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Primary central nervous system lymphoma (PCNSL) refers specifically to lymphomas of the brain, pia mater, spinal cord, and posterior bulbar tissues without signs of lymphoma elsewhere in the body, 95% of which are subtypes
of diffuse large B-cell lymphoma 。 The incidence of PCNSL is low, accounting for about 1% of non-Hodgkin lymphoma (NHL) and 2.
2% of central nervous system tumors, the median age of onset of PCNSL is 65 years, and the overall prognosis is poor, data from a 2019 study from Denmark and Canada published in the journal Leukemia & Lymphoma suggest that the 5-year OS rate of PCNSL patients is less than 50%, and the 5-year DFS rate is about 25%.
How has the treatment of treatment-naïve PCNSL progressed in recent years? Yimaitong specially invited Professor Huang Wenrong of the Fifth Medical Center of PLA General Hospital to share the research progress
of first-line induction and consolidation therapy of PCNSL.
Professor Huang Wenrong, an exploration
of first-line induction therapy for PCNSL, said that the current first-line induction treatment regimen for PCNSL is based on high-dose methotrexate (MTX), in which MTX is once every 2-3 weeks and the dose should not be less than 3.
5g/m2 , patients can receive up to 4 courses if they can tolerate it; Patients with PCNSL who can tolerate intensive chemotherapy may be considered first-line high-dose MTX plus chemotherapy such as MATRix (high-dose MTX, cytarabine, thietipper, rituximab) and R-MPV (rituximab, high-dose MTX, methylbenzhydrazine, vincristine).
For the basic efficacy of high-dose MTX in patients with PCNSL, a 2010 study published in the British Journal of Cancer showed that the objective response rate (ORR) of high-dose MTX in patients with PCNSL was only 52.
7%, and the complete response (CR) rate was only 18%.
。 For the exploration of first-line treatment of PCNSL, a 2009 trial published in the journal Lancet compared the efficacy of high-dose MTX and high-dose MTX+ cytarabine in PCNSL, and the results showed that high-dose MTX+ cytarabine could achieve ORR of 69% and CR rate of 46% in PCNSL patients.
A 2016 study published in the journal Lancet Hematology showed that the MATRix regimen had an ORR of 87% and a CR rate of 49%
compared to a high-dose MTX + cytarab regimen and a high-dose MTX + cytarab + rituximab regimen 。 Professor Huang Wenrong said that although the MATRix regimen has significant efficacy, the regimen is highly toxic, and adverse events such as agranulocytosis and thrombocytopenia are high and more serious.
Therefore, patients with PCNSL older than 70 or greater than 65 with ECOG score >2 or other organ comorbidities are not recommended to receive the MATRix regimen
.
In addition to the exploration of the above first-line treatment options, the team of Professor Huang Wenrong of the Fifth Medical Center of the PLA General Hospital led a national multi-center prospective study with six other centers across the country, adding the BTK inhibitor orelabrutinib on the basis of the high-dose MTX + rituximab regimen, and enrolled 34 patients with an ORR of 100% and a CR rate of 62%.
With an overall safety and well-tolerated profile and the study selected as an oral presentation at this year's ASH Annual Meeting, this combination of traditional drugs and new drugs promises to lead to new first-line treatment options
for PCNSL patients.
Previous studies of first-line
consolidation therapy for PCNSL have shown that the median duration of response in patients with PCNSL receiving high-dose MTX or high-dose MTX + cytarabine regimens is less than 1 year
.
Therefore, patients with PCNSL who have been in remission with first-line therapy are recommended to receive consolidation therapy, including non-myeloablative intensive chemotherapy, autologous hematopoietic stem cell transplantation (ASCT), and whole-brain radiotherapy
.
So how do patients with PCNSL who are in remission with first-line therapy choose between non-myeloablative chemotherapy, ASCT, and whole-brain radiotherapy? Professor Huang Wenrong said that previous prospective studies have proved that ASCT and whole-brain radiotherapy can significantly improve the median progression-free survival (PFS)
of patients with first-line therapy remission of PCNSL compared with non-myeloablative high-dose consolidation chemotherapy.
For the difference in prognosis between ASCT and whole-brain radiotherapy, data from a 2017 trial published in the journal Lancet Hematology randomized PCNSL patients in response to first-line therapy to ASCT and whole-brain radiotherapy, with a basal dose of 36 Gy in the whole-brain radiotherapy group and carmustine (BCNU; 400 mg/m2) + thitipipra (TT; 20mg/kg）； After a median follow-up of 40 months, the 2-year PFS rates in the whole-brain radiotherapy group and the ASCT group were 76% and 75%, and the 2-year OS rates were 82%, respectively, and there were no significant differences
.
Although there was no significant difference in the long-term prognosis of PCNSL patients who received ASCT or whole-brain radiotherapy, the quality of life was better
for patients who received ASCT.
