Clinical Studies

Management of Central Nervous System Lymphomas Using Monoclonal Antibodies: Challenges and Opportunities Eric T. Wong

Abstract Monoclonal antibodies (mAb) may change the management of central nervous system (CNS) lymphomas. This is due to the fact that traditional lackspecificity for B-lymphoma cells and blood-brain barrier prevents adequate dosing in the CNS without significant systemic side effects. But in the past 5 years, the emergence of mAbs against specific receptors on B-lymphoma cells, either as a single agent or in combination with cytotoxic chemotherapies, may offer a better therapeutic index than conventional chemothera- pies. The advantages of mAbs include high affinity to targets on lymphoma cells, their lackof pharmacodynamic or pharmacokinetic interactions with other drugs, and a potential for a synergistic therapeutic response when combined with conventional chemotherapies. Our review summarizes the biological behaviors of CNS lymphomas and the challenges and oppor- tunities in using mAbs for CNS lymphomas.

Central nervous system (CNS) lymphomas in immunocom- CNS lymphomas, primary ocular lymphomas, and CNS petent patients are predominantly B-cell lymphoid malignan- intravascular lymphomatosis (Table 1). It is important to point cies that have heterogeneous presentations in the brain, spinal out that this classification is imprecise, because it is based on cord, and subarachnoid space, whereas only 5% have T-cell clinicopathologic behavior and not on molecular features. phenotype (1). Unlike their systemic counterparts, CNS Unlike systemic non-Hodgkin’s lymphomas in which patients lymphomaspresentaformidablechallengeforneuro-oncologists could undergo repeated lymph node biopsies with acceptable due to toxicities associated with conventional chemotherapies risk, brain tissues from patients with CNS lymphoma cannot be because of poor specificity and the blood-brain barrier that so easily obtained because of potentially serious complications limits systemically given chemotherapies into the brain and associated with craniotomies. This is further complicated by subarachnoid space. Our incomplete understanding of the rapidly progressive neurologic deterioration in patients that underlying biology also hampers efforts to design better requires dexamethasone treatment before brain biopsy. Thus, treatments. Although high-dose methotrexate (2–6) remains the diagnostic B-lymphoma cells frequently disappear from the standard therapy at present, it has major limitations. This biopsied tissues. Nevertheless, existing data suggest that review will highlight the multifaceted nature of CNS lympho- lymphoma metastasis is the most common form of CNS mas in immunocompetent patients, our assumptions of their lymphomas. Intermediate-grade and high-grade lymphomas biological behaviors, the limitations of existing therapies, and have the greatest propensity of CNS spread, and their respective emerging (mAb) treatments that may frequencies are 6.5% and 16.7% (7, 8). Angiocentricity of have an improved therapeutic index. lymphoma cells (Fig. 1) is a typical histologic feature in brain parenchyma, but leptomeningeal spread is possible and often occurs simultaneously. Other noteworthy clinical features, such Pleomorphic Presentations of Central Nervous as lymphomatous involvement of testes, paranasal sinuses, System Lymphomas orbits, and bone marrow, increase the risk of CNS spread (7, 8). The second major category of lymphomas in CNS is primary Lymphomas in the CNS have pleomorphic presentations, CNS lymphomas. Although they are also angiocentric, primary and they could be separated into four major categories: CNS lymphomas have a propensity of invading adjacent white systemic lymphomas that metastasized to the CNS, primary matters, resulting in homogeneously enhancing masses that follow the contour of white matter or corpus callosum on magnetic resonance imaging (Fig. 2). In addition to presenta- Author’s Affiliation: Department of Neurology and Neuro-Oncology Unit, tion as a solitary mass, primary CNS lymphomas may show up Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, Massachusetts as multiple subependymal nodules or as leptomeningeal Presented in part at theTenth Conference on CancerTherapy with Antibodies and collection of lymphoma, also known as meningoencephalitic Immunoconjugates, October 20-23, 2004, Princeton, NewJersey. form of primary CNS lymphoma (1) and primary leptome- Requests for reprints: Eric T. Wong, Brain Tumor Center, Department of ningeal lymphoma (9, 10), respectively. Furthermore, T cells Neurology and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, are found in the vicinity of B-lymphoma cells (11) and may 330 Brookline Avenue, Boston, MA 02215. Phone: 617-667-1665; Fax: 617- 667-1664; E-mail: [email protected]. have a role in sustaining and propagating these B-lymphoma F 2005 American Association for Cancer Research. cells. Whether or not these T cells are ah or gy subtypes, have doi :10.1158/1078-0432.CCR-10 04-00 02 monoclonal or polyclonal T-cell receptor rearrangements, or

