Central nervous system chemoprophylaxis in non-Hodgkin lymphoma: current practice in the UK

Central nervous system (CNS) involvement in non-Hodgkin lymphoma (NHL) is a well-recognised complication. There is no consensus regarding indications for prophylaxis or a standard CNS chemoprophylaxis regimen. Current UK practice was evaluated using a questionnaire. A total of 223 questionnaires were sent to clinicians who administered chemotherapy to patients with NHL; 158 (71%) evaluable questionnaires were returned. The overwhelming majority of respondents used prophylaxis in all cases of lymphoblastic lymphoma (97%) and Burkitt lymphoma (96%). Ninety-six per cent of respondents required risk factors to be present before prophylaxis was initiated in cases of diffuse large B-cell lymphoma. The commonest risk factor was site of involvement (paranasal sinus 88%, testicular 85%, orbital cavity 78%, bone marrow 65% and bone 28%). Other risk factors included stage IV, high International Prognostic Index score, >1 extranodal site and raised lactate dehydrogenase levels (34%, 21%, 16% and 10%). A total of 82% did not give prophylaxis in follicular lymphoma and 90% used intrathecal chemotherapy as their preferred method of prophylaxis. The most popular regimen was 12.5 mg methotrexate with each cycle of chemotherapy for six courses. Thirty-nine per cent used systemic chemotherapy for CNS prophylaxis either alone (4%) or as an adjunct to intrathecal prophylaxis (35%). These variations in the indications and methods of prophylaxis indicate that this subject deserves further review.     

Central nervous system involvement in diffuse large B‐cell lymphoma

Background: Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse large B‐cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) ‐CHOP chemotherapy. Patients and methods: We studied 375 consecutive patients who were newly diagnosed with DLBCL between 1996 and 2006. Patients with primary CNS involvement and patients who received CNS prophylaxis were excluded. All the patients received CHOP (n = 172) or R‐CHOP (n = 203) chemotherapy. The following variables were assessed for their potential to predict CNS involvement: gender, age, serum lactate dehydrogenase (LDH) level, performance status, clinical stage, number of extranodal involvements, International Prognostic Index (IPI), bone marrow involvement, presence of a bulky mass, presence of B symptom, and treatment. Results: CNS involvement was observed in 13 cases (3.5%). In univariate analysis, LDH more than normal range, LDH more than twice as normal range, high IPI, bone marrow involvement, and systemic relapse were the predictors for CNS involvement. In multivariate analysis, no risk factors were detected for CNS involvement. The use of rituximab did not have an impact on CNS involvement. Conclusions: The incidence of CNS involvement dose not decrease in rituximab‐era.     

Central nervous system relapse in malignant lymphomas: risk factors and implications for prophylaxis

The records of 292 patients with malignant lymphoma other than Hodgkin's disease, registered in our protocols from 1967 to 1977, were reviewed to identify those with central nervous system (CNS) involvement. Thirty-one patients were encountered with this complication, an incidence of 11%. Patients with a diffuse histology had a higher frequency of CNS recurences (27/174 = 16%) in contrast to only 4/118 (3%) for those with nodular types. However, if only patients with diffuse histology in CR are considered, the frequency of CNS relapse is 13.5% (13/98). The risk factors that predict for the development of this complication were studied using multivariate analysis. Diffuse poorly differentiated lymphocytic and diffuse undifferentiated lymphomas were found to be associated with a high risk of CNS relapse. Prior chemotherapy, bone marrow involvement, age less than 35, and extranodal disease were also identified as high-risk factors. Using the information generated by a logistic regression model, patients with malignant lymphoma of diffuse type can be classified into three categories when first seen: low-risk group, intermediate, and high-risk group. CNS prophylaxis is recommended for the intermediate and high-risk group, while only close follow-up is advised for the low-risk group patients who have one adverse characteristic.     

