Liposomal Cytarabine in the Central Nervous System (CNS) Prophylaxis of Elderly Patients with Aggressive B-Cell Non-Hodgkin’s Lymphoma (NHL) and Undifferentiated Acute Leukemia (UAL): Preliminary Results of a Single-Center Experience.

Abstract Background: CNS involvement in acute lymphoblastic leukemia/AUL is a well-recognized event and CNS prophylaxis is considered mandatory. In NHL, meningeal relapse occurs more rarely, ranging from 4–14% depending on histology, anatomical location and biological parameters. Flow cytometric analysis of cerebrospinal fluid (CSF), however, detected occult lymphomatous meningitis in 22% of NHL cases at risk at diagnosis (Hegde et al. Blood2005;105:496). CNS prophylaxis is currently recommended only in high-risk disease (stage IV/high IPI score) and in patients with extranodal NHL. Sustained-release liposomal cytarabine (DepoCyte®), which is licensed for meningeal relapse in NHL, has proved effective in treating lymphomatous and leukemic meningitis (Glantz et al. J Clin Oncol1999;17:3110; Sancho et al. Haematologica2006;91:ECR02). Intrathecal (IT) liposomal cytarabine is distributed throughout the CSF and has an extended half-life, allowing administration once every 2–4 weeks (Chamberlain et al. Arch Neurol1995;52:912). We therefore tested the efficacy of liposomal cytarabine in CNS prophylaxis for elderly patients with aggressive NHL or AUL, with the aim of testing the safety of IT treatment in elderly patients and the efficacy of liposomal cytarabine in preventing lymphoma/leukemia CNS relapse. Methods: From June to November 2005, 4 patients > 70 years of age entered the study. Diagnoses were: 2 stage IV, IPI 3, diffuse large B-cell lymphoma (DLBCL); 1 mantle cell lymphoma (MCL), and 1 AUL; 2 patients had extranodal bulky disease (1 psoas muscle, 1 retro-orbital plus paranasal sinus involvement). As first-line treatment, the 3 NHL cases were given R-CHOP every 21 days for 6 cycles. The patient with AUL received conventional 3-drug induction (vincristine/idarubicine/prednisone) every week for 3 weeks, followed by 3 courses of L-VAMP (vincristine/cytarabine/intermediate-dose methotrexate/leucovorin rescue) and then conventional maintenance (6-mercaptopurine/methotrexate and monthly re-induction with vincristine/prednisone). All patients received CNS prophylaxis with IT liposomal cytarabine 50 mg followed by systemic steroid injection. In NHL cases, IT therapy was given the day before systemic chemotherapy for a total of 4 administrations; in AUL, prophylaxis was given every 4 weeks during induction and maintenance for a total of 6 doses. Results: Three (2 NHL and 1 AUL) patients achieved a complete response (CR) and 1 (NHL) achieved a partial response, with response durations of 4, 5, 6+ and 8+ months, respectively. As of July 2006, after a median follow-up of 10 months (range 9–12), all patients were alive; 2 (1 DLBCL, 1 AUL) were in continuous CR, and 2 (1 DLBCL, 1 MCL) had progressive disease and were receiving second-line treatment. Isolated relapse of leukemia/lymphoma in the CNS was not seen. Liposomal cytarabine was well tolerated; no drug-related side effects or hematological toxicities were recorded. Conclusions: As occult CNS involvement has been shown to occur in >20% of newly diagnosed patients with high-risk NHL, flow cytometry and cytospin analysis of CSF at diagnosis should be implemented in order to adequately target CNS prophylaxis. Liposomal cytarabine should be the drug of choice for CNS prophylaxis, particularly in elderly patients.

Download Full-text

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

Blood ◽

10.1182/blood.v116.21.4899.4899 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4899-4899

Author(s):

Lorenzo Falchi ◽

Marco Gunnellini ◽

Ilaria Angeletti ◽

Laura Franco ◽

Anna Marina Liberati

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Elderly Patients ◽

Contrast Enhancement ◽

Cell Lymphoma ◽

Cns Lymphoma ◽

Liposomal Cytarabine ◽

Delayed Neurotoxicity ◽

Cns Prophylaxis

Abstract Abstract 4899 Treatment 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.

