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Keywords:

  • mantle cell lymphoma;
  • CNS disease;
  • CNS relapse;
  • CNS prophylaxis

Summary

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. References

Reported rates of central nervous system (CNS) involvement in mantle cell lymphoma (MCL) are highly variable but substantial (4–26%). Data is lacking regarding risk factors for CNS relapse, and for those patients in whom CNS prophylaxis could be beneficial. We present single institution retrospective analysis of data of baseline features, clinical course, rate of CNS disease and putative risk factors in 62 patients with MCL (18 female, 44 male). CNS disease (all cases were symptomatic) occurred in four patients at a median of 12 months (range 1–58) from diagnosis, with a crude incidence of 6·5% and 5-year actuarial incidence of 5 ± 3%. Two cases had blastic MCL at diagnosis. Survival after CNS relapse ranged from 2–9 months. Patients who developed CNS disease had a significantly shorter survival from diagnosis than those who did not (P = 0·0024). Symptomatic CNS disease in patients with MCL either at presentation or relapse is an uncommon but devastating complication. In younger patients, more aggressive immuno-chemotherapy regimens containing CNS-penetrating agents may reduce the incidence of CNS disease. While not routinely justified for all patients, CNS prophylaxis may particularly benefit patients with blastic histology at diagnosis, or those with systemic relapse after first-line treatment.

Mantle cell lymphoma (MCL) constitutes approximately 6% of non-Hodgkin lymphoma (NHL) cases (Swerdlow et al, 2008). Patients typically present with advanced stage disease and a propensity for leukaemic and gastrointestinal involvement (Hiddemann et al, 1998). The best validated clinical scoring system for MCL (the MCL International Prognostic Index, MIPI) incorporates age, lactate dehydrogenase (LDH) level, performance status, and leucocyte count to identify high-, intermediate- and low-risk groups in advanced stage MCL. The high-risk group has an overall survival of less than 30 months and is associated with aggressive biology (Hoster et al, 2008). The prognostic utility of the MIPI may however be regimen-dependent and apparently adverse presenting characteristics in MCL may be overcome by more dose intense approaches (Shah et al, 2008). The cellular proliferation marker Ki-67 provides an additional outcome predictor that may further refine the likely prognosis (Determann et al, 2008; Hoster et al, 2008). Multi-gene polymerase chain reaction panels may yet prove superior for prognostication in the longer term (Hartmann et al, 2008).

Central nervous system (CNS) involvement is an uncommon but devastating outcome in any lymphoma subtype, and MCL is no exception. Reported rates among patients with MCL vary widely, from 4–26% (Oinonen et al, 1999; Valdez et al, 2002; Ferrer et al, 2008), making it challenging to identify which patients are at highest risk, and therefore may benefit most from CNS prophylaxis. Aggressive disease biology, as evidenced by blastoid morphology, is associated with increased risk of early relapse and an association with CNS involvement (Bosch et al, 1998; Tiemann et al, 2005). Ferrer et al (2008) noted 11 cases of CNS involvement in 82 cases of MCL (actuarial 5-year incidence of 26%); one at diagnosis and 10 developing subsequently. Univariate analysis yielded blastoid histology, high proliferative index (Ki 67 expression ≥50%) high LDH level and intermediate or high International Prognostic Index. High LDH level and blastoid histology remained predictive of CNS involvement on multivariate analysis.

Recent trends in the management of MCL, such as more intensive combination chemo-immunotherapy regimens and consolidative autologous stem cell transplantation, have led to complete remission rates of 30–87% and median progression-free survival of 14–40 months or longer. Some studies indicated a plateau in progression-free survival curves although longer follow up is required (Ritchie et al, 2007; Geisler et al, 2008; Tam et al, 2009).

It has been long recognised that the risk of CNS involvement in NHL, and appropriate management of that risk, varies dramatically with histological sub-type. For example, CNS prophylaxis is routine in Burkitt lymphoma. In contrast, the risk of CNS involvement in follicular NHL is negligible. In diffuse large B cell lymphoma (DLBCL) increased risk is identifiable by predictive indices, but may also relate to unique tumour biology that is dependent on tissue site of origin (Zucca et al, 2003; van Besien et al, 2008). MCL would appear to occupy an intermediate position in terms of overall risk of CNS disease. Ideally, CNS prophylaxis would be offered only to patients at significant risk, as is the case in the treatment of DLBCL (van Besien et al, 2008).