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lumena of cerebral vasculature (Fig. 3). Patients present with Table 1. Multifaceted presentations of CNS multiple and recurrent stroke-like events (14, 15), and lesions lymphomas are without enhancement on magnetic resonance imaging. Although timely diagnosis by a brain biopsy and treatment may Type Histologic features reverse neurologic deficits (16, 17), most patients are diagnosed Metastatic CNS lymphomas Angiocentric too late in the course of their disease. Primary CNS lymphomas Angiocentric and invasive Primary ocular lymphomas Originated in the eye (i.e., vitreous humor, choroidal Assumptions in Central Nervous System membrane, or retinal vasculature) Lymphomas with a propensity for CNS spread CNS intravascular Primarily aggregate in the There are a number of assumptions made about the nature of lymphomatosis lymphomas lumena of brain vasculature CNS lymphomas, and these assumptions may lead to the design of suboptimal therapies. Separating CNS lymphomas into the above four categories seems rather arbitrary, because they are all within a spectrum of extranodal lymphomas in the function in a reactive mode or help to maintain the viability of CNS. Some investigators would even argue that primary CNS B-lymphoma cells remain to be determined. lymphomas may not be exclusive to the CNS but are residual The presenting signs and symptoms of primary ocular systemic lymphomas that have escaped systemic immune lymphomas are nonspecific, primarily consist of floaters and surveillance and purging (18). There is support for this concept, blurry vision. A disproportionate number of patients are because B lymphocytes typically do not reside in the brain, elderly over the age of 60. Unlike other diseases of the retina except at times of infection or noninfectious inflammatory in this population, such as benign inflammatory uveitis and state. Furthermore, unlike primary gliomas in the brain in macular degeneration, the tempo of vision loss is rapid and which analogous platelet-derived growth factor receptor and occurs over weeks. A slit lamp examination may provide a epidermal growth factor receptor signal transduction pathways clue to diagnosis, because clumps of floating lymphoma cells are important for the development and maintenance of native can be seen, and retina may show signs of choroidal glial cells, CNS lymphomas are driven by signal transducers and lymphoma infiltrates or vasculopathy manifesting as leakage activators of transcription and Janus-activated kinase signaling of fluorescein dye (12). A vitreous aspiration may be pathways (19) that are not used by intrinsic cells in the CNS diagnostic if lymphoma cells are seen on cytologic or flow (Table 2). Immunohistochemical staining of key in cytometry examination (13). Because the eyes are extensions primary gliomas and CNS lymphomas also highlights differ- of the brain from a developmental perspective, it is not ences between these brain tumors. Primary gliomas have surprising that these patients frequently have lymphomatous positive staining for glial fibrillary acidic protein, which is also spread into the CNS. In fact, it is not unusual for primary found in normal glial cells. However, CD20 , which is a ocular lymphomas to be diagnosed only when CNS lympho- common antigen in normal and malignant B cells, is nowhere mas are detected. Therefore, this disorder should be consid- to be found in neurons or glia (Table 2). Third, there are ered in the elderly with rapid vision loss. striking similarities between primary CNS lymphomas and CNS CNS intravascular lymphomatosis is a rare but unusual form intravascular lymphomatosis. In primary CNS lymphomas, the of CNS lymphomas, as the lymphoma cells seem stuck in the lymphoma cells are located in the brain parenchyma and

Fig. 1. H&E staining of metastatic CNS lymphoma demonstrating angiocentricity of this tumor. The B-lymphoma cells have large nuclei (arrow)andare primarily located in the perivascular region.The smaller cells areT lymphocytes (arrowheads).Whether they are reactive in response to the presence of B-lymphoma cells or function to maintain the viability of B-lymphoma cells remains unclear.

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Fig. 2. Gadolinium-enhanced magnetic resonance imaging of a patient with primary CNS lymphoma showing the infiltrative nature of this tumor across the corpus callosum (arrow).ThebulkoftheprimaryCNS lymphoma is located in the right basal ganglia (asterisk).

