Types of Lymphoma >  CNS (Central Nervous System) Lymphoma

Last update: 06/01/2018

TOPICS
  Overview | Natural History | Treatments 
Blood-brain barrier - drugs that may cross it
Clinical Trials | Resources & Research News

TOPIC SEARCH: PubMed: Diagnosis | Review | Therapies | Prognosis

Overview of 
Central Nervous System (CNS) Lymphoma

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Lymphoma is a blood cell cancer - a condition where abnormal lymphocytes (a type of white blood cell) expand in number forming tumors often in lymph nodes but also in other regions, such as the bone marrow, or, uncommonly, in the central nervous system.

See for details: Lymphoma Simplified

Primary central nervous system lymphoma (PCNSL) is a "high-grade non-Hodgkin B-cell neoplasm, usually large cell or immunoblastic type."

Secondary CNS: Lymphomas can  sometimes migrate to the central nervous system.  This secondary form of CNS lymphoma is not common, however. 

In the News and What's New:

	ASCO 2018: R-CHOP preceded by blood-brain barrier permeabilization (BBBp) by NGR-tumor necrosis factor (NGR-hTNF) in patients with relapsed or refractory primary CNS lymphoma (rrPCNSL): First results of the “INGRID” phase II trial. | 2018 ASCO Annual Meeting Abstracts http://bit.ly/2LbFAA8   Small study with encouraging results reported.
	A Systematic Approach to the Diagnosis of Suspected Central Nervous System #Lymphoma http://1.usa.gov/1Y6UJUf
	Lymphomatous Meningitis in Primary Central Nervous System Lymphoma http://wb.md/1SlZkBi
	J Clin Onc 2013: Rituximab, Methotrexate, Procarbazine, and Vincristine Followed by Consolidation Reduced-Dose Whole-Brain Radiotherapy and Cytarabine in Newly Diagnosed Primary CNS Lymphoma: Final Results and Long-Term Outcome http://bit.ly/1atL3aT
	ASCO 2012 - CNS Lymphoma abstracts compiled by PAL

Natural History - treated and untreated

TOPIC SEARCH: Scholar | PubMed

The "natural history" of a lymphoma refers to the expected clinical course of the disease if it is untreated.   Along with the availability of effective treatments, the natural history provides the context that guides the most appropriate timing and approach to treatment.  For example, a lymphoma with a very short natural history would require prompt and effective therapy - with curative intent; while a less aggressive type of lymphoma might be observed and treated (managed) as needed with less aggressive therapy.

"The clinical course of CNS lymphoma is  ... coming soon.

See Summary of factors that can influence the timing and choice of therapy

Which illustrates the complexity of treatment decisions and how they can interact; and how each case and lymphoma can be unique, thus treatments may need to be tailored accordingly - the reason professional guidance is required. 

Symptoms of primary CNS Lymphoma:

Source: Medscape review article Eichler, Batchelor

"The presenting symptoms and signs in one large case series of 248 immunocompetent patients with PCNSL included the following:

	focal (limited to a small area) neurological deficits in 70% of patients;
	neuropsychiatric symptoms in 43%;
	headache/nausea/vomiting suggestive of increased intracranial pressure in 33%;
	seizures in 14%; and
	ocular symptoms in 4%.[8]

Common focal deficits include

	aphasia (Loss of ability to understand or express speech),
	hemiparesis (weakness on one side of the body), and
	ataxia (loss of full control of bodily movements) due to discrete intracerebral lesions as well as less common cranial nerve palsies secondary to leptomeningeal deposits.

Neuropsychiatric (neurological and psychiatric) changes such as

apathy (loss of interest),

depression, slowed thinking, and confusion have been attributed to the infiltration of white matter tracts by PCNSL lesions that involve the periventricular regions or the corpus callosum. The fact that seizures occur as the initial manifestation of PCNSL in less than 15% of immunocompetent patients who have these tumors may be partially explained by the fact that PCNSL lesions less often involve excitable cerebral cortex than do other types of brain tumors.[37]

How is it diagnosed? 

