Treatment of CNS dissemination in systemic lymphoma

Summary The frequency of central nervous system (CNS) dissemination in non-Hodgkin’s lymphoma (NHL) varies and is dependent on NHL histology. More than 50% of patients with CNS involvement have advanced and progressive systemic disease. While CNS involvement at initial diagnosis may be treated curatively, treatment of CNS involvement in systemic relapsing or refractory lymphoma is challenging and most often palliative. Due to a paucity of randomized trials, treatment of lymphomatous metastases is not standardized. Nonetheless, treatment of LM entails administration of both CNS-directed and systemic chemotherapy that often includes high-dose chemotherapy regimens with stem cell support. Gleissner and Chamberlain contributed equally.     

High-dose Thiotepa,Busulfan, Cyclophosphamide,and Autologous Stem Cell Transplantation as Upfront Consolidation for Systemic Non-Hodgkin Lymphoma With Synchronous Central Nervous System Involvement

IntroductionSynchronous involvement of the central nervous system (CNS) at the diagnosis of systemic non-Hodgkin lymphoma (NHL) is associated with an increased risk for relapse despite complete remission to initial therapy. High-dose chemotherapy with a CNS-directed conditioning regimen followed by autologous stem cell transplantation (ASCT) holds promise as a consolidative approach.Patients and MethodsWe conducted a retrospective analysis of all patients with systemic B-cell NHL and synchronous CNS involvement who received upfront consolidation with high-dose chemotherapy with thiotepa, busulfan, cyclophosphamide, and ASCT while in first complete remission between July 2008 and June 2016 at 2 partner academic institutions.ResultsTwenty patients were identified through the transplant database. The median age at diagnosis was 53 years (range, 37-65 years). The majority had diffuse large B-cell lymphoma histology (n = 17; 85%). The sites of CNS involvement were parenchymal (n = 12; 60%) and leptomeningeal disease (n = 9; 45%). All patients received systemic and CNS-directed therapy prior to transplant, with the most common approaches being R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone) (n = 13; 65%) and high-dose intravenous methotrexate (n = 16; 80%), respectively. With a median follow up of 4.4 years after ASCT (range, 2 months-8.5 years), the Kaplan-Meier estimates of 4-year progression-free and overall survival were 77% (95% confidence interval, 48%-91%) and 82% (95% confidence interval, 54%-94%), respectively.ConclusionCNS-directed high-dose chemotherapy and ASCT provides durable remission for patients with synchronous aggressive lymphoma and should be strongly considered as consolidative therapy for eligible patients with systemic NHL with CNS involvement in first complete remission.     

Epidemiology, clinical characteristics, and management of AIDS-related lymphoma

Although primary central nervous system (CNS) lymphoma was considered part of the spectrum of AIDS from the outset, systemic non-Hodgkin's lymphoma is considered a rather late manifestation of HIV infection. Any group at risk for AIDS may develop HIV-related lymphoma, and the characteristics of disease in all groups appear identical. The majority of these lymphomas are of the high-grade, B-cell types, including B-immunoblastic lymphoma and small noncleaved, Burkitt or non-Burkitt. Advanced, extranodal disease is seen at diagnosis in the majority of patients, who often present with widespread disease involving multiple organs. Central nervous system disease may be seen in the absence of systemic lymphoma ("primary CNS lymphoma") and carries a particularly poor prognosis. Leptomeningeal involvement is the most common central nervous system manifestation of systemic HIV-related lymphoma, and its presence does not imply a worse prognosis. Although very intensive regimens of multiagent chemotherapy have been employed in patients with HIV-related lymphoma, several studies indicate that these patients may not be able to tolerate such dose intensity. Newer regimens, employing lower dose-intensive regimens with early CNS prophylaxis, may be effective in inducing remissions in approximately half of treated individuals, who may attain long-term, lymphoma-free survival.     

Therapie von ZNS-Lymphomen

Primary central nervous system lymphoma (PCNSL) differs from nodal lymphoma with similar histological findings, usually diffuse large B-cell lymphoma, by its strong affinity for the central nervous system (CNS), aggressive course and unusual sensitivity to high-dose methotrexate (HDMTX). Thus, primary therapy of PCNSL is currently based on HDMTX but the optimal chemotherapy regimen has not yet been defined due to the rarity of this disease. In younger patients a cure should be the goal and thus intensified chemotherapy protocols should be considered. Whole brain irradiation does not prolong overall survival when used in primary therapy and thus should not be used routinely. Similar to PCNSL the infrequent CNS involvement of a systemic lymphoma, also called secondary CNS lymphoma, has a very poor prognosis. The scarce data suggest a role for HDMTX-based systemic chemotherapy and high-dose chemotherapy followed by stem cell transplantation for outcome improvement. Avoidance of late neurotoxicity is an important goal in the treatment of PCNSL.     