surround blood vessels. In CNS intravascular lymphomatosis ma cells. Although mAbs are large molecules, they may leak however, the lymphoma cells seem stuck in the lumena of across sites with disrupted blood-brain barriers and their high blood vessels on their way into the brain or subarachnoid target specificity would still have therapeutic efficacy for space. This migrational defect could be a result of differences in lymphoma cells in the CNS (18). h1 and intercellular adhesion molecule-1 expression that help lymphoma cells trafficking from systemic circulation into the Limitations of ExistingTreatment Modalities brain or subarachnoid space (20). Lastly, there are tantalizing molecular data to suggest a systemic origin for primary CNS The principal treatment modality for CNS lymphomas is lymphomas. Pels et al. (21) reported a patient with primary high-dose methotrexate. Although it is excluded by the blood- CNS lymphoma who had the same immunoglobulin gene brain barrier due to its large molecular size and hydrophilicity, rearrangement but different sets of somatic mutations in methotrexate could still penetrate the brain parenchyma when surgical specimens obtained at initial diagnosis and at disease rapidly infused at high doses. Its efficacy is suboptimal because recurrence, suggesting that there was a common clonal it only produces a complete response rate of 0% to 60% before precursor for both lymphoma specimens. cranial irradiation (2–6). Although methotrexate delivery to Because CNS lymphomas are traditionally thought to be the CNS could be improved with osmotic blood-brain barrier malignancies present exclusively in the CNS, drug treatment disruption (22, 23), an equally important treatment issue were designed to overcome pharmacokinetic obstacles posted has to do with the emergence of resistant clones of lym- by the blood-brain barrier. However, evidence for a common phoma cells. Treating CNS lymphomas with single-agent clonal progenitor for CNS lymphomas suggests that drug methotrexate alone or in sequential combination with other treatment directed primarily to the CNS may not be enough. chemotherapies is in distinct contrast to combination chemo- A concerted treatment approach to both CNS and systemic therapy regimens that are used for systemic non-Hodgkin’s sources of lymphoma may be necessary (18). Traditional lymphomas. Regimens that are used for systemic lymphomas, cytotoxic chemotherapies also suffered from low specificity such as cyclo-phosphamide, doxorubicin, vincristine, and pre- for B-lymphoma cells. The high target specificities of mAbs dnisone; methotrexate, cyclophosphamide, doxorubicin, vin- would offer increased efficacy for eradicating systemic lympho- cristine, and prednisone; and etoposide, methylprednisolone,

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Fig. 3. In CNS intravascular lymphomatosis, B-lymphoma cells with CD20+ immunohistochemical staining (arrows) are primarily localized in the lumena of cerebral vasculature (arrowheads).

high-dose cytarabine, and cisplatin (24, 25), were all designed when patients’ creatinine clearance is z90 mg L/min. When the based on the concept of simultaneous multiagent chemo- creatinine clearance decreases below 90 mg L/min, a dose therapies with different mechanisms of action and nonover- reduction of methotrexate proportional to the drop in creatinine lapping toxicity to prevent the emergence of drug-resistant clearance would be necessary to prevent the emergence of lymphoma clones. The fact that primary CNS lymphoma has systemic toxicities like mucositis, leukopenia, thrombocytope- an overall survival less than that for systemic lymphoma, 3-year nia, elevated liver enzymes, and leukoencephalopathy. In survival 30% versus 50% (2, 24), may be a result of such addition, patients with cardiomyopathy cannot withstand single-agent treatment. Unfortunately, drugs such as cyclo- aggressive fluid hydration, whereas those with diabetic nephrop- phosphamide, doxorubicin, and vincristine do not work for athy or transplanted kidney risk losing their kidneys. CNS lymphomas, because they are large water-soluble mole- Another major problem associated with high-dose metho- cules excluded by the blood-brain barrier (26, 27). Likewise, in trexate is neurotoxicity. Elderly patients are particularly pediatric non-Hodgkin’s lymphomas, multiagent combination susceptible to developing a subacute leukoencephalopathy, chemotherapy regimens, including cyclophosphamide, doxo- characterized by dementia, unsteady gait, and urinary inconti- rubicin, etoposide, methotrexate, cytarabine, vincristine, and nence, as a result of methotrexate damage to white matter of the intrathecal methotrexate, have produced increased event-free brain (34, 35). This side effect, when severe, can be detected as survival across all stages of disease, including those with hyperintense signals on T2 and FLAIR magnetic resonance lymphomatous involvement in the CNS (28, 29). However, imaging, and it could occur even without whole brain cranial dose intensification of methotrexate and cytarabine in patients irradiation. Although one could minimize the risk of leukoen- with CNS disease resulted in increased toxicity (28, 29). cephalopathy by administering high-dose methotrexate before Furthermore, the relative efficacy and toxicity of delivering or without consolidative cranial irradiation, this type of systemic chemotherapy into the brain by osmotic blood-brain methotrexate-induced neurotoxicity is not reversible despite barrier disruption remains to be determined (30). our best effort to prevent it. In addition to the brain parenchyma, lymphoma in the subarachnoid space requires a different therapeutic strategy. Although high-dose methotrexate and high-dose cytarabine could penetrate the cerebrospinal fluid space, intrathecal Ta b l e 2 . Differences between primary CNS injection of chemotherapy is the primary treatment modality lymphomas and primary gliomas (31) and the prolonged pharmacokinetic profile of liposomal cytarabine has proven efficacy for lymphomatous meningitis Normal Primary Primary CNS (32). However, intrathecal chemotherapy has no effect on brain gliomas lymphoma parenchymal brain lymphomas, because penetration into the brain parenchyma is at most 3 mm from the ependymal Glial cells Cells of glial origin B cells surface (33). Craniospinal irradiation would limit further GFAP+ GFAP+ CD20+ chemotherapy treatment, and palliative radiotherapy is only PDGFR/EGFR PDGFR/EGFR STAT/JAK used to treat symptomatic sites in the neuraxis. signaling signaling signaling Another shortcoming of high-dose methotrexate has to do Abbreviations: PDGFR, platelet-derived growth factor receptor; EGFR, epider- with its clearance. Because methotrexate is primarily cleared mal growth factor receptor; STAT, signal transducers and activators of tran- renally, patients must have adequate glomerular filtration. scription; JAK, Janus-activated kinase. Methotrexate could be given at full doses (range, 3.5-8.0 g/m2)

