Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Sep 6.
Published in final edited form as: Best Pract Res Clin Haematol. 2018 Jul 21;31(3):262–269. doi: 10.1016/j.beha.2018.07.006

Improving outcomes in primary CNS lymphoma

Maya S Graham 1, Lisa M DeAngelis 1,*
PMCID: PMC10481403  NIHMSID: NIHMS1926638  PMID: 30213395

Abstract

Primary central nervous system lymphoma (PCNSL) is an aggressive disease with previously poor prognosis. The advent of high-dose methotrexate-based induction regimens as well as use of consolidation therapy has greatly improved this prognosis in recent decades, but durable remission still eludes half of patients. In this review, we summarize the progress made in the treatment of PCNSL as well as the challenges that remain, with a focus on defining optimal induction and consolidation regimens, including the promise of developing biotherapies. Future studies will help delineate the best combination of existing and novel treatment strategies, with the goal of expanding the cohort of patients achieving a cure.

Keywords: Primary central nervous system lymphoma, Induction chemotherapy, Consolidation chemotherapy, Targeted therapy, Elderly, Primary refractory disease

1. Introduction

Primary central nervous system lymphoma (PCNSL) is a rare aggressive non-Hodgkin lymphoma confined to the brain, spine, eyes and leptomeninges. It represents only 4% of intracranial neoplasms, and 4–6% of extranodal lymphomas [1]. Phenotypically, PCNSL is almost always a diffuse large B-cell lymphoma (DLBCL), and histological analysis has demonstrated an overwhelming majority fit an activated B cell or non-germinal center B cell subtype, which has been hypothesized to contribute to its relatively poor prognosis [2]. The incidence of PCNSL has increased in recent years, particularly in patients over the age of 60 years [3], and is now at an overall rate of 0.5 per 100,000 [4,5]. There have been improvements in treatment outcomes over the past several decades, reflecting advances in therapeutic strategies during this time, and the disease is now considered curable in some patients. However, survival is still inferior to extranodal lymphomas outside the CNS. This is in part due to persistently poor outcomes in certain subpopulations, such as the elderly [6] and patients with refractory disease [7], coupled with a relapse rate of up to 50%. In this review, we hope to highlight the challenges that remain in the treatment of PCNSL, with the goal of elucidating promising means of increasing the cure rate without debilitating neurotoxicity.

2. Increasing complete response: induction strategies

Historically, the initial treatment of PCNSL focused on whole brain radiotherapy (WBRT) alone, and while responses were common, durable responses were rare [8]. Induction chemotherapy regimens that have proven highly effective in systemic non-Hodgkin lymphoma, such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), failed to improve survival in PCNSL over radiation alone [9]. The introduction of high-dose intravenous methotrexate (optimally doses >3 g/m2 in 2 week intervals, but even doses of 1 g/m2 afford blood-brain barrier penetration) robustly increased response rates and median overall survival (OS) [10], but use of methotrexate alone was not sufficient [11]. Current consensus is that a multimodal regimen with high-dose methotrexate as the backbone is essential [12]. Considerable controversy remains, however, regarding the optimal chemotherapies to be used in combination with methotrexate, as well as whether different combinations are required for special patient populations, such as the elderly or those with primary refractory disease.

2.1. Optimum induction regimen

Most trials evaluating combination chemotherapy regimens in PCNSL have been single arm studies. In a rare randomized Phase II trial directly comparing methotrexate alone to methotrexate plus cytarabine, the addition of cytarabine increased the overall response rate (ORR) from 40% to 69%, an effect attributable entirely to a significant increase in complete response (CR) rate, from 18% to 46% [13]. However, there was a substantial increase in high grade hematologic toxicity as well (15% versus 96%), including three deaths. Furthermore, the methotrexate or methotrexate plus cytarabine were combined with WBRT and the OS was not better than WBRT alone, unlike any other Phase II trial combining methotrexate with WBRT [14]. Combining methotrexate with vincristine and procarbazine (MVP) demonstrated even more impressive response rates (CR 58%, ORR 94%) with diminished hematologic toxicity [14]. However, this regimen included intrathecal methotrexate as well as subsequent WBRT. The addition of rituximab, a monoclonal antibody targeting the B cell marker CD20, is also a seminal development in the treatment of PCNSL. A retrospective single institution study of high-dose methotrexate with or without rituximab revealed an impressive increase in both CR rate (36% versus 73%) and median progression-free survival (PFS, 4.5 months versus 26.7 months) [15]. This improved outcome is seen even though rituximab has low penetration in the CSF [16,17], possibly due to focal blood-brain barrier disruption or slow penetration into the brain parenchyma [18]. Multiple alternate chemotherapy regimens including rituximab have been investigated, including rituximab, methotrexate, vincristine and procarbazine (R-MVP) [19]; rituximab, methotrexate, cytarabine and thiotepa (MATRix) [20]; rituximab, methotrexate and temozolomide (MR-T) [21,22]; and rituximab, methotrexate, etoposide, carmustine and prednisone (R-MBVP) [23]. To date, only one prospective randomized comparison trial has been performed in the general population, demonstrating the superiority of MATRix over a 2 or 3 drug combination of the same agents [20]. None of these regimens is clearly superior, and thus the choice of induction regimen is largely determined by geographic tendencies and physician preferences at present (Table 1).

