ORIGINALES Prospective study on the practice of central nervous

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ORIGINALES
Prospective study on the practice of central nervous system
prophylaxis and treatment in non-Hodgkin’s lymphoma in Spain
226.782
Juan-Manuel Sanchoa, Mireia Morgadesa, Natalia Alonsob, Guillermo Debenc, Alberto Fernández
de Sevillad, Lourdes Vázqueze, Concepción Nicolásf, José-Antonio García Velag, Reyes Arranzh,
Eugenia Abellai, Miguel-Ángel Canalesj, Pilar Mirallesk, Eva Sánchezl, Mar Hermosillam, Eulogio
Conden, Antonio Ruedao, Josep-Maria Riberaa, on behalf of investigators of QUIT Study
(PETHEMA, GELTAMO and GOTEL Groups)
a
Servicio de Hematología Clínica. ICO-Hospital Germans Trias i Pujol. Universitat Autònoma de Barcelona. Badalona.
Barcelona. bServicio de Hematología. Complejo Hospitalario Universitario de Santiago. Santiago de Compostela. La Coruña.
Servicio de Hematología. Hospital Juan Canalejo. La Coruña. dServicio de Hematología. ICO-Hospital Duran i Reynals.
L’Hospitalet de Llobregat. Barcelona. eServicio de Hematología. Hospital Universitario de Salamanca. Salamanca. fServicio
de Hematología. Hospital Universitario Central de Asturias. Oviedo. Asturias. gHospital Universitario de Getafe. Getafe.
Madrid. hServicio de Hematología. Hospital Universitario de la Princesa. Madrid. iServicio de Hematología. Hospital del Mar.
Barcelona. jServicio de Hematología. Hospital Universitario La Paz. Madrid. kHospital General Universitario Gregorio Marañón.
Madrid. lServicio de Hematología. Hospital Vall d’Hebron. Barcelona. mServicio de Hematología. Hospital Josep Trueta. Lleida.
n
Servicio de Hematología. Hospital Marqués de Valdecilla. Santander. Cantabria. oServicio de Oncología. Hospital Clínico
Virgen de la Victoria. Málaga. España.
BACKGROUND AND OBJECTIVE: Central nervous system (CNS) involvement in patients diagnosed with nonHodgkin’s lymphoma (NHL) or other lymphoproliferative disorders is an infrequent complication with a
poor prognosis. The prophylaxis and treatment of CNS involvement in these patients are not homogenous. The aim of this prospective longitudinal study was to report the current practice of CNS prophylaxis and treatment in patients with lymphoproliferative disorders in Spain.
ⱖ 18 yr) diagMETHODS: Prospective study conducted from June 2005 to June 2006. Adult patients (ⱖ
nosed with NHL or other lymphoproliferative disorders who received CNS prophylaxis or treatment
were consecutively included through online registration.
RESULTS: 228 patients from 33 hospitals were included. The mean (SD) age was 52 (16) yr and 144
(63%) were males. CNS therapy was given to 41 cases and consisted of triple intrathecal (IT) therapy
(TIT, methotrexate, cytarabine and hydrocortisone) in 22, liposomal depot cytarabine in 18 and methotrexate in one. In addition, 4 patients received cranial radiotherapy. CNS prophylaxis (n = 187)
consisted of TIT (166 cases), IT methotrexate (17), IT liposomal depot cytarabine (3) and IT cytarabine (1), whereas cranial or craniospinal radiotherapy was administered to 2 patients. The main reasons
for CNS prophylaxis cited by the investigators included extranodal involvement (89 patients), raised
serum lactate dehydrogenase level (87), IPI score > 2 (62), bulky mass (43), extranodal involvement
in more than one organ (33), age over 60 yr (28) and human immunodeficency virus infection (13).
CONCLUSIONS: The results of this study point out the generalized use of TIT therapy both for CNS
prophylaxis and therapy in patients with lymphoproliferative disorders in Spain. The introduction of
the new formulations of drugs, especially liposomal depot cytarabine for CNS involvement, and the
scarce use of radiotherapy are also of note. Similar to other studies, the absence of homogeneous criteria for CNS prophylaxis is of note.
Key words: Non-Hodgkin’s lymphoma. Lymphoproliferative disorders. Central nervous system
involvement. Intrathecal. Prophylaxis. Treatment.
