In recent years, the field of hematologic malignancies has witnessed remarkable breakthroughs, with Chinese researchers making increasingly significant contributions, particularly in cellular therapy. Their work has played a crucial role in advancing both scientific progress and clinical practice. As we step into the new year, Hematology Frontier has invited Dr. Huilai Zhang from Tianjin Medical University Cancer Institute and Hospital to provide an in-depth review of the current landscape and key developments in follicular lymphoma in 2024. This comprehensive analysis aims to offer valuable insights for clinical practice and future research directions.

Follicular lymphoma (FL), a malignant tumor of the lymphatic system, is gradually moving toward the goal of “functional cure.” Clinical data indicate that approximately one-third of FL patients require only first-line treatment throughout their lifetime, while another one-third of patients receiving second-line therapy may also achieve survival spanning several decades. This promising trend highlights significant advancements in FL treatment.

The concept of “functional cure” refers to patients achieving long-term survival despite not completely eradicating the disease, with lymphoma having minimal impact on their quality of life and life expectancy. However, it is important to note that FL prognosis varies significantly among individuals. Around 10% of patients survive less than five years, particularly those who experience early relapse after first-line chemoimmunotherapy, histologic transformation, or multiple relapses. These patients face a poorer prognosis and greater treatment challenges.

In 2024, numerous studies on FL have introduced new approaches and strategies in treatment. This article will review the latest research progress in first-line therapy and relapsed/refractory (R/R) FL treatment, offering insights to guide clinical practice.

01. Timing of Treatment in Elderly FL Patients

The optimal timing of treatment for elderly patients with follicular lymphoma (FL) has been a key focus in 2024, with several studies providing new insights and perspectives. One notable single-center retrospective study explored how differences in treatment strategies between elderly and younger patients impact prognosis.

This study included patients diagnosed with grade 1-3A FL between January 2008 and January 2023 and classified individuals aged ≥75 years as elderly based on the FLIPI-24 risk model. Among the 188 patients enrolled, 19% were aged 75 or older. Compared to younger patients, elderly patients were significantly more likely to meet the Groupe d’Etude des Lymphomes Folliculaires (GELF) criteria for treatment initiation, with 57.6% meeting the criteria compared to 36.1% of younger patients. Despite this, the proportion of patients managed with watch-and-wait (W&W) was similar between the two groups, at 55.6% for elderly patients and 59.9% for younger ones. The time to first treatment (TTFT) did not differ significantly between elderly and younger patients (P=0.51).

However, elderly patients had significantly shorter progression-free survival (PFS) and overall survival (OS) compared to younger patients. These findings suggest that elderly FL patients generally have worse prognoses, and delayed treatment initiation may contribute to poorer outcomes. Further multicenter studies are needed to validate these conclusions.

Another noteworthy retrospective study was conducted across eight research centers in Australia, focusing on the potential risks and practical applications of the watch-and-wait strategy for newly diagnosed FL patients in the rituximab era. This study included patients diagnosed with grade 1-3A FL between 2004 and 2018 who had undergone an observation period of at least three months before treatment initiation.

The findings, based on data from 276 patients, revealed that with a median follow-up of 5.5 years, the median time to next treatment (TTNT) was 4.98 years. At the five-year mark, 49% of patients had still not required treatment, though 28.7% experienced adverse events during the watch-and-wait period. While this strategy was generally safe for most patients, 10% developed end-organ dysfunction, and the five-year transformation rate reached 11.2%.

Additionally, the study identified key factors associated with TTNT, including elevated baseline lactate dehydrogenase (LDH) levels and involvement of more than four lymph nodes. These findings suggest that a more refined and proactive approach to the watch-and-wait strategy may be beneficial, offering valuable guidance for patient counseling and risk stratification.

02. Exploring Chemotherapy-Free or Chemotherapy-Reduced Strategies

With continuous advancements in medical science and technology, targeted therapies have demonstrated remarkable efficacy in the treatment of follicular lymphoma (FL). Unlike traditional chemoimmunotherapy regimens, these novel agents exhibit distinct safety profiles, driving a paradigm shift in first-line FL treatment toward chemotherapy-free or chemotherapy-reduced approaches.

The RELEVANCE study represents a milestone in this field, comparing the efficacy and safety of rituximab plus chemotherapy versus rituximab combined with lenalidomide (R2) in FL patients. The findings revealed that compared to chemoimmunotherapy, the R2 regimen significantly reduced the incidence of grade 3/4 adverse events (32% vs. 50%) and lowered the occurrence of febrile neutropenia at any grade (2% vs. 7%). However, the R2 regimen was associated with a higher incidence of grade 3/4 skin reactions (7% vs. 1%). In terms of efficacy, no significant differences were observed between the two groups in progression-free survival (PFS) and overall survival (OS). These results further underscore the potential value and promising future of chemotherapy-free strategies in first-line FL treatment.

