Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa,Busulfan, and Cyclophosphamide Conditioning Regimen

BackgroundHigh-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.Patients and MethodsA retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).ResultsThe 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.ConclusionHDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.     

Autologous Stem Cell Transplantation in Central Nervous System Lymphoma: A Multicenter Retrospective Series and a Review of the Literature

BackgroundCentral nervous system (CNS) lymphoma is associated with poor outcomes. Autologous stem cell transplantation (ASCT) has been reported to improve outcomes when used as a consolidation strategy in primary CNS lymphoma (PCNSL) and as a salvage strategy in patients with disease relapse limited to the CNS. Herein, we describe our experience of using ASCT in PCNSL and secondary CNS lymphoma (SCNSL).Patients and MethodsWe evaluated clinical outcomes of 18 patients from 2 major academic centers with a median age of 55 (range, 46-72) years. Thirteen patients had PCNSL and 5 patients had SCNSL. Most of the cases were in the first (CR1) or second (CR2) complete remission (CR1 = 7, CR2 = 7) at the time of ASCT. Carmustine with thiotepa (n = 12, 67%) was the most commonly prescribed preparative regimen.ResultsThe median follow-up from ASCT for surviving patients was 12 (range, 0.9-115) months. The 2-year progression-free survival (PFS) and overall survival (OS) were 74% (95% confidence interval [CI], 48%-99%) and 80% (95% CI, 55%-100%), respectively. Two-year non-relapse mortality was 0%. The 2-year cumulative incidence of relapse/progression was 27% (95% CI, 10%-72%). In subgroup analysis of PCNSL patients, 2-year PFS, OS, and relapse were 71% (95% CI, 38%-100%), 71% (95% CI, 38%-100%), and 29% (95% CI, 9%-92%), respectively.ConclusionIn this retrospective study of patients with CNS lymphoma, consolidation with ASCT after high-dose methotrexate-based chemotherapy is safe and effective in reducing disease relapse.     

Genetic evidence implies that primary and relapsed tumors arise from common precursor cells in primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare subtype of lymphoma that arises within the brain or the eyes. PCNSL recurs within the central nervous system (CNS) in most relapsed cases, whereas extra‐CNS relapse is experienced in rare cases. The present study aimed at identifying the presence of common precursor cells (CPC) for primary intra‐ and relapsed extra‐CNS tumors, and further assessing the initiating events in bone marrow (BM). Targeted deep sequencing was carried out for five paired primary intra‐ and relapsed extra‐CNS tumors of PCNSL. Two to five mutations were shared by each pair of intra‐ and extra‐CNS tumors. In particular, MYD88 mutations, L265P in three and P258L in one, were shared by four pairs. Unique somatic mutations were observed in all five intra‐CNS tumors and in four out of five extra‐CNS tumors. Remarkably, IgH clones in the intra‐ and the extra‐CNS tumors in two pairs were distinct from each other, whereas one pair of tumors shared identical monoclonal IgH rearrangement. In a cohort of 23 PCNSL patients, L265P MYD88 mutations were examined in tumor‐free BM mononuclear cells (MNC) in which the PCNSL tumors had L265P MYD88 mutations. L265P MYD88 mutations were detected by a droplet digital PCR method in nine out of 23 bone marrow mononuclear cells. These results suggest that intra‐ and extra‐tumors are derived from CPC with MYD88 mutations in most PCNSL, arising either before or after IgH rearrangement. The initiating MYD88 mutations may occur during B‐cell differentiation in BM.     

Occult systemic Non-Hodgkin's Lymphoma (NHL) in patients initially diagnosed as Primary Central Nervous System Lymphoma (PCNSL): How much staging is enough?

