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.     

Ki-67 is a strong predictor of central nervous system relapse in patients with mantle cell lymphoma (MCL)

High Ki-67 is strongly associated with the risk of CNS relapse in patients with mantle cell lymphoma. Two-year incidence of CNS relapse in patients with Ki-67 ≥ 30 exceeds 25%. The incidence was not decreased by rituximab, high-dose cytarabine, high-dose methotrexate or consolidative ASCT. Development of new prophylactic strategies for CNS involvement is mandatory in patients with high Ki-67.BackgroundCentral nervous system (CNS) relapse is an uncommon but challenging complication in patients with mantle cell lymphoma (MCL). Survival after CNS relapse is extremely poor. Identification of high-risk populations is therefore critical in determining patients who might be candidates for a prophylactic approach.Patients and methodsA total of 608 patients (median age, 67 years; range 22–92) with MCL newly diagnosed between 1994 and 2012 were evaluated. Pretreatment characteristics and treatment regimens were evaluated for their association with CNS relapse by competing risk regression analysis.ResultsNone of the patients received intrathecal prophylaxis. Overall, 33 patients (5.4%) experienced CNS relapse during a median follow-up of 42.7 months. Median time from diagnosis to CNS relapse was 20.3 months (range: 2.2–141.3 months). Three-year cumulative incidence of CNS relapse was 5.6% [95% confidence interval (95% CI) 3.7% to 8.0%]. Univariate analysis revealed several risk factors including blastoid variant, leukemic presentation, high-risk MCL International Prognostic Index and high Ki-67 (proliferation marker). Multivariate analyses revealed that Ki-67 ≥ 30 was the only significant risk factor for CNS relapse (hazard ratio: 6.0, 95% CI 1.9–19.4, P = 0.003). Two-year cumulative incidence of CNS relapse in patients with Ki-67 ≥ 30 was 25.4% (95% CI 13.5–39.1), while that in the patients with Ki-67 < 30 was 1.6% (95% CI 0.4–4.2). None of the treatment modalities, including rituximab, high-dose cytarabine, high-dose methotrexate or consolidative autologous stem-cell transplant, were associated with a lower incidence of CNS relapse. Survival after CNS relapse was poor, with median survival time of 8.3 months. There was no significant difference in the survival by the site of CNS involvement.     

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.     

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。     

Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma

BackgroundThe incidence and risk factors of central nervous system (CNS) involvement in peripheral T-cell lymphomas (PTCLs) are still unclear.Patients and methodsWe analyzed 228 patients with PTCLs, excluding cases of extranodal natural killer/T-cell lymphoma and primary cutaneous T-cell lymphoma, by retrospectively collecting the clinical features and outcomes of the patients.ResultsTwenty events (8.77%, 20/228) of CNS involvement were observed during a median follow-up period of 13.9 months (range 0.03–159.43). Based on univariate analysis, elevated serum lactate dehydrogenase (LDH) level [P = 0.019, relative risk (RR) 5.904, 95% confidence interval (CI) 1.334–26.123] and involvement of the paranasal sinus (P = 0.032, RR 3.137, 95% CI 1.105–8.908) adversely affect CNS involvement. In multivariate analysis, both were independently poor prognostic factors for CNS relapse [elevated LDH level: P = 0.011, hazard ratio (HR) 6.716, 95% CI 1.548–29.131; involvement of the paranasal sinus: P = 0.008, HR 3.784, 95% CI 1.420–10.083]. The survival duration of patients with CNS involvement was significantly shorter than that of the patients without CNS involvement (P = 0.009), with median overall survival of 7.60 months (95% CI of 4.92–10.28) versus 27.43 months (95% CI of 0.00–57.38), respectively.ConclusionsElevated LDH level and involvement of the paranasal sinus are two risk factors for CNS involvement in patients with PTCLs. Considering the poor prognoses after CNS relapse, prophylaxis should be considered with the presence of any risk factor.     

High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy.