Impact of central nervous system (CNS) prophylaxis on the incidence and risk factors for CNS relapse in patients with diffuse large B-cell lymphoma treated in the rituximab era: a single centre experience and review of the literature

Central nervous system (CNS) prophylaxis for diffuse large B‐cell lymphoma (DLBCL) is controversial with even less evidence in the era of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. We reviewed the impact of CNS prophylaxis in DLBCL patients treated with R‐CHOP at a tertiary care centre over a 7‐year period. CNS prophylaxis was recommended for ‘higher risk’ patients and consisted of intrathecal methotrexate and/or high‐dose methotrexate. Of 214 patients 12·6% received CNS prophylaxis. With a median follow‐up of 27 months, eight patients (3·7%) developed CNS relapse (75% isolated to the CNS and 62·5% as parenchymal brain disease) at a median time of 17 months. Patients who did not receive CNS prophylaxis had lower events (2·7%) than those who did (11·1%). Half of the CNS relapses occurred in testicular lymphoma patients, 75% of whom had received CNS prophylaxis. In multivariate analysis, testicular involvement was the only significant prognostic factor for CNS relapse (hazard ratio 33·5, P < 0·001). In conclusion, CNS relapse in DLBCL appears to present as a later, more isolated parenchymal event and at a lower rate in the rituximab era compared with historical data. R‐CHOP may negate the need for CNS prophylaxis with the exception of testicular lymphoma.     

Central nervous system complications of non-Hodgkin's lymphoma. The potential role for prophylactic therapy.

In 38 patients with non-Hodgkin's lymphoma, involvement of the central nervous system (CNS) by malignant lymphoma developed during an eight year period. All patients had lymphomatous meningitis; clinical involvement of the spinal nerves or cranial nerves suggested the diagnosis. Spinal fluid was abnormal in 97 per cent of the patients although a positive cytology could be documented in only 67 per cent by lumbar puncture. The histology in 82 per cent of the patients was diffuse. Involvement of the CNS in nodular lymphoma was uncommon (3 per cent), and the histology in virtually all of these patients had converted to diffuse. At the time of diagnosis of CNS disease, 95 per cent of the patients had other evidence of advanced disease; 66 per cent had bone marrow involvement. In only 18 per cent of the patients did CNS disease develop while they were in clinical remission. Eighty-five per cent of the patients treated with whole brain irradiation and intrathecal chemotherapy had a good clinical response. Knowledge of these risk factors permits definition of a group of patients who may benefit from CNS prophylaxis.     

CNS prophylaxis in lymphoma: who to target and what therapy to use

The purpose of this article is to review the current data on the risk of CNS relapse in patients with lymphoma and the efficacy of CNS directed prophylactic therapy. CNS relapse occurred in 30-50% of those with Burkitt lymphoma and acute lymphoblastic leukaemia/lymphoma prior to the introduction of intensified regimens that include CNS prophylaxis. Most patients with AIDS-related-lymphoma receive a short course of intrathecal prophylaxis but a re-evaluation of type and targeting of CNS prophylaxis is needed. Patients with diffuse large B-cell lymphoma (DLBCL) have a 5% overall risk of CNS relapse but a high risk sub-population can be identified on the basis of raised LDH and >1 extranodal site, testicular or primary breast involvement. CNS prophylaxis for selected patients with DLBCL may be justified by risk but its benefit is not yet proven. Intravenous methotrexate > or = 3 g/m(2) achieves therapeutic levels in CSF and parenchyma and in combination with intrathecal methotrexate would be a reasonable option for prophylaxis.     

Significance of Haematological Parameters in the Non-Hodgkin''s Malignant Lymphomas

Blood findings at diagnosis, in 140 adults with lymphoma, were correlated with bone marrow involvement and survival. An abnormal haemoglobin, leucocyte count or platelet count was found in 57% of patients. Lymphocytopenia occurred in 46%. All patients with thrombocytopenia or neutropenia, 69% with leucopenia and 63% with anaemia had marrow involvement with lymphoma. Marrow involvement in histiocytic and stem cell lymphoma was always associated with anaemia. Marrow involvement in poorly differentiated lymphocytic lymphoma (PDL) was associated with anaemia, thrombocytopenia, leucopenia, lymphocytopenia or lymphoma cells in the blood in 93% of patients. Bone marrow involvement was found in only 13% of patients with normal haematological parameters. In the absence of marrow involvement blood abnormalities at diagnosis did not generally correlate with survival. However, among patients with diffuse PDL who had marrow involvement, anaemia, thrombocytopenia and leucopenia adversely affected survival. Lymphocytopenia did not correlate with survival.     

Central nervous system complications in patients with diffuse histiocytic and undifferentiated lymphoma: leukemia revisited.

