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Risk Factors, Treatment, and Outcome of Central Nervous System Recurrence
in Adults With Intermediate-Grade and Immunoblastic Lymphoma
By Koen van Besien, Chul S. Ha, Sandy Murphy, Peter McLaughlin, Alma Rodriguez, Kamal Amin,
Arthur Forman, Jorge Romaguera, Fredrick Hagemeister, Anas Younes, Carlos Bachier,
Andreas Sarris, Kathleen S. Sobocinski, James D. Cox, and Fernando Cabanillas
To evaluate the incidence, risk factors, and outcome of
central nervous system (CNS) recurrence in adult patients
with non-Hodgkin’s lymphoma, we evaluated 605 newly
diagnosed patients with large-cell and immunoblastic lymphoma who participated in prospective chemotherapy studies. The Kaplan-Meier estimate of probability of CNS recurrence at 1 year after diagnosis was 4.5% (95% confidence
interval [CI], 4.4 to 4.6). Twenty-four patients developed CNS
recurrence after a median of 6 months from diagnosis
(range, 0 to 44 months). In univariate analysis, an increased
risk for CNS recurrence was associated with an advanced
disease stage (P 5 .0014), an increased LDH (P 5 .0000), the
presence of B-symptoms (P 5 .0037), involvement of more
than one extranodal site (P 5 .0000), poor performance
status (P 5 .0005), and B-cell phenotype (P 5 .008). Bone
marrow involvement (P 5 .005), involvement of parenchymal organs (P 5 .03), and involvement of skin, subcutaneous
tissue, and muscle (P 5 .002) were also associated with an
increased risk for CNS disease. Multivariate logistic regres-
sion analysis identified only involvement of more than one
extranodal site (P 5 .0005) and an increased LDH (P 5 .0008)
as independent predictors of CNS recurrence. Established
CNS recurrence had a poor prognosis. Only 1 of 24 patients
remains alive and the Kaplan-Meier estimate of probability
of survival at 1 year after the diagnosis of CNS recurrence is
only 25.3% (95% CI, 6.9 to 43.7). Intrathecal treatment
provided symptomatic benefit in only 1 of 6 patients. Radiation treatment provided symptomatic improvement in 6 of 9
patients treated. However, remissions were short and followed by systemic or CNS recurrence. Serum LDH and
involvement of more than one extranodal site are independent risk factors for CNS recurrence in patients with largecell lymphoma. The presence of both risk factors identifies a
patient group at high risk for CNS recurrence. Established
CNS recurrence can be rapidly fatal. Transient responses
occur after radiation treatment.
r 1998 by The American Society of Hematology.
C
patients with intermediate-grade NHL treated with modern
combination chemotherapy. For this purpose, we analyzed the
outcome of 605 patients who participated in chemotherapy
studies at MD Anderson Cancer Center. We analyzed the
incidence, risk factors, treatment, and outcome of patients with
CNS recurrence in this large prospectively collected patient
cohort. Our results indicate that the use of simple staging
parameters such as serum LDH and number of sites of
extranodal involvement allows the identification of a subgroup
of patients at high risk for CNS recurrence.
In addition, we evaluated the outcome of patients with
established CNS recurrence and confirmed their extremely poor
outcome. These patients do not appear to benefit from intrathecal treatment and derive only symptomatic benefit from radiation treatment.
ENTRAL NERVOUS SYSTEM (CNS) recurrence is a
devastating and almost uniformly fatal complication of
intermediate-grade or immunoblastic lymphoma (non-Hodgkin’s
lymphoma [NHL]).1-10 Its incidence is not sufficiently high to
warrant the use of CNS prophylaxis in all patients. The
identification of patient subgroups for whom CNS prophylaxis
may be of benefit is therefore important.
