Feasibility of BU, CY and etoposide (BUCYE), and auto-sct in patients with newly diagnosed primary CNS lymphoma: a single-center experience

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1 (2011) 46, & 2011 Macmillan Publishers Limited All rights reserved /11 ORIGINAL ARTICLE Feasibility of BU, CY and etoposide (BUCYE), and auto-sct in patients with newly diagnosed primary CNS lymphoma: a single-center experience DH Yoon 1, DH Lee 1, DR Choi 1, BS Sohn 1, S Kim 1, SW Kim 1, JS Lee 1, SW Lee 2, J Huh 3 and C Suh 1 1 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea and 3 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea We investigated the feasibility of i.v. BU, CY and etoposide (BUCYE), followed by auto-sct (ASCT) in patients with newly diagnosed primary central nervous system lymphoma (PCNSL). The planned treatment consisted of induction chemotherapy with five cycles of high-dose MTX and two cycles of high-dose cytarabine followed by conditioning with BUCYE (BU 3.2 mg/m 2, day 7 to day 5; CY 50 mg/kg, day 3 to day 2 and etoposide 200 mg/m 2, twice a day, days 5 and 4) and then ASCT. Between May 2005 and November 2008, 11 consecutive PCNSL patients were treated. All patients completed the treatment as planned, with no cases of treatment-related death or veno-occlusive disease. After BUCYE and ASCT, 10 patients achieved complete response (CR) or unconfirmed CR (CRu). Two patients, one partial response and one CRu, received further wholebrain radiotherapy, with all achieving CR. At a median follow-up of 25.0 months ( months), six patients had relapsed, with a median event-free interval of 15.0 months (95% confidence interval, months). Median survival time was not reached yet with a 2-year survival rate of 88.9%. The current treatment was feasible with a favorable tolerance profile. However, further regimen optimization is necessary because of high relapse rate. (2011) 46, ; doi: /bmt ; published online 12 April 2010 Keywords: primary CNS lymphoma; auto-sct; BU; CY; etoposide Introduction Treatment of primary central nervous system (CNS) lymphoma (PCNSL) has evolved with radiotherapy and high-dose chemotherapy. High-dose MTX (HD-MTX)- based chemotherapy followed by whole-brain radiotherapy (WBRT) has been regarded as the standard therapy, especially with a median survival time of 4 years in patients younger than 60 years. 1,2 However, there are increasing concerns about delayed neurotoxicity of WBRT, which results in significant morbidity and mortality. As an alternative strategy for PCNSL patients, high-dose chemotherapy followed by auto-sct (ASCT) has been evaluated in several trials, and shown to be feasible as firstline therapy as well as salvage treatment. In those studies, many conditioning regimens were used before ASCT, including high-dose chemotherapy with BEAM, 3 5 and thiotepa-based treatments However, none of the conditioning regimens showed the superiority, and the optimal regimen should be identified. Conversely, BU, CY and etoposide (BUCYE), commonly used in conjunction with allo-sct in patients with leukemia, has additionally been used as conditioning chemotherapy for systemic lymphoma, resulting in 43 58% long-term survival However, this regimen has not been evaluated for PCNSL. Another similar conditioning regimen of BU, CY and thiotepa (BUCYT) has been shown to have high antitumor activity against PCNSL, leading to complete response (CR) rates between 80 and 100% However, this was associated with increased toxicity, particularly in elderly patients. Of note, although etoposide has low blood brain barrier permeability, high-dose etoposide could penetrate into cerebrospinal fluid (CSF) enough to kill tumor cells and eradicate the CNS involvement of non-hodgkin s lymphoma. 17,18 On the basis of these findings, we have used BUCYE as the conditioning regimen for ASCT to treat PCNSL. Here, we investigated the feasibility of high-dose BUCYE followed by ASCT in the treatment of patients with PCNSL showing response to induction chemotherapy of high-dose MTXbased therapy. Correspondence: Dr C Suh, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Songpa-gu, Seoul , Korea. csuh@amc.seoul.kr Received 23 October 2009; revised 1 February 2010; accepted 17 February 2010; published online 12 April 2010 Materials and methods Patients and diagnosis Eleven PCNSL patients newly diagnosed between May 2005 and November 2008 were included in this analysis. All

