Intrathecal Central Nervous System Research Articles

Incidence of Central Nervous System Relapse in Primary Mediastinal Large B-Cell Lymphoma: Implications for Central Nervous System Prophylaxis

BackgroundPrimary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL. Therefore, it may be expected that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL treated with standard chemoimmunotherapy. Patients and MethodsThis retrospective single center analysis included 154 patients with newly diagnosed PMBCL seen at Mayo Clinic. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. ResultsWith a median follow-up of 39 months, 3 patients experienced CNS relapse, all associated with systemic relapse. The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI, 0.3%-4.6%) at 1 year and 2.21% (95% CI, 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n = 131), the incidence was 0.85% (95% CI, 0.1%-4.2%) at 1 year and 1.80% (95% CI, 0.3%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; 2 patients did not receive any CNS prophylaxis, while 1 patient received intrathecal CNS prophylaxis. ConclusionThe risk of CNS relapse in PMBCL appears to be very low after treatment with standard chemoimmunotherapy, suggesting routine CNS prophylaxis is not necessary.

Incidence of central nervous system relapse in primary mediastinal B-cell lymphoma: Implications for central nervous system prophylaxis.

7080 Background: Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of aggressive B-cell non-Hodgkin lymphoma. PMBCL has distinct clinicopathologic features compared to diffuse large B-cell lymphoma but shares some clinical and biologic features with nodular sclerosis classic Hodgkin lymphoma (cHL). Central nervous system (CNS) relapse is exceedingly rare in cHL, therefore one may expect that CNS relapse in PMBCL is also uncommon. Herein, we examined the incidence of CNS relapse in patients with PMBCL. Methods: Patients with newly diagnosed PMBCL seen at Mayo Clinic between 1/2002 and 4/2023 were identified from the Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from medical records. The CNS relapse rate was calculated using a competing risk model, with death considered as a competing risk. Results: A total of 154 PMBCL cases were identified. The median age at diagnosis was 38 years (range 18-77) and 60.4% were female. The distribution of CNS-IPI was low-risk in 80 (51.9%) patients, intermediate-risk in 43 (27.9%), and high-risk in 3 (1.9%), and data were missing for 28 patients (18.2%). 78 patients (50.6%) received R-CHOP and 76 patients (49.4%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 5 patients (all treated with R-CHOP). 20 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis (4 with R-CHOP [1 received HD-MTX too],16 with R-DA-EPOCH). The median follow-up was 39 months (95% CI 28.2-49.8). Only 3 patients had CNS relapse, all associated with systemic relapse (1 concurrent, 1 had CNS relapse 8.8 months after systemic relapse, 1 had CNS relapse 2 months before systemic relapse). The cumulative incidence of CNS relapse for the entire cohort was 1.43% (95% CI 0.3%-4.6%) at 1 year and 2.21% (95% CI 0.6%-5.8%) at both 2 and 5 years. For those who did not receive CNS prophylaxis (n=130), the incidence was 0.86% (95% CI 0.1%-4.3%) at 1 year and 1.82% (95% CI 0.4%-5.8%) at both 2 and 5 years. All 3 patients who experienced CNS relapse had R-CHOP as frontline therapy; two patients did not receive any CNS prophylaxis, while 1 patient received IT CNS prophylaxis. Conclusions: The risk of isolated CNS relapse in PMBCL appears to be very low, even in patients who did not receive CNS prophylaxis. While some patients may experience CNS relapse associated with systemic relapse, the overall incidence was low (1.43% at 1 year and 2.21% at 2 and 5 years). The rarity of isolated CNS relapse in PMBCL suggests that routine CNS prophylaxis may not be necessary as part of initial therapy.

IELSG30 phase 2 trial: intravenous and intrathecal CNS prophylaxis in primary testicular diffuse large B-cell lymphoma

AbstractPrimary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Incidence of Central Nervous System Relapse in Patients with Primary Mediastinal Large B-Cell Lymphoma: A Retrospective Study