Objective To demonstrate the extent of staging necessary to exclude occult systemic stage IV NHL before making a diagnosis of stage I AE PCNSL.Background The diagnosis of PCNSL requires the demonstration of malignant lymphocytes within the CNS (usually by biopsy) and finding no evidence of systemic NHL. Different staging approaches have been recommended, ranging from extensive systemic evaluation (including bone marrow examination) to a more focused approach (abdominal and pelvic CT) to no systemic evaluation. We have employed a staging regimen that included: ophthalmologic evaluation (including slit lamp examination); CT of chest, abdomen, and pelvis; bilateral iliac crest aspirate and biopsy; flow cytometry of circulating lymphocytes; and, in men, testicular ultrasound.Design/methods We carried out a retrospective review of 128 patients entered into the Mayo Lymphoma Project data bank (1975–1994).Results Between the years 1975 and 1994, five patients (3.9%) were identified who fulfilled criteria for the diagnosis of PCNSL (typical clinical history, pathognomonic neuro-imaging, and histologie proof of NHL in brain tissue) but who had occult systemic NHL on staging (bone marrow 1, abdominal lymph nodes 3), or at autopsy (colon 1). Case histories are presented.Conclusions Patients with apparent PCNSL may have systemic NHL. Complete staging is essential to the initial management of patients presenting as PCNSL to exclude systemic stage IV disease.Presented at the First Congress of the European Association for Neuro-Oncology October 17, Maastricht, The Netherlands     

The value of routine bone marrow biopsy in patients with diffuse large B-cell lymphoma staged with PET/CT: a Danish-Canadian study

BackgroundThe added diagnostic and prognostic value of routine bone marrow biopsy (BMB) in patients with diffuse large B-cell lymphoma (DLBCL) undergoing positron emission tomography combined with computed tomography (PET/CT) staging is controversial.Patients and methodsPatients with newly diagnosed DLBCL who underwent both staging PET/CT and BMB were retrospectively identified in British Columbia, Aalborg, and Copenhagen. Original written PET/CT and pathology reports were retrospectively reviewed to determine Ann Arbor stage and outcomes, with and without the contribution of BMB.ResultsA total of 530 patients were identified: 146 (28%) had focal bone marrow (BM) lesions on PET/CT and 87 (16%) had positive BMB. Fifty-two of 146 patients (36%) with positive PET/CT had a positive BMB [39 DLBCL, 13 indolent non-Hodgkin lymphoma (iNHL)], while 35 of 384 patients (9%) with negative PET/CT had positive BMB (12 DLBCL, 23 iNHL). BMB upstaged 12/209 (6%) of stage I/II patients to stage IV, although this was the case for only 3 (1%) patients with DLBCL in the BMB. PET/CT identified BM involvement by BMB with sensitivity 60%, specificity 79%, positive predictive value 36%, and negative predictive value 91%. Concordant histological involvement of the BM by DLBCL was associated with worse overall survival and progression-free survival than discordant or no involvement in univariate and multivariate analyses.ConclusionsIn patients with DLBCL, staging PET/CT can miss BM involvement with concordant DLBCL (less common) or discordant iNHL (more common). Routine BMB does not add relevant diagnostic or prognostic value over PET/CT alone in the majority of patients with DLBCL.     

Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-hodgkin lymphoma.

BACKGROUND: Central nervous system involvement is a common manifestation of non-Hodgkin lymphoma (NHL) in human immunodeficiency virus (HIV)-infected individuals. The purpose of this study was to review the frequency and pattern of neurologic manifestation of lymphoma in a cohort of HIV-infected individuals with systemic NHL. METHODS: Sixty-two patients with HIV-associated systemic NHL received infusional cyclophosphamide, doxorubicin, and etoposide. Five patients with lymphomatous meningitis at presentation received whole brain radiation therapy plus intrathecal chemotherapy (ITC). Of the remaining 57 patients, prophylactic ITC was recommended only for those patients with lymphomatous bone marrow involvement and/or high grade histology (N = 31). RESULTS: Thirteen patients (21%) had histologically documented (N = 6) or presumed (N = 7) central nervous system involvement, including 7 patients (11%) with meningeal lymphoma discovered either at presentation (N = 5) or soon after diagnosis (N = 2), and 6 patients (10%) with cerebral mass lesions at the time of disease recurrence consistent with parenchymal brain involvement. Five of six parenchymal brain recurrences occurred in the setting of progressive systemic disease. Four of 7 patients (57%) with meningeal lymphoma detected at presentation (N = 5) or within 3 months of presentation (N = 2) responded to therapy and survived >1 year. Of the 26 patients assigned to receive no prophylactic ITC, no patient developed an isolated meningeal recurrence and 1 patient developed an isolated parenchymal brain recurrence. CONCLUSIONS: The findings of the current study suggest that in patients with HIV-associated systemic lymphoma, meningeal lymphoma is potentially curable, parenchymal brain recurrence usually occurs in the setting of uncontrolled systemic disease, and prophylactic ITC may not be necessary for patients with intermediate grade histology and uninvolved bone marrow.     