Estudio prospectivo sobre la práctica habitual de profilaxis y tratamiento de la
infiltración neuromeníngea en pacientes con linfoma no hodgkiniano en España
FUNDAMENTO Y OBJETIVO: La infiltración del sistema nervioso central (SNC) en pacientes diagnosticados de linfoma no hodgkiniano (LNH) u otros síndromes linfoproliferativos es una complicación infrecuente y de mal
pronóstico. La profilaxis y el tratamiento de la infiltración neuromeníngea en estos pacientes no son homogéneos. El objetivo de este estudio longitudinal y prospectivo fue describir la práctica habitual de profilaxis y
tratamiento de la infiltración neuromeníngea en pacientes con síndromes linfoproliferativos en España.
MÉTODOS: Estudio prospectivo efectuado entre junio de 2005 y junio de 2006. Se incluyó a pacientes
de edad ⱖ 18 años diagnosticados de LNH u otros síndromes linfoproliferativos que recibieron profilaxis o tratamiento de la infiltración del SNC.
RESULTADOS: Se incluyó a 228 pacientes en 33 hospitales. La media (desviación estándar) de edad fue
de 52 (16) años, y 144 (63%) eran varones. Un total de 41 pacientes recibieron tratamiento por infiltración neuromeníngea, que consistió en tratamiento triple intratecal (TIT, metotrexato, citarabina e
hidrocortisona) en 22 casos; citarabina liposómica depot intratecal (IT) en 18, y metotrexato IT en
uno. Cuatro pacientes recibieron además radioterapia (RT) craneal. En los 187 pacientes restantes, se
administró profilaxis del SNC, que incluyó tratamiento TIT en 166 casos, metotrexato IT en 17, citarabina liposómica depot IT en 3 y citarabina IT en uno, además de RT craneal o craneoespinal a 2 pacientes. Las principales razones para administrar profilaxis del SNC fueron: afectación extraganglionar
(89 casos), aumento de la lactatodeshidrogenasa sérica (87), puntuación del índice pronóstico internacional > 2 (62), enfermedad voluminosa (43), más de una afectación extraganglionar (33), edad
superior a 60 años (28) e infección por el virus de la inmunodeficiencia humana (13).
CONCLUSIONES: Este estudio pone de manifiesto el uso generalizado del tratamiento TIT para la profilaxis y el tratamiento de la infiltración neuromeníngea en pacientes con síndromes linfoproliferativos en
España. La RT holocraneal o craneoespinal apenas se emplea, mientras que destaca la administración
de nuevos fármacos, como la citarabina liposómica depot. Al igual que en estudios previos, no hay criterios homogéneos para la profilaxis neuromeníngea.
Palabras clave: Linfomas no hodgkinianos. Síndromes linfoproliferativos. Infiltración del sistema nervioso
central. Intratecal. Profilaxis. Tratamiento.
This study was partially supported by an unrestricted grant from Mundipharma Pharmaceuticals SL
and supported in part by grant P-EF/06 from the Jose Carreras International Leukemia Foundation.
Correspondence: Dr. J.M. Ribera.
Clinical Hematology Department. Institut Català d’Oncologia-Hospital Germans Trias i Pujol.
Canyet, s/n. 08916 Badalona. Barcelona. España.
E-mail: [email protected]
Recibido el 16-10-2007; aceptado para su publicación el 23-10-2007.
Central nervous system (CNS) involvement in patients diagnosed with nonHodgkin lymphoma (NHL) occurs in
about 5% of all patients, either at the
time of diagnosis of NHL or during the
course of progressive disease. In addition
to the well-recognized poor prognosis of
the patients with NHL and CNS involvement, this complication has been associated with a reduction in the quality of
life due to both CNS involvement itself
and to the side effects of CNS-directed
therapies such as cranial irradiation, intrathecal (IT) drugs and systemic therapy
with drugs able to cross the blood-brain
barrier1,2.