Background Primary mediastinal large B-cell lymphoma (PMBCL) is an uncommon type of non-Hodgkin lymphoma. Clinicopathologic features are distinct from diffuse large B cell lymphoma, but it shares some clinical and biologic features with Nodular sclerosis classic Hodgkin lymphoma. Central nervous system (CNS) relapse appears to be rare in patients with PMBCL, with limited literature reporting a rate of approximately 1.5% to 4%. We examined the incidence of CNS relapse, treatment approaches and survival outcomes in patients with PMBCL. Methods Patients with newly diagnosed PMBCL seen at Mayo Clinic between 2002 and 2022 were identified using the prospective Mayo Clinic Lymphoma Database. Clinical features, treatment details and outcomes were abstracted from the medical record. Cumulative incidence of CNS relapse was analyzed with death as a competing risk. The association of CNS-IPI, systemic treatment, and CNS prophylaxis approach with CNS relapse rate was analyzed using competing risk models and descriptively. Event-free survival (EFS) for the cohort was defined as time from PMBCL diagnosis to first recorded CNS and/or systemic relapse or death from any cause. Overall survival (OS) was defined as time from PMBCL diagnosis (or CNS relapse) to death from any cause. Survival analysis was performed using the Kaplan-Meier method. Results A total of 124 PMBCL cases were identified. The median age at diagnosis was 37 years and 61% were female. The distribution of CNS-IPI was low-risk in 67 (61%), intermediate-risk in 41 (37%), and high-risk in 2 (2%). 64 patients (52%) received R-CHOP and 54 patients (44%) received R-DA-EPOCH as frontline therapy. High-dose methotrexate (HD-MTX) for CNS prophylaxis was administered to 6 patients (5%), 5 with R-CHOP and 1 with R-DA-EPOCH. 16 patients received intrathecal (IT) chemotherapy (methotrexate and/or cytarabine) for CNS prophylaxis, 3 with R-CHOP and 13 with R-DA-EPOCH. The median follow-up was 56.0 months. The 5-year EFS rate was 75.1% and the 5-year OS rate was 90.7% for the entire cohort. 20 patients had systemic relapse only and 3 had CNS relapse. The cumulative incidence of CNS relapse was 1.84% (95% CI 0.46%-7.17%) at 2 years and 2.92% (95% CI 0.50%-8.84%) at 5 years (Figure 1). No statistically significant association of CNS-IPI, systemic therapy or CNS prophylaxis regimen with CNS relapse rate was found in competing risk models; however, this analysis was limited by a small event number (n=3). Among the 3 patients with CNS relapse, 1 had high-risk CNS-IPI and 2 had intermediate risk. All 3 patients were treated initially with R-CHOP. Two patients did not receive any CNS prophylaxis and 1 patient received IT CNS prophylaxis. All three patients who had CNS relapse were female. Patient #1 was diagnosed at age 48 and had simultaneous CNS and systemic relapse 6 months later. The patient was treated with HD-MTX, temozolomide and rituximab for CNS relapse, and subsequently received multiple therapies for systemic disease including R-DHAP, R-ICE, and died 17 months after CNS relapse. Patient #2 was diagnosed at age 22 and had CNS relapse after 8.7 months, followed by systemic relapse 2 months later. The patient received HD-MTX, temozolomide and rituximab for CNS relapse, followed by systemic and whole-brain radiation therapy (RT) for both systemic and CNS relapse. Subsequently the patient received salvage chemotherapy, autologous and allogeneic stem cell transplant for systemic relapse. The patient died 26.8 months after CNS relapse. Patient #3 was diagnosed at age 24 and had systemic relapse after 20.7 months, followed by CNS relapse 5.4 months later. The patient received methotrexate and whole-brain RT following CNS relapse and died 1.2 months after CNS relapse. Besides these 3 patients, we identified 6 PMBCL patients with CNS relapse who were diagnosed at other medical centers and subsequently referred to our institution for management of refractory disease. The survival after CNS relapse was poor, with a median OS of 10.4 months (95% CI 5.6-15.2). Conclusion Our study showed that the CNS relapse rate (1.84% at 2 years and 2.92% at 5 years) was overall low in patients with PMBCL, consistent with previous reports. CNS relapse was associated with poor survival despite aggressive treatment approaches. Novel approaches utilizing biological risk factors for CNS relapse, such as circulating tumor DNA, are needed to identify patients with CNS relapse.

Low Incidence of Central Nervous System (CNS) Relapse of Diffuse Large B-Cell Lymphoma despite Limited Use of Intrathecal Prophylaxis

