Int J Hematol (2011) 93:720726 DOI 10.

1007/s12185-011-0848-1

ORIGINAL ARTICLE

High-dose methotrexate with R-CHOP therapy for the treatment of patients with primary central nervous system lymphoma
Yasufumi Masaki Miyuki Miki Yue Sun Takuji Nakamura Haruka Iwao Akio Nakajima Nozomu Kurose Tomoyuki Sakai Zhe-Xiong Jin Toshioki Sawaki Takafumi Kawanami Yoshimasa Fujita Masao Tanaka Toshihiro Fukushima Yuko Hirose Hisanori Umehara

Received: 28 January 2011 / Revised: 30 March 2011 / Accepted: 30 March 2011 / Published online: 15 May 2011 The Japanese Society of Hematology 2011

Abstract We describe MR-CHOP therapy, a novel treatment regimen consisting of high-dose methotrexate and R-CHOP that provides systemic anti-tumor activity with penetration of the bloodbrain barrier in patients with newly diagnosed primary central nervous system lymphoma. The MR-CHOP regimen was administered with 2 g/m2 of methotrexate and 375 mg/m2 of rituximab on day 1, 750 mg/m2 of cyclophosphamide on day 3, 50 mg/ m2 of doxorubicin on day 3, 1.4 mg/m2 of vincristine on day 3 and 100 mg of prednisolone on days 15 in this pilot study of seven patients. Six cycles of MR-CHOP therapy were administered every 3 weeks, followed by high-dose chemotherapy with stem cell rescue in young patients, or an additional two cycles of 4 g/m2 methotrexate and rituximab in older patients. The overall response rate was 100%, with 85.7% complete remission (CR). One patient showed partial response, relapsed and subsequently died. Another relapsed following CR, and was rescued by further salvage therapy. The others survive without relapse at a median observation period of 24 months. Hematological toxicity included grade 4 leukocytopenia in 4/7 and neutropenia in 5/7, which were transient and tolerated well. Non-hematological toxicities were tolerated well. The
Y. Masaki (&) M. Miki Y. Sun T. Nakamura H. Iwao A. Nakajima T. Sakai Z.-X. Jin T. Sawaki T. Kawanami Y. Fujita M. Tanaka T. Fukushima Y. Hirose H. Umehara Department of Hematology and Immunology, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan e-mail: yasum@kanazawa-med.ac.jp N. Kurose Department of Pathology and Laboratory Medicine, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Ishikawa 920-0293, Japan

efcacy of this novel regimen as remission induction therapy was found to be promising in this pilot study, although the number of patients was small and follow-up short. Keywords Bloodbrain barrier Rituximab Intra-ocular lymphoma Non-germinal center B-cell type Whole-brain radiotherapy

1 Introduction Primary central nervous system lymphoma (PCNSL) is a rare subtype of diffuse large B-cell lymphoma (DLBCL) that usually occurs in the central nervous system (CNS), including the intra-ocular region, and rarely involves extraCNS lesions [1]. Few patients show expression of elevated serum lactate dehydrogenase (LDH), beta-2 microglobulin (b2MG) and soluble interleukin-2 receptor (sIL2R), even in cases where computed tomography (CT) or magnetic resonance computed tomography (MRCT) shows the presence of a large mass. PCNSL rarely involves extra-CNS lesions, and recurrence and dissemination occur only within the CNS, though extra-nodular lymphomas usually involve a number of non-sequential extra-nodular sites without lymph node metastasis. PCNSL is associated with poor prognosis for several reasons. (1) PCNSL develops in the CNS where it is difcult to detect or obtain biopsy samples, and therefore treatment is often delayed. Furthermore, it is difcult to determine if the treatment is sufcient because most patients are senile and have poor performance status at the time of their diagnosis. (2) Standard chemotherapeutic agents are prevented from reaching brain tissue by the bloodbrain barrier (BBB). (3) The non-germinal center

