Central Nervous System Prophylaxis In Patients Research Articles

Risk reduction of CNS relapse in diffuse large B cell lymphoma with intrathecal methotrexate prophylaxis: A single institution retrospective study.

e19531 Background: Central nervous system (CNS) relapse is an infrequent but serious and challenging complication in diffuse large B-cell lymphoma (DLBCL) that carries a dismal prognosis. While several risk factors have been identified to stratify the risk for CNS relapse including the 2015 CNS internal Prognostic index (CNS-IPI), controversy still remains regarding the indication, timing, and method of CNS prophylaxis. The purpose of this study was to determine whether IT-MTX reduced the risk of CNS relapse, as well as treatment related and financial toxicity of CNS prophylaxis. Methods: We performed a single-center, retrospective analysis on a cohort of 192 patients with DLBCL who had received treatment between January 2010- August 2022. Patients were identified by using ICD10 code diagnosis in the electronic medical records system. We included patients of all stages of disease and CNS-IPI scores along with patients with testis, breast, sinus, and bone marrow extranodal involvement. Patients with primary CNS disease and primary mediastinal disease were excluded from the study. Clinical data collected by chart review included age at time of diagnosis, sex, performance status, LDH level, disease stage, number and type of therapies administered including IT-MTX, extranodal involvement, MYC/BCL2/BCL6 translocation status, HIV status, cell of origin (COO), treatment response. Toxicities and complications thought to be associated with IT-MTX prophylaxis were also documented in addition to total costs of treatment for each patient. Patient characteristics were compared using Fisher exact test or Pearson’s chi-square test. Results: In patients with intermediate to high CNS relapse risk (CNS-IPI 2-5) IT-MTX did not reduce the 1 year risk of CNS relapse (RR 1.1296, 95% CI 0.1933 to 6.6012, P = 0.08924). The median time to CNS relapse was longer in patients who had received IT-MTX (13.5 months) vs those who did not (7 months). Thirty eight (52.8%) patients reported adverse side effects of any kind as a result of IT-MTX administration, with 23.6% of patients developing grade 2-3 adverse events. The average cost for CNS-prophylaxis was estimated to be approximately $8,059.04 over a patient’s treatment course, but as high as $20,140. Conclusions: In conclusion, our study highlights the necessity to develop improved standardized guidelines for use of CNS prophylaxis in patients with DLBCL. The results from our retrospective study add to the growing body of literature showing IT-MTX has limited and potentially transient effectiveness in preventing CNS relapse. Given the high rate of side effects and significant cost of IT-MTX, we recommend that clinicians carefully consider the risks and benefits of prophylaxis before prescribing IT-MTX for CNS-prophylaxis.

[Risk assessment and prophylactic treatment strategies for central nervous system relapse of diffuse large B-cell lymphoma].

Rituximab treatment significantly improved the outcomes of diffuse large B-cell lymphoma (DLBCL). A central nervous system (CNS) relapse remains a serious and fatal event for patients with DLBCL; therefore, the clinical question of the optimal treatment regimen for reducing the risk of CNS relapse remains unknown. The CNS-International Prognostic Index was identified as a predictive model for CNS relapse. No factors can completely predict CNS relapse although several reports regarding high-risk factors for CNS relapse have been reported. In practice, intrathecal methotrexate (MTX) and high-dose MTX therapy have been used for CNS prophylaxis. Unfortunately, evidence of the optimal therapy for CNS prophylaxis in patients with DLBCL remains lacking. This study aimed to review CNS relapse assessment and discuss study results with clinical impacts on CNS prophylaxis treatment strategies in DLBCL.

Outcomes of high‑dose methotrexate for CNS prophylaxis in diffuse large B‑cell lymphoma with an intermediate or high CNS‑International Prognostic Index: A single‑center retrospective cohort study.

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is rare (2-5% of cases), but is a devastating complication with a poor survival rate. The administration of high-dose methotrexate (HDMTX) for CNS prophylaxis in patients with DLBCL is controversial and variable in the literature. The present study aimed to evaluate the clinical outcomes of HDMTX CNS prophylaxis in patients with intermediate and high CNS-International Prognostic Index (IPI) DLBCL using real-world data. An observational retrospective cohort study was conducted of all patients with intermediate and high CNS-IPI DLBCL treated at Princess Noorah Oncology Center (King Abdulaziz Medical City, Jeddah, Saudi Arabia) between January 2010 and December 2020. Patients were treated with HDMTX either intravenously or intrathecally, according to the physician's evaluation of the patient. Data on patient clinical characteristics, CNS relapses, risk factors and survival rates were obtained from hospital records. Data were analyzed using Student's unpaired t-test and the χ2 test to compare the two subgroups, the Kaplan-Meier survival method with log-rank test to calculate and compare the survival rates, and regression analysis to determine the risk factors for CNS relapse and death. The study included 358 patients (n=32 with HDMTX CNS prophylaxis and n=326 without CNS prophylaxis). Patients in the CNS prophylaxis group had a significantly higher CNS relapse rate than those in the non-CNS prophylaxis group (12.5% vs. 1.8%; P=0.008). Patients who received CNS prophylaxis were younger and had an advanced stage of disease, with extranodal involvement and a high serum lactate dehydrogenase level at presentation. CNS prophylaxis was significantly associated with CNS relapse, while relapsed disease was associated with the risk of death (all P<0.05). In conclusion, the present study found that patients with intermediate and high CNS-IPI who received HDMTX CNS prophylaxis did not have fewer CNS relapses; however, those without CNS relapse had higher survival rates. In addition to CNS prophylaxis, Stage of DLBCL and IPI were significantly associated with CNS relapse. Future randomized control trials are needed to evaluate the efficacy of HDMTX CNS prophylaxis in patients with DLBCL.

Updates in the Management of Early-Stage Diffuse Large B-Cell Lymphoma

Several important updates have emerged in the management of early-stage diffuse large B-cell lymphoma. Three trials resulted in the approval of rituximab + cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) for use in these patients internationally. Furthermore, studies have been initiated to determine whether 4 or 6 cycles of this regimen should be administered without radiation therapy (RT). Six cycles of R-CHOP plus central nervous system (CNS) prophylaxis and prophylactic testicular RT are recommended for patients with extranodal disease occupying the testicles. Although controversial, there is a reasonable consensus in the literature to consider 6 cycles of R-CHOP plus involved-site RT and CNS prophylaxis for patients with extranodal disease of the breast. Patients with primary bone and gastric extranodal disease do not seem to derive a significant survival benefit from RT. Molecular subtype evaluations may change treatment approaches.