Diffuse large B cell lymphoma (DLBCL) is the commonest sub type of non-Hodgkin's lymphoma (NHL) accounting for 30–50 % of NHL cases. Around 2% to 10% of patients with diffuse large B-cell lymphoma (DLBCL) experience central nervous system (CNS) relapse after initial therapy which is associated with a poor prognosis and most often a fatal outcome. The incidence of CNS relapse can vary from <1% in younger, good-risk patients, to around 30% in patients with multiple risk factors, however, the relapse risk was reported to be lower in the rituximab era in some studies. Moreover, optimal modality of CNS prophylaxis remains to be defined, with both systemic and intrathecal (IT) chemotherapy being widely used. As the incidence of CNS relapse and type of prophylaxis used varies in different reports, it is important to study this risk in different populations to implement optimal prophylaxis strategies. The Objectives of this study was to evaluate the incidence of CNS relapse in DLBCL patients at our institution and to study risk factors and the type and role of CNS prophylaxis. We retrospectively analyzed patients diagnosed with DLBCL at King Khalid University Hospital, Riyadh, from January 2011 to June 2019. Data were collected from computerized hospital information system and from the files of the patients. Variables studied included age at diagnosis, stage at diagnosis, international prognostic index (IPI) and CNS-IPI score, site(s) of extra-nodal involvement, type of chemotherapy received, CNS prophylaxis and CNS relapse. CNS prophylaxis was administered on the basis of presence of high-risk features like presence of ≥2 extranodal sites, involvement of bone marrow, bone, testes, nasopharynx and paranasal sinuses. Patients with presence of CNS involvement at diagnosis and primary CNS lymphoma were excluded. A total of 101 patients were diagnosed with DLBCL during the study period. There were 58 males and 43 females with a median age of 56 (range: 16-87) years. Ann Arbor stage of I-IV was assigned in 9, 21, 17 and 50 patients, respectively. The lung was the most common extranodal site involved in 27 (26.7%) patients, and liver and bone marrow involved in 20 (19.8%) patients each. Gastrointestinal tract was involved in 9 (8.9%) patients, kidneys in 5 (4.95%), breast in 4 (4%), and testis and adrenal in 2 (2%) patients each. Twenty-five (24.75%) patients had high risk CNS-IPI score, 44 (43.5%) had intermediate risk score and 32 (31.7%) had low risk score. Ninety-four (93%) patients received R-CHOP chemotherapy while rest of the patients received other types of chemotherapy, mostly a milder regimen (R-CVP), because of comorbidities and poor performance status. Sixteen patients received CNS prophylaxis, which was IT methotrexate (MTX) ± cytarabine/hydrocortisone in all patients. Nine of 25 (36%) patients with high-risk CNS-IPI score did not receive CNS prophylaxis. After a median follow up of 36 months (range 4-114), 2 (2%) patients developed CNS relapse and died shortly after this diagnosis. Both the patients with CNS relapse had high risk CNS-IPI score and did not receive CNS prophylaxis. CNS relapse of DLBCL was uncommon in this patient population despite limited use of IT CNS prophylaxis in high-risk patients. Low incidence of CNS relapse in many high-risk patients despite limited use of IT prophylaxis may be related to rituximab use and/or other factors. Our data indicate that IT CNS prophylaxis may be adequate for DLBCL patients at high risk of CNS relapse.

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

INTENSIFIED (INTRAVENOUS AND INTRATHECAL) CNS PROPHYLAXIS IN PRIMARY TESTICULAR DIFFUSE LARGE B‐CELL LYMPHOMA: 5‐YEAR RESULTS OF THE IELSG30 TRIAL

Introduction: Primary diffuse large B-cell lymphoma of the testis (PTL) represents a unique condition characterized by high long-term risk of contralateral testis and central nervous system (CNS) relapse (>30% at 15 years) in historical series (Zucca et al, JCO 2002). Immunochemotherapy associated with intrathecal CNS prophylaxis and contralateral testis radiotherapy (RT) improved patient outcome, with a virtual elimination of contralateral recurrences and significant reduction (6% at 5 years) of CNS relapses in the IELSG10 trial (Vitolo et al., JCO 2011). The International Extranodal Lymphoma Study Group (IELSG), in cooperation with the Italian Lymphoma Foundation (FIL), coordinated the multicenter phase II IELSG30 study to assess activity and feasibility of intensified CNS prophylaxis in combination with chemoimmunotherapy and RT. Patients and Methods: Patients with stage I-II PTL were eligible. Treatment consisted of 6 cycles of the standard R-CHOP21 regimen (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone every 21 days); 4 doses of intrathecal liposomal cytarabine; 2 courses of intravenous (iv) intermediate-dose methotrexate (1.5 gr/m2) and RT (25-30 Gy) to the contralateral testis. The study was designed to demonstrate (80% power, a = .05) a PFS improvement from 67% to 82% at 10 years (primary endpoint). Results: Fifty-four patients (median age: 66 years, range: 37-79 years) with untreated stage I (n = 32) or II (n = 22) PTL were treated with R-CHOP21, 53 received at least 3 doses of intrathecal CNS prophylaxis, 48 received at least one dose of iv methotrexate and 50 received prophylactic RT. No unexpected side effects were observed. At a median follow-up of 5 years, 7 patients progressed and 7 died, with 5-year PFS of 88% (95%CI, 74-94%) and 5-year OS of 92% (95%CI, 79%-97%). No CNS relapses occurred. In 4 cases, both nodal and extranodal relapses were reported, the latter including the gastrointestinal tract and the pleurae in the same patient, as well as, 1 patient each, the kidneys, the spinal canal (extra-axial) and the contralateral testis (9 years after RT). Two patients relapsed only at extranodal sites (skin, adrenal gland), 1 had nodal relapse. Notably, 4 of 7 failures were late relapses occurring after 6 to 10 years from treatment. Causes of death were lymphoma (n = 4), second cancer (n = 1), cerebral vasculopathy (n = 1), unknown (n = 1). The research was funded by: Mundipharma provided the drug depocyte free of charge Keywords: Combination Therapies, Radiation Therapy Conflicts of interests pertinent to the abstract A. J. M. Ferreri Consultant or advisory role: Adienne - Gilead - Novartis - Juno - PletixaPharm Research funding: BMS - Beigene - Pharmacyclics - Hutchison - Medipharma - Amgen - Genmab - ADC - Therapeutics - Gilead - Novartis - Pfizer E. Zucca Consultant or advisory role: Beigene - Celgene - Incyte - Janssen - Merck - Roche - Celltrion Healthcare - Kite (Gilead) Research funding: AstraZeneca - Celgene - Incyte - Janssen - Merck - Roche Educational grants: Roche – Abbvie