An increased risk for CNS recurrence in NHL has been associated with features of advanced disease and involvement of
extramedullary sites such as blood,8 bone marrow,2-4,7,9 testicular,8,11 gastro-intestinal,12 or sinus or orbital13 involvement; with
serum lactate dehydrogenase (LDH)10; or with specific histologic subtypes of disease.13 However, the relative importance of
any of these risk factors has not been well defined, and data
specific for intermediate-grade lymphoma are scarce. Indeed, in
the one study that focuses on patients with intermediate-grade
lymphoma, no predictive value was assigned to involvement of
any specific disease site except for epidural disease.5
We attempted to develop a risk model that would be both
sensitive and specific for an increased risk of CNS recurrence in
From The Division of Medicine, Department of Hematology and
Neuro-oncology, and the Division of Radiation Oncology, MD Anderson Cancer Center, Houston, TX; and The Statistical Center, International Bone Marrow Transplant Registry, Medical College of Wisconsin, Milwaukee, WI.
Submitted June 17, 1997; accepted October 10, 1997.
Address reprint requests to Koen van Besien, MD, Hematology/
Oncology Section, University of Illinois at Chicago, 840 S Wood St (MC
787), Chicago, IL 60612.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to indicate
this fact.
r 1998 by The American Society of Hematology.
0006-4971/98/9104-0023$3.00/0
1178
PATIENTS AND METHODS
Patient selection and work-up. The outcome of 605 patients with newly diagnosed intermediate-grade or immunoblastic lymphoma who participated in four consecutive studies of
newly diagnosed NHL was analyzed for this study. No prophylactic intrathecal treatment was administered in any of these
study protocols.
Protocols DM88-087 and DM90-093 accrued patients with
favorable prognostic features. In protocol DM88-087, this was
defined as stage A by the MD Anderson staging system,14 and in
protocol DM93-003 this was defined as a tumor score of less
than 3.15 Patients with disease involving 1 single nodal or
extranodal site or 1 single chain of lymph nodes less than 5 cm
received 3 cycles of CHOP-Bleo16 (750 mg/m2 cyclophosphamide intravenously [IV] on day 1, 50 mg/m2 doxorubicin IV on
day 1, 2 mg vincristine IV on day 1, 100 mg prednisone orally
[PO] on days 1 through 5, and 15 U bleomycin IV on day 1)
followed by involved field radiation. All other patients on these
protocols received 3 courses of CHOP-Bleo alternating with 3
Blood, Vol 91, No 4 (February 15), 1998: pp 1178-1184
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
CNS RECURRENCE OF NHL
courses of OPEN (2 mg vincristine IV on day 1, 100 mg
prednisone PO on days 1 through 5, 100 mg/m2 etoposide IV on
days 1 through 3, and 10 mg/m2 mitoxantrone IV on day 1),
followed by involved field radiation to nodal disease that was
$5 cm in diameter at presentation. Protocols DM88-089 and
DM92-054 were designed to treat patients with poor prognostic
features. Patients with MD Anderson stages B, C, and D were
eligible for protocol DM88-089.14 Treatment consisted of
alternating triple therapy in which ASHAP, M-BACOS, and
MINE were alternated for a total of nine treatment cycles.
Details of this treatment have been reported.17,18 In short,
ASHAP consists of 50 mg/m2 doxorubicin administered by
continuous infusion over 96 hours, 500 mg methylprednisolone
IV daily for 5 days, 1.5 gr/m2 cytarabine IV over 2 hours on day
5, and 100 mg/m2 cisplatinum administered by continuous
infusion over 96 hours. M-BACOS consists of 10 mg/m2
bleomycin IV on day 1, 50 mg/m2 doxorubicin IV administered
by continuous infusion over 72 hours on days 1 through 3, 750
mg/m2 cyclophosphamide IV on day 1, 1.4 mg/m2 vincristine
IV on day 1, 500 mg methylprednisolone IV on days 1 through
3, and 1 g/m2 methotrexate IV on day 10. Methotrexate was
followed by leucovorin rescue. MINE consists of 1.5 g/m2
ifosfamide IV on days 1 through 3, 10 mg/m2 mitoxantrone IV
on day 1, and 80 mg/m2 etoposide IV on days 1 through 3.
