specific survival in very elderly DLBCL patients aged 80 yearsPatients and Methods. Data were collected retrospectively from two multicentre, open-label, single arm phase II LYSA trials (LNH 03-7B (NCT01087424) between 2004 and 2007, LNH09-7B (NCT01195714) between 2009 and 2013) evaluating the addition of rituximab or ofatumumab to miniCHOP as front-line therapy.Results. A total of 270 elderly patients were included in the two trials, 150 treated with R-miniCHOP and 120 with O-miniCHOP. Median age was 83 years (range 79-95) and none received CNS prophylaxis. At inclusion, most patients (76%) presented with disseminated disease (Ann Arbor stage III or IV), and 37% had at least two extra-nodal sites. Overall 18% of patients had bone marrow involvement, while renal, adrenal, testis or cavum involvement was rare (4%, 2%, 3%, and 2%, respectively). After a median follow-up of 28.7 months (range 0.1-72.1), 8 (3%) cases of CNS relapse were reported. Median time between inclusion and CNS relapse was 19.2 months (range 3.2 - 32.6). Cumulative 1 and 2-year incidence of CNS relapse was 1.4% (95% CI 3.2-25.4) and 2.5% (95% CI 6.9-9.2), respectively. At inclusion, clinical characteristics of the CNS relapse patients were not significantly different from patients without relapse. At CNS relapse, all patients except one present a performance status ECOG > 2. neurological symptoms were either mild with loss of autonomy, asthenia, hearing impairment, urinary incontinence, or more prominent with delirium, aphasia, intracranial hypertension, or consciousness disorder. Treatment of CNS relapse was a supportive care based- treatment with corticosteroid only in 5 patients, radiation therapy in one patient, and chemotherapy for 2 patients including rituximab-temodal (5 cycles) in one patient and rituximab -aracytine-vepeside (2 cycles) for the other one. Patients survived for a median of 1.5 months after CNS relapse diagnosis (range, 0.4 to 4). The CNS international prognostic index (CNS-IPI) classified 33 (12%) patients in the low-risk group, 164 (62%) in the intermediate-risk group, and 71 (26%) in the high-risk group. The low-risk and intermediate-risk CNS-IPI groups showed 2-year rate of CNS disease of 3%, and the high-risk of 2.8% (p=0.9483). Conclusion. Incidence of CNS relapse in very elderly previously untreated patients is approximately 3% and is associated with a very poor survival. The absence of prophylaxis in this population did not appear to have a strong impact on CNS relapse incidence. Higher number of patients is warranted to identify risk factors for CNS relapse in this population DisclosuresCoiffier:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MorphoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees. Salles:Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Thieblemont:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The Risk of Central Nervous System (CNS) Relapses in Patients with Peripheral T-Cell Lymphoma