Toxicity of high-dose methotrexate administration at the Sidney Kimmel Cancer Center (SKCC): A retrospective review to guide establishment of an outpatient treatment program.

30 Background: High-dose methotrexate (HDMTX) is administered for the treatment of primary central nervous system (CNS) lymphoma (PCNSL), leptomeningeal metastases, and osteosarcoma, as well as CNS prophylaxis in patients with high-risk lymphoma and leukemia. Treatment is typically administered in an inpatient setting to enable aggressive hydration, urinary alkalinization, and frequent lab monitoring given the risk of acute kidney injury. Multiple pediatric centers have published experiences with outpatient administration of HDMTX. We aim to determine the toxicity rate in adult patients at SKCC receiving HDMTX to identify a population in which to pilot an outpatient HDMTX program. Methods: We performed a retrospective review of all patients receiving inpatient HDMTX at SKCC between January 1, 2018 and October 31, 2019. Results: Seventy-three patients (52% male) with median age of 60 years (range 22-81) received 255 cycles total of HDMTX. Diagnoses include PCNSL/vitreoretinal lymphoma (n=22), diffuse large B-cell lymphoma (n=17), B-cell acute lymphoblastic leukemia (n=16) and other diagnoses (n= 18). Thirty-one cycles were administered as CNS prophylaxis and 224 cycles as treatment, with a median prophylactic dose of 3.5 g/m2 (range 1-3.5) and median treatment dose of 3.5 g/m2 (range 0.25-12). The most common toxicity was acute kidney injury at a median day 3 of the cycle (range 1-7). See the table for details. Conclusions: Acute kidney injury occurred more often in the treatment group compared to prophylaxis group. Of all patients with AKI in the treatment group, 45% had a diagnosis of PCNSL. In the prophylactic group, only 21% of patients (3/14) experienced AKI of which all resolved. Of all AKI events, 90% were Grade 2 and 90% resolved. Based on these results, we plan to pilot an outpatient HDMTX program in patients receiving prophylactic HDMTX to determine its effect on patient quality of life and cost of care. [Table: see text]

Central nervous system prophylaxis with intrathecal liposomal cytarabine in a subset of high-risk patients with diffuse large B-cell lymphoma receiving first line systemic therapy in a prospective trial.

The dissemination in the central nervous system (CNS) is an uncommon but fatal complication occurring in patients with diffuse large B-cell lymphoma (DLBCL). Standard prophylaxis has been demonstrated to reduce CNS relapse and improve survival rates. Intrathecal (IT) liposomal cytarabine allows maintaining elevated drug levels in the cerebrospinal fluid for an extended period of time. Data on the efficacy and safety of liposomal cytarabine as CNS prophylaxis in patients with DLBCL are still insufficient. The objective of the present study was to evaluate the effectiveness and safety of the prophylaxis with IT liposomal cytarabine in prevention of CNS relapse in high-risk patients with DLBCL who were included in a trial of first line systemic therapy with 6 cycles of dose-dense R-CHOP every 14 days. Twenty-four (18.6 %) out of 129 patients were identified to have risk factors for CNS involvement, defined as follows: >30 % bone marrow infiltration, testes infiltration, retroperitoneal mass ≥10 cm, Waldeyer ring, or bulky cervical nodes involvement. Liposomal cytarabine (50 mg) was administered by lumbar puncture the first day of the 1st, 2nd, and 6th cycle of R-CHOP14 scheme. Among 70 IT infusions, grade 3–4 adverse events reported were headache (one patient) and nausea/vomiting (one patient). With a median follow-up of 40.1 months, no CNS involvement by DLBCL was observed in any patient. In conclusion, IT liposomal cytarabine is safe, feasible, and effective for CNS prophylaxis, causing few associated risks and little discomfort to patients with DLBCL.

Risk Factors for CNS Relapse Among Patients with DLBCL Treated with EPOCH-R

Background: Central nervous system (CNS) relapse in pts with aggressive non-Hodgkin lymphoma (NHL) is a generally fatal complication, with median overall survival (OS) of less than six months (Abramson et al., 2010). Several studies have identified features associated with increased risk of CNS relapse, such as extranodal (EN) sites of disease, elevated lactate dehydrogenase (LDH), presence of B symptoms, and bone marrow involvement (Bernstein et al., 2009; van Besien et al., 1998). Moreover, multivariate analyses have suggested that LDH greater than 3x upper limit of normal (ULN) is strongly associated with increased risk of death or progression among patients with aggressive NHL (Zhou et al., 2014). Despite little evidence on its true efficacy, prophylaxis (ppx) intrathecal (IT) chemotherapy, most frequently with methotrexate (MTX), is often used to among pts thought to be at high risk for CNS relapse. Data on efficacy or need for CNS prophylaxis in patients receiving infusional therapy with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (R-EPOCH) is not available. As R-EPOCH, is being increasingly used in pts with lymphoma, we sought to evaluate the role of IT chemotherapy when used with this regimen.Methods: We conducted a retrospective chart review analysis of patients with diffuse large B-cell lymphoma (DLBCL) who received R-EPOCH as frontline therapy, between 2005 and 2014. Use of IT ppx was at the discretion of the treating physician. We excluded patients under the age of 18, those receiving fewer than two cycles of R-EPOCH, those with CNS involvement at time of diagnosis, and those who received high-dose intravenous CNS ppx. Two-tailed Fisher's exact test was used to determine whether any of the following baseline features was associated with risk of CNS relapse: age>60, ECOG PS>1, LDH>normal and/or >3x ULN, presence of B symptoms, two or more EN sites, anatomic location of EN sites, international prognostic index (IPI) score > 1, bone marrow involvement, and HIV infection. In order to determine whether IT ppx was associated with any improvement in CNS and/or systemic control of disease, we compared, using Kaplan-Meier survival curves with log-rank analyses, the patterns of overall survival (OS), progression-free survival (PFS), and freedom from CNS progression (FFCP, in which death is not counted as an event) between patients receiving IT ppx and those not receiving it.Results: We identified 117 patients for analysis. Median age was 53 (range 19-80). 26% had ECOG PS>1; 76% had LDH above upper limit of normal (ULN). 38% had two or more EN sites of disease, and 68% had stage III-IV disease. 62 patients received IT ppx, and 55 did not. Of those receiving IT ppx, 95% received MTX, with the remainder receiving cytarabine. Those receiving IT ppx were more likely to have >1 EN site of disease, and IPI score >1 (Table 1). A total of seven had observed CNS relapse, occurring at a median of 6 months from time of NHL diagnosis (range 2-24 months). At a median follow up of 18 months, the 24-month PFS and OS were 80% and 83%, respectively. Median PFS and OS were not reached. The only factors associated with increased risk of CNS relapse were genitourinary EN disease and LDH >3x ULN (Table 2). There were no significant differences in OS, PFS, or FFCP among patients who did and did not receive CNS prophylaxis (Figure 1, panels A-C).Conclusions: The risk of CNS progression among DLBCL patients receiving R-EPOCH was similar to previous reports with R-CHOP, at 6%. GU location of EN disease and LDH >3xULN were associated with increased risk of CNS relapse. IT ppx was not associated with improved outcomes. Despite the common use of IT PPX in pts treated with R-EPOCH, our data suggest that this practice might not impact CNS progression and/or relapse, though randomized studies would be needed to answer this. Such studies are warranted in order to better determine what factors are associated with CNS progression, and whom, if anyone, may benefit from IT ppx. [Display omitted] [Display omitted] DisclosuresNabhan:Celgene Corporation: Honoraria, Research Funding. Petrich:Seattle Genetics: Consultancy, Honoraria, Research Funding.