PURPOSE: To determine whether high-dose therapy (HDT) with autologous stem-cell transplantation (ASCT) should be included in the initial consolidative treatment of patients with advanced, unfavorable Hodgkin's lymphoma (HL). PATIENTS AND METHODS: One hundred sixty-three patients achieving complete remission (CR) or partial remission (PR) with four initial courses of doxorubicin, bleomycin, vinblastine, and dacarbazine, or other doxorubicin-containing regimens, were randomly assigned to receive HDT plus ASCT (83 patients) versus four courses of conventional chemotherapy (80 patients). Unfavorable HL was defined as the presence of at least two of the following poor prognostic factors: high lactate dehydrogenase level, large mediastinal mass (greater than at least 33% of the thoracic diameter), more than one extranodal site, low hematocrit level, and inguinal involvement. RESULTS: At the end of the treatment program, 92% of patients in arm A and 89% in arm B achieved a CR (P =.6). After a median follow-up of 48 months, the 5-year failure-free survival rates were 75% (95% confidence interval [CI], 65 to 85) in arm A and 82% (95% CI, 73 to 90) in arm B (P =.4). The 5-year overall survival rates were 88% (95% CI, 80 to 96) in arm A and 88% (95% CI, 79 to 96) in arm B (P =.99). The 5-year relapse-free survival rates were 88% in arm A (95% CI, 80 to 96) and 94% in arm B (95% CI, 88 to 100), and the difference was not significant (P =.3). CONCLUSION: Patients with advanced unfavorable HL achieving CR or PR after four courses of doxorubicin-containing regimens have a favorable outcome with conventional chemotherapy. No benefit from an early intensification with HDT and ASCT was shown.     

The Outcomes of Diffuse Large B-cell Lymphoma Patients with Synchronous and Early Central Nervous System Involvement: A Single-Center Experience

Background: Diffuse large B cell lymphoma (DLBCL) is the most commonly diagnosed subtype of non-Hodgkin’s lymphoma (NHL). R-CHOP has significantly improved clinical outcomes in patients with DLBCL, however, its indication in the prevention of CNS relapse and recurrence is still inconsistent. Moreover, prophylactic methotrexate and/or cytarabine have been used prophylactically for DLBCL patients is at high risk of CNS relapse and to treat CNS DLBCL, however, their efficacy remains unclear. Methods: The aim of our retrospective study was to determine the incidence of CNS in-volvement in patients with DLBCL and to describe its risk factors and survival outcomes. Results: A total of 406 patients with DLBCL were identified, and 17 (4.2%) of DLBCL patients had CNS involvement i.e. 9 (2.2 %) at diagnosis and 8 (~2%) at relapse. The patients were younger, had advanced stage, high CNS-IPI, and had extra nodal involvement. Seven out of the 17 patients who survived received chemotherapy and a prophylactic methotrexate. Considering the CNS-IPI, of the 146 patients with high CNS-IPI at presentation, 18 received the prophylactic HDMTX and 3 (16.7%) of them had CNS relapse. Two (1.6%) out of 128 who did not receive the prophylactic HDMTX had CNS relapse. On the other hand, of the 223 patients with intermediate CNS-IPI, 25 received the prophylactic HDMTX and 2 (8%) of them had CNS relapse and in 198 patients who did not receive the prophylactic HDMTX, 2 (1.01%) had CNS relapse. The 5-year progression-free survival and overall survival rates for the entire cohort were 73% and 84%, respectively. The median OS for those who had CNS involvement was 17 months and the 2-year OS was 40%. Conclusion: CNS involvement in DLBCL has a poor prognosis, thus, aggressive CNS-directed therapy should be considered, especially in young patients.     

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.     

Intensive therapy and autotransplant for patients with an incomplete response to front-line therapy for lymphoma