Risk factors for lymphomatous meningeosis have been identified from the analysis
of large case series3-11. Histology is cited
as one of the main risk factors, and thus,
patients with certain high-grade histologic
subtypes such as lymphoblastic lymphoma and Burkitt’s lymphoma systematically received CNS prophylaxis because
of the well known propensity of these
lymphomas to involve the CNS. In contrast, the risk of meningeal involvement
from unstransformed low-grade NHL is
low, and CNS prophylaxis is generally not
recommended1,2,12. Controversy on CNS
prophylaxis is open in other aggressive
lymphomas, especially diffuse large Bcell lymphomas (DLBCL), in which no
consensus on CNS prophylaxis in specific
situations has been reached. On the other hand, the new diagnostic tools for the
detection of meningeal involvement, such
as flow cytometry of cerebrospinal fluid
(CSF), have led to the detection of a greater number of patients with occult CNS
disease compared to conventional cytology13-15. In some of these studies patients with occult CNS disease showed a
trend to high-risk of CNS relapse13.
In addition to this poorly clarified situation, and contrary to the proven efficacy
of CNS prophylaxis in patients with acute
Med Clin (Barc). 2008;131(12):441-6
441
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SANCHO JM ET AL. PROSPECTIVE STUDY ON THE PRACTICE OF CENTRAL NERVOUS SYSTEM PROPHYLAXIS AND TREATMENT
IN NON-HODGKIN’S LYMPHOMA IN SPAIN
lymphoblastic leukemia (ALL), conclusions regarding the efficacy of CNS
prophylaxis on CNS disease remain controversial in some studies1,16,17. This is
mainly due to the heterogeneity in drugs
and schedules administered, the small
number of patients and/or the lack of a
control arm in most studies.
Besides the heterogeneity for indications
of CNS prophylaxis, schedules of prophylaxis and treatment of CNS involvement
in NHL homogeneous in different countries are lacking, even within the same
country, and have been scarcely investigated18,19. The QUIT (Registro Español de
Pacientes que Reciben Quimioterapia Intratecal) registry was an initiative of the
PETHEMA (Programa Español de Tratamiento de las Hemopatías Malignas, Asociación Española de Hematología y Hemoterapia), GEL/TAMO (Grupo Español
de Linfomas/Trasplante Autólogo de Médula Ósea) and GOTEL (Grupo Oncológico para el Tratamiento y Estudio de los
Linfomas) groups designed to prospectively know the current practice of CNS
prophylaxis and therapy in patients diagnosed with hematological malignancies
(acute leukemias [AL] and lymphoproliferative disorders) in Spain. The results in
AL patients have recently been reported20.
The objective of this study was to report
the practice of CNS prophylaxis and treatment in patients with lymphoproliferative
disorders.
Patients and methods
The QUIT study was presented at meetings of the
Spanish PETHEMA, GELTAMO and GOTEL groups to
select participant hospitals as has been previously
described20. Briefly, from June 2005 to June 2006
adult patients (ⱖ 18 yr) diagnosed with NHL or other
lymphoproliferative disorders who received CNS
prophylaxis or CNS treatment were consecutively included through online registration in 33 hospitals.
Each patient was included only once. The questionnaire included sociodemographic variables (age, sex,
hospital), NHL subtype (or type of lymphoproliferative disorder according to WHO classification)21 and
date of diagnosis, stage (Ann Arbor)22, B symptoms,
ECOG score, presence or absence of extranodal involvement (testis, liver, lung, gastrointestinal tract,
bone marrow, skin, paranasal sinus, orbita and others) and number of extranodal sites and lymph
node regions involved, bulky mass (over 10 cm in
diameter), serum levels of lactate dehydrogenase
(LDH) (raised or normal) and International Prognostic Index (IPI) score23.
With regard to meningeal involvement, the timing of
the CNS involvement (at diagnosis or at relapse), date
of diagnosis of neoplastic meningeosis, neurological
symptoms at the time of CNS involvement (including
headache, nausea and vomiting, mental status abnormalities, muscular weakness, impairment of
march, sensorial neuropathy, dyplopia and others) as
well as the method used for diagnosis of CNS involvement (detection of blast cells in a sample of CSF by
cytology or by flow cytometry, computed tomography
[CT] scan or magnetic resonance imaging [MRI])
were recorded.
The following data of CNS therapy were recorded: reason of CNS-directed therapy (prophylaxis or treatment, and in the case of prophylaxis, the reason
[hystologic subtype, extranodal involvement (1 or
ⱖ 2), site of extranodal involvement, raised LDH, age
> 60 yr, bone marrow involvement, bulky mass, inter-
442
Med Clin (Barc). 2008;131(12):441-6
mediate-high IPI score, and others]), date of the onset of IT therapy (methotrexate [MTX], cytarabine, triple therapy [including MTX, cytarabine and hydrocortisone]), route (IT through lumbar puncture or
intraventricular) and schedule of administration, as
well as other CNS-directed therapies such as cranial
irradiation or the use of new drugs.