Central nervous system prophylaxis with intrathecal liposomal cytarabine in diffuse large B‑cell lymphomas

Central nervous system (CNS) involvement is a serious and potentially fatal complication in patients with lymphoma because it is associated with a particularly poor prognosis (median progression‑free survival [PFS] of 4-6 months). Although CNS prophylaxis is considered necessary, there are no clear guidelines on identifying high‑risk patients or selecting treatment regimen. The aim of the study was to assess the safety and efficacy of CNS prophylaxis with intrathecal liposomal cytarabine. We analyzed the data of 79 patients (46 men and 33 women; median age, 48.5 years [20-79]) with diffuse large B‑cell lymphoma (83.5% of the patients) and primary mediastinal large B‑cell lymphoma (16.5%). Patients were treated in the departments of hematology in Kraków and Wrocław, Poland, between the years 2009-2012. They were considered to be at a high risk of developing CNS involvement associated with a lymphoma. Adverse reactions after intrathecal liposomal cytarabine were reported in 59 patients (74.7%); in 7 cases, the reactions were severe. The most common side effect was headache (67.1%). During antilymphoma therapy and prophylaxis, the functional status assessed by the Karnofsky score improved in 56 patients (70.9%) and remained unchanged in the remaining cases. A median follow‑up time did not exceed 28 months (range, 1.4-52.1); during follow‑up, neither median overall survival (OS) nor PFS were reached (projected OS and PFS at 48 months are 86.1% and 90.1%, respectively). Our results encourage the use of intrathecal liposomal cytarabine in CNS prophylaxis in patients with lymphoma.