Fifteen of 52 patients (29%) with diffuse histiocytic and undifferentiated pleomorphic lymphoma developed central nervous system (CNS) complications, primarily leptomeningeal lymphoma. Lumbar puncture with cerebrospinal fluid cytology was the most useful test for diagnosis, and for following the response to therapy. Leptomeningitis developed during all stages of the patients' clinical course: at time of diagnosis, during progression of systemic disease, and most importantly as the initial site of relapse within 7 mo of attaining a complete clinical remission. Patients with bone marrow involvement are at high risk for the development of leptomeningeal lymphoma. Pathologic findings suggest that entry into the leptomeninges involves extension from the medullary bone marrow cavity along perforating vessels through dura into the arachnoid space. The leptomeningeal lymphoma has been successfully controlled in all patients receiving intensive central nervous system therapy consisting of a combination of intrathecal drug administration and radiotherapy. The high frequency of this syndrome and the success in its control suggest that a controlled trial of prophylactic CNS therapy be instituted in patients with these histologic types of non-Hodgkin's lymphomas.     

Risk factors for poor treatment outcome and central nervous system relapse in diffuse large B-cell lymphoma with bone marrow involvement

Although several studies have described the prognostic implication of bone marrow (BM) involvement (BMI) in lymphoma, studies focused on BM-involved diffuse large B-cell lymphoma (DLBCL) are very rare and small-sized. This study was performed to examine the prognostic impact of morphologic findings of BMI by lymphoma and risk factors for central nervous system (CNS) relapse in BM-involved DLBCL. Between 1993 and 2005, 675 patients were diagnosed with DLBCL, and 88 patients who had BMI at initial diagnosis were eligible for this study. The median overall survival (OS) and failure-free survival (FFS) of 88 patients were 36.6 and 20.1 months, respectively. When three variables from BM morphologic findings (the pattern of BM infiltration, extent of BMI by lymphoma, and percentage of large cells in the infiltrate) were simultaneously included into multivariate model, the increased extent of BMI by lymphoma (≥10%) in BM area was the only negative prognostic factor, independent of the International Prognostic Index (IPI). Patients with both lower IPI scores and less extent of BMI showed an excellent prognosis with chemotherapy alone (5-year OS and FFS rates, 80% and 69%). However, morphologic BM features were not independent predictive factors for CNS recurrences. An increased lactate dehydrogenase (LDH) level at initial diagnosis was the only independent predictive factor for CNS relapse. Further efforts should be directed toward finding optimal treatment modalities based on the IPI and the extent of BMI by lymphoma. CNS prophylaxis may be considered only in patients with initial elevated LDH levels. K.-W. Lee and J. Yi equally contributed to this study.     

Combination chemotherapy of advanced non-Hodgkin lymphoma with bleomycin, adriamycin, cyclophosphamide, vincristine, and prednisone (BACOP).

Seventy-three patients with advanced non-Hodgkin lymphoma were treated with bleomycin, Adriamycin, cyclophosphamide, vincristine (Oncovin) and prednisone (BACOP), administered intensively during a 7-wk induction course followed by intermittent cycles every 3 wk for a total of 28 wk. The objective response in 44 evaluable nonleukemic patients with diffuse histology was 86%, with 66% achieving a complete remission (CR), varying from 80% for diffuse poorly differentiated lymphocytic (DPDL) to 56% for diffuse histiocytic (DH) lymphoma. In patients with nodular histology 89% (8/9) achieved a CR with a projected 75% of patiients in CR at 14 mo. Median follow-up from time of CR for nodular histology was 17 mo. The projected median duration of CR in diffuse histology was 14 mo. with median survival 14 mo. Patients with a partial response survived a median of 7 mo, compared to 3 mo for nonresponders. Of 29 patients with diffuse histology, 17 (59%) have remained disease free for 5-34 mo with a median follow-up of 12 mo. Survival beyond 20 mo has been projected for 42% of patients with diffuse histology (58% with DPDL and 32% with DH). The central nervous system (CNS) was involved in a total of 11/44 (25%) patients with diffuse histology, including 5 with primary CNS relapse. BACOP resulted in a higher CR rate and longer survival than a previous three-drug program (COP), especially in patients with diffuse histology.     

Editorial Board

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

Mantle cell lymphoma with central nervous system involvement: frequency and clinical features

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4–26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1–58) from diagnosis, with a crude incidence of 6·5% and 5-year actuarial incidence of 5 ± 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2–9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not ( P  = 0·0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.     