The abovementioned series (Oinonen et al, 1999; Valdez et al, 2002; Ferrer et al, 2008) mostly included patients treated with combination chemotherapy alone, although more recent studies include patients also treated with Rituximab-containing combinations. In the setting of DLBCL at least, there is no clear impact of Rituximab use on the rate of CNS relapse (Feugier et al, 2004; Boehme et al, 2009).

Given the variation in the incidence of CNS involvement in MCL described by several groups, in addition to the uncertainties surrounding management and CNS prophylaxis, we sought to further define both the risk factors and the outcome of CNS disease in MCL.

Methods

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. References

To allow for at least a 3-year follow up, patients with a diagnosis of MCL treated at the Peter MacCallum Cancer Centre between 1996 and 2005 were identified from the institutional database. Prior to entry on to the database the diagnosis and morphological sub-classification of MCL was subject to central pathological review and made according to standard criteria using appropriate immunohistochemical, immunophenotypic, cytogenetic and molecular techniques (Swerdlow et al, 2008). The blastic variant of MCL was further identified on the database using available histopathological (cells resembling lymphoblasts with dispersed chromatin and a high mitotic rate with >20–30 mitotic figures per high power field) and immunocytochemical criteria (Bernard et al, 2001; Swerdlow et al, 2008). Immunocytochemical estimate of the tumour proliferative index using Ki-67 expression was not available for all patients, particularly those from earlier years of diagnosis. To reflect this, where there was doubt as to the sub-classification of MCL based on histological grounds, patients without immunocytochemical estimate of tumour proliferation were excluded from sub-group analysis.

All patients underwent standard staging investigations at presentation, including computed tomography (CT) imaging of the chest, abdomen and pelvis as well as bone marrow biopsy. Eight patients also underwent positron emission tomography scanning at diagnosis (Gill et al, 2008).

Data were collected on patients’ baseline demographics and Eastern Cooperative Oncology Group (ECOG) performance status, as well as possible prognostic features including sites of initial disease involvement, histological subtype, LDH, albumin, serum β2-microglobulin, haemoglobin, leucocyte and platelet counts. Treatment regimens and response, duration of follow-up and status at last follow-up were determined using standard response criteria.

Examination of the cerebrospinal fluid (CSF) was not routinely performed at presentation but CSF was sampled at the time of the development of clinical symptoms. CNS involvement was defined as consistent clinical features along with either (i) the presence of malignant lymphocytes in the CSF, or (ii) typical parenchymal or leptomeningeal involvement on magnetic resonance imaging (MRI).

Survival times were calculated according to the method of Kaplan and Meier and differences between groups were calculated using the log-rank method. All statistical analyses were performed using GraphPad Prism (San Diego, CA, USA). A P value of <0·05 was used to determine statistical significance.

The ethics of study design and conduct was as laid down and approved by the Institutional Review Board of The Peter MacCallum Cancer Centre.

Results

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. References

Sixty-two patients were identified. Their baseline characteristics and initial therapy are presented in Table I. The median follow-up at time of reporting was 56 months (range 39–143). The median age was 64 years (range 33–85). At diagnosis, stage III/IV disease was present in 81%, and blastic morphology identified in 11%.

Table I.   Patient characteristics.
CharacteristicPercentage (no. evaluable)
  1. LDH, Lactate dehydrogenase; ECOG, Eastern Co-operative Oncology Group; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; Hyper-CVAD, hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, cytarabine; RT, Radiotherapy; ASCT, Autologous stem cell transplant.