2 106 of them were diagnosed pathologically as primary CNS diffuse large B-cell lymphoma, which was confirmed by an experienced pathologist (JH) based on the World Health Organization criteria. 19 The additional criteria required to proceed to high-dose chemotherapy followed by ASCT after completion of induction chemotherapy included age of 15 years or older, Eastern Cooperative Oncology Group performance status of 0 2, adequate renal, cardiac, pulmonary and hepatic functions, and absence of HIV infection. until 13 August CR duration was from the time when CR was achieved to the first documentation of relapse or progression. OS was calculated from the first day of induction chemotherapy until death from any cause or last follow-up date for surviving patients. Event-free survival (EFS) was assessed from the first day of induction chemotherapy until relapse, disease progression and death from any cause or last follow-up. CR duration, OS and EFS rates were estimated using the Kaplan Meier productlimit method. Staging Staging evaluation for each patient involved a physical examination, including slit-lamp assessment by an ophthalmologist, contrast-enhanced magnetic resonance imaging of the brain, CT scans of the thorax, abdomen and pelvis, lumbar puncture and CSF cytology, bilateral BM aspiration and biopsy, serology testing for HIV, complete blood cell count with differential, liver and kidney function tests, and serum lactate dehydrogenase measurements. Lumbar puncture was not performed in a patient as increased intracranial pressure was suspected. Prognostic score was based on age, performance status, lactate dehydrogenase level, CSF protein and involvement of deep structures in the brain. 20 Treatment Induction chemotherapy consisted of five cycles of highdose MTX (3.5 g/m 2, once daily, every 2 weeks) and two cycles of high-dose cytarabine (3.0 g/m 2, once daily, every 4 weeks). 5 Peripheral hematopoietic stem cells were collected in nine patients after the first cycle of cytarabine and in two patients after the second cycle of cytarabine. Leukapheresis was performed for 2 consecutive days. The conditioning BUCYE chemotherapy consisted of i.v. BU (3.2 mg/kg, from day 7 to day 5), i.v. CY (50 mg/kg, from days 3 and 2) and etoposide (200 mg/m 2, every 12 h from days 5 and 4). Autologous stem cells were infused on day 0. Patients received 5 mg/kg per day G-CSF s.c., beginning on day 1 until hematopoietic recovery. All patients received seizure prophylaxis with phenytoin before the first dose of BU. The uroepithelial prophylaxis for CY administration consisted of hydration and mesna. Standard institutional protocols were used for administration of antiemetics, antibiotics, transfusions and other supportive care measures. WBRT was reserved for patients failing to achieve CR after ASCT. Response criteria Responses to treatment were assessed according to the criteria of the International Group for PCNSL. 21 Routine follow-up imaging analysis and eye tests were performed every 3 months for the first 2 years, every 6 months for the next 3 years and yearly thereafter or whenever clinically indicated. Statistical analysis All patient data were collected prospectively and stored on a computerized database. Follow-up data were collected Results Patient characteristics and treatment The clinical characteristics of patients are summarized in Table 1. The median age was 52 years (range, years). Ten patients (90.9%) had Eastern Cooperative Oncology Group performance score p1. All patients had parenchymal brain disease, and five showed single lesions. Two patients were positive for CSF cytology. No patient had intraocular or systemic lymphoma. All 11 patients completed five cycles of HD-MTX and two cycles of cytarabine as induction chemotherapy. The median numbers of collected and infused CD34 þ cells were cells per kg (range, 27.2 to cells per kg) and cells per kg (range, 14.4 to cells per kg), respectively. Engraftment of neutrophils and platelets was achieved at a median of 9 days (range, 8 12) and 7 days (range, 5 12), respectively. Response to therapy After the induction chemotherapy, eight (72.7%) out of eleven patients had already achieved CR (including one unconfirmed CR (CRu)) but three had reached partial response (PR) (Table 1). Two of the three patients in PR achieved CR after ASCT. Two patients, one PR and one CRu, were referred to WBRT at the physician s discretion. The patient in PR even after ASCT achieved CR after WBRT. A nonenhancing residual lesion of the patient in CRu remained unaltered during follow-up, and was later concluded as a post-biopsy change. The median duration of first CR was 12.8 months (95% confidence interval (CI), months) with a median follow-up of 25.0 months (range, months). Salvage treatment Relapse of disease occurred in six patients (54.5%); four in the brain parenchyma only, one in both the brain and left eye, and another in the leptomeninges. Among them, five patients received salvage treatment; specifically, WBRT for three patients, intrathecal chemotherapy for another patient with leptomeningeal relapse and sequential chemotherapy of HD-MTX/Ara-C and intravitreal MTX for the patient showing brain and eye involvement (Table 1). Two of the five patients receiving salvage treatment achieved CR again, and had sustained remission for more than 2 years.