Risk‐tailored CNS prophylaxis in a mono‐institutional series of 200 patients with diffuse large B‐cell lymphoma treated in the rituximab era

The most effective strategy to prevent central nervous system (CNS) dissemination in diffuse large B‐cell lymphoma (DLBCL) remains an important, unmet clinical need. Herein, we report a retrospective analysis of risk‐tailored CNS prophylaxis in 200 human immunodeficiency virus‐negative adults with DLBCL treated with rituximab‐CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or similar. High risk of CNS relapse was defined by involvement of specific extranodal organs, or simultaneous presence of advanced stage and high serum lactate dehydrogenase level; CNS prophylaxis with high‐dose methotrexate ± intrathecal chemotherapy (IT) was routinely used in high‐risk patients diagnosed after 2007. CNS relapse risk was low in 93 patients and high in 107; 40 high‐risk patients received prophylaxis, which consisted of IT alone in 7. At a median follow‐up of 60 months, one low‐risk and nine high‐risk patients (1% vs. 8%; P = 0·01) experienced CNS relapse. In the high‐risk group, CNS relapses occurred in 8/67 (12%) patients who did not receive prophylaxis and in 1/40 (2·5%) patients who did; the latter occurred in a patient managed with IT alone. CNS relapse rate was 12% (9/74) for patients treated with “inadequate” prophylaxis (none or IT only) and 0% (0/33) for patients managed with intravenous prophylaxis (P = 0·03). In conclusion, high‐dose methotrexate‐based prophylaxis significantly reduces CNS failures in high‐risk patients stratified by involvement of specific extranodal sites and International Prognostic Index.     

An effective therapy for both undifferentiated (including Burkitt''s) lymphomas and lymphoblastic lymphomas in children and young adults

We have used a single intensive chemotherapy regimen in the treatment of young patients with diffuse, aggressive, malignant lymphomas. There were two major histologic types of lymphoma in our series: lymphoblastic lymphomas, which presented most often with mediastinal tumor (64%), and undifferentiated lymphomas (mostly Burkitt's lymphomas), which occurred predominantly in the abdomen (86%). Our objective was to examine the determinants of prognosis in a uniformly treated patient group that included 31 children (2-16 yr) and 34 young adults 17-35 yr). Patients with extensive bone marrow involvement (greater than 50% replacement by tumor cells) were included in the study. Treatment consisted essentially of a 4-drug combination (cytoxan, adriamycin, vincristine, and prednisone) alternating with a 42-hr methotrexate infusion, followed by leukovorin rescue, and included intrathecal prophylactic therapy against central nervous system (CNS) disease. Patients with localized or resected undifferentiated lymphoma received 6 therapy cycles; all other patients received 15 cycles. Radiation therapy was used only in exceptional circumstances. Fifty-eight of 65 patients (89%) achieved complete remission: 97% of children and 82% of adults. The estimated 3-yr survival was 60% (SE 6.4%) with a median follow-up of 3 yr. Analysis of factors associated with remission duration and survival indicated that bone marrow involvement at referral and extensive disease were poor prognostic variables. Patients with lymphoblastic lymphomas and patients with completely resected undifferentiated lymphomas had the best prognosis (81% +/- 12% and 94% +/- 6% estimated 3-yr survival, respectively). Patients with extensive intraabdominal undifferentiated lymphoma (stage D) had the worst prognosis (33% +/- 11% estimated 3 yr survival), but even in this subgroup, bone marrow involvement was an adverse factor (estimated survival in stage D patients with and without bone marrow involvement was 14% +/- 13% and 43% +/- 15%, respectively). Elevated uric acid and/or lactic dehydrogenase (LDH) were also of prognostic significance, but predominantly reflected state, i.e., extent of disease. Age did not significantly influence prognosis. In the undifferentiated lymphoma subgroup, histology (i.e., Burkitt's lymphoma versus non-Burkitt's lymphoma) was not of prognostic significance. Total white count was below 1,000/cu mm in 39% of cycles, and fever associated with granulocytopenia occurred in 17% of cycles. Stomatitis of moderate to severe extent occurred in 50% of cycles.(ABSTRACT TRUNCATED AT 400 WORDS)     

A unique pattern of extranodal involvement in Korean adults with sporadic Burkitt lymphoma: a single center experience