Age at diagnosis ≥60 years61% (62)
Male gender71% (62)
Blastic histology11% (47)
Stage III/IV81% (57)
LDH elevated43% (28)
Extranodal site involvement (excludes bone marrow)28% (57)
ECOG performance status >23% (40)
Circulating abnormal lymphocytes present61% (28)
First-line therapy
 Alkylator-based18%
 Fludarabine-based6%
 CHOP-like50%
 Hyper-CVAD16%
 RT only3%
 Other6%
Rituximab as part of first line therapy39%
ASCT consolidation of first line therapy13%

Initial therapy was alkylator-based in 18%, fludarabine-based in 6%, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like in 50%, hyper-CVAD (hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, cytarabine) in 16%, and contained rituximab in 39%. With the exception of patients receiving hyper-CVAD as part of initial therapy, in which CNS prophylaxis was via CNS-penetrating doses of systemic cytarabine and methotrexate alone in four patients, and combined with intrathecal chemotherapy in five patients, only one additional patient received CNS prophylaxis with intrathecal methotrexate given at the discretion of the attending physician.

For the group as a whole, response rates to first line therapy were: complete remission (CR) 57%, partial remission (PR) 30%, stable disease (SD) 9% and progressive disease (PD) 4%. The median number of systemic therapeutic regimens that the patients had received at the time of analysis was 3 (range 0–6). The median time to relapse or progression after first line therapy was 17 months.

Four patients developed CNS disease, at a median of 12 months (range 1–58) from diagnosis. The crude incidence of CNS involvement was 6·5% with an actuarial incidence of 5 ± 3% at 5 years (Fig 1). The clinical features of these patients are described in Table II.

image

Figure 1.  Incidence of CNS disease. Incidence of central nervous system (CNS) involvement with mantle cell lymphoma from time of initial diagnosis.

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Table II.   Characteristics of patients with CNS disease.
Patient/age (years)Sites of CNS diseaseTime from initial diagnosis of MCLPrevious treatmentTreatment of CNS diseaseSurvival post CNS diseaseInitial histology Subtype (site)
  1. MRI, Magnetic resonance imaging; CSF, Cerebrospinal fluid; CP, cyclophosphamide, prednisolone; FR, fludarabine, rituximab; PACEBOM, prednisolone, doxorubicin, cyclophosphamide, etoposide, bleomycin, vincristine, methotrexate; CHOP-R, cyclophosphamide, doxorubicin, vincristine, prednisolone, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; FCR, fludarabine, cyclophosphamide, rituximab; ENZ, enzastaurine (Morschhauser et al, 2008); DEX, dexamethasone; IT MTX, intrathecal methotrexate; RT, Radiotherapy; Hyper-CVAD, hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone, methotrexate, cytarabin.

M/55 Brain-multiple parenchymal lesions (MRI). CSF not examined58 monthsRT CP x12 FR x6 RT PACEBOMDEX2 monthsBlastic (Abdominal nodes)
M/65 Leptomeningeal Brain (MRI). CSF positive1 monthCHOP-R x1DEX IT MTX RT Hyper-CVAD9 monthsBlastic (Bone marrow)
M/74 Leptomeningeal Spinal cord (MRI). CSF positive8 monthsCHOP x6DEX IT MTX RT2 monthsNon-blastic (Neck nodes)
F/64 Leptomeningeal Cauda equina (MRI). CSF negative16 monthsCHOP-R x2 FCR x2 ENZDEX RT4 monthsNon-blastic (Bone marrow)

All patients with CNS disease were symptomatic. One patient developed CNS disease soon after diagnosis, one developed symptoms as the first indication of relapse after achieving CR and two developed CNS disease in the context of relapsed refractory MCL.

CNS disease occurred in two of five patients with confirmed blastic MCL and two of 42 with non-blastic MCL (P = 0·03; Fisher’s exact test).

Median survival after development of CNS disease was 3 months, with all patients dead from progressive disease by 9 months. When analysed from baseline, patients who developed CNS disease had a significantly shorter survival than those who did not (P = 0·0024).

Of 10 patients treated with CNS penetrating drugs at baseline, none developed CNS disease, compared with four of 52 not receiving such treatment (P > 0·5; Fishers exact test).

Discussion

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. References

Extra-nodal disease is a well recognised presenting feature of MCL, but CNS disease is unusual at presentation with no documented cases in five previously reported series of over 300 patients (Argatoff et al, 1997; Vandenberghe et al, 1997; Bosch et al, 1998; Hiddemann et al, 1998; Weisenburger et al, 2000). More typically, as in the study of Ferrer et al (2008), CNS involvement occurs at the time of relapse, and may be associated with blastic morphology at presentation.