XVI. CNS prophylaxis in aggressive lymphomas: for whom and how

Dissemination in the central nervous system (CNS) in patients with aggressive lymphoma is a relatively rare but a frequently deadly complication that occurs between 5 (diffuse large B-cell lymphoma, DLBCL) and 30% (Burk itt lymphoma, BL and B-cell lymphoblastic lymphoma, B-LL) 1 in different subtypes of non-Hodgkin lymphoma (NHL). However, although a CNS prophylaxis is normally included into treatment regimens for BL and B-LL, in other NHL a prophylactic treatment is not systematically warranted because it may increase the toxicity of systemic chemotherapy. Central nervous system relapse occurs in about 5% of DLBCL patients. Median time from diagnosis to detection of CNS disease is less than 1 year, suggesting that seeding of the CNS occurs early in the course of the disease. The outcome of patients with CNS relapse is poor, with median survival times of 2–5 months 2, 3. Prophylactic treatment likely reduces the incidence of CNS relapse but may increase the toxicity of systemic chemotherapy, and the incidence of CNS dissemination is not high enough to suggest the use of prophylaxis treatment in all patients affected by DLBCL. In addition, the best strategy to prevent CNS dissemination remains to be defined, and most of commonly used strategies are inadequate to prevent intraparenchymal and/or meningeal relapses. The major issue remains to identify the patients at high risk of CNS relapse. Central nervous system dissemination is more common in DLBCL patients with high international prognostic index score (IPI), which increased lactate dehydrogenase serum level and the involvement of more than one extranodal site. Moreover, DLBCL arising in some extranodal organs, such as the testis, paranasal sinuses, the hard palate, the orbit, paravertebral masses, and the bone marrow seems to have a high risk of CNS relapse 4. A retrospective review of nearly 800 patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone) suggested that initial implication of bone marrow in DLBCL raises the likelihood of CNS relapse 5. A large retrospective series of primary lymphoma of the testis (373 patients) conducted by the International Extranodal Lymphoma Study Group, reported 5-year and 10-year risks of CNS relapse of 20 and 35%, respectively 6. More recently, in a multicenter phase II prospective study (International Extranodal Lymphoma Study Group 10, IELSG-10) 7 addressing the role of R-CHOP21 plus CNS prophylaxis with intrathecal methotrexate (IT-MTX), 12 mg total dose, weekly for four times, during the first two R-CHOP21 courses plus irradiation to the contralateral testis at 25 to 30 Gy, Vitolo et al. showed a cumulative incidence of CNS relapse at 5 years only about 6%. However, in the absence of a comparison group without CNS prophylaxis, authors cannot ascribe these results to the introduction of CNS prophylaxis only. The addition of rituximab (R) to CHOP chemotherapy has been shown to improve the clinical outcomes of DLBCL. A cohort of 399 elderly patients treated with CHOP with or without systemic rituximab was analyzed in a French study showing that age-adjusted IPI of at least 2 was the only independent predictive factor of CNS recurrence 8. In a German study, the estimated 2-year incidence of CNS disease was 6.9% (CI 4.5; 9.3) after CHOP-14 and 4.1% (CI 2.3; 5.9) after R-CHOP-14. R-CHOP was able to reduce the relative risk for CNS disease to 0.58 (95% CI 0.3; 1.0, p = 0.046) 9. More recently, Guirguis et al. showed that addition of rituximab to CHOP may decrease the incidence of CNS relapse in patients with DLBCL compared with historical data. Relapses appear to be more parenchymal and occur after one year from diagnosis with median time to CNS relapse of 17 months (6–35 months) and most of them were isolated CNS events. However, the outcomes following CNS relapse remain poor. This may again reflect the superior effect of rituximab in controlling systemic disease. Authors suggested that R-CHOP may overcome the need for CNS prophylaxis in patients with DLBCL, with the exception of testicular lymphoma 10. A small subset of patients with DLBCL harbouring MYC gene rearrangements or a combination of MYC and BCL-2 translocations was associated with CNS involvement of about a rate of 30% 11. The diagnosis of CNS dissemination is frequently suspected on the presence of related signs or symptoms, and it is confirmed by standard conventional cytology (CC) examination of cerebrospinal fluid (CSF) and neuroimaging techniques. Recent studies demonstrated that flow cytometry (FCM) assessment of CSF is more sensitive than CC to detect occult leptomeningeal disease in patients with aggressive lymphoma at risk of CNS dissemination. FCM-positive CSF is an adverse prognostic value on survival and is associated with a significantly high risk of CNS progression 12. Data concerning the risk of CNS involvement in patients with mantle cell lymphoma (MCL) are controversial and based mainly on the results of small retrospective single-centre case series. Although it is very rare at diagnosis, at the time of relapse the incidence of CNS involvement in MCL patients is 4–22%. In two retrospective studies, the median time of CNS relapse from diagnosis was 12–51 months, and the median survival from the time of CNS involvement was 2–9 months. Although CNS relapse in MCL has not been investigated extensively, its frequency appears to be higher than that observed in indolent lymphoma subtypes and may vary widely from 4 to 26% in different case series, being comparable with that of DLBCL. CNS relapse is often a feature of relapsed/refractory MCL and is mainly associated with systemic relapse. 13 In a recent trial, Conconi et al. analyzed 142 MCL patients: disease relapse at the CNS was observed in 11 of 142 patients (7.8%; 95% CI, 3.9–13.4%). CNS involvement occurred after a median of 13.8 months (range: 3.7–95 months). The cumulative risk of CNS relapse steadily increased until 10 years: 7.2% (95% CI, 3.6–13.9%) at 2 years, 10.6% (95% CI, 5.6–19.4%) at 5 years and 13.6% (95% CI, 7–25%) at 10 years. CNS relapse had a dismal impact on outcome: median survival after CNS relapse was 6.3 months (range: 1.5–78 months). Blastoid variant, high Mantle Cell Lymphoma International Prognostic Index score, high ki67 and high LDH serum level are predictors of CNS involvement.14 Among several clinical variables at diagnosis, only blastoid variant, high Mantle Cell Lymphoma International Prognostic Index score, high ki67 and high LDH serum level are predictors of CNS. Results were similar also when limiting the analysis to the risk of CNS involvement at first relapse: blastoid variant and elevated serum LDH levels retained their prognostic impact. It is controversial whether prophylaxis can really prevent CNS relapse. According to European Mantle Cell Lymphoma Network recommendations 15, pre-treatment work-up in patients with MCL does not include routine assessment of the CSF. Intrathecal chemotherapy (usually including methotrexate, cytarabine and steroids) has been largely used in high-risk patients as a strategy for CNS prophylaxis 4, but recently, the RICOVER-60 trial showed that IT-MTX failed to reduce the risk of CNS relapse progression in a series of elderly patients with DLBCL treated with R-CHOP14 9. Following the large experience in acute lymphoblastic leukaemia and Burkitt lymphoma, another therapeutic option regards the use of drugs with good CNS bioavailability when administered at high doses, like cytarabine, methotrexate and ifosfamide. The GELA randomized trial, which compared CHOP without rituximab to a combination containing high doses of methotrexate and ifosfamide plus IT-MTX delivery (ACVBP regimen), has demonstrated that ACVBP has been associated with a significantly lower CNS relapse rate (8.3% for CHOP vs 2.7% for ACVBP; p = 0.002). These results prompted the French group to treat with these prophylaxis patients with DLBCL except those with an age-adjusted IPI equal to 0 who do not currently receive IT-MTX, also in rituximab era. In a recent study, the Nordic Lymphoma Group treated 156 high-risk DLBCL patients with six courses of R-CHOEP-14 (R-CHOP plus etoposide) followed by a course of high-dose cytarabine and a course of high-dose methotrexate. Authors observed a 3-year FFS of 65%, an OS of 81% and a CNS relapse rate of 4.5%. In the International Extranodal Lymphoma Study Group 10 study 7, addressing the role of R-CHOP21 plus CNS prophylaxis with IT-MTX plus irradiation to the contralateral testis in patients with primary testicular lymphoma, the 5-year overall outcome was good with a PFS and OS of 74 and 85% and the 5-year cumulative incidence of CNS relapse was reduced but still present at 6%. To further reduce of CNS relapse, the new International Extranodal Lymphoma Study Group 30 study intensified CNS prophylaxis with the addition of an intermediate dose of MTX at the end of R-CHOP and substitution of liposomal cytarabine for IT-MTX. The aggressive clinical course observed in most cases has led to the design of intensive treatment protocols, including high-dose chemotherapy followed by autologous stem cell transplant. It is controversial whether prophylaxis can really prevent CNS relapse. In a series of MCL patients, the incidence of CNS infiltration observed in patients receiving high dose MTX-containing regimens was the same as that detected in the remaining patients. Because of the lack of comparative data, it is even more difficult to evaluate the CNS-prophylactic effect of HD-Ara-C and high dose MTX-containing regimens given to young and fit MCL patients, as in the HyperCVAD/MA regimen. Despite the relatively low frequency of CNS relapse in aggressive lymphoma, the devastating effects of this condition and the potential toxicity of CNS-directed therapy justify efforts to better define the target population and to optimize CNS prophylaxis. Risk models developed so far showed a low sensitivity in predicting CNS involvement implying a potential overtreatment in up to 70% of patients deemed at high risk. New updated risk models in rituximab treated patients should be implemented along with a better identification of patients at risk who really should receive CNS prophylaxis can be focused on detection of occult CNS disease at diagnosis by using more sensitive methods for CSF evaluation such as FCM 12. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established, thus far and should be modulated among different level of ‘intensity’ such as standard intrathecal chemotherapy, ‘active’ intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs with a good CNS bioavailability reserved to patients at true high risk of CNS dissemination. Umberto Vitolo is a member of a Roche global advisory board. Giulia Benevolo and Annalisa Chiappella have no conflicts of interest to declare.

