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high dose; BCNU: carmustine; TT: thiotepa; BEAM: carmustine, etoposide, cytarabine, melfalan; BEAC: carmustine, etoposide, cytarabine, cyclophosphamide.

Stem Cell Transplantation

Central nervous system recurrence of systemic lymphoma in the era of stem cell transplantation – an International Primary Central Nervous System Lymphoma Study Group project Jacoline E. Bromberg,1 Jeanette K. Doorduijn,2 Gerald Illerhaus,3 Kristoph Jahnke,4 Agniezka Korfel,4 Lars Fischer,4 Kristina Fritsch,3 Outti Kuittinen,5 Samar Issa,6 Cees van Montfort,7 and Martin J. van den Bent1 1

Depts. of Neuro-Oncology, 2Hematology, and 7Trials and Statistics, Daniel den Hoed Cancer Center, Erasmus MC University Medical Center, Rotterdam, The Netherlands; 3Dept. of Hematology, Freiburg University Hospital, Freiburg, Germany; 4Dept of Hematology and Oncology, Charité-University Hospital, Berlin, Germany; 5Dept. of Hematology, Oulu University Hospital, Oulu, Finland; and 6Dept. of Hematology, Middlemore Hospital, Auckland, New Zealand ABSTRACT

Autologous stem cell transplantation has greatly improved the prognosis of systemic recurrent non-Hodgkin’s lymphoma. However, no prospective data are available concerning the feasibility and efficacy of this strategy for systemic lymphoma relapsing in the central nervous system. We, therefore, we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centers in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World Health Organization performance status of 2, of whom 76% had diffuse large B-cell histology. The majority (79%) of these patients were treated with systemic chemotherapy with or without intravenous rituximab. Twenty-seven patients (29%) were transplanted; age and insufficient response to induction chemotherapy were the main reasons for not being transplanted in the remaining 65 patients. The median overall survival was 7 months (95% confidence interval 2.6-11.4), being 8 months (95% confidence interval 3.8-5.2) for patients ≤ 65 years old. The 1-year survival rate was 34.8%; of the 27 transplanted patients 62% survived more than 1 year. The Memorial Sloan Kettering Prognostic Index for primary central nervous system lymphoma was prognostic for both undergoing transplantation and survival. In conclusion, despite the availability of autologous stem cell transplantation for patients with central nervous system progression or relapse of systemic lymphoma, prognosis is still poor. Longterm survival is, however, possible and more likely in patients able to undergo stem cell transplantation.

Introduction Patients with a relapsed systemic non-Hodgkin’s lymphoma (NHL) with central nervous system (CNS) localization have a poor prognosis with a median survival of 2-4 months and a 1year survival rate of less than 10% after various conventional treatments.1-3 In relapsed systemic lymphoma without CNS localization, survival is much improved by myelo-ablative therapy followed by autologous stem cell transplantation (ASCT), especially when combined with rituximab.4-7 Patients with relapsed lymphoma with a CNS localization have always been excluded from protocols studying ASCT and no prospective data are available concerning the feasibility and efficacy of this treatment in such patients. Retrospective studies of transplanted patients have shown that treatment with high-dose chemotherapy and stem cell transplantation can result in long-term survival in selected patients.8-11 However, there are virtually no data concerning the whole population of patients with a CNS localization of a recurrent systemic lym-

phoma. The prognosis of these patients is, therefore, unknown. Likewise, it is not known what proportion of these patients actually reach transplantation or which patient- or treatment related factors influence prognosis. We, therefore, aimed to assess outcome in patients with a first recurrence of systemic NHL in the CNS in the era of stem cell transplantation in a retrospective multicenter study. The International Primary CNS Lymphoma Collaborative Group (IPCG) is an international multidisciplinary group from Europe, North America and Australasia set up to advance knowledge on CNS lymphoma. Given the rarity of CNS recurrence of systemic lymphoma the platform of the IPCG was used to gather information on a larger number of patients than would be possible in a single center or national setting.

Design and Methods From collaborating centers, patients with a CNS recurrence or progression of systemic lymphoma were selected from local databases.

©2013 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2012.070839 Manuscript received on June 9, 2012. Manuscript accepted on November 5, 2012. Correspondence: [email protected] 808

haematologica | 2013; 98(5)

CNS recurrence of systemic lymphoma

Patients were included if they had been diagnosed with systemic NHL and had a first recurrence in the cerebrospinal fluid (CSF), brain parenchyma or both and were treated for their recurrence between January 2000 and January 2010. Concurrent systemic lymphoma was allowed but not required. For these patients data were collected on baseline characteristics, prognostic factors such as age, performance status, and International Prognostic Index (IPI) score as well as on treatment of both the primary disease and the recurrence or progression. With regard to the treatment of the recurrence or progression, the information recorded was the result and toxicity of the treatment, and survival. Data were rendered anonymous locally and collected in a central database. Independent review board approval was obtained for all participating centers, according to local regulations in the various countries. Primary outcome measures were overall survival and percentage of patients transplanted. The secondary outcome was toxicity. Patient- and treatment-related factors were analyzed and compared descriptively. Kaplan-Meier survival estimates were used to predict overall survival. Log-rank statistics to compare times to event across stratification variables were used to describe potential trends. Univariate Cox regression analysis was performed for age at relapse, both as a continuous variable and divided into age up to and over 65 years, and up to and over 50 years. These age limits were chosen since 65 is a commonly used age limit for stem cell transplantation and 50 has been found to be a prognostic factor in primary CNS lymphoma.12 Additionally, the value of the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score for primary CNS lymphoma was evaluated in this population of patients with secondary CNS lymphoma.12 There are three prognostic categories in this score: category 1 being age ≤50 years, category 2 being age >50 years and Karnofsky performance status ≥70, and category 3 being age >50 years and Karnofsky performance status 65 years. The difference between patients up to the age of 65 and those Table 2. Clinical features of the patients at relapse.

