Open access peer-reviewed chapter

Primary Central Nervous System Lymphoma: Focus on Indian Perspective

Written By

Praful Pandey, Ahitagni Biswas, Saphalta Baghmar, Mukesh Patekar and Ranjit Kumar Sahoo

Submitted: 06 October 2021 Reviewed: 15 October 2021 Published: 04 February 2022

DOI: 10.5772/intechopen.101235

From the Edited Volume

Lymphoma

Edited by Yusuf Tutar

Chapter metrics overview

185 Chapter Downloads

View Full Metrics

Abstract

Early suspicion, withholding steroids, stereotactic biopsy, and high-dose methotrexate (HD-MTX) are essential for the treatment of primary CNS lymphoma (PCNSL) making its management in lower-middle-income countries (LMIC) challenging. Novel radiological methods, clinician awareness about the disease, and utilization of drugs like thiotepa and ibrutinib which can be given on an outpatient basis may allow better management of these patients in resource-poor settings. Combined with a late presenting demographic, this results in poorer outcomes in the Indian subcontinent as compared to its western counterparts. In this review, we summarize the currently available data on PCNSL in the Indian subcontinent. We also review the current standard of care for PCNSL and present potential modifications or research areas that may potentially improve outcomes in LMIC.

Keywords

  • primary central nervous system lymphoma
  • PCNSL
  • lower middle income countries
  • LMIC
  • methotrexate
  • TEDDI
  • ibrutinib

1. Introduction

WHO 2016 classification for lymphomas [1] defines primary central nervous system lymphoma as a rare and aggressive form of extranodal diffuse large B-cell lymphoma (DLBCL) involving the brain, leptomeninges, or eyes without any systemic involvement. However, this entity responded poorly to conventional DLBCL regimens [2, 3] despite using radiotherapy or dexamethasone to enhance CNS efficacy. Further evidence supporting PCNSL as a distinct entity comes from studies showing unique GEP signatures [4] and transcriptomics (with heavy reliance on NF-KB) [5] compared to its nodal counterparts.

PCNSL is predominantly a disease of the elderly [6] and presents with focal deficits followed by features of raised intracranial pressure [7]. Initially suspected on MRI, it is typically diagnosed by a stereotactic biopsy or by cerebrospinal fluid evaluation in exceptional circumstances [8]. Modern management is based on HD-MTX based polychemotherapy followed by consolidative therapy in the form of WBRT, standard-dose chemotherapy or high-dose chemotherapy followed by stem cell transplantation. Rituximab addition may improve outcomes [9]. Novel ibrutinib-based combinations are used in relapsed settings and are being evaluated in the frontline settings as well [10].

In the LMIC, the lack of availability of HD-MTX and neurosurgical suites make management of PCNSL difficult. Novel MRI-based sequences, ibrutinib-based regimes, and utilization of consolidative WBRT may ease the burden. This review details the epidemiological, clinical, and radiological features of PCNSL with a focus on the Indian subcontinent. Furthermore, the current standard of therapy and potential modifications for easier delivery in the LMIC is also detailed.

Advertisement

2. Epidemiology

2.1 Incidence

Overall, the age-adjusted incidence rate (SEER database) of PCNSL is .47 cases per 10,000,000 people per year [11].

The incidence is increasing in elderly males for unclear reasons. Variations in CD4 subpopulations could be a likely cause [12].

From India, only two studies have reported temporal incidence trends. One study reported a 3.5× increase in the number of cases without any change in the proportion of all CNS neoplasms from 1980 to 2003 [13]. Another study done at a single center in northern India found no temporal variation in incidence [14].

2.2 Place in the lymphoma landscape

PCNSL accounts for 4% of all primary CNS tumors as per western data [15]. Two Indian studies, however, report a more conservative estimate of 0.92–0.95% [13] and 1.2% [14].

PCNSL is an uncommon NHL accounting for 4–6% of all extranodal lymphomas [11] and less than 1% of all NHLs as per western literature. A study from Southern India reports that PCNSL accounts for 9.6% of all primary extranodal lymphomas and roughly 3% of all NHLs [16].

2.3 Demographics

Table 1 contains the demographic details of PCNSL patients recruited in Indian studies.

Study (n)DemographicsClinical presentationInvestigations
Median age (years)Males (%)HIV positive (%)Median duration of symptoms (Months)Most common presenting featureEye involvement (%)Leptomeningeal involvement (%)ECOG PSRaised LDH (%)HistopathologyStereotactic biopsy (%)Inadvertent resection (%)Multiple lesions (%)
Patekar et al.
(n = 99)
5065.601.103.5Neurological deficit19.4015.858.5% PS ≥ 319.40DLBCL (97.7%)494081.80
Adhikari et al.
(n = 22)
51.55904Neurological deficit22.7013.6459.9% PS ≥ 345.45DLBCL (100%)505075
Patel et al.
(n = 73)
466602.5Raised ICPDLBCL (95.9%)54.8045.2064.40
Powari et al.
(n = 40)
50660Raised ICPDLBCL (100%)10087.50
Paul et al.
(n = 56)
42600.90Raised ICPDLBCL (93.2%)21.40
Mahadevan et al.
(n = 24)
5358.330Raised ICPDLBCL (100%)
Dash et al.
(n = 41)
5253.400Raised ICPDLBCL (100%)
Sarkar et al.
(n = 116)
44.469.300.80DLBCL (100%)
Parischa et al.
(n = 66)
46500Raised ICPDLBCL (100%)15
Sharma et al.
(n = 65)
4958.3003DLBCL (100%)41.53
Yadav et al.
(n = 32)
50710Raised ICP00DLBCL (100%)68.80
Rudresha et al.
(n = 26)
42.565.30Raised ICP0430.70DLBCL (96%)465438.50
Rudresha et al.
(n = 53)
44643.70Raised ICP0632DLBCL (100%)495130
Kumari et al.
(n = 30)
47.8600Raised ICP70% with PS ≥ 370DLBCL (100%)66
Puligundla et al.
(n = 42)
4668.704.70Raised ICP015.8080.9% PS ≥ 2DLBCL (97.6%)42.8057.1023.80
Agarwal et al.
(n = 26)
5961.507.603Neurological deficit19.2034.60DLBCL (96.1%)77

Table 1.

Demographic and clinical details of patients enrolled in Indian studies.

In Western settings, non-HIV infected PCNSL is typically diagnosed at 45–65 years of age (median age of diagnosis in the fifth decade) with no gender predilection [6, 17, 18, 19]. However, the Indian demographic differs in having a younger affected population (median age at diagnosis ranging from 42 to 59 years) with slight male preponderance [13, 14, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. These changes are more likely from different population demographics rather than inherent disease biology, given that individuals aged more than 60 or 65 consistently amount to less than 9% and 7% of the total Indian population respectively [32].

HIV-infected individuals are also a younger cohort (Median age: 37 years) with a male preponderance [12].

Among transplant recipients: CNS involvement is present in 15% of all NHL cases [33] and is associated with a poorer prognosis [34]. However, amounting to only 0.9% of all PCNSL cases, this subset is not well studied [12].

2.4 Global vs. Indian burden of HIV in PCNSL

The prevalence of HIV in PCNSL patients is estimated to be 6.1% globally, with significant variation among nations [35]. Prevalence in India is significantly lesser [35], with some studies not reporting even a single case [14, 25, 26, 27, 30]. Similarly, PCNSL accounts for 2.5% of all CNS lesions in HIV-positive patients compared to 10–17% in the western population [36]. Autopsy series show similar findings with the only published Indian series reporting no cases of PCNSL over 8 years [37] while western studies report the share to be between 1.4 and 3% [38, 39]. Shorter survival among AIDS patients in the Indian subcontinent could be the likely cause [40].