CSF neopterin level as a diagnostic marker in primary central nervous system lymphoma

BackgroundThe diagnosis of primary central nervous system lymphoma (PCNSL) can be challenging. PCNSL lesions are frequently located deep within the brain, and performing a cerebral biopsy is not always feasible. The aim of this study was to investigate the diagnostic value of CSF neopterin, a marker of neuroinflammation, in immunocompetent patients with suspected PCNSL.MethodsWe retrospectively reviewed the characteristics of 124 patients with brain tumor (n = 82) or an inflammatory CNS disorder (n = 42) in whom CSF neopterin levels were assessed. Twenty-eight patients had PCNSL, 54 patients had another type of brain tumor (glioma n = 36, metastasis n = 13, other n = 5), and 13 patients had a pseudotumoral inflammatory brain lesion.ResultsCSF neopterin levels were significantly higher in the patients with PCNSL than in those with other brain tumors (41.8 vs 5.1 nmol/L, P < .001), those with pseudotumoral inflammatory brain lesions (41.8 vs 4.3 nmol/L, P < .001), and those with nontumefactive inflammatory CNS disorders (41.8 vs 3.8 nmol/L, P < .001). In the 95 patients with space-occupying brain lesions, at a cutoff of 10 nmol/L, the sensitivity of this approach was 96% and the specificity was 93% for the diagnosis of PCNSL. The positive and negative predictive values were 84% and 98%, respectively.ConclusionAssessing CSF neopterin levels in patients with a suspected brain tumor might be helpful for the positive and differential diagnosis of PCNSL. A prospective study is warranted to confirm these results.     

Retrospective study of pemetrexed as salvage therapy for central nervous system lymphoma

There is currently no standard therapy for recurrent or chemotherapy-refractory central nervous system lymphoma (CNSL). Pemetrexed has been reported to have activity in patients with primary CNSL (PCNSL). The use of pemetrexed in secondary CNS lymphoma (SCNSL) has not previously been reported. Here we retrospectively review the outcomes and toxicities of standard and modified doses of pemetrexed as salvage therapy in 18 PCNSL and 12 SCNSL patients. The overall response rate for PCNSL patients was 64.7 %, all of whom achieved a complete response (CR). The median progression-free survival (PFS) was 5.8 months. For the SCNSL patients, RR was 58.3 % with 2 CR (16.7 %); the median PFS was 2.5 months. Grade ≥3 adverse events included leukopenia in 5 patients (16.7 %), neutropenia in 1 patient (3.3 %), and fatigue in 3 patients (10.0 %). 3 patients died while on treatment, 2 due to infections and 1 due to pulmonary embolism. Our results indicate that pemetrexed has activity as salvage therapy in recurrent PCNSL, even with modified dosing, but outcomes trend towards less favorable in SCNSL.     

