Prof. Qingyuan Zhang: Advances in the treatment of relapsed and refractory diffuse large B-cell lymphoma 2021 China Oncology Congress

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), accounting for 50% of B-cell lymphomas in China
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R-CHOP is the standard first-line treatment for DLBCL, but 40%-50% of patients still experience relapse or refractory (R/R)
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The current standard treatment for R/R DLBCL patients is salvage chemotherapy followed by transplantation, but the efficacy is not satisfactory, and there is still a very high unmet medical need
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At the 2021 China Oncology Conference (CCO) held online from April 14 to 17, 2022, Professor Zhang Qingyuan from the Cancer Hospital Affiliated to Harbin Medical University summarized and shared the research progress of R/R DLBCL treatment.
The editor will organize the main contents as follows: For readers' reference
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Antibody-conjugated drug (ADC) Polatuzumab Vedotin (Pola): ADC targeting CD79b was approved for marketing in the United States in 2019 by Pola, with breakthrough therapy designation, priority review and orphan drug status, and will be approved for marketing in the European Union in 2020
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The GO29365 study updated and expanded the treatment of Pola + rituximab combined with bendamustine (BR) in patients with R/R DLBCL.
The median PFS (9.
2 months vs 3.
7 months) and median OS (12.
4 months vs 4.
7 months) were significantly prolonged, and the significant survival benefit in the Pola+BR group persisted with longer follow-up, with a 2-year PFS rate was 28.
4%, the 2-year OS rate was 38.
2%, and the major adverse events were hematological toxicity
.

Loncastuximab Tesirine (Lonca): humanized anti-CD19 ADC2021 US Food and Drug Administration (FDA) accelerated approval of Lonca for the treatment of R/R DLBCL who have received 2 or more lines of therapy
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The LOTIS-2 study explored the efficacy of Lonca monotherapy for 3rd-line and above R/R DLBCL treatment of R/R DLBCL.
The results of the study showed that the objective response rate (ORR) of Lonca monotherapy could reach 48.
3%, The median duration of response (DOR) was 10.
3 months, the median PFS was 4.
9 months, and the median OS was 9.
9 months; in addition, Lonca was also effective in patients who relapsed after CAR-T cell therapy
.

The LOTIS-3 study explored the efficacy of the combination of Lonca and ibrutinib in the treatment of R/R DLBCL.
The results showed that the ORR of Lonca + ibrutinib reached 57.
1% in R/R DLBCL patients, showing antitumor activity and Manageable security features
.