Advertisement

3. Clinical features and diagnosis

3.1 Presenting features

The most common presenting features reported are focal neurological deficits, neuropsychiatric symptoms, headache from raised intracranial pressure (ICP), seizures, and ocular symptoms [7]. Diagnosis may not be evident at presentation, with one study reporting a median time lag of 70 days from symptom onset to neuroimaging [41]. Personality changes and visual hallucinations are usually detected late, and a lower threshold to pursue neuroimaging is needed [41].

3.2 Clinical evaluation

Any suspected case of PCNSL should undergo neuroimaging in the form of a contrast-enhanced MRI of the brain and spine, CSF analysis unless contraindicated (ideally before stereotactic biopsy), slit-lamp examination, and testicular examination (in males) [42].

In some cases, pathological evaluation of ocular material or CSF may diagnose. In most cases, however, a stereotactic biopsy is needed [43]. The stark difference in the initial management of PCNSL, compared to high-grade gliomas, underlines the importance of early clinical suspicion and radiological expertise.

3.3 The Indian scenario

Table 1 contains the clinical features of patients enrolled in studies in Indian settings.

In the Indian subcontinent, delayed health-seeking behavior combined with high initial misdiagnosis rates leads to a high disease burden at presentation. Median time from symptom onset to diagnosis is reported around 3.5–5 months in Indian studies [20, 24, 29, 44], compared to 2.5–3 months in western studies [7, 41].

Delayed health-seeking behavior is evident if we compare clinicoradiological features at index presentation. While two studies report focal neurological deficits as the most common presenting feature [20, 29], most studies report headache from raised ICP as the index presentation [14, 21, 22, 23, 27, 28, 30, 31], which is typically a late feature in the western literature. Furthermore, while most western patients are ambulatory and capable of self-care at presentation [7], roughly 2/3rd of Indian patients are ECOG performance status (ECOG-PS) three or worse in retrospective [22, 25, 29] and prospective [44] studies. Similarly, multifocal lesions, reported in 25% of patients at presentation as per western literature [7], are seen in 30–82% of all patients presenting in the Indian settings [20, 22, 24, 25, 26, 27, 28, 29, 31, 44]. However, some studies do give estimates nearing their western counterparts [14, 23, 30], perhaps highlighting differential health-seeking behavior.

Erroneous evaluation and emergent management are also common. Indian studies report misdiagnosis rates as high as 54% [20] to 100% [29], and inadvertent open surgical resection in 36-57% [20, 44] of PCNSL patients compared to 25% in western literature. In addition, inadvertent steroids are given before diagnosis in up to 2/3rd patients referred from primary care [20] although prospective studies document only 9% requiring corticosteroid therapy for life-threatening indications [44].

These delays and errors result in a patient population with advanced disease and a poorer prognosis. While the proportion of patients with LDH elevation (1/3rd) and CSF Protein elevation (2/3rd) are similar in Indian [22, 25, 28, 29, 31] and western studies [45], fewer patients are IESLG low risk in the Indian settings with concomitant better outcomes [22, 25, 29]. However, the MSKCC risk classification seems to underestimate the risk in the Indian population because of its weightage to older age [28, 31].

Advertisement

4. Treatment modalities and outcomes

Table 2 shows treatment details and outcomes of important studies from the Indian subcontinent.

Study (n)Pre-treatment detailsInduction chemotherapy detailsPost-induction chemotherapyLong-term outcomes
IESLG low risk (%)Treatment received (%)Type of chemotherapyMedian induction cyclesRituximabOverall response rate, complete response rate (ORR/CR %)Median follow-up duration (months)Median event-free survival (months)Median overall survival (months)Severe late neurotoxicity (%)
Patekar et al.
(n = 99)
7.1077.70MVP with Rituximab (94.8%)
CHOP + HTMTX (2.6%)
CHOP + IT MTX (1.3%)
HD - MTX only (1.3%)
5In affording patients81.8% (46.8%)WBRT in 54%
(Ara - C in 86% of WBRT recipients)
11% HiDAC only
3420.431.710
Adhikari et al.
(n = 22)
100MVP5In affording patients93.7% (52.63%)50% WBRT
50% reduced dose WBRT
68.18% post-WBRT HiDAC
11.25Not reached19
Parischa et al.
(n = 66)
100MPV followed by WBRT + HiDAC (DeAngelis protocol)No
Yadav et al.
(n = 32)
100WBRT (36-50 Gy) followed by 6 cycles CHOP6No87.5% (75%)None1814 months
Rudresha et al.
(n = 26)
100DeAngelis protocol (92%), MTR followed by EA (8%)5NoORR for DeAngelis: 92%, ORR for MTR regime: 100%WBRT followed by HiDAC given in DeAngelis protocol, EA given to MTR recipients20.5
Rudresha et al.
(n = 53)
100DeAngelis protocol (n = 31)
CHOP + WBRT (n = 14)
WBRT only (n − 6)
NoWBRT followed by HiDAC in DeAngelis protocol23 months for DeAngelis protocol, 13 months for standard CHOP + WBRT treated, 6 months for WBRT only subset26% in DeAngelis treated, 14% in CHOP + WBRT subset
Kumari et al.
(n = 30)
1010040–52 Gy WBRT followed by 6 cycles of CHOP/PCVNo
Puligundla et al.
(n = 42)
1980.90Modified DeAngelis (50%)
Modified DeAngelis protocol + rituximab (29.4%)
Steroids + radiotherapy (17.7%)
BFM- NHL protocol (3%)
Given to 29.4% of patients181115.9
Agarwal et al.
(n = 26)
36.384.60MVP + CytarabineNoCR: 72.7%WBRT in patients aged <60 years (45%)14.51031.25%

Table 2.

Treatment administered and long term prognosis of PCNSL patients enrolled in Indian studies.

4.1 Survival outcomes

4.1.1 Evolution of treatment modalities

Left untreated, PCNSL has a uniformly dismal prognosis (median OS = 2 months) [46]. Only marginally better are conventional DLBCL regimes with response rates ranging from 19 to 59% and less than half patients surviving at two years from diagnosis [2, 3]. A significant improvement in prognosis comes from modern multi-drug regimens incorporating high-dose methotrexate (HD-MTX) with appropriate consolidation (2 years OS of 80% and a five-year OS of 77%) [47]. More recent regimes utilizing autologous stem cell transplantation as consolidation report two-year OS as high as 81% [48].

4.1.2 Outcomes reported in India

Indian studies report modest outcomes. Up to 20% of PCNSL patients never receive therapy [20, 22, 29]. A single-institution reported a median EFS of 20.4 months and a median OS of 31.7 months at a median follow–up of 34 months with HD-MTX-based multiagent regimes and Rituximab and consolidative WBRT. [20] A prospective phase 2 trial evaluating response adapted radiotherapy showed a median OS of 19 months, underlining the necessity of consolidative WBRT to optimize outcomes [44]. A study evaluating the importance of HD-MTX therapy in the Indian setting [28] reported a median OS of 8 months, 13 months, and 23 months in WBRT, R-CHOP with WBRT, and HD-MTX with WBRT, respectively. Thus, there is a scope for improvement in the outcomes of PCNSL seen in the Indian sub-continent.

