Successful Treatment of Elderly Diffuse Large B-Cell Lymphoma with Central Nervous System Recurrence by Rituximab, Ranimusutine, Ifosfamide, Procarbazine, Dexamethasone, and Etoposide Therapy

doi:10.4236/jct.2013.43A054

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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.

Email: *[email protected]

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)

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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