AIDS-related Central Nervous System Lymphomas

Purpose: To evaluate combined radio-chemotherapy in patients with AIDS-related lymphomatous meningitis (LM) or primary central nervous system lymphoma (PCNSL).Patients and methods: Eighteen men and 2 women with AIDS had cytologically documented LM. Fifteen patients had systemic non-Hodgkin's lymphoma with LM and 5 patients had PCNSL with CSF dissemination. Standardized pre-treatment evaluations included contrast cranial MRI, placement of an intraventricular reservoir, contrast spine MRI, ophthalmologic evaluation and ¹¹¹Indium-DTPA CSF flow studies. Regions of bulky or symptomatic disease were treated with limited-field irradiation. Concurrent systemic chemotherapy was administered in 18 patients. All patients were scheduled to receive intraventricular methotrexate (MTX) according to a concentration×time (C×T) drug schedule. In cytologic or clinical failures, patients were treated with salvage therapy using intraventricular ara-C and in a similar manner, patients were treated with intraventricular thio-TEPA following cytologic relapse or clinical failure intraventricular following intraventricular ara-C.Sixty-seven patients (63 men; 4 women) with PCNSL underwent a standardized pre-treatment evaluation as in patients with LM and were treated according to 3 schedules. In the first group (n=15), comfort care was offered. In the second group (n=45), whole brain radiotherapy was administered. In the third group (n=7), patients were treated with combined radio- and chemotherapy using systemic procarbazine, CCNU and vincristine (PCV-3). The third group was selected based on a Karnofsky performance status 60, no evidence of disseminated PCNSL, a CD4 count 200, no concurrent opportunistic infection and a patient's desire for aggressive therapy.Results: In the LM patient group, 16 patients were evaluable as 4 patients subsequently withdrew consent for treatment. Median time to tumor progression/survival were as follows: not-treated (n=4) 12 days/1 month; treated non-responding (n=6) 30 days/2 months; and treated responding (n=10) 130 days/6 months. In the PCNSL patient group, median range survival were as follows: comfort care (n=15) 1.5/0.5–3 months; whole brain radiotherapy (n=45) 4/1.5–5 months; and combined radio-chemotherapy (n=7) 13/10–18 months.Conclusions: Combined radio- and chemotherapy is appropriate for a small subset of patients with AIDS and either LM or PCNSL. This approach results in meaningful palliation not strikingly dissimilar from that seen in non-AIDS patients.     

The utility of body FDG PET in staging primary central nervous system lymphoma

(18)F-Fluorodeoxyglucose (FDG) PET has become an important tool in the management of non-Hodgkin's lymphoma (NHL), but its role in the evaluation of primary CNS lymphoma (PCNSL) has not been established. We investigated the ability of body FDG PET to detect systemic disease in the staging and restaging of PCNSL. The records of 166 PCNSL patients seen at Memorial Sloan-Kettering Cancer Center were examined. Forty-nine patients who underwent body FDG PET for staging of PCNSL were identified. Clinical data were reviewed to determine FDG PET results and their influence on therapy. Body FDG PET disclosed a systemic site of malignancy in 15% of patients. NHL was found in 11% of all patients, 7% of patients at diagnosis, and 27% of patients at CNS relapse. Four percent had a second systemic neoplasm. Workup with conventional staging did not reveal systemic disease, and in 8% of patients, body FDG PET was the only abnormal diagnostic exam suggestive of lymphoma. FDG PET findings altered patient treatment and resulted in additional chemotherapy, surgery, or radiotherapy. Our findings suggest that FDG PET may be more sensitive than conventional body staging and may disclose higher rates of concomitant systemic disease at PCNSL diagnosis. Body FDG PET may be an important noninvasive adjunct to conventional PCNSL staging, and its utility should be evaluated prospectively.     

Central nervous system occurrence in elderly patients with aggressive lymphoma and a long-term follow-up.