4.2 Long term toxicity

Studies using HD-MTX-based induction and WBRT consolidation report 15% long-term neurotoxicity rates [49]. However, no such delayed sequelae are documented in prospective studies using abbreviated WBRT [50, 51]. On the other hand, regimes using ASCT as consolidation report continuous cognitive improvement until 12–18 months after completion of therapy [48].

In the Indian setting, reliable estimates of long-term neurological toxicity are lacking given that most of the reported literature does not have adequate follow-up or assessment [22, 25, 26, 27, 30, 31]. However, limited studies report severe long-term neurotoxicity rates of 10–33%, with elderly patients and WBRT recipients at a higher risk [20, 28, 29].

Advertisement

5. How can we improve?

PCNSL requires multi-disciplinary care in resource-intense settings to optimize outcomes. However, in lower-middle-income countries (LMIC), the main barriers to applying modern evidence-based management of PCNSL are the lack of neurosurgical facilities and oncology units capable of handling HD-MTX.

5.1 Improving diagnosis

5.1.1 Better radiological support

Radiological differential diagnosis of PCNSL includes high-grade gliomas, tumefactive demyelinating lesions, metastasis, and granulomatous diseases/infections. Although, the radiological appearance of PCNSL is very distinctive with homogenous contrast enhancement, optic pathway, and cranial nerve infiltration, a predilection for deeper structures, lesser necrosis, and nearly no bleeding, many studies still report diagnostic difficulties while using conventional MRI only [52]. This differentiation is crucial because while PCNSL requires stereotactic biopsy followed by systemic chemotherapy, high-grade gliomas are usually treated with upfront gross total resection. With 40% of patients responding, prior steroid usage compounds this problem with high false-negative biopsy rates [53]. Thus, early radiological suspicion may allow many patients to undergo appropriate management in the form of no inadvertent steroid therapy, stereotactic biopsy, and early institution of HD-MTX-based therapy.

5.1.2 Conventional MRI sequences

Diffusion-weighted imaging is an essential diagnostic tool. PCNSL shows more restricted ADC than high-grade gliomas, given its higher cellular density and N: C ratio. However, solid portions of high-grade gliomas may mimic [52]. Therefore, a different measure,“ Relative minimum ADC,” is often used given its reasonable diagnostic certainty [54]. Furthermore, dynamic contrast-enhanced MRI adds to ADC’s diagnostic performance as well [55].

Another crucial diagnostic aid is the 1H-magnetic resonance spectroscopy (1H-MRS). Choline to creatine ratio, a marker of membrane turnover, is identical for PCNSL and high-grade gliomas. However, N-acetyl aspartate peaks (NAA), a marker of neuronal damage, may have variable results. The lipid peak arises from necrosis in GBM and release of fatty moieties via lymphocytes in PCNSL, making lipid resonance without necrosis the most specific finding [56].

1H-MRS may allow assessment of other peaks as well. Conventional 1.5 T MRI cannot differentially assess glutamate (Glu) and glutamine (Gln) peaks, and there is no difference in Glutamate + Glutamine/ Creatinine peaks among PCNSL and high-grade gliomas. However, because of impaired Glutamate internalization in high-grade gliomas, glutamate to glutamine conversion is upscaled. Thus, 3 Tesla MRI machines which can differentially quantify glutamate and glutamine, allow assessment of Glu/Glu + Gln ratios which are reproducibly different in PCNSL and high-grade gliomas [57].

5.1.3 Newer MRI based modalities

Amide proton transfer weighted studies (based on 3 T MRI machines) also detect endogenous mobile proteins and peptides predominantly seen in the cytoplasm. PCNSL, with its high N:C ratio and thus, a low concentration of mobile proteins, shows much shows limited hyperintensities as compared to heterogenous hyperintensities much larger than the gadolinium-enhancing areas in high grade gliomas [55].

Dynamic susceptibility contrast-enhanced MRI can differentiate based on different tumor microenvironments. PCNSL lacks florid neovascularization compared to high-grade gliomas, as assessed by FVIII staining on resected specimens [58]. Contrast enhancement stems from breakage of the blood-brain barrier rather than increased vascularity resulting in a relatively lower rCBV than high-grade gliomas [59]. Neovascularization of surrounding infiltrated tissue can result in a specific shoulder-like pattern of signal intensity and enhance diagnostic performance [60]. Prospectively validated studies report an rCBV threshold of 2.56 having >90% sensitivity and specificity [54].

5.1.4 Machine learning: better analysis of conventional MRI meta-data

Fundamental differences of neovascularization and necrosis between PCNSL and high-grade gliomas may lead to subtle differences in imaging, which, although may not be evident to the human eye, are picked by metadata-based machine learning (ML) models. A recent meta-analysis assessing the utility of ML models for PCNSL diagnosis reports 0.878 as the lowest AUC across eight studies [61]. Another prospectively validated model reported an AUC of 0.978 using only T1 weighted images [62]. ML-based algorithms have advantages of being open access, easily accessible, and minimal reliance on novel machines or software. However, overfitting of models compromising external validity and prompting institute-specific algorithms is a challenge.

5.1.5 Metabolic imaging

Given its high cellular density, PCNSL shows intense homogenous FDG uptake (as opposed to heterogeneous uptake in high-grade gliomas) with SUVmax values around 12–14 (2.5 times of normal gray matter). However, surrounding physiological gray matter uptake hinders accurate assessment [63]. A study assessing the diagnostic utility of PET/CT for PCNSL reported an optimal SUVmax cut-off of 15 with only a single false positive [64]. Another study reported that a SUVmax cut-off of 12 had 86% accuracy as a standalone modality and 95% when combined with CE-MRI with DWI [65].

The tumor/normal (T/N) ratio overcomes the reliance of SUVmax on plasma glucose concentrations. A study reported good diagnostic performance with a cut-off 2.0. Prior Steroids may hinder both SUVmax, as well as T/N ratio [66]. PET/CT has additional utility in ruling out secondary CNS lymphoma and a 7% additional yield over CT and bone marrow examination [67].

5.2 Cerebrospinal fluid analysis

CSF analysis may allow diagnosis without neurosurgical procedures and its associated complications in up to 40% of patients. Therefore, patients without evidence of raised ICP should undergo CSF analysis with cytomorphology, flow-cytometry, and PCR for IGHV rearrangements either before or at least 1 week after the stereotactic biopsy [42].

A recent systematic review of 27 studies evaluating CSF cytomorphology and flow cytometry across different lymphoid neoplasms with meningeal involvement reported around 0.3-42.9% positive results with dual testing. Furthermore, 48% and 89% of studies reported samples positive on cytomorphology or flow cytometry alone, respectively, highlighting the importance of co-testing [68]. Another study assessing only PCNSL patients reported 13.3% and 23.3% positivity rates with CSF cytomorphology and flow cytometry, respectively [69].

CSF cell fragility impairs the diagnostic performance of cytomorphology and flow cytometry. However, PCR-based analysis of IGHV rearrangements to assess clonality does not require intact cells and may circumvent this problem. A study assessing IGHV rearrangement status in CSF among patients with PCNSL reported a sensitivity of 54% and specificity of 97% among the 84% patients having CSF with extractable DNA. The positive predictive value was 93%, with a further rise if only therapy naïve patients were considered [70]. However, a study prospectively evaluating CSF of 282 patients with PCNSL reported 10% samples with positive IGHV rearrangement PCR but negative cytomorphology and 12% samples with positive cytomorphology but negative IGHV rearrangement analysis [71]. Thus, IGHV rearrangement analysis may be better suited as an add-on than a replacement.