Non-Hodgkin's lymphoma of the brain after Hodgkin's disease. An immunohistochemical study

Non-Hodgkin's lymphoma (NHL) of the central nervous system (CNS) is a rarely reported complication of Hodgkin's disease (HD). Two patients with NHL of the brain after HD were studied by histologic and immunohistochemical methods. Both patients were in the second decade, had been treated with radiation and chemotherapy, had experienced a relapse of HD before development of NHL, had no evidence of HD at the time of diagnosis of NHL, and died within 1 year of diagnosis. Both brain neoplasms were large cell immunoblastic lymphomas of B-cell lineage. Patients with HD appear to be at increased risk for NHL of the CNS, which may have a poor prognosis.     

Treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare neoplasm that has captured popular attention because of its rising incidence and marked chemosensitivity. It is a non-Hodgkins B-cell lymphoma (NHL) that appears confined to the central nervous system (CNS) at presentation but may be multifocal within the brain or involve the leptomeninges or eyes at diagnosis. Like systemic lymphoma, it is highly sensitive to corticosteroids, and administration of steroids should be withheld until the diagnosis has been confirmed histologically. Currently, the initial treatment of choice incorporates high-dose methotrexate (HD-MTX) either as a single agent or in combination with other systemic chemotherapies. Whole-brain radiotherapy (WBRT) can be a highly effective treatment modality when combined with MTX, but the combination causes an unacceptably high incidence of severe permanent neurotoxicity, particularly in patients over age 60. Therefore, chemotherapy alone is the initial treatment of choice in older patients. This approach is also being explored in younger patients, but it is possible that deferring radiotherapy may compromise disease control. Consequently, the role of radiotherapy remains to be clarified in newly diagnosed younger patients with PCNSL.     

Advances in the Therapy of Primary Central Nervous System Lymphoma

Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma (NHL) confined to the nervous system. The management of PCNSL is quite different from the usual treatment of either primary brain tumors or systemic NHL. First-generation chemotherapy regimens used successfully in systemic NHL are ineffective in PCNSL, in large part due to the existence of the blood-brain barrier. Whole-brain radiation therapy (WBRT) results in high response rates but rapid relapse, and this treatment is associated with delayed neurotoxicity in patients with PCNSL. The addition of methotrexate-based chemotherapy has improved survival and lessened toxicity for this patient population. Fundamental issues that remain unresolved in PCNSL include identification of the optimal chemotherapy regimen for newly diagnosed and relapsed PCNSL, the role of WBRT and intrathecal chemotherapy in the treatment of PCNSL, and the optimal management of intraocular lymphoma. Finally, the optimal clinical study design for this rare disease has yet to be defined and implemented.     

Treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL) describes a malignant non-Hodgkin's lymphoma (NHL) whose sole site of involvement is the central nervous system (CNS). The diagnosis of PCNSL must be differentiated from systemic NHL with metastasis to the CNS, which usually occurs late in the course of systemic disease. PCNSL accounts for approximately 4% to 7% of primary brain tumors, and its incidence has been increasing since the mid-1970s. Compared with other more common malignant primary brain tumors, PCNSL tends to be more amenable to radiotherapeutic and chemotherapeutic intervention. In this article, the authors review the standard treatment for upfront and recurrent PCNSL.     

Central nervous system relapse of systemic non-Hodgkin's lymphoma: results of treatment based on high-dose methotrexate combination chemotherapy