Download Full-text

Survival and Risk of Central Nervous System Recurrence in Burkitt or High-Grade B-Cell Lymphoma in the DA-EPOCH-R Era

Blood ◽

10.1182/blood-2018-99-115676 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2983-2983

Author(s):

Dominic Decker ◽

Pamela C Egan ◽

Diana O Treaba ◽

Adam J Olszewski

Keyword(s):

B Cell ◽

High Intensity ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Grade ◽

Cns Involvement ◽

Cns Prophylaxis ◽

Cns Relapse

Abstract Background: The 2017 World Health Organization (WHO) classification distinguished new categories of high-grade B-cell lymphoma (HGBCL). Treatment of these lymphomas is in flux, as some were historically classified as DLBCL and treated with the RCHOP regimen, while others, akin to Burkitt lymphoma (BL), were treated using high-intensity regimens (e.g. CODOX-M/IVAC or hyper-CVAD) that include systemic high-dose methotrexate (HDMTX) as central nervous system (CNS) prophylaxis . Recently, the less intensive DA-EPOCH-R regimen has been increasingly applied for BL or HGBCL with concurrent MYC and BCL2 and/or BCL6 rearrangements based on phase 2 data (Dunleavy et al., NEJM 2013). We examined progression-free survival (PFS) and risk of CNS relapse among HGBCL/BL patients treated in our institution. Methods: In this retrospective series from an academic center, we integrated cancer registry and electronic medical records for all patients treated for BL or HGBCL at Lifespan Cancer Institute in 2005-2017. We designated as "HGBCL" all cases with concurrent MYC and BCL2/BCL6 rearrangements, or those previously diagnosed as "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" (per WHO 2008). We compared characteristics of patients treated with intensive regimens or with DA-EPOCH-R, as well as their PFS (using log-rank test) and cumulative incidence function (CIF) of CNS relapse (using Gray's test). Results: Among 64 patients with BL (n=38) and HGBCL (n=26), those with BL were somewhat younger (median age 52 versus [vs.] 61 years), more often male (84% vs. 58%), HIV-positive (29% vs. 8%), or with CNS involvement at baseline (21% vs. 4%). Among HGBCLs, 58% had a MYC rearrangement, whereas 31% had concurrent MYC and BCL2/BCL6 rearrangements. Eight patients who did not receive chemotherapy (median age, 78 years) were excluded from outcome analysis. Compared with patients with BL, those with HGBCL more often received DA-EPOCH-R (41% vs. 15%) or R-CHOP (27% vs. 12%), and less often high-intensity regimens (32% vs. 73%, P=.027). Compared with patients treated using high-intensity regimens, those treated with DA-EPOCH-R were significantly older (61 vs. 49 years, P=.023), with high/high-intermediate International Prognostic Index (IPI, 86% vs. 50%, P=.027), or diagnosis after 2010 (86% vs. 53%, P=.049). There was no difference in baseline CNS involvement (P=.68) or receipt of intrathecal prophylaxis (P=.16) between DA-EPOCH-R and high-intensity regimens. After median follow-up of 5.7 years, we observed 12 recurrences, including 5 (42%) in the CNS. Median PFS was not reached, whereas 3-year PFS was 56% (95% confidence interval [CI], 42-68%), numerically better in BL than in HGBCL (63% vs. 45%, P=.33, Fig. A). Overall survival at 3 years was also 56% (95%CI, 41-68%). Factors associated with shorter PFS included age >60 years (log-rank P=.017), poor performance status (P<.001), high/high-intermediate IPI (P=.0003), and lack of CNS prophylaxis (P=.021). Treatment with DA-EPOCH-R rather than a high-intensity regimen was also associated with worse PFS (P=.001), but not when stratified by histology and age (P=.14). HIV status (P=.53) or CNS involvement at baseline (P=.15) were not prognostic. Survival after recurrence was dismal (median, 1 month, 95%CI, 0.2-3.4), despite 58% of patients receiving salvage therapy. The 3-year CIF of CNS recurrence was 9% (95%CI, 3-18%), and higher in patients with CNS involvement at baseline (P=.002). All CNS recurrences occurred during the first year of follow-up and were among patients receiving DA-EPOCH-R (35.7% vs. 0% for other regimens, P=.0004). Administration of HDMTX for CNS prophylaxis was associated with a numerically lower risk of CNS recurrence (3% vs. 16% without, P=.09, Fig. B). Conversely, we observed no difference in CNS relapse with or without intrathecal prophylaxis (9% vs. 8%, P=.84, Fig. C). Conclusions: The high proportion of CNS recurrences despite prophylaxis, and very poor outcomes at relapse, indicate persistent major areas of need in BL/HGBCL. Outcomes of DA-EPOCH-R were heavily influenced by selection bias (as evidenced by unfavorable characteristics of patients selected for this regimen), so evaluation of this regimen in comparison with high-intensity approaches is warranted in a larger sample. However, our data suggest that in BL/HGBCL systemic HDMTX may be essential for effective CNS prophylaxis. Disclosures Olszewski: TG Therapeutics: Research Funding; Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding.