Novel approaches such as digital droplet PCR (ddPCR) analysis of MYD88 mutations [72], IL-10 levels [73], Osteopontin levels [74], neopterin levels [75], and miR-21 levels [76] may allow further diagnostic aid and potential negation of neurosurgical procedures in the future. Specifically, a meta-analysis reported that CSF IL-10 levels have a sensitivity of 81%, specificity of 97%, and an area under ROC of 0.95 at a cut-off of 6.88 pg/ml [77].

5.2.1 Slit lamp and intra-ocular biopsy

Like CSF analysis, Ocular involvement may also allow early diagnosis without reliance on neurosurgical procedures. Ocular involvement is seen in 15–25% of PCNSL patients, and slit-lamp examination is the diagnostic procedure of choice [78]. If involvement is suspected, a biopsy of vitreous fluid, choroid, or retina may allow histopathological diagnosis. Routine use of slit-lamp microscopy and a high index of suspicion is warranted given that more than 1/3rd of patients with ocular involvement are asymptomatic [79]. In cases with equivocal appearances, ocular ultrasound, fundus fluorescein angiography, and optical coherence tomography are adjunctive studies used for diagnosis [80].

Combined cytopathology, flow cytometry, and analysis of IGHV gene arrangement studies on multiple vitrectomy specimens have a combined sensitivity and specificity of 64% and 100%, respectively [81]. A chorioretinal biopsy is an option in suspicious cases with a normal vitreous biopsy [82].

Novel techniques may enhance diagnostic yields. For example, ARMS PCR-based MYD88 L265P mutation analysis is diagnostic in 86.7% FFPE samples of primary vitreoretinal lymphoma [83]. Techniques independent of DNA input such as ddPCR allow similar rates of MYD88 mutation detection from less invasive specimens like aqueous humor [72]. Lastly, elevated IL-10 levels or an IL-10/IL-6 ratio > 1 is suggestive but not diagnostic, and its utility as a standalone modality requires validation [78].

5.3 Improving therapy

5.3.1 Non-methotrexate containing induction regimes

High-dose methotrexate-based multiagent chemotherapy followed by consolidation with WBRT or autologous stem cell transplantation is the modern standard of care for PCNSL [42]. However, centers with facilities and experience for HD-MTX are lacking, necessitating the evaluation of alternative regime backbones.

Methotrexate doses of more than 3 g/m2 are needed to cross the BBB and doses as high as 8 g/m2 have been used without any guiding prospective randomized data. A recent observational study has reported higher CR rates and PFS with higher dose HD-MTX (8 g/m2) [84]. An infusion time of 3 hours and 6 hours for doses of 3 g/m2 and 8 g/m2 respectively allows better CNS penetration per unit dose, allowing enhanced efficacy and an attenuated toxicity profile [85]. 5–7 cycles of HD-MTX-based polychemotherapy spaced at 2 weeks intervals rather than 3-week intervals are associated with optimal oncological outcomes [86]. Leucovorin rescue is typically started 24 h after infusion and at least 12 doses are given at 6-hour intervals [51]. The utility of therapeutic drug monitoring remains to be proven in these settings with a recommendation for assessment at 24 h, 48 h, and 72 h after initial infusion [87].

Thiotepa, a lipid-soluble organophosphorus-derived alkylator, is a potential answer. Evidence suggests that Methotrexate is optimally given in doses more than 3.5 g/m2 over shorter infusion times (3 h) at a gap of 2–3 weeks for 5–8 cycles [42]. High dose cytarabine (Ara-C) addition to HD-MTX therapy led to more than doubling of responses, likely from prolonged exposure to S-phase cytostatics [88]. Subsequently, the IESLG32 study evaluated Rituximab addition and autologous SCT’s utility in PCNSL and added Thiotepa to a third induction arm (MATRIx regime), which outperformed both combination chemotherapy and chemoimmunotherapy arms [9]. Thus, with a 100% plasma-to-cerebrospinal fluid ratio, 30-min infusion time, and synergy with anti-metabolites, Thiotepa might be a convenient alternative to HD-MTX, and the comparative efficacy of Thiotepa-high-dose Ara-C vs. HD-MTX is worth exploring. Notably, a study using high dose Ara-C with Thiotepa after initial HD-MTX showed an increase in responses [89].

Single-agent temozolomide [90], topotecan [91], and temsirolimus [92] have also shown modest activity in relapsed PCNSL settings, and different combinations may be worth evaluating.

Frequent mutations in the BCR subunit CD79B and Toll-like receptor adaptor protein MYD88 suggest addiction of PCNSL to BCR signaling [93], making Ibrutinib an attractive option. However, since Ibrutinib-driven responses in ABC DLBCL last for less than a year [94], cotherapy with blood-brain barrier crossing synergistic drugs is prudent. Recent studies have built on this, and Ibrutinib-based combination regimes are a promising HD-MTX-free approach. While Ibrutinib is antagonistic with most anti-folate drugs, it is synergistic with etoposide, doxorubicin, Ara-C, and mitomycin C [95]. Additionally, doxorubicin, a broad spectrum lymphocytic but BBB impermeable agent, may be given as a liposomal formulation that maintains CSF concentrations throughout therapy duration, likely from a reservoir-like effect [96]. On these lines, the dose-adjusted TEDDi-R regime given after a 14-day run-in of ibrutinib monotherapy showed 86% complete responses in a phase 1b study with 18 patients [97]. Notably, the activity of this regime did not become dependent on the presence of the specific MYD88 L265P mutation. However, severe adverse effects in the form of grade 4 neutropenia, grade 4 thrombocytopenia, and invasive fungal infections (most commonly aspergillosis) were noted in 53%, 30%, and 50%, respectively. These rates of invasive fungal infections are not found in other studies evaluating Ibrutinib (with or without steroids), and monocyte BTK inhibition may be causative [98]. Recognizing the need for prophylaxis, a recent phase 1b trial reported 75% CR rates and no invasive fungal infections with DA-TEDDi R with Isavuconazole prophylaxis [95]. In the Indian settings, concomitant dose reduction of both ibrutinib and liposomal doxorubicin [99] makes Voriconazole prophylaxis an attractive option offering maintained efficacy and reduced financial toxicity.

Lenalidomide may offer a potentially less intensive ibrutinib-based option. Given its capability to expand NK-cell pools, Lenalidomide is known to be synergistic with Rituximab (R2-regimen) [100]. A proof-of-concept phase 2 study documented ORR and CR rates of 32% and 29%, respectively, in relapsed/refractory PCNSL with a tolerable safety profile [101]. Building on data from systemic DLBCL, ibrutinib and R2 (IR2) leads to complete responses in 1/3rd relapsed/ refractory PCNSL cases, and studies testing this regime in frontline settings are eagerly awaited [10].