See Medscape review article

Tendencies:

Previously a rare tumor accounting for less than 2% of cerebral neoplasms, PCNSL is being seen with increasing frequency in immunocompetent patients, patients with AIDS, and transplant recipients. ^[2]

Factors influencing prognosis: Age, performance status (PS), LDH serum level, CSF protein concentration, and involvement of deep structures of the brain were independent predictors of survival. A prognostic score including these five parameters seems advisable in distinguishing different risk groups in PCNSL patients. The proposed score and its relevance in therapeutic decision deserve to be validated in further studies."^[7]

Resources

1. About Primary CNS Lymphoma:
       Cancer.gov (illustrated)
       NCI PDQ for Patients  
       Asheducationbook.org
       Cancerbackup.org.uk  
       Cancernetwork.com 
       Medscape (free reg. req.)
       Medscape review article

2. Primary CNS Lymphoma emedicine (free login req.) Amy A Pruitt, MD,

3. ONCOLOGY 2000: Update on the Management of Primary CNS Lymphoma - full text
   
   Syed Nasir, MD, and Lisa M. DeAngelis, MD Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York
   
   "Age and performance status are important prognostic factors, regardless of specific treatment. Methotrexate in high doses is the single most effective chemotherapeutic agent for primary CNS lymphoma.
   
   It substantially improves survival when combined with radiation therapy and is better than radiotherapy alone as a single agent. Multimodality treatment results in delayed cognitive neurotoxicity, particularly in older patients. New treatment protocols have focused on the use of chemotherapy alone."

4. Central Nervous System Disease in Hematological Malignancies: Historical Perspective and Practical Applications ncbi.nlm.nih.gov
   
   "In this article, we review current and past practice of intrathecal therapy in ALL and NHL and the risk-models that aim to identify predictors of CNS relapse in NHL."

5. HIV-1 Associated Opportunistic Neoplasms: CNS Lymphoma emedicine

6. Central Nervous System Lymphoma asheducationbook.org 
   
   Andrew Lister, Lauren E. Abrey and John T. Sandlund 
    
   "Central nervous system involvement with malignant lymphoma whether primary or secondary is an uncommon but not rare complication observed in the management of patients with hematological malignancy. "

7. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol. 2005 Apr 1;23(10):2233-9. PMID: 15800313 | Related articles

8. Imaging of central nervous system lymphomas with iodine-123 labeled rituximab. Eur J Haematol. 2005 Apr;74(4):348-52. PMID: 15777348

9. Gene expression and angiotropism in primary CNS lymphoma  http://bit.ly/5pQTqi

10. CNS lymphoma - MRCC: Primary CNS Lymphoma Treatment (PDQ®)

Treatments

Questions for your doctor - Patients Against Lymphoma
General, Treatment & Side Effects, and Tests

For help with locating 
Experts - See Doctors

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TOPIC SEARCH: PubMed | ClinicalTrials.gov

"Due to the unsatisfactory results of whole-brain irradiation alone and to the neurologic toxic effects of chemotherapy and radiation therapy, there is now a major focus on trials with chemotherapy alone. There are now several single-institution reports in which systemic chemotherapy has been employed alone or with osmotic blood-brain barrier disruption. Currently, most regimens are employing high-dose Methotrexate and require hospitalization. For patients who do not respond to chemotherapy alone or with radiation therapy, but are still responsive to salvage chemotherapy with cytarabine and etoposide, intensive chemotherapy with autologous peripheral stem cell transplantation is under evaluation." ^[5] - cancerweb.ncl.ac.uk 