Central nervous system event in patients with diffuse large B‐cell lymphoma in the rituximab era

Central nervous system (CNS) events, including CNS relapse and progression to CNS, are known to be serious complications in the clinical course of patients with lymphoma. This study aimed to evaluate the risk of CNS events in patients with diffuse large B-cell lymphoma in the rituximab era. We performed a retrospective survey of Japanese patients diagnosed with diffuse large B-cell lymphoma who underwent primary therapy with R-CHOP chemoimmunotherapy between September 2003 and December 2006. Patients who had received any prophylactic CNS treatment were excluded. Clinical data from 1221 patients were collected from 47 institutions. The median age of patients was 64 years (range, 15-91 years). We noted 82 CNS events (6.7%) and the cumulative 5-year probability of CNS events was 8.4%. Patients with a CNS event demonstrated significantly worse overall survival (P < 0.001). The 2-year overall survival rate after a CNS event was 27.1%. In a multivariate analysis, involvement of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were identified as independent risk factors for CNS events. We conclude that patients with these risk factors, in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events in the rituximab era. The efficacy and manner of CNS prophylaxis in patients for each involvement site should be evaluated further.

Central Nervous System (CNS) Prophylaxis Does Not Decrease the Rates of CNS Relapse From Diffuse Large B-Cell Lymphoma In the Era of R-CHOP

AbstractAbstract 4161 Background:While some clinical characteristics/sites of diffuse large B-cell lymphoma (DLBCL) are associated with increased rates of central nervous system (CNS) relapse, the role/benefits of CNS prophylaxis are controversial, particularly in the era of better disease control with R-CHOP chemotherapy. We evaluated the benefits of high dose methotrexate (HDMTX 3 g/m2) and intrathecal (IT) chemotherapy (MTX 12 mg) as primary CNS prophylaxis (CNSPr) in patients with DLBCL (de novo or transformed) treated with curative intent R-CHOP chemotherapy between the years of January 2002-December 2008. During this period, we adopted a local ‘informal’ clinical practice recommendation for CNS prophylaxis for patients with testicular involvement, increased lactate dehydrogenase enzyme (LDH) and greater than 1 extranodal (EN) site, epidural disease, invasive sinus or skull involvement. Compliance with and efficacy of this treatment recommendation was the catalyst for this retrospective audit. Methods:Using the cancer pharmacy database, we retrospectively identified 214 patients who received 1–8 cycles of R-CHOP chemotherapy (median 6) for DLBCL. Patients with transformed histologies were included if they had not yet received R-CHOP chemotherapy. Patients with HIV or CNS involvement at diagnosis were excluded. Results:The median age was 64 with 54% male patients. 71% had stage III-IV disease, 49% had an elevated LDH, 57% EN disease (35% >1 EN site), 49% had high or high-intermediate international prognostic index scores (IPI), 14% had transformed disease, 8 patients had testicular lymphoma, 11% had increased LDH + > 1 EN site. 27 patients (12.6%) received some form of CNS prophylaxis (37% IT MTX alone (median 1.5 times (1-3)); 7% with HDMTX 3g/m2 alone (median 1.5 times (1-3)) and 56% with both HDMTX and IT chemotherapy (median 2 HDMTX (1-6) and 3 IT chemotherapy (1-9)). Compared with patients that did not receive CNSPr, patients that did had higher stage disease (p=.0061), more EN disease (P <0.0001), more testicular involvement (p<0.0001), higher IPI (p=.029), age adjusted IPI (aaIPI) (p=.048) and revised international prognostic index (R-IPI) (p=.016). Of those deemed to be at higher risk of CNS relapse defined by high IPI (20%; Haioun et al. 2000), high-intermediate and high aaIPI (52%; Feugier et al. 2004), or increased LDH and > 1 EN site (11%; Van Besien et al. 1998), 23%, 18% and 29% received CNSPr respectively, demonstrating imperfect compliance with local practice guidelines. 75% of patients with testicular lymphoma received CNSPr, 83% inclusive of both HDMTX (median 2) and IT chemotherapy (median 3). Eight patients (3.7% of all patients) relapsed in the CNS at a median time of 17 months (6-35 months range). Five patients developed parenchymal CNS relapse, 2 had leptomeningeal disease and 1 had both parenchymal and leptomeningeal involvement. The relapse rates in those that received or did not receive prophylaxis were 7.4% (2/27) and 3.2% (6/187) respectively. Six out of the 8 relapses were isolated relapses in the CNS and 4/8 were in testicular lymphoma patients. If the 8 testicular lymphoma patients were excluded, the overall rate of CNS relapse was 1.9% (0% in the 21 with prophylaxis and 2% in the 185 that did not). 62% (5/8) of those with CNS relapse have died with a median survival post CNS relapse of 2 months (range 0.5–16). Of the 4/8 patients with testicular involvement that relapsed, 3 had received CNS prophylaxis with HDMTX and IT chemotherapy (median 2 (range 1–5)). By multivariate analysis, testicular involvement was the only negative risk factor for CNS relapse (HR 33.5, p<.0001 (95% CI 8.3–135). Conclusion:R-CHOP chemotherapy may negate the need for CNS prophylaxis in patients with DLBCL, even those formerly identified as higher risk using standard prognostic scoring systems with the exception of testicular lymphoma. Better forms of CNS prophylaxis are needed in these patients. CNS relapses appear to occur later as isolated parenchymal events compared with the pre rituximab era, but survival post CNS relapse remains short. Disclosures:No relevant conflicts of interest to declare.