BACKGROUND: Secondary central nervous system (CNS) involvement by aggressive lymphoma is a well-known and dreadful clinical complication. The incidence and risk factors for CNS manifestation were studied in a large cohort of elderly (>60 years) patients with aggressive lymphoma. PATIENTS AND METHODS: In all, 444 previously untreated patients were randomized to receive 3-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone or cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) (doxorubicin substituted by mitoxantrone) chemotherapy with or without filgrastim. Prophylactic intrathecal methotrexate was given to patients with lymphoma involvement of bone marrow, testis and CNS near sites. RESULTS: In all 29 of 444 (6.5%) developed CNS disease after a median observation time of 115 months. CNS was the only site of progression/relapse in 13 patients while part of a systemic disease manifestation in 16 patients. In univariate risk factor analysis, CNS occurrence was associated with extranodal involvement of testis (P = 0.002), advanced clinical stage (P = 0.005) and increased age-adjusted International Prognostic Index score (aaIPI; P = 0.035). In multivariate analysis, initial involvement of testis remained significant and clinical stage was of borderline significance. The median survival time was 2 months after presentation of CNS disease. CONCLUSION: A significant proportion of elderly patients with advanced aggressive lymphoma will develop CNS disease. CNS occurrence is related to testis involvement, advanced clinical stage and high aaIPI and the prognosis is dismal.     

继发性骨淋巴瘤的18F-FDG PET/CT影像诊断及与骨髓活检诊断效能的比较

目的:分析继发性骨淋巴瘤的PET/CT影像特点,比较骨髓活检（bone marrow biopsy,BMB）及PET/CT诊断骨淋巴瘤各自的优势,探讨如何进一步提高骨淋巴瘤的检出率。方法:回顾性分析放化疗前在我院行PET/CT检查的68例继发性骨淋巴瘤影像及骨髓活检资料。所有病例均病理确诊为淋巴瘤。骨淋巴瘤病灶的诊断标准:BMB阳性或骨局灶性FDG代谢增高且治疗后代谢减低或消失。采用SPSS 16.0统计分析不同分组的SUVmax及诊断效能差异。结果:PET/CT与BMB诊断灵敏度比较:68例中63例行BMB。PET/CT的总体诊断灵敏度及对非惰性淋巴瘤的诊断灵敏度高于BMB（P＜0.05）,而对惰性淋巴瘤,BMB灵敏度略高于PET/CT(P＞0.05)。PET/CT表现与BMB结果:根据PET/CT所见分为骨质破坏组（18例）和骨髓浸润组（50例）,骨质破坏组的SUVmax明显高于骨髓浸润组（P＜0.01）。骨质破坏组以弥漫大B细胞淋巴瘤（diffuse large B cell lymphoma,DLBCL）为主,PET/CT均阳性。骨髓浸润组PET/CT阳性41例,表现为局灶性增高、弥漫不均匀性增高和弥漫均匀性增高,弥漫均匀性增高组的SUVmax明显低于其它两组。BMB阴性21例,其中骨质破坏组8例,局灶性骨髓浸润13例。病理类型与PET/CT表现:31例DLBCL、10例其它侵袭性非霍奇金淋巴瘤（non-Hodgkin's lymphoma,NHL）及6例霍奇金淋巴瘤（Hodgkin's lymphoma,HL）均PET/CT阳性;18例惰性淋巴瘤PET/CT仅11例阳性。DLBCL的SUVmax明显高于惰性淋巴瘤（P＜0.05）。结论:继发性骨淋巴瘤骨髓浸润多于骨质破坏。骨质破坏和局灶性骨髓浸润多见于侵袭性骨淋巴瘤,而弥漫性骨髓浸润更多见于惰性淋巴瘤。PET/CT对骨质破坏、局灶性骨髓浸润的诊断优于BMB,而BMB对弥漫性骨髓浸润的诊断优于PET/CT。联合BMB和PET/CT才能更准确地诊断骨淋巴瘤。     

Outcomes of Autologous Stem Cell Transplantation as a Consolidative Strategy for the Treatment of Primary and Isolated Secondary Central Nervous System Diffuse Large B Cell Lymphomas

