Bone Marrow Transplantation (2011) 46, 105–109
& 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11
www.nature.com/bmt
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 Yoon1, DH Lee1, DR Choi1, BS Sohn1, S Kim1, SW Kim1, JS Lee1, SW Lee2, J Huh3 and C Suh1
1
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 2Department of Radiation
Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea and 3Department 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/m2,
day 7 to day 5; CY 50 mg/kg, day 3 to day 2 and
etoposide 200 mg/m2, 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 (8.8–50.7 months), six patients
had relapsed, with a median event-free interval of 15.0
months (95% confidence interval, 4.5–25.6 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.
Bone Marrow Transplantation (2011) 46, 105–109;
doi:10.1038/bmt.2010.71; 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
Correspondence: Dr C Suh, Department of Oncology, Asan Medical
Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil,
Songpa-gu, Seoul 138-736, Korea.
E-mail: [email protected]
Received 23 October 2009; revised 1 February 2010; accepted 17
February 2010; published online 12 April 2010
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.6–11 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.12–16 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%.9–11
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.
Materials and methods
Patients and diagnosis
Eleven PCNSL patients newly diagnosed between May
2005 and November 2008 were included in this analysis. All
BUCYE and ASCT for PCNSL
DH Yoon et al
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.
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/m2, once daily, every 2 weeks) and two
cycles of high-dose cytarabine (3.0 g/m2, 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/m2, 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
Bone Marrow Transplantation
until 13 August 2009. 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.
Results
Patient characteristics and treatment
The clinical characteristics of patients are summarized in
Table 1. The median age was 52 years (range, 33–65 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 45.3 106 cells
per kg (range, 27.2 to 172.7 106 cells per kg) and
36.4 106 cells per kg (range, 14.4 to 96.9 106 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),
1.5–24.0 months) with a median follow-up of 25.0 months
(range, 8.8–50.7 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.
2
1
1
1
1
1
Increased
Increased
Normal
Normal
Increased
Normal
Increased
Normal
Normal
Intermediate
Low
Intermediate
Low
Intermediate
Low
Intermediate
Intermediate
Low
Yes
No
Yes
Yes
Yes
No
No
Yes
No
Increased
Increased
Increased
Normal
Normal
Normal
Normal
Normal
Normal
PR
CR
CR
CR
CR
CR
CR
PR
CR
PR
CRub
Intermediatea
Low
Yes
No
NEa
Normal
CR
CR
CR
CR
CR
CR
CR
CR
CR
PR
CRub
PrePostASCT ASCT
Prognostic
score20
Deep structure
involvement20
CSF
protein20
—
—
—
—
—
—
—
—
—
48
45
Brain RT
(Gy)
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
CR
Overall
response
8.1
12.8
6.2
—
—
—
Brain
Brain
Brain
33.1
1.6
4.1
6.4
6.4
6.3
—
Brain and
eye
—
Brain
CSF
41.6
13.2
First CR Relapse
duration site
(months)
—
—
—
WBRT
WBRT
None
—
WBRT
IT-chemo
—
Chemoc
Salvage
treatment
—
—
—
NE
PR
—
—
CR
CR
—
PR
12.9
9.5
8.8
9.7
18.9
7.8
34.8
6.8
6.0
50.7
15.0
12.9
9.5
8.8
25.0
22.7
9.9
34.8
34.7
31.2
50.7
48.2
AWoD
AWoD
AWoD
Alived
AWD
DOD
AWoD
AWoD
AWoD
AWoD
AWD
Response
EFS
OS
Status
to salvage (months) (months)
treatment
ND
ND
ND
ND
ND
ND
ND
ND
LEP
Leg weakness
LEP
Neurotoxicity
b
Survival (%)
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.
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.
a
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.