Feature Median age at relapse (range) Interval between NHL diagnosis and CNS relapse (median, range) CNS symptoms Cranial nerve palsy Peripheral sensory/motor symptoms Mental status changes Headache Gait/balance disturbance Nausea/vertigo Seizures Focal CNS signs Concurrent systemic recurrence Yes No Not reported/unknown Localization of CNS disease Brain parenchyma Leptomeningeal Both Other or unknown ECOG/WHO performance status 0 1 2 3 4 Not reported


Value 59 (22-88) years 9 (0.5-281) months

28 (30%) 23 (25%) 8 (20%) 6 (17%) 9 (10%) 4 (4%) 4 (4%) 4 (4%) 53 (58%) 5 (5%) 34 (37%) 40 (43%) 37 (40%) 7 (8%) 8 (9%) 6 (7%) 28 (30%) 25 (27%) 8 (9%) 2 (2%) 23 (25%)

older was not statistically significant (log rank P=0.25). The overall survival rate was 35% at 1 year and 22% at 3 years. The median overall survival for transplanted patients was not reached. The overall survival rates in patients who had undergone ASCT were 62%, 54% and 42% at 1 year, 2 years and 3 years, respectively. The corresponding rates for patients who were not transplanted were 25%, 17% and 14% at 1, 2 and 3 years. At the end Table 3. Treatment of relapse.


N. of patients (%)

Systemic chemotherapy MTX+araC combinations MTX + ifosfamide MTX + other Bonn combination MTX monotherapy Any including HD-MTX HD-araC + other Any including HD-araC Other (no HD-MTX or ara-C) Intravenous rituximab Yes No Not reported Radiotherapy Cranial radiotherapy only Cranial radiotherapy + chemotherapy Brain + spinal cord Focal other Intrathecal/intraventricular MTX Ara-C, native or sustained release MTX + ara-C None Not reported Myeloablative treatment Chemotherapy BCNU/TT BEAM/BEAC Busulfan and cyclophosphamide Other Total body irradiation Transplantation Yes No No treatment

73 (79%) 18 (25%) 13 (18%) 14 (19%) 3 (4%) 6 (8%) 54 (74%) 12 (16%) 30 (41%) 7 (9%) 23 (25%) 53 (58%) 16 (17%) 22 (24%) 1 10 (11%) 7 ( 8%) 3 ( 3%) 2 ( 2%) 56 (60%) 25 6 25 34 2 28 (30%) 24 (26%) 10 3 3 8 4 (4%) 27 (29%) 65 (71%) 4 (4%)

MTX: methotrexate; ara-C: cytarabine; Bonn combination: HD-methotrexate, ifosfamide, vincristine, dexamethasone, cytarabine; cyclophosphamide, vindesine combination; HD: high dose; BCNU: carmustine; TT: thiotepa; BEAM: carmustine, etoposide, cytarabine, melfalan; BEAC: carmustine, etoposide, cytarabine, cyclophosphamide.

Table 4. Response to induction chemotherapy at recurrence. Complete response Partial response Stable disease Progressive disease Not reported



26/73 (36%) 22/73 (30%) 4/73 (5%) 16/73 (22%) 5/73 (7%)

15/73 (21%) 10/73 (14%) 3/73 (4%) 16/73 (22%) 29/73 (40%)

haematologica | 2013; 98(5)

CNS recurrence of systemic lymphoma

of the follow-up 66 patients (72%) had died; the median follow-up for patients still alive was 51 months (range, 2 147 months), while that for transplanted patients was 56 months (range, 5-147 months). The cause of death was lymphoma in 38 patients (41%); in 15% this was the systemic lymphoma, in 17% the CNS lymphoma and in 9% both. Twenty-one patients (23%) died of sepsis with or without other metabolic factors, and seven (8%) died of neurotoxicity (n=1) and unknown causes. At univariate analysis prognostic factors for overall survival were age at relapse (P=0.003, Figure 1A), ECOG/WHO status at relapse (P=0.006, Figure 1B), and the combination of these as summarized in the MSKCC prognostic score (P=0.001, Figure 1C). The median overall


Overall survival by age

survival in patients with a MSKCC prognostic score of 1 (age ≤50 years) was 16 months, and differed significantly from the 9 months in patients with a MSKCC score of 2 (age >50 years and ECOG/WHO score 0-2) and 2 months in patients with a MSKCC score of 3 (age >50 years and ECOG/WHO score >2) (P=0.001). No treatment factors other than transplantation (P 50 and WHO/ECOG 3,4 age ≤ 50-censored age > 50 and WHO/ECOG 0-2-censored age > 50 and WHO/ECOG 3,4-censored


Overall survival by transplatation stem cell transplantation stem cell transplantation performed no stem cell transplantation performed stem cell transplantation performed-censored no stem cell transplantation performed-censored


MSKCC score

0.8 Cumulative survival



0.4 Long Rank P

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