Abstract PD13-06: Incidence and management of central nervous system metastases in patients with inflammatory breast cancer

Abstract Background: Patients (pts) with inflammatory breast cancer (IBC) have a high risk of central nervous system (CNS) metastasis (mets) with their associated impact on longevity and quality of life. Given evolving CNS-directed treatments, including focal radiation (RT), we compared the proportion of pts diagnosed with asymptomatic CNS mets before and after 2012 as data from Phase III trials in the preceding years (yr) increasingly supported the use of stereotactic radiosurgery (SRS). Specific attention was paid to pts treated with tri-modality therapy (TMT), defined as preoperative systemic therapy, surgery, and RT to determine whether screening for asymptomatic CNS mets would be beneficial. Methods: We retrospectively reviewed the records of pts diagnosed with IBC 1997-2019 and enrolled in an IRB-approved registry at a dedicated IBC center. CNS met-free survival time was defined as the time from IBC diagnosis to date of CNS mets. Alive CNS met-free pts were censored at their latest survival date and death was treated as a competing risk. Cumulative CNS mets incidence was computed. Analyses were stratified based on stage at diagnosis (III vs. de novo IV) and receipt of TMT. For pts completing TMT, the completion date was the starting point for cumulative incidence calculations. Overall survival (OS) was estimated as the time from CNS mets diagnosis to death, with censoring for pts who were still alive. Results: A total of 531 pts were identified; 372 (70%) with stage III; 159 (30%) with de novo Stage IV disease. The median follow-up for pts presenting with stage III and stage IV disease at diagnosis was 5.6 yr and 1.8 yr, respectively. 124 pts had CNS mets; 5 of them at diagnosis. CNS was the first site of mets or progression in 50 pts (9.4%). The cumulative incidence of CNS mets stratified by stage at diagnosis and receipt of TMT is seen in Table 1. Among the 50 de novo Stage IV pts who completed TMT, 4 developed CNS mets prior to surgery. The median overall survival (mOS) after CNS mets was 0.6 yr (IQR: 0.2 - 1.4). Results stratified by tumor subtype were: HER2+ disease (n=51) 1.4 yr (IQR: 0.6 - 3.7); hormone receptor+/HER2- (n=27) 0.6 yr (IQR: 0.2 - 1.2); triple negative (n=40) 0.2 yr (IQR: 0.1 - 0.5). Most pts with CNS mets (87/124, 70%) had neurologic symptoms prompting imaging. There was no difference in the proportion of asymptomatic pts diagnosed with CNS mets prior to or after 2012. Management of CNS mets was as follows: 47 pts (38%) received whole brain RT (WBRT) alone, 22 (18%) SRS alone, 15 WBRT + SRS (12%), 6 resection + WBRT (5%), and 5 resection + SRS (4%). The remaining pts received several of these modalities with or without intrathecal chemotherapy (13, 11%) or CNS treatment was not documented (16, 13%). A total of 258/531 pts have died (49%). Of these pts, 103 (40%) had CNS mets. 67/103 (65%) died due to CNS mets. Conclusions: Among pts with IBC completing TMT, the incidence of CNS mets is as high as 20% both in de novo Stage IV pts at 1 yr and in Stage III pts within 5 yrs, supporting routine surveillance brain MRI among pt with Stage IV disease. The majority of pts continue to receive WBRT with its resultant toxicities. Efforts should be made to identify CNS mets early to facilitate more focal therapy. Future research on systemic therapy with CNS penetrance for IBC patients should be pursued. These data support an ongoing prospective study of screening brain MRI in pts with Stage III IBC to quantify the incidence of CNS mets, utilization of WBRT and impact on neurologic quality of life (NCT04030507). Cumulative Incidence of CNS MetsNo.1 year (95% CI)2 year (95% CI)3 year (95% CI)Stage III (All)3725% (3-7)9% (6-12)18% (14-23)Stage IV (All)15417% (12-24)30% (22-37)42% (32-51)Stage III (TMT)3045% (3-8)11% (8-16)19% (14-24)Stage IV (TMT)4621% (10-34)28% (16-43)35% (20-50) Citation Format: Laura Warren, Samuel M Niman, Marie Claire Remolano, Jean Landry, Faina Nakhlis, Jennifer R Bellon, Meredith M Regan, Beth A Overmoyer. Incidence and management of central nervous system metastases in patients with inflammatory breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-06.

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Patterns and Risk of CNS Recurrence after R-EPOCH Treatment for Double/Triple Hit Lymphoma

Long-term outcome evaluation of medium/high risk acute lymphoblastic leukaemia children treated with or without cranial radiotherapy in the EORTC 58832 randomized study.