IntroductionStandard consolidation for primary diffuse large B cell lymphoma (DLBCL) of the central nervous system (CNS) (PCNSL) is not established. This single center, retrospective observational study aims to define the outcomes of consolidative high dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) in patients with PCNSL and isolated secondary CNS DLBCL (SCNSL) and evaluate the prognostic factors.Patients and MethodsAll consecutive patients performed an HDC/ASCT for PCNSL or isolated SCNSLs between October 2012 and February 2022 were identified. Primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsAmong 35 patients included, 28 had PCNSL and 7 had isolated SCNSL. Median age was 51 (16-78). Males constituted 48.6%. Median follow-up after HDC/ASCT was 42.0 months. MATRIX (51.4%) and TEAM (80.0%) were the most frequent regimens of induction and conditioning, respectively. OS and PFS 1- and 2-year after HDC/ASCT were 68.0%, 57.0%, 58.0%, 48.0%, respectively. Increasing age, poor performance and comorbidities were associated with lower OS and PFS and higher non-relapse mortality (NRM). Complete response (CR) 1 at HDC/ACST was independently associated with higher OS and PFS [hazard ratio (HR): 4.67 and 6.99, respectively].ConclusionIn patients < 60 years consolidative HDC/ASCT yields promising OS and PFS. Patients ≥ 60 years may less likely benefit from consolidative HDC/ASCT and should be studied further in trials of novel agents, lower doses of consolidative radiotherapy and dose-adjusted conditioning regimens. Not only age, but also comorbidities, clinical performance and response to induction correlate with outcomes. Patients with isolated SCNSL may achieve similar outcomes.     

Fotemustine,Teniposide and Dexamethasone in Treating Patients with CNS Lymphoma

Purpose: We developed and evaluated a regimen including fotemustine, teniposide and dexamethasone (FTD)for treating patients with central nervous system (CNS) lymphoma based on pharmacokinetic properties ofindividual agents and in combination. Patients and Methods: In a comparison study, 8 patients with primaryCNS lymphoma (PCNSL) and 8 with secondary CNS lymphoma (SCNSL) were treated with FTD (comprisingfotemustine 100 mg/m2, 1h infusion, day 1; teniposide 60 mg/m2, >0.5 h infusion, on day 2, 3, 4; dexamethasone 40mg, 1h infusion, on day 1, 2, 3, 4 and 5; and methotrexate 12 mg, cytosine arabinoside 50 mg plus dexamethasone5 mg intrathecally, on day 2 and 7). Cycles were repeated every 3 weeks. After response assessment, patientsreceived whole brain radiotherapy. Results: Of the 8 PCNSL patients, 4 (50%) achieved CR and 3 (38%) PR, anoverall response rate of 88%. Four patients (50%) were in continuing remission at the end of this study after amedian follow-up of 30 months (range 10 to 56 months). Of the 8 SCNSL patients the overall response rate was63% (CR+PR: 38%+25%). All responses were achievable with predictable toxicity mainly reflecting reversiblemyelosuppression. Conclusion: This study suggests that FTD could be an effective treatment for CNS lymphoma,and is worthy of further evaluation.     

Exploring the role of FDG-PET in the assessment of bone marrow involvement in lymphoma patients as interpreted by qualitative and semiquantitative disease metabolic activity parameter

