Editor’s Note: The 17th International Conference on Malignant Lymphoma (ICML) took place from June 13 to 17, 2023, in Lugano, Switzerland. As the largest international conference in the field of malignant lymphoma, it brought together global lymphoma experts to share and discuss cutting-edge research. During this conference, Dr. Zhang Huilai’s team from Tianjin Medical University Cancer Institute, China, presented multiple studies on follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). We had the opportunity to invite Dr. Zhang Huilai to provide in-depth interpretations.
Oncology Frontier: Your team’s study (abstract 268) at this ICML conference explored the gene mutation status associated with early progression in follicular lymphoma (FL). Could you please interpret this study?
Dr. Zhang Huilai: FL is the most common indolent non-Hodgkin lymphoma, exhibiting high heterogeneity in clinical manifestations, biological characteristics, and prognosis. Approximately 20% to 30% of FL patients experience disease progression within 2 years of first-line treatment (POD24). These patients have a poorer prognosis, with a 5-year overall survival (OS) rate of about 34% to 50%, significantly lower than non-POD24 patients with a 90% survival rate. However, the risk factors associated with POD24 are still undetermined. Furthermore, the prognostic value of driver gene mutations and copy number variations has not been systematically evaluated in FL.
We analyzed the clinical and biological characteristics of 415 FL patients to identify clinical features associated with POD24. Additionally, we conducted whole-exome sequencing and transcriptomic analysis on 102 FL patients to explore genetic changes associated with early progression.
The results showed that 21% of evaluable FL patients experienced POD24, with a 5-year OS rate of 82.9%, significantly lower than non-POD24 patients with a rate of 96.2%. Patients with B symptoms, elevated lactate dehydrogenase and β2-microglobulin levels, low hemoglobin, Ann Arbor stage III-IV, and high FLIPI risk had an increased risk of POD24. High FLIPI was identified as an independent risk factor for POD24 through logistic regression analysis. Among all non-silent mutations occurring in somatic cells, 23 genes were identified as cancer driver genes, with the HIST1H1D gene mutation significantly associated with POD24. Gains in 6p22.2 (HIST1H1D), 18q21.33 (BCL2), and loss in 1p36.13 (NBPF1) independently predicted POD24 in addition to FLIPI. Integrating these four types of variations identified 76% of POD24 patients. Gene expression profiling (GEP) of 41 FL patients showed significant enrichment of pathways related to inflammation response and cell cycle regulation in the POD24 group.
In summary, we conducted a comprehensive genomic and transcriptomic study of FL patients with POD24 and non-POD24, revealing unique clinical, genetic, and molecular features in patients with POD24. This study provides insights for the development of new treatment strategies in the future.
Oncology Frontier: In abstract 467, the study elaborates on the correlation between PIM1 gene translocation and the phenotype and drug treatment response in diffuse large B-cell lymphoma (DLBCL). Could you please interpret this study?
Dr. Zhang Huilai: PIM1 is one of the highly mutated genes in DLBCL. The aim of our study was to explore the specific genetic changes of the PIM1 gene in DLBCL patients and its value in identifying high-risk patients and guiding personalized treatment.
The study conducted targeted sequencing of 307 lymphoma-related genes in 162 samples from our center, along with analysis of genomic profiles, PIM1 gene mutation types, and mutually exclusive and co-mutated genes. Additionally, transcriptome sequencing was performed on 140 DLBCL patients to predict the treatment response to common chemotherapy and targeted drugs based on establishing gene features associated with PIM1 mutations.
The results showed that patients with PIM1 mutations had higher IPI scores, were more prone to disease recurrence and involvement of the testes and/or central nervous system, and had poorer progression-free survival (PFS) and overall survival (OS). The forms of PIM1 gene mutations were mainly missense and nonsense mutations and frame-shift mutations, occurring primarily in the protein kinase domain. The study also found co-mutations of the PIM1 gene with SETD1B, CD79B, MYD88, and mutual exclusion with the SPEN gene. At the transcriptome level, PIM1 gene mutations may lead to dysregulation of signaling pathways such as JAK-STAT and NF-κB. Furthermore, we constructed a risk score prognosis model related to PIM1 mutations, with patients in the high-risk group having a worse prognosis and higher sensitivity to TGFβ receptor inhibitors, lenalidomide, NF-κB inhibitors, and JAK inhibitors.
In summary, we elucidated the potential pathogenic mechanisms by which PIM1 mutations lead to poorer prognosis in DLBCL, providing personalized treatment strategies for DLBCL patients with PIM1 mutations. We will continue to explore this in more depth in the future.
Oncology Frontier: Could you introduce the progress in the application of new drugs for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) at this ICML conference?
Dr. Zhang Huilai: The survival outcomes of DLBCL patients have significantly improved with the emergence of new treatment methods, but still, one-third of patients eventually develop into relapsed/refractory (R/R) disease, becoming a major cause of death in DLBCL patients. In China, there are limited effective treatment options for R/R DLBCL, especially for patients who are not suitable for high-dose chemotherapy/stem cell transplantation (HDT/SCT). Therefore, selecting effective and safe low-toxicity treatment strategies has become a clinical challenge for these DLBCL patients.
The new generation BTK inhibitor zanubrutinib is a potent and highly selective Bruton’s tyrosine kinase inhibitor (BTKi) approved for the treatment of various B-cell malignancies. Preclinical data also suggest a synergistic effect of zanubrutinib in combination with lenalidomide. At this ICML conference, our center led the BGB-3111-110 study using a Chemo-Free strategy, combining zanubrutinib with lenalidomide for the treatment of R/R DLBCL patients who are not suitable for HDT/SCT. We presented the interim analysis results of this study for the first time, showing that in all populations under the recommended phase 2 dose (RP2D), the objective response rate (ORR) of zanubrutinib in combination with lenalidomide was 56.7%, with a complete response (CR) rate of 30%. The efficacy seemed to be better in the non-germinal center B-cell (Non-GCB) population: ORR was 60.9%, and CR was 34.8%. The safety profile of patients in the study was tolerable, and adverse events were manageable.
The interim analysis results of the 110 study suggest that the combination of zanubrutinib and lenalidomide may provide an effective and low-toxic Chemo-Free treatment strategy for R/R DLBCL patients who cannot tolerate HDT/SCT. The study is still ongoing, and we will continue to evaluate the feasibility of the combination regimen in a larger sample size and longer follow-up in the future.
TAG: ICML 2023, Interview, Voice of China，Hematological Malignancy, Follicular Lymphoma，DLBCL