We investigated the long-term outcome, the incidence of second neoplasms (SN) and the rate of late adverse effects (LAE) in children with central nervous system (CNS) negative medium/high-risk de novo acute lymphoblastic leukaemia (ALL), in first complete remission (CR1) at end of late intensification, randomized to receive no cranial radiotherapy (No CRT, n=92) versus CRT (standard arm, n=84) in the non-inferiority EORTC 58832 study (1983-1989). Median follow-up was 20years (range 4-32years). The 25-year disease-free survival rate (±SE) was 67·4±4·9% without CRT and 70·2±5·0% with CRT. The 25-year incidence of isolated (6·5±2·6% vs. 4·8±2·3%) and any CNS relapse {8·7±2·9% vs. 11·9±3·5%; hazard ratio (HR) 0·71 [95% confidence interval (CI) 0·28-1·79]; test of non-inferiority: P=0·01} was not increased without CRT. The 25-year SN incidence in CR1 was 7·9±4·6% vs. 11·0±4·2%. The 25-year event-free and overall survival rates were quite similar in both arms [59·5±6·3% vs. 60·5±5·9%, HR 0·94 (95% CI 0·57-1·52), and 78·1±4·3% vs. 78·5±4·5%, HR 1·00 (95% CI 0·53-1·88)]. Omission of CRT was associated with dramatic decrease in CNS and endocrine LAE rates. In conclusion, our data suggest that, with proper systemic and intrathecal CNS prophylaxis, CRT could totally be omitted in CR1 without jeopardizing survival, while decreasing LAE in childhood ALL.

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.

Central nervous system involvement in AIDS-related lymphomas.

Central nervous system (CNS) involvement is reportedly more common in acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). We describe factors and outcomes associated with CNS involvement at baseline (CNS(B) ) and relapse (CNS(R) ) in 886 patients with newly diagnosed ARL. Of 886 patients, 800 received either intrathecal (IT) therapy for CNS(B) or IT prophylaxis. CNS(B) was found in 13%. CNS(B) was not associated with reduced overall survival (OS). There was no difference in the prevalence of CNS(B) between the pre-combination antiretroviral therapy (cART) and cART eras. 5·3% of patients experienced CNS(R) at a median of 4·2months after diagnosis (12% if CNS(B) ; 4% if not). Median OS after CNS(R) was 1·6months. On multivariate analysis, only CNS(B) [hazard ratio (HR) 3·68, P=0·005] and complete response to initial therapy (HR 0·14, P<0·0001) were significantly associated with CNS(R) . When restricted to patients without CNS(B) , IT CNS prophylaxis with 3 vs. 1 agent did not significantly impact the risk of CNS(R) . Despite IT CNS prophylaxis, 5% of patients experienced CNS(R) . Our data confirms that CNS(R) in ARL occurs early and has a poor outcome. Complete response to initial therapy was associated with a reduced frequency of CNS(R) . Although CNS(B) conferred an increased risk for CNS(R) , it did not impact OS.

The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial aggressive B-cell lymphomas

To define the role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement (ECFI) of aggressive B-cell lymphoma, we analyzed 11 consecutive German High-Grade Non-Hodgkin Lymphoma Study Group trials. ECFI occurred in 290/4155 (7.0%) patients (orbita, 31; paranasal sinuses, 93; main nasal cavity, 38; tongue, 27; remaining oral cavity, 99; salivary glands, 54). In a multivariable analysis adjusted for International Prognostic Index rituximab improved event-free and overall survival both in patients with and without ECFI. Three-year event-free (79% vs 79%; P = .842) and overall survival (86% vs 88%; P = .351) rates were similar in 145 patients receiving and 57 not receiving radiotherapy. Without rituximab, the 2-year cumulative rate of central nervous system (CNS) disease was increased in 205 ECFI patients compared with 2586 non-ECFI patients (4.2% vs 2.8%; P = .038), whereas this was not observed with rituximab (1.6% in 83 ECFI vs 3.4% in 1252 non-ECFI patients; P = .682). In 88 ECFI patients who received intrathecal prophylaxis with methotrexate, the 2-year rate of CNS disease was 4.2% compared with 2.3% in 191 patients who did not (P = .981). In conclusion, rituximab eliminates the increased risk for CNS disease in patients with ECFI. This retrospective analysis does not support intrathecal prophylaxis or radiotherapy to ECFI patients in complete remission/unconfirmed complete remission. These findings should be confirmed in a prospective study.

