TO THE EDITOR:

Primary vitreoretinal lymphoma (PVRL) is a rare non-Hodgkin lymphoma, frequently associated with primary central nervous system (CNS) lymphoma (PCNSL).1  It particularly concerns elderly subjects with limitations to receive chemotherapies. The prognosis is poor due to the risk of CNS involvement. Between 60% and 85% of patients will develop CNS localization within 29 months.2  Publications on subsequent treatments are scarce. Temozolomide (TMZ) is a well-tolerated, second-generation alkylating agent with excellent penetration into to the CNS and the cerebrospinal fluid (CSF). Its activity in PCNSL has been demonstrated in small studies,3-6  but never in PVRL. Here, we present the results of a retrospective, multicentric study evaluating the efficacy and safety of TMZ as treatment of relapsed or refractory (R/R) patients or in patients not eligible for intensive treatment in first line.

Adults with R/R PVRL or not eligible for intensive treatments were treated with TMZ orally at a dose of 150 mg or 200 mg/m2, 5 days a month, every month. TMZ was proposed through the French National Lymphome Oculo-Cérébral (LOC) network, which brings together experts on PVRL and gives therapeutic guidelines. In accordance with the Declaration of Helsinki, the study was approved by the LOC network institutional review board. The diagnosis of PVRL was made by cytological examination and staining with anti-CD3, anti-CD20, and anti-CD79b antibodies of vitrectomy material or by histological examination of cerebral biopsy in case of associated brain lesions. Interleukin (IL)-10 and IL-6 assays were performed on the vitreous and/ or the aqueous humor (AH) using the Cytometric Bead Array (CBA) technique.7  The IL Score for intraOcular Lymphoma Diagnosis (ISOLD), with a published sensitivity and specificity of 93% and 95%, respectively, was used.7  According to the literature, an ISOLD score >4.6 in vitreous or AH has a 99% probability of PVRL. Clonality assay was performed on the vitreous by multiplex polymerase chain reaction–based analysis of immunoglobulin heavy and light chain gene rearrangements following the BIOMED-2 protocol.8  Patients underwent gadolinium magnetic resonance imaging (MRI), lumbar puncture, and positron emission tomography or computed tomography scan. CSF was analyzed by cytology, flow cytometry, clonality, and IL-10 and IL-6 assays when possible. Responses were evaluated by ophthalmological examination, supplemented by gadolinium MRI in the case of associated brain lesions, according to International Primary CNS Lymphoma Collaborative Group criteria.9  IL levels were measured periodically in the AH during the follow-up of some patients. Survival functions and median survivals were estimated using the Kaplan-Meier method, and survival rates and 95% confidence intervals (CIs) were calculated using Greenwood variance.

Twenty-one patients were included. Median age was 75 years (range, 35-90 years), 1 patient had associated brain localization, and all patients tested for CSF were negative. Nine patients had received 1 line of treatment before, 7 patients 2 lines, 2 patients 3 lines, and 1 patient 4 lines. Two patients, aged 85 and 90 years, had never been treated before. Anterior lines treatments contained high-dose (HD) methotrexate (MTX) for 14 patients. The remaining 5 patients had received HD cytarabine (n = 3) or intravitreous injections of MTX (n = 2). Two patients had received an autologous stem cell transplant (ASCT), and 1 patient cerebral radiotherapy prior to TMZ. One patient with cerebral localization was refractory to lenalidomide, and 2 patients were refractory to ibrutinib. Median duration of treatment with TMZ was 5.2 months (range, 1-40 months). Patients’ therapeutic history is summarized in Table 1.

Table 1.