CD19 monoclonal antibody Tafasitamab: a novel humanized monoclonal antibody optimized for the Fc domain of CD19 In 2020, Tafasitamab was approved in the United States in combination with lenalidomide for the treatment of adult patients with unspecified relapsed or refractory DLBCL , including low-grade lymphoma-transformed DLBCL and patients with DLBCL who are not candidates for ASCT
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The L-MIND study explored the efficacy of Tafasitamab combined with lenalidomide in the treatment of R/R DLBCL not suitable for transplantation.
The results showed that the ORR of Tafasitamab combined with lenalidomide could reach 57.
5%, and 40% of patients could achieve complete remission (CR), patients who achieve CR or partial remission (PR) can obtain longer remission time
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XOP1 inhibitor (XOP1i) selenisol: the first oral selective nuclear export protein inhibitor 2020 FDA approved selenisol for R/R DLBCL patients who have received ≥2 lines of therapy, recommended by NCCN guidelines in 2021 Selinesol is used in the third-line and subsequent treatment of DLBCL
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The SADAL study explored the efficacy of selenisole in the treatment of R/R DLBCL patients, and the results showed that selenisole monotherapy achieved deep and durable efficacy in some R/R DLBCL patients
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The relevant clinical studies of selinisol in R/R DLBCL are shown in Table 1
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Table 1 Bruton's tyrosine kinase inhibitor (BTKi) Tirabrutinib According to genotype, DLBCL can be divided into EZB type, ST2 type, BN2 type, A53 type, N1 type and MCD type (MYD88 and CD79B mutation)
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Lymphomas with extranodal involvement have a poor prognosis and frequently have MYD88 and CD79B mutations
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Studies have shown that BTKi is more effective in DLBCL patients with MCD subtypes (MYD88 and CD78B mutations)
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In addition, primary central nervous system lymphoma (PCNSL) is often accompanied by MYD88 and CD78B mutations.
The results of a phase 1/2 study showed that tirabrutinib monotherapy in R/R PCNSL had an ORR of 64% and a CR rate of up to 64%.
34%, which provides a good reference for the precise treatment of DLBCL
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CD20/CD3 bi-antibodies Currently, a variety of CD20/CD3 bispecific antibodies are undergoing clinical research in NHL
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Relevant drug research is mainly concentrated in phase 1/2 trials
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Glofitamab The results of a Phase I/II study of Glofitamab as a single-agent fixed-course treatment in R/R NHL showed that Glofitamab treatment has high response rates and durable responses
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The results of a phase Ib/II study of Pola combined with Glofitamab in the treatment of R/R DLBCL showed that the combination therapy achieved ORR of 79.
6% and 51% of patients achieved CR
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Mosunetuzumab A phase Ib/II study of Pola combined with Mosunetuzumab in patients with R/R aggressive NHL showed that ORR was 65% in DLBCL patients and 62.
5% in DLBCL patients who had previously received CAR-T therapy
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Regarding the innovative ADC and dual antibody combination therapy, Prof.
Qingyuan Zhang concluded: (1) Glofitamab combined with Pola showed safe tolerable and encouraging preliminary efficacy in R/R DLBCL patients; (2) Mosunetuzumab combined with Pola Treatment of R/R mature B-cell NHL patients (focus on DLBCL) showed a high remission rate; (3) this type of combination therapy has a manageable safety profile, and the overall safety profile is consistent with the safety of each drug; (4) Pola Both studies in combination with dual antibody support a confirmatory phase III study
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CAR-T vs second-line standard treatment At present, CAR-T has achieved good results in the treatment of R/R DLBCL after second-line treatment, and whether CAR-T can be advanced for second-line treatment has also become a clinical concern
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The efficacy of CAR-T therapy versus standard second-line therapy in R/R DLBCL was analyzed in 3 studies at ASH 2021: TRANSFORM (Liso-cel) and ZUMA-7 (Axi-cel) with positive results
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The BELINDA study (Tisa-cel) did not yield positive results
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See Table 2 for test details
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Table 2 Summary and Outlook Professor Zhang Qingyuan concluded that for R/R DLBCL patients who are not suitable or unable to receive high-dose chemotherapy combined with ASCT, immune/chemotherapy regimens have limited efficacy, and more effective and well-tolerated drugs are needed
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For the new drugs currently under study: ADC (Pola, Lonca) and monoclonal antibody (Tafasitamab) have been marketed abroad and have good curative effect; XOP1i (Selineniso) is used for third-line and follow-up treatment, with good tolerance and elderly patients.
Better tolerance can also be achieved in the patient population; BTKi treatment will still be a personalized treatment under the guidance of precise treatment in the future; although double-antibody drugs have achieved good efficacy, the research is still in the early stage, and the future phase III can be expected Confirmatory study; CAR-T therapy has achieved good efficacy in R/R high-risk patients, but CAR-T therapy is expensive, the accessibility of this therapy should be increased in the future, and the best suitable population for this therapy should be explored and Best time
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Professor Zhang Qingyuan Chief Physician, Second-level Professor, Doctoral Supervisor, Provincial Teaching Famous Teacher, Director of Heilongjiang Cancer Prevention and Control Institute, Vice President of Harbin Medical University Affiliated Cancer Hospital, Chief Scientist of Harbin Medical University Specialist leader National Million Talent Project Selected National Outstanding Contribution Young and Middle-aged Expert Chairman-designate of Lymphoma Professional Committee of China Anti-Cancer Association : Wenting pokes "read the original text", let's make progress together