Intrathecal delivery may enhance synergy between rituximab and lenalidomide. At conventional doses (375 mg/m2), CSF compartment achieves only 0.1% of systemic rituximab concentrations [102]. Evidence suggesting that incorporation of systemic rituximab in lymphoma protocols does not impact the incidence of CNS relapse also points to potential inadequacy of intravenous rituximab in clearing the leptomeningeal compartment [103]. Given the acceptable safety profile of intrathecal rituximab in non-human primates [104], intrathecal rituximab-based combinations deserve consideration for further research. On these lines, a phase 1 study reported 25 mg as the optimal intraventricular dose (via ommaya reservoir) leading to an ORR of 60% and a CR rate of 40% with one parenchymal remission as well [105]. A subsequent study reported a CR rate of 43% in relapsed PCNSL when treated with a combination of intraventricular rituximab and methotrexate [106]. Thus, while intraventricular rituximab is an option with promising efficacy and cost benefits, larger studies are needed. Additionally, the utility of intrathecal rather than intraventricular therapy also requires consideration.

5.3.2 Optimizing consolidation therapy

More than 50% of PCNSL patients relapse within 5 years of therapy if treated with induction alone, necessitating some form of consolidation therapy [107]. The two largest comparative trials indicate comparable efficacy but lesser long-term neurotoxicity with HDT-ASCT than WBRT [108, 109]. While a longer follow-up may tell a different story [50], upfront HDT-ASCT for all PCNSL patients is not feasible for resource-limited settings.

In Indian settings, WBRT followed by HiDAC [107] remains the most common consolidation therapy. However, while western studies report comparable efficacy and lesser neurotoxicity by reduced dose WBRT [51, 110], studies in the Indian settings in our experience are less favourable [44].

Non-myeloablative chemotherapy may offer a balance of efficacy and cognition. For example, Etoposide-Cytarabine (EA regimen) showed efficacy comparable to historic WBRT treated cohorts in a single-arm phase 2 study. However, lack of randomized comparisons and high rates of grade ¾ hematological toxicity with the possible requirement of autologous stem-cell rescue are barriers to frequent utilization [111].

Maintenance with oral procarbazine, assessed in a phase 2 trial of elderly PCNSL patients, is a safe alternative, although randomized evidence is lacking [112]. Another study showed lesser relapse rates (non-randomized) with oral Temozolomide maintenance than WBRT, although atypical induction protocols used in this study negatively impact the external validity of findings [113]. Lenalidomide maintenance is also a safe option in elderly patients, although the efficacy in this setting is yet to be proven [114].

Advertisement

6. Conclusion

PCNSL, although morphologically like any other DLBCL, has distinct pathobiology and prognosis. The requirement of early radiological diagnosis and referral to a center equipped with neurosurgical facilities and safe administration of HD-MTX for every patient makes management of PCNSL challenging in resource-limited settings. Non-invasive methods of diagnosis and non-HD-MTX-based therapies need more research to allow PCNSL cases to be managed optimally in such settings.