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(GC) type of DLBCL is a biological poor prognostic factor [2], and most cases of PCNSL present as the non-GC type (activated B-cell type) [1]. R-CHOP therapy (rituximab; cyclophosphamide, CPA; doxorubicin, DOX; vincristine, VCR; and prednisolone, PSL), the standard chemotherapy regimen for the general type of DLBCL [3, 4], is insufcient for PCNSL because it cannot cross the BBB. PCNSL is generally treated with a different combination of agents, in comparison to DLBCL in other sites, and high-dose (HD) methotrexate (MTX) is a key component of these regimens [5, 6]. However, HD-MTX alone is also insufcient [7, 8], and is used in combination with other drugs. No optimal combination therapy has been established for PCNSL. Here, we describe a new concurrent combined regimen of HD-MTX with R-CHOP (MR-CHOP) as the induction therapy for patients with PCNSL with promising results. MR-CHOP therapy provides both BBB penetration and systemic anti-tumor activity.

2 Patients and methods We analyzed seven cases treated at Kanazawa Medical University Hospital from October 2006 to December 2009

(Table 1). Patients with CNS involvement from other primary sites of DLBCL and intravascular large B-cell lymphoma (IVLBCL) were excluded. The cohort included three males and four females, ranging from 19 to 76 years of age (median age 57 y/o; Table 1). All of the patients were serologically negative for HIV and HTLV-1 with no history of other malignancy. The histopathology demonstrated that all of the patients had DLBCL with positive immunohistochemical staining for CD20 and negative results on EpsteinBarr Virus-encoded small non-polyadenylated RNA-in situ hybridization (EBER-ISH). The ECOG performance status of the patients on diagnosis was 1 (2 cases), 2 (2 cases), 3 (1 case), and 4 (2 cases). The PCNSL-international prognostic index (PCNSL-IPI: Ferreri et al., International Extra-nodal Lymphoma Study Group; IELSG) [9] showed that 4 cases were risk level 2, and 3 cases were risk level 4 (Table 2). Other markers, such as serum sIL2R, b2MG, and involved cells in CSF, are also shown in Table 2. The MR-CHOP regimen was administered with 2 g/m2 of MTX (3-h infusion) and 375 mg/m2 of rituximab on day 1, 750 mg/m2 of CPA, 50 mg/m2 of DOX, and 1.4 mg/m2 of VCR (maximum dose 2.0 mg) on day 3 and 100 mg of PSL on days 15. The patients received sufcient hydration

Table 1 Symptoms and site of disease of the PCNSL patients Case 1 2 3 4 5 6 7 Age, sex 53, M 40, F 19, F 73, F 57, F 76, M 65, F Symptoms Diplopia, third nerve palsy, SIADH Numbness of left arm and leg Headache, vomiting, hydrocephalus Vertigo, vomiting Left homonymous hemianopia Left hemiparesis, gait disturbance Right facial numbness, vertigo Site of disease Lateral ventricle, third ventricle, hypothalamus Right temporal lobe Left caudate nucleus Cerebellum Bilateral parietal and occipital lobe, intra-ocular Cerebellum, right hypothalamus Cerebellum, right brain stem

M male F female, SIADH syndrome of inappropriate secretion of antidiuretic hormone Table 2 Predictive factors of PCNSL-IPI and clinical characteristics of the PCNSL patients Case Age PS LDH (U/l) CSF protein Deep structures PCNSL-IPI score Serum sIL2R (U/ml) Serum b2MG (mg/l) CSF cells (/mm3) 1 2 3 4 5 6 7 53 40 19 73 57 76 65 2 1 4 4 1 4 2 146 192 152 172 175 225 162 160: NE 35 NE 71: 46 78: (-) (?) (?) (?) (?) (?) (?) 2 2 2 4 2 4 4 498 494 405 567 441 579 513 3.9 2.4 1.0 2.1 1.4 2.2 1.1 29 NE 8 NE 4 21 4

PCNSL-IPI (prognostic scoring system for primary CNS lymphomas) based on age [ 60 years, ECOG PS 24, elevated LDH serum level, elevated protein CSF concentration, and involvement of the deep structure of the brain [9]. The deep structures of the brain include the periventricular regions, basal ganglia, corpus callosum, brainstem and/or cerebellum. Normal range of LDH is 119229 U/l, sIL2R 145519 U/ml and b2MG 0.82.0 mg/l NE not examined