F/47
M/45
M/48
M/43
M/62
M/63
Brain
Brain
Brain and
CSF
Brain
Brain
Brain and
CSF
Brain
Brain
Brain
M/53
F/52
M/33
1
1
1
1
1
Brain
Brain
M/65
F/55
Normal
Increased
PS LDH
Patient data
Sex/Age Extent of
disease
Table 1
BUCYE and ASCT for PCNSL
DH Yoon et al
100
107
OS
80
60
40
EFS
20
0
0
6
12
18
24
30
36
42
48
Figure 1 Kaplan–Meier survival curve of OS and EFS.
Months
Survival analysis
Median EFS was 15.0 months (95% CI, 4.5–25.6 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
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
Bone Marrow Transplantation
BUCYE and ASCT for PCNSL
DH Yoon et al
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.9–11 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/m2),22 the
CSF concentration reached up to 0.54 mg/mL upon high
dose (900–2500 mg/m2) i.v. administration, which was
sufficient to kill tumor cells.17 In this study, patients
received etoposide 800 mg/m2, 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/m2), 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
Bone Marrow Transplantation
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.
Acknowledgements
We thank the nurses in the oncology wards and house staff
members of the Department of Internal Medicine at Asan
Medical Center for their dedication and excellent patient care.
References
1 Abrey LE, DeAngelis LM, Yahalom J. Long-term survival in
primary CNS lymphoma. J Clin Oncol 1998; 16: 859–863.
2 DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ.
Combination chemotherapy and radiotherapy for primary
central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 2002; 20: 4643–4648.
3 Brevet M, Garidi R, Gruson B, Royer B, Vaida I, Damaj G.
First-line autologous stem cell transplantation in primary CNS
lymphoma. Eur J Haematol 2005; 75: 288–292.
4 Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P,
Brion A et al. High-dose chemotherapy with autologous stem
cell transplantation as first-line therapy for primary CNS
lymphoma in patients younger than 60 years: a multicenter
phase II study of the GOELAMS group. Bone Marrow
Transplant 2006; 38: 417–420.
5 Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D,
Forsyth P et al. Intensive methotrexate and cytarabine
followed by high-dose chemotherapy with autologous stemcell rescue in patients with newly diagnosed primary CNS
lymphoma: an intent-to-treat analysis. J Clin Oncol 2003; 21:
4151–4156.
6 Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C,
Derigs G et al. High-dose chemotherapy with autologous stemcell transplantation and hyperfractionated radiotherapy as
first-line treatment of primary CNS lymphoma. J Clin Oncol
2006; 24: 3865–3870.
7 Illerhaus G, Muller F, Feuerhake F, Schafer AO, Ostertag C,
Finke J. High-dose chemotherapy and autologous stem-cell
transplantation without consolidating radiotherapy as first-line
treatment for primary lymphoma of the central nervous
system. Haematologica 2008; 93: 147–148.
BUCYE and ASCT for PCNSL
DH Yoon et al
109
8 Montemurro M, Kiefer T, Schuler F, Al-Ali HK, Wolf HH,
Herbst R et al. Primary central nervous system lymphoma
treated with high-dose methotrexate, high-dose busulfan/
thiotepa, autologous stem-cell transplantation and responseadapted whole-brain radiotherapy: results of the multicenter
Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53
phase II study. Ann Oncol 2007; 18: 665–671.
9 Cheng T, Forsyth P, Chaudhry A, Morris D, Gluck S, Russell JA
et al. High-dose thiotepa, busulfan, cyclophosphamide and ASCT
without whole-brain radiotherapy for poor prognosis primary
CNS lymphoma. Bone Marrow Transplant 2003; 31: 679–685.
10 Soussain C, Hoang-Xuan K, Taillandier L, Fourme E,
Choquet S, Witz F et al. Intensive chemotherapy followed by
hematopoietic stem-cell rescue for refractory and recurrent
primary CNS and intraocular lymphoma: Société Franc¸aise de
Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol
2008; 26: 2512–2518.
11 Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levy V,
Azar N et al. Results of intensive chemotherapy followed by
hematopoietic stem-cell rescue in 22 patients with refractory or
recurrent primary CNS lymphoma or intraocular lymphoma.