As reported for the results of AL patients included in
the QUIT study20, an intermediate analysis was performed 6 months after starting the registry and the
results were reported at meetings of PETHEMA,
GEL/TAMO and GOTEL groups. Results were expresed as crude frequencies and percentages, and were
analysed separately for CNS prophylaxis and therapy.
For the comparison of type and route of administration of IT therapy between patients receiving CNS
prophylaxis and therapy, a Fisher exact test was
used. A p value of less than 0.05 was considered statistically significant.
Results
A total of 228 patients diagnosed with
lymphoproliferative disorders from 33
hospitals were included. The mean
(standard deviation [SD]) age was 52
(16) yr. (range 18-83), with 63 (34%)
patients older than 60 years, and 144
(63%) males. DLBCL was the most frequent histologic subtype (133 patients
[58%]), followed by Burkitt’s lymphoma
(37 patients [16%]) and MCL (11 cases
[4.8%]). Table 1 provides a complete list
of the lymphoproliferative disorders. At
the time of diagnosis, half of the patients
presented with B symptoms and three
quarters had advanced disease (stage IV
in 149 [65%]). A total of 228 patients
(79%) showed extranodal involvement,
being bone marrow the most frequent
extranodal site involved (81 patients) followed by CNS, liver and lung (30 cases
each one). The LDH level was increased
in 63% of the cases and 62% had an IPI
score higher than 2. The main demographic and clinical characteristics are
listed in table 2.
IT therapy was administered for neoplastic meningeosis in 41 cases and as CNS
prophylaxis in 187. Thirty out of 41 pa-
tients showed CNS involvement at the
time of diagnosis of lymphoproliferative
disorders, whereas 11 showed CNS relapse. Diagnosis of CNS involvement was
established by the observation of malignant cells in CSF in 33 cases, with a median of cell count of 18 cells/µl (range 2100), or by imaging techniques (MRI in
15 and CT scan in 8). In 17 patients
(41%) CSF involvement was confirmed
by flow cytometry. Neurological symptoms included: impairment in march in
18, headache in 17, mental status impairment in 14 cases, cranial nerve palsy
in 14, muscle weakness in 12, nausea
and vomiting in 10, diplopy in 9, sensorial neuropathy in 7, loss of vision in 6
and seizures in 1.
As can been observed in table 3, the
most common CNS-directed therapy reported in cases with CNS involvement
was TIT, although it is of note that almost
half of the patients were treated with IT
depot liposomal cytarabine. Regarding IT
administration schedule, in most of the
cases (n = 15) IT therapy was administered every 15 days (to almost all the patients corresponding to those receiving IT
depot liposomal cytarabine) or 2-3 times
weekly, whereas lumbar puncture was
the preferred route for IT administration
(37 out of the 41 patients). Cranial irradiation was used in 4 cases (local radiotherapy in 3 and craniospinal radiotherapy
in the remaining).