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Ta b l e 3 . Durable responses in patients treated with rituximab and temozolomide

Patient Age Disease Cycles Dose Cycles Response Duration of Survival Initial Intrathecal Final of of T of T response (mo) CSF chemotherapy CSF R+T (mg/m2/d) (mo) cytology cytology 164CD20+ 4 150 8 CR 23+ 23+ Negative None Negative relapsed PCNSL 271CD20+ 4 200 8 CR 12+ 12+ Negative None Negative relapsed PCNSL 3 76 NHL 4 75-150 8 CR 26+ 26+ Negative None Negative relapsed in the brain only, CD20+

NOTE: All patients received 375 mg/m2 of rituximab. Abbreviations: R, rituximab;T, temozolomide; NHL, non-Hodgkin’s lymphoma; CSF, cerebrospinal fluid; CR, complete response.

Emerging Monoclonal Antibody Treatments for toxicity of rituximab and temozolomide consisted of myelo- Central Nervous System Lymphomas suppression and was primarily related to the temozolomide dose. The data available thus far suggest that rituximab and In the past 5 years, the emergence of mAb therapies for temozolomide combination has efficacy against CNS lympho- lymphoproliferative malignancies has expanded the therapeutic mas and this immunochemotherapy combination has accept- option for CNS lymphomas. Although they are large molecules able toxicity. A prospective evaluation would be warranted. 90 excluded by an intact blood-brain barrier, mAbs could leak Radioimmunotherapy with yttrium-90 ( Y) ibritummomab 131 90 across permeable tumor vasculature into CNS lymphomas. tiuxetan or iodine-131 ( I) tositumomab. Y ibritumomab 131 More importantly, the favorable pharmacodynamic properties tiuxetan (Zevalin) and I tositumomab (Bexxar) are murine of mAbs may overcome their pharmacokinetic limitations, as mAbs against CD20 antigen that are conjugated to a radioactive their high specificity targeting lymphoma cells does not source. They have proven efficacy for relapsed or refractory necessitate a high concentration in CNS lymphomas, and non-Hodgkin’s lymphomas, even in patients previously treated 90 may result in a better therapeutic index than methotrexate. with rituximab. Y ibritumomab tiuxetan offers a response rate Another advantage of mAbs is their lack of pharmacodynamic ranges from 74% to 83%, whereas the rate for 131I tositumo- interactions with conventional chemotherapies and anticon- mab ranges from 57% to 86% (45). The addition of radiation vulsants. Their combination with conventional chemotherapies to CD20 antigen binding by mAb most likely contributes to the may result in a synergistic therapeutic response. added efficacy against B-cell lymphomas. Although radiation in Immunochemotherapy with rituximab and temozolomide. general has a neurotoxic effect in the CNS, both antibodies give Rituximab (Rituxan) is a chimeric murine mAb against the off low-dose rate radiation. Compared with high-dose rate CD20 antigen on B-lymphoma cells. Its mechanisms of action radiation from conventional external beam cranial irradiation, include complement-mediated cytotoxicity, antibody-mediated low-dose rate radiation may have less CNS toxicity (46). phagocytosis, antibody-dependent cell-mediated cytotoxicity, Therefore, the combination of anti-CD20 antibody with low- and antibody-dependent growth inhibition and apoptosis (36). dose rate radiation may result in a synergistic therapeutic As a single agent, it had limited efficacy against CNS lym- response, whereas CNS toxicity is minimized. The systemic phomas, because it only produced partial responses (37). This toxicities, however, consist of asthenia and infusion reactions may be due to the poor penetration of rituximab into the such as rigors, fevers, and nausea (45). Myelosuppression is a cerebrospinal fluid, which is 0.1% of that in the serum (38). major toxicity because both antibodies also accumulate in the However, intrathecal administration of rituximab increases the bone marrow, and patients with low bone marrow reserve are level in the cerebrospinal fluid (39). Whether or not this would at risk for neutropenia, thrombocytopenia, or both (45). translate into an increase in efficacy remains to be determined. Epratuzumab. Epratuzumab, a humanized mouse anti- Furthermore, single-agent temozolomide (Temodar), an alky- CD22 mAb, has shown efficacy against indolent and aggressive lator that does not have cumulative myelotoxicity, was used to non-Hodgkin’s lymphomas. Although its precise function in B- treat CNS lymphomas (40, 41). However, when the two agents lymphoma cells is unclear, CD22 seems to mediate survival and were combined, rituximab, and temozolomide resulted in a migration (47, 48). As a single agent, epratuzumab offers an 70% response rate in a group of elderly patients with poor renal objective response rate of 43% for follicular lymphomas (49) functions (42). Three of the cohort (40%) had durable and 10% for aggressive lymphomas (50). Like rituximab alone, responses that lasted for z26, z23, and z12 months to date epratuzumab as a single agent probably has limited efficacy (43) (Table 3). Other investigators also noted a 53% objective against aggressive lymphomas in the CNS. But its efficacy may response rate in relapsed primary CNS lymphomas (44). The be improved with concomitant cytotoxic chemotherapies, such