The objective of this study was to evaluate the feasibility and possible response to pre-radiation chemotherapy given to patients with central nervous system (CNS) relapse of systemic non-Hodgkin's lymphoma (NHL). Twenty-three consecutive adult patients with systenic NHL and first CNS relapse were evaluated by CSF cytology and neuroaxis MRI. Treatment was based on weekly high-dose methotrexate (HD-MTX) 3.5 g/m2 and weekly intra-CSF cytarabine (ARA-C). Oral procarbazine 100 mg/m2 days 2-15 was added to patients whose bone marrow reserve could tolerate this drug. Radiation therapy (RT) to the CNS was deferred in responding/stable CNS disease. All patients with leptomeningeal seeding, but without parenchymal involvement responded to treatment prior to RT with 33% achieving a complete response (CR). Concomitant response of systemic disease was noted in 36% of the cases with 9% CR. Addition of RT to the CNS did not significantly change the overall rate of CR. Progression free survival for CNS disease was 5 months and for systemic disease 2 months. All patients with parenchymal involvement responded to therapy prior to RT with only 9% achieving CR, and the addition of RT in these cases increased the rate of CR to 24%. In this group, three of four patients who had active systemic disease responded systemically. Progression free survival was 3 months for both CNS and systemic disease. The median survival of the whole group was 6 months; 1-year survival 32% and 2-year survival 15%. In conclusion, systemic HD-MTX-based combination chemotherapy yields an initial response rate of 100% in the CNS and a 47% concomitant systemic response. A complete CNS response can be obtained prior to RT but this adds little to the overall CR rate. Durable responses are rare. Since both CNS and systemic relapses appear in tandem, future trials should evaluate alternative modalities in order to enhance drug delivery into the CNS.     

Central nervous system involvement in indolent lymphomas.

BACKGROUND: Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. PATIENTS AND METHODS: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. RESULTS: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1-9 years for treated patients (median 2 years). Three patients died of CNS disease. CONCLUSIONS: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.     

Changes in acquired immunodeficiency syndrome-related non-Hodgkin lymphoma in the era of highly active antiretroviral therapy: incidence, presentation, treatment, and survival

BACKGROUND: The authors sought to determine whether the availability of highly active antiretroviral therapy (HAART) coincided with changes in the epidemiology of acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin lymphoma (NHL). METHODS: Cancer registry data from 1988-2000 were linked with AIDS registry data from 1981 to July 2003 for San Diego County to identify 537 AIDS-NHL patients. By using the total number of patients with AIDS who were alive as of July 1 annually as the AIDS population denominator, the average annual incidence of NHL was estimated among patients with AIDS for the pre-HAART period (1988-1995) and post-HAART period (1996-2000). The chi-square test was used to compare proportions, and a Cox proportional hazards model was used to compare survival between the pre-HAART and post-HAART periods. RESULTS: The incidence of NHL decreased from 29.6 per 1000 person-years pre-HAART to 6.5 per 1000 person-years post-HAART. The proportion of patients who had NHL of central nervous system (CNS) origin decreased from 28% pre-HAART to 17% post-HAART. Among patients with systemic NHL, 54% received chemotherapy pre-HAART, and 72% received chemotherapy post-HAART. The percentage of intermediate-grade NHL increased from 33% pre-HAART to 49% post-HAART, and the percentage of high-grade NHL decreased from 38% to 19%, respectively. A diagnosis of human immunodeficiency virus infection preceding the NHL diagnosis and Stage IV NHL were associated with worse survival, whereas a diagnosis of NHL in the post-HAART period and chemotherapy were associated with better survival. The median survival was 4 months pre-HAART and 9 months post-HAART. CONCLUSIONS: Since the introduction of HAART, there has been a decrease in the incidence of systemic and CNS NHL among patients with AIDS. Among patients with systemic, AIDS-related NHL, there has been decreased high-grade histology, increased use of chemotherapy, and improved survival.     

Prevention of recurrence and prolonged survival in primary central nervous system lymphoma (PCNSL) patients treated with adjuvant high-dose methylprednisolone

Five patients at risk for primary central nervous system lymphoma (PCNSL) recurrence were treated with high-dose methylprednisolone (HDMP) to prevent 'trafficking' of malignant lymphocytes into the central nervous system (CNS). HDMP was chosen because of its ability to stabilize the 'blood brain barrier (BBB)'. Three men with newly diagnosed PCNSL, ages 62, 76 and 78y, whose survival was projected to be 6.6 months, began treatment after achieving complete response (CR) to initial radiation therapy alone and survived 27, 37 and 59 months after treatment. In none was death from recurrent disease in CNS but one patient did die of systemic non-Hodgkin's lymphoma (NHL) five years after PCNSL diagnosis. A 20 y old man was treated with HDMP after successful combined modality therapy and is alive 75+ months after initial diagnosis without evidence of disease recurrence. A 34 y old man relapsed after combined modality initial treatment and failed to respond to HDMP when treatment was begun after unsuccessful salvage therapy; he died of disease 12 months after initial diagnosis. There were no treatment complications. The promising results in this pilot study from the basis for a North Central Cancer Treatment Group (NCCTG) 96-73-51, a Phase 2 clinical trial of brain radiotherapy and HDMP for PCNSL patients 70y of age and older, a group of patients at high risk for toxicity from intensive combined modality therapy.     