	Cytarabine (ARA-C) Plus Methotrexate Superior for Patients With Primary CNS Lymphoma http://bit.ly/3am1t8
	New: Intravenous Rituxan® Effective in Primary Central Nervous System Lymphomas  professional.cancerconsultants.com  Related studies: ClinicalTrials.gov
	Primary non-Hodgkin's lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: long-term survival and prognostic factors. Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):501-8. PMID: 15145169  Patients with primary CNS non-Hodgkin's lymphoma aged <60 years treated with CHOD/BVAM or BVAM followed by radiotherapy have a similar long-term survival to that of patients with large B cell non-Hodgkin's lymphoma at other extranodal sites.
	Intensive Chemotherapy Followed by Hematopoietic Stem-Cell Rescue for Refractory and Recurrent Primary CNS and Intraocular Lymphoma: Societe Francaise de Greffe de Moelle Osseuse-Therapie Cellulaire. J Clin Oncol. 2008 Apr 14; PMID: 18413641   The respective median progression-free survival (PFS) times after IC + HCR were 11.6 and 41.1 months. The 2-year overall survival probability was 45% in the whole population and 69% among the 27 patients who received IC + HCR. The 2-year PFS probability was 43% among all the patients and 58% in the IC + HCR subpopulation. CONCLUSION: IC + HCR is an effective treatment for refractory and recurrent PCNSL.
	Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007 Oct 20;25(30):4730-5. PMID: 17947720 The addition of Rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.
	Primary CNS lymphoma treated with combined intra-arterial ACNU and radiotherapy - http://www.springerlink.com  The intra-arterial administration of ACNU combined with radiation therapy yielded a high response rate at acceptable toxicity levels in younger patients with PCNSL. However, late neurotoxicity was a serious complication in patients above 60 years of age.
	Management of central nervous system lymphomas using monoclonal antibodies: challenges and opportunities. Clin Cancer Res. 2005 Oct 1;11(19 Pt 2):7151s-7157s. Review. PMID: 16203815
	Case report of a patient with primary central nervous system lymphoma treated with radioimmunotherapy. Clin Lymphoma Myeloma. 2006 Nov;7(3):236-8.  PMID: 17229341
	Salvage therapy for primary central nervous system lymphoma with (90)Y-Ibritumomab and Temozolomide. J Neurooncol. 2007 Jul;83(3):291-3. Epub 2007 Jan 24. PMID: 17245621  Aggressive initial treatment of Primary Central Nervous System Lymphoma (PCNSL) has achieved prolonged survival and occasional cures. However, some patients do not respond to initial therapy and others relapse after an initial remission. The optimal salvage regimen is not known and many different strategies have been proposed. In this report we describe the efficacy of a combination of (90)Y-Ibritumomab Tiuxetan (Zevalin) and Temozolamide as a maintenance therapy for recurrent PCNS Lymphoma in two patients that are both alive and in complete remission after 9 and 10 months respectively. This combination merits further study and provides a reasonable therapeutic alternative for older patients with progressive PCNSL.
	Phase II Trial of the Bonn Polychemotherapy Protocol with Deferred Radiotherapy in Patients with Primary Central Nervous System Lymphoma. - ASH 2006 Conclusions: Primary chemotherapy based on high-dose MTX and ara-C is highly efficient in PCNSL. A substantial fraction of patients < 60 years can obviously be cured with this regimen.
	High-Dose Chemotherapy With Autologous Stem-Cell Transplantation and Hyperfractionated Radiotherapy As First-Line Treatment of Primary CNS Lymphoma.  J Clin Oncol. 2006 Jul 24; PMID: 16864853  With a median follow-up of 63 months (range, 4 months to 84 months), 5-year overall survival probability is 69% for all patients and 87% for the 23 patients receiving HDT plus ASCT. The 5-year probability of relapse-related death is 21% for all patients (n = 30) and 8.7% for patients treated with HDT plus ASCT (n = 23). CONCLUSION: Sequential systemic methotrexate and AraC and thiotepa followed by HDT plus ASCT and hyperfractionated WBRT is very effective with little toxicity as initial therapy for PCNSL.
	Intraventricular application of rituximab as a treatment option in patients with CNS lymphoma and leptomeningeal disease. ASCO
	Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma - http://jco.ascopubs.org The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response.  Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy. Conclusion: These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.
	Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer. 2000 Feb 1;88(3):637-47. PMID: 10649259 | Related articles
	Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: the Sherbrooke experience. Cancer. 2005 Jun 15;103(12):2606-15. PMID: 15880378 | Related articles
	Due to the difficulties in treating PCNSL (as of 2004), we think it reasonable  to specifically ask your treating physician about  investigational treatments.           See Studies for CNS in ClinicalTrials.gov         Contact investigators listed in protocols.         Arrange to have the investigator talk with your treating physician.
	Salvage chemotherapy with temozolomide in primary CNS lymphomas: preliminary results of a phase II trial. Eur J Cancer. 2004 Jul;40(11):1682-8. PMID: 15251157
	Primary cerebral lymphoma: a retrospective study in 22 immunocompetent patients. Tumori. 2004 May-Jun;90(3):294-8 PMID: 15315308
	Treatment of Primary CNS Lymphoma With Methotrexate and Deferred Radiotherapy: A Report of NABTT 96-07. J Clin Oncol. 2003 Mar 15;21(6):1044-9. PMID: 12637469 PubMed
	What's New in Primary Central Nervous System Lymphoma, An interview with Virginia Stark-Vance, M.D. dfw-neuronetwork.com
	Treatment of Primary CNS Lymphoma With Methotrexate and Deferred Radiotherapy: A Report of NABTT 96-07 Tracy Batchelor, Kathryn Carson, Alison O’Neill, Stuart A. Grossman, Jane Alavi, Pamela New, Fred Hochberg, Regina Priet  jco.org   "These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens. "
	High-dose methotrexate for primary CNS lymphoma in the elderly  neuro-oncology.dukejournals.org  pdf
	Prophylactic intrathecal methotrexate and hydrocortisone reduces central nervous system recurrence and improves survival in aggressive non-Hodgkin lymphoma cat.inist.fr/