Patients with a single area of extensive involvement or with a
single residual tumor mass less than 5 cm at the end of
chemotherapy were referred for involved field radiotherapy.
Patients with a tumor score $3 were eligible for protocol
DM92-054.15 On this protocol, patients were randomized
between idarubicin- and adriamycin-containing regimens. Treatment consisted of 2 cycles of ASHAP (or IDSHAP) alternating
with 2 cycles of MBACOS (or MBIDCOS), followed by three
cycles of MINE chemotherapy. IDSHAP and MBIDCOS are
identical to ASHAP and MBACOS, except that doxorubicin
was replaced by 10 mg/m2 idarubicin. Patients with a partial
remission after three cycles of chemotherapy were referred for
intensification with high-dose thiotepa, busulfan, and cyclophosphamide and autologous stem cell rescue.19
Staging procedures included physical exam; computed tomographic (CT) scan of chest, abdomen, and pelvis; gallium scan;
bilateral bone marrow biopsy; and aspirate and lymphangiogram when indicated. A lumbar puncture was not performed
unless CNS involvement was suspected. Patients who were
seropositive for human immunodeficiency virus or hepatitis B
were excluded. Patients with active CNS disease at presentation
were eligible for these studies, but are not included in the
analysis. At the time of analysis, the median follow-up for
patients enrolled on these protocols was 4 years (range, 1 to 8
years).
Diagnosis of CNS disease. For this analysis, only patients
whose initial site of recurrence included symptomatic CNS
disease were included. The diagnosis of CNS disease was based
on the presence of malignant cells on cytocentrifuge preparations of spinal fluid in 19 cases and on brain biopsy in 2 cases. In
3 cases of parenchymal brain involvement, the diagnosis of
CNS disease was based on symptoms and radiologic findings.
Statistical methods. Probability of CNS recurrence and of
survival after CNS recurrence was estimated using KaplanMeier plots.20 Exact methods of analysis were applied for
1179
further analysis of the data because of the low incidence of CNS
recurrence.21 Because CNS recurrence is most likely to occur
within the first year after diagnosis, the outcome of interest for
the multivariate analysis was CNS recurrence at 1 year. Patients
who died without CNS recurrence within 1 year from diagnosis
were excluded from the analysis. The Fisher-Freeman-Halton
exact test was used to assess the ability of covariates to predict
CNS recurrence.22 Those covariates with a P value less than .10
were included in the multivariate analysis. An exact logistic
model was built using forward selection.21 Covariates were
added as long as the P value of a factor adjusted for all other
factors already in the model was less than .05.
RESULTS
Patient characteristics and prognostic factors for CNS
recurrence. Patient-, disease-, and treatment-related characteristics of the 605 patients are listed in Table 1. The median age
was 54 years (range, 16 to 84 years). As expected, more than
half of the patients were men, half had an elevated LDH, and
one third had B-symptoms. Most (88.7%) were classified as
having diffuse large-cell lymphoma, 9.5% as follicular largecell lymphoma and 1% as diffuse mixed-cell lymphoma. Thirty
six percent of the patients had stage IV disease, 14% had stage
III disease, and 48% had stage I or II disease. Approximately
one fifth of the patients had more than one site of extranodal
involvement. Involvement of the sinuses and testicular involvement occurred in only 9 patients (1.5%) and 5 patients (1%),
respectively. The international index could be calculated for 564
patients. Ten percent had high-risk disease, 20% had highintermediate risk disease, 22.5% had low-intermediate risk
disease and 42.5% had low-risk disease.
Incidence of CNS recurrence and risk factors. The Kaplan
Meier estimate of probability of CNS recurrence at 1 year after
diagnosis is 4.5% (95% confidence interval [CI], 4.4 to 4.6).
