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

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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 In the last issue of the article, we summarized the surgical treatment, radiotherapy and chemotherapy of PCNSL (for details, please click "Professor Liu Jiajun on the treatment progress of primary central nervous system lymphoma (part 1)".
Today, let's take a look.
Progress in PCNSL's hematopoietic stem cell transplantation and targeted therapy! The use of hematopoietic stem cell transplantation high-dose chemotherapy combined with autologous stem cell transplantation (HDC-ASCT) in PCNSL has attracted more and more attention, and is often used as the main salvage treatment for patients with relapsed and refractory disease
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studies have proven its effectiveness in improving PCNSL remission rates, extended terms of OS [24,29,30], and this treatment in young patients better [31]
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Soussain et al [32] on A cohort study of patients with PCNSL recurrence showed that the 5-year event-free survival (EFS) rate and OS rate of patients treated with thiotepa-based intensive chemotherapy plus hematopoietic stem cell transplantation were 37.
8% and 51.
4%, respectively
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Schorb E et al.
A retrospective multicenter study showed that [33], among elderly PCNSL patients (≥65 years old) who received HDC-ASCT, 69.
2% achieved CR, 17.
3% achieved partial remission (PR), median PFS and median OS was 51.
1 months and 122.
3 months, but its efficacy still needs further support from prospective studies
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It is also
reported that the 3-year OS rate of patients receiving HDC-ASCT is 60%, and the 3-year EFS rate is 53% [34,35 ]
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There are also studies that have evaluated the efficacy and toxicity of HD-ASCT and WBRT in the intensive treatment of PCNSL patients[36].
A total of 140 newly diagnosed PCNSL patients aged 18-60 were included in the study.
The 2-year PFS rate of patients in the HDC-ASCT group was 87%.
And after HDC-ASCT, it was observed that the patient's neurocognitive score improved overall, and WBRT was associated with worsening cognitive results
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However, many patients do not meet the conditions of HCT-ASCT at the time of relapse, and the prognosis of these patients is still very poor
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Targeted therapy 01 Rituximab The pathological phenotype of PCNSL is mostly diffuse large B cell lymphoma (DLBCL).
In the WHO classification, PCNSL derived from diffuse large B cells is considered to be a unique subtype of DLBCL.
One type of tumor tissues widely express B cell antigens, such as CD19, CD20, and CD79a.
At the same time, Mum-1 and IRF4 are almost all positively expressed, with 50% expressing BCL-6 and about 10% expressing CD10
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Therefore, rituximab may improve the prognosis of the disease, but due to its poor BBB penetration, its efficacy is still uncertain
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A retrospective cohort study analyzed the efficacy and survival rate of patients receiving HD-MTX + temozolomide or HD-MTX + temozolomide + rituximab.
The median PFS of the two groups were 7.
3 months and 56.
7 months, respectively.
HD -MTX+Temozolomide+Rituximab has a definite short-term curative effect in the treatment of PCNSL patients, and can improve the survival rate of patients, with mild side effects and generally tolerable by patients [38]
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Another randomized controlled study of 108 PCNSL patients found [39] that compared with HD-MTX combined with WBRT, the ORR of HD-MTX combined with rituximab group was significantly higher (81.
5% vs 57.
4%), 1 The annual OS rates were 83.
3% (45/54) ​​and 63.
0% (34/54), the 1-year PFS rates were 70.
4% (38/54) and 46.
3% (25/68), and the 3-year OS rates were 57.
4 % (31/54) and 31.
5% (17/54), the 3-year PFS rate was 27.
8% (15/54) ​​and 14.
8% (8/54)
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The NCCN guidelines have recommended rituximab as the first-line combination drug for PCNSL
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However, a retrospective study by researchers such as Miyakita on 19 patients with relapsed PCNSL[40] showed that 66.
6% of relapsed patients in the HD-MTX+rituximab group achieved CR/unconfirmed complete remission (CRu), 13.
3 % Of patients achieved PR, which was comparable to the HD-MTX monotherapy group, and there was no significant difference in the median time to tumor progression between the two groups
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In addition, in a prospective multicenter study of rituximab combined with temozolomide in the treatment of recurrent PCNSL [41], only 14% of evaluable patients achieved CR, with a median PFS of 7 weeks
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 02BTK inhibitors have a high degree of somatic mutations in proto-oncogenes in PCNSL.
Mutations that lead to activation of the nuclear factor kappa B (NF-κB) signaling pathway have been observed in almost all PCNSLs.