BACKGROUND:: Patients with Hodgkin's disease (HD) and intermediate or high-gradenon-Hodgkin's lymphoma (NHL) who fail to achieve a completeremission (CR) with standard induction therapy have a poor prognosiswith conventional-dose salvage therapy alone. We examined therole of subsequent intensive therapy and autologous bone marrowtransplantation (ABMT) in patients who demonstrated a responseto conventional-dose salvage therapy. PATIENTS AND METHODS:: Sixty-six patients with either HD (n = 30) or NHL (n = 36) underwentintensive therapy with etoposide (60 mg/kg), intravenous melphalan(160–180 mg/m²) followed by infusion of unpurged autologousbone marrow and/or blood cells. All patients had advanced stageor bulky disease at diagnosis and failed to achieve a CR afteran anthracycline-containing front-line chemotherapy regimen(NHL) or ABVD or equivalent regimen (HD). Patients who achieveda CR after involved-field radiotherapy were excluded. All patientsdemonstrated sensitivity to conventionaldose salvage treatmentbefore advancing to intensive therapy and ABMT. RESULTS:: The CR, partial response (PR) and overall response rate (RR)following ABMT for HD patients was 48%, 17% and 65%, respectively.At a median follow-up of 35 months, the predicted three-yearoverall survival (OS) is 51% (95% CI: 44%–60%) and event-freesurvival (EFS) is 34% (95% CI: 26%–54%). For patientswith NHL, the CR, PR and RR were 68%, 9% and 77%, respectively.At a median follow-up of 28 months, the predicted three-yearOS is 51% (95% CI: 35%–66%) and EFS is 39%(95% CI: 21%–57%). CONCLUSIONS:: Intensive therapy with etoposide and melphalan followed by ABMTresults in prolonged survival in selected patients with lymphomawho fail to achieve a complete remission to front-line chemotherapy.Based on our previous studies of outcome to conventionaldosesalvage chemotherapy, we estimate that of all patients failinginduction therapy, 28% with HD and 15% with NHL will be eventfreeat three years after ABMT. induction failure, Hodglun's disease, non-Hodgkin's lymphoma, refractory lymphoma     

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.     

Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis and/or at first relapse: results from the GET-LALA group

Outcome of adult acute lymphoblastic leukemia (ALL) with central nervous system (CNS) involvement is not clearly defined. We studied 104 patients presenting with CNS involvement at diagnosis among 1493 patients (7%) included into the LALA trials, and 109 patients presenting CNS disease at the time of first relapse among the 709 relapsing patients (15%). Eighty-seven patients (84%) with CNS leukemia at diagnosis achieved complete remission (CR). Fifty-three patients underwent stem cell transplantation (SCT): 25 allogeneic SCT, 28 autologous SCT, while 34 continued with chemotherapy alone. Seven-year overall survival (OS) and disease-free survival (DFS) were 34% and 35%, respectively. There were no significant differences in terms of CR, OS and DFS among patients with CNS involvement at diagnosis and those without CNS disease. There were also no differences among the two groups regarding T lineage ALL, B lineage ALL, and among those who underwent SCT. After a first relapse, 38 patients with CNS recurrence (35%) achieved a second CR. The median OS was 6.3 months. Outcome was similar to that of relapsing patients without CNS disease. CNS leukemia in adult ALL is uncommon at diagnosis as well as at the time of first relapse. With intensification therapy, patients with CNS leukemia at diagnosis have a similar outcome than those who did not present with CNS involvement. CNS leukemia at first relapse remains of similar poor prognosis than all other adult ALL in first relapse.     

High-dose therapy and autologous stem cell transplantation in Korean patients with aggressive T/NK-cell lymphoma

The proportion of aggressive T/NK-cell lymphoma in Korea is larger than in the West, and it shows a lower response to conventional chemotherapy and poorer survival than diffuse large B-cell lymphoma. This study was undertaken to evaluate the response rate and survival and to document the prognostic factors in patients with T/NK-cell lymphoma who have undergone high-dose therapy (HDT). Eligibility for the study was a mature T/NK-cell lymphoma with initially poor risk (as high or high intermediate risk on age-adjusted International Prognostic Index) or relapsed cases. Twenty-eight patients from 6 centers were reviewed retrospectively. The M : F ratio was 20:8, and median age was 36 years (range 16--60 years). Twelve patients had unspecified peripheral T-cell lymphomas, 7 anaplastic large-cell lymphomas, 6 nasal T/NK-cell lymphomas, and 3 angioimmunoblastic T-cell lymphomas. Disease status at transplant were initially poor risk in 15, chemosensitive relapse in 8 and chemo-resistant relapse in 5 patients, respectively. A complete response (CR) after HDT comprised 20 patients, including 16 with continued CR. Absolute neutrophil count ( > 500/microl) recovered at a median 11 days after autologous stem cell transplantation in 26 patients. Two therapy-related mortalities occurred. Estimated 3-year event-free survival and overall survival (OS) (+/- SE) were 24+/- 9 and 42+/- 10 months, respectively. Only CR status after HDT influenced OS (P=0.000). Therefore, an initial approach with effective induction and HDT may result in a better outcome in T/NK-cell lymphoma.     

