Professor Bai Ou: DHL/DEL diagnosis, treatment and progress | Jinling Lymphatic Tumor Forum 2021

In order to further explore the clinical pathological diagnosis, treatment and translational medicine research progress of lymphatic tumors, and to further improve the overall diagnosis and treatment of lymphatic tumors in my country, the "2021 Jinling Lymphatic Tumor Forum" will be held in Nanjing, Jiangsu Province from May 14th to 16th, 2021.
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At this meeting, Professor Bai Ou from Bethune First Hospital of Jilin University gave a report on "DHL (Double Strike Lymphoma)/DEL (Dual Expression Lymphoma) Diagnosis, Treatment and Progress".
Yimaitong organized the main contents as follows.

Definition, characteristics and prognosis of DHL/DEL DHL is a lymphoma with MYC and BCL2/BCL6 gene rearrangement, mostly from diffuse large B-cell lymphoma (DLBCL), accounting for 5%-7% of DLBCL.

In 2016, the WHO classified DHL and triple-hit lymphoma (THL) as high-grade B-cell lymphoma (HGBL) with MYC/BCL2/BCL6 rearrangement, of which 65% are DHL with MYC/BCL2 rearrangement and 14% are associated MYC/BCL6 rearrangement of DHL, 21% is THL.

 DEL is a lymphoma with MYC/BCL2 overexpression (IHC detection: MYC≥40%; BCL2>50%), which has nothing to do with gene rearrangement.

DEL is a poor prognostic factor, not an independent subtype.

Compared with DHL, DEL has a higher proportion in DLBCL, accounting for about 20%-30% of DLBCL.

 The clinical features of DHL/DEL are highly aggressive, and clinically, it mostly occurs in patients with high-risk IPI scores, stage III-IV, and accompanied by extranodal disease.

DHL/DEL patients do not respond well to R-CHOP regimen, and the prognosis is relatively poor.

Related studies have shown that the median progression-free survival (PFS) of DHL/DEL patients after receiving R-CHOP regimen is only 7.
8 months, and the median overall survival (OS) is only 1.
4 years; the 5-year PFS rate is 18% , The 5-year OS rate is 27%.

 Related studies have explored the prognostic progress of patients with DHL/DEL.

A study published in 2019 performed RNA sequencing analysis of 157 newly diagnosed GCB-DLBCL patients and 25 HGBL-DH/TH-BCL2 patients, and showed significant differences in the expression of 104 genes, defined as double-hit marker genes (DHITsig).

88% of DHITsig-positive patients in the study were HGBL-DH/TH-BCL2 patients, and the rest were GCB-DLBCL patients.

Compared with FISH detection, DHITsig can more accurately predict the prognosis of patients and is expected to guide individualized clinical treatment.

DHL/DEL treatment and progress Professor Bai Ou then introduced the progress of DHL/DEL treatment.

At present, many important studies have shown that the R-EPOCH program can significantly improve the event-free survival (EFS) and PFS of DHL patients, but it cannot improve the OS of DHL patients.

Other enhancement programs (such as R-HyperCVAD/MA program, R-CODOX-M/IVAC program) have no better efficacy than R-EPOCH program, and the side effects are more serious.

Therefore, the current R-EPOCH program is the first choice for DHL patients.


A study published at the 2020 ASH Conference explored the efficacy of autologous hematopoietic stem cell transplantation (ASCT) in DHL/THL patients after induction therapy with the R-DA-EPOCH regimen.

The study enrolled 63 patients, of which 24 (38%) received ASCT.

Compared with patients who did not receive ASCT, patients who received ASCT had a better prognosis, with better 3-year PFS rate (94% vs 72%) and 3-year OS rate (100% vs 76%).

Multivariate analysis showed that ASCT was significantly related to the survival rate of patients (HR: 0.
146; 95% CI: 0.
032-0.
667; P=0.
013).

For DHL/THL patients, the R-DA-EPOCH program sequential ASCT is an important treatment option.

 Professor Bai Ou said that in the process of DHL treatment, special attention needs to be paid to the prevention of the central nervous system (CNS), the choice of transplantation methods, and the application of chimeric antigen receptor T cells (CAR-T) immunotherapy.

CNS prevention is necessary for DHL patients.

MD Anderson Cancer Research Center's research results showed that the cumulative incidence of CNS recurrence in DHL patients reached 13% in 3 years.
Compared with patients who did not receive CNS prevention, patients who received CNS prevention had a better prognosis (median OS: 45 months) vs 15 months; P=0.
06).