Twenty-four patients developed CNS recurrence a median of 6
months after diagnosis (range, 0 to 44 months). Only 1 CNS
recurrence occurred more than 13 months after initial diagnosis,
ie, in a patient with a testicular lymphoma who developed a
brain lesion 44 months after diagnosis.
A variety of symptoms led to the diagnosis of CNS recurrence (Table 2). The most common findings were mental status
changes, headaches, and cranial nerve palsies. Seizures occurred in only 1 patient. In 18 of 22 cases, lymphoma cells were
detected in the spinal fluid. Leptomeningeal disease was
documented radiographically in 7 patients and intraparenchymal disease in 8 of 21 patients.
Five patients had systemic disease documented at the time of
recurrence or within 40 days thereafter. Seven other patients
developed systemic relapse between 40 days and 6 months after
recurrence of CNS disease. In 5 patients who survived from 40
days to 3 years after diagnosis of CNS recurrence, no systemic
disease recurrence was ever documented.
By univariate analysis an increased risk for CNS recurrence
was associated with more advanced stage (P 5 .0014), an
increased LDH (P 5 .00008), the presence of B-symptoms
(P 5 .005), and involvement of more than one extranodal site
(P 5 .00009) (Table 2). There was also an increased risk for
CNS recurrence associated with the use of the alternating
triple-therapy regimen. However, this association is explained
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1180
VAN BESIEN ET AL
Table 1. Initial Features of 605 Patients With NHL and Kaplan Meier
Estimate of Probability of CNS Recurrence at 1 Year After Diagnosis
N (%)
Age (yr)
#60
.60
Sex
Male
Female
Histology
DLCL
FLCL
DMCL
Phenotype
B
T
Unknown
LDH
Elevated
Normal
Unknown
B2 microglobulin
Elevated (.3)
Normal (,3)
Unknown
Stage
I-II
III
IV
Unknown
B symptoms
Yes
No
Unknown
Performance status
0-1
.1
Unknown
Extranodal sites
0-1
.1
Unknown
International index
Low (0-1)
Low intermediate (2)
High intermediate (3)
High (4-5)
Unknown
Treatment (for details, see text)
CHOP-Bleo/OPEN
Alternating triple therapy
Probability of CNS
Recurrence (95% CI)
P*
375 (62)
230 (38)
4.4 (4.3-4.5)
4.8 (4.6-5.0)
.46
347 (57.3)
258 (42.6)
5.2 (5.1-5.3)
4.5 (4.4-4.6)
.19
537 (88.7)
58 (9.5)
8 (1)
4.2 (4.1-4.3)
7.7 (7.4-8.0)
0
.3
300
23
282
7.0 (6.8-7.2)
4.8 (4.3-5.2)
.008
318 (52.6)
277 (45.7)
10 (1.6)
9.8 (9.7-9.9)
1.1 (1.0-1.2)
.0000
140 (23.1)
398 (65.7)
67 (11.1)
8.7 (8.4-9.1)
4.7 (4.6-4.8)
.012
294 (48.6)
87 (14.3)
217 (35.9)
7 (1)
2.2 (2.1-2.3)
3.0 (2.8-3.2)
9.0 (8.8-9.2)
.0014
191 (31.6)
408 (67.4)
6 (1)
8.6 (8.4-8.8)
2.8 (2.7-2.9)
.0037
488 (80.6)
96 (15.8)
21 (3.4)
3.3 (3.2-3.4)
13.2 (12.8-13.6)
.0005
480 (79.3)
119 (19.7)
7 (1)
2.8 (2.7-2.9)
13.3 (12.9-13.7)
.0000
257 (42.4)
141 (22.5)
121 (20)
60 (10.0)
41 (6.7)
0.8 (0.7-0.9)
6.5 (6.3-6.7)
7.8 (7.6-8.0)
11.6 (5.7-17.5)
217 (35.9)
388 (64.1)
1.5 (0.5-2.5)
6.5 (6.4-6.6)
.0000
.003
*Fisher-Freeman-Halton exact test.