Extranodal involvement is common in patients with Burkitt lymphoma (BL). We evaluated the pattern of extranodal involvement and its impact on clinical outcomes in a single center cohort of adult Korean patients with sporadic BL. We retrospectively identified 64 patients with BL in the registry of non-Hodgkin lymphoma of the Asan Medical Center between 1996 and 2009. We assessed their clinical features and distribution of extranodal sites and analyzed clinical outcomes, including complete response rate after chemotherapy, overall survival, and progression-free survival, relative to baseline characteristics and involved extranodal sites. Extranodal involvement was found in 57 patients (89?%), with 34 (53.1?%) having two or more extranodal sites. The stomach (26.6?%) was the most common site, followed by the small and large intestines (25?%), bone marrow (23.4?%), genitourinary tract (21.9?%), and bones (18.8?%). Two patients (3.1?%) showed central nervous system (CNS) involvement. Complete response rates to chemotherapy were not related to sites of extranodal involvement. Two-year overall survival rates were lower in patients with bone marrow (33.3 vs. 74.6?%, p?=?0.010) and CNS (0.0 vs. 66.6?%, p?=?0.048) involvement than in patients with involvement at other extranodal sites. The stomach, genitourinary tract, and bones were the most commonly involved extranodal sites in Korean BL patients, but site had no prognostic significance.     

Secondary central nervous system involvement in 599 patients with diffuse large B-cell lymphoma: are there any changes in the rituximab era?

The introduction of rituximab has improved the overall prognosis of diffuse large B-cell lymphoma (DLBCL). However, the impact of rituximab on central nervous system (CNS) involvement in DLBCL remains a matter of debate. Patients with DLBCL and no CNS involvement at initial diagnosis were eligible for this analysis. Patients must have received treatment either with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP plus rituximab (R-CHOP). We analyzed the incidence, clinical features and outcomes of CNS involvement that developed during or after completion of therapy. A cohort of 599 patients was eligible for this analysis. With a median follow-up of 26 and 21 months, respectively, 19 of 294 (6.5 %) in the CHOP group and 13 of 305 (4.3 %) in the R-CHOP group developed CNS involvement. Rituximab did not significantly reduce the risk of CNS involvement either in the univariate (P = 0.354) or in the multivariate analysis (RR 0.632, 95 % CI 0.301–1.327, P = 0.225). No patient developed CNS disease after 19 months in the R-CHOP group whereas four patients (21.1 %) in the CHOP group developed CNS disease 2 years after initial diagnosis (range 34–83 months). Systemic disease prior to or coincident with CNS occurrence was more common in the CHOP group than in the R-CHOP group (73.7 versus 38.5 %, P = 0.046). Isolated CNS events were more common in the R-CHOP group than those in the CHOP group (53.8 versus 10.5 %, P = 0.015). This study indicates that isolated CNS events are more common in DLBCL patients treated with R-CHOP than those treated with CHOP alone. Our data also suggest that the time and pattern of CNS events and systemic disease status differ with the addition of rituximab. Better methods for earlier detection and prophylaxis of CNS involvement are needed in the rituximab era.     

Bulky disease has an impact on outcomes in primary diffuse large B-cell lymphoma of the breast: a retrospective analysis at a single institution

Objectives: Primary breast lymphoma (PBL) is rare, and its clinical behavior and standard initial treatment are not yet established. Methods: We retrospectively analyzed the clinicopathological features and treatment outcomes of 14 patients with primary breast diffuse large B‐cell lymphoma. Results: There were nine patients with stage IE and five with stage IIE disease. The median largest tumor diameter was 4.5 cm, and five patients had bulky disease >5 cm. The complete response rate was 94%. However, the 5‐year progression‐free survival rate was 52% with a median follow‐up of 5.2 years. Patients with bulky disease had an unfavorable prognosis. All five patients with bulky disease progressed or relapsed. Of the four patients that recurred in the central nervous system (CNS), three had bulky disease although some received rituximab. There were no CNS recurrences in the three patients who received CNS prophylaxis. All eight patients who responded to radiotherapy (RT) did not have recurrences in the ipsilateral breast, although one patient with bulky disease relapsed in the adjacent regional lymph nodes within the RT field despite immunochemotherapy. Conclusions: Patients with bulky disease had a poorer prognosis and recurred frequently in the CNS. CNS prophylaxis might yield better outcomes, but a larger, prospective trial is needed to elucidate the optimal initial treatment of PBL in the rituximab era.     

Effective multiagent chemotherapy in children with advanced B-cell lymphoma: who remains the high risk patient?

