Journal of Cancer Therapy, 2013, 4, 448-451
http://dx.doi.org/10.4236/jct.2013.43A054 Published Online March 2013 (http://www.scirp.org/journal/jct)
Successful Treatment of Elderly Diffuse Large B-Cell
Lymphoma with Central Nervous System Recurrence by
Rituximab, Ranimusutine, Ifosfamide, Procarbazine,
Dexamethasone, and Etoposide Therap y
Junya Miyahara1, Naoki Takezako1, Miyuki Wagatsuma2, Kiyoe Midorikawa2, Ichiro Fukuda3,
Satoshi Noto1, Ikuo Saito4, Kazuaki Yamada2, Akiyoshi Miwa5, Naohiro Sekiguchi1*
1Division of Hematology, National Hospital Organization Disaster Medical Center, Tokyo, Japan; 2Division of Pathology, National
Hospital Organization Disaster Medical Center, Japan; 3Division of Radiology, National Hospital Organization Disaster Medical
Center, Japan; 4Division of Pathology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan; 5Hematology Divi-
sion, National Center for Global Health and Medicine, Japan.
Received January 11th, 2013; revised January 25th, 2013; accepted February 4th, 2013
ABSTRACT
The prognosis of CD20-positive (CD20+) diffuse large B-cell lymphoma (DLBCL) with central nervous system (CNS)
recurrence is still poor. A standard treatment for CD20+ DLBCL with CNS recurrence in elderly patients has not been
established mainly due to adverse effects. We previously reported the efficacy and safety of MIND-E (ranimustine,
ifosfamide, procarbazine, dexamethasone, and etoposide) therapy for elderly CD20+ DLBCL patients with CNS recur-
rence. Here, we report the use of R-MIND-E therapy (rituximab, ranimustine, ifosfamide, procarbazine, dexamethasone
and etoposide) in an elderly CD20+ DLBCL patient with CNS recurrence. The patient achieved a complete response
according to Revised Response Criteria for Malignant Lymphoma, and treatment-related toxicity was tolerable.
R-MIND-E therapy may be a feasible and useful treatment option for elderly CD20+ DLBCL patients with CNS recur-
rence.
Keywords: Diffuse Large B-Cell Lymphoma; Central Nervous System Recurrence; Rituximab; MIND-E
1. Introduction
The prognosis of CD20-positive (CD20+) diffuse large
B-cell lymphoma (DLBCL) has been improved by com-
bining CHOP therapy (cyclophosphamide, doxorubicin,
vincristine, and predonisone) and rituximab, a chimeric
monoclonal antibody against the CD20 B-cell antigen [1].
However, the prognosis of CD20+ DLBCL with central
nervous system (CNS) recurrence is still poor [2]. Whole
brain irradiation or high dose chemotherapy including
methotrexate (MTX) and cytarabine is useful for younger
patients; however, these therapies are not appropriate for
elderly CD20+ DLBCL patients with CNS recurrence be-
cause of treatment-related toxicities including leukoen-
cephalopathy. We previously reported the efficacy and
safety of MIND-E therapy (ranimustine (MCNU), ifosfa-
mide (IFO), procarbazine (PCZ), dexamethasone (DEX),
and etoposide (ETP)) (Table 1(a)). On the other hand, we
did not use rituximab in the study [3]. Recently, regard-
ing primary CNS lymphoma (PCNSL), intravenous ri-
tuximab in addition to combined chemotherapy has been
accepted as the standard treatment strategy [4-7]. Fur-
thermore, CNS recurrence of systemic DLBCL is usually
premonitory symptom of systemic recurrence, therefore,
administration of rituximab in the salvage therapy may
be considered as prevention for systemic reoccurrence.
Here, we report a case of an elderly CD20+ DLBCL pa-
tient with CNS recurrence treated with R-MIND-E ther-
apy.
