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Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma with a poor prognosis, short overall survival, and no standard treatment
available.
As the world's first orally selective nuclear export protein inhibitor, Celiniso (trade name: Xivio ®) selectively binds nuclear export protein 1 (XPO1) to promote tumor cell cycle arrest and apoptosis
.
It is currently approved by the US Food and Drug Administration (FDA) for the treatment of multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL).
In September 2022, Professor Chen Li's team published a research paper entitled "Clinical Exploration of Celiniso Combination Chemotherapy in Relapsed/Refractory Plasmablastic Lymphoma"1 in the prestigious academic journal Journal of Clinical Hematology, which explored the possibility
of celinisol to improve the status of PBL treatment based on specific cases.
On this occasion, Yimaitong specially invited Professor Chen Li of Shanghai Changhai Hospital to interpret this literature for us and share the experience
of celinisol combined with chemotherapy in the treatment of relapsed refractory (R/R) PBL.
PBL is a rare aggressive, poor-prognostic non-Hodgkin lymphoma with morphological and immunophenotypes common to DLBCL and plasma cell tumors, commonly seen in human immunodeficiency virus (HIV)-positive individuals
.
In recent years, HIV-negative immunocompromised and immunocompetent PBL have also been reported
.
PBL currently has a median overall survival time of 6~19 months, rapid disease progression, poor prognosis, no standard treatment options to choose from, and currently mostly use CHOP-based combination chemotherapy, accounting for about 52%, and its overall response rate is 60%~70%, but the long-term survival rate is low
.
Based on the current status of treatment, the National Comprehensive Cancer Network (NCCN) guidelines point out that standard CHOP regimens are insufficient for PBL treatment, recommend more aggressive chemotherapy regimens such as EPOCH, CODOX-M/IVAC, HyperCVAD, and autologous hematopoietic stem cell transplantation (ASCT) after the first complete response (CR) for high-risk patients, and HIV-positive patients need to receive antiviral therapy
.
However, there is controversy about whether to use intensive chemotherapy, and some studies have not shown survival benefits
for patients with PBL.
Therefore, the treatment of PBL urgently needs the exploration of new drugs and new schemes to seek better and longer survival
for patients.
In recent years, celiniso has attracted much attention
as a drug with a new mechanism of action.
Selinisol specifically blocks XPO1, resulting in the accumulation and reactivation of tumor suppressor proteins such as IκB, p53, p73, p21, p27, Rb, BRCA1/2 in the nucleus, reducing the level of tumor proteins such as c-myc, BCL-2, BCL-6 and cyclinD1, and activating the glucocorticoid receptor pathway, thereby inducing apoptosis of tumor cells, but normal hematopoietic stem cells and their functions are largely unaffected
。 Celiniso has been approved for the treatment of MM and DLBCL in many countries and regions, and multiple clinical studies have confirmed its clinical benefits
for patients with R/R MM and DLBCL.
The SADAL Study 2, a single-arm, multicenter, open-label Phase 2b clinical study of celinisol monotherapy for R/R DLCL, showed an overall response rate (ORR) of 28% and a CR rate of 12% in 127 patients, with a median duration of response (DOR) of 23 months
for patients who obtained CR.
At the same time, celiniso has also shown synergistic effects with a variety of drugs, including gemcitabine, cisplatin and other chemotherapy drugs
.
A phase Ib clinical study preliminarily showed that the ORR of celinisol combined with R-GDP in the treatment of R/R B-cell lymphoma was 66.
7%, and the CR rate was 38.
9%, with a good
safety profile.
Phase III clinical studies of celiniso combined with R-GDP for the treatment of R/RDLLCL are also underway3,4
.
Based on the mechanism of action of celinisol, its broad-spectrum anti-tumor effect and synergistic effect with a variety of chemotherapy drugs, Professor Chen Li's team applied celiniso combined with GDP chemotherapy to patients with PBL, and sorted out the specific cases and published them in the Journal of Clinical Hematology, which is also the first public report on the treatment of PBL by celiniso.
Case 1, patient, male, 25 years old, initially diagnosed as PBL stage II.
A, IPI score 0
.
The patient was given 2 courses of bortezomib combined with CHOP regimen, 1 course of bortezomib combined with Hyper-CVAD regimen, and radiotherapy failed to achieve remission, the disease progressed rapidly, and the results of re-examination PET-CT were shown in Figure 1 below, and the diagnosis was PBL stage IV.
A, with an IPI score of 2 points
.
Celiniso 60 mg was then given once a week with chemotherapy with a combined GDP regimen for 21 days for one course
.
The re-examination of PET-CT showed that the lesions were significantly reduced compared with the control of the previous film, FDG metabolism was reduced, and the efficacy was evaluated as partial remission (Figure 2).
The patient then entered the warehouse for ASCT
.
After transplantation, patients continued oral salvage of celinisol 60 mg once weekly for maintenance therapy until the end of this publication and the patient continued to remission and survived for 13 months
.
The overall treatment history and efficacy evaluation of the patient are shown
in Figure 3.
Figure 1.
Whole-body PET-CT imaging before treatment of celiniso combined with GDP regimen showed multiple system involvement of lymphoma
Figure 2.
After the whole body PET-CT imaging of the patients underwent celiniso combined with the GDP regimen, the lesions were significantly reduced, the FDG metabolism was reduced, and the efficacy was partially relieved
Figure 3.