Table 1.

Upfront induction regimens for PCNSL.

Regimen Reference Consolidation ORR Median PFS Median OS
R-MVP Rituximab, methotrexate, vincristine, procarbazine Morris [18] rdWBRT + HDC-ASCR 95% 3.3 years 6.6 years
Omuro [45] HDC-ASCR 97% NR NR
Omuroa [26] Cytarabine 82% 9.5 months 31 months
MR-T Methotrexate, rituximab, temozolomide Rubenstein [20] Etoposide + cytarabine 77% 2.4 years NR
Glass [21] WBRT + mTMZ 85% 5.4 years 7.5 years
Omuroa [26] N/A 71% 6.1 months 14 months
MATRix Methotrexate, cytarabine (ara-C), thiotepa, rituximab Ferreri [19,41] WBRT or HDC-ASCR 87% 4.2 years NR
Open in a new tab

Abbreviations: HDC-ASCR=high dose chemotherapy with autologous stem cell rescue; mTMZ=maintenance temozolomide; N/A=not applicable; NR=not reached; rdWBRT=reduced dose whole brain radiotherapy; WBRT=whole brain radiotherapy.

a

Patients > 60 years old, no rituximab.

2.2. Special population: elderly

Elderly patients comprise half of those with PCNSL. They are also the population most likely to suffer consequences from standard treatments, such as renal insufficiency requiring methotrexate dose reduction [24]. Given concerns that elderly patients may be poor candidates for consolidative treatments such as myeloablative chemotherapy or WBRT, the choice of induction regimen in the elderly is of paramount importance. Unfortunately, many PCNSL trials exclude elderly patients, due to age or performance status restrictions. Several studies have investigated the feasibility and efficacy of different high-dose methotrexate-based regimens specifically in this population. Rituximab, methotrexate and procarbazine with lomustine yielded a median PFS of 10 months and an overall survival (OS) of 20 months [25]. Similarly, R-MVP followed by cytarabine produced a median PFS of 10 months and OS of 28 months [26]. Subgroup analysis in this study demonstrated an increase in CR rate in patients receiving rituximab. Neither of these studies included WBRT as consolidation. Only one study directly compared different methotrexate-based regimens in the elderly, R-MVP and methotrexate/temozolomide. While the outcomes did not show a statistically significant difference, there was a trend towards improved PFS (9.5 months versus 6.1 months) and OS (31 months versus 14 months) in the R-MVP group [27]. Overall, these studies suggest that induction chemotherapy with a regimen combining rituximab and high-dose methotrexate is recommended even in elderly patients, a proposal supported by meta-analysis data [28]. Even patients greater than 80 years of age can tolerate and benefit from high-dose methotrexate-based regimens [29]. In elderly patients whose comorbidities may preclude upfront treatment with methotrexate, monotherapy with other agents such as pemetrexed [30] and temozolomide [31] has been explored in small trials, suggesting these may be viable alternatives, though larger scale prospective studies are warranted.

2.3. Special population: primary refractory disease

Despite advances in the initial treatment of PCNSL, relapse is common. Furthermore, 10–15% of patients in every study have primary refractory disease, meaning they do not demonstrate a response to initial methotrexate therapy. This designation portends a particularly poor prognosis, with median survival of less than 2 months without additional treatment [7]. The optimal salvage regimen for these patients has not been established. While numerous small studies have been performed, they are often retrospective in nature and the results generally do not distinguish between primary refractory disease and relapsed disease. This heterogeneity renders application of findings to the population of primary refractory patients fraught with possible error. Only one study delineates efficacy in patients with primary refractory disease, showing that treating these patients with cytarabine and etoposide (CVYE) followed by high dose chemotherapy and autologous stem cell rescue (HDC-ASCR) yielded a PFS of 10.3 months, similar to the PFS in relapsed patients (12 months) [32]. Another prospective study using rituximab, cytarabine and thiotepa again followed by HDC-ASCR included 28% primary refractory patients and demonstrated a comparable PFS of 12.4 months, but did not analyze the refractory patients separately [33]. Furthermore, many primary refractory patients are not candidates for autologous stem cell transplantation. Multiple other salvage regimens that did not involve autologous stem cell rescue have been explored in the combined relapsed and refractory population, such as pemetrexed [34,35], bendamustine [36], temsirolimus [37], and rituximab with lenalidomide [38], but it is unclear whether these regimens were effective in refractory patients. Considerable work remains to define the biology of primary refractory patients and determine their optimal treatment.

