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Recently, based on the development of related research fields at home and abroad, the team of the Department of Hematology of the Second Hospital of Zhejiang University published an original research paper 1: Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma
。 The study found that zebratinib combined with conventional salvage chemotherapy regimen had high efficacy and controllable tolerability, and may be a potential treatment option for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), creating conditions
for subsequent smooth bridging of CAR-T cell therapy.
Research background
DLBCL is the most common type of aggressive lymphoma, accounting for 30%-40% of non-Hodgkin lymphomas2,3
.
R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimens are the standard first-line treatment and achieve long-term remission
of approximately 50% to 60%.
However, up to 50% of patients are ultimately incurable4,5
.
Autologous hematopoietic stem cell transplantation after salvage chemotherapy is currently the standard of care
for R/R DLL.
HOWEVER, IN THE SCHOLAR-1 STUDY6, ONLY 26% OF PATIENTS RESPONDED TO THE NEXT SALVAGE TREATMENT, AND ONLY A FEW WERE ELIGIBLE FOR AUTOLOGOUS TRANSPLANTATION, WITH A MEDIAN OVERALL SURVIVAL (OS) OF ONLY 6.
3 MONTHS
.
Therefore, it is necessary to explore better salvage chemotherapy
regimens for the treatment of R/R LLBCL.
Bruton tyrosine kinase inhibitors (BTKi) have been shown to be highly effective against a wide range of B-cell malignancies, with an overall response rate (ORR) of 23% for R/R DLBCL with first-generation BTKi ibrutinib7
.
Compared with ibrutinib, the new generation of BTKi zebratinib has shown high efficacy and safety in the treatment of chronic lymphocytic leukemia and Waldenstrom macroglobulinemia8,9
.
The BGB-3111-207 phase II study showed that zebratinib monotherapy for R/R DLLBCL had an ORR of 29.
3% and a complete response rate (CRR) of 17.
1%, moderate antitumor activity and good safety profile
.
This review retrospectively explores the efficacy and safety
of zebratinib in combination with conventional salvage chemotherapy in the treatment of R/R DLLCL.
Study results
This review included 27 patients with R/R DLLBCL, with a median age of 59 years (range 15-72 years), mostly non-GCB (85.
2%), 74.
1% of patients treated ≥ 2nd line therapy, and 74.
1%
of patients with stage III-IV.
The optimal ORR was 74.
1% and CRR was 33.
3%.
With a median follow-up of 11 months (range 1-17), median progression-free survival (PFS) was 8.
1 months, and overall survival (OS) was not reached
.
The most common grade 3/4 adverse events were neutropenia (70.
4%), thrombocytopenia (66.
7%), and febrile neutropenia (33.
3%)
.
In multivariate analysis, ORR after front-line therapy and chemotherapy was an independent favorable prognostic factor for PFS, and ORR after chemotherapy was an independent favorable factor
for OS.
The genetic characteristics
of eight patients who did not respond well to zebratinib combined with chemotherapy were also explored.
The results showed that all 8 patients had NOTCH2 mutation and 7 patients had TP53 mutation
.
All 8 patients subsequently received CD19-CAR-T cell therapy, and the ORR reached 75% at 3 months after CAR-T therapy (4 patients had complete response and 2 patients had partial remission).
The median follow-up after CAR-T cell infusion was 9 months (range 1-16 months), the median PFS was 14.
5 months, and the median OS was not reached
.
It suggests that CAR-T cell therapy may be an effective treatment
for BTKi-resistant R/R DLCL.
Conclusion of the study
In summary, zebratinib combined with salvage chemotherapy regimen has high efficacy and controllable tolerability, which is a potential treatment option for patients with R/R DLLBCL, and creates conditions
for subsequent smooth bridging of CAR-T cell therapy.