Incidence, Method and Covariates of Central Nervous System (CNS) Prophylaxis for Diffuse Large B-Cell Lymphoma In the National Comprehensive Cancer Network (NCCN) Lymphoma Database

AbstractAbstract 1756 Background:The optimal criteria to determine which patients with diffuse large B-cell lymphoma (DLBCL) should receive central nervous system (CNS) prophylaxis remain controversial. We aimed to characterize patterns of CNS prophylaxis administration in patients with DLBCL in a large multi-institutional database. Methods:The National Comprehensive Cancer Network (NCCN) Non-Hodgkin's Lymphoma Outcomes Database is a prospective cohort study collecting clinical, treatment, and outcomes data for patients at seven participating NCCN centers. Patients who presented between January 1, 2001 and July 1, 2008 with newly-diagnosed DLBCL, without CNS disease at baseline, and who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) within 180 days of diagnosis were eligible for this analysis. We assessed clinical and sociodemographic covariates of receipt of CNS prophylaxis and type of prophylaxis received (either ≥2 doses of intrathecal methotrexate and/or cytarabine or ≥1 dose of systemic methotrexate). Extrapolating from prior studies (e.g., Boehme et al, Ann Oncol, 2007), we defined high-risk features as >1 extranodal site involvement, elevated lactate dehydrogenase (LDH), bone marrow involvement, or other high-risk site involvement (orbit, testis, peripheral blood, bone/vertebrae, nasal/paranasal sinuses), and assessed rates of CNS prophylaxis in patients with ≥1 high-risk feature. We also determined rates of CNS recurrence for patients with ≥ 2 high-risk features who received prophylaxis versus those who did not. Results:Of a total of 989 patients with DLBCL (mean age 56; 44.4 % female; 70.2% with low or low-intermediate international prognostic index (IPI) score), 117 received CNS prophylaxis (11.8% [95% Confidence Interval (CI) 9.8%-13.8%]). Considered individually, patients with bone marrow involvement, other high-risk site involvement, >1 extranodal site involvement, high versus low IPI score, and advanced stage (III or IV) were significantly more likely to receive CNS prophylaxis (all p<0.0001); those with elevated LDH or presence of B-symptoms were not. In addition, age, gender, race/ethnicity, performance status, and cancer center were not associated with CNS prophylaxis receipt. Rates of CNS prophylaxis, in descending order of frequency, are shown below for significant clinical factors:Individual Clinical Factor+ CNS prophylaxisOther high-risk site involvement36.0%Bone marrow involvement28.2%>1 Extranodal site involvement23.1%High IPI18.6%Stage III/IV15.8%Of those who received CNS prophylaxis, 71.8% received intrathecal therapy and 28.2% received systemic therapy. There were significant center-specific differences regarding type of CNS prophylaxis used (p<0.0001). In addition, other high-risk site involvement was associated with use of systemic versus intrathecal prophylaxis (p=0.04), while higher mean age was associated with the reverse (p=0.05). Patients with increasing number of the four specific high-risk features (>1 extranodal site involvement, elevated LDH, bone marrow involvement, or other high-risk site involvement) were increasingly likely to receive CNS prophylaxis (0 features: 4.3%; 1 feature: 8.1%; 2 features: 20.1%; 3 features: 31.0%; 4 features: 61.1%; p<0.0001). Of all patients with ≥1 high-risk feature (n= 617), 16.4% received CNS prophylaxis. With median follow-up of 2.5 years, there were 20 CNS recurrences (2.0% [95% CI 1.1%-2.9%]). For those with ≥2 high-risk features (n=284), rates of CNS relapse were not significantly different in those who did and did not receive prophylaxis. Conclusion:In our cohort, several classic clinical high-risk variables were associated with receipt of CNS prophylaxis. The modality of prophylaxis used, whether intrathecal or systemic, appeared predominantly mediated by site-specific clinician preference rather than clinical or sociodemographic factors. While an increasing number of widely-accepted high-risk features was associated with higher rates of CNS prophylaxis, surprisingly, a minority of patients with high-risk features received CNS prophylaxis. In conclusion, we found no standard of care for administration of CNS prophylaxis in DLBCL; moreover, as the rate of CNS recurrence was low, our data suggest the need for further evaluation of the efficacy of CNS prophylaxis in the R-CHOP era. Disclosures:No relevant conflicts of interest to declare.

Central nervous system prophylaxis in adults with acute lymphoblastic leukemia: current and emerging therapies.

Central nervous system (CNS) recurrence continues to be a significant complication in the treatment of adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence has been a therapeutic challenge and has not been addressed critically in many clinical trials. Adult studies modeled on childhood ALL studies have used multiple treatment modalities, including radiation therapy, systemic therapy, intrathecal therapy, and combinations thereof. Cranial irradiation is effective but is offset by substantial toxicity, including neurologic sequelae. Systemic chemotherapy, especially with cytarabine (AraC) and methotrexate, has demonstrated promise in decreasing CNS recurrence, but therapeutic levels of drugs in the cerebrospinal fluid (CSF) are not maintained. Intrathecal chemotherapy with or without high-dose systemic therapy is the most common approach to CNS prophylaxis. Liposomal AraC recently has become available and confers prolonged levels of free AraC in the CSF, a critical requirement for CNS prophylactic therapy. This review discusses the various modalities used for CNS prophylaxis in patients with ALL and the emerging trends, with specific emphasis on the outcome in terms of event-free survival and toxicity.

Rituximab Based Regimen May Decrease the Incidence of CNS Relapse in Patients with Diffuse Large B-Cell Lymphoma.