Characteristics of the study population at the start of TMZ treatment and response to TMZ

CharacteristicsPrevious treatmentsTMZ treatment
PtAge (y)ISOLD scoreCSF testsLines of previous treatmentHD MTXHD cytarabineITV MTXRituxASCTOtherTMZ duration (mo)TMZ responsePFS (mo)OS (mo)Vital status at last FU/ cause of death
53 ND Cy First line × 3 Second line × 2 Second line/ C: TCB 40 CR 115+ 115+ Alive in CR 
74 9.2  ND First line × 2 Third line Y (second line) Second line: Ritux + idarubicin + ifosfamide CR 73+ 73+ Alive in CR 
81 ND Cy, Ck First line CR 52+ 52+ Alive in CR 
85 18.8 ND CR 47+ 47+ Alive in CR 
90 9.2 ND CR (cerebral and ocular) 40 44 Alive with relapse 
79 6.7 Cy, Cl, Ck, F_ First line × 6 Second line ibrutinib 25 CR 29+ 29+ Alive in CR 
75 ND ND First line × 3 Second line × 2 Fourth line Y (third line) Third line: Ritux + idarubicin + ifosfamide CR 17 18 Death due to cerebral progression 
72 11.4 Cy First line × 6 First line × 2: dose reduction 16 CR 16 30 Alive with relapse 
87 18.8 ND First and second line CR 13 26 Death due to cerebral progression 
10 73 15 Cy, Cl First line × 6 First line × 2 2nd line/ C: TCB Second line: ICE 11 CR 11 14 Death due to cerebral progression 
11 80 7.3 Cy, Ck, F First line × 6 First line × 6 Second line: ibrutinib 10 CR 10 11 Alive with relapse 
12 67 16 Cy, F First line × 6 First line × 6 9+ CR 9+ 9+ Alive with CR 
13 56 6.6 ND First line × 4 Second and third line CR 15 Death due to cerebral progression 
14 70 ND ND First line unknown doses First line unknown doses Y (first line) CR 43 Alive with relapse 
15 75 12.9 Cy First line × 6 First line × 2 Y (first line) Second line: lenalidomide CR 22 Alive with relapse 
16 75 ND Cy First line × 3 First line × 2 First line: cerebral Rx 11 Gy PR 11 81 Alive with relapse 
17 44 16 ND First line × 5 First line × 5 Second line: ICE PR 28 Alive with relapse 
18 74 ND Cy First line × 6 First line × 2 11 PD 11 16 Lost to FU 
19 75 9.4 Cy First line × 6 First line × 2 PD 17 Death due to cerebral progression 
20 84 ND ND First line × 6 First line × 2 Unknown PD 12 Death due to unknown cause 
21 35 ND Cy First line × 5 PD 21 Lost to FU 
CharacteristicsPrevious treatmentsTMZ treatment
PtAge (y)ISOLD scoreCSF testsLines of previous treatmentHD MTXHD cytarabineITV MTXRituxASCTOtherTMZ duration (mo)TMZ responsePFS (mo)OS (mo)Vital status at last FU/ cause of death
53 ND Cy First line × 3 Second line × 2 Second line/ C: TCB 40 CR 115+ 115+ Alive in CR 
74 9.2  ND First line × 2 Third line Y (second line) Second line: Ritux + idarubicin + ifosfamide CR 73+ 73+ Alive in CR 
81 ND Cy, Ck First line CR 52+ 52+ Alive in CR 
85 18.8 ND CR 47+ 47+ Alive in CR 
90 9.2 ND CR (cerebral and ocular) 40 44 Alive with relapse 
79 6.7 Cy, Cl, Ck, F_ First line × 6 Second line ibrutinib 25 CR 29+ 29+ Alive in CR 
75 ND ND First line × 3 Second line × 2 Fourth line Y (third line) Third line: Ritux + idarubicin + ifosfamide CR 17 18 Death due to cerebral progression 
72 11.4 Cy First line × 6 First line × 2: dose reduction 16 CR 16 30 Alive with relapse 
87 18.8 ND First and second line CR 13 26 Death due to cerebral progression 
10 73 15 Cy, Cl First line × 6 First line × 2 2nd line/ C: TCB Second line: ICE 11 CR 11 14 Death due to cerebral progression 
11 80 7.3 Cy, Ck, F First line × 6 First line × 6 Second line: ibrutinib 10 CR 10 11 Alive with relapse 
12 67 16 Cy, F First line × 6 First line × 6 9+ CR 9+ 9+ Alive with CR 
13 56 6.6 ND First line × 4 Second and third line CR 15 Death due to cerebral progression 
14 70 ND ND First line unknown doses First line unknown doses Y (first line) CR 43 Alive with relapse 
15 75 12.9 Cy First line × 6 First line × 2 Y (first line) Second line: lenalidomide CR 22 Alive with relapse 
16 75 ND Cy First line × 3 First line × 2 First line: cerebral Rx 11 Gy PR 11 81 Alive with relapse 
17 44 16 ND First line × 5 First line × 5 Second line: ICE PR 28 Alive with relapse 
18 74 ND Cy First line × 6 First line × 2 11 PD 11 16 Lost to FU 
19 75 9.4 Cy First line × 6 First line × 2 PD 17 Death due to cerebral progression 
20 84 ND ND First line × 6 First line × 2 Unknown PD 12 Death due to unknown cause 
21 35 ND Cy First line × 5 PD 21 Lost to FU 