3. From complete response to durable cure: consolidation strategies

3.1. Radiation therapy

For patients who do successfully achieve a complete response with upfront therapy, a consolidative treatment approach helps to achieve durable remission [39]. Most of the initial trials of high-dose methotrexate regimens used WBRT followed by high dose cytarabine as consolidation. However, subsequent longitudinal studies have revealed delayed neurotoxicity following the combination of high-dose methotrexate and WBRT at the standard dose of 45 Gy, particularly in elderly patients, likely due to synergistic toxicity of chemoradiation [40,41]. To maximize antineoplastic effect while minimizing neurotoxicity, a reduced dose of WBRT (23.4 Gy) with high dose cytarabine for patients who achieved a CR or near CR was explored. R-MVP followed by reduced dose WBRT resulted in an impressive ORR of 95%, as well as median PFS (3.3 years) and OS (6.6 years) that surpassed historical controls [19]. Outcomes were also favorable in the subpopulation of elderly patients. Importantly, neurocognitive and quality of life assessments were far superior to standard dose WBRT. These data suggest that the combination of rituximab and methotrexate-based induction chemotherapy followed by consolidative reduced dose WBRT is an attractive treatment option. A randomized phase II clinical trial has completed enrollment and will determine the independent benefit of low dose WBRT consolidation as well as whether there are cognitive consequences to this approach (NCT01399372).

3.2. High dose chemotherapy with autologous stem cell rescue (HDC-ASCR)

Available data, though flawed, suggest that replacing WBRT with chemotherapy-based approaches may yield equivalent outcomes [42]. Consolidation methods aiming to avoid radiotherapy consist of non-myeloablative chemotherapy such as high dose cytarabine and etoposide [21], high dose cytarabine alone or HDC-ASCR, which aims to eradicate microscopic residual disease in the CNS. Retrospective data established HDC-ASCR as a feasible and tolerable strategy [43], particularly when using thiotepa-based regimens that allow for blood-brain barrier penetration. Prospective studies have corroborated these findings [44] and demonstrated impressive outcomes, with median PFS of 74 months and median OS not yet reached [45,46]. However, these patients were heavily pre-selected to receive this aggressive approach, and results may not be generalized to all patients with PCNSL. Quality of life metrics and neurocognitive testing in this most recent study confirm that HDC-ASCR can be used for consolidation without accruing compromising neurologic toxicities, although cognitive impairment and leukoencephalopathy can occur with stem cell transplantation [47]. An ongoing phase III trial aims to directly compare HDC-ASCR to non-myeloablative cytarabine plus etoposide [48]. Overall, HDC-ASCR should be considered a leading method of consolidation in eligible patients, and is particularly effective in those who have achieved a CR and near CR to induction. It remains to be determined which patients are most suitable for HDC-ASCR, though retrospective data suggest that elderly patients may fair more favorably with this treatment than typically thought [49].

3.3. Maintenance treatment

Given the substantial hematologic toxicity and infectious risk of HDC-ASCR, not all patients will be candidates. In this more vulnerable population, less vigorous consolidation or maintenance treatment may be reasonable alternatives [50]. Initial studies exploring maintenance therapy in PCNSL used a continuation of methotrexate therapy at a longer interval, and demonstrated feasibility [51,52]. With the addition of rituximab to the induction phase followed by methotrexate maintenance, a median OS of 29 months in an unselected population was achieved [53]. Subsequent trials investigated continuation of other components of the induction regimen as maintenance. Six monthly cycles of maintenance procarbazine following a three-cycle R-MP induction in elderly PCNSL patients yielded a median PFS of 11.2 months and median OS of 22.6 months [25]. While these results are clearly inferior to those of more modern trials with WBRT or HDC-ASCR consolidation, these studies used only 3–6 cycles of high-dose methotrexate as induction therapy, which may be insufficient to achieve maximal efficacy of maintenance treatment. A small retrospective study in patients with relapsed PCNSL with continuation of rituximab as maintenance therapy revealed suitable tolerability of long term rituximab use and suggested rituximab maintenance as a plausible treatment approach in patients unable to undergo conventional consolidation [54].