Active Lymphoma Drugs that May Cross Blood-Brain Barrier?

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TOPIC SEARCH: Web | toxnet.gov

keywords:  antineoplastic small molecule drugs blood brain barrier

Articles and Tools:

Bridging the Blood-Brain Barrier: New Methods Improve the Odds of Getting Drugs to the Brain Cells That Need Them PDF

Drugs that appear to cross blood brain barrier
(some of these are investigational)

	Obatoclax mesylate (small molecule pan–Bcl-2 family antagonist) (GX15-070)  Treatment Pipeline
	Salvage Therapy With Temozolomide in Patient With Primary Brain Lymphoma  http://bit.ly/bH3IgR Temozolomide-based Clinical trials: http://bit.ly/cTcM0O Temozolomide as salvage treatment in primary brain lymphomas http://bit.ly/biziKd
	Revlimid (Lenalidomide) for CNS involvment?  http://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=10641
	Vorinostat? http://www.drugs.com/clinical_trials/crosses-blood-brain-barrier-reduces-formation-brain-metastases-mice-8157.html
	Bendamustine for CNS involvement?  http://jco.ascopubs.org/cgi/content/abstract/22/17/3608

Clinical Trials

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Resources & 
Research News

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Resources & Research News

1. Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment. Br J Haematol. 2004 Jul;126(2):202-8. PMID: 15238140

2. Methotrexate Induction Therapy Followed by High-Dose Chemotherapy ... 
   Doctor's Guide  ... followed by high-dose chemotherapy with autologous stem-cell rescue may be a feasible treatment approach for primary central nervous system (CNS) lymphoma ... docguide.com  (press release)

3. Primary Central Nervous System Lymphoma: Results of a Pilot and Phase II Study of Systemic and Intraventricular Chemotherapy With Deferred Radiotherapy. J Clin Oncol. 2003 Nov 3 PMID: 14597744 | More

4. Importance of radiotherapy in the outcome of patients with primary CNS lymphoma: an analysis of the CHOD/BVAM regimen followed by two different radiotherapy treatments. J Clin Oncol. 2002 Jan 1;20(1):231-6. PMID: 11773174  - PubMed

5. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. Bull Cancer. 2004 Feb;91(2):189-92. French  PMID: 15047459

6. Primary CNS lymphoma of T-cell origin: a descriptive analysis from the international primary CNS lymphoma collaborative group. J Clin Oncol. 2005 Apr 1;23(10):2233-9. PMID: 15800313

7. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003 Jan 15;21(2):266-72. PMID: 12525518

8. Initial response to glucocorticoids: an important prognostic factor in patients with primary CNS lymphoma (PCNSL) - ASCO 2002

9. Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer. 2004 Jul 1;101(1):139-45.
   PMID: 15221999 | Related articles