Patient treatment history and efficacy evaluation
Case 2, female, 26 years old, first diagnosed as PBL stage II.
A, IPI score 1 point
.
Bortezomib combined with CHP regimen, HyperCVAD-A regimen and other chemotherapy regimens were given, and the disease continued to progress.
Subsequently, the patient presented to the doctor due to "abdominal distension and anuria", considering that the patient's serious renal function damage was related to tumor compression, so he was given celiniso 60mg orally from October 25, and targeted therapy
was given once a week.
After treatment with celiniso, serum creatinine was reduced to 286.
5 μmol/L, urine output was about 2000 mL per day, and then chemotherapy was started with celiniso combined with GDP regimen, and the patient's renal function gradually returned to normal (Figure 4), and the patient was still closely followed up by the end of this paper
.
Figure 4.
Curve of changes in serum creatinine of the patient taking celiniso
Both of the above two patients were young, HIV-negative and immunocompetent patients who had previously received multiple lines of chemotherapy and radiotherapy, and both received bortezomib-containing combination chemotherapy regimens, but the disease continued to progress.
The first patient did not achieve remission in previous treatment, and achieved a very good partial response after 1 course of treatment with celinisol combined with chemotherapy, which is the best response of all treatments and provides a valuable opportunity
for the patient to undergo ASCT.
The second patient, who had tumor invasion and compression to acute renal failure, had no indication for chemotherapy, and tried treatment with celiniso, and the patient's renal function gradually returned to normal, allowing him to receive follow-up treatment
.
The two patients had good tolerance to celiniso during treatment and had controllable
safety.
At present, the research on PBL at home and abroad is mainly a case report, and the treatment plan has not seen obvious efficacy, especially in patients with R/R PBL, there is a lack of effective treatment methods, and it is urgent to explore the pathogenesis of the disease and more effective treatment measures
in depth.
In this report, the XPO1 inhibitor with a novel mechanism of action is applied to patients with PBL for the first time, and good clinical benefits have been achieved, and it is necessary to further expand the treatment population, provide more clinical guidance for the treatment of PBL, and improve the prognosis
of patients.
*R: rituximab; EPOCH regimen: etoposide + doxorubicin + vincristine + prednisone + cyclophosphamide; CODOX-M/IVAC regimen: cyclophosphamide + vincristine + doxorubicin + high-dose methotrexate, alternating ifosfamide + etoposide + cytarabine; GDP regimen: gemcitabine + cisplatin + dexamethasone; CHOP regimen: cyclophosphamide + doxorubicin liposomes + vinpoceine + dexamethasone; Hyper-CVAD regimen: cyclophosphamide + doxorubicin liposomes + vinpoceine + dexamethasone; CHP regimen: cyclophosphamide + doxorubicin liposomes + dexamethasone
Professor Chen Li
Chief physician, associate professor, master supervisor
Chief physician of the Department of Hematology, Shanghai Changhai Hospital
He has presided over and completed 7 general projects of the National Natural Science Foundation of China, logistics scientific research projects of the whole army, scientific research projects of Shanghai Municipal Science and Technology Commission, science and technology development fund projects of Shanghai Municipal Health Bureau and key projects of Shanghai Municipal Science and Technology Commission
He has participated in the completion of more than ten major projects of the National Natural Science Foundation of China and major basic projects of Shanghai
published 120 papers; The first and corresponding author of 35 papers, including 7 SCI papers
As the first completer, he won the third prize of military medical achievements; He has won the second prize of Shanghai Medical Science and Technology Award and the second prize of Military Medical Achievement Award, 1 Shanghai Science and Technology Achievement, and 1 national invention patent authorization
He has been rated as an advanced individual in hospital and school teaching for many times, presided over and completed 1 key project of school-level education reform fund, edited 1 textbook, and participated in the compilation of 6 textbooks
References:
1.
Fu Yuhua, Bao Renjun, Yao Yonghua, et al.
Clinical exploration of seleniso combined chemotherapy in relapsed/refractory plasmablastic lymphoma.
Journal of Clinical Hematology,2022,35(9):678-681,686.
2.
Nagesh Kalakonda, et.
al.
Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, muluticentre, open-label, phase 2 trial.
Lancet Haematol.
2020 Jul; 7(7):e511-e522.
3.
Maerevoet M, et al.
Selinexor in Combination with R-GDP for Patients with Relapsed/Refractor yB-Cell Lymphoma:Results of the Selinda Phase Ib Lysa Study.
2021Dec.
Presented at:63rd ASH Annual Meeting and Exposition.
Poster 1411.
4.
Lee ST, et al.
A Phase2/3, Multicenter Randomized Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) with or without SelinexorinPatients with Relapsed/Refractory Diffuse Large B-CellLymphoma(RRDLBCL).
2021 Dec.
Presented at:63rd ASH Annual Meeting and Exposition.
Poster1420.
Note: Silvio ® is the trade name
of Celiniso.
In December 2021, China's National Medical Products Administration (NMPA) approved Antengene's new drug application for celinisol for the treatment of previously treated relapsed or refractory multiple myeloma (R/R MM)
in combination with dexamethasone for the treatment of at least one proteasome inhibitor, one immunomodulator, and one anti-CD38 monoclonal antibody.
In June 2020, the US Food and Drug Administration (FDA) approved celinisol for the treatment of patients with diffuse large B-cell lymphoma (DLBCL) above the third line; In addition, Seliniso has also received multinational approval for the treatment of patients
with relapsed and refractory DLBCL.
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