References

  1. 1. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-2390
  2. 2. Schultz C, Scott C, Sherman W, Donahue B, Fields J, Murray K, et al. Preirradiation chemotherapy with cyclophosphamide, doxorubicin, vincristine, and dexamethasone for primary CNS lymphomas: Initial report of radiation therapy oncology group protocol 88-06. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 1996;14(2):556-564
  3. 3. O’Neill BP, O’Fallon JR, Earle JD, Colgan JP, Brown LD, Krigel RL. Primary central nervous system non-Hodgkin’s lymphoma: Survival advantages with combined initial therapy? International Journal of Radiation Oncology, Biology, Physics. 1995;33(3):663-673
  4. 4. Tun HW, Personett D, Baskerville KA, Menke DM, Jaeckle KA, Kreinest P, et al. Pathway analysis of primary central nervous system lymphoma. Blood. 2008;111(6):3200-3210
  5. 5. Courts C, Montesinos-Rongen M, Martin-Subero JI, Brunn A, Siemer D, Zühlke-Jenisch R, et al. Transcriptional profiling of the nuclear factor-κB pathway identifies a subgroup of primary lymphoma of the central nervous system with low BCL10 expression. Journal of Neuropathology and Experimental Neurology. 2007;66(3):230-237
  6. 6. Miller DC, Hochberg FH, Harris NL, Gruber ML, Louis DN, Cohen H. Pathology with clinical correlations of primary central nervous system non-Hodgkin’s lymphoma. The Massachusetts General Hospital experience 1958-1989. Cancer. 1994;74(4):1383-1397
  7. 7. Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, et al. Primary intracerebral malignant lymphoma: Report of 248 cases. Journal of Neurosurgery. 2000;92(2):261-266
  8. 8. Green MR, Chowdhary S, Lombardi KM, Chalmers LM, Chamberlain M. Clinical utility and pharmacology of high-dose methotrexate in the treatment of primary CNS lymphoma. Expert Review of Neurotherapeutics. 2006;6(5):635-652
  9. 9. Ferreri AJM, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, et al. Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: Results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematology. 2016;3(5):e217-e227
  10. 10. Houillier C, Moluçon-Chabrot C, Moles M-P, Willems L, Ahle G, Waultier A, et al. Combination of Rituximab-Lenalidomide-Ibrutinib in relapsed/refractory primary Cns lymphoma: A Cohort study of the Loc network. Hematology & Oncology. 2021;39(S2):1. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/hon.73_2880
  11. 11. Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. British Journal of Cancer. 2011;105(9):1414-1418
  12. 12. Shiels MS, Pfeiffer RM, Besson C, Clarke CA, Morton LM, Nogueira L, et al. Trends in primary central nervous system lymphoma incidence and survival in the U.S. British Journal of Haematology. 2016;174(3):417-424
  13. 13. Sarkar C, Sharma MC, Deb P, Singh R, Santosh V, Shankar SK. Primary central nervous system lymphoma—A hospital based study of incidence and clinicopathological features from India (1980-2003). Journal of Neuro-Oncology. 2005;71(2):199-204
  14. 14. Powari M, Radotra B, Das A, Banerjee AK. A study of primary central nervous system lymphoma in northern India. Surgical Neurology. 2002;57(2):113-116
  15. 15. Hoffman S, Propp JM, McCarthy BJ. Temporal trends in incidence of primary brain tumors in the United States, 1985-1999. Neuro-Oncology. 2006;8(1):27-37
  16. 16. Arora N, Manipadam MT, Nair S. Frequency and distribution of lymphoma types in a tertiary care hospital in South India: Analysis of 5115 cases using the World Health Organization 2008 classification and comparison with world literature. Leukemia & Lymphoma. 2012:1008 (Table IV). Available from: https://www.meta.org/papers/frequency-and-distribution-of-lymphoma-types-in-a/22971239
  17. 17. Braaten KM, Betensky RA, de Leval L, Okada Y, Hochberg FH, Louis DN, et al. BCL-6 expression predicts improved survival in patients with primary central nervous system lymphoma. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2003;9(3):1063-1069
  18. 18. Herrlinger U, Schabet M, Clemens M, Kortmann RD, Petersen D, Will BE, et al. Clinical presentation and therapeutic outcome in 26 patients with primary CNS lymphoma. Acta Neurologica Scandinavica. 1998;97(4):257-264
  19. 19. Fine HA, Mayer RJ. Primary central nervous system lymphoma. Annals of Internal Medicine. 1993;119(11):1093-1104
  20. 20. Patekar M, Adhikari N, Biswas A, Raina V, Kumar L, Mohanti BK, et al. Primary CNS lymphoma in India: A 17-year experience from the all India institute of medical sciences. Journal of Global Oncology. 2019;5:JGO.18.00124
  21. 21. Mahadevan A, Rao CR, Shanmugham M, Shankar SK. Primary central nervous system diffuse large B-cell lymphoma in the immunocompetent: Immunophenotypic subtypes and Epstein-Barr virus association. Journal of Neurosciences in Rural Practice. 2015;6(1):8-14
  22. 22. Puligundla CK, Bala S, Karnam AK, Gundeti S, Paul TR, Uppin MS, et al. Clinicopathological features and outcomes in primary central nervous system lymphoma: A 10-year experience. Indian Journal of Medical and Paediatric Oncology: Official Journal of Indian Society of Medical & Paediatric Oncology. 2017;38(4):478-482
  23. 23. Paul TR, Challa S, Tandon A, Panigrahi MK, Purohit AK. Primary central nervous system lymphomas: Indian experience, and review of literature. Indian Journal of Cancer. 2008;45(3):112
  24. 24. Patel B, Chacko G, Nair S, Anandan J, Chacko AG, Rajshekhar V, et al. Clinicopathological correlates of primary central nervous system lymphoma: Experience from a tertiary care center in South India. Neurology India [Internet]. Available from: https://www.neurologyindia.com/article.asp?issn=0028-3886;year=2015;volume=63;issue=1;spage=77;epage=82;aulast=Patel
  25. 25. Kumari N, Krishnani N, Rawat A, Agarwal V, Lal P. Primary central nervous system lymphoma: Prognostication as per international extranodal lymphoma study group score and reactive CD3 collar. Journal of Postgraduate Medicine. 2009;55(4):247
  26. 26. Sharma MC, Gupta RK, Kaushal S, Suri V, Sarkar C, Singh M, et al. A clinicopathological study of primary central nervous system lymphomas & their association with Epstein-Barr virus. The Indian Journal of Medical Research. 2016;143(5):605-615
  27. 27. Yadav. Primary Central Nervous System Lymphoma: An Experience of a Regional Cancer Center from India [Internet]. Available from: https://www.journalrcr.org/article.asp?issn=2588-9273;year=2019;volume=10;issue=2;spage=104;epage=107;aulast=Yadav
  28. 28. Rudresha. Evolution of the treatment of primary central nervous system lymphoma in a Regional Cancer Center of South India: Impact of high-dose methotrexate on treatment outcome [Internet]. Available from: https://www.cancerjournal.net/article.asp?issn=0973-1482;year=2020;volume=16;issue=1;spage=13;epage=17;aulast=Rudresha
  29. 29. Agarwal PA, Menon S, Smruti BK, Singhal BS. Primary central nervous system lymphoma: A profile of 26 cases from western India. Neurology India. 2009;57(6):756
  30. 30. Pasricha S, Gupta A, Gawande J, Trivedi P, Patel D. Primary central nervous system lymphoma: A study of clinicopathological features and trend in western India. Indian Journal of Cancer. 2011;48(2):199-203
  31. 31. Rudresha AH, Chaudhuri T, Lakshmaiah KC, Babu G, Lokesh KN, Rajeev LK. Primary central nervous system lymphoma in immunocompetent patients: A regional cancer center experience. South Asian Journal of Cancer. 2017;6(4):165-168
  32. 32. India—age distribution 2020 [Internet]. Statista. Available from: https://www.statista.com/statistics/271315/age-distribution-in-india/
  33. 33. Buell JF, Gross TG, Hanaway MJ, Trofe J, Roy-Chaudhury P, First MR, et al. Posttransplant lymphoproliferative disorder: Significance of central nervous system involvement. Transplantation Proceedings. 2005;37(2):954-955
  34. 34. Evens AM, Choquet S, Kroll-Desrosiers AR, Jagadeesh D, Smith SM, Morschhauser F, et al. Primary CNS posttransplant lymphoproliferative disease (PTLD): An international report of 84 cases in the modern era. American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013;13(6):1512-1522
  35. 35. Franca RA, Travaglino A, Varricchio S, Russo D, Picardi M, Pane F, et al. HIV prevalence in primary central nervous system lymphoma: A systematic review and meta-analysis. Pathology—Research and Practice. 2020;216(11):153192
  36. 36. Sharma S, Dwivedi N, Kumar N, Bharti A, Meena L. Neurological manifestation of HIV infection in North-Eastern part of India. National Journal of Physiology Pharmacy and Pharmacology. 2014;4(1):4