Diagnosis and treatment of central nervous system involvement in non-Hodgkin's lymphoma

The diagnosis of lymphoma of the central nervous system (CNS) has been facilitated by advances in neuroimaging and laboratory analysis of cerebrospinal fluid. The most common form of central nervous system CNS involvement in non-Hodgkin's lymphoma (NHL) is leptomeningeal disease. After a diagnosis is established, the use of intrathecal or systemic chemotherapy and radiotherapy can improve survival and palliate symptoms. High-dose systemic chemotherapy with hematopoietic stem cell transplantation is an important treatment option at central nervous system relapse of NHL and for primary CNS lymphoma. The prognosis for disease-free survival and cure is better for patients who have treatment of CNS disease before transplantation than for patients who have active central nervous system disease at the time of transplant.     

Risk factors for relapse after complete remission with high-dose therapy for multiple myeloma

Complete remission (CR) is an important surrogate for long-term survival for patients with multiple myeloma. However, most patients achieving CR eventually relapse and die from their disease. To better define the predictors of relapse, we conducted a retrospective review of outcomes for patients who achieved CR after autografting at our institution. From January 1990 to December 2002, among >400 patients transplanted, 81 (54 males and 27 females) achieved CR. With a median follow up of 58 months for all surviving patients, the 5-year progression-free survival (PFS) was 33% [95% confidence interval (CI) = 23 - 44] and 5-year overall survival (OS) was 67% (95% CI = 54 - 77). Median PFS was 37 months and median OS has not yet been reached. On multivariate analysis, high tumor mass at diagnosis emerged as a predictor of poor outcome. We conclude that high tumor mass at diagnosis predicts a significantly shorter remission duration for myeloma patients undergoing autografting.     

CHOP Versus CHOP Plus ESHAP and High-Dose Therapy with Autologous Peripheral Blood Progenitor Cell Transplantation for High-Intermediate–Risk and High-Risk Aggressive Non-Hodgkin's Lymphoma

The purpose of the study was to compare conventional cyclophosphamide/doxorubicin/vincristine/prednisolone (CHOP) chemotherapy with CHOP (3 courses) plus etoposide/methylprednisolone/high-dose cytarabine/cisplatin (ESHAP), high-dose therapy (HDT), and autologous peripheral blood progenitor cell transplantation (PBPCT) as front-line treatment for poor-prognosis aggressive non-Hodgkin's lymphoma (NHL). Between May 1, 1995, and April 30, 1998, 58 patients, aged 15-55 years, newly diagnosed with poor-prognosis aggressive NHL (category F-H by the Working Formulation) were enrolled. According to the age-adjusted international prognostic index, 65% of the patients were high-risk cases and 35% made up the high-intermediate group. After 3 courses of CHOP, 25 of 48 patients were randomized to continue with CHOP, and 23 were randomized to receive 2-4 cycles of ESHAP followed by HDT and PBPCT. There was no significant difference in the rate of complete remission between the two groups (36%, 95% confidence interval [CI]: 18%–57% in CHOP vs. 43%, 95% CI: 23%–65% in ESHAP/HDT) (P = 0.77). With a median follow-up duration of 39 months, the 4-year failure-free survival (FFS) was superior in the ESHAP/HDT group (38%, 95% CI: 18%–58% vs. 15%, 95% CI: 4%–32%) (P = 0.04). The disease-free survival was marginally different in favor of the ESHAP/HDT arm (90%, 95% CI: 47%–98% vs. 37%, 95% CI: 7%–69%) (P = 0.06). The 4-year overall survival between the two treatment arms was comparable (51%, 95% CI: 28%–70% for ESHAP/HDT vs. 30%, 95% CI: 13%–48% for CHOP) (P = 0.25). Treatment-related mortalities were not significantly different between both groups (17%, 95% CI: 5%–39% for ESHAP/HDT vs. 8%, 95% CI: 1%–26% for CHOP) (P = 0.41). However, only 61% of the patients assigned to the ESHAP/HDT arm underwent HDT and PBPCT. As compared with CHOP, the corporate regimen of CHOP/ESHAP/HDT seems to improve the FFS in patients with newly diagnosed, poor-prognosis aggressive NHL.     