2. Case Report
A 69-year-old male was admitted to our hospital in
March 2010 because of right hemilateral sensory distur-
bance, short-term memory disturbance, alexia, and agra-
phia. He had been diagnosed with CD20+ primary tes-
ticular DLBCL in 2005, and underwent orchidectomy, 6
cycles of CHOP therapy, irradiation, and intrathecal in-
jection for CNS prophylaxis. He achieved a complete
response (CR). T2 weighted magnetic resonance imaging
*Corresponding author.

Successful Treatment of Elderly Diffuse Large B-Cell Lymphoma with Central Nervous System Recurrence
by Rituximab, Ranimusutine, Ifosfamide, Procarbazine, Dexamethasone, and Etoposide Therapy
449
Table 1. (a) Regimen of MIND-E therapy; (b) Regimen of R-MIND-E therapy.
(a)
Dose Day 1 Day 2 Day 3 Day 4 Day 5
Ranimustine 50 mg/m2 div ○
Ifosfamide 500 mg/m2 div ○ ○ ○ ○ ○
Procarbazine 80 mg/m2 po ○ ○ ○ ○ ○
Etoposide 100 mg/m2 div ○ ○ ○ ○ ○
Dexamethasone 40 mg/body div ○ ○ ○ ○ ○
(b)
Dose Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 or 7
Ranimustine 50 mg/m2 div ○
Ifosfamide 500 mg/m2 div ○ ○ ○ ○ ○
Procarbazine 100 mg/m2 po ○ ○ ○ ○ ○
Etoposide 80 mg/m2 div ○ ○ ○ ○ ○
Dexamethasone 40 mg/body div ○ ○ ○ ○ ○
Rituximab 375 mg/m2 div ○
po: per os; div: drip infusion of vein.
(MRI) revealed a high-intensity mass in the left temporal
lobe to parietal lobe (Figure 1(a)). Laboratory results
were as follows: WBC 5900/μL, Hb 12.8 mg/dL, and
LDH 209 IU/L. The total cell count in the cerebrospinal
fluid (CSF) was 63/3 μL. May-Giemsa staining of the
CSF smear showed the diffuse infiltration of atypical
large lymphocytes (Figure 2). Therefore, he was diag-
nosed with CNS recurrence of DLBCL.
He was evaluated to be a poor candidate for whole
brain irradiation and high-dose chemotherapy because of
his age and poor performance status. Therefore, he was
treated with MIND-E therapy. After 4 cycles of MIND-E
therapy, MRI (Figure 1(b)) and [18F]-fluorodeoxyglu-
cose positron emission tomography (PET) scans showed
no evidence of a tumor, and all detectable clinical evi-
dence of disease and disease-related symptoms disap-
peared; thus, he achieved CR according to Revised Re-
sponse Criteria for Malignant Lymphoma [8]. Six months
later, MRI revealed second CNS recurrence (Figure
1(c)). At that time, he was treated with 3 cycles of R-
MIND-E therapy (Table 1(b)). One cycle of R-MIND-E
therapy consisted of the intravenous administration of 50
mg/ m2 MCNU on day 1, intravenous administration of
500 mg/m2 IFO on days 1 - 5, oral administration of 100
mg/ m2 PCZ on days 1 - 5, intravenous administration of
80 mg/m2 ETP on days 1 - 5, intravenous administration
of 40 mg/body DEX on days 1 - 5, and intravenous ad-
ministration of 375 mg/m2 rituximab on day 6 or 7. After
3 cycles of R-MIND-E therapy, no evidence of the tumor
was found including MRI (Figure 1(d)) and PET scans,
therefore, he achieved a 3rd CR according to Revised
(a) (b)
(c) (d)
Figure 1. (a) High-intensity mass in the left temporal lobe to
parietal lobe on T2 weighted MRI (Arrow); (b) T2 weighted
MRI after four cycles of MIND-E therapy; (c) Second CNS
recurrence in the left frontal lobe on T2 weighted MRI
(Arrow); (d) T2 weighted MRI after three cycles of R-
MIND-E therapy.