Methotrexate and Temozolomide Plus Intrathecal Liposomal Cytarabine for Primary or Secondary Central Nervous System Lymphoma

AbstractAbstract 4899Treatment of central nervous system (CNS) lymphoma remains challenging, and balance between therapeutic effectiveness and toxicity is difficult to find. The addition of systemic chemotherapy to whole brain radiotherapy has significantly improved the outcome of these patients. However, this combined strategy is burdened with possible acute and/or delayed severe neurotoxicity, particularly in elderly patients. Chemotherapy-only approaches, with or without concomitant intrathecal (IT) therapy, for CNS lymphoma have been explored. Moreover, deferring radiotherapy to the time of first or subsequent relapse may reduce the risk of severe neurotoxicity, without altering outcome. Recently, high-dose methotrexate and temozolomide (HD-MTX-TMZ) without IT CNS prophylaxis have been studied in PCNSL elderly patients. This regimen appears effective, while substantially decreasing acute and/or delayed neurotoxicity. Conflicting data exist regarding the safety of combining IT liposomal cytarabine (LC) and systemic CNS-penetrating therapy. We report our preliminary experience with HD-MTX-TMZ plus IT LC used upfront or as salvage in 4 primary or secondary CNS lymphoma patients, only one of which under the age of 60 (56). Treatment consisted of induction: MTX 3g/ms d 1, 10, 20, TMZ 100 mg/ms d 1–5; and maintenance for ≥SD patients, and for up to 5 additional cycles: MTX 3g/ms d 1, TMZ 100 mg/ms d 1–5, every month. Fifty mg IT LC were given concomitantly for up to 6 doses planned. LC doses were separated by at least 14 days from one another and at least 7 days from HD-MTX. Pt n. 1 (56 year-old male) had a history of testicular diffuse large B cell lymphoma (DLBCL), stage IVA. He received chemo-radiotherapy with 4 concomitant IT LC injections as CNS prophylaxis. Complete response (CR) was achieved. Two months later, he presented with headache and dizziness. MRI and PET revealed metabolically active righ cerebellar lesion. Karnofsky performance status (KPS) was 50%. Rituximab plus TMZ and IT MTX were initiated but soon discontinued due to a G4 CMV-related pneumonia. After complete recovery, HD-MTX-TMZ was started with concomitant 4 IT LC injections, and precautionary stem cell harvest. No significant G3-4 toxicities were observed during treatment. At 9 months of follow-up post-treatment, the lesion is stable with no contrast enhancement at MRI and PET is negative, suggesting a CRu. Pt 2 (76 year-old male) was referred in May 2009 with a diagnosis of CNS peripheral T-cell lymphoma not otherwise specified with MRI- and PET-documented multiple brain localizations (i.e. hypophyseal infundibulum, cavernous sinus, cerebellum). KPS was 60%. He was treated with systemic steroids and TMZ 150 mg/ms d 1–5/28. In August 2009 disease progressed after two cycles, and HD-MTX-TMZ was started. IT LC was added as CNS prophylaxis with 4 drug injections. Toxicity consisted of G2 renal insufficiency and G3 steroid-induced diabetes mellitus, both resolved. Treatment resulted in marked shrinkage of all lesions, with no contrast enhancement and PET is negative, indicating CRu, which is stable at 5 months of follow-up. Pt 3 (68 year-old female) was diagnosed with PCNSL, DLBCL, with left cerebellar localization. KPS was 50%. HD-MTX-TMZ and concomitant IT LC injections were initiated as first-line therapy. Four maintenance cycles and 5 IT LC injections have been performed so far. Toxicities included G3 atrial fibrillation. Interim MRIs documented very good partial remission of the disease. Pt 4 (71 year-old female) was diagnosed with DLBCL stage IIIE (i.e. subcutaneous facial localization) in July 2009, and treated with R-COMP (liposomal doxorubicine in lieu of the free formulation) for 8 cycles. She obtained CR, but in July 2010 presented with aphasia and facial hemiparesis. Brain MRI showed multiple subcortical lesions in both hemispheres, biopsy-confirmed to be lymphoma. The first IT LC injection and HD-MTX dose were given without significant toxicity. All patients completed induction and 5 maintenance cycles. HD-MTX-TMZ and concomitant IT LC therapy appeared feasible and overall well tolerated. No acute neurologic complications were observed. Follow-up is too short to make comments on delayed neurotoxicity. Increasing the number of LC injections might be reasonable and at least 7 days should be interposed between systemic and IT therapy. HD-MTX-TMZ plus IT LC deserves further evaluation in a larger prospective setting. Disclosures:No relevant conflicts of interest to declare.

Central Nervous System (CNS) at First Relapse In APL. A Report on 2 Multicenter Trials.