www.aacrjournals.org 7155s Clin Cancer Res 2005;11(19 Suppl) October 1, 2005 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2005 American Association for Cancer Research. Clinical Studies as temozolomide. More importantly, the side effects of rosis, was found to decrease cerebral inflamma- epratuzumab are mild and primarily consist of fatigue in 22% tion as detected on gadolinium-enhanced magnetic resonance and 18% of treated patients (49, 50). imaging (56, 57). Because a4 integrin is expressed by mantle Alemtuzumab. Alemtuzumab (Campath-1H) is a human- zone lymphocytes and strong immunohistochemical staining ized mAb against CD52 antigen on B- and T-lymphoma cells. of a4 integrin correlates with poor survival in patients with In clinical trials for chronic lymphocytic leukemia, it has a diffuse large cell lymphomas (58), natalizumab may stop the response rate of 38% and a median time to tumor progression trafficking of B-lymphoma cells from systemic circulation into of 15.4 months (51–53). However, aletuzumab has less the CNS and block the invasive behavior of primary CNS efficacy against relapsed non-Hodgkin’s lymphoma, with a lymphomas in the brain. response rate of 8% to 17% (54, 55), and this low response rate could be due to variable expression of CD52 antigen in Conclusion B-lymphoma cells. Although preclinical data is lacking at pre- sent, alemtuzumab may be an option in selected patients with The management of CNS lymphomas is poised for another CD52 expression in biopsied specimens, or it may help to revolution with emergence of mAbs with high specificity against remove T cells that support the viability of B-lymphoma cells in lymphoma cells. Such , radioimmunotherapy, the CNS. Further clinical studies would be necessary to define or immunochemotherapy combination, like rituximab and the therapeutic index, because alemtuzumab can cause a pro- temozolomide, 90Y ibritumomab tiuxetan, 131I tositumomab, found loss of T lymphocytes, resulting in cell-mediated im- aletuzumab, epratuzumab, and natalizumab, may offer treat- munosuppression and opportunistic infections such as herpes ments for CNS lymphomas with a better therapeutic index than zoster reactivation or Pneumocystis pneumonia (51–53). existing methotrexate-based therapies. Natalizumab. Natalizumab (Antegren) is a humanized mAb against a4 subunit of a4h1 and a4h7 integrins. These integrens Acknowledgments mediate lymphocyte and monocyte trafficking from systemic circulation into the brain. In randomized, double-blinded, I thankJeffrey Joseph, M.D., Ph.D. for providing the microscopic and magnetic placebo-controlled trials for relapsing-remitting multiple scle- resonance imaging figures and Anand Mahadevan, M.D. for helpful discussion.

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Eric T. Wong

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