Download Full-text

Young High Risk Patients with MYC/BCL2 Double Hit Lymphoma, BCL2+ and/or Germinal Centre B-Cell like Diffuse Large B-Cell Lymphoma Benefit from Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis: Analysis of Data from the Nordic Lymphoma Group CRY-04 and Chic Trials

Blood ◽

10.1182/blood-2018-99-120057 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2955-2955 ◽

Cited By ~ 1

Author(s):

Sirpa Leppa ◽

Judit Jørgensen ◽

Leo Meriranta ◽

Klaus Beiske ◽

Jan M.A. Delabie ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cns Prophylaxis ◽

Large B Cell Lymphoma ◽

Dose Dense ◽

In The Beginning ◽

Large B Cell

Abstract Background. Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two Nordic trials including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these trials to compare clinical outcome and biological prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) versus at the end (CRY-04) of therapy. Patients and methods. In CRY-04 study, patients were treated with six courses of R-CHOEP14 followed by HD-Mtx and HD-Ara-C. In CHIC trial, treatment started with two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP-14 and one course of R-HD-AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. For the correlative studies, formalin fixed paraffin embedded pretreatment tumor samples were analyzed by fluorescent in situ hybridization for BCL2 and c-MYC breakpoints and by immunochemistry for CD10, BCL6, MUM1, MYC and BCL2 expression. Germinal center B-cell-like (GCB)/non-GCB) subclassification was performed according to Hans algorithm. Results. Among 303 patients enrolled in the trials (CRY-04, n=160 and CHIC, n=143), 295 (CRY-04, n=154 and CHIC, n=139) were evaluable for baseline characteristics and outcome. Median age (54 and 56 years, p=0.222), male/female ratio, stage, and aaIPI scores were comparable in the two cohorts. CHIC regimen improved outcome over CRY-04; the findings included 4-year estimates of PFS (81% vs 66%, p=0.003), OS (83% and 79%, p=ns) and cumulative incidence rates of CNS progression (2.4% and 5.0%, p=ns). Treatment with the CHIC regimen reduced the risk of systemic progression (aaIPI adjusted RR=0.489, 95%CI 0.308-0.777, p=0.002). PFS benefit with CHIC over CRY-04 was observed across pre-specified subgroups, and particularly in patients less than 60 years old (p=0.008). In the entire study population, dual protein expression (DPE) of BCL2 and MYC was the only parameter to be significantly correlated with a worse PFS (4-y PFS 77% vs 50%, p=0.024; RR=2.300, 95% CI 1.088-4.860, p=0.029). Neither any single immunohistochemical marker nor the GCB/non-GCB subtype or MYC/BCL2-translocations significantly affected outcome. However, when treatment interaction was tested, MYC/BCL2 double hit status (DHL; 13%) predicted poor outcome among patients treated with CRY-04 regimen compared with patients who received CHIC regimen (4-y PFS; 38% vs 78%, p=0.086). GCB subtype and BCL2 positivity were also associated with better outcome in the CHIC cohort (4 y PFS; 63% vs 84%, p=0.011 and 61% vs 80%, p=0.007, respectively), whereas there were no significant survival differences between these regimens among the patients with non-GCB subtype, BCL2 negative DLBCL or DPE lymphomas. Conclusions. Our results derived from trial data with homogenous treatment support the use of HD-Mtx in the beginning rather than at the end of therapy. The survival benefit related to CHIC regimen over CRY-04 is due to better systemic control of the disease, and at least partly linked to improved survival among patients with GCB subtype, BCL2 positivity and DHL. Disclosures Leppa: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding.