Bone marrow biopsy (BMB) is currently the standard method to evaluate marrow involvement in malignant lymphomas. However, there exist a number of pitfalls in this technique that can have important implications for initial staging, prognostification, and treatment of the disease. The present study was undertaken to investigate the utility of FDG-PET imaging in the detection of bone marrow involvement in untreated lymphoma patients. Forty untreated patients (36 males and 12 females) with either Hodgkin's disease (HD) (n = 17) or non-Hodgkin's lymphoma (NHL) (n = 31) underwent whole body FDG-PET study for disease evaluation. Bone marrow uptake of FDG was graded as absence or presence of disease activity at marrow sites by qualitative assessment. Semiquantitative analysis involved deriving disease metabolic index (DMI) using the following formula: DMI = SUV max of suitable circular ROI over PSIS or trochanteric region/ SUVmax of similar ROI over adjoining background. Findings of BMB and FDG-PET were compared for final analysis. Eleven out of 17 HD patients (12 males and 5 females) demonstrated concordance between FDG PET findings and BMB reports. Remaining 6 cases showed discordance of FDG-PET demonstrating presence of marrow involvement at marrow sites and uninvolved marrow on BMB. Twenty six of the 31 NHL cases (24 males and 7 females) demonstrated concordance between FDG PET findings and BMB reports. Remaining 5 cases showed discordance of FDG-PET demonstrating presence of marrow involvement at marrow sites and uninvolved marrow on BMB. All the BMB positive patients (2 of HD and 5 of NHL) demonstrated disease activity in bone marrow on FDG-PET study. All patients with absence of disease activity at marrow sites on FDG-PET scan (9 of HD and 21 of NHL) had histology proven uninvolved marrow. The quantitative assessment by DMI showed a mean of > 2.5 in HD and NHL patients at the PSIS region and the trochanteric region bilaterally in cases of bone marrow involvement by the disease. FDG-PET is a useful adjuvant to BMB for the evaluation of bone marrow involvement in lymphoma patients. The disease metabolic index of > 2.5 at the marrow sites can serve as a semiquantitative parameter for such diagnosis on FDG-PET in untreated patients of lymphoma.     

For which patients with aggressive non-Hodgkin's lymphoma is prophylaxis for central nervous system disease mandatory?

Purpose: Data of a multicenter study in non-Hodgkin's lymphoma (NHL) by the Dutch Hovon Group were reanalyzed to assess the risk of relapse in the central nervous system (CNS) related to the international risk index for NHL. In addition we assessed the risk for CNS disease in relation to the presence of bone marrow localisation at presentation.Design: We focused our analysis on those patients reaching a complete remission (CR). Two hundred eighty-six patients (histological subtypes D–H Working Formulation) and with stages II–IV were analyzed. One hundred ninety-three (67%) patients reached a CR.Results: Relapse occurred in 78 patients of whom 10 patients with concomitant or isolated CNS disease. According to the international risk index the following observations were made: low risk (n = 38) nine out of 34 CR relapsed, none had CNS involvement; low-intermediate risk (n = 115) 27 out of 83 CR relapsed, three had CNS involvement; high-intermediate risk (n = 110) 37 out of 68 CR relapsed, six had CNS involvement; high risk (n = 22) four out of seven CR relapsed, one had CNS involvement. Two out of 10 developed isolated CNS disease and eight out of 10 patients developed CNS disease with systemic relapse.Conclusion: Our data show that the number of CNS relapses after CR is relatively low (10 out of 193 = 5%), with an increasing incidence in the high-risk groups according to the international risk index. The occurrence of CNS relapse seems to be related to the risk of systemic relapse after CR. No subgroup could be discriminated in which prophylactic treatment would be of substantial benefit.     

Primary central nervous system lymphomas: incidence and survival in the Southern and Eastern Netherlands