by the fact that this regimen was used exclusively for patients
with advanced disease stages. Complete information on disease
sites was available for 369 patients. Bone marrow involvement
(P 5 .005), involvement of parenchymal organs (P 5 .01), and
involvement of skin, subcutaneous tissue, and muscle (P 5
.002) were associated with an increased risk for CNS disease in
these patients (Table 3). However, multivariate logistic regression analysis only identified involvement of more than one
extranodal site (P 5 .0005) and an increased LDH (P 5 .0008)
Table 2. Features of Patients With CNS Recurrence
Neurologic symptoms at recurrence
Coma
Seizures
Mental status changes, lethargy, confusion
Headache
Cranial nerve palsy
Peripheral sensory or motor symptoms
Gait and balance
Lumbar puncture
Not done
Negative
Lymphoma cells
Other abnormalities/no lymphoma cells
Radiologic findings
Leptomeningeal involvement
Brain parenchymal involvement
Negative radiologic studies
No radiologic studies
Status of systemic disease
Simultaneous CNS and systemic relapse
Systemic relapse with 40-180 days after CNS relapse
Death within 40 days after CNS recurrence without
systemic restaging
Survival beyond 40 days after CNS recurrence, no
systemic recurrence
1
1
10
7
7
5
2
2
1
19
2
7
8
7
3
5
7
7
5
as independent predictors of CNS recurrence (Table 4). The risk
of CNS recurrence associated with these covariates is illustrated
in Fig 1. Ninety-three patients (15.4%) had both an increased
LDH and involvement of more than one extranodal site. For
these patients, the Kaplan-Meier estimate of probability of CNS
recurrence at 1 year after diagnosis was 17.4% (95% CI, 7.0 to
Table 3. Sites of Extranodal Involvement (369 Patients)
and Kaplan Meier Estimate of Probability of CNS Recurrence
at 1 Year After Diagnosis
Bone marrow
Yes
No
Bones
Yes
No
Lungs/pleura
Yes
No
GI tract
Yes
No
Sinuses
Yes
No
Liver/kidney/GU/adrenals/thyroid
Yes
No
Skin/scalp/subcutaneous tissue/
muscle
Yes
No
N (%)
Probability of CNS
Recurrence (95% CI)
47 (12.7)
322 (87.3)
18.5 (12.1-24.9)
5.2 (5.1-5.3)
.005
36 (9.8)
333 (90.2)
9.1 (5.1-13.1)
6.4 (6.3-6.5)
.61
29 (7.9)
340 (92.1)
11.9 (5.5-18.3)
6.3 (6.2-6.4)
.116
39 (9.2)
330 (90.8)
9.3 (4.2-14.4)
6.4 (6.3-6.5)
.347
9 (2.4)
360 (97.6)
12.5 (0.9-24.1)
6.6 (6.5-6.7)
.432
33 (8.9)
330 (91.1)
19.0 (12.3-26.7)
5.7 (5.6-5.8)
.03
23 (6.2)
346 (93.8)
23.9 (14.5-33.3)
5.6 (5.5-5.7)
.002
*Fisher-Freeman-Halton exact test.
P*
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CNS RECURRENCE OF NHL
1181
Table 4. Covariates Associated With CNS Recurrence in Final
Multivariate Logistic Regression Analysis
LDH elevated at diagnosis
Involvement of more than one
extranodal site at diagnosis
P Value
Relative Risk (95% CI)
.0008
7.0 (2.0-38.0)
.0005
5.5 (2.1-14.9)
27.8). For the remaining 512 patients (84.6%), the KaplanMeier estimate of probability of CNS recurrence at 1 year after
diagnosis was 2.8% (95% CI, 2.7 to 2.9).
Treatment of CNS recurrence and outcome. Patients with
leptomeningeal involvement without focal neurologic deficits
received intrathecal cytarabine, methotrexate, and hydrocortisone twice a week. An Ommaya reservoir was usually placed.