AbstractAbstract 1084 Background:CNS relapse is rare in APL, and predominates in patients (pts) with increased WBC counts. (De Botton, Leukemia, 2006,20,35; Montesinos, Haematologica,2009,94,1242). We report the incidence, risk factors and outcome of CNS relapse in 2 multicenter clinical trials of the European APL group. Methods:Between 1993 and Feb 2004 (when randomization for AraC in APL 2000 trial ended), 916 APL patients (pts) were included in APL93 (n=576) and APL 2000 (n=340) trials, and 92.2% of them achieved CR (Ades L, Blood 2010, Ades L, JCO 2006). In both trials, induction treatment consisted of ATRA (45 mg/m2/d until CR) and DNR 60mg/m2/d x3 + AraC 200 mg/m2/dx7 followed by a first similar consolidation course and a second course with DNR 45 mg/m2/d x3 and AraC 1g/m2/12hx8 (except in one arm of APL 2000 trial where pts with WBC<10G/L received no AraC for induction and consolidation). A 2 year maintenance treatment, consisting of intermittent ATRA (15d/3 months) and continuous 6MP+ MTX, was administered or not (randomized) in APL 93 trial, and was systematic in APL 2000 trial. In APL 2000 trial, intrathecal CNS prophylaxis with MTX+ AraC (5 injections) was made during consolidation cycles in all pts with baseline WBC > 10G/L. Median follow up was 10 and 5 years, respectively, in APL 93 and APL 2000 trial. Results:6 first relapses involving the CNS were seen (3 in APL 93 and 3 in APL 2000 trial), after 6 to 37 months (median 15 months), representing 3% of the relapses (2% and 6% in APL 93 and 2000, respectively) and 0.7% of the pts who had achieved CR (0.56% and 0.9% in APL 93 and 2000, resp). Of the 6 CNS relapses, 1 was isolated and 5 accompanied by relapse in the bone marrow (haematological in 4 cases, and only molecular in 1 case). Median age was similar (46y) in pts who had or not CNS relapse. Median WBC count was 7.9 G/l in pts with CNS relapse vs 2.5G/l in pts without CNS relapse (p=0.07). 5 of the 6 pts with CNS relapses had WBC> 5G/L, but only 2 had WBC > 10G/l. Among pts who achieved CR, 3 of the 146 (2.05%) pts who received no Ara C had CNS relapse versus 3 of the 699.(0.4%) pts who received AraC (with HD araC in the last consolidation course) (p= 0.06). In pts with WBC > 10G/l, none of 72pts in APL 2000 (who received both HD araC and intrathecal CNS prophylaxis) had CNS relapse, compared 2 of the the 123 (1.6%) pts in APL 93 trial (who received HD araC and no intrathecal CNS prophylaxis). The 6 pts with CNS relapse were all salvaged by intrathecal CT, combined to ATRA and systemic CT in APL 93, and ATO in APL 2000 trial.4 of them were durably salvaged, 3 after auto SCT and 1 after ATO and CT. Conclusion:CNS relapse was very rare in APL in our experience, and only 2 of 6 pts with CNS relapse had baseline WBC > 10G/l. CNS relapse was generally associated to concomitant marrow relapse (sometimes only molecular), and was seen in 0.4% and 2.05% pts treated with and without HD AraC, respectively (p=0.06), suggesting a possible preventive role of HD AraC, although numbers were small to conclude. Interestingly, by comparison, in the Spanish PETHEMA experience where pts received no AraC, 1.6% of the 667 pts who achieved CR had CNS relapse (Montesinos, Haematologica, 2009, 94, 1242). On the other hand, the role of intrathecal CNS prophylaxis was unclear in our experience. Finally, outcome of CNS relapses was better than in our previous report (De Botton, Leukemia, 2006,20,35), possibly due in part to the recent treatment of relapses by ATO, known to penetrate the blood brain barrier (Au et al, Blood, 2008,3587) and which could also play a role in CNS prophylaxis when administered during first line treatment. Disclosures:Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement

The role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age > or =18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated.

Intrathecal Chemotherapy alone is Inadequate Central Nervous System Prophylaxis in Patients with Intermediate-grade Non-Hodgkin's Lymphoma

Central nervous system (CNS) relapse of non-Hodgkin's lymphoma (NHL) is usually fatal despite therapy and effective prophylaxis is desirable. Patients at high-risk usually receive intrathecal (IT) prophylaxis, although its efficacy is unproven. We therefore analyzed the outcome of all patients with newly diagnosed "intermediate-grade" NHL receiving IT prophylaxis from 1991 to 1999. Twenty-six patients were identified and analyzed. All were free of CNS involvement at diagnosis with negative cerebrospinal fluid (CSF) cytology. Disease stage was IE in 7, and IV in 19, with a median of two extranodal sites involved. Serum lactate dehydrogenase was elevated in 65%, and the median International Prognostic Factors Index score was 3 (range 0-5). Anthracycline-based chemotherapy was used in all cases and included high-dose methotrexate ± ara-C in six patients. The median number of IT treatments was 5 (range 1-12) and comprised methotrexate ± steroid in 15, together with ara-C in 11. The actuarial 3-year CNS-relapse rate was 26 ± 10%. Six CNS-relapses were observed and involved the spinal cord or brain parenchyma in two cases each, and the leptomeninges in four patients. Treatment-related variables associated with higher CNS-relapse rates (34-50%) were: delay of ≥ 14 days from diagnosis to first IT injection, <5 IT treatments, delay of IT prophylaxis until after attaining CR and systemic treatment lacking high-dose methotrexate ± ara-C (each P ≤ 0.17). IT CNS prophylaxis, as used here, was inadequate. Alternative approaches should be pursued.