3 Table 1 Patient data Status Neurotoxicity OS EFS Response to salvage treatment Salvage treatment Relapse site First CR duration Overall response Brain RT (Gy) Post- ASCT PS LDH CSF Deep structure Prognostic Preprotein 20 involvement 20 score 20 ASCT Sex/Age Extent of disease M/65 Brain 1 Normal NE a Yes Intermediate a PR PR 48 CR AWoD Leg weakness Chemo c PR AWD LEP F/55 Brain 1 Increased Normal No Low CRu b CRu b 45 CR 13.2 Brain and eye M/53 Brain 1 Increased Increased Yes Intermediate CR CR CR AWoD ND F/52 Brain 1 Normal Increased No Low PR CR CR 1.6 Brain WBRT CR AWoD ND M/33 Brain and 1 Normal Increased Yes Intermediate CR CR CR 4.1 CSF IT-chemo CR AWoD LEP CSF M/43 Brain 1 Normal Normal Yes Low CR CR CR 8.1 Brain WBRT NE Alive d ND M/62 Brain 1 Increased Normal Yes Intermediate CR CR CR 12.8 Brain WBRT PR AWD ND M/63 Brain and 1 Normal Normal No Low CR CR CR 6.2 Brain None DOD ND CSF F/47 Brain 2 Increased Normal No Intermediate PR CR CR AWoD ND M/45 Brain 1 Increased Normal Yes Intermediate CR CR CR AWoD ND M/48 Brain 1 Normal Normal No Low CR CR CR AWoD ND Abbreviations: ASCT ¼ autologous SCT; AWD ¼ alive with disease; AWoD ¼ alive without disease; CRu ¼ unconfirmed CR; DOD ¼ dead of disease; EFS ¼ event-free survival; F ¼ female; IT-chemo ¼ intrathecal chemotherapy composed of hydrocortisone, MTX and cytarabine; LDH ¼ lactate dehydrogenase; LEP ¼ leukoencephalopathy; M ¼ male; ND ¼ not definite; NE ¼ not evaluated; PS ¼ performance status; RT ¼ radiotherapy; WBRT ¼ whole-brain RT. a Lumbar puncture was not performed in the patient as raised intracranial pressure was suspected and CSF protein level was not available. However, the values of the other four variables of prognostic score were added together to arrive at a score of two. Accordingly, the patient corresponds to intermediate group (score, 2 3) irrespective of the value of CSF protein. b The patient was administered WBRT after ASCT, as she was assessed as CRu at that time. However, the residual nonenhancing lesion by MRI did not change during follow-up, and showed no hypermetabolism on PET. The lesion was later proposed as a post-biopsy change. c Chemotherapy comprising high-dose MTX/cytarabine and intravitreal MTX injection. d The patient was lost to follow-up after WBRT, but presumed to be alive according to data from the National Health Insurance Corporation. Survival (%) Figure 1 0 Survival analysis Median EFS was 15.0 months (95% CI, months). One patient died due to disease progression, and a median OS was not reached yet. The 2-year EFS rate was 30.3% and estimated 2-year OS rate was 88.9% (Figure 1). Toxicity During BUCYE chemotherapy and ASCT, we observed grade 1 aspartate aminotransferase/alanine aminotransferase elevation in eight (72.7%) patients, and grade 1 or 2 hyperbilirubinemia in two (18.2%) patients, respectively. Two (18.2%) patients showed grade 1 or 2 mucositis. We also observed grade 3 diarrhea in two (18.2%) patients. Febrile neutropenia was observed in 10 (90.9%) patients. One patient experienced transient leg weakness 3 years after ASCT, which spontaneously improved. However, no patient experienced renal toxicity, bleeding or venoocclusive disease. No patient died due to treatment-related causes. In two of the patients subjected to WBRT or chemotherapy after ASCT, follow-up brain MRI revealed demyelination. Discussion Months In this study, BUCYE as a conditioning regimen before ASCT showed moderate antitumor activity and manageable toxicity. The estimated 2-year OS of 88.9% seems to be favorable compared with results with other conditioning regimens. ASCT with BEAM combined with or without WBRT resulted in a 4-year OS of 64% and a 2-year OS of 55%, respectively. 4,5 Thiotepa-based regimens led to a 2-year OS of 48% or a 3-year OS of 50 77%. 7 9 The median EFS of 15.0 months did not seem inferior to those of 9.3 months recorded with BEAM chemotherapy and 17 months with BU/thiotepa. 5,8 The 2-year EFS of 30.3% was similar to the 20% reported with BEAM, 5 but appeared rather inferior to that reported with thiotepabased regimens; specifically, 77% 3-year disease-free OS EFS Kaplan Meier survival curve of OS and EFS. 107