Between 1981 and 1985, 50 patients, mainly children and adolescents, with advanced B-cell lymphoma were entered on a protocol comprising eight drugs: cyclophosphamide, vincristine, prednisolone, high dose methotrexate, adriamycin, BCNU, cytosine arabinoside and thioguanine. Treatment to the central nervous system consisted of intrathecal methotrexate and cytosine-arabinoside in association with high dose methotrexate without irradiation. Data was collected prospectively with regard to response rate, treatment related complications and survival. Histology was reviewed in all referred cases and in 21 there was supportive evidence from immunological and cytogenetic studies. The overall complete response rate was 86%: 31/36 stage III and 12/14 stage IV. There were four treatment related deaths. The overall disease-free survival is 75% with a median follow up of 32 months. In the group of stage IV patients 5/7 with only marrow involvement, 2/4 with isolated CNS involvement and 1/3 with combined CNS and marrow infiltration survive. All the patients with CNS involvement at presentation underwent consolidation treatment with high dose chemotherapy and bone marrow transplant. These results demonstrate the very high curability of B-cell lymphoma using intensive multiagent therapy even with advanced abdominal disease. Bone marrow infiltration does not appear to be an adverse prognostic factor in isolation from bulk disease or CNS involvement. There remain, however, two groups of patients in whom further intensification of therapy is indicated, namely, those with initial CNS involvement, especially in combination with marrow infiltration, and those with extensive multiorgan involvement at presentation who fail to achieve remission with initial therapy. For the other patients, the large majority, a reduction in the intensity and duration of therapy is currently under study.     

Intensive chemotherapy regimen (LMB86) for St Jude stage IV AIDS-related Burkitt lymphoma/leukemia: a prospective study

Prognosis of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma has improved since the introduction of highly active antiretroviral therapy. Burkitt lymphomas (BLs) still have poor outcome in patients with bone marrow (BM) or central nervous system (CNS) involvement when treated with standard-dose chemotherapy. We have prospectively evaluated the LMB86 regimen in 63 human immunodeficiency virus (HIV)-infected patients with stage IV (BM and/or CNS involvement) BL consecutively recruited between November 1992 and January 2006. At BL diagnosis, the median CD4 cell count was 239 x 10(6)/L (range, 16-1188 x 10(6)/L). BM and CNS involvement were present in 55 (80%) and 48 (76%) patients, respectively. Forty-four patients (70%) achieved complete response. Seven treatment-related deaths occurred and all patients experienced severe BM toxicity. With a median follow-up of 66 months (range, 6-165 months), 11 patients relapsed. The estimate 2-year overall survival and disease-free survival were 47.1% (95% CI, 34-59.1) and 67.8% (95% CI, 51-80), respectively. We identified 2 poor prognosis factors: low CD4 count and ECOG more than 2. Patients with 0 or 1 factor had good outcome (2-year survival: 60%) contrasting with patients with 2 factors (2-year survival: 12%). We conclude that LMB86 regimen is highly effective in advanced HIV-related BL and should be proposed for patients with CD4 count higher than 200 x 10(6)/L or ECOG of 2 or less.     

Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathologic review of the National Cancer Institute experience

CLM developed in 60 of 526 patients (11%) with SCLC seen at the NCI between August 1969 and June 1980. Life table analysis revealed an overall 25% risk of CLM at 3 years. CLM was diagnosed during all phases of the patients' clinical course, but the majority (83%) were cases diagnosed at the time of progressive systemic disease. Univariate log rank analysis indicated that pretreatment factors associated with the development of CLM included: involvement of the brain, spinal cord, bone marrow, liver or bone; extensive disease; and male sex. Patients who did not obtain a complete response to systemic therapy were at greater risk of developing CLM than complete responders. Multivariate analysis of these factors indicated that liver metastases were most strongly associated with the time to development of CLM, followed in order of importance by bone and CNS metastases. Patients usually presented with signs and symptoms reflecting involvement of multiple areas of the neuraxis including the cerebrum, cranial nerves and spinal cord; 51 of the 60 patients had intracerebral metastases and 27 had spinal cord lesions during their clinical course. Autopsy features including focal or diffuse involvement of the leptomeninges with infiltration of the Virchow-Robin spaces were similar to meningeal lymphoma and leukemia, except that CLM was rarely the sole manifestation of CNS tumor. Median survival following the diagnosis of CLM was 7 weeks. However, most deaths were attributed to systemic disease, and treatment with intrathecal chemotherapy and irradiation often provided palliation. With the increased awareness of this complication, an antemortem diagnosis increased from 39% prior to 1977, to 88% of patients after 1977.