Primary non-Hodgkin lymphoma of the breast: The Mayo Clinic Experience

BACKGROUND AND OBJECTIVES: To retrospectively evaluate the characteristics, natural history, results of treatment, and prognostic factors for patients diagnosed with primary breast lymphoma. METHODS: Between 1973 and 1998, 25 women and 1 man with the diagnosis of primary breast non-Hodgkin lymphoma (PNHLB) were seen at Mayo Clinic Rochester and Mayo Clinic Scottsdale. Patient characteristics, treatment methods, and outcome were analyzed. RESULTS: The median follow-up for surviving patients was 6.6 years (range: 1.8-22.1 years). There were 11 low-grade NHL, 13 intermediate-grade NHL, and 2 high-grade NHL. Three patients underwent mastectomy while 23 had local excision. The Ann Arbor stage of disease included: Stage I-21 patients, Stage II-5 patients. Sixteen patients received radiation after surgery (15 after biopsy, 1 after mastectomy). Chemotherapy was given to 10 patients as part of the initial treatment. Four patients with low-grade disease were treated with excision only. The 5-year overall survival rate was 70% and relapse-free survival rate 42%, while local control rate was 75% and distant control rate 51%. Five-year survival and relapse-free survival rates for patients with low-grade disease were 91 and 61%, respectively. Three of four patients with low-grade disease treated with excision alone were free of local recurrence. For intermediate- and high-grade PNHLB, 5-year survival rate was 61% for those treated with chemotherapy, compared to 31% for those without chemotherapy (P = 0.35), and the 5-year relapse-free survival rates were 49%, compared to 0%, respectively (P = 0.0017). Three patients with intermediate- or high-grade disease developed central nervous system (CNS) dissemination. On univariate analysis, Ann Arbor stage was the only significant prognostic factor for survival (P = 0.0021). CONCLUSIONS: The management of PNHLB should be based on histologic grade. Patients with low-grade disease may be managed with local therapy alone. The role of chemotherapy in this group is unclear. Patients with intermediate- or high-grade disease have better outcome if chemotherapy is included. An unusual site of distant dissemination for these patients is the CNS. The only significant prognostic factor for survival is Ann Arbor stage.     

Secondary involvement of the central nervous system in malignant non-Hodgkin's lymphoma. A study of 30 cases in a series of 498 patients

Of 498 patients with non-Hodgkin's lymphoma (NHL), 30 showed secondary central nervous system (CNS) involvement. Of these 30 patients, 26 had high-grade malignancy and 21 lymphoblastic lymphoma, mainly convoluted (n = 8) or Burkitt (n = 6) type according to the Kiel classification. In half of the 30 patients, CNS involvement was associated with progressive lymphoma. Bone marrow involvement was found in half of the patients before or at the time of the diagnosis of CNS involvement, which was 12 months (mean) after the diagnosis of NHL. Eight patients received CNS prophylaxis. Results of treatment for CNS involvement are poor (mean survival time from CNS involvement: 3.5 months). The Kiel classification allows good identification of patients at high risk of CNS lymphoma: systematic CNS prophylaxis is indicated only in the convoluted and Burkitt types. An efficient prophylaxis must be found and results must be confirmed by other studies.     

Clinical aspects and management of AIDS-related lymphoma

The incidence of non-Hodgkin's lymphoma (NHL) is increased by approximately 100-fold in patients with advanced HIV infection. Clinical presentations may include systemic lymphoma, primary central nervous system (CNS) lymphoma, and primary effusion lymphoma. Systemic lymphoma is the most common presentation, is almost always of intermediate or high-grade histology and B-cell phenotype, and usually involves extranodal sites. The disease is potentially curable with combination chemotherapy used for immunocompetent patients with lymphoma, although cure is achieved in only approximately 10–35% of patients. Primary CNS lymphoma may be difficult to distinguish from cerebral infection. The prognosis is very poor, although approximately 10% of patients selected for therapy may survive beyond 1 year with brain irradiation. Attention to infection prophylaxis and antiretroviral therapy is important. Evidence suggests that highly active antiretroviral therapy (HAART) has resulted in a decreased incidence of lymphoma, and that patients with systemic lymphoma treated in the post-HAART era have a better prognosis.     