4 108 survival has been reported with BCNU/thiotepa and 45% 2-year EFS with BU/thiotepa. 7,8 Unfortunately, four (36.3%) patients experienced relapse within 1 year in this study. Inactivity of conventional chemotherapy for non-hodgkin s lymphoma has been attributed to poor blood brain barrier permeability of the drugs. In light of blood brain barrier permeability, BU achieves therapeutic levels in the CSF, and CY may reach 20 30% of the serum levels Etoposide has been introduced into high-dose conditioning regimens in combination with BU, because of its substantial dose response. Although etoposide penetrates into the CSF poorly after i.v. administration of a standard dose (o300 mg/m 2 ), 22 the CSF concentration reached up to 0.54 mg/ml upon high dose ( mg/m 2 ) i.v. administration, which was sufficient to kill tumor cells. 17 In this study, patients received etoposide 800 mg/m 2, divided into four doses administered over 2 days; the CSF levels might have been suboptimal to achieve activity against PCNSL. All five patients who received salvage treatment after relapse were alive at the time of analysis, and two of them achieved CR again. This high efficacy of salvage therapy would have contributed to the high 2-year OS rate, despite the relatively low 2-year EFS rate. WBRT was highly active in inducing CR in patients who failed to achieve CR after ASCT or who had relapsed after achieving CR; although two of the five patients who underwent radiotherapy experienced late neurotoxicity. In view of this high antitumor activity but known significant toxicity profile, WBRT may be reserved for salvage treatment rather than a component of routine first-line therapy. Thiotepa-based regimens have shown high efficacy in the treatment of PCNSL. 9,11,23,24 However, this treatment is known to be associated with increased toxicity in elderly patients. Two of the three patients aged more than 60 years in a series involving a total of seven patients experienced significant complications. 9 In a separate study, three of five patients aged more than 60 years who underwent ASCT after BUCYT died from treatment-related complications. 11 Notably, no serious complications during treatment or TRM were observed in this series, despite major limitations such as small patient number, young patient ages and the relatively short follow-up period. Moreover, no leukoencephalopathy was reported among patients who did not receive radiotherapy or salvage chemotherapy. In addition, in this series, HD-MTX/Ara-C induction chemotherapy led to a high CR rate (eight of eleven patients; 72.7%), compared with 14 21% in other reports with HD-MTX. 5 9 The CR rate is remarkable considering that it was 44% even after a combination chemotherapy of HD-MTX (3 g/m 2 ), BCNU, etoposide and methylprednisolone (MVBP regimen), which showed higher activity compared with HD-MTX alone in other trials. 3,4 This discrepancy may be attributed to differences in administration of dose and schedule, or patient populations. All patients completed five cycles of HD-MTX and two cycles of Ara-C in this series, whereas 2 5 cycles of HD-MTX chemotherapy were administered in other studies. Moreover, another factor that should be considered is that the patients included in this investigation were largely young patients with good performance status. A 50% CR rate with HD-MTX chemotherapy has been reported in a Korean study of PCNSL; 25 thus, ethnicity is possibly another variable that requires evaluation, although there are no available data to support variations in the biology of PCNSL among different ethnicities, yet. As shown in a previous study, HD-MTX/Ara-C was effective in mobilizing hematopoietic stem cells. 3 This might enable salvage ASCT or tandem ASCT, as shown in a few PCNSL patients who experienced relapse after BEAM therapy but achieved a durable remission after salvage thiotepa-buconditioning chemotherapy and ASCT. 5,9 In conclusion, the use of BUCYE chemotherapy as a conditioning regimen for ASCT resulted in good response rates and a favorable toxicity profile in PCNSL treatment. However, further optimization of the regimen is required because of the high relapse rate. Conflict of interest The authors declare no conflict of interest. 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