Background: CNS relapse is a rare but fatal complication of patients with peripheral T-cell lymphoma (PTCL). Several large studies have identified risk factors for CNS relapse in PTCL, such as elevated serum lactate dehydrogenase (LDH), >1 extranodal sites of involvement and high International Prognostic Index (IPI) score. We performed an analysis of histologic type of PTCL to identify additional risk factors for CNS relapse.Patients and Methods: A total of 616 patients with PTCL diagnosed between 1999 and 2014 were analyzed retrospectively including: 174 not otherwise specified (NOS), 144 angoimmunoblastic T-cell lymphoma (AITL), 76 ALK+ anaplastic large cell lymphoma (ALCL), 103 ALK-ALCL, 55 nasal type T/NK cell lymphoma (NK/T), 23 hepatopslenic T-cell lymphoma (HSTL), 16 enteropathy-type T-cell lymphoma (EATL), 13 adult T-cell leukemia/lymphoma (ATLL), and 12 subcutaneous panniculitis-like T-cell lymphoma (SPTL). Patients with CNS involvement at diagnosis (n=15) were excluded from this study. Progression-free survival (PFS) and overall survival (OS) were calculated and pretreatment characteristics were evaluated for association with survival outcomes by hazard ratio (HR). Cumulative incidence of CNS relapse was calculated by competing risk (death without CNS relapse) regression analysis.Results: The median age of the patients was 56 years (range, 17-93 years). With a median follow up of 57 months, 15 patients (4 PTCL-NOS, 1 AITL, 4 ALK+ALCL, 2 ALK-ALCL, 2 NK/T, and 2 ATLL) experienced CNS relapse, and 321 patients (52%) died without having had CNS relapse. One-year and 5-year cumulative incidence of CNS relapse were 1.8% (95%CI: 1.0-3.1%), 2.4% (95%CI: 1.3-3.8%), respectively. The 5-year cumulative incidence of CNS relapse was 1.8% in PTCL-NOS, 0.7% in AITL, 5.3% in ALK+ALCL, 2.1% in ALK-ALCL and 3.6% in NK/T (Figure). All patients with CNS relapse eventually died, with median OS duration from CNS relapse of 1.6 months. Extranodal sites of involvement >1 (HR: 6.0, 95%CI: 2.0-17.4) and higher IPI score (HR: 1.8, 95%CI: 1.1-3.1, by one increase in IPI score) were risk factors of CNS relapse by univariate analysis. ALK+ALCL patients who had > 1 extranodal site of involvement (N=19) had very high risk of CNS relapse with one year cumulative incidence of 15% (95%CI: 3.7%-33.5%), with all occurring within six months after diagnosis.Summary: CNS relapse in patients with PTCL is rare as reported previously. However, the risk varies by histologic type. Specifically ALK+ALCL patients with > 1 extranodal site of involvement have a very high risk of CNS relapse in early phase of treatment, and CNS evaluation at the time of diagnosis and possibly CNS targeted prophylaxis may be appropriate. [Display omitted] DisclosuresWestin:ProNAi: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Fayad:Seattle Genetics: Consultancy, Research Funding. Wang:BeiGene: Research Funding; Kite Pharma: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Dava Oncology: Honoraria; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Acerta: Consultancy, Research Funding; Juno Therapeutics: Research Funding. Fowler:Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Gilead: Research Funding; Infinity: Consultancy, Research Funding; TG Therapeutics: Consultancy. Oki:Novartis: Research Funding.

Addition of Intermediate-Dose Methotrexate Is Beneficial in Terms of Both Progression-Free Survival and Overall Survival for Patients with Diffuse Large B Cell Lymphoma Receiving Either R-CHOP or CHOP

Introduction: Patients with diffuse large B cell lymphoma (DLBCL) and high International Prognostic Index (IPI) or extra-nodal disease are at an increased risk of systemic and central nervous system (CNS) relapse. Presently, the management of DLBCL patients at the Rambam Health Care Campus (Haifa, Israel) and Hadassah Medical Center (Jerusalem, Israel) includes 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) along with 4 doses of intrathecal (IT) methotrexate (MTX), which may be followed by 2 additional cycles of an intermediate dose (3 g/m2) of intravenousMTX (ID-MTX). The current study compared progression-free survival (PFS), overall survival (OS) and CNS relapse rate in a cohort of DLBCL patients with risk factors for CNS relapse who did or did not undergo prophylactic therapy with ID-MTX.Methods: Four hundred and eighty DLBCL patients treated at two tertiary care centers (Rambam and Hadassah) between the years 1991 and 2013 were retrospectively evaluated. The cohort included 224 females and 256 males at a median age of 58 years (range18-76). OS, PFS and CNS involvement at relapse were analyzed. The study incorporated all patients with the primary diagnosis of DLBCL and risk factors for CNS relapse, i.e., Waldeyer ring (2%), breast (1%), testicular (3%) or orbita (1%) involvement, bone marrow involvement (21%), stage IV disease (64%), LDH higher than normal (70%), ≥1 extra-nodal site (28%), IPI ≥3 (36%). Eight percent of patients had stage I-IE disease, 17% - stage II-IIE, 11% - stage III, 64% - stage IV, 29% had B symptoms. Patients with CNS involvement at diagnosis were excluded from the analysis.Results: Four hundred and seventy three patients (99%) were treated with either CHOP or CHOP-like regimen, and 384 (80%) patients received rituximab (R). In the R-CHOP cohort, 23% of patients with IPI 0/1, 28% with IPI 2 and 42% with IPI ≥3 were given prophylaxis. One hundred and thirty patients received ID-MTX (27%), 35 patients (7%) received IT-MTX only, while no prophylaxis was administered to 315 patients (66%). The cumulative incidence of CNS relapse at 5 years was 6%, with no difference in the incidence between the patients who received prophylaxis with ID-MTX, IT-MTX or were given no prophylaxis at all. Patients with IPI ≥3 treated with ID-MTX had a decreased overall relapse rate and significantly superior OS and PFS (Table 1; Figure 1).Conclusion: In the current study, the addition of two cycles of ID-MTX to the standard R-CHOP regimen resulted in improved 5-year PFS and OS of DLBCL patients with IPI ≥3. These data need to be further confirmed in a randomized controlled study. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Lenalidomide Plus R-CHOP (R2CHOP) in Patients with DLBCL Is Associated with a Lower Risk of CNS Relapse: Combined Analysis from Two Phase 2 Studies