Response Criteria for Malignant Lymphoma [8]. Grade 4
neutropenia, Grade 3 thrombocytopenia, and Grade 3 in-
fection were observed according to the Common Termi-
nology Criteria for Adverse Events version 4.0. CR has

Successful Treatment of Elderly Diffuse Large B-Cell Lymphoma with Central Nervous System Recurrence
by Rituximab, Ranimusutine, Ifosfamide, Procarbazine, Dexamethasone, and Etoposide Therapy
450
Figure 2. Invasion of atypical large lymphocytes in the cere-
brospinal fluid (original magnification ×1000). The size of
atypical lymphocytes was double to triple as big as eryth-
rocytes.
been maintained for 4 months.
3. Discussion
The prognosis of systemic DLBCL has improved with
the use of rituximab [1]. However, CNS recurrence oc-
curs in 1.1% to 10.4% of patients, and the prognosis re-
mains poor [2]. Whether the addition of rituximab de-
creases the risk of CNS recurrence for systemic DLBCL
has not yet been proven [9-12]. The concentration of ri-
tuximab in the CSF is low even after its intravenous in-
fusion. Some reports have suggested that a high-dose
intravenous rituximab infusion or intrathecal rituximab
infusion may be an effective treatment option [13], al-
though the clinical safety of such treatments has not been
yet been confirmed. In order to prevent CNS recurrence
of DLBCL, intrathecal chemotherapy such as MTX and
cytarabine is currently performed in many institutions,
although its efficacy has been controversial [2,14-18].
Kim et al. described the treatment of 73 DLBCL pa-
tients with secondary CNS involvement in 11 institutions
in Korea [14]. They reported that high-dose MTX or lo-
calized CNS-directed therapy such as whole brain irra-
diation was favorable for DLBCL patients with isolated
secondary CNS involvement. However, they also re-
ported that the prognosis of DLBCL patients with se-
condary CNS involvement was still poor, systemic recur-
rence occurred, and no effective treatment had been es-
tablished yet. Furthermore, elderly patients who received
whole brain irradiation had an increased risk of treat-
ment-related neurotoxicity [19,20], and high-dose che-
motherapy was also not feasible for these patients due to
a poor performance status or disturbance of conscious-
ness. Therefore, no effective treatment for elderly DL-
BCL patients with CNS recurrence had been established.
We previously reported on the use of MIND-E therapy
in 8 elderly DLBCL patients with CNS recurrence. The 5
drugs used in MIND-E therapy consist of drugs that cross
the blood-brain barrier or blood-retina barrier to some
extent. Of the 8 patients, three achieved CR, two patients
achieved a partial response, and no treatment-related
mortality (TRM) was observed [3]. On the other hand,
this regimen did not include rituximab; therefore, in the
present case, we administered rituximab in addition to
MIND-E therapy. The patient achieved a third CR after
R-MIND-E therapy, and treatment-related toxicities were
tolerable. Although reports concerning the treatment and
response of elderly CD20+ DLBCL patients with CNS
recurrence remain limited, we successfully achieved CR
using R-MIND-E therapy without whole brain irradiation
or high-dose chemotherapy.
To the best of our knowledge, regarding the treatment
of primary CNS lymphoma, addition of rituximab for
primary CNS lymphoma may be considered as standard
therapy. Bimbaum et al. recently reported the benefits of
rituximab in addition to MTX and IFO over MTX and
IFO in 36 cases of primary CNS lymphoma in a retro-
spective analysis [6]. In prospective study, some investi-
gators described promising response rate and survival in
primary CNS lymphoma by multi-agent chemotherapy
including rituximab as induction therapy [4,5,7]. There-
fore, intravenous administration of rituximab for CNS re-
currence in systemic DLBCL may be considered as a
treatment option.
In conclusion, R-MIND-E therapy may be an effective
and safe treatment option for elderly CD20+ DLBCL pa-
tients with CNS recurrence. However, a prospective study
should be carried out to confirm the efficacy and safety
of R-MIND-E therapy for elderly CD20+ DLBCL pa-
tients with CNS recurrence.
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