Other trials have examined the prospect of ongoing treatment with an agent not included in the induction regimen. A phase II clinical trial evaluating temozolomide maintenance after chemotherapy and WBRT showed an estimated median OS of 7.5 years in a general PCNSL population [22]. Elderly patients receiving a de-escalated induction regimen followed by maintenance temozolomide had the same outcomes as younger patients receiving a more intensive version of the regimen, with a 2-year OS of 56–61% [55]. However, four of the older patients died from treatment-related complications. Lenalidomide monotherapy as maintenance has been explored in the relapsed population, with a small retrospective study showing some encouraging responses [56], and a phase II trial of lenalidomide maintenance following rituximab and lenalidomide induction is ongoing [38]. Overall, these findings suggest maintenance therapy is a promising alternative to traditional consolidation approaches, though this promise remains to be proven with large-scale prospective trials, and the optimal agent remains uncertain.

4. New agents: the potential of biotherapies

While the regimens described have allowed for striking improvements in the treatment of PCNSL, they largely consist of standard cytotoxic agents combined with the ability to overcome the blood-brain barrier. They do not exploit markers or pathways specific to PCNSL biology. In part, this is due to a relative lack of knowledge about the molecular alterations that typify this disease, which are beginning to be elucidated. These molecular developments have revealed potential new means of targeting PCNSL [57].

4.1. Immune-mediated therapies

The success of adding rituximab to methotrexate-based induction regimens has fueled interest in other immune-based treatment strategies. Immunomodulatory drugs such as lenalidomide have shown some potential in small trials as discussed [38,56]. A phase I trial of the related compound pomalidomide demonstrated an acceptable safety profile and suggested efficacy, with an ORR of 43% in relapsed/refractory patients [58]. As immune checkpoint inhibitors have revolutionized the treatment of other malignancies such as melanoma, they have also been investigated in PCNSL. Genetic studies have identified frequent copy number gains and translocations involving the programmed death-ligand 1 (PD-L1) and PD-L2 loci in PCNSL [59], highlighting the potential of this therapeutic approach. Indeed, an immunocompetent preclinical mouse model confirmed potent biological effect of PD-1 inhibition, with a CR rate of 50% [60]. In a small pilot trial of the PD-1 inhibitor nivolumab in refractory or relapsed PCNSL, all four patients demonstrated a clinical response sustained for over a year [61], though long term follow up was not within the scope of the study. These preliminary findings underscore the possible power of immune checkpoint inhibition in PCNSL, and several phase II studies of PD-1 inhibitors in recurrent disease are currently underway (NCT02857426, NCT02779101). Finally, CD19-targeted chimeric antigen receptor (CAR) T cell therapy has generated tremendous interest given its ability to induce durable remissions in systemic diffuse large B-cell lymphoma (DLBCL), even in patients with heavily pretreated disease [62], leading to landmark FDA approval. A recent provocative case report described sustained remission of secondary CNS lymphoma in a patient treated with anti-CD19 CAR T cells [63], intimating intracranial efficacy and laying the foundation for subsequent trials evaluating this novel treatment modality in PCNSL. It should be noted, however, that neurological toxicities are one of the most frequent adverse effects of CAR T cells in systemic lymphoma, and it remains to be seen whether these toxicities would be amplified beyond an acceptable level in patients with intracranial disease.

4.2. Targeted therapies

Beyond immune manipulation, targeting molecular pathways of defined relevance in PCNSL biology has also garnered interest (Fig. 1). Elegant genetic interrogation of PCNSL has revealed perturbations in the B cell receptor subunit CD79 and the Toll-like receptor adaptor protein MYD88 [59,64], common to the activated B-cell subtype of systemic DLBCL. Bruton tyrosine kinase (BTK) integrates B cell receptor and Toll-like receptor signaling, linking them to downstream nuclear factor kappa B (NFκB) signaling, thus rendering it an attractive candidate for targeted inhibition. Ibrutinib, a small molecule BTK inhibitor with promising CNS distribution and clinical activity in secondary intracranial lymphoma [65], has emerged as one of the most exciting new therapeutic agents for PCNSL. A small retrospective study in refractory PCNSL demonstrated the feasibility of ibrutinib treatment, with promising responses in several patients [66]. A phase Ib trial investigating ibrutinib monotherapy for two weeks followed by combination with conventional chemotherapies including dexamethasone demonstrated a PR rate of 83% prior to initiation of the combination regimen, with a subsequent CR rate of 86% [67], a statistic that is particularly impressive given that the majority of enrolled patients had relapsed or refractory disease. A similar response rate was seen in a phase I trial evaluating ibrutinib monotherapy in relapsed/refractory PCNSL, where therapeutic CSF levels were achieved with escalation of ibrutinib dose to 840 mg/day [68]. These seminal studies highlight the promise of targeted therapies, ibrutinib specifically, in the treatment of PCNSL, and phase II trials in relapsed/refractory patients are ongoing (NCT02315326) [69]. Importantly, a disproportionate fraction of patients in trials using combination regimens with ibrutinib developed invasive Aspergillus infections, some of which proved fatal. This troubling adverse effect suggests the possible need for Aspergillus prophylaxis in any ensuing studies. Transgenic murine models demonstrated markedly increased mortality of invasive aspergillosis in BTK knockout mice, indicating BTK may contribute to the innate immune control of aspergillosis [67].