Abstract 4770 BACKGROUNDRelapse in the central nervous system (CNS) following initial treatment of diffuse large B-cell lymphoma (DLBCL) is an uncommon but fatal complication. However, the addition of rituximab improves the clinical outcome dramatically in DLBCL patients; its influence on CNS relapse is unproven. AimThis single centre retrospective study was conducted to investigate the incidence of CNS relapse, and to evaluate the impact of adding rituximab to standard CHOP (RCHOP) regimen without CNS prophylaxis in patients at risk of CNS relapse. PATIENTS AND METHODSAll patients with DLBCL diagnosed from April 2002 to December 2007 at sunnybrook cancer center were retrospectively identified in the Cancer Database. Patients were included if they were >16 years old, had advanced stage (stage III /IV, or stage I /II with B symptoms, elevated LDH or bulky disease, were treated with RCHOP regimen with curative intent and were free of CNS involvement at diagnosis. CNS relapse was diagnosed by CSF cytology, radiology or clinically. ResultsA total of 155 patients were newly diagnosed with DLBCL and treated with RCHOP only. 22 pts were excluded, 20 had CNS prophylaxis and 2 pts had CNS involvement. 133 pts were eligible (69 male and 64 female) Median age was 64 (Age'60 was 59.4%). Stage III/IV was 69.9%. LDH was elevated in 59.4%. Bone marrow (BM) involvement and Extra nodal “>2 were 18.05% and 25.6% respectively. EN sites were: (liver 4.5%, Bone 6.8%, Pulmonary 4.5%, kidney 3.01%, cardiac 1.5%, intestine 2.3%, testicular 1.5%). The International Prognostic Index was high-intermediate/high in 55.6%. Pathologically transformed was 12.03% and were transformed from indolent histologies. BCL2 was positive in 65.4%, BCL6 was 48.9%, CD10 was positive in 49.6%, Ki-67 was >80% in 25%. All patients received RCHOP (Median 6 cycles, (range 2-8). Overall response (ORR) was 88.6%, CR/CRU 72.7% with a median follow up 24.6 months (range 2.6-75.5). 28 patients (21.05%) relapsed systemically. Two patients (1.5%) had a CNS relapse 1 brain parenchyma and 1 leptomeningeal one month after systemic relapse. The median time to CNS relapse was 10.4 mos (6.24-14.5 mos). In univariate risk factor analysis (LDH (p=0.8), IPI>3 (p=0.9), No of EN (p=0.9). Actuarial 5 y Overall Survival (OS) was 67.3% (95% CI (57-77%) and progression free Survival (PFS) was 65.7% (95% CI (52.3-78.6%). ConclusionOur data suggest that the addition of rituximab may reduce the risk of CNS relapse for poor risk patients likely through systemic control. Future prospective studies of rituximab-containing chemotherapies with CNS prophylaxis are warranted Disclosures:No relevant conflicts of interest to declare.

Should Intra-cerebrospinal Fluid Prophylaxis Be Part of Initial Therapy for Patients With Non-Hodgkin Lymphoma: What We Know, and How We Can Find Out More

Central nervous system (CNS) involvement is a serious complication of non-Hodgkin lymphoma (NHL), with an extremely poor outcome. In most cases, relapse in the CNS manifests as leptomeningeal disease. The relatively short interval between the initial diagnosis of NHL and CNS involvement implies that seeding of the cerebrospinal fluid occurs early in the natural history of the disease and suggests a role for CNS prophylaxis during initial treatment. However, CNS prophylaxis in patients with aggressive NHL remains controversial because of the relatively low incidence of CNS recurrence (5%-7%) in these patients and lack of consensus on the best therapies and protocols. Risk factors for CNS relapse in patients with aggressive NHL have been identified and may help define a subpopulation of patients for whom CNS prophylaxis is justified. Because of variation in current practice and a paucity of high-quality evidence, well-designed and controlled trials are needed to assess the benefits of prophylactic treatment in such a population. This article reviews the current role of CNS prophylaxis in patients with NHL and discusses issues in the conception, design, and execution of a clinical trial to elucidate the role of CNS prophylaxis in patients with aggressive NHL.

CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)

AbstractOne thousand two hundred twenty-two patients treated in the Rituximab with CHOP over age 60 years (RICOVER-60) trial were examined for central nervous system (CNS) disease developing during first-line therapy or after a complete or partial remission had been achieved. Patients received 6 or 8 courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) administered every 2 weeks (CHOP-14) with or without rituximab. CNS prophylaxis for patients with involvement of bone marrow, testes, upper neck, or head consisted of intrathecal (i.th.) methotrexate (days 1 and 5 of first 2 courses). Fifty-eight cases of lymphoma in the CNS were observed (36/609 patients in the CHOP-14 and 22/608 patients in the arituximab–CHOP-14 [R-CHOP–14] arm). The estimated 2-year incidence of CNS disease was 6.9% (confidence interval [CI] 4.5; 9.3) after CHOP-14 and 4.1% (CI 2.3; 5.9) after R-CHOP–14. R-CHOP reduced the relative risk for CNS disease to 0.58 (95% CI 0.3; 1.0, P = .046). Cox regression analysis identified “involvement of more than 1 extranodal site” and “B-symptoms” as significant risk factors for CNS disease. Patients treated with R-CHOP–14 did not show any benefit from i.th. methotrexate. We conclude that elderly patients with aggressive CD20-positive lymphoma show a significantly lower incidence of CNS disease if treated with R-CHOP–14 instead of CHOP-14. Intrathecal methotrexate has no role in preventing CNS disease for patients treated with combined immunochemotherapy (R-CHOP–14)—with the possible exception of patients with testicular involvement. The original clinical trials are registered on www.clinicaltrials.gov as NCT000052936.

Central Nervous System (CNS) Relapse in Extranodal NK/T Cell Lymphoma, Nasal Type: When Do We Need CNS Prophylaxis in Patients with Extranodal NK/T Cell Lymphoma?