Although intrathecal treatment invariably resulted in a decrease
in the percentage of blasts in the spinal fluid, symptomatic
improvement occurred in only 1 of 6 patients.
Patients with focal neurologic deficits or intraparenchymal
lesions in the brain or spinal cord were offered radiation
treatment. This consisted of whole brain radiation for those with
brain lesions or cranial nerve palsies and of spinal irradiation or
irradiation to segments of the spinal cord for those with lesions
of the spinal cord. Radiation treatment resulted in symptomatic
neurologic improvement in 6 of 9 patients. However, the
responses were transient. The principal cause of treatment
failure was progression of CNS disease in 5 patients and
systemic recurrence in 4.
Five patients received systemic chemotherapy, combined in 2
cases with intrathecal treatment. The chemotherapy was platinum-based in 4 patients and consisted of MINE in the fifth
patient. Responses of the CNS disease were observed in 3
patients and 1 patient has obtained a durable remission.
Of the 24 patients, only 1 is currently alive and in remission
at 1,150 days after diagnosis of CNS recurrence. Kaplan-Meier
Fig 1. Incidence of CNS recurrence in patients with increased
LDH and involvement of more
than one extranodal site (n 5 93;
· · ·) versus all other patients (n 5
512; —).
estimate of probability of survival at 1 year after diagnosis of
CNS recurrence is 25.3% (95% CI, 6.9% to 43.7%).
DISCUSSION
The identification of risk factors for CNS recurrence in
intermediate-grade NHL has been attempted previously. Several
large studies containing analysis of potential risk factors are
summarized in Table 5. Whereas these and similar studies
contributed in important ways to the identification of risk
factors for CNS disease, all of them have a number of problems
that makes their interpretation difficult. Most studies are based
on retrospective analysis of heterogeneously treated patients. In
addition, the majority of studies concern patients treated in the
1970s before the widespread use of modern chemotherapeutic
regimens and at a time when important entities such as
lymphoblastic lymphoma were not reliably recognized. The
assessment of risk factors for intermediate-grade NHL is
therefore obscured by the inclusion of patients with other
histologies. We are aware of only one study that specifically
addresses the issue of CNS recurrence in intermediate-grade
lymphoma in patients treated with modern chemotherapy.5 This
report, like many others, does not differentiate between patients
with CNS involvement at presentation, those in which CNS
involvement occurs at the time of initial recurrence, and those in
which CNS involvement is an expression of terminal disease. In
this study, only the presence of epidural disease (P , .001) and
age younger than 60 years (P 5 .046) were found to be
significant risk factor for CNS recurrence. Other risk factors,
including gender, response to treatment, stage of disease (P 5
.083 stage I-II v stage III-IV), involvement of more than one
extranodal site (P 5 .077), and involvement of specific disease
sites were not found to be significantly correlated with the risk
of CNS recurrence. Hence, considerable controversy remains
regarding the impact of patient and disease characteristics on
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1182
VAN BESIEN ET AL
Table 5. Incidence of and Risk Factors for CNS Recurrence: Selected Studies With Univariate Analyses of Risk Factors
Risk Factors
Author,
Year,
Reference
Litam et al,
19799
Systemic
Treatment
Received*
No. of
Patients
% CNS
% CNS Involvement
Disease† at Diagnosis
Histology
BM, other, extranodal
,35
NE
NE
NE
NE
NE
Yes
NE
NE
Marrow
NE
All histologies HGL . IGL . LGL
Yes
Yes
NE
DMCL, DLCL,
IBL
No
No
No
No
Orbit, testis,
PB, bone,
sinuses, BM
Epidural disease‡ ,60
NS
5.1
1.1
NS
1039
COP, CHOP-HOP,
CHOP-BLeo
5
1
Levitt et al,
19807
Liang et al,
199012
592
COP, CHOP-BLeo
9
833
NS
Bashir et al,
19915
277
CAP-BOP
Age
(yr)
NE
6.1
11
Disease Sites
NE
1.7
COP, CHOP-HOP,
CHOP-BLeo
No. of
Extranodal
Advanced
Sites
Stage
B- Symptoms
Yes
All histologies Diffuse . nodular
DUL and LBL .