  37. 37. Lanjewar DN, Jain PP, Shetty CR. Profile of central nervous system pathology in patients with AIDS: An autopsy study from India. AIDS (London England). 1998;12(3):309-313
  38. 38. Silva ACAL, Rodrigues BSC, Micheletti AMR, Tostes S, Meneses ACO, Silva-Vergara ML, et al. Neuropathology of AIDS: An autopsy review of 284 cases from Brazil comparing the findings pre- and post-HAART (Highly Active Antiretroviral Therapy) and Pre- and Postmortem Correlation. AIDS Research and Treatment. 2012;2012:186850
  39. 39. Lang W, Miklossy J, Deruaz JP, Pizzolato GP, Probst A, Schaffner T, et al. Neuropathology of the acquired immune deficiency syndrome (AIDS): A report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathologica. 1989;77(4):379-390
  40. 40. Jha P, Kumar R, Khera A, Bhattacharya M, Arora P, Gajalakshmi V, et al. HIV mortality and infection in India: Estimates from nationally representative mortality survey of 1.1 million homes. BMJ. 2010;340:c621
  41. 41. Haldorsen IS, Espeland A, Larsen JL, Mella O. Diagnostic delay in primary central nervous system lymphoma. Acta Oncologica. 2005;44(7):728-734
  42. 42. Fox CP, Phillips EH, Smith J, Linton K, Gallop-Evans E, Hemmaway C, et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. British Journal of Haematology. 2019;184(3):348-363
  43. 43. Abrey LE, Batchelor TT, Ferreri AJM, Gospodarowicz M, Pulczynski EJ, Zucca E, et al. Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. Journal of Clinical Oncology. 2005;23(22):5034-5043
  44. 44. Adhikari N, Biswas A, Gogia A, Sahoo RK, Garg A, Nehra A, et al. A prospective phase II trial of response adapted whole brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma-analysis of acute toxicity profile and early clinical outcome. Journal of Neuro-Oncology. 2018;139(1):153-166
  45. 45. Ferreri AJM, Blay J-Y, Reni M, Pasini F, Spina M, Ambrosetti A, et al. Prognostic scoring system for primary CNS lymphomas: The International Extranodal Lymphoma Study Group experience. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2003;21(2):266-272
  46. 46. Reni M, Ferreri AJ, Villa E. Second-line treatment for primary central nervous system lymphoma. British Journal of Cancer. 1999;79(3–4):530-534
  47. 47. Yu J, Du H, Ye X, Zhang L, Xiao H. High-dose methotrexate-based regimens and post-remission consolidation for treatment of newly diagnosed primary CNS lymphoma: Meta-analysis of clinical trials. Scientific Reports. 2021;11(1):2125
  48. 48. Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015;125(9):1403-1410
  49. 49. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation therapy oncology group study 93-10. Journal of Clinical Oncology. 2002;20(24):4643-4648
  50. 50. Correa DD, Rocco-Donovan M, DeAngelis LM, Dolgoff-Kaspar R, Iwamoto F, Yahalom J, et al. Prospective cognitive follow-up in primary CNS lymphoma patients treated with chemotherapy and reduced-dose radiotherapy. Journal of Neuro-Oncology. 2009;91(3):315-321
  51. 51. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2007;25(30):4730-4735
  52. 52. Malikova H, Koubska E, Weichet J, Klener J, Rulseh A, Liscak R, et al. Can morphological MRI differentiate between primary central nervous system lymphoma and glioblastoma? Cancer Imaging. 2016;16(1):40
  53. 53. Paydas S. Primary central nervous system lymphoma: Essential points in diagnosis and management. Medical oncology (Northwood London England). 2017;34(4):61
  54. 54. Wen J-B, Huang W-Y, Xu W-X-Z, Wu G, Geng D-Y, Yin B. Differentiating primary central nervous system lymphomas from glioblastomas and inflammatory demyelinating pseudotumor using relative minimum apparent diffusion coefficients. Journal of Computer Assisted Tomography. 2017;41(6):904-909
  55. 55. Zhao J, Yang Z, Luo B, Yang J, Chu J. Quantitative evaluation of diffusion and dynamic contrast-enhanced MR in tumor parenchyma and peritumoral area for distinction of brain tumors. PLoS One. 2015;10(9):e0138573
  56. 56. Harting I, Hartmann M, Jost G, Sommer C, Ahmadi R, Heiland S, et al. Differentiating primary central nervous system lymphoma from glioma in humans using localised proton magnetic resonance spectroscopy. Neuroscience Letters. 2003;342(3):163-166
  57. 57. Aburano H, Ueda F, Yoshie Y, Matsui O, Nakada M, Hayashi Y, et al. Differences between glioblastomas and primary central nervous system lymphomas in 1H-magnetic resonance spectroscopy. Japanese Journal of Radiology. 2015;33(7):392-403
  58. 58. Roser F, Saini M, Meliss R, Ostertag H, Samii M, Bellinzona M. Apoptosis, vascularity, and proliferation in primary central nervous system lymphomas (PCNSL): A histopathological study. Surgical Neurology. 2004;62(5):393-399; discussion 399
  59. 59. Lee IH, Kim ST, Kim H-J, Kim KH, Jeon P, Byun HS. Analysis of perfusion weighted image of CNS lymphoma. European Journal of Radiology. 2010;76(1):48-51
  60. 60. Blasel S, Jurcoane A, Bähr O, Weise L, Harter PN, Hattingen E. MR perfusion in and around the contrast-enhancement of primary CNS lymphomas. Journal of Neuro-Oncology. 2013;114(1):127-134
  61. 61. Nguyen AV, Blears EE, Ross E, Lall RR, Ortega-Barnett J. Machine learning applications for the differentiation of primary central nervous system lymphoma from glioblastoma on imaging: A systematic review and meta-analysis. Neurosurgical Focus. 2018;45(5):E5
  62. 62. Chen C, Zheng A, Ou X, Wang J, Ma X. Comparison of radiomics-based machine-learning classifiers in diagnosis of glioblastoma from primary central nervous system lymphoma. Frontiers in Oncology. 2020;10:1151
  63. 63. Kawai N, Miyake K, Yamamoto Y, Nishiyama Y, Tamiya T. 18F-FDG PET in the diagnosis and treatment of primary central nervous system lymphoma. BioMed Research International. 2013;2013:247152
  64. 64. Kosaka N, Tsuchida T, Uematsu H, Kimura H, Okazawa H, Itoh H. 18F-FDG PET of common enhancing malignant brain tumors. American Journal of Roentgenology. 2008;190(6):W365-W369
  65. 65. Makino K, Hirai T, Nakamura H, Murakami R, Kitajima M, Shigematsu Y, et al. Does adding FDG-PET to MRI improve the differentiation between primary cerebral lymphoma and glioblastoma? Observer performance study. Annals of Nuclear Medicine. 2011;25(6):432-438
  66. 66. Zhang Q, Gao X, Wei G, Qiu C, Qu H, Zhou X. Prognostic value of MTV, SUVmax and the T/N Ratio of PET/CT in patients with glioma: A systematic review and meta-analysis. Journal of Cancer. 2019;10(7):1707-1716
  67. 67. Mohile NA, DeAngelis LM, Abrey LE. The utility of body FDG PET in staging primary central nervous system lymphoma. Neuro-Oncology. 2008;10(2):223-228
  68. 68. Canovi S, Campioli D. Accuracy of flow cytometry and cytomorphology for the diagnosis of meningeal involvement in lymphoid neoplasms: A systematic review. Diagnostic Cytopathology. 2016;44(10):841-856
  69. 69. Schroers R, Baraniskin A, Heute C, Vorgerd M, Brunn A, Kuhnhenn J, et al. Diagnosis of leptomeningeal disease in diffuse large B-cell lymphomas of the central nervous system by flow cytometry and cytopathology. European Journal of Haematology. 2010;85(6):520-528
  70. 70. Ekstein D, Ben-Yehuda D, Slyusarevsky E, Lossos A, Linetsky E, Siegal T. CSF analysis of IgH gene rearrangement in CNS lymphoma: Relationship to the disease course. Journal of the Neurological Sciences. 2006;247(1):39-46
  71. 71. Fischer L, Martus P, Weller M, Klasen HA, Rohden B, Röth A, et al. Meningeal dissemination in primary CNS lymphoma: Prospective evaluation of 282 patients. Neurology. 2008;71(14):1102-1108
  72. 72. Hiemcke-Jiwa LS, Leguit RJ, Snijders TJ, Jiwa NM, Kuiper JJW, de Weger RA, et al. Molecular analysis in liquid biopsies for diagnostics of primary central nervous system lymphoma: Review of literature and future opportunities. Critical Reviews in Oncology/Hematology. 2018;127:56-65
  73. 73. Cerebrospinal Fluid IL-10 and IL-10/IL-6 as Accurate Diagnostic Biomarkers for Primary Central Nervous System Large B-cell Lymphoma | Scientific Reports [Internet]. 2021. Available from: https://www.nature.com/articles/srep38671
  74. 74. Strehlow F, Bauer S, Martus P, Weller M, Roth P, Schlegel U, et al. Osteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma. Journal of Neuro-Oncology. 2016;129(1):165-171
  75. 75. Viaccoz A, Ducray F, Tholance Y, Barcelos GK, Thomas-Maisonneuve L, Ghesquières H, et al. CSF neopterin level as a diagnostic marker in primary central nervous system lymphoma. Neuro-Oncology. 2015;17(11):1497-1503