 Some studies have explored the choice of transplantation methods after induction therapy in DHL patients.

A multi-center retrospective study showed that for patients with DHL who achieved complete remission (CR) through enhanced regimens, ASCT and non-ASCT had no difference in prognosis; for patients who achieved CR after R-CHOP regimen, ASCT was compared with Non-ASCT can significantly improve the prognosis of patients.

A study conducted in Australia compared the effects of ASCT and Allo-SCT on the prognosis of DHL patients.

The results of the study showed that there was no significant difference in overall OS between patients receiving the two transplantation methods, but for patients with poor R-IPI scores, Allo-SCT can bring a better prognosis.

 At present, CAR-T therapy in the treatment of DHL/DEL has shown good results in multiple studies (phase I TRANSCEND NHL 001 study, single-arm phase I/II ZUMA-1 study, single-arm phase II JULIET study).

At present, lenalidomide combined with CAR-19 and CAR-20 T cell treatment of DHL/DEL exploratory research is also underway.
CAR-T therapy may change the treatment mode of DHL in the future.

New treatment plan for DHL/DEL The current new treatment plan for DHL/DEL focuses on inhibitors of MYC and BCL-2 signaling pathways, including Bcl-2 inhibitors, BTK inhibitors, lenalidomide and other drugs.

The results of the PHOENIX study showed that the combination of the BTK inhibitor ibrutinib on the basis of the R-CHOP regimen can improve the EFS of DEL patients.

For DEL patients less than 60 years old, the program can also significantly improve OS.

The results of the CAVALLI study showed that the combination of the Bcl-2 inhibitor Veneclax on the basis of the R-CHOP regimen can significantly improve the CR rate of DHL patients and at the same time improve the PFS of DEL patients.

The results of the Smart start study showed that after rituximab combined with lenalidomide and ibrutinib regimen (RLI) treatment, there was no difference in time to tumor progression (TTP) between DEL patients and non-DEL patients.
This regimen can improve DEL patients The poor prognosis.

 China has also carried out a number of studies to explore treatment options for DHL/DEL.

West China Hospital of Sichuan University explored the efficacy of chidamide combined with R-CHOP regimen in the treatment of newly treated DE-DLBCL patients.

Research results show that the CR rate of the program can reach 82.
9%, and the safety is reliable.

The team of Professor Weilai Zhao from Ruijin Hospital Affiliated to Shanghai Jiaotong University also explored the efficacy of chidamide combined with R-CHOP in the middle and high-risk elderly patients with DE-DLBCL.

The results of the study showed that the CR rate of the program reached 86%, and the overall response rate (ORR) reached 94%.

At present, the combined program has been included in the annotations of the CSCO lymphoma diagnosis and treatment guidelines.
A phase III controlled study of the combined program for the treatment of DE-DLBCL is also being carried out nationwide.
It is hoped that the publication of future research results can bring better results for DHL/DEL patients Treatment options improve the patient’s prognosis.

 Summary Professor Bai Ou finally concluded: DHL/DEL is related to MYC/BCL2 gene and protein changes and determines the poor prognosis of the patient.

The R-ECHOP program can partially improve the prognosis of DHL/DEL patients, but the program still needs follow-up exploration.

The improvement of ASCT's prognosis for DHL/DEL needs to be further confirmed by subsequent studies with larger sample sizes.

The combination of CAR-T therapy and new drugs is a treatment option worth paying attention to in the future DHL/DEL treatment.

Professor Bai Ou, Deputy Director, Department of Hematology, Bethune First Hospital, Jilin University, Head of the Lymphoma Specialist Alliance, Bethune First Hospital, Jilin University, Member of the Lymphocytic Disease Group of the 11th Committee of the Chinese Medical Association Hematology Branch, Chinese Society of Clinical Oncology (CSCO) Member of the Standing Committee of the Lymphoma Professional Committee of the Chinese Anti-Cancer Association CSCO Member of the Standing Committee of the Chinese Anti-Lymphoma Alliance (UCLI) Member of the Standing Committee of the 5th Clinical Chemotherapy Committee of the Chinese Anti-Cancer Association Member of the Standing Committee of the First Committee of the Hematology Branch of the Chinese Society of Geriatrics China Healthcare Member of the Standing Committee of the Oncology Branch of the International Exchange Promotion Association CSCO Member of the Chinese Anti-Leukemia Alliance (UCLI) stamp "Read the original text", we make progress together