The results of the 2019 French PRECIS trial, published in the Journal of Clinical Oncology, included 140 PCNSL patients aged 18-60 years who were randomly assigned to receive ASCT or whole-brain radiotherapy consolidation therapy after first-line remission, and the 2-year PFS rate in the ASCT and whole-brain radiotherapy groups was 87%, respectively, in PCNSL patients who met the primary endpoint and 63% (P=0.
01); Three years after consolidation therapy, scores on neurocognitive scales decreased in nearly one-half of patients in the whole-brain radiotherapy group, while scores improved in more than one-half of patients in the ASCT group
.
The 2022 PRECIS trial updated the follow-up results, and the 8-year PFS rates in the ASCT and whole-brain radiotherapy groups were 67% and 39%, respectively (P = 0.
03).
Professor Huang Wenrong said that compared with whole-brain radiotherapy, ASCT consolidation therapy has a better long-term prognosis and higher quality of life in PCNSL patients aged 18-60, which is more conducive to patients returning to normal life and reducing family burden.
Do differences in ASCT conditioning regimens have an impact on the prognosis of patients with PCNSL? Professor Huang Wenrong continued to introduce that the International Center for Blood and Marrow Transplantation (CIBMTR) retrospectively analyzed 603 PCNSL patients who received ASCT consolidation therapy from 2010.
1 to 2018.
12, and the results showed that the 3-year PFS rate corrected by the BEAM regimen (carmustine/etoposide/cytarabine/melphalan) was 58%, while the TT-BCNU and TBC (ticipipa/busulfan/cyclophosphamide) regimen with thietipipa had better efficacy.
The corrected 3-year PFS rates were 75% and 76%, respectively; In addition, previous studies have shown that TBC conditioning regimens are also relatively safe, with the main adverse event being agranulocytosis with persistent infection
.
Finally, Professor Huang Wenrong concluded that PCNSL has a low incidence and poor prognosis, and first-line induction therapy is based on high-dose MTX, and combination chemotherapy and small molecule targeted drugs can improve the remission rate
of patients.
Setepa is preferred as pretreatment consolidation therapy for ASCT in younger PCNSL patients who are remission naïve and can tolerate intensive chemotherapy, while consolidation therapy with whole-brain radiotherapy is recommended for older PCNSL patients who do not tolerate chemotherapy
.
of diffuse large B-cell lymphoma 。 The incidence of PCNSL is low, accounting for about 1% of non-Hodgkin lymphoma (NHL) and 2.
2% of central nervous system tumors, the median age of onset of PCNSL is 65 years, and the overall prognosis is poor, data from a 2019 study from Denmark and Canada published in the journal Leukemia & Lymphoma suggest that the 5-year OS rate of PCNSL patients is less than 50%, and the 5-year DFS rate is about 25%.
How has the treatment of treatment-naïve PCNSL progressed in recent years? Yimaitong specially invited Professor Huang Wenrong of the Fifth Medical Center of PLA General Hospital to share the research progress
of first-line induction and consolidation therapy of PCNSL.
Professor Huang Wenrong, an exploration
of first-line induction therapy for PCNSL, said that the current first-line induction treatment regimen for PCNSL is based on high-dose methotrexate (MTX), in which MTX is once every 2-3 weeks and the dose should not be less than 3.
5g/m2 , patients can receive up to 4 courses if they can tolerate it; Patients with PCNSL who can tolerate intensive chemotherapy may be considered first-line high-dose MTX plus chemotherapy such as MATRix (high-dose MTX, cytarabine, thietipper, rituximab) and R-MPV (rituximab, high-dose MTX, methylbenzhydrazine, vincristine).
For the basic efficacy of high-dose MTX in patients with PCNSL, a 2010 study published in the British Journal of Cancer showed that the objective response rate (ORR) of high-dose MTX in patients with PCNSL was only 52.
7%, and the complete response (CR) rate was only 18%.
。 For the exploration of first-line treatment of PCNSL, a 2009 trial published in the journal Lancet compared the efficacy of high-dose MTX and high-dose MTX+ cytarabine in PCNSL, and the results showed that high-dose MTX+ cytarabine could achieve ORR of 69% and CR rate of 46% in PCNSL patients.
A 2016 study published in the journal Lancet Hematology showed that the MATRix regimen had an ORR of 87% and a CR rate of 49%
compared to a high-dose MTX + cytarab regimen and a high-dose MTX + cytarab + rituximab regimen 。 Professor Huang Wenrong said that although the MATRix regimen has significant efficacy, the regimen is highly toxic, and adverse events such as agranulocytosis and thrombocytopenia are high and more serious.
Therefore, patients with PCNSL older than 70 or greater than 65 with ECOG score >2 or other organ comorbidities are not recommended to receive the MATRix regimen
.
In addition to the exploration of the above first-line treatment options, the team of Professor Huang Wenrong of the Fifth Medical Center of the PLA General Hospital led a national multi-center prospective study with six other centers across the country, adding the BTK inhibitor orelabrutinib on the basis of the high-dose MTX + rituximab regimen, and enrolled 34 patients with an ORR of 100% and a CR rate of 62%.