other diffuse
lymphoma
All histologies Diffuse . nodular
DUL and LBL .
other diffuse
lymphoma
All histologies Diffuse . nodular
292
Herman et al,
19796
Subtypes
Included
No
Abbreviations: NS, not specified; NE, not evaluated; HGL, high-grade lymphoma; IGL, intermediate-grade lymphoma; LGL, low-grade
lymphoma; DUL, diffuse undifferentiated lymphoma; LBL, lymphoblastic lymphoma; DMCL, diffuse mixed-cell lymphoma; DLCL, diffuse
large-cell lymphoma; IBL, immunoblastic lymphoma; PB, peripheral blood; BM, bone marrow.
*For details of chemotherapy-regimens, see references.
†The percentage of patients with CNS involvement. In most reports, this includes patients with CNS involvement at presentation. When
specified, the percentage of patients with CNS involvement at presentation is shown in the next column.
‡B-symptoms, histology, extranodal involvement, response to therapy and gender are not associated with risk for CNS recurrence.
the incidence of CNS disease in intermediate-grade lymphoma,
preventing a rational approach to preventive strategies.
The current study documents the incidence of CNS recurrence in a cohort of 605 patients with intermediate-grade
lymphoma who received their initial treatment at a single
institution and who participated in four prospective studies of
modern combination chemotherapy. Therefore, the patients
received uniform and consistent treatment throughout the
course of the study. Our regimen for patients with unfavorable
characteristics includes three doses of high-dose cytarabine and
three doses of intermediate-dose methotrexate. These drugs
penetrate into the CNS and are thought to be useful in the
treatment and prophylaxis of CNS leukemia.23 The incidence of
CNS recurrence in this patient cohort may therefore be slightly
lower than would be anticipated if all patients were treated with
CHOP-like regimens. Nevertheless, the cumulative incidence
of CNS recurrence of 5.1% (95% CI, 4.9% to 5.3%) is
consistent with the incidence reported in one other recent
study.5 Almost all the risk occurred in the first year after
diagnosis.
It is important to distinguish between patients whose CNS
disease is the initial site of recurrence from those where CNS
disease occurs long after systemic recurrence. In the former
group, CNS recurrence may be potentially treatable. In the
latter, CNS recurrence is an expression of end-stage disease, not
necessarily predicted by the same risk factors and unlikely to be
amenable to therapeutic strategies with curative intent. Our
study excluded from analysis the latter patients. Thus defined,
the risk for CNS recurrence was associated with indicators of
advanced disease such as serum LDH and stage of disease, bone
marrow involvement, and skin and parenchymal involvement.
For reasons that are unclear to us, B-cell phenotype was also
associated with a significantly increased risk of CNS recurrence. The importance of other risk factors, such as sinus
involvement, testicular involvement, pulmonary involvement,
and gastro-intestinal involvement, could not be confirmed. In
cases of testicular and sinus involvement, this may be due to the
very low accrual of cases with this particular site of involvement.
A multivariate logistic regression identified only the presence
of more than one site of extranodal involvement and an
increased LDH as independent risk factors for CNS recurrence.
This suggest that, in the majority of cases, the risk for CNS
recurrence is determined by disease extent and proliferation
rather than by any particular disease localization. The use of
these two factors allowed us to identify a group of patients for
whom the cumulative risk for CNS recurrence is almost 20%.
Serum LDH and involvement of more than one extranodal site
are also associated with increased overall risk for treatment
failure in patients receiving conventional chemotherapy regimens.24 Radically new treatment approaches are needed for
such patients, taking into account their risk for CNS recurrence.