Figure 1:

Figure 1:

Open in a new tab

Key signaling pathways in PCNSL and their putative therapeutic targets. Abbreviations: AKT = Protein kinase B, BCR = B cell receptor; BTK = Bruton tyrosine kinase; CAR = chimeric antigen receptor; MAPK = mitogen-activated protein kinase; mTOR = mechanistic target of rapamycin; MYD88 = myeloid differentiation protein response 88; NFKB = nuclear factor kappa B; PDL1 = programmed death ligand 1; PI3K = phosphoinositide-3-kinase; PKC = protein kinase C; TLR = Toll-like receptor.

The translational nature of these preliminary investigations also afforded dissection of synergy and resistance mechanisms. For instance, in vitro data scrutinizing the optimal chemotherapy agents to combine with ibrutinib indicated synergy with DNA damaging agents but antagonism of antifolates, including methotrexate [67], a finding with clear implications for the future use of this agent given the pivotal role of high-dose methotrexate in the upfront treatment of this disease. Unexpectedly, CD79-mutant tumors seemed more prone to ibrutinib resistance, and transcriptome analysis revealed phosphoinositide-3-kinase/mechanistic target of rapamycin (PI3K/mTOR) signaling as a key mediator of this resistance. Inhibition of PI3Kα/δ isoforms or mTOR in combination with ibrutinib resulted in synergistic cell death in CD79-mutant PCNSL cells at concentrations below their individual thresholds [68], suggesting combined inhibition as a promising means of overcoming ibrutinib resistance. This pathway has also been investigated as a potential target for monotherapy, with the mTOR inhibitor temsirolimus demonstrating reasonable outcomes in relapsed/refractory PCNSL, but with substantial accompanying toxicity [37]. Conversely, a phase II study of the pan-PI3K inhibitor buparlisib was terminated prematurely due to a lack of efficacy, thought to be due in part to an inability to achieve therapeutic CNS concentrations [70]. This failure poignantly illustrates the multifaceted challenge of successful targeted therapy execution, and underscores the need for thoughtfully designed clinical trials to determine the ideal implementation of such biotherapies in the treatment of PCNSL. Unanswered questions include the optimal combination of new agents with conventional approaches as well as the timing of their application during the course of the disease.

5. Summary

Significant progress has been made in the treatment of PCNSL over the past several decades. Current consensus is that a regimen incorporating high dose methotrexate and rituximab should be used for induction in nearly all patients, including the elderly. Consolidation is important, with HDC-ASCR effective for some patients but it is not an option for all, and it is possible that less toxic approaches may be equivalent. Consensus is lacking on what upfront treatment to use in patients with a true contraindication to methotrexate treatment, such as renal failure. The ideal approach to patients with primary refractory disease is also unclear. Resolving these issues with clinical trials will be challenging given the rarity of PCNSL and the resultant difficulty in accruing subjects in these subpopulations. The limited resource of PCNSL patients must be allocated thoughtfully as new clinical trials are designed to answer emerging questions, such as the optimal use of targeted therapies like ibrutinib, so that PCNSL outcomes can continue to improve.

Practice points.

  • Outcomes for PCNSL have improved in recent decades, but survival is still poor compared with systemic lymphomas.

  • Rituximab and high-dose methotrexate should form the basis of multimodal induction chemotherapy, even in elderly patients.

  • Consolidation with either WBRT, chemotherapy or intensive chemotherapy with autologous stem cell rescue can increase durable remission.

  • Targeted agents, including the BTK inhibitor ibrutinib, are under investigation, and may prove useful in combination with current treatments.

Research agenda.

  • The biology of primary refractory disease, and the appropriate approach to treatment of these patients, remains to be elucidated.

  • Additional studies are required to clarify the optimal application of targeted therapies.

  • Thoughtful clinical trial design is essential given the low incidence of PCNSL and consequent difficulty with accrual.

Footnotes

Conflicts of interest

There are no conflicts of interest to disclose.