Excessive spinal cord toxicity from intensive central nervous system -directed therapies

Intrathecal chemotherapy, radiation therapy, and systemic chemotherapy are used for both prophylaxis and treatment of central nervous system (CNS) disease in hematologic malignancies. Twenty-three cases of myelopathy that occurred in patients who received intensive CNS-directed therapy were evaluated to identify the determinants of this severe CNS toxicity. Nine cases treated by the authors and 14 collected from the literature are discussed. Twelve had Burkitt's leukemia/lymphoma. Patient ages ranged from 3 to 30 years (median, 15 years). The dose intensity of CNS-directed therapies, including intrathecal cytosine arabinoside (ara-C), intrathecal methotrexate (MTX), systemic high dose (HD) MTX, systemic HD ara-C, systemic thiotepa, and CNS radiation, was evaluated by the determination of single drug doses and cumulative total drug or irradiation doses over elapsed treatment durations. Central nervous system treatment was prophylactic in 10 cases; active CNS disease was being treated in 13 cases. One patient received only intrathecal ara-C before toxicity occurred; other received intrathecal ara-C and varying combinations of intrathecal MTX, HD ara-C, HD MTX, CNS radiation, and systemic thiotepa. Eight patients died of toxicity, of whom 6 had autopsy-proven cord necrosis; 3 were ventilator-dependent; 10 had persistent paraplegia or paraparesis; and 2 recovered completely. Both highly intensive, short CNS treatment sequences and lower intensity, long term cumulative treatments may result in this rare but severe myelopathy. The cause is multifactorial, with systemic chemotherapy, intrathecal chemotherapy, and radiation therapy contributing to toxicity. Multiple intrathecal ara-C and/or MTX doses given at frequent (daily) intervals should be avoided. Concurrent intrathecal ara-C and systemic HD ara-C also appear to be especially toxic. Intrathecal hydrocortisone given with intrathecal ara-C does not protect against myelopathy. Multiple, frequently spaced courses of CNS-directed therapies must be avoided, especially in patients who have received prior CNS radiation.

Localized extradural lymphoma: survival, relapse pattern and functional outcome

Between 1967 and 1988, 22 patients were treated at The Princess Margaret Hospital (PMH) for localized (stage IE) non-Hodgkin's lymphoma (NHL) presenting with spinal extradural compression. The median age of the patients was 55 years (range 18–76). Back pain (20 patients) and leg weakness (18 patients) were the commonest complaints at presentation. Seven patients (30%) were non-ambulatory (paraplegic or severely paretic) and four had impaired sphincter function. Diffuse histiocytic lymphoma (12 cases) was the commonest histology. All patients initially had laminectomy decompression and were referred to PMH post-operatively. One patient (with coincident metastatic carcinoma of the breast) was treated palliatively. The remaining 21 patients received radical post-operative treatment: radiation therapy (XRT) alone in 12 cases (25–45 Gy), radiation therapy plus systemic combination chemotherapy (combined modality therapy, CMT) in 9 cases. The overall actuarial survival for the radically treated patients was 55% at 10 years and there was a significant difference ( p = 0.037) between those treated by XRT alone (33%) and those who received CMT (86%). Only one patient from each treatment group failed locally but the distant recurrence-free survival for the XRT group was 32% compared to 100% for the CMT group ( p = 0.017). One patient developed primary central nervous system (CNS) relapse. The functional results of treatment were excellent: 19 of the 21 radically treated patients regained or retained normal ambulatory status and the remaining two patients had only minor disability. Decompressive surgery and radiotherapy for localized extradural lymphoma ensures a high rate of local control and functional recovery. With the addition of combination chemotherapy the distant relapse-free and overall survival rates are also excellent. Routine use of intrathecal CNS prophylaxis does not appear to be necessary for the majority of patients.

Second central nervous system prophylaxis in children with acute lymphoblastic leukemia who relapse after elective cessation of therapy.

A treatment plan to achieve better disease control in patients with acute lymphoblastic leukemia (ALL) who relapse after elective cessation of therapy was assessed. The principal modifications were (1) a second preventive treatment of the central nervous system (CNS) at relapse and every six weeks throughout therapy, using intrathecal methotrexate with cytosine arabinoside, and (2) a four-week course of systemic chemotherapy given immediately before therapy was stopped a second time. Twenty-four patients were studied. There have been no meningeal relapses, in contrast to seven among 16 similar patients who were retreated without CNS prophylaxis. Although the median length of second hematologic remission was not significantly different from the outcome in the comparison group, a much higher proportion of patients (eight of 24 versus zero of 17) remain in prolonged reinduced complete remission (48-79 months). Children whose first relapse occurred later than six months after cessation of therapy had significantly longer subsequent remissions. These end results establish the value of intrathecal CNS prophylaxis in relapsed ALL and suggest that a late intensive phase of therapy will extend remissions in a substantial proportion of patients.