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722 Table 3 Outcome Case 1 2 3 4 5 6 7 Treatment MR-CHOP 96 ? CHASER/LEED MR-CHOP 96 ? CHASER/LEED MR-CHOP 96 ? CHASER/LEED MR-CHOP 96 ? R-MTX (4 g/m ) 92 MR-CHOP 96 ? CHASER/LEED MR-CHOP 96 ? R-MTX (4 g/m2) 92 MR-CHOP 96 ? CHASER/LEED
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Y. Masaki et al.

Response CR CR CR CR PR CR CR

Time to recurrence

D/A A

Survival duration 40M 38M 27M 24M 19M 15M 12M

8M

A A A

3.5M

D A A

MR-CHOP methotrexate, rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone; CHASER cyclophosphamide, cytosine arabinoside, etoposide, dexamethasone and rituximab; LEED melphalan, cyclophosphamide, etoposide and dexamethasone; R-MTX rituximab and high-dose methotrexate; CR complete remission; PR partial remission; M months; D/A dead or alive; A alive; D dead

and 21 mg of leucovorin rescue was administered four times per day on days 24. The doses of MTX, CPA, DOX, and VCR were reduced to 80% in senile patients[65 years of age. Six cycles of MR-CHOP therapy were administered every 3 weeks, followed by CHASER therapy (CPA, cytosine arabinoside; Ara-c, etoposide, dexamethasone and rituximab) [10] for peripheral blood stem cell harvest (PBCSH) and LEED therapy (melphalan, CPA, etoposide and dexamethasone) [11] as high-dose chemotherapy (HDC) with stem cell rescue. Two elderly patients were treated with 2 additional cycles of 4 g/m2 MTX and rituximab, instead of HDC with PBSCT. The complete remission (CR) rate, the overall response rate (ORR), and adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. were assessed. CR was dened as both improvement of neurological and general symptoms due to PCNSL, and the disappearance of the mass lesion on MRCT (gadolinium enhancement was required). The MR-CHOP regimen was developed as salvage therapy for relapsed PCNSL, and the efcacy and safety were assessed. A pilot study of MR-CHOP therapy as the rst-line induction therapy was conducted with the approval of the institutional review board (IRB) of Kanazawa Medical University Hospital, and with written informed consent from all patients.

Fig. 1 KaplanMeier curve of overall survival of the patients (upper graph). KaplanMeier curve of relapse-free survival of the patients (lower graph)

3 Results (Table 3) All of the patients completed the treatment. Six of 7 patients achieved CR (Figs. 1, 2), and one showed a partial response (PR) with remaining vitreous oaters (ORR 100%, CR rate 85.7%). The patient who showed PR (Case 5) subsequently experienced CNS relapse and later died. One patient (Case 2) relapsed 8 months after achieving CR, and second CR occurred after salvage therapy (rituximab with MTX, procarbazine, and VCR; R-MPV therapy followed by 45 Gy of whole-brain radiotherapy, WBRT). The

remaining patients with CR were still alive without relapse at the time of a short follow-up. The oldest age PS 4 patient remained at PS 3 at the end of treatment. However, the other patients showed dramatic improvement to PS 1 or 0 at the end of treatment, even if the pretreatment PS was quite poor. The median observation period of surviving patients was 24 months. Hematological adverse events included grade 4 leukocytopenia in 4/7 patients (57.1%), neutropenia 5/7 (71.4%), anemia in 1/7 (14.3%), and thrombocytopenia 2/7 (28.6%), but all were transient and well-tolerated. In addition, grade 2 constipation occurred in 4/7 patients (57.1%), and grade 2 mucositis of the oral cavity occurred in 1 case (14.3%).

