The first-line standard treatment of lymphoma can not be shaken for 20 years?

Article source: Med

Author: Mu Mu

The annual American Society of Hematology (ASH) annual meeting is one of the largest international academic events in the field of hematology in the world.

At the 2021 ASH Annual Meeting held recently, Vibotuzumab combined with R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) compared with R-CHOP (rituximab) , Cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line treatment of diffuse large B-cell lymphoma (DLBCL) phase III POLARIX study as the "latest breakthrough study (LBA-1)" released detailed data, and Simultaneously published in NEJM[1]

Since then, Pola-R-CHP has become the first DLBCL treatment regimen in a phase III study that has a curative effect over R-CHOP in the past 20 years

Heavy! Significant progress in the first-line treatment of lymphoma in the past 20 years

DLBCL is the most common histological subtype of non-Hodgkin's lymphoma (NHL), accounting for about 30-40% of NHL

In the past two decades, researchers have initiated several studies to try to improve the first-line treatment effect of DLBCL through intensive treatment, consolidation treatment, maintenance treatment, optimization of anti-CD20 antibodies, and new targeted drugs.

Figure: Important Phase 3 clinical studies and primary endpoint results for DLBCL first-line treatment; Remarks: Although R-ACVBP and HDT/ASCT consolidation programs reach the primary endpoint, the former is more toxic, the latter does not show OS benefit and NCCN guidelines are not recommended for patients Routine use, in addition, lenalidomide maintenance therapy only showed EFS benefit in elderly patients and did not show OS benefit

Verbotuzumab (PolatuzumabVedotin, Pola) is a CD79b-targeted ADC drug that specifically binds to the CD79b antigen on the surface of B cells, and releases MMAE through internalization and enzyme cleavage.

Source: Roche official website

In 2019, the FDA approved the combination of bendamustine and rituximab (Pola-BR) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R /RDLBCL), Pola became the world's first approved ADC drug in the DLBCL field

POLARIX study: Reduce the risk of disease progression or death by 27%

The POLARIX study is a global multi-center, randomized, double-blind, placebo-controlled phase III clinical study, carried out in 243 centers around the world (including 15 Chinese clinical centers), and enrolled previously untreated DLBCL patients (18-80 Years old, IPI2-5, ECOG PS 0-2), randomized to receive Pola-R-CHP or R-CHOP + placebo (6 cycles) + rituximab (2 cycles) treatment at a ratio of 1:1

POLARIX trial design (Source: ASH2021)

The study enrolled a total of 879 patients, including 160 Asian patients, with a median age of 65 (19-80) years old.

POLARIX baseline characteristics (Source: ASH2021)

The results of the study showed that at a median follow-up of 28.

(Source: N Engl J Med.

In terms of key secondary endpoints, the 2-year EFS rate of the Pola-R-CHP group was significantly higher than that of the R-CHOP group (75.

In addition, there was no significant difference in CR rate at the end of treatment between the two groups (78% vs 74%, p=0.

In terms of safety, the data of the Pola-R-CHP group and the R-CHOP group were roughly the same, no unexpected safety signals were found, and the incidence of serious adverse events was 34% and 30.

Subgroup analysis showed that Pola-R-CHP group can see PFS benefit in patients with age> 60 years, IPI3-5 points, activated B cell subtype (ABC) subtype, but in patients ≤60 years old, IPI 2 points, with There was no significant difference in PFS between the two groups in patients with bulky disease (bulkydisease) and GCB subtypes, and the PFS value of the R-CHOP regimen was better for patients with double/triple-hit lymphoma

In summary, the POLARIX study confirmed that compared to R-CHOP, the Pola-R-CHP regimen significantly improved the PFS of newly treated DLBCL patients, and successfully broke through the "ceiling" of the first-line treatment of DLBCL
.
However, considering that OS is susceptible to posterior-line treatment, and the proportion of patients in the R-CHOP group receiving transplantation and CAR-T treatment is higher than that in the Pola-R-CHP group, it is still necessary to wait patiently for a longer follow-up time to update the evidence
.

What's more: Where is the way for the first-line precision treatment of DLBCL?

As we all know, diffuse large B-cell lymphoma (DLBCL) is a type of malignant tumor with large heterogeneity that originates from B lymphocytes
.
The ideal state is that each patient can be genotyped, and the precise treatment given based on the genotype
.

Although three phase III studies based on DLBCL cell origin (COO) typing (PHOENIX: Ibrutinib + R-CHOP, REMoDL-B: Bortezomib + R-CHOP, ROBUST: Lenalidomide + R-CHOP) ) Did not reach the end point, but with the deepening of understanding of the heterogeneity of DLBCL, especially the DLBCL Cluster [5] and LymphGen classification proposed by Professor Shipp and Professor Staudt based on sequencing technology [6], it is a more accurate choice for patients And targeted therapy provides the basis
.

The post-mortem analysis of the PHOENIX study showed that the EFS and OS of patients with MCD and N1 subtypes less than 60 years old can reach 100% after 3 years of treatment with Ibrutinib + R-CHOP, which is significantly higher than that of the control group [7]
.
At the International Conference on Lymphoma (ICML) in July this year, Professor Zhao Weilai from Shanghai Ruijin Hospital also reported that the first-line treatment of DLBCL in the Phase 2 Guidance-01 study "R-CHOP+X based on molecular classification" has significantly better efficacy than R-CHOP Scheme (CR 87% vs 66%, p=0.
003)
.

COO, DLBCL Cluster, LymphGen classification and its relationship (Source: N Engl JMed.
2021;384(9))

This time, at this ASH conference, CAR-T cell therapy Akirensai (ZUMA-12, abstract #739), a multi-drug combination regimen of Zebutinib + lenalidomide + R-CHOP (Abstract #3559), Anti-CD20/CD3 double antibody epcoritamab combined with R-CHOP (Abstract #1413), anti-CD19 monoclonal antibody Tafasitamab±lenalidomide combined with R-CHOP (Abstract #3556) also showed that it is against naive DLBCL in the phase 2 study Good curative effect for the crowd
.

At present, a number of Phase III studies on the first-line treatment of DLBCL are underway, and we look forward to more evidence-based results in the future to explore options for first-line treatment of DLBCL based on genotyping
.

Table: Ongoing Phase III studies of the first-line treatment of DLBCL (Source: Clinicaltrials)

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