原发性中枢神经系统淋巴瘤诊治进展

原发性中枢神经系统淋巴瘤(primarycentralnervoussystemlymphoma,PCNSL)是原发于脑、眼和脊髓的非霍奇金氏淋巴瘤,临床上较罕见,近数十年来发病率逐渐上升。PCNSL多见于老年患者,病理类型、预后因素和治疗方案有别于全身性非霍奇金淋巴瘤(NHL)。PCNSL病理类型以弥漫大B细胞为主,年龄和(performancestatus)PS是最重要的预后因素,预后较全身性NHL差。目前PCNSL尚无标准治疗方法,一般采用化疗和放疗联合的治疗措施。手术仅起到诊断作用。PCNSL对放疗高度敏感,但单纯放疗有效维持时间短。化疗在治疗PCNSL中不可缺少,但CHOP方案对PCNSL无效。大剂量甲氨蝶呤(HD-MTX)是最有效的药物,大剂量阿糖胞苷(HD-AraC)是常用的药物之一。因此,现阶段PCNSL采用含HD-MTX或/和HD-AraC等的联合化疗,同时鞘内注射MTX、AraC和地塞米松(DXM)。放疗疗效差,放疗应在化疗结束后进行。联合化、放疗对60岁以上患者可造成严重的远期神经毒性,对老年患者可选择单纯化疗和延迟放疗的治疗方法。自体造血干细胞支持下超大剂量化疗疗效优于历史对照。新药Temozolomide、Temozolomide联合美罗华、Topotecan、放射免疫治疗药物Y90标记CD20单抗等对PCNSL取得一定效果,值得进一步研究。     

Combined chemotherapy in 76 children with non-Hodgkin's lymphoma excluding Burkitt's lymphoma

From January 1983 to December 1986 seventy-six previously untreated children with non-Hodgkin's lymphoma (NHL) were treated by combination chemotherapy. Burkitt's lymphoma patients were ineligible. The treatment regimens include intermittent chemotherapy and for non-localized patients, prophylactic central nervous system chemotherapy. Intrathoracic non-Hodgkin's lymphoma patients also had cranial prophylactic radiotherapy. Sixty-six patients (86.8%) achieved complete remission. Two year failure-free survival rate was 82.1% for localized (stage I and II) NHL and 53.3% for non-localized (stage III and IV) NHL patients. Failure-free survival did not differ significantly for the two major histologic diagnoses, but two year survival rate was lower in diffuse poorly differentiated lymphoblastic than undifferentiated non-Burkitt's lymphoma (50% versus 66.8% respectively). Failure-free survival rate was 53.7% in mediastinal disease and, 73.2% in abdominal disease at 24 months. Relapse rate was higher in mediastinal cases (46.1%) than primary abdominal cases (24.3%) at 24 months. Eleven (13.5%) died of treatment related sepsis. Although the overall survival rate was 72.4% at 2 years we need novel or more intensive programmes for mediastinal and non-localized disease.     

非霍奇金淋巴瘤中枢神经系统累及的诊断和预防

 非霍奇金淋巴瘤（NHL）患者中枢神经系统（CNS）累及预后不良,其中位生存期2～6个月。与NHL CNS累及相关参数是年轻、进展期、累及结外部位数、乳酸脱氢酶（LDH）增高和国际预后指标（IPI）积分。最有希望的治疗为自体造血干细胞移植,可延长中数生存期10～26个月。处于CNS侵袭高危状态的某些NHL亚型患者需要早期进行CNS预防,如伯基特淋巴瘤（BL）和淋巴母细胞淋巴瘤（LBL）。弥漫性大B细胞淋巴瘤（DLBCL）初期治疗时是否需应用CNS预防久有争议,因为它属于CNS累及（≈5 ％）的低危群体。危险模式的确定有助于预示NHL的CNS复发。     

原发性睾丸非霍奇金淋巴瘤

原发性睾丸非霍奇金淋巴瘤(NHL)极少见,仅占所有NHL的1%～2%,弥漫大B细胞淋巴瘤是最常见的病理类型.多发于60岁以上老年人.对侧睾丸受侵率高,易侵及中枢神经系统、皮肤等结外器官.ⅠE/ⅡE期病人睾丸切除术后综合治疗可降低复发率,提高生存率.晚期病人以化疗为主.对侧睾丸预防照射可降低其复发率,但中枢神经系统的预防性鞘内注药是否降低复发率还有争议.该病复发率高,预后差,国际预后指数与其预后相关.