J Clin Oncol 2001; 19: 742–749.
12 Kroger N, Hoffknecht M, Hanel M, Kruger W, Zeller W,
Stockschlader M et al. Busulfan, cyclophosphamide and
etoposide as high-dose conditioning therapy in patients with
malignant lymphoma and prior dose-limiting radiation therapy. Bone Marrow Transplant 1998; 21: 1171–1175.
13 Hanel M, Kroger N, Sonnenberg S, Bornhauser M, Kruger W,
Kroschinsky F et al. Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with
malignant lymphoma. Ann Hematol 2002; 81: 96–102.
14 Aggarwal C, Gupta S, Vaughan WP, Saylors GB, Salzman
DE, Katz RO et al. Improved outcomes in intermediate- and
high-risk aggressive non-Hodgkin lymphoma after autologous
hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and
etoposide preparative regimen. Biol Blood Marrow Transplant
2006; 12: 770–777.
15 Copelan EA, Penza SL, Pohlman B, Avalos BR, Goormastic
M, Andresen SW et al. Autotransplantation following busulfan,
etoposide and cyclophosphamide in patients with non-Hodgkin’s lymphoma. Bone Marrow Transplant 2000; 25: 1243–1248.
16 Kim JG, Sohn SK, Chae YS, Yang DH, Lee JJ, Kim HJ et al.
Multicenter study of intravenous busulfan, cyclophosphamide,
and etoposide (i.v. Bu/Cy/E) as conditioning regimen
for autologous stem cell transplantation in patients with
non-Hodgkin’s lymphoma. Bone Marrow Transplant 2007;
40: 919–924.
17 Postmus PE, Holthuis JJ, Haaxma-Reiche H, Mulder NH,
Vencken LM, van Oort WJ et al. Penetration of VP 16-213 into
cerebrospinal fluid after high-dose intravenous administration.
J Clin Oncol 1984; 2: 215–220.
18 Kohara H, Ueoka H, Tabata M, Shinagawa K, Hayashi K,
Harada M. High-dose etoposide treatment for CNS involvement in a patient with primary non-Hodgkin’s lymphoma of
the breast. Intern Med 1997; 36: 738–741.
19 Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein
H et al. WHO Classification of Tumours Haematopoietic and
Lymphoid Tissues. International Agency for Research on
Cancer. WHO: Geneva, 2008.
20 Ferreri AJ, Blay JY, Reni M, Pasini F, Spina M, Ambrosetti A
et al. Prognostic scoring system for primary CNS lymphomas:
the International Extranodal Lymphoma Study Group experience. J Clin Oncol 2003; 21: 266–272.
21 Abrey LE, Batchelor TT, Ferreri AJ, Gospodarowicz M,
Pulczynski EJ, Zucca E et al. Report of an international
workshop to standardize baseline evaluation and response
criteria for primary CNS lymphoma. J Clin Oncol 2005; 23:
5034–5043.
22 Creaven PJ. The clinical pharmacology of VM26 and VP16213. A brief overview. Cancer Chemother Pharmacol 1982; 7:
133–140.
23 Ferreri AJ, Crocchiolo R, Assanelli A, Govi S, Reni M. Highdose chemotherapy supported by autologous stem cell
transplantation in patients with primary central nervous
system lymphoma: facts and opinions. Leuk Lymphoma 2008;
49: 2042–2047.
24 Morris PG, Abrey LE. Therapeutic challenges in primary CNS
lymphoma. Lancet Neurol 2009; 8: 581–592.
25 Yang SH, Lee KS, Kim IS, Hong JT, Sung JH, Son BC et al.
Long-term survival in primary CNS lymphoma treated by
high-dose methotrexate monochemotherapy: role of STAT6
activation as prognostic determinant. J Neurooncol 2009; 92:
65–71.
Bone Marrow Transplantation