The initial staging work-up for such patients should include a
lumbar puncture. Their treatment should contain CNS prophylaxis similar to what is recommended for patients with acute
lymphoblastic leukemia (ALL) or high-grade lymphoma.23,25,26
This should include the use of systemic drugs with activity
across the blood-brain barrier as well as frequent intrathecal
injections. A similar approach may be necessary for the
relatively uncommon patients who present with primary testicular or sinus lymphoma. On the other hand, for the large majority
of patients, the risk for CNS recurrence is very low with
currently used chemotherapy, and no specific CNS prophylaxis
or work-up appears to be necessary.
An ideal risk model would allow identification of all patients
at risk for a particular event. The discomfort and side-effects of
preventive therapy would be avoided for those not at risk.
Because of the low incidence of CNS disease in this patient
population, our model is less than optimal. Its use would have
resulted in specific CNS-directed treatment for 15% of all
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CNS RECURRENCE OF NHL
patients with intermediate-grade NHL accrued to this study.
However, only 11 of the 24 patients destined to develop CNS
recurrence would have been identified. Therefore, the sensitivity of our model in predicting CNS recurrence is slightly less
than 50%, only marginally better than could be achieved if
patients had been selected on the basis of bone marrow,
testicular, and sinus involvement. On the other hand, an
increased serum LDH correctly identified 21 of the 24 patients
destined to develop CNS prophylaxis, but more than 50% of the
patients in this study had an elevated LDH.
The median survival after CNS recurrence was only 88 days,
consistent with the known poor prognosis of CNS recurrence.27
Prior studies of end-stage lymphoma have emphasized the fact
that most patients die from systemic disease rather than from
CNS complications. Our study included a more selected patient
group; the patients had received adequate systemic treatment
and had CNS involvement as their initial site of recurrence.
CNS complications were the main cause of death in these
patients.
Intrathecal treatment did not result in meaningful responses.
Radiation therapy resulted in rapid but transient symptomatic
relief in most cases. Five of 9 patients developed recurrences in
the CNS. The fact that most patients had lymphoma cells in the
spinal fluid is consistent with findings from previous reports1,3,4,6,28 and indicates that CNS involvement is a complication that affects the entire neuraxis. Effective long-term treatment at the time of CNS relapse should be aimed at sites of
systemic disease and at the craniospinal axis. Chemotherapy,
using agents that are effective across the blood-brain barrier, is
theoretically appealing. However, in our series, it was rarely
possible to devise such regimens, because most patients had
relapse during or shortly after completing programs incorporating most known active agents. Because allogeneic or autologous transplantation can overcome chemotherapy resistance,
this approach may prove beneficial for selected patients.29,30
In conclusion, the risk of CNS recurrence in intermediategrade lymphoma treated with modern chemotherapy regimens
is approximately 5%. Our analysis confirms the importance of
previously identified risk factors, but in addition establishes the
predictive value of increased serum LDH and the involvement
of multiple extranodal sites as risk factors for CNS recurrence.
In univariate analysis, these two features are stronger predictors
than any of the commonly used risk factors. In multivariate
analysis, they emerge as the only significant ones. The identification of additional independent risk factors in future studies
may allow a more accurate identification of those at risk for
CNS recurrence.
Established CNS recurrence is usually rapidly fatal. Intrathecal chemotherapy alone is not effective palliation for intermediate-grade lymphomas, and radiation treatment results in rapid
symptomatic improvement but is usually followed by systemic
or CNS recurrence. New treatment strategies should be developed for patients at high risk for CNS recurrence and explored
in a prospective fashion.
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1998 91: 1178-1184
Risk Factors, Treatment, and Outcome of Central Nervous System
Recurrence in Adults With Intermediate-Grade and Immunoblastic
Lymphoma
Koen van Besien, Chul S. Ha, Sandy Murphy, Peter McLaughlin, Alma Rodriguez, Kamal Amin, Arthur
Forman, Jorge Romaguera, Fredrick Hagemeister, Anas Younes, Carlos Bachier, Andreas Sarris,
Kathleen S. Sobocinski, James D. Cox and Fernando Cabanillas
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