Purpose: Extranodal natural killer (NK)/T cell lymphoma, nasal type frequently involves paranasal sinuses. Although involvement of the paranasal sinuses has been regarded as a possible risk factor for central nervous system (CNS) relapse, its incidence was variable from 0% to 6% in extranodal NK/T cell lymphoma. Thus, an exact incidence of CNS relapse and a definitive role of CNS prophylaxis are still controversial in extranodal NK/T cell lymphoma, nasal type. Therefore, we performed this study to assess the incidence of CNS relapse and identify risk factors that predict CNS relapse to establish guidelines for CNS prophylaxis in patients with extranodal NK/T cell lymphoma.Patients and methods: We analyzed 208 patients with extranodal NK/T cell lymphoma, nasal type from June 1995 to March 2008. CNS relapse was defined as a brain parenchyma lesion or leptomeningeal relapse during the follow-up after a complete response (CR) or CNS involvement during the first-line therapy or salvage chemotherapy. For subgroup analysis, we used the international prognostic index (IPI), and NK/T cell prognostic index (NKPI), proposed previously for extranodal NK/T cell lymphoma, which includes the presence of B symptoms, stage III or IV, elevated serum LDH concentration, and lymph node involvement. We designated group III/IV patients (those in group III with 2 risk factors and those in group IV with 3 or 4 risk factors) as a high risk group. Second, we dichotomized patients into two groups based on the primary site of involvement. Upper aerodigestive tract NK/T cell lymphoma (UNKTL) included all lymphomas confined to the nasal cavity, nasopharynx, and upper aerodigestive tract including the oral cavity, larynx, and pharynx. NK/T cell lymphomas involving all other sites were defined as extra-upper aerodigestive tract NK/T cell lymphoma (EUNKTL).Results: Of the 208 patients, 12 (5.76%) patients experienced CNS relapse (median 11.62 months, range 0.2–123.2 months). The median time to CNS relapse was 6.03 months (95% confidence interval: 5.23–6.83 months). Eight patients showed CNS relapse during or immediately after the completion of the first-line treatment while four patients showed CNS relapse combined with systemic relapse. The pattern of CNS relapse was balanced: 6 had lesions of brain parenchyma and 6 leptomeningeal relapse. The prognosis after CNS relapse was poor even though some patients showed complete resolution of the CNS lesion because systemic disease progression followed in most patients. Four responders to CNS-directed therapy showed disease progression, and one responder was lost during follow-up. Even though all patients received CNS-directed therapy including intrathecal chemotherapy or whole-brain radiotherapy combined with systemic chemotherapy, most patients died within 6 months after CNS relapse because of disease progression. Age, sex, Eastern Cooperative Oncology Group (ECOG) performance, the presence of B symptoms, serum LDH concentration, bone marrow invasion, the primary site of involvement, and IPI risk were balanced between patients with and without CNS relapse (p > 0.05). The clinical variables associated with CNS relapse were as follows: Ann Arbor stage III or IV (15.87%, P < 0.001), presence of regional lymph node involvement (10.41%, P = 0.006), group III/IV of NKPI (NK/T cell lymphoma prognostic index, 10.20%, P = 0.003), and extra-upper aero-digestive primary sites (9.75%, P = 0.008). In multivariate analysis, NKPI retained the strongest statistical power to predict CNS relapse (p = 0.007, relative risk 9.289, 95% confidence interval: 1.828–47.212) in extranodal NK/T cell lymphoma, nasal type. Thus, the risk of CNS relapse might be higher in patients with group III/IV of NKPI than group I/II of NKPI.Conclusion: Despite NK/T cell lymphoma frequently involves paranasal sinus, a routine CNS evaluation and prophylaxis do not seem to be necessary in NKPI group I or II patients due to a very low incidence. However, CNS prophylaxis should be considered in NKPI groups III and IV.

Prophylactic intrathecal methotrexate and hydrocortisone reduces central nervous system recurrence and improves survival in aggressive non-hodgkin lymphoma.

Central nervous system (CNS) recurrence is almost invariably fatal in patients with aggressive non-Hodgkin lymphoma (NHL). Although some protocols are intended to prevent CNS disease, the value of CNS prophylaxis in patients with aggressive NHL remains to be determined. We retrospectively analyzed a cohort of 68 adults with NHL who had been treated uniformly with systemic chemotherapy and had attained complete remission (CR) of disease. Patients ranged in age from 15 to 77 years (median, 56 years). Median follow-up after CR was 40 months. After CR was attained, 29 patients (Group A) received CNS prophylaxis consisting of four doses of intrathecal methotrexate 10 mg/m(2) and hydrocortisone 15 mg/m(2) as soon as they could tolerate it. The other 39 patients (Group B) did not receive CNS prophylaxis. Although bulky mass (45% vs. 21%, P = 0.03) was more frequent in Group A than in Group B, none of the patients in Group A experienced CNS recurrence (0%), whereas CNS recurrence occurred in six patients in Group B (15%). This difference was significant (P = 0.03). Multivariate logistic regression analysis for CNS recurrence identified no CNS prophylaxis (P = 0.01) and bone marrow involvement (P = 0.02) as independent predictors. Among patients without CNS disease, systemic recurrence occurred in 5 patients in Group A and in 11 patients in Group B (P = 0.12). The 5-year overall survival rate from CR was 80% in Group A and 58% in Group B (P = 0.05). The 5-year recurrence-free survival rate from CR was 85% in Group A and 51% in Group B (P = 0.01). Prophylactic intrathecal methotrexate and hydrocortisone injection reduces the incidence of CNS recurrence following CR in patients with aggressive NHL and improves the chance of long-term survival.

Central nervous system relapse in non-Hodgkin lymphoma. A single-center study of 532 patients.

To define the cumulative risk of central nervous system (CNS) relapse in systemic non-Hodgkin lymphoma (NHL); to assess the risk factors of age, sex, malignancy grade, stage, localization, and response to initial therapy; and to evaluate the effect of CNS prophylaxis. An unselected group of 532 patients with systemic NHL. A retrospective analysis. Eleven patients presented with systemic as well as CNS localization, whereas in 55 patients, CNS relapse occurred later. The cumulative risk of CNS relapse at 4 years for all 532 patients was 19%. High-grade NHL carried a 39% risk of CNS relapse, with the vast majority of relapses occurring in the first 14 months after the initial diagnosis. The cumulative risk in patients with intermediate-grade NHL was considerable (22%) and dispersed throughout a much longer period (6 years). Patients with low-grade NHL still carried a 7% risk of CNS relapse; in all these patients, low malignancy grade was transformed into a higher malignancy grade at that time. In a multivariate analysis, high- and intermediate-grade NHL and advanced stage were independent risk factors for CNS relapse. There was not any strong evidence for a beneficial role of CNS prophylaxis in patients with intermediate- and high-grade NHL, but a retrospective analysis cannot be conclusive with regard to the effect of therapy. Systemic relapse occurred rapidly after CNS relapse, resulting in a median survival time after CNS relapse of only 2 months. Patients with high- and intermediate-grade NHL carry a considerable risk of CNS relapse. Advanced stage is an additional independent risk factor. The role of CNS prophylaxis seems to be disappointing, but a retrospective analysis cannot be conclusive. Prognosis after CNS relapse is poor.