BackgroundCentral nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a devastating event occurring in approximately 5% of patients treated with standard R-CHOP (Thanarajasingam et al, ASH 2015, abs 1456). Isolated CNS relapse is associated with significant morbidity and mortality. New treatment regimens with agents that cross the blood-brain barrier (BBB) are needed. The combination of lenalidomide with R-CHOP (R2CHOP) has shown promising results in activated B-cell (ABC) type DLBCL in phase 2 studies and is currently being evaluated in randomized trials. Lenalidomide crosses the BBB and has been demonstrated to have single-agent activity in relapsed CNS lymphoma. Accordingly, the addition of lenalidomide to R-CHOP may decrease the risk of CNS relapse. Here we characterize the combined incidence of isolated CNS relapse in a population of DLBCL patients who received R2CHOP for induction therapy in two independent phase 2 studies.MethodsWe analyzed the incidence of isolated CNS relapse in patients with histologically-confirmed DLBCL enrolled in two R2CHOP phase 2 trials - one conducted by Mayo Clinic (MC) and the other by Italian Lymphoma Foundation (FIL) - in the context of clinical variables that included age, gender, disease stage, cell of origin, and administration of CNS prophylaxis. We assessed CNS-International Prognostic Index (CNS-IPI) factors (age, stage, lactate dehydrogenase level, ECOG performance status, extranodal sites, adrenal/kidney involvement) and classified patients into groups of low, intermediate, and high risk of CNS relapse. The risk of CNS relapse in R2CHOP-treated patients was then estimated and compared against published rates in RCHOP-treated patients based on CNS-IPI score.ResultsOne hundred thirty-six patients with DLBCL from both cohorts (87 MC patients, 49 FIL patients) were included in this analysis. Mean age was 65 and median follow-up in 104 patients still alive was 48.2 months (range: 2.1-88.5). 61.8% of patients were male; 86.0% had stage III disease or higher; 44.1% had ECOG performance status of 0; cell of origin phenotype by immunohistochemistry according to Hans algorithm was germinal center B-cell (GCB), non-GCB (ABC), and not available in 43.4%, 36.8%, and 19.8%, respectively; 14.7% received intrathecal (IT) methotrexate for CNS prophylaxis per local practice. No patients received intravenous methotrexate. 10.3%, 71.3%, and 18.4% of patients were classified into low, intermediate, and high-risk CNS-IPI groups, respectively. Only one of 136 patients developed isolated CNS relapse, corresponding to an estimated incidence of CNS relapse of 0.007 (0.7%).ConclusionsDespite a large proportion of patients with intermediate and high risk of CNS relapse treated in both phase 2 studies, induction therapy with R2CHOP in patients with DLBCL is associated with a lower-than-expected rate of isolated CNS relapse. The latter is unlikely to be explained by use of IT chemotherapy, which is considered to be marginally effective in this setting and was implemented only in a small proportion of patients. This suggests that addition of CNS-penetrating small molecules, such as lenalidomide, to R-CHOP may decrease the risk of CNS relapse. DisclosuresChiappella:Celgene: Speakers Bureau; Teva: Speakers Bureau; Roche: Speakers Bureau; Pfizer: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Amgen: Speakers Bureau. Nowakowski:Morphosys: Research Funding; Celgene: Research Funding; Bayer: Consultancy, Research Funding. Cavallo:Janssen-Cilag: Honoraria; Onyx: Honoraria; Celgene: Honoraria. Gaidano:Roche: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Vitolo:Takeda: Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures.

Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma.

Although HER2-positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2-positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2-targeted therapies that penetrate the blood-brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative-intent surgery during a time period (1980-1997) when no patient received HER2-targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow-up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2-positive (vs -negative) primary tumors showed a higher 5-year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non-breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2-positive EACs have a predilection for CNS metastases.

Central nervous system prophylaxis in diffuse large B-cell lymphoma.

Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.