Download Full-text

YOUNG HIGH RISK PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA INCLUDING BCL-2/MYC DOUBLE HIT LYMPHOMAS BENEFIT FROM DOSE-DENSE IMMUNOCHEMOTHERAPY WITH EARLY CNS PROPHYLAXIS

Hematological Oncology ◽

10.1002/hon.92_2629 ◽

2019 ◽

Vol 37 ◽

pp. 132-132

Author(s):

S. Leppä ◽

J. Jørgensen ◽

A. Tierens ◽

L. Meriranta ◽

I. Østlie ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Risk Patients ◽

Cns Prophylaxis ◽

Large B Cell Lymphoma ◽

Risk Patients ◽

Dose Dense ◽

Large B Cell

Download Full-text

Feasibility and Efficacy of BEAM as a Frontline High Dose Chemotherapy Supported by Autologous PBSCT in Elderly Patients (≥60 Years) with DLBCL

Blood ◽

10.1182/blood.v112.11.4449.4449 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4449-4449

Author(s):

Vadim Ivanov ◽

Diane Coso ◽

Jerome Rey ◽

Therese Aurran ◽

Anne-Marie Stoppa ◽

...

Keyword(s):

High Risk ◽

Elderly Patients ◽

Older Patients ◽

Disease Stage ◽

High Dose ◽

Line Treatment ◽

First Line ◽

High Risk Patients ◽

Risk Patients ◽

Autologous Pbsct

Abstract Limited data is available concerning feasibility and efficacy of high dose therapy (HDT) supported by autologous PBSCT in elderly patients with non-Hodgkin lymphoma (NHL). In young patients with poor prognostic features intensification supported by PBSCT as a part of first-line treatment suggests survival benefit. It is not clear if the same strategy is applicable to the older patients. The Institute Paoli-Calmettes database was reviewed for all DLBCL patients who received BEAM followed by PBSCT in patients >=60 years old between January 1998 and December 2006 (9 years). All patients were HIV-negative and received BEAM intensification as a part of front-line treatment. All of them were in a complete or partial response after CHOP or R-CHOP induction prior to autograft. Twenty seven auto-transplanted patients were identified (median age 63 y, range 60–68). This cohort was compared with closely matched group of 37 patients of same age range, who received first-line CHOP or R-CHOP regimen without intensification in the same 9-years interval. Only patients in a complete response after first line were included. As frontline autoPBSCT was performed in high-risk patients, the group without HDT was naturally privileged in the terms of Ann-Arbor stage and aaIPI index. There was significant difference in the localised vs disseminated disease (stage I–II: 54% in no-HDT vs 26% in HDT group, p=0.03)) and aaIPI (0–1: 66% in no-HDT vs 37% in HDT, p=0.046) between the two groups. Factors evaluated included treatment-related mortality (TRM), overall survival (OS) and event-free survival (EFS). TRM in the HDT group (1/27 pts (3,7%)) was comparable with previously published data. The estimated 5-year OS was 75,5% (95%CI 52–90 %) for HDT group compared to 79,9% (95%CI 58–92%) in the no-HDT group (p=0,75). There were 8 events (1 TRM and 7 relapses) in the HDT group and 11events (all relapses) in no-HDT (5-year EFS 49,4% vs 64,2%, p=0.45). We conclude that frontline autologous PBSCT with BEAM conditioning can be safely performed in patients aged 60 years or above with DLBCL after CHOP of R-CHOP induction. There was no difference in OS and EFS between cohorts with and without intensification even if the auto-transplantation procedure was reserved for the high risk patients. We conclude that first-line HDT with autologous PBSCT in older patients with high-risk IPI score might improve survival in this group and produce results similar to those in the low-risk group.

Download Full-text

Risk-Tailored CNS Prophylaxis In 194 Patients With Diffuse Large B-CELL Lymphoma (DLBCL) Treated In The Rituximab ERA: Risk Definition By Clinical Variables and Ontogenic Stratification

Blood ◽

10.1182/blood.v122.21.4365.4365 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4365-4365

Author(s):

Marta Bruno Ventre ◽

Marco Foppoli ◽

Giovanni Citterio ◽

Giovanni Donadoni ◽

Maurilio Ponzoni ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Risk Group ◽