References

  • [1].Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Canc 2011;105(9). 1414–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [2].Camilleri-Broet S, Criniere E, Broet P, Delwail V, Mokhtari K, Moreau A, et al. A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 2006;107(1). 190–6. [DOI] [PubMed] [Google Scholar]
  • [3].Mendez JS, Ostrom QT, Gittleman H, Kruchko C, DeAngelis LM, Barnholtz-Sloan JS, et al. The elderly left behind - changes in survival trends of primary central nervous system lymphoma over the past four decades. Neuro Oncol 2018;20(5):687–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Grommes C, DeAngelis LM. Primary CNS lymphoma. J Clin Oncol 2017;35(21). 2410–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].O’Neill BP, Decker PA, Tieu C, Cerhan JR. The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin’s lymphoma. Am J Hematol 2013;88(12):997–1000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [6].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. Br J Haematol 2016;174(3):417–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [7].Jahnke K, Thiel E, Martus P, Herrlinger U, Weller M, Fischer L, et al. Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neuro Oncol 2006;80(2):159–65. [DOI] [PubMed] [Google Scholar]
  • [8].Nelson DF, Martz KL, Bonner H, Nelson JS, Newall J, Kerman HD, et al. Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 1992;23(1):9–17. [DOI] [PubMed] [Google Scholar]
  • [9].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. J Clin Oncol 1996;14(2):556–64. [DOI] [PubMed] [Google Scholar]
  • [10].Batchelor T, Carson K, O’Neill A, Grossman SA, Alavi J, New P, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07. J Clin Oncol 2003;21(6):1044–9. [DOI] [PubMed] [Google Scholar]
  • [11].Herrlinger U, Kuker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, et al. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol 2005;57(6):843–7. [DOI] [PubMed] [Google Scholar]
  • [12].DeAngelis LM, Yahalom J, Thaler HT, Kher U. Combined modality therapy for primary CNS lymphoma. J Clin Oncol 1992;10(4):635–43. [DOI] [PubMed] [Google Scholar]
  • [13].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. Lancet 2009;374(9700):1512–20. [DOI] [PubMed] [Google Scholar]
  • [14].DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ. Radiation Therapy Oncology Group S. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: radiation Therapy Oncology Group Study 93–10. J Clin Oncol 2002;20(24):4643–8. [DOI] [PubMed] [Google Scholar]
  • [15].Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, et al. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology 2014;83(3):235–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Ruhstaller TW, Amsler U, Cerny T. Rituximab: active treatment of central nervous system involvement by non-Hodgkin’s lymphoma? Ann Oncol 2000;11(3):374–5. [DOI] [PubMed] [Google Scholar]
  • [17].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. J Clin Oncol 2007;25(30):4730–5. [DOI] [PubMed] [Google Scholar]
  • [18].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):466–8. [DOI] [PubMed] [Google Scholar]
  • [19].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. J Clin Oncol 2013;31(31):3971–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [20].Ferreri AJ, 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 Haematol 2016;3(5):e217–27. [DOI] [PubMed] [Google Scholar]
  • [21].Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013;31(25):3061–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, et al. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG oncology RTOG 0227. J Clin Oncol 2016;34(14):1620–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].De Wilde VD D, Schroyens W, Van Den Neste E, Bonnet C, Andre M, Janssens A, Van Hende V, Van Hoof A. BHS guidelines for primary central nervous system lymphoma. Belg J Hematol 2016;7(2):69–78. [Google Scholar]
  • [24].Roth P, Hoang-Xuan K. Challenges in the treatment of elderly patients with primary central nervous system lymphoma. Curr Opin Neurol 2014;27(6):697–701. [DOI] [PubMed] [Google Scholar]
  • [25].Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Mohle R, et al. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia 2017;31(4):846–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Houillier C, Ghesquieres H, Chabrot C, Soussain C, Ahle G, Choquet S, et al. Rituximab, methotrexate, procarbazine, vincristine and intensified cytarabine consolidation for primary central nervous system lymphoma (PCNSL) in the elderly: a LOC network study. J Neuro Oncol 2017;133(2):315–20. [DOI] [PubMed] [Google Scholar]
  • [27].Omuro A, Chinot O, Taillandier L, Ghesquieres H, Soussain C, Delwail V, et al. Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial. Lancet Haematol 2015;2(6):e251–9. [DOI] [PubMed] [Google Scholar]