In our patient cohort, CNS relapse was also seen in the context of blastic morphology or relapsed/refractory disease. The incidence, at around 5%, is at the lower end of the reported range (Oinonen et al, 1999; Valdez et al, 2002; Ferrer et al, 2008) and differs from that reported recently by Ferrer et al (2008). It is unclear why reported rates are so variable but this does not appear to be due to case ascertainment bias as only occasional patients in reported series present with asymptomatic disease. Indeed the significance of the detection of clonal B lymphocytes in the CSF of asymptomatic MCL patients remains uncertain as patients do not necessarily go on to develop clinical CNS disease (Nowakowski et al, 2005). Given this data, routine evaluation of the CSF at presentation in asymptomatic patients with MCL does not appear to be justified outside of the context of a clinical trial.

Not withstanding the above, the management of clinical CNS disease complicating MCL raises significant issues. Although data are limited, several key themes emerge from the literature. The risk factors for the development of CNS disease in MCL overlap those which predict for an aggressive systemic course and include: blastic morphology, raised LDH, and a high tumour proliferation index (Bosch et al, 1998; Raty et al, 2002; Tiemann et al, 2005; Gill & Seymour, 2008). However, these factors, although useful, are essentially only predictive for the development of CNS disease at some stage in the patient’s illness and do not therefore necessarily guide initial management. Perhaps of more therapeutic relevance is the correlation of these identifiable risk factors with the clinical course of the disease.

At initial presentation, CNS disease is uncommon and the data does not justify routine CNS prophylaxis or CSF examination as part of initial management for all patients. It is unclear whether specific CNS prophylaxis given to patients at high risk offers any benefit, particularly with regard to the prevention of isolated CNS relapse as a first event in a patient otherwise in systemic complete response. This may however occur even in patients with documented molecular systemic remission (Ladetto et al, 2001). The available data would support the assertion that initial treatment with immuno-chemotherapy followed by high-dose treatment that includes CNS-penetrating agents (with or without intrathecal therapy) may be sufficient in terms of CNS prophylaxis, at least in the younger patient (Romaguera et al, 2005; Ritchie et al, 2007; Geisler et al, 2008). In this study we were not able to demonstrate a statistically significant reduction in CNS disease in patients initially treated with CNS-penetrating drugs. This finding should however be interpreted in the light of small patient numbers and the consequent lack of statistical power.

The optimum approach for the high risk older patient remains essentially unknown, but control of systemic disease is likely to be critical.

When CNS disease complicates the initial presentation of MCL, data on optimal management is sparse. One approach may be the use of CNS-targeted therapy, ideally as part of, or in concert with systemic treatment, as this approach does have utility in other sub-types of NHL including DLBCL (Moreton et al, 2004). This may allow the younger patient to proceed to high dose therapy and transplantation, which appears to offer the only prospect of long term disease control (Tam et al, 2009).

The vast majority of CNS disease in MCL is seen in the context of relapsed systemic disease (Ferrer et al, 2008). Treatment of symptomatic CNS disease at relapse will depend to an extent on the presence or absence of systemic disease and potential for systemic disease control. Treatment of CNS disease in this situation should however be considered palliative with the possible exception of patients who attain both CNS and systemic disease response and are eligible for allogeneic transplantation.

The role of CNS prophylaxis in the context of systemic relapse can be related to response to therapy. In the presence of progressive or poorly responding systemic disease there appears to be no role for CNS prophylaxis. Consideration should however be given to CNS prophylaxis in patients at high risk who have systemically responsive disease (Ferrer et al, 2008). This would include patients proceeding to salvage allogeneic transplantation. There is however no evidence to guide either the choice of method, nor to confirm the efficacy of this approach.

The management of CNS disease complicating MCL remains challenging. However, progress has been made that allows proposal of tentative therapeutic algorithms. Controlled studies in this area are difficult but the continuing collection of high quality population-based data promises further advances in management.

Author contributions

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. References

All the authors were involved in accrual of patients, chart review, draft review and manuscript approval. SG, JD and JS were responsible for data collection. SG, KH, JD and JS were involved in conception, design and data analysis of the study. JD, KH and JS were responsible for manuscript production.

References

  1. Top of page
  2. Summary
  3. Methods
  4. Results
  5. Discussion
  6. Author contributions
  7. References
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