In the group of patients who received
CNS prophylaxis (n = 187), TIT was
also the most frequent schedule (table
3), followed by IT MTX. However, significant differences were observed in the
type of IT therapy administered as
prophylaxis and therapy (table 3), and,
in fact, only three patients received IT
depot liposomal cytarabine as CNS
prophylaxis. Two were patients diagnosed with DLBCL (one with elevated
TABLE 1
Lymphoproliferative disorders according to the World Health Organisation
classification included in the QUIT registry
n
B-Cell neoplasms (n = 206 [90%])
Precursor B-cell neoplasm
B-cell chronic lymphocytic leukemia / B-cell prolymphocytic leukemia
Plasma cell myeloma / plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Splenic marginal zone B-cell lymphoma
Nodal marginal zone B-cell lymphoma
Follicular lymphoma
Mantle-cell lymphoma
Diffuse large B-cell lymphoma / Mediastinal large B-cell lymphoma
Burkitt’s lymphoma
T-Cell and NK-cell neoplasms (n = 22 [10%])
Precursor T-cell neoplasm
T-cell prolymphocytic leukemia
Extranodal NK / T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Peripheral T-cell lymphoma
Total
4
2
2
2
1
3
8
11
136
37
8
1
3
1
9
228
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SANCHO JM ET AL. PROSPECTIVE STUDY ON THE PRACTICE OF CENTRAL NERVOUS SYSTEM PROPHYLAXIS AND TREATMENT
IN NON-HODGKIN’S LYMPHOMA IN SPAIN
TABLE 2
TABLE 3
Characteristics of the 228 patients
diagnosed with lymphoproliferative
disorders included in the QUIT registry
Intrathecal and other central nervous system directed therapies used
in patients diagnosed with lymphoproliferative disorders included in the QUIT
registry
Variable
Age (yr)
< 60
> 60
Sex
Male
Female
ECOG score
0-1
02-abr
Stage
I-II
III-IV
B symptoms
No
Yes
Extranodal involvement
No
Yes
1 site involved
> 1 site involved
Site of extranodal involvement
Bone marrow
CNS
Liver
Lung
Skin
Gastrointestinal tract
Testis
Bulky disease
LDH level
Normal
Increased
IPI score
0-1
2
3
4-5
n (%)
125 (66)
63 (34)
144 (63)
84 (37)
86 (38)
142 (62)
53 (23)
175 (77)
113 (49.6)
115 (50.4)
40
228
100
88
81
30
30
30
27
11
10
64 (28)
85 (37)
143 (63)
45 (20)
42 (18)
62 (27)
79 (35)
CNS: central nervous system; ECOG: Eastern Cooperative
Group; IPI: International Prognostic Index; LDH: lactate dehydrogenase.
LDH) whereas the remaining was a patient diagnosed with follicular lymphoma who had involvement of 2 extranodal sites, raised LDH and bulky disease
at diagnosis. In most of the patients in
which the schedule of administration
was available, IT prophylaxis was administered with each cycle of chemotherapy, followed by those who received
just one IT administration, probably during screening lumbar puncture. On the
other hand, although the most frequent
route for IT administration was, again,
lumbar puncture, an Ommaya reservoir
was used for intraventricular administration in only one patient. Radiotherapy
was administered as CNS prophylaxis in
2 cases. The main reasons for CNS
prophylaxis cited by the investigators included extranodal involvement in 89 patients, raised LDH level in 87, IPI score
higher than 2 in 62, bulky mass in 43,
extranodal involvement in more than
one organ in 33, age over 60 yr in 28
and human immunodeficency virus
(HIV) infection in 13. Table 4 shows reasons for CNS prophylaxis by the main
histologic subtypes.
Type of intrathecal therapy
TIT
MTX
Ara-C
Liposomal depot cytarabine
Route of administration of IT therapy
Lumbar puncture
Intraventricular
Frequency of administration of IT therapy
2-3 times per week
Weekly
1 every 2 weeks
1 every 4 weeks
1 each chemotherapy cycle
Only one dose
Not specified
Radiotherapy
CNS involvement
(n = 41)
CNS prophylaxis
(n = 187)
22
1
0
18
166
17
1
3
37
4
186
1
14
3
15
5
4
4
2
2
5
3
94
40
41
2
p
< 0.001
0.004
NA
0.01
Ara-C: cytarabine; CNS: central nervous system; IT: intrathecal; MTX: methotrexate; NA: not applicable; TIT: triple intrathecal therapy.
Discussion
Similar to a previous study by our group
focused on CNS prophylaxis and therapy
for AL patients20, this is the first study
that prospectively describes the current
practice of prophylaxis and therapy for
neoplastic meningeosis by lymphomas
and other lymphoproliferative disorders in
Spain. As observed in AL study, the most
frequent therapy for CNS involvement or
CNS prophylaxis was TIT, and lumbar
puncture was the preferred route for IT
administration. The introduction of new
drugs, especially liposomal depot cytarabine for therapy of CNS infiltration and
the scarce use of radiotherapy are also of
note. On the other hand, and conversely
to patients with AL, one of the most relevant findings of this study was the marked differences between investigators in
the indications of CNS prophylaxis for
most of the cases, reflecting the disparity
in criteria for CNS prophylaxis, a feature
also described in other studies18,19.