For example, the MYD88 and CD79b mutations have been identified as PCNSL.
Among the most common mutations, the above emphasizes the dependence of the pathogenesis of PCNSL on the BCR signaling pathway [37]
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Luton's tyrosine kinase (BTK) plays an important role in regulating the oncogenic signal transduction downstream of BCR and TLR[42,43]
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This provides a theoretical basis for the treatment of PCNSL with BTK inhibitors
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A phase Ⅰb clinical trial [44] explored the efficacy of ibrutinib/HD-MTX/rituximab combination therapy on relapsed and refractory PCNSL.
80% of patients had clinical response and no grade 3-5 toxicity Event or dose limiting toxicity
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Another meta-analysis on ibrutinib[45] showed that among PCNSL patients, including newly diagnosed PCNSL and relapsed and refractory PCNSL, the combined ORR of patients who included ibrutinib in treatment was 72% (95%).
CI: 63%-80%, I2=49.
20%, p=0.
06), combined CR rate and PR rate were 53% (95% CI: 33%-73%, I2=75.
04%, p=0.
00) and 22 % (95% CI: 14%-30%, I2=46.
30%, p=0.
07)
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Tirabrutinib is a second-generation, highly selective oral BTK inhibitor.
In the study of the treatment of relapsed and refractory PCNSL[46], the patient’s ORR was 64%, the median PFS was 2.
9 months, and the common ≥3 grade poor The events were neutropenia (9.
1%), lymphopenia (6.
8%), leukopenia (6.
8%), and erythema multiforme (6.
8%).
Only one patient in the study who took a daily dose of 480 mg appeared Grade 5 adverse events (Pneumocystis jiroveci pneumonia and interstitial lung disease)
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In addition, the phase II trial (CT04548648) of acatinib in relapsed and refractory PCNSL is currently underway
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 03mTOR and PI3K inhibitor mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that belongs to the phosphoinositide 3-kinase (PI3K) related kinase family
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The PI3K/AKT/mTOR pathway regulates protein synthesis by integrating signals from growth factors, hormones, nutrients and energy metabolism to regulate cell growth and proliferation [47]
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Inhibitors for the PI3K/AKT/mTOR signaling pathway mainly include PI3K inhibitors, mTOR inhibitors and PI3K-mTOR dual inhibitors
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mTOR and PI3K inhibitors are gradually appearing in clinical trials of relapsed and refractory PCNSL, but the efficacy is not satisfactory
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The first targeted drug reported was the mTOR inhibitor temsirolimus in a German multicenter phase II trial [48].
Its ORR for the treatment of PCNSL was 54%, but the median PFS was only 2.
1 months.
OS is 3.
7 months, and treatment-related toxicity is very high, the most common are hyperglycemia, bone marrow suppression, infection (mainly pneumonia) and fatigue
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Five patients died of treatment-related complications, accounting for 13% of treatment-related mortality
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Another study on the PI3K/mTOR axis used the pan-PI3K inhibitor Buparlisib, whose ORR for single-agent treatment of relapsed and refractory PCNSL was only 25% [64]
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Although the existing evidence of mTOR or PI3K inhibitors is not convincing, preclinical studies have shown that the combination of BTK inhibitors and PI3K inhibitors or mTOR inhibitors has a synergistic anti-lymphoma effect, especially in CD79B mutant cells [48 ] Therefore, the application of mTOR inhibitors and PI3K inhibitors in PCNSL still has research prospects
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 The increase of 04BCL-2 inhibitor 18q21 (including the BCL-2 locus) is one of the most common genetic imbalances in PCNSL [49-51]
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It was found by immunohistochemistry that 41.
8%-93% of PCNSL expressed BCL-2 [52]
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Studies have shown that the high expression of BCL-2 in PCNSL is associated with poor prognosis [53]
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BCL-2 can be targeted by the small molecule Venecla, which is a highly selective BCL-2 inhibitor and has been approved by the FDA for the treatment of chronic lymphocytic leukemia
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It has also been found in animal models that Venecla appears to have limited CNS penetration [54]
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BCL-2 inhibitors may become potential therapeutic drugs for BCL-2 overexpression of PCNSL, but their true application value still needs further support from prospective clinical drug trial evidence
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To be continued The research progress of PCNSL will be introduced here first
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In the third issue of "Professor Liu Jiajun Talks about the Progress in the Treatment of Primary Central Nervous System Lymphoma (Part 2)", we will take you to continue to understand the progress of the immunotherapy of PCNSL, 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.
, Primary intracerebral malignant lymphoma:
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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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