BACKGROUND: An excessive increase in the incidence of primary central nervous system lymphoma (PCNSL) has been reported since the mid-1980s in the U.S. and U.K. Clinical studies have shown that radiotherapy and chemotherapy may prolong survival. In the current study, the authors describe the incidence, treatment, and survival of an unselected group of patients with PCNSL in the southern and eastern Netherlands. METHODS: Data regarding patients diagnosed between 1989-1994 were obtained from 4 population-based regional cancer registries in the southern and eastern Netherlands (n = 86) and the Eindhoven Cancer Registry for 1980-1988 (n = 6). Lymphomas were registered as PCNSL when a tissue diagnosis of CNS lymphoma was established for a patient with neurologic symptoms (i.e., lymphomas were not necessarily restricted to the CNS at the time of diagnosis). Only patients diagnosed during their lifetime with Stage I disease, Stage "IV" disease (i.e., diffuse CNS lymphoma), or disease of unknown stage were included (63 patients, 8 patients, and 15 patients, respectively, between 1989-1994). For 80 patients (93%) follow-up was complete until January 1, 1997. RESULTS: Between 1989-1994, an average World Standardized Rate of 2.3 cases and 1.7 cases per 1 million person-years, respectively, was reported for males and females. The median age of the patients at the time of diagnosis was 62 years, and was 66 years for patients with an unknown disease stage. In the area of the Eindhoven Cancer Registry the occurrence of PCNSL more than doubled from < 2% of all histologically confirmed primary CNS malignancies diagnosed between 1980-1985 to approximately 4% of cases diagnosed between 1986-1994. The median survival of all the patients was 4.1 months; the median survival was 5.8 months for patients with limited (Stage I and Stage IV) disease and was 0.6 months for patients with an unknown stage of disease. Approximately 65% of the patients with limited disease received radiotherapy and approximately 35% of such patients received chemotherapy. Furthermore, chemotherapy was given more often to patients age < 60 years who tended to have a slightly better survival than patients age > or = 60 years. CONCLUSIONS: The increase in the incidence of PCNSL in the 1980s may be explained in large part by changes in diagnostics and registration. The relatively high incidence and low survival rate of PCNSL in the southern and eastern Netherlands reported in the 1990s may be due in part to the inclusion of patients with systemic lymphoma and immunodeficiency disorders. However, a significant improvement in the prognosis of patients with PCNSL in the southern and eastern Netherlands diagnosed in the 1990s is unlikely.     

A case of large cell CNS lymphoma associated with a systemic small cell lymphocytic lymphoma

Summary A case is reported of a 59 y/o woman with a large cell CNS lymphoma and a small cell lymphocytic lymphoma in the bone marrow. The brain tumor underwent spontaneous regression and subsequent regrowth while there was slow progression of the systemic small cell lymphoma. The CNS lymphoma regressed rapidly following treatment with prednisone and cyclophosphamide. We hypothesize that the small cell lymphoma in this patient may represent an underlying immunodeficiency disorder. Dr. Weissman is a recipient of an American Cancer Society Career Development Award.     

Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas

BACKGROUND: Methotrexate-based and alkylator-based chemotherapy regimens are associated with renal and bone marrow toxicities, which limit their use in patients with central nervous system (CNS) lymphomas. The authors report their experience with an immunochemotherapy regimen consisting of rituximab and temozolomide in patients with primary or metastatic CNS lymphoma. METHODS: Seven patients who had received rituximab and temozolomide were identified from the database of the brain tumor clinic at the authors' institution: three patients had developed recurrent primary CNS lymphoma (PCNSL), one patient had newly diagnosed PCNSL but had poor renal function, and three other patients with systemic non-Hodgkin lymphoma developed recurrent lymphoma in the brain only. Patients were scheduled to receive 4 cycles of induction rituximab on Day 1 and temozolomide on Days 1-5 of a 28-day cycle. Thereafter, their treatment included a total of up to 8 maintenance cycles of temozolomide alone on Days 1-5 of a 28-day cycle. A gadolinium-enhanced magnetic resonance image of the head was obtained after every two cycles of treatment. RESULTS: All patients received rituximab without toxicity. Of the 4 patients who received induction temozolomide at doses > 150 mg/m(2) daily on Days 1-5, 2 experienced Grade 2 leukopenia and thrombocytopenia. Five patients achieved a radiographic complete response, and two patients had partial responses after induction treatment. The median response duration was 6 months (range 3-12+ months), and the median survival was 8 months (range 3+-12+ months). CONCLUSIONS: Although median survival was short, immunochemotherapy with rituximab and temozolomide was well tolerated and exhibited efficacy in this elderly and heavily pretreated cohort. The data obtained in the current study suggest that the optimal induction dose combination consists of rituximab 375 mg/m(2) on Day 1 and temozolomide 150 mg/m(2) daily on Days 1-5.