In addition to RELEVANCE, multiple ongoing clinical trials are actively investigating novel therapeutic combinations to refine and optimize chemotherapy-free or chemotherapy-reduced regimens. These studies explore a diverse range of agents, including Bruton’s tyrosine kinase (BTK) inhibitors, bispecific antibodies, molecular glues, and EZH2 inhibitors. The integration of these targeted therapies is expanding treatment options for FL patients, offering more personalized and innovative approaches to disease management.

03. Advances in Clinical Research on Novel Therapies

A study evaluating the combination of acalabrutinib with the R2 regimen in previously untreated follicular lymphoma (FL) enrolled 24 patients with a median age of 62 years (range: 40-82 years). Based on FLIPI scores, 46% of patients were classified as intermediate risk, while 25% were categorized as high risk. The treatment protocol consisted of 13 cycles of acalabrutinib, with the R2 regimen administered from cycle 2 to cycle 13.

The study demonstrated an objective response rate (ORR) of 100%, with the complete response (CR) rate increasing from 62.5% at 3 months to 92% at 6 months. At the two-year follow-up, progression-free survival (PFS) was 79.2%, while overall survival (OS) reached 91.7%. The regimen was well-tolerated, with a favorable safety profile.

Additionally, the study indicated that incorporating acalabrutinib into the R2 regimen had a positive impact on CD4+ T cells, monocytes, and regulatory NK cells. These findings highlight the potential of this combination therapy in improving disease control while maintaining manageable toxicity, paving the way for more effective and well-tolerated treatment options in FL.

The LEVERAGE study, a phase Ib/II trial in previously untreated follicular lymphoma (FL) patients, investigated the efficacy and safety of the triplet regimen obinutuzumab (OBI), lenalidomide (LEN), and venetoclax (VEN). A total of 50 patients were enrolled, and results showed an overall response rate (ORR) of 91% across all dose groups, with a complete response (CR) rate of 83%. In the RP2D (recommended phase II dose) group, the ORR remained at 91%, while the CR rate increased to 86%. The two-year progression-free survival (PFS) rate was 92%, and the two-year overall survival (OS) rate reached 100%. However, cumulative hematologic toxicity was observed with this regimen, necessitating close monitoring and management.

The MITHIC-FL1 study, a phase II trial, evaluated the efficacy and safety of subcutaneous mosunetuzumab in previously untreated high-tumor-burden grade 1-3A FL patients. With a median follow-up of 13.3 months, the CR rate was 80% in the evaluable population and 78% in the intent-to-treat (ITT) population. In the ITT group, the 12-month PFS rate was 90.7%, and the 12-month OS rate was 98.7%. Additionally, 86% of evaluable patients experienced at least an 80% reduction in tumor burden from baseline.

This treatment regimen demonstrated a favorable safety profile. Subcutaneous mosunetuzumab showed good tolerability in an outpatient setting, with injection site reactions and cytokine release syndrome (CRS) mostly limited to grade 1. These findings support the potential of subcutaneous mosunetuzumab as a promising treatment option for FL with a manageable toxicity profile.

In the phase I/II clinical trial evaluating tazemetostat in combination with a shortened course of bendamustine plus rituximab (BR) as first-line therapy for high-tumor-burden (HTB) follicular lymphoma (FL), a total of 12 patients were enrolled in the phase I stage. At the end of treatment, the complete response (CR) rate reached 100%, and the regimen demonstrated good overall tolerability. No dose-limiting toxicities (DLT) were observed, and the maximum tolerated dose (MTD) was established at 800 mg twice daily (BID), which has been selected as the recommended phase II dose (RP2D).

These findings provide new treatment options and evidence for FL patients, contributing to the ongoing refinement of FL treatment strategies.

Advances in the Treatment of Relapsed/Refractory FL in 2024

Currently, there is no standardized approach for treating relapsed/refractory follicular lymphoma (R/R FL), and clinical decisions must be tailored based on multiple factors. These include the effectiveness and duration of prior treatments, patient age, overall physical condition, and individual treatment goals. For patients who experience early relapse, non-cross-resistant treatment regimens are recommended, with careful assessment of anthracycline-related dose-limiting toxicities to ensure both safety and efficacy.

In recent years, a wave of novel therapies has expanded treatment options for R/R FL, including Bruton’s tyrosine kinase (BTK) inhibitors, EZH2 inhibitors, immunotherapies, and chimeric antigen receptor T-cell (CAR-T) therapy, all of which have demonstrated promising efficacy. Additionally, clinical trial participation has become a critical avenue for accessing cutting-edge therapies, such as bispecific T-cell engagers (BiTEs), antibody-drug conjugates (ADCs), and novel combination regimens, offering new hope to patients.

At the same time, traditional treatment options remain integral to R/R FL management. Immunochemotherapy, radiotherapy, and high-dose chemotherapy combined with autologous stem cell transplantation (ASCT) continue to play a vital role