In most of the studies on the risk of CNS
relapse in patients with lymphoma, the histologic subtype has been indicated as one
of the main risk factors. Thus, there is a
consensus on the need of CNS-directed
therapy in some aggressive lymphomas
such as Burkitt’s lymphoma and lymphoblastic lymphoma, in which the risk of CNS
relapse in the absence of prophylaxis could
achieve 20%-25%8,12,24. This explains why,
in the QUIT registry, patients diagnosed
with these histologies received homogeneous IT prophylaxis following specific Spanish protocols that include systematic IT
prophylaxis, generally with TIT25. Conversely, the risk of CNS relapse in the untransformed low-grade lymphomas is low8, and
there is no evidence for the routine use of
CNS prophylaxis, with the exception of
high-grade transformation4. However, 10
patients diagnosed with follicular or marginal zone lymphoma in the QUIT registry received IT prophylaxis, mostly due to the
presence of other risk factors for CNS disease identified in studies focused on aggressive NHL (table 4).
The controversy in the criteria used for
CNS prophylaxis especially arises in other
aggressive lymphomas such as the blastic variant of MCL, anaplastic large cell
lymphoma, peripheral T cell lymphomas
and, especially, DLBCL. Case-series studies have estimated that the risk of CNS
relapse for patients diagnosed with
DLBCL is about 5%5,8,9. The use of systematic prophylaxis in these cases could
lead to the treatment of patients who may
never have CNS relapse. For this reason,
many of these studies have tried to identify which of these patients are at risk of
developing CNS disease based on the
presence of other risk factors. One of the
largest studies is that by Hollender et al8
in which more than 2,500 patients diagnosed with NHL were studied for the incidence and risk factors for CNS disease.
These authors described a score system
based on the findings of five independent
risk factors: raised serum LDH level, serum albumin over 35 g/L, age less than
60 yr, retroperitoneal lymph node involvement and involvement of more than one
extranodal site. The presence of 4 or 5 of
these factors increased the risk of CNS
recurrence by 25%. In the study by
Haioun et al7, the risk of CNS relapse increased in patients with raised LDH or
with involvement of more than one extranodal site; although when IPI was added
to multivariate analysis it remained as the
only parameter with statistical significance, identical to the report by Feugier et
al9. In a recent article10, increased serum
LDH level or involvement of more than
Med Clin (Barc). 2008;131(12):441-6
443
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SANCHO JM ET AL. PROSPECTIVE STUDY ON THE PRACTICE OF CENTRAL NERVOUS SYSTEM PROPHYLAXIS AND TREATMENT
IN NON-HODGKIN’S LYMPHOMA IN SPAIN
TABLE 4
Reasons most frequently cited for central nervous system prophylaxis by the main
histologic subtypes*
Histology
DLBCL
Burkitt’s lymphoma
n
Reasons for CNS prophylaxis
117
31
T cell lymphoblastic lymphoma
8
Mantle cell lymphoma
6
Follicular lymphoma
6
Peripheral T cell lymphoma
6
Marginal zone lymphoma
4
Extranodal involvement
Increased LDH
Intermediate-high IPI score
Bulky disease
Age > 60 yr
Extranodal involvement ⱖ 2 sites
HIV infection
Conditioning SCT
Requirement protocol
Increased LDH
Extranodal involvement
Bulky disease
Intermediate-high IPI score
Extranodal involvement ⱖ 2 sites
Requirement protocol
Increased LDH
Extranodal involvement
Intermediate-high IPI score
Bulky disease
Conditioning SCT
Extranodal involvement
Increased LDH
Intermediate-high IPI score
Blastic variant
SCT
Extranodal involvement
Increased LDH
Extranodal involvement ⱖ 2 sites
Intermediate-high IPI score
Bulky disease
Age > 60 yr
Extranodal involvement
Intermediate-high IPI score
Increased LDH
Extranodal involvement ⱖ 2 sites
Age > 60 yr
HIV infection
Extranodal involvement
Extranodal involvement ⱖ 2 sites
Increased LDH
n
55
53
40
24
23
18
12
2
29
18
17
12
11
7
2
2
1
1
1
1
2
1
1
1
1
5
4
3
3
3
2
4
4
3
2
1
1
2
2
2
*Patients can have more than one reason for CNS prophylaxis.
CNS: central nervous system; DLBCL: diffuse large B cell lymphoma; HIV: human immunodeficiency virus; IPI: International
Prognostic Index; LDH: lactic dehydrogenase; SCT: stem cell transplantation.
one extranodal site were, again, the main
risk factors associated with higher CNS
relapse.