With an overall safety and well-tolerated profile and the study selected as an oral presentation at this year's ASH Annual Meeting, this combination of traditional drugs and new drugs promises to lead to new first-line treatment options
for PCNSL patients.
Previous studies of first-line
consolidation therapy for PCNSL have shown that the median duration of response in patients with PCNSL receiving high-dose MTX or high-dose MTX + cytarabine regimens is less than 1 year
.
Therefore, patients with PCNSL who have been in remission with first-line therapy are recommended to receive consolidation therapy, including non-myeloablative intensive chemotherapy, autologous hematopoietic stem cell transplantation (ASCT), and whole-brain radiotherapy
.
So how do patients with PCNSL who are in remission with first-line therapy choose between non-myeloablative chemotherapy, ASCT, and whole-brain radiotherapy? Professor Huang Wenrong said that previous prospective studies have proved that ASCT and whole-brain radiotherapy can significantly improve the median progression-free survival (PFS)
of patients with first-line therapy remission of PCNSL compared with non-myeloablative high-dose consolidation chemotherapy.
For the difference in prognosis between ASCT and whole-brain radiotherapy, data from a 2017 trial published in the journal Lancet Hematology randomized PCNSL patients in response to first-line therapy to ASCT and whole-brain radiotherapy, with a basal dose of 36 Gy in the whole-brain radiotherapy group and carmustine (BCNU; 400 mg/m2) + thitipipra (TT; 20mg/kg）； After a median follow-up of 40 months, the 2-year PFS rates in the whole-brain radiotherapy group and the ASCT group were 76% and 75%, and the 2-year OS rates were 82%, respectively, and there were no significant differences
.
Although there was no significant difference in the long-term prognosis of PCNSL patients who received ASCT or whole-brain radiotherapy, the quality of life was better
for patients who received ASCT.
The results of the 2019 French PRECIS trial, published in the Journal of Clinical Oncology, included 140 PCNSL patients aged 18-60 years who were randomly assigned to receive ASCT or whole-brain radiotherapy consolidation therapy after first-line remission, and the 2-year PFS rate in the ASCT and whole-brain radiotherapy groups was 87%, respectively, in PCNSL patients who met the primary endpoint and 63% (P=0.
01); Three years after consolidation therapy, scores on neurocognitive scales decreased in nearly one-half of patients in the whole-brain radiotherapy group, while scores improved in more than one-half of patients in the ASCT group
.
The 2022 PRECIS trial updated the follow-up results, and the 8-year PFS rates in the ASCT and whole-brain radiotherapy groups were 67% and 39%, respectively (P = 0.
03).
Professor Huang Wenrong said that compared with whole-brain radiotherapy, ASCT consolidation therapy has a better long-term prognosis and higher quality of life in PCNSL patients aged 18-60, which is more conducive to patients returning to normal life and reducing family burden.
Do differences in ASCT conditioning regimens have an impact on the prognosis of patients with PCNSL? Professor Huang Wenrong continued to introduce that the International Center for Blood and Marrow Transplantation (CIBMTR) retrospectively analyzed 603 PCNSL patients who received ASCT consolidation therapy from 2010.
1 to 2018.
12, and the results showed that the 3-year PFS rate corrected by the BEAM regimen (carmustine/etoposide/cytarabine/melphalan) was 58%, while the TT-BCNU and TBC (ticipipa/busulfan/cyclophosphamide) regimen with thietipipa had better efficacy.
The corrected 3-year PFS rates were 75% and 76%, respectively; In addition, previous studies have shown that TBC conditioning regimens are also relatively safe, with the main adverse event being agranulocytosis with persistent infection
.
Finally, Professor Huang Wenrong concluded that PCNSL has a low incidence and poor prognosis, and first-line induction therapy is based on high-dose MTX, and combination chemotherapy and small molecule targeted drugs can improve the remission rate
of patients.
Setepa is preferred as pretreatment consolidation therapy for ASCT in younger PCNSL patients who are remission naïve and can tolerate intensive chemotherapy, while consolidation therapy with whole-brain radiotherapy is recommended for older PCNSL patients who do not tolerate chemotherapy
.
Professor Wong Wenrong
Doctor of Medicine, Chief Physician, Master Supervisor
Director of the Department of Lymphoma-Plasma Cell Diseases, Department of Hematology, PLA General Hospital
Vice Chairman of the Lymphoid Hematology and Cancer Committee of Beijing Anti-Cancer Association
Vice Chairman of the Hematology Committee of the Chinese Geriatrics Society
Member of the Standing Committee of the Blood Precision Diagnosis and Treatment Committee of the Chinese Association of Research Hospitals
The project leader undertakes the National Natural Science Foundation of China, military projects, capital health development research special projects and other projects
.
Won the second prize of military scientific and technological progressThe first author or corresponding author has published 21 clinical SCI papers in international journals such as Oncogene, Bone marrow transplant, Cell Transplantation, Frontier Oncology, Transfusion, Annals of Hematology, Clinical transplant, Leukemia & Lymphoma, etc.
He has published more than 50 papers in domestic journals
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