LETTER TO THE EDITOR

Maintenance therapy for central nervous system lymphoma withrituximab

DOUGLAS E. NEY & LAUREN E. ABREY

Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

(Received 11 May 2009; revised and accepted 16 June 2009)

Primary central nervous system lymphoma (PCNSL)

is a rare type of malignant non-Hodgkin lymphoma

(NHL) that is confined to the brain, eyes, and

cerebrospinal fluid. Response rates of 490% have

been reported following high-dose methotrexate

regimens for newly diagnosed PCNSL with a median

survival of up to 5 years [1,2]. However, at least 50%

of the patients relapse, usually within 2 years of initial

diagnosis. At relapse many patients achieve a second

remission; however, the duration of a second remis-

sion is typically short, averaging 6–10 months.

Parenchymal brain relapse following systemic NHL

is often treated with methotrexate or whole brain

radiotherapy, but prognosis is generally poor with

survivals in the range of 2–5 months [3,4].

The high rate of recurrence after successful

treatment of central nervous system (CNS) lympho-

ma highlights the need for consolidation therapy to

maintain disease control. The most widely used

consolidation approaches include whole brain radio-

therapy and myeloablative chemotherapy. However,

whole brain radiotherapy carries a risk of significant

neurocognitive morbidity particularly in older pa-

tients. Myeloablative chemotherapy has been shown

to be ineffective for patients with systemic NHL who

have CNS metastases although most patients studied

in this context have had leptomeningeal lymphoma

[5]. Although there are promising preliminary data

for myeloablative chemotherapy in PCNSL, the

benefit has been limited to young patients with

good prognostic features which preclude this ap-

proach for the majority of patients.

The concept of maintenance therapy as consolida-

tion was originally developed for patients with acute

lymphoblastic leukemia to maintain remission. More

recently, this strategy has been used for patients with

indolent lymphoma; however, in this patient popula-

tion the goal of maintenance rituximab has been to

minimize or control residual tumor burden [6–9].

The CNS lymphoma is an aggressive B-cell lympho-

ma; therefore, we hypothesized that maintenance

therapy may be effective in patients with PCNSL at

high risk for relapse after they have achieved a

complete response (CR) with standard treatments.

As this strategy has minimal morbidity, we used

maintenance rituximab for a series of patients with

CNS lymphoma who were at high risk for relapse

and/or unable to receive alternate consolidation

treatment.

Nine patients with CD20þ CNS lymphoma were

treated with maintenance rituximab between No-

vember 2004 and March 2009. Maintenance ritux-

imab was defined as delivery of regularly scheduled

rituximab following a radiographic CR after treat-

ment for CNS lymphoma. Hospital charts, radiology

and pathology reports, and clinical notes were

reviewed. Permission for this retrospective study

was granted by the Institutional Review Board at

Memorial Sloan-Kettering Cancer Center.

Disease-free survival was calculated from the date

of the MRI scan documenting a CR after therapy for

CNS lymphoma and immediately prior to initiation

of maintenance rituximab until documented progres-

sion or last follow-up. The OS was calculated from

the date of this MRI scan until the date of death or

last follow-up. The date of original tissue diagnosis

was used as the date of diagnosis. The Kaplan–Meier

product limit method was used to generate survival

Correspondence: Lauren E. Abrey, Department of Neurology, 1275 York Avenue, New York, NY 10065, USA. Tel: þ1-212-639-5122.

Fax: þ1-917-432-2310. E-mail: abreyl@mskcc.org

Leukemia & Lymphoma, September 2009; 50(9): 1548–1551

ISSN 1042-8194 print/ISSN 1029-2403 online � 2009 Informa Healthcare USA, Inc.

DOI: 10.1080/10428190903128645

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curves. Toxicity was graded according to the

National Cancer Institute common toxicity criteria

version 3.0.

Five men and four women with a median age of 59

(range, 40–76) at the start of treatment received

maintenance rituximab. Six patients had a diagnosis

of PCNSL and three had CNS relapse of systemic

NHL (Table I). The median Karnofsky performance

status was 80 (range, 70–90). All patients except one

had received prior treatment with rituximab as a

component of either initial or salvage therapy.

The median interval between the initial diagnosis

and the first progression was 26.7 months (range, 1–

156). The median number of relapses prior to

initiation of maintenance rituximab was 2 (range,

0–6). Seven patients received maintenance rituximab

after successful salvage treatment for recurrent CNS

lymphoma whereas two patients received mainte-

nance rituximab after successful induction for

PCNSL. These two patients were treated with

maintenance rituximab because of presumed high

risk of recurrence after initial treatment; one was

unable to complete standard treatment because of

severe methotrexate (8 gm/m2)-related toxicity, and

the other was an immunosuppressed multiorgan

transplant recipient.

Eight patients received rituximab at a dose of

750 mg/m2 on a monthly basis, one patient received

the same dose at 6-week intervals. After a treatment

period of 1 year or more with rituximab, the

treatment interval was often increased; four patients

were eventually switched to every 3 months, four to

every 2 months, and one remained on a 6-week cycle.

The median duration of rituximab maintenance

therapy was 24.4 months (range, 11.5–58.9þ).

Administration of rituximab was well tolerated:

Grade 2 neutropenia was seen in one patient and

Grade 3 hypogammaglobulinemia requiring IVIG

infusion was seen in one patient who had received

multiple prior chemotherapy regimens.

At the last follow up, four patients had relapsed

while on maintenance rituximab, two in the CNS at

18.9 and 21.4 months and two systemically at 22.5

and 25.9 months. All relapses were observed when

the rituximab dosing interval was extended to every 3

months. Among the seven patients treated following

relapse, five have remained in remission for longer

than their best prior disease-free intervals. Eight

patients remain alive with a median follow-up of 33.9

months (range, 24.7–58.9þ).