Patient 12 is still receiving treatment with TMZ. Patients 6 and 8 were treated with MTX ITV for 2 months and lenalidomide for 5 months, respectively. ISOLD score was done in vitreous or AH; a score >4.6 has a 99% probability of LVRP. All patients tested for CSF were negative with all the tests used.

C, cerebral; CR, conditioning regimen; Cl, clonality; Ck, cytokine dosage; CR, complete response; Cy, cytology; F, flow cytometry; FU, follow-up; ICE, ifosfamide + carboplatin + etoposide; ITV, intravitreal; N, no; ND, no data; PD, progressive disease; PFS, progression-free survival; PR, partial response; Pt, patient; Ritux, rituximab; Rx, radiotherapy; OS, overall survival; SD, stable disease; TCB, thiotepa + cyclophosphamide + busulfan; Y, yes.

B-cell clonality was positive in 14 out of 15 tested patients. In the single patient with a negative search for clonality, the diagnosis was confirmed by cytological test and antibodies, and the IL-10/ IL-6 ratio was 30. Median IL-10 concentration in the vitreous was 1805 pg/mL (range, 346-5000 pg/mL). IL-10/IL-6 ratio was >1 in the 13 tested patients (range, 1.4-29.6).

Median follow-up was 42 months (range, 9-115). Overall response rate was 81%; 15 patients (71%) achieved a CR, including 1 patient with an ocular and cerebral response and 2 patients (10%) with a PR. Four patients had PD. Median duration of response was 10.9 months (range, 3-109 months). At last follow-up, 6 patients are still in CR, including 1 treated in front line, and all but one had stopped TMZ. One patient who had previously received an ASCT is still in CR 115 months after starting treatment. Three patients previously treated with lenalidomide (n = 1) or ibrutinib (n = 2) obtained a CR. Some patients described a visual acuity improvement within a few days. For the patients tested, the course of the IL-10 assays dramatically decreased during the treatment of 9 responder patients and increased for 1 patient who had PD 8 months later.

Median PFS was 12 months (95% CI, 8 not reached) with a 2-year PFS of 30% (95% CI, 15-61) (Figure 1A). Median OS has not yet been reached (Figure 1B). Six patients died, 5 due to cerebral progression.

Figure 1.

Patient outcomes. (A) PFS and (B) OS from TMZ initiation.

Figure 1.

Patient outcomes. (A) PFS and (B) OS from TMZ initiation.

Three patients had grade 3 toxicities (anemia and vomiting), and 1 patient had 2 grade 4 toxicities (neutropenia and thrombocytopenia). One patient requested discontinuation because a feeling of worsening of memory impairment, but neurological dysfunction had begun before TMZ.

We report here a cohort of patients with PVRL treated with TMZ. The results of molecular and cytokine analyses propose strong arguments for the correct diagnosis and follow-up. First-line IV chemotherapy usually consists of a combination of HD MTX and cytarabine.10,11  There have been few publications on R/R PVRL and no consensus exists in this field.12-19  The interest of ASCT in R/R patients has been demonstrated but it concerns only younger patients.20-22  The efficacy of lenalidomide in PVRL and PCNSL was suggested by Rubenstein et al12  and was recently confirmed by the LOC network13,14 . Similarly, ibrutinib has been reported to be effective in the treatment of PVRL and PCNSL.15,16  However, PFS with these 2 new drugs remains short, toxicity is not negligible, and costs are high.