10. Trends in survival from primary central nervous system lymphoma, 1975-1999. Cancer. 2005 Oct 20; PMID: 16240449

11. Prospective trial on topotecan salvage therapy in primary CNS lymphoma - annonc.oxfordjournals.org  
    
    The response rate was 33% with five complete (CR) and four partial remissions (PR). The median follow-up was 37.7 months. All complete responders had sustained remissions lasting for 9 to 28 months. The median event-free survival (EFS) was 2.0 months (9.1 months in responders), the overall survival (OAS) was 8.4 months. CTC grade 3–4 leukopenia occurred in 26% and thrombocytopenia in 11% of the patients. Eight of 12 patients alive without cerebral lymphoma six months after topotecan exhibited deficits attributable to late neurotoxicity.

12. CNS outcomes predicted by gene expression: Retrospective analysis of P-STAT6 expression as a predictive marker in primary nervous system lymphoma patients assigned to high-dose methotrexate - ASCO 2007 

13. Feasibility study: Study of radiolabeled indium-111 and Zevalin in primary central nervous system lymphoma. Cancer. 2007 Oct 11; PMID: 17932895 

14. Brain parenchyma involvement as isolated central nervous system (CNS) relapse of systemic non-Hodgkin lymphoma: an International Primary CNS Lymphoma Collaborative Group report.
    Blood. 2007 Oct 25; PMID: 17962515 
    
    Our results suggest systemic methotrexate is the optimal treatment for isolated CNS relapse involving the brain parenchyma. Long-term survival is possible in some patients.

15. Outcomes CNS Lymphoma : Methotrexate May Cure up to 20% of Patients With CNS lymphoma
    
    "In this small, multicenter study we found that at almost 7 years of follow-up, 5 of the original 25 patients were still in remission after treatment with high-dose methotrexate alone and that toxicity was modest," principal investigator Tracy Batchelor, MD, told Medscape Neurology & Neurosurgery. 
    
    The study is published in the January 29 issue of Neurology.

16. Biomarkers: Del(6)(q22) and BCL6 Rearrangements in Primary CNS Lymphoma Are Indicators of an Aggressive Clinical Course. J Clin Oncol. 2008 Jul 21. PMID: 18645192  
     
    Comment:  Markers such as these, when validated, can be used to tailor therapy to the risk of the disease. 
     
    RESULTS: The prevalence of del(6)(q22) and BCL6, IGH, and MYC translocations was 45%,17%, 13%, and 3%, respectively. The presence of del(6)(q22) and/or a BCL6 translocation was associated with inferior overall survival (OS; P = .0097). The presence of either del(6)(q22) alone or a BCL6 translocation alone was also associated with inferior OS (P = .0087).

17. Maculopathy in patients with primary CNS lymphoma treated with chemotherapy in conjunction with blood–brain barrier disruption  http://bjo.bmj.com/

18. Primary Central Nervous System Lymphoma: The Memorial Sloan-Kettering Cancer Center Prognostic Model. J Clin Oncol. 2006 Nov 20; PMID: 17116938 
     
    "The MSKCC prognostic score is a simple, statistically powerful model with universal applicability to patients with newly diagnosed PCNSL. We recommend that it be adopted for the management of newly diagnosed patients and incorporated into the design of prospective clinical trials."

19. Primary central nervous system mucosa-associated lymphoid tissue lymphoma: case report and literature review.  Razaq W, Goel A, Amin A, Grossbard ML. Clin Lymphoma Myeloma. 2009 Jun;9(3):E5-9.
    PMID: 19525185 

20. Is Single-Agent Temozolomide the Treatment of Choice for Recurrent Primary Central Nervous System Lymphoma? medscape.com 

    The authors conclude that in a heavily pretreated population, temozolomide shows potential in the treatment of PCNSL, with modest toxicity. The authors suggest that temozolomide should be further developed as induction, consolidation and maintenance therapy for primary lymphomas.

21. NEW New strategies to deliver anticancer drugs to brain tumors (technical, Oct 2009) http://bit.ly/37NTog 

22. Temozolomide as salvage treatment in primary brain lymphomas http://bit.ly/biziKd