Use of maintenance rituximab appeared to be a

successful strategy to maintain disease control and

Table I. Treatment characteristics of nine patients treated with maintenance rituximab.

Age, y/sex KPS

Initial

site of

disease Initial treatment

TTP

(months)

Site of

relapse Treatment at relapse Response

PFS

(months)*

OS

(months)

66/F 80 PCNSL R-MVP/WBRT 12.6 Ocular RT CR

Brain R-TMZ, MVP CR 18.9 33.9þ59/M 80 PCNSL R-MVP 13.3 Brain R-TMZ, MVP CR 58.9þ{ 58.9þ71/F 90 PCNSL MVP 8.6 Brain/CSF R-TMZ, IT MTX

Brain/CSF R-MVP, IT MTX CR 54.9þ 54.9þ76/F 70 PCNSL MVP 13.2 Brain R-TMZ, MTX,

Ibritumomab

CR 43þ 43þ

56/M 90 PCNSL R-MVP, TMZ{ – – – CR 21.4 30þ40/Mx 90 PCNSL MVP – – – CR 27.1þ 27.1þ54/M 90 Systemic R-CHOP, RICE, RT 4.4 Brain MVP, WBRT CR 22.5 24.7

49/F 70 Systemic R-CHOP, ICE, MTX 2.6 Brain MVP

Brain Cytarabine, WBRT

Brain R-TMZ CR 32.2þ 32.2þ63/M 80 Systemic MTX, Cytarabine 69 Brain MTX

BEAM, ASCT Brain R-MVP

Ocular RT

Brain R-TMZ

Brain MVP CR 45.9þ 45.9þ

KPS, Karnofsky performance status; EOD, extent of disease; TTP, time to progression; CR, complete response; PFS, progression free

survival; OS, overall survival; R-MPV, rituximab, methotrexate, procarbazine, vincristine, cytarabine; MVP, methotrexate, procarbazine,

vincristine, cytarabine; RT, radiation therapy; WBRT, whole-brain radiation therapy; R-TMZ, rituximab, temozolomide; MTX,

methotrexate; IT MTX, intrathecal methotrexate; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RICE,

rituximab, ifosfamide, carboplatin, etoposide; BEAM, carmustine, etoposide, cytarabine, melphalan; ASCT, autologous stem cell transplant.

*Progression-free survival from start of maintenance rituximab.{Relapse in fibula, remains in CR in brain.{Could not complete treatment secondary to toxicity (MTX 8 gm/m2).xImmunocompromized postorgan transplant.

Letter to the Editor 1549

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extend survival in this selected group of patients with

CNS lymphoma. Although this is a small retro-

spective series, we feel that this observation merits

reporting given the durability of disease control.

Seven of our patients had been treated for one or

more prior CNS relapses, three had failed prior

WBRT and one had failed myeloablative chemother-

apy with autologous peripheral blood progenitor

support, so they were a heavily pretreated group at

high risk for subsequent failure. Two patients

received maintenance rituximab following initial

therapy, both were too sick to tolerate other con-

solidation approaches and one had received less than

50% of the initial planned therapy because of severe

methotrexate-related toxicity. The only positive

prognostic feature shared among these nine patients

was the ability to attain a radiographic CR in the

brain.

Other attempts to use maintenance therapy as a

consolidation strategy for CNS lymphoma have

largely been unsuccessful. O’Neill et al. [10] reported

prolonged survival in five patients treated with high-

dose methylprednisolone following a CR after

systemic therapy. This led to a larger trial using

maintenance methylprednisolone following whole-

brain radiotherapy [11]. This approach yielded a 6

month survival of only 33% leading to early closure

of that study. Monthly maintenance methotrexate

following a CR to single agent methotrexate yielded a

median progression-free survival of only 12.8 months

[12]. Our results with an average disease control

interval of 22 months or longer compares favorably to

these results.

The dose of maintenance rituximab used in our

patients was double the standard recommended dose

administered monthly and differs significantly from

maintenance rituximab schedules used for systemic

lymphoma [6,7,8,13]. This dose was selected to

increase the CNS penetration, recognizing that the

large molecular weight of rituximab has limited

transport across an intact blood–brain-barrier with

estimated levels of only 1% of serum [14]. However,

it is unknown whether the CNS or systemic exposure

to rituximab was most valuable in protecting our

patients. As the underlying etiology of PCNSL is

unknown and the malignant lymphocyte population

in CNS lymphoma may theoretically arise from a

systemic reservoir, it is possible that systemic therapy

was protective. This hypothesis is supported by

recent data showing that rituximab protected against

CNS relapse in elderly patients with systemic NHL

[15]. Conversely, intrathecal administration of ritux-

imab has been shown to result in response of bulky

brain lymphoma [14], presumably as a result of very

low serum levels suggesting that low-dose rituximab

may be beneficial even in the CNS. Finally, relapse

was only seen in patients where the dosing interval

was increased to 3 months suggesting a possible

threshold effect of periodic infusions. This may

support the concept that maintenance rituximab is

suppressing growth of a persistent microscopic clone.

Maintenance rituximab for CNS lymphoma in this

small series proved safe, but the optimal duration and

long-term safety are unknown. Maintenance ritux-

imab has been administered safely for more than 4

years in four of our patients, all of whom continue to

receive treatment. This study has several limitations:

sample size is small and selection bias is likely in a

retrospective series. However, the potential benefit of

maintenance rituximab in this heavily pretreated

population was notable. Maintenance rituximab

might be particularly useful in older patients who

want to avoid RT, and have had a CR following

initial chemotherapy. This strategy warrants further

study in patients with CNS lymphoma.

Acknowledgment

The authors thank Judy Lampron for her editorial

assistance.

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