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MR-CHOP therapy for PCNSL Fig. 2 MRCT imaging of Case 3 showing dramatic improvement following MRCHOP therapy. The patient was admitted complaining of a headache and vomiting due to hydrocephalus. A mass 3 cm in diameter was seen in the left caudate nucleus on lowintensity T1 imaging (right column), high-intensity T2 imaging (center), and showed enhanced homogeneously with gadolinium (left) before chemotherapy (top row). The mass projected into the lateral ventricle, and obstructed the foramen of Monro, causing hydrocephalus and a midline shift. However, the mass was markedly reduced by only one course of MR-CHOP (middle row), and disappeared completely when the treatment was completed (bottom row)

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Transient grade 4 hepatic toxicity due to HD-MTX with elevated transaminases (AST, ALT) was observed in the rst course of treatment in only one case (case 7); however, her hepatic function remained intact without jaundice. Therefore, after a consultation with a gastroenterologist, the MR-CHOP treatment was continued with intravenous administration of monoammonium glycyrrhizin for liver protection and the patient completed the course of treatment. The patient recovered normal liver function after discontinuation of monoammonium glycyrrhizin.

4 Discussion Lymphomatous lesions in CNS include PCNSL or CNS involvement and recurrence of primary lymphomas from other sites. PCNSL is dened as a lymphoma that is restricted to the CNS (including intra-ocular), and usually shows DLBCL histopathology [1]. Furthermore, it is divided into lesions that develop in immunocompetent patients and those that develop in non-immunocompetent patients, such as those with acquired immune deciency or post-transplantation patients.

WBRT has been administered as the initial treatment for PCNSL. However, recurrence often occurred during the therapy [12], causing poor prognosis, in addition to a high frequency of neurotoxicity, adversely affecting the patients quality of life. The effects of standard chemotherapy for DLBCL in other organs, such as CHOP, are limited and shortlived for PCNSL. The drugs that are used in the CHOP regimen do not penetrate the BBB. However, the BBB may be damaged at the site of the tumor, and thus CHOP treatment may be transiently effective. Drug combinations that cannot penetrate the BBB do not improve the prognosis of PCNSL. Even though there is some lymphoma cell inltration in site that appears normal on CT or MRCT (these sites may have a normal BBB), HD-MTX can penetrate the BBB and is effective against PCNSL. However, HD-MTX alone provides only transient progression-free survival of 1012.8 months, a low CR rate, and recurrence during the treatment, even if the dose of MTX is increased up to 8 g/m2, and thus the clinical studies were terminated [7, 8]. HD-MTX must be the key drug for the treatment of PCNSL. However, the effect of HD-MTX alone is limited and insufcient. Although no studies have demonstrated the dose dependency of its efcacy, MTX is often combined at dose

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of 33.5 g/m2 with other drugs in many protocols. The outcomes of using HD-MTX-containing multi-drug regimens, such as MPV therapy [1315] or HD-MTX with high-dose Ara-c (HD-AraC) [1622], are better than those of HD-MTX alone. Signicant increases in the CR rate and event-free survival were found when adding HD-AraC to HD-MTX [21]. The additional drugs in these protocols were selected with BBB penetration as the most important factor. However, no standard doses or combinations have yet been established. Although the BBB complicates the treatment of PCNSL, BBB penetration is probably not the only selection criteria required for chemotherapeutic agents. Some extra-nodal lymphomas, such as mucosa-associated lymphoid tissue (MALT) lymphomas, develop in the presence of chronic inammation, while others including PCNSL develop in the absence of inammation without lymphoid tissue. Lymphocytes are circulating and able to reach every organ. However, chronic inammation, such as MALT, occurs rarely in the CNS, and the most common histopathological subtype in the CNS is DLBCL. It has been suggested that PCNSL initially develops at another site, such as the bone marrow or spleen, and selectively migrates to the CNS, rather than developing spontaneously in the CNS. A recent study indicated that tumor-related clones are present in the blood and bone marrow with evidence of independent development [23]. Thus, not only BBB penetration activity, but also systemic anti-tumor effects are important in PCNSL treatment. The MEDOCH-R (MTX, etoposide, DOX, VCR, CPA, dexamethasone, and rituximab) regimen was administered in our institute for the treatment of PCNSL prior to the MR-CHOP study and with relatively good outcomes (data not shown). However, the MEDOCH-R regimen requires continuous infusion and complicated administration of chemotherapy. We developed MR-CHOP therapy that combined the standard dose of R-CHOP therapy with HDMTX to eliminate the need for continuous infusion, and conducted a pilot study with informed consent of the patients. Both MEDOCH-R and MR-CHOP therapy are chemotherapy regimens that provide BBB penetration as well as systemic anti-tumor activity. One senile relapsed patient with poor PS, experienced sepsis and disseminating intravascular coagulation (DIC) at the time of nadir after the rst course of MR-CHOP in a previous study of relapsed and refractory patients, and thus the safety dose of 2 g/m2 MTX in the MR-CHOP regimen was selected in this pilot study for newly diagnosed PCNSL patients at Kanazawa Medical University Hospital. In the previous reports, the efcacy of rituximab for the treatment of PCNSL was considered to be questionable because rituximab cannot pass through the BBB due to its high molecular weight. Intrathecal injection of rituximab