PFS and OS of patients with isolated PVRL treated in first line are 29.6 and 58 months,23  and there are no OS data in R/R patients, but the prognosis is usually poor. In our study, patients had usually been treated several times, and some patients had received 4 lines of treatment or ibrutinib, lenalidomide, or ASCT, thus representing a population with a very poor prognosis and very limited available treatments. All but 1 patient treated for R/R PRVL had received MTX and/or aracytine before, which represents the main drugs for vitreal localization. Few patients received rituximab or local radiation because of lack of proof efficacy.

We report an excellent overall response rate of 81%, a CR of 71%, and long-lasting responses, which represent the best response rates published to date. Median OS was not reached, while median follow-up was 42 months.

No unusual toxicity was observed and, compared with chemotherapy, radiotherapy, lenalidomide, and ibrutinib, TMZ seems to be better tolerated. Comparatively, HD aracytine is associated with 62% grade 3 or 4 myelosuppression.24 

In economic terms, the very low ratio of cost/benefits of TMZ compared with other drugs used in the same clinical context and until progression, such as ibrutinib or lenalidomide, appears to be very interesting. Limitations include retrospective analysis and lack of central pathologic confirmation.

In summary, TMZ, with its very high overall response rate, low toxicity, and affordable cost, can be considered as a very good therapeutic option and a new reference for elderly patients or R/R PVRL.

For original data, please e-mail the corresponding author.

Acknowledgment

The authors acknowledge Network LOC for patients' recruitment and treatments' decisions.

Authorship

Contribution: M. Baron and S.C. wrote the manuscript; L.B. analyzed statistical data; N.C., C.F., M. Blaizeau, C.S., C.H., K.H.-X., E.G., M.-L.L.L., A.L., P.S., B.B., V.L., V.T., M.-H.E., and D.R.-W. took care of the patients and completed the data forms for the study; C.S., C.H., K.H.-X., P.S., E.G., and S.C. participated in the LOC network and made treatment decisions; and K.M., M.C., and M.L.G.-T. provided biological diagnosis.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Marine Baron, Groupe Hospitalo-Universitaire Pitié-Salpêtrière, 47-83 Boulevard de l’Hôpital, 75013 Paris, France; e-mail: marine.baron@aphp.fr.