Although many patients with DLBCL included in the QUIT registry received CNS
prophylaxis according to some of the
above mentioned reasons (raised LDH levels and intermediate-high IPI score),
some findings were of note. The first is
that the main criteria for CNS prophylaxis
was the presence of only one extranodal
site in 55 patients with this histologic
subtype, a risk factor not cited in the aforementioned studies. In fact, this finding
probably reflects the trend to use CNS
prophylaxis in patients with involvement
of anatomical sites associated, in some
studies, with a higher risk of CNS involvement, such as bone marrow3, paranasal
sinuses26, breast27, epidural space28,29 or
testicular involvement30,31, yet the significance of this increased involvement is
difficult to detect by multivariate analysis12. In this sense, the guidelines of the
National Comprehensive Cancer Network
(NCCN)32 recommend CNS prophylaxis
in patients with DLBCL and involvement
444
Med Clin (Barc). 2008;131(12):441-6
of these mentioned sites. Identical results
to those of our study were observed in similar studies conducted in the UK18 and
Canada19, in which only a minority of clinicians used a high IPI score, increased
serum LDH level or more than one extranodal site as criteria for CNS prophylaxis.
The second remarkable finding in our
study is that bulky disease was also mentioned as a reason for CNS prophylaxis in
24 patients with DLBCL. Bulky disease
has not been associated with a high-risk
of CNS involvement and, in fact, in the
study by Tomita et al33, CNS relapse was
observed more frequently in the group of
patients with less frequency of bulky
masses. Third, HIV infection was included as a reason for CNS prophylaxis in
13 cases (12 diagnosed with DLBCL),
despite the results of the study by Desai
et al34, suggesting that CNS prophylaxis
should be administered only for aggressive lymphomas or bone marrow involvement. In addition, in one study35, the
frequency of CNS involvement had significantly decreased in patients with HIVrelated lymphomas who were receiving
highly active antiretroviral therapy (HAART). Finally, although a high risk of CNS
disease has been associated with younger age3,8,28, in our study age over 60 yr
was included as criteria for CNS prophylaxis in 28 patients (23 diagnosed with
DLBCL), probably reflecting the fact that
advanced age is a risk factor included in
the IPI score.
As described for patients diagnosed with
AL20, there was a massive use of TIT as
the prefered schedule for CNS prophylaxis, conversely to reports in other foreign
studies in which IT MTX alone or combined with soluble steroids was the most
frequent IT therapy7,8,18,33. The reason
has been previously discussed20 and was
a consequence of the wide use of the
risk-adapted protocols from the PETHEMA group in Spain for treatment of patients with ALL, Burkitt’s and lymphoblastic lymphoma, that could exert a mimetic
effect leading to a generalization of this
schedule for CNS prophylaxis for the remaining lymphoid malignancies.
Another remarkable feature of the QUIT
study was the administration of IT depot
liposomal cytarabine in almost 50% of
the cases of lymphomas with CNS involvement. Due to its long half time in CSF,
IT depot liposomal cytarabine can be administered every two weeks, allowing fewer IT administrations36,37. The efficacy of
this drug in lymphomatous meningeosis
has been established in several studies38,39, and it indeed constitutes an accepted indication by the regulatory agencies. It is note, however, that 3 patients
also received IT depot liposomal cytarabine as CNS prophylaxis despite the scarce
information available in this setting. Mc
Clune et al40 included 14 patients with
ALL or high-grade non-Hodgkin’s lymphoma treated with systemic chemotherapy. IT depot liposomal cytarabine was
administered in 40 out of 81 cycles as
CNS prophylaxis and at the time of the
analysis no CNS relapse was observed.
Several ongoing trials are attempting to
establish the role of IT liposomal cytarabine in the prophylaxis of lymphomatous
meningeosis41.