has been administered in combination with autologous serum containing complement factors to expect the potential complement determining cytotoxicity (CDC) [24]. In contrast, no serum was used in the phase I study reported by Rubenstein et al. [25]. The concentration of rituximab was not signicantly elevated in the CSF of the patients treated with MR-CHOP therapy in the present study (data not shown). However, a portion of the BBB was damaged at the site of brain tumors by the lesions themselves, potentially allowing the drugs to cross the blood brain tumor barrier. Enting et al. [26] reported that salvage therapy with rituximab and temozolomide showed promising outcomes. Furthermore, Shah et al. [27] reported a prospective study of newly diagnosed PCNSL patients treated with rituximab with MPV (R-MPV) as induction therapy, followed by a reduced dose of WBRT for CR patients, or standard dose of WBRT for non-CR patients. The combination of rituximab and MPV was associated with a slightly elevated risk of neutropenia, but the rate of CR was doubled with reduced neurotoxicity. Therefore, the strategy of R-MPV followed by WBRT is promising. Although the numbers of patients treated with MRCHOP therapy in the present study was small and the duration of the follow-up was short, the efcacy of this protocol as remission induction therapy is promising, because 6 of the 7 patients achieved CR (response rate 100%, CR rate 85.7%). In addition, the long-term outcome is promising because some patients have survived without relapse for more than 3 years. The current protocol was designed without WBRT, because we feel that it is preferable to avoid WBRT in the treatment of PCNSL, as many PCNSL patients exhibit senility. However, two cases showed recurrence: one (Case 5) with vitreous oaters, relapsed due to remnant tumor cells in the eye, and the other (Case 2) relapsed 8 months after the treatment, despite demonstrating CR in monthly follow-up MRCT examinations. The ocular tissue is part of the CNS, and the bloodretinal barrier may be more difcult to penetrate than the BBB. Therefore, remnant intra-ocular lesions (vitreous oaters) must be treated using an alternative approach, such as intra-ocular injection of MTX. Intensive phase therapy must be reassessed because one patient, who did not have an intra-ocular lesion, experienced a relapse. The use of drugs such as carmustine or thiotepa is not permitted under the terms of current health insurance treatment in Japan, reducing the potential efcacy of doseintensied chemotherapy followed by the administration of autologous stem cells. We are currently planning a multicenter phase I/II study of MR-CHOP to establish whether there is any denite evidence of efcacy in CHOP with HD-MTX in combination with the dose-modied administration of WBRT, based on the patients disease status following chemotherapy.

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MR-CHOP therapy for PCNSL Acknowledgments We are grateful to the members of Hokuriku Hematological Tumor Research Group for their critical contributions. This work was supported by grants from Intractable Diseases, the Health and Labour Sciences Research Grants from the Ministry of Health, Labor and Welfare and the Japanese Ministry of Education, Culture, Sports, Science and Technology (22249041 to Umehara and 17591060 to Masaki), Uehara Memorial Foundation (to Umehara), The Vehicle Racing Commemorative Foundation, and the Kanazawa Medical University Research Foundation (C2009-4, C2010-1 to Umehara and S2004-16 and S2007-5 to Masaki). Conict of interest manuscript. The authors declare no competing nancial

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