"Phoenix" reborn!

By Arale

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30% to 40% of non-Hodgkin lymphomas (NHLs) and is highly heterogeneous

Currently, the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) is the first-line standard of care for DLBCL

Studies have shown that sustained activation of the B cell antigen recognition receptor (BCR) signaling pathway plays a key role in the proliferation and survival of lymphoid tumor cells

Previous studies have found that ibrutinib shows good clinical efficacy in relapsed/refractory DLBCL, and the efficacy in ABC subtype is better than that in GCB subtype, which may be related to the continuous activation of BCR signaling pathway in ABC subtype

Lost "Phoenix"

The Phoenix study, a double-blind phase III clinical trial, aims to evaluate the efficacy of ibrutinib combined with R-CHOP regimen in newly-treated non-GCB DLBCL patients.

A total of 838 patients were included in the trial, randomized into two groups, and 75.

Investigator-assessed EFS in the ITT population.

A preplanned analysis showed a significant interaction between treatment and age

Investigator-assessed EFS in patients <60 years old.

In patients aged ≥60 years, ibrutinib combined with R-CHOP had poorer EFS, PFS and OS, significantly increased the incidence of serious adverse events (63.

Continuous improvement of DLBCL genotyping

Existing studies suggest that COO typing based on gene expression profile (GFP) cannot fully explain the differences in the efficacy of DLBCL targeted therapy

In 2018, Schmitz et al.

The proportion of each molecular type.

Subsequent studies found that "quartiles" only covered less than 50% of cases

Gene characteristics and prognosis of DLBCL "septyping".

Precisely divide the crowd, "Phoenix" is reborn

As mentioned above, the Phoenix study showed that in young patients with non-GCB DLBCL (≤60 years old), ibrutinib combined with R-CHOP regimen can bring a survival benefit, but the molecular basis of this benefit is unclear

The scientists further analyzed tissue samples from patients in the Phoenix study, which were divided into 3 subtypes: MCD, BN2, and N1
.
The specific results were officially published as a cover study in Cancer Cell on December 13, 2021 [6]
.
In patients with MCD and N1 subtypes (age ≤60 years), the 3-year EFS of ibrutinib combined with R-CHOP was 100%, while the EFS of patients who received only R-CHOP was significantly worse, 42.
9% and 50%, respectively
.

EFS of MCD, BN2, and N1 subtypes.
Image from: Cancer Cell.
2021; 39(12): 1643-1653.

The researchers mentioned in the Discussion section that the effect of age on the efficacy of ibrutinib may be secondary, rather than primary, and this correlation can be viewed as a subset analysis
.
The most significant benefit of ibrutinib was observed in specific subtypes of younger patients, and is supported by biological basis
.
Due to specimen limitations, this study was not able to assess genotypes such as A53
.
Therefore, the benefit of ibrutinib may not be limited to the two subtypes of MCD and N1
.

According to the existing research, COO classification can no longer meet the clinical needs
.
The Phoenix results have implications for clinical treatment, and treatment based on new genotype molecular typing is the future direction of development
.
However, the high cost of sequencing and the complexity of data analysis also limit the practical application in clinical practice
.
We look forward to further improving and standardizing the sequencing platform in the future to bring practical help to clinical diagnosis and treatment and patients
.

references

1.
China Oncology Clinic.
2021; 48(5): 264-268.

2.
Chinese Journal of Hematology.
2013; 34(5): 471-472.

3.
J Clin Oncol.
2019; 37(15): 1285-1295.

4.
N Engl J Med.
2018; 378(15): 1396-1407.

5.
Cancer Cell.
2020; 37(4): 551-568.

6.
Cancer Cell.
2021; 39(12): 1643-1653

(Original abridged)