The incorporation of new diagnostic tools
for CNS involvement in the QUIT study is
of note. Although in most of the cases of
our registry (33 patients) the diagnosis
was based on the presence of atypic
lymphoid cells detected in a cytocentrifuged sample of CSF, more sensitive techniques for the detection of neoplastic
cells in CSF, such as flow cytometry for
the detection of aberrant phenotypes
were employed. In our study, flow cytometry confirmed the presence of neoplastic cells in CSF in 17 out of 41 patients with CNS involvement. The use of
these more sensitive techniques has
been associated with the detection of
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SANCHO JM ET AL. PROSPECTIVE STUDY ON THE PRACTICE OF CENTRAL NERVOUS SYSTEM PROPHYLAXIS AND TREATMENT
IN NON-HODGKIN’S LYMPHOMA IN SPAIN
more frequent CSF involvement compared to conventional cytology13-15. In a recent study by Hedge et al13, the detection
of CSF disease by flow cytometry was associated with the presence of more than
one extranodal site, one of the main risk
factors for CNS relapse reported in several studies5,7,8,10, suggesting that patients
with CNS involvement detected by cytometry could be at risk for meningeal relapse. In addition, among the patients
with evidence of occult CSF lymphoma
by flow cytometry, CNS relapse was observed in 45% vs 8% in patients with negative CSF flow cytometry13. It is of note,
however, that this technique is not currently accepted as standard for CNS involvement detection, but could become a
standard procedure in the future.
The lack of the systematic inclusion of all
the cases in which CNS-directed therapy
was administered constitutes the main limitation of the present study. However,
the design of this survey (cross sectional
and consecutive) and the similar results
obtained in other surveys conducted in
foreign countries18,19 indicate that this registry probably was a representative sample of the practice of CNS prophylaxis
and treatment in patients with lymphoproliferative disorders in Spain.
In conclusion, the results of this study
point out the generalized use of IT therapy both for CNS prophylaxis and therapy in patients with NHL and other
lymphoproliferative disorders, as well as
the increasing use of new formulations of
drugs, such as IT depot liposomal cytarabine, and the scarce use of radiotherapy.
As has been reported in similar studies,
the absence of homogeneous criteria for
CNS prophylaxis in some aggressive
lymphomas, especially DLBCL, is of note.
Acknowledgements
The following institutions and clinicians participated in the study: Hospital Universitari Germans Trias i Pujol, Badalona: J.M. Ribera,
J.M. Sancho, M. Morgades. Complejo Hospitalario Universitario de Santiago, Santiago de
Compostela: N. Alonso. Hospital Juan Canalejo, La Coruña: G. Deben. ICO-Hospital Duran i
Reynals, L’Hospitalet de Llobregat: A. Fernández de Sevilla. Hospital Universitario de Salamanca, Salamanca: L. Vázquez. Hospital Universitario Central de Asturias, Oviedo: C.
Nicolás. Hospital Universitario de Getafe, Madrid: J.A. García Vela. Hospital Universitario de
la Princesa, Madrid: R. Arranz. Hospital del
Mar, Barcelona: E. Abella. Hospital Universitario La Paz, Madrid: M.A. Canales. Hospital General Universitario Gregorio Marañón, Madrid:
P. Miralles, J. Berenguer. Hospital Vall d’Hebron, Barcelona: E. Sánchez García. Hospital
Josep Trueta, Lleida: M. Hermosilla. Clínica
Universitaria de Navarra, Pamplona: C. Panizo. Hospital 12 de Octubre, Madrid: R. Toscazo. Fundación Jiménez Díaz, Madrid: F. Lobo.
Hospital Universitario Príncipe de Asturias,
Madrid: J. García Suárez, D. de Miguel. Hospi-
tal Universitario de Canarias, Santa Cruz de
Tenerife: M.J. Rodríguez Salazar, M. Llanos.
Hospital General Universitario de Alicante, Alicante: P. Fernández-Abellán. Hospital Marqués de Valdecilla, Santander: E. Conde.
Hospital Xeral, Lugo: J. Arias. Complejo Hospitalario de Jaén, Jaén: J.A. López. Hospital Universitario La Fe, Valencia: M. Blanes. Hospital
Universitario Miguel Servet, Zaragoza: A. Rubio. Hospital de Fuenlabrada, Madrid: J.A.
Hernández. Hospital Virgen del Camino, Pamplona: M.C. Mateos. Complexo Hospitalario
Universitario de Vigo, Pontevedra: C. Albo.
Hospital Clínico Universitario de Valladolid, Valladolid: F.J. Fernández. Hospital de Pontevedra, Pontevedra: F.R. García Arroyo. Hospital
de Basurto, Bilbao: J.A. Márquez. Hospital Clínico de Zaragoza, Zaragoza: L. Palomera. Hospital Virgen de la Arrixaca, Murcia: P. Rosique.
Hospital Clínico Virgen de la Victoria, Málaga:
A. Rueda.
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