Professor Qian Wenbin
Professor, chief physician, doctoral supervisor
Director of the Department of Hematology, The Second Affiliated Hospital of Zhejiang University School of Medicine
Deputy Director of the Institute of Hematology, Zhejiang University
Member of Hematologist Branch of Chinese Medical Doctor Association
Member of the Standing Committee of the Oncology and Hematology Professional Committee of the Chinese Anti-Cancer Association
Member of the Standing Committee of the Hematology and Oncology Professional Committee of the Chinese Anti-Cancer Association
Member of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association
Vice Chairman of the Lymphoma Professional Committee of the Chinese Geriatric Health Care Association
Chinese Society of Hematology, Member of Lymphocyte Disease Group and Infectious Disease Group
Chairman of Hematology Branch of Zhejiang Medical Association
Vice President of Hematologist Branch of Zhejiang Medical Doctor Association
Vice Chairman of the Hematology and Lymphatic Committee of Zhejiang Anti-Cancer Association
First / corresponding author in Clin Cancer Res, Leukemia, J Hematol & Oncol, Signal Transduction and Target Therapy, Cell Mol Immunol, Blood Cancer Journal, Cancer Communication and Lancet Hematology and other internationally renowned journals have published more than 80 SCI papers
[Guidelines for the Clinical Management of Toxic Side Effects of NHL in CAR T-cell Therapy], Co-editor, Tsinghua University Press, 2021
[CAR-T cell immunotherapy], Associate Editor, People's Medical Publishing House, 2021
He has presided over 1 key project and 5 general projects of the National Natural Science Foundation of China, the key special project of precision medicine research of the National Key R&D Program, the sub-project of the National Science and Technology Support Plan and the key R&D plan of Zhejiang Province
As a person in charge or a major member, he has won 2 second prizes of National Science and Technology Progress Award and nearly 10 first and second prizes of Provincial Science and Technology Progress Award
References:
1.Yuan Xianggui, et al.
Zanubrutinib plus salvage chemotherapy for relapsed or refractory diffuse large B-cell lymphoma[J].
Front Immunol.
2022 Nov 24; 13:1015081.
2.
Teras LR, DeSantis CE, Cerhan JR, Morton LM, Jemal A, Flowers CR.
USLymphoid malignancy statistics by world health organization subtypes.
CA: CancerJ Clin (20162016) 66(6):443–59.
doi: 10.
3322/caac.
213573.
Sun J, Yang Q, Lu Z, He M, Gao L, Zhu M, et al.
Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the world healthorganization classification.
Am J Clin Pathol (2012) 138(3):429–34.
doi: 10.
1309/AJCP7YLTQPUSDQ5C4.
Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA,Cohn JB, et al.
Rituximab-CHOP versus CHOP alone or with maintenancerituximab in older patients with diffuse large b-cell lymphoma.
J Clin Oncol(2006) 24(19):3121–7.
doi: 10.
1200/JCO.
2005.
05.
10035.
Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, et al.
Long-term outcome of patients in the LNH-98.
5 trial, the first randomizedstudy comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the groupe d'Etudes des lymphomes de l'Adulte.
Blood (2010)116(12):2040–5.
doi: 10.
1182/blood-2010-03-2762466.
Crump M, Neelapu SS, Farooq U, Van Den Neste E, Kuruvilla J, Westin J, et al.
Outcomes in refractory diffuse large b-cell lymphoma: results from theinternational SCHOLAR-1 study.
Blood (2017) 130(16):1800–8.
doi: 10.
1182/blood-2017-03-7696207.
Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al.
Targeting b cell receptor signaling with ibrutinib in diffuse large b cell lymphoma.
Nat Med (2015) 21(8):922–6.
doi: 10.
1038/nm.
38848.
Tam CS, Opat S, D'Sa S, Jurczak W, Lee H-P, Cull G, et al.
A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic waldenströmmacroglobulinemia: the ASPEN study.
Blood (2020) 136(18):2038–50.
doi: 10.
1182/blood.
20200068449.
Peter Hillmen, Barbara Eichhorst, Znubrutinib Versus Ibrutinib in Relapsed/Refractory Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma: Interim Analysis of a Randomized Phase III Trial.
JOURNAL OF CLINICAL ONCOLOGY publish: ascopubs.
org/journal/jco on November 17,2022: DOI https://doi.
org/10.
1200/JCO.
22.
00510 Revised: MolyTypesetting: Moly Executed by: Cherry
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