REFERENCES

1.
Chan
C-C
,
Rubenstein
JL
,
Coupland
SE
, et al
.
Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium
.
Oncologist
.
2011
;
16
(
11
):
1589
-
1599
.
2.
Coupland
SE
,
Heimann
H
,
Bechrakis
NE
.
Primary intraocular lymphoma: a review of the clinical, histopathological and molecular biological features
.
Graefes Arch Clin Exp Ophthalmol
.
2004
;
242
(
11
):
901
-
913
.
3.
Enting
RH
,
Demopoulos
A
,
DeAngelis
LM
,
Abrey
LE
.
Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide
.
Neurology
.
2004
;
63
(
5
):
901
-
903
.
4.
Pitini
V
,
Baldari
S
,
Altavilla
G
,
Arrigo
C
,
Naro
C
,
Perniciaro
F
.
Salvage therapy for primary central nervous system lymphoma with (90)Y-ibritumomab and temozolomide
.
J Neurooncol
.
2007
;
83
(
3
):
291
-
293
.
5.
Reni
M
,
Zaja
F
,
Mason
W
, et al
.
Temozolomide as salvage treatment in primary brain lymphomas
.
Br J Cancer
.
2007
;
96
(
6
):
864
-
867
.
6.
Wong
ET
,
Tishler
R
,
Barron
L
,
Wu
JK
.
Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas
.
Cancer
.
2004
;
101
(
1
):
139
-
145
.
7.
Costopoulos
M
,
Touitou
V
,
Golmard
J-L
, et al
.
ISOLD: a new highly sensitive interleukin score for intraocular lymphoma diagnosis
.
Ophthalmology
.
2016
;
123
(
7
):
1626
-
1628
.
8.
van Dongen
JJM
,
van der Velden
VHJ
,
Brüggemann
M
,
Orfao
A
.
Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies
.
Blood
.
2015
;
125
(
26
):
3996
-
4009
.
9.
Abrey
LE
,
Batchelor
TT
,
Ferreri
AJ
, et al;
International Primary CNS Lymphoma Collaborative Group
.
Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma
.
J Clin Oncol
.
2005
;
23
(
22
):
5034
-
5043
.
10.
Plotkin
SR
,
Betensky
RA
,
Hochberg
FH
, et al
.
Treatment of relapsed central nervous system lymphoma with high-dose methotrexate
.
Clin Cancer Res
.
2004
;
10
(
17
):
5643
-
5646
.
11.
Pentsova
E
,
Deangelis
LM
,
Omuro
A
.
Methotrexate re-challenge for recurrent primary central nervous system lymphoma
.
J Neurooncol
.
2014
;
117
(
1
):
161
-
165
.
12.
Rubenstein
JL
,
Treseler
PA
,
Stewart
PJ
.
Regression of refractory intraocular large B-cell lymphoma with lenalidomide monotherapy
.
J Clin Oncol
.
2011
;
29
(
20
):
e595
-
e597
.
13.
Houillier
C
,
Choquet
S
,
Touitou
V
, et al
.
Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma
.
Neurology
.
2015
;
84
(
3
):
325
-
326
.
14.
Ghesquieres
H
,
Houillier
C
,
Chinot
O
, et al
.
Rituximab-lenalidomide (REVRI) in relapse or refractory primary central nervous system (PCNSL) or vitreo retinal lymphoma (PVRL): results of a “proof of concept” phase II study of the French LOC Network
.
Blood
.
2016
;
128
(
22
):
785
-
785
.
15.
Chamoun
K
,
Choquet
S
,
Boyle
E
, et al
.
Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: A retrospective case series
.
Neurology
.
2017
;
88
(
1
):
101
-
102
.
16.
Choquet
S
,
Houillier
C
,
Bijou
F
, et al
.
Ibrutinib monotherapy in relapse or refractory primary CNS lymphoma (PCNSL) and primary vitreo-retinal lymphoma (PVRL). Result of the interim analysis of the iLOC phase II study from the Lysa and the French LOC Network
.
Blood
.
2016
;
128
(
22
):
784
-
784
.
17.
de Smet
MD
,
Vancs
VS
,
Kohler
D
,
Solomon
D
,
Chan
CC
.
Intravitreal chemotherapy for the treatment of recurrent intraocular lymphoma
.
Br J Ophthalmol
.
1999
;
83
(
4
):
448
-
451
.
18.
Ohguro
N
,
Hashida
N
,
Tano
Y
.
Effect of intravitreous rituximab injections in patients with recurrent ocular lesions associated with central nervous system lymphoma
.
Arch Ophthalmol
.
2008
;
126
(
7
):
1002
-
1003
.
19.
Larkin
KL
,
Saboo
US
,
Comer
GM
, et al
.
Use of intravitreal rituximab for treatment of vitreoretinal lymphoma
.
Br J Ophthalmol
.
2014
;
98
(
1
):
99
-
103
.
20.
Soussain
C
,
Merle-Béral
H
,
Reux
I
, et al
.
A single-center study of 11 patients with intraocular lymphoma treated with conventional chemotherapy followed by high-dose chemotherapy and autologous bone marrow transplantation in 5 cases
.
Leuk Lymphoma
.
1996
;
23
(
3-4
):
339
-
345
.
21.
Soussain
C
,
Hoang-Xuan
K
,
Taillandier
L
, et al;
Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire
.
Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire
.
J Clin Oncol
.
2008
;
26
(
15
):
2512
-
2518
.
22.
Soussain
C
,
Choquet
S
,
Fourme
E
, et al
.
Intensive chemotherapy with thiotepa, busulfan and cyclophosphamide and hematopoietic stem cell rescue in relapsed or refractory primary central nervous system lymphoma and intraocular lymphoma: a retrospective study of 79 cases
.
Haematologica
.
2012
;
97
(
11
):
1751
-
1756
.
23.
Grimm
SA
,
Pulido
JS
,
Jahnke
K
, et al
.
Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report
.
Ann Oncol
.
2007
;
18
(
11
):
1851
-
1855
.
24.
Abrey
LE
,
Yahalom
J
,
DeAngelis
LM
.
Treatment for primary CNS lymphoma: the next step
.
J Clin Oncol
.
2000
;
18
(
17
):
3144
-
3150
.