  76. 76. Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, et al. Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system. Blood. 2011;117(11):3140-3146
  77. 77. Wang L, Luo L, Gao Z, Liu S-F, Liu C-J, Ma D-X, et al. The diagnostic and prognostic value of interleukin-10 in cerebrospinal fluid for central nervous system lymphoma: A meta-analysis. Leukemia & Lymphoma. 2017;58(10):2452-2459
  78. 78. Chan C-C, Wallace DJ. Intraocular lymphoma: Update on diagnosis and management. Cancer Control: Journal of the Moffitt Cancer Center. 2004;11(5):285-295
  79. 79. Grimm SA, McCannel CA, Omuro AMP, Ferreri AJM, Blay J-Y, Neuwelt EA, et al. Primary CNS lymphoma with intraocular involvement. Neurology. 2008;71(17):1355-1360
  80. 80. Ursea R, Heinemann MH, Silverman RH, DeAngelis LM, Daly SW, Coleman DJ. Ophthalmic, ultrasonographic findings in primary central nervous system lymphoma with ocular involvement. Retina (Philadelphia PA). 1997;17(2):118-123
  81. 81. Baehring JM, Androudi S, Longtine JJ, Betensky RA, Sklar J, Foster CS, et al. Analysis of clonal immunoglobulin heavy chain rearrangements in ocular lymphoma. Cancer. 2005;104(3):591-597
  82. 82. Mastropasqua R, Thaung C, Pavesio C, Lightman S, Westcott M, Okhravi N, et al. The role of chorioretinal biopsy in the diagnosis of intraocular lymphoma. American Journal of Ophthalmology. 2015;160(6):1127-1132.e1
  83. 83. Raja H, Salomão DR, Viswanatha DS, Pulido JS. Prevalence of MYD88 L265P mutation in histologically proven, diffuse large B-cell vitreoretinal lymphoma. Retina (Philadelphia PA). 2016;36(3):624-628
  84. 84. Li Q, Ma J, Ma Y, Lin Z, Kang H, Chen B. Improvement of outcomes of an escalated high-dose methotrexate-based regimen for patients with newly diagnosed primary central nervous system lymphoma: A real-world cohort study. Cancer Management and Research. 2021;13:6115-6122
  85. 85. Hiraga S, Arita N, Ohnishi T, Kohmura E, Yamamoto K, Oku Y, et al. Rapid infusion of high-dose methotrexate resulting in enhanced penetration into cerebrospinal fluid and intensified tumor response in primary central nervous system lymphomas. Journal of Neurosurgery. 1999;91(2):221-230
  86. 86. Aoki H, Ogura R, Tsukamoto Y, Okada M, Natsumeda M, Isogawa M, et al. Advantages of dose-dense methotrexate protocol for primary central nervous system lymphoma: Comparison of two different protocols at a single institution. Neurologia Medico-Chirurgica (Tokyo). 2013;53(11):797-804
  87. 87. Ramsey LB, Balis FM, O’Brien MM, Schmiegelow K, Pauley JL, Bleyer A, et al. Consensus guideline for use of glucarpidase in patients with high-dose methotrexate induced acute kidney injury and delayed methotrexate clearance. The Oncologist. 2018;23(1):52-61
  88. 88. Ferreri AJ, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: A randomised phase 2 trial. The Lancet. 2009;374(9700):1512-1520
  89. 89. Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, et al. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. Journal of Clinical Oncology. 2006;24(24):3865-3870
  90. 90. Reni M, Zaja F, Mason W, Perry J, Mazza E, Spina M, et al. Temozolomide as salvage treatment in primary brain lymphomas. British Journal of Cancer. 2007;96(6):864-867
  91. 91. Fischer L, Thiel E, Klasen H-A, Birkmann J, Jahnke K, Martus P, et al. Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Annals of Oncology. 2006;17(7):1141-1145
  92. 92. Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, et al. Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. Journal of Clinical Oncology. 2016;34(15):1757-1763
  93. 93. Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88-92
  94. 94. Wilson WH. Treatment strategies for aggressive lymphomas: What works? Hematology. 2013;2013(1):584-590
  95. 95. Roschewski M, Lionakis MS, Melani C, Butman JA, Pittaluga S, Lucas AN, et al. Dose-adjusted Teddi-R induces durable complete remissions in relapsed and refractory primary CNS lymphoma. Blood. 2018;132(Supplement 1):4195-4195
  96. 96. da Ros M, Iorio AL, Lucchesi M, Stival A, de Martino M, Sardi I. The use of anthracyclines for therapy of CNS tumors. Anti-Cancer Agents in Medicinal Chemistry. 2015;15(6):721-727
  97. 97. Lionakis MS, Dunleavy K, Roschewski M, Widemann BC, Butman JA, Schmitz R, et al. Inhibition of B cell receptor signaling by ibrutinib in primary CNS lymphoma. Cancer Cell. 2017;31(6):833-843.e5
  98. 98. Grommes C, Younes A. Ibrutinib in PCNSL: The curious cases of clinical responses and aspergillosis. Cancer Cell. 2017;31(6):731-733
  99. 99. de Jong J, Hellemans P, De Wilde S, Patricia D, Masterson T, Manikhas G, et al. A drug-drug interaction study of ibrutinib with moderate/strong CYP3A inhibitors in patients with B-cell malignancies. Leukemia & Lymphoma. 2018;59(12):2888-2895
  100. 100. Hernandez-Ilizaliturri FJ, Reddy N, Holkova B, Ottman E, Czuczman MS. Immunomodulatory drug CC-5013 or CC-4047 and rituximab enhance antitumor activity in a severe combined immunodeficient mouse lymphoma model. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research. 2005;11(16):5984-5992
  101. 101. Ghesquieres H, Chevrier M, Laadhari M, Chinot O, Choquet S, Moluçon-Chabrot C, et al. Lenalidomide in combination with intravenous rituximab (REVRI) in relapsed/refractory primary CNS lymphoma or primary intraocular lymphoma: A multicenter prospective ‘proof of concept’ phase II study of the French Oculo-Cerebral lymphoma (LOC) Network and the Lymphoma Study Association (LYSA)†. Annals of Oncology. 2019;30(4):621-628
  102. 102. Petereit H, Rubbert-Roth A. Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Multiple Sclerosis Journal. 2009;15(2):189-192
  103. 103. Feugier P, Virion JM, Tilly H, Haioun C, Marit G, Macro M, et al. Incidence and risk factors for central nervous system occurrencein elderly patients with diffuse large-B-cell lymphoma: Influence of rituximab. Annals of Oncology. 2004;15(1):129-133
  104. 104. Rubenstein JL, Combs D, Rosenberg J, Levy A, McDermott M, Damon L, et al. Rituximab therapy for CNS lymphomas: Targeting the leptomeningeal compartment. Blood. 2003;101(2):466-468
  105. 105. Rubenstein JL, Fridlyand J, Abrey L, Shen A, Karch J, Wang E, et al. Phase I study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. Journal of Clinical Oncology. 2007;25(11):1350-1356
  106. 106. Rubenstein JL, Li J, Chen L, Advani R, Drappatz J, Gerstner E, et al. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013;121(5):745-751
  107. 107. DeAngelis LM, Hormigo A. Treatment of primary central nervous system lymphoma. Seminars in Oncology. 2004;31(5):684-692
  108. 108. Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosée P, et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: Results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematology. 2017;4(11):e510-e523
  109. 109. Houillier C, Taillandier L, Dureau S, Lamy T, Laadhari M, Chinot O, et al. Radiotherapy or autologous stem-cell transplantation for primary CNS lymphoma in patients 60 years of age and younger: Results of the intergroup ANOCEF-GOELAMS randomized phase II PRECIS study. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2019;37(10):823-833
  110. 110. Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, et al. 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. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2013;31(31):3971-3979
  111. 111. Rubenstein JL, Hsi ED, Johnson JL, Jung S-H, Nakashima MO, Grant B, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS Lymphoma: CALGB 50202 (Alliance 50202). Journal of Clinical Oncology. 2013;31(25):3061-3068
  112. 112. Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Möhle R, et al. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017;31(4):846-852
  113. 113. Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, et al. Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: Results from a phase II study by The Nordic Lymphoma Group. Haematologica. 2015;100(4):534-540
  114. 114. Rubenstein JL, Hwang J, Mannis G. Preliminary analysis of lenalidomide maintenance after methotrexate-temozolomide-rituximab induction in older patients with PCNSL. Hematological Oncology. 2017;35(S2):343-344

Written By

Praful Pandey, Ahitagni Biswas, Saphalta Baghmar, Mukesh Patekar and Ranjit Kumar Sahoo

Submitted: 06 October 2021 Reviewed: 15 October 2021 Published: 04 February 2022