  • [28].Kasenda B, Ferreri AJ, Marturano E, Forst D, Bromberg J, Ghesquieres H, et al. First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)–a systematic review and individual patient data meta-analysis. Ann Oncol 2015;26(7):1305–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Welch MR, Omuro A, Deangelis LM. Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro Oncol 2012;14(10):1304–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Han S, Wang M, Liu B, Yu J. Pemetrexed for primary central nervous system lymphoma in the elderly. Clin Transl Oncol 2016;18(2):138–43. [DOI] [PubMed] [Google Scholar]
  • [31].Kurzwelly D, Glas M, Roth P, Weimann E, Lohner H, Waha A, et al. Primary CNS lymphoma in the elderly: temozolomide therapy and MGMT status. J Neuro Oncol 2010;97(3):389–92. [DOI] [PubMed] [Google Scholar]
  • [32].Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, et al. 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;26(15):2512–8. [DOI] [PubMed] [Google Scholar]
  • [33].Kasenda B, Ihorst G, Schroers R, Korfel A, Schmidt-Wolf I, Egerer G, et al. High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group. Leukemia 2017;31(12):2623–9. [DOI] [PubMed] [Google Scholar]
  • [34].Raizer JJ, Rademaker A, Evens AM, Rice L, Schwartz M, Chandler JP, et al. Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma. Cancer 2012;118(15):3743–8. [DOI] [PubMed] [Google Scholar]
  • [35].Zhang JP, Lee EQ, Nayak L, Doherty L, Kesari S, Muzikansky A, et al. Retrospective study of pemetrexed as salvage therapy for central nervous system lymphoma. J Neuro Oncol 2013;115(1):71–7. [DOI] [PubMed] [Google Scholar]
  • [36].Chamberlain MC. Salvage therapy with bendamustine for methotrexate refractory recurrent primary CNS lymphoma: a retrospective case series. J Neuro Oncol 2014;118(1):155–62. [DOI] [PubMed] [Google Scholar]
  • [37].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. J Clin Oncol 2016;34(15):1757–63. [DOI] [PubMed] [Google Scholar]
  • [38].Ghesquieres HH C, Chinot O, Choquet S, Molucon-Chabrot C, Beauchene P, Gressin R, Morschhauser F, Schmitt A, Gyan E, Hoang-Xuan K, Nicolas-Virelizier E, Chevrier M, Savignoni A, Turbiez I, Veillas F, Soumelis V, Soussain C. Rituximab-lenalidomide (REVRI) in relapse or refractory primary central nervous system (PCNSL) or vitreo retinal lymphoma (PVRL): results of a “proof of concept” phase II study of the French LOC network. Blood 2016;128:785. [Google Scholar]
  • [39].Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, et al. Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 2006;24(36):5711–5. [DOI] [PubMed] [Google Scholar]
  • [40].Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 2006;24(28):4570–4. [DOI] [PubMed] [Google Scholar]
  • [41].Omuro AM, Ben-Porat LS, Panageas KS, Kim AK, Correa DD, Yahalom J, et al. Delayed neurotoxicity in primary central nervous system lymphoma. Arch Neurol 2005;62(10):1595–600. [DOI] [PubMed] [Google Scholar]
  • [42].Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, Schorb E, La Rosee 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 Haematol 2017;4(11):e510–23. [DOI] [PubMed] [Google Scholar]
  • [43].Cho H, Chang JH, Kim YR, Kim SJ, Chung H, Park H, et al. The role of upfront autologous stem cell transplantation in high-risk younger patients with primary central nervous system lymphoma. Br J Haematol 2016;174(3):444–53. [DOI] [PubMed] [Google Scholar]
  • [44].Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, et al. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant 2006;38(6):417–20. [DOI] [PubMed] [Google Scholar]
  • [45].Illerhaus G, Kasenda B, Ihorst G, Egerer G, Lamprecht M, Keller U, et al. High-dose chemotherapy with autologous haemopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: a prospective, single-arm, phase 2 trial. Lancet Haematol 2016;3(8):e388–97. [DOI] [PubMed] [Google Scholar]
  • [46].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):1403–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Correa D, Anderson ND, Glass A, Mason WP, DeAngelis LM, Abrey LE. Cognitive functions in primary central nervous system lymphoma patients treated with chemotherapy and stem cell transplantation: preliminary findings. Clin Adv Hematol Oncol 2003;1(8):490. [PubMed] [Google Scholar]
  • [48].Schorb E, Finke J, Ferreri AJ, Ihorst G, Mikesch K, Kasenda B, et al. High-dose chemotherapy and autologous stem cell transplant compared with conventional chemotherapy for consolidation in newly diagnosed primary CNS lymphoma–a randomized phase III trial (MATRix). BMC Canc 2016;16:282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Schorb E, Fox CP, Fritsch K, Isbell L, Neubauer A, Tzalavras A, et al. High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study. Bone Marrow Transplant 2017;52(8):1113–9. [DOI] [PubMed] [Google Scholar]
  • [50].Bairey O, Siegal T. The possible role of maintenance treatment for primary central nervous system lymphoma. Blood Rev 2018. [DOI] [PubMed] [Google Scholar]
  • [51].Cher L, Glass J, Harsh GR, Hochberg FH. Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results. Neurology 1996;46(6):1757–9. [DOI] [PubMed] [Google Scholar]
  • [52].Yang SH, Lee KS, Kim IS, Hong JT, Sung JH, Son BC, et al. Long-term survival in primary CNS lymphoma treated by high-dose methotrexate monochemotherapy: role of STAT6 activation as prognostic determinant. J Neuro Oncol 2009;92(1):65–71. [DOI] [PubMed] [Google Scholar]
  • [53].Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol 2010;12(7):736–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Ney DE, Abrey LE. Maintenance therapy for central nervous system lymphoma with rituximab. Leuk Lymphoma 2009;50(9):1548–51. [DOI] [PubMed] [Google Scholar]
  • [55].Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fossa 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):534–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [56].Houillier C, Choquet S, Touitou V, Martin-Duverneuil N, Navarro S, Mokhtari K, et al. Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology 2015;84(3):325–6. [DOI] [PubMed] [Google Scholar]
  • [57].Royer-Perron L, Hoang-Xuan K, Alentorn A. Primary central nervous system lymphoma: time for diagnostic biomarkers and biotherapies? Curr Opin Neurol 2017;30(6):669–76. [DOI] [PubMed] [Google Scholar]
  • [58].Tun HWJ PB, Grommes C, Reeder CB, Omuro AMP, Menke DM, Copland JA, DeAngelis LM, Witzig TE. Phase I clinical trial on pomalidomide and dexamethasone in treating patients with relapsed/refractory primary central nervous system lymphoma (PCNSL) or primary vitreoretinal lymphoma (PVRL). J Clin Oncol 2017;35(15_suppl):7516. [Google Scholar]
  • [59].Chapuy B, Roemer MG, Stewart C, Tan Y, Abo RP, Zhang L, et al. Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 2016;127(7):869–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [60].Qiu Y, Li Z, Pouzoulet F, Vishnu P, Copland JA 3rd, Knutson KL, et al. Immune checkpoint inhibition by anti-PDCD1 (anti-PD1) monoclonal antibody has significant therapeutic activity against central nervous system lymphoma in an immunocompetent preclinical model. Br J Haematol 2017. 10.1111/bjh.15009. [DOI] [PubMed] [Google Scholar]
  • [61].Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B, et al. PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 2017;129(23):3071–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [62].Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-Cell lymphoma. N Engl J Med 2017;377(26):2531–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Abramson JS, McGree B, Noyes S, Plummer S, Wong C, Chen YB, et al. Anti-CD19 CAR T cells in CNS diffuse large-B-cell lymphoma. N Engl J Med 2017;377(8):783–4. [DOI] [PubMed] [Google Scholar]
  • [64].Ngo VN, Young RM, Schmitz R, Jhavar S, Xiao W, Lim KH, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011;470(7332):115–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Bernard S, Goldwirt L, Amorim S, Brice P, Briere J, de Kerviler E, et al. Activity of ibrutinib in mantle cell lymphoma patients with central nervous system relapse. Blood 2015;126(14):1695–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [66].Chamoun K, Choquet S, Boyle E, Houillier C, Larrieu-Ciron D, Al Jijakli A, et al. Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: a retrospective case series. Neurology 2017;88(1):101–2. [DOI] [PubMed] [Google Scholar]
  • [67].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. Canc Cell 2017;31(6):833–843 e5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [68].Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, et al. Ibrutinib unmasks critical role of bruton tyrosine kinase in primary CNS lymphoma. Canc Discov 2017;7(9):1018–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [69].Choquet SHC, Bijou F, Houot R, Boyle E, Gressin R, Nicolas-Virelizier E, Barrie M, Molucon-Chabrot C, Blonski M, El Yamani A, LeLez M, Clavert A, Coisy S, Ertault de la Bretonnière M, Touitou V, Cassoux N, Boussetta S, Broussais F, Gelas-Dore B, Barzic N, Ghesquieres H, Hoang-Xuan K, Soussain C. Ibrutinib monotherapy in relapse or refractory primary CNS lymphoma (PCNSL) and primary vitreo-retinal lymphoma (PVRL). Result of the interim analysis of the iLOC phase II study from the lysa and the French LOC network. Blood 2016;128. [Google Scholar]
  • [70].Grommes CP E, Nolan C, Wolfe J, Mellinghoff IK, DeAngelis L. Phase II study of single agent buparlisib in recurrent/refractory primary (PCNSL) and secondary CNS lymphoma (SCNSL). Ann Oncol 2016;27(suppl_6). [Google Scholar]

RESOURCES