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.     

CNS involvement in children with newly diagnosed non-Hodgkin's lymphoma.

PURPOSE: To determine the frequency of CNS involvement at diagnosis of non-Hodgkin's lymphoma (NHL), to characterize its pattern of presentation, and to determine its prognostic significance. PATIENTS AND METHODS: We reviewed the records of 445 children (1975 through 1995) diagnosed with NHL (small noncleaved cell NHL/B-cell acute lymphoblastic leukemia [SNCC NHL/B-ALL], 201 patients; lymphoblastic, 113; large cell, 119; other, 12). Tumor burden was estimated by serum lactate dehydrogenase (LDH) measurement and reclassification of disease stage irrespective of CNS involvement (modified stage). RESULTS: Thirty-six of 445 children with newly diagnosed NHL had CNS involvement (lymphoma cells in the CSF [n = 23], cranial nerve palsy [n = 9], both features [n = 4]), representing 13%, 7%, and 1% of small noncleaved cell lymphoma, lymphoblastic lymphoma, and large-cell cases, respectively. By univariate analysis, CNS disease at diagnosis did not significantly impact event-free survival (P =. 095), whereas stage and LDH did; however, children with CNS disease at diagnosis were at 2.0 times greater risk of death than those without CNS disease at diagnosis. In a multivariate analysis, CNS disease was not significantly associated with either overall or event-free survival, whereas both serum LDH and stage influenced both overall and event-free survival. Among cases of SNCC NHL/B-ALL, CNS disease was significantly associated with event-free and overall survival (univariate analysis); however, in multivariate analysis, only LDH had independent prognostic significance. Elevated serum LDH or higher modified stage were associated with a trend toward poorer overall survival among children with CNS disease. CONCLUSION: A greater tumor burden at diagnosis adversely influences the treatment outcome of children with NHL and CNS disease at diagnosis, suggesting a need for ongoing improvement in both systemic and CNS-directed therapy.     

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.     

Primary breast lymphoma

Primary breast lymphoma (PBL) is a rare form of localized extranodal lymphoma. Few reports are available in the literature concerning its treatment and outcome. Of the 34 cases of PBL seen at our institution over a 25-year period, 20 consecutive cases were treated with CHOP or CHOP-like chemotherapy regimen and had adequate biopsy specimens for histological review. All these 20 PBL were of B-cell origin including one case of Burkitt lymphoma, and 2 cases of low-grade histologic type. Sixteen of the 20 patients achieved a complete remission (CR) and 2 achieved a partial remission (PR) (>75% tumor regression). Two patients had progressive disease while on therapy. With a median follow-up period of 80 months, 6 patients relapsed. Median time to relapse from diagnosis was 23 months (range, 3-41 months). Two of the relapses involved the central nervous system (CNS): isolated CNS relapse in one case and associated with other relapse sites in 1 case. The two patients who achieved a PR after chemotherapy also had disease progression to the CNS, 4 and 8 months after the end of CHOP chemotherapy. All 4 patients died of their disease 3, 6, 10 and 13 months after CNS involvement. Of the 16 centroblastic diffuse large B-cell lymphoma (DLCL), 3 had CNS disease at relapse. Three (15%) of our study patients developed a controlateral breast relapse. Twelve of the initial 20 patients were alive, including 11 with a persistent CR, 6 patients died of their lymphoma and 2 of unrelated diseases. In conclusion, we observed a high incidence of CNS relapse in this group of localized extranodal lymphoma, strongly suggesting that CNS prophylaxis should be associated with systemic chemotherapy in localized PLB.