High Risk Group ◽

Low Risk ◽

Cns Involvement ◽

First Line ◽

Clinical Variables ◽

Cns Prophylaxis ◽

Cns Relapse

Abstract Background CNS dissemination is an uncommon but lethal event in non-Hodgkin lymphomas. Early detection of CNS disease and a timely and effective CNS prophylaxis are the main strategies to reduce related mortality. However, both the criteria for recognition of lymphoma patients (pts) with increased risk of CNS involvement and the most effective prophylaxis modality remain important, unmet clinical needs. Some international guidelines recommend intrathecal chemotherapy by lumbar injection as exclusive prophylaxis; however, this strategy results in erratic, short-lived drug bioavailability and does not prevent brain parenchymal relapses. Herein, we report a retrospective analysis of the value of clinical variables and immunohistochemical ontogenic stratification in predicting CNS dissemination and of risk-tailored CNS prophylaxis in a mono-institutional series of 194 pts with DLBCL treated in the rituximab era. Methods Consecutive HIV- adults with DLBCL without CNS involvement at diagnosis treated with first-line rituximab-CHOP or similar ± radiotherapy were considered. Primary CNS, mediastinal and cutaneous leg-type lymphomas were excluded. ‘High risk’ of CNS relapse was defined by the involvement of the testis, spine, skull, orbit, nasopharynx, kidney, and/or breast or by IPI ≥2 (including two among extranodal sites ≥2, advanced stage and high serum LDH). DLBCLs were ontogenically subclassified in ‘germinal-centre B-cell-like’ (GCB) and ‘non-germinal-centre B-cell-like’ (non-GC) by immunohistochemistry following the Hans algorithm. Results 194 patients were analyzed (median age 65, range 18-89; M:F ratio 1.1). Risk of CNS relapse was low in 90 pts and high in 104. Low-risk pt did not receive CNS prophylaxis, while 40/104 (38%) high-risk pts received 3-4 courses of methotrexate 3 g/m2 ± intrathecal (IT) liposomal cytarabine (n=30), cytarabine 16 g/m2 in 4 days (n=2) or IT chemotherapy (n=8). In the high-risk group, IPI ≥2 was more common among pts who did not receive prophylaxis (89% vs. 68%; p=0.006), while “high-risk” extranodal lymphomas were more common among pts who did (88% vs. 33%; p= 0.0001). One hundred and forty-one cases were assessable for Hans algorithm: 74 (52%) were GCB and 67 (48%) were non-GCB DLBCL. GCB DLBCLs were significantly associated with low CNS risk (55% vs. 31%; p= 0.004), and normal LDH levels (57% vs. 36%; p= 0.02); ontogenic stratification was not associated with high-risk extranodal sites, IPI ≥2, bone marrow infiltration, stage and systemic symptoms. After first-line treatment, 160 pts achieved a CR (82%; 95%CI= 77-87%), 34 pts had PD. At a median follow-up of 60 months (13-156), a single low-risk pt and 9 high-risk pts (1% vs. 9%; p= 0.016) experienced CNS relapse (exclusive site in all cases; brain in 5 pts, meninges in 5), with a median TTP of 12 months (7-55). CNS relapses occurred in 3 pts with IPI ≥2, in 1 pt with extranodal disease (testis) and in 5 pts with both features (kidney 3; testis, orbit). Ontogenic stratification was not associated with CNS recurrence, which was 5% for GCB and 6% for non-GCB; these figures were confirmed when analysis was limited to high-risk pts managed without prophylaxis. In the high-risk group, CNS relapses occurred in 7/64 (11%) pts who did not receive prophylaxis, in 2/8 (25%) pts who received only IT chemotherapy, whereas no CNS relapses were detected in the 32 pts treated with intravenous (IV) prophylaxis. CNS relapse rate was 13% for pts treated with “inadequate” prophylaxis (none or IT only) and 0% (p= 0.03) for pts managed with IV prophylaxis. Eight pts with CNS relapses died of lymphoma after 7-37 months (median 12), which represented 28% of all lymphoma-related deaths (n=29) in the high-risk group. Pts treated with IV prophylaxis had a significantly better OS than the other high-risk pts (5-yr: 94 ± 7% vs. 49 ± 6%; p= 0.001). Conclusions Stratification by specific extranodal sites and IPI is superior to ontogenic stratification to recognize CNS risk groups in DLBCL. However, the low sensitivity of predictive clinical variables suggests that molecular studies focused on the predictive and pathogenic role of molecules involved in CNS tropism will contribute to a more accurate definition of lymphoma candidates for CNS-directed strategies. In this context, IV high-dose methotrexate-based prophylaxis may significantly reduce CNS failures in high-risk pts. Disclosures: No relevant conflicts of interest to declare.

Download Full-text