R-CHOP With Added Genetic Subtype-Based Targeted Therapy Improves CR Rates in Newly Diagnosed DLBCL

A genetic subtype-guided approach to giving immunochemotherapy for patients with diffuse large B-cell lymphoma (DLBCL) showed encouraging rate of complete response (CR) in first reports from the phase 2 Guidance-01 trial (NCT04025593).¹

According to findings presented at the 2021 International Conference on Malignant Lymphoma, 5 of the regimens using R-CHOP (rituximab [Rituxan] plus cyclophosphamide, doxorubicin, vincristine, and prednisone) plus a genetic subtype–related treatment led to durable remissions and manageable toxicity. Presenter Mu-Chen Zhang, MD, reminded that DLBCL is associated with a degree of heterogeneity in terms of clinical and biological features. R-CHOP immunochemotherapy, the standard of care for patients with newly diagnosed DLBCL, leads to CRs in about 60% of patients.

“Genetic subtypes of DLBCL have distinct oncogenic pathway features, gene expression profiles, and variable clinical outcomes. Thismay explain why these patients are varied from the standard R-CHOP regimen,” said Zhang, of the Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine in Shanghai, China.

The investigators sought to determine if adding novel targeted agents to R-CHOP (R-CHOP-X) based on the genetic subtype of each patient’s disease could lead to improved clinical efficacy in the frontline setting.

All patients received at least 1 cycle of standard R-CHOP prior to randomization and stratification. Then, patients randomized to the R-CHOP-X arm were classified into 1 of 6 genetic subtypes by targeted sequencing and fluorescence in situ hybridization testing into classification groups defined in 2018 in the New England Journal of Medicine.2 The subtypes were MCD-like, BN2-like, N1-like, EZB-like, TP53-mutated, and others.

In the MCD-like and BN2-like groups, patients received ibrutinib (Imbruvica) 420 mg twice daily; the N1-like and other subtype groups received lenalidomide (Revlimid) 25 mg once daily for days 1 to 10; those with EZB-like disease received tucidinostat, an HDAC inhibitor, at 20 mg on days 1, 4, 8, and 11; and the group with TP53-mutant disease received decitabine at 10 mg/m2 on days 1 through 5. All patients also received R-CHOP and treatment was given for 5 cycles. Granulocyte colony-stimulating factor prophylaxis was given in the case of grade 3 or higher neutropenia.

The primary end point was CR rate, and secondary end points included progression- free survival (PFS), overall survival, objective response rate, and safety. The study assumed that 65% of patients in the R-CHOP control group and 85% of patients in the R-CHOP-X group would achieve a CR.

All patients had to have newly diagnosed disease, be aged 18-80 years, and have an International Prognostic Index (IPI) score of 2 or higher, ECOG performance status of 0 to 2, ejection fraction greater than 50%, and preserved organ and bone marrow function. Those with primary central nervous system lymphoma; uncontrollable cardio-cerebral vascular, coagulation, autoimmune, or infectious disease; active hepatitis B virus; or a history of HIV were excluded from the trial.

Patients were required to have absolute neutrophil count levels greater than 1500/mL and platelet levels greater than 75,000/mL at the time of retreatment, or immunochemotherapy would be delayed. If delayed by 8 to 14 days because of thrombocytopenia or neutropenia, the dose of cyclophosphamide and doxorubicin would be reduced. Targeted therapies were not held and doses were not modified midcycle.

Baseline characteristics were similar between the 2 arms. Among all 128 patients, the median age was 64 years (range, 25-74), and the majority were male (52%), had stage III-IV disease (77%), at least 2 extranodal sites (52%), an ECOG performance status of 0 or 1 (83%), and an IPI score of 3 to 5 (65%). Zhang noted that this indicated that this was a high-risk population.

Thirty-eight percent of patients had germinal center B-cell like disease, and 36% had MYC/BCL2 double expression.

The primary end point was met with 87% (95% CI, 79%-96%) of patients in the R-CHOP-X arm and 66% (95% CI, 54%-78%) in the R-CHOP control arm achieving CR (P = .003). Partial responses were observed in 5% of patients in the R-CHOP-X arm and in 9% of the R-CHOP arm, stable disease was reached in 5% and 8% of patients, respectively, and 3% and 17% of patients had progressive disease.

Patients were followed for survival for a median of 16.1 months. At 1 year, the PFS rate was 93% (95% CI, 81%-97%) in the R-CHOP-X arm and 73% (95% CI, 60%-83%) in the R-CHOP arm.

By genetic subtype groupings, the CR rate was higher in the R-CHOP-X arm than in the R-CHOP arm (TABLE1). Significant increases in CR were observed in the MCDlike (85% with R-CHOP and ibrutinib vs 54% with R-CHOP), BN2-like (91% with R-CHOP and ibrutinib vs 67% with R-CHOP), and TP53-mutant (82% with R-CHOP and decitabine vs 60% with R-CHOP) groups where the patient populations were larger and able to show a difference. In the “others” group, the rate was similar, at 88% with R-CHOP plus lenalidomide (n = 25) compared with 80% with R-CHOP alone (n = 25).

Zhang noted that grade 3 or 4 hematologic adverse events were common in the 2 arms. Neutropenia was observed in 81% of patients in the R-CHOP-X arm vs in 75% of the R-CHOP arm; thrombocytopenia in 31% and 11%, respectively; anemia in 25% and 20%; and febrile neutropenia in 20% and 11%. Cytopenia and thrombocytopenia were manageable with supportive care and without treatmentrelated mortality. No grade 4 non-hematologic adverse events were reported.

Despite the increased rate of AEs, the dose intensity of chemotherapy was maintained at similar levels between the 2 arms, Zhang said. She highlighted that this was the first study of genetic subtype–guided therapy in DLBCL.

_REFERENCES:

_{1. Zhang MC, Xu PP, Wang L, Cheng S, Zhao WL. Genetic subtype guided rituximab-based immunochemotherapy improves outcome in newly diagnosed diffuse large B-cell lymphoma: first report of a randomized phase 2 study (Guidance-01). Presented at: 16th International Conference on Malignant Lymphoma; June 19-22, 2021; virtual. Abstract 026.}

_{2. Schmitz R, Wright GW, Huang DW, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378(15):1396- 1407. doi:10.1056/NEJMoa1801445}