Professor Liu Jiajun talks about the treatment progress of primary central nervous system lymphoma (part 1)

Author: LIU Jia Jun, Third Affiliated Hospital of Sun Yat-sen Hematology article is the author's permission NMT Medical publish, please do not reprint without authorization
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Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin’s lymphoma that originates in the central nervous system.
And spinal cord) [1]
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The disease has a low incidence, accounting for only 4% of intracranial tumors and 4%-6% of all extranodal lymphomas.
The prognosis is poor and the recurrence rate is high.
Nearly half of patients relapse within 2 years [2,3]
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One of the main risk factors for the onset of PCNSL is immunodeficiency.
Since 2000, the incidence of PCNSL has been increasing at an annual rate of 1.
6%, especially in patients with normal immune function and the elderly (>60 years old) [ 4]
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Because of the blood-brain barrier, standard lymphoma chemotherapy has limited effects on PCNSL.
High-dose methotrexate (HD-MTX) with or without whole brain radiation therapy (WBRT) is the most effective treatment
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Although PCNSL has a high response rate to initial treatment, the overall prognosis is still poor
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With the continuous in-depth study of the pathophysiology of PCNSL, it has been found that the B cell receptor pathway (BCR), Toll-like receptor pathway (TLR), immune evasion mechanism, and suppression of tumor immune microenvironment are the key mechanisms in the pathogenesis of PCNSL
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The treatment of PCNSL gradually has a new direction, and targeted therapy, immunotherapy and related combination drugs have become research hotspots
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This article systematically reviews the treatment of PCNSL from six aspects: surgical treatment, radiotherapy, chemotherapy, hematopoietic stem cell transplantation, targeted therapy and immunotherapy, and summarizes the existing clinical evidence of new drugs for the reference of readers
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The goal of surgical treatment of PCNSL is to eliminate the lesion and obtain a lasting complete remission (CR).
It mainly relies on chemotherapy and radiotherapy.
The role of surgery in PCNSL is limited to obtaining tumor specimens to complete pathological diagnosis, and because the lesions of PCNSL mostly involve the deep brain And it occurs frequently, so the therapeutic effect of surgery is very limited
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The application of stereotactic brain biopsy has further reduced the status of surgical resection
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Previous studies have suggested [5] that aggressive surgical treatment may increase the risk of postoperative neurological deficits without survival benefit
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However, in a recent large randomized phase III study, it was found that aggressive removal of PCNSL can improve progression-free survival (PFS) [6]
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In addition, studies have confirmed that PCNSL surgical resection has a survival advantage compared with biopsy [7-9]
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Therefore, some scholars suggest that for lesions with significant space-occupying effects and clear boundaries, aggressive surgical cytoreduction measures can be taken
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In addition, the advancement of neurosurgery technology has also become one of the reasons for the rise of surgical treatment in PCNSL
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 Radiotherapy for PCNSL is different from other intracranial tumors, which has a higher remission rate for radiotherapy, but radiotherapy alone cannot fully control the disease, and its delayed neurotoxicity can also cause neurocognitive disorders, affecting the quality of life and even survival of patients [10, 11]
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It is generally believed that WBRT is limited to the following three points: (1) insufficient local control of lymphoma; (2) dissemination of lymphoma cells in the cerebrospinal fluid circulation and in the radiation field; (3) damage to brain function by radiotherapy
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In previous studies, the use of WBRT (36-40Gy) as the only treatment for PCNSL resulted in an overall response rate (ORR) of 90%, but the median overall survival (OS) was only 11.
6 months, and more than 60% of patients Lymphoma progression [12]
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Over time, the long-term neurotoxicity of WBRT has gradually emerged, such as incontinence, abnormal gait, and memory impairment
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Studies have confirmed that patients over 60 years of age are most prone to WBRT-related complications
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Although the neurotoxicity of low-dose WBRT is not obvious, the neurotoxicity caused by radiation may be a continuous variable [13].
Therefore, in the past ten years, WBRT is no longer recommended as an induction therapy or a consolidation treatment for patients with CR for the first time.
But it can be used as a first-line rescue therapy for methotrexate resistance [12]
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 The survival rate of PCNSL patients undergoing chemotherapy is not as good as other extranodal lymphomas.
In addition to the unique biological characteristics of lymphomas in the nervous system, the blood-brain barrier (BBB) ​​also plays a significant role in blocking chemotherapy drugs
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BBB is composed of pericytes, astrocytes and endothelial cells tightly connected to form a dynamic and complex structure, which regulates the biochemical components of the brain's interstitial environment and protects the brain from toxic molecules (including exogenous substances)
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Due to its physical and chemical properties, the blood-brain barrier is relatively impermeable to many water-soluble compounds, and most of the cytotoxic drugs entering the brain pass through the BBB through passive diffusion
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In addition to the pharmacokinetic properties, the main factors affecting the penetration of these compounds through the BBB include fat solubility, molecular weight, charge, and the ability to bind to plasma proteins
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Therefore, this limits the delivery of certain chemotherapeutics (such as the CHOP regimen: cyclophosphamide, doxorubicin, vincristine, and prednisone), antibody and cell therapy delivery, and cancer cell exposure
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In the 1970s, HD-MTX monotherapy was considered to be effective in the treatment of PCNSL, with an ORR of 35%-74%, a median PFS of 10-12.
8 months, and a median OS of 25-55 months [14-16 ], it is currently believed that large cell lymphoma in the brain microenvironment has approximately twice the sensitivity to HD-MTX-based treatment than systemic lymphoma with the same histology [17]
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Therefore, HD-MTX has become the backbone of most of the induction programs for PCNSL
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The optimal dose of methotrexate has not been determined
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The study of Skarin et al.
showed that in the brain parenchyma, MTX dose ≥ 1g/m2 can achieve tumor killing effect [18]
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The dose used in most studies is between 3-8g/m2.
The National Comprehensive Cancer Network (NCCN) guidelines recommend a dose of 3.
5g/m2 or higher for MTX [19], but attention should be paid to the effect of MTX on renal function.
Influence
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A previous large retrospective study [20] suggested that MTX≥3g/m2 can improve the survival rate of PCNSL patients
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The study of Batchelor T et al.
[14] showed that the CR rate and ORR of patients receiving an MTX dose of 8g/m2 were 52% and 74%, respectively, the median PFS and median OS were 12.
8 months and 22.
8 months, respectively, and the toxicity was moderate
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A recent retrospective study of 73 newly diagnosed PCNSL patients [21] compared the remission of patients receiving HD-MTX 8g/m2 and 3.
5g/m2.
The CR rates were 68.
29% and 43.
75% (p= 0.
03), the median PFS was 17.
7 months and 9.
05 months (p=0.
03), there was no significant difference in OS between the two groups, and serious adverse reactions were relatively rare
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Increasing the dose of MTX has favorable results for patients with good physical status and low-risk prognostic stratification at the initial diagnosis [22]
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Regarding the mode of administration, studies by Glantz et al.
have shown that intravenous methotrexate (8g/m2, 4 hours) produces a higher level of cytotoxicity in serum and cerebrospinal fluid than intrathecal methotrexate (12mg)
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The retrospective analysis of PCNSL results by the Memorial Sloan-Kettering Cancer Center also showed that [23] whether intrathecal injection does not affect the efficacy of patients receiving 3.
5g/m2 HD-MTX treatment, so there is no need for intravenous injection combined with intrathecal injection Methotrexate
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Previous studies have shown that the remission rate of MTX single-agent chemotherapy is 52%–88%, and the remission rate of multi-drug chemotherapy using MTX and other chemotherapeutic drugs is 70%–94% [24]
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Combination medications include temozolomide, rituximab, procarbazine, cytarabine, thiotepa, vincristine, carmustine, etoposide, ifosfamide and cyclophosphamide
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A multi-center phase II clinical trial showed that adding cytarabine to HD-MTX as an induction therapy can increase the CR rate (46% vs 18%), 3-year PFS rate (38% vs 21%) and 3-year OS rate (46% vs 32%) [25]
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Another phase II clinical trial showed that adding thiotepa and rituximab to HD-MTX+cytarabine can increase the CR rate (49% vs 23%) and the 2-year PFS rate (61% vs 36%) ) And the 2-year OS rate (69% vs 42%) [26]
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Temozolomide is an oral alkylating agent with good safety and high ability to pass BBB.
It can effectively induce CR in 25% of patients with relapsed or refractory PCNSL, and is especially suitable for elderly patients
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A recent meta-analysis of PCNSL patients receiving HD-MTX-based combination therapy showed that [27], the CR rate of combination chemotherapy including HD-MTX was 41%, and the CR rate of the three-drug and four-drug regimen was better than that of HD- MTX monotherapy
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Among all drug combinations, the CR rates of HD-MTX + procarbazine + vincristine regimen with or without rituximab were 63% and 58%, respectively, and the rituximab + HD-MTX + temozolomide regimen CR The rate is 60%
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Another meta-analysis showed that [28], compared with HD-MTX alone, PCNSL patients treated with HD-MTX+cytarabine had benefits in terms of PFS, ORR, and CR rates (HR: 0.
54; 95%) CI: 0.
31-0.
92; p=0.
01), but there was no significant statistical difference in OS (HR: 0.
65; 95% CI: 0.
38-1.
13; p=0.
07)
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To be continued The research progress of PCNSL will be introduced here first
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In the second and third issues of "Professor Liu Jiajun on the treatment progress of primary central nervous system lymphoma (middle)" and "Professor Liu Jiajun on the treatment progress of primary central nervous system lymphoma (part 2)", we will bring Everyone will continue to learn about the research progress of PCNSL's hematopoietic stem cell transplantation, targeted therapy and immunotherapy, so stay tuned! References: [1].
Louis, DN, et al.
, The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.
Neuro Oncol, 2021.
23(8): p.
1231-1251.
[2].
Ostrom, QT, et al.
, CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014.
Neuro Oncol, 2017.
19(suppl_5): p.
v1-v88.
[3].
Yuan, XG, et al.
, Primary central nervous system lymphoma in China: a single-center retrospective analysis of 167 cases.
Ann Hematol, 2020.
99(1): p.
93-104.
[4].
Langner-Lemercier, S.
, et al.
, Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network.
Neuro Oncol, 2016.
18(9): p.
1297-303.
[5] .
Bataille, B.
, et al.
,
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Medical expertise: More than 20 years of clinical medical work in internal medicine and hematology
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For many years, he has been engaged in the research of leukemia cell apoptosis signal transduction mechanism and molecular targeted therapy of hematological tumors
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Proficient in diagnosis and treatment of various anemias, bleeding diseases and hematological tumors
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Diagnosis and treatment of diseases including hematopoietic stem cell transplantation for hematological diseases, chemotherapy for leukemia, malignant lymphoma and multiple myeloma and other individualized treatment options for malignant hematological diseases, various unexplained anemia, unexplained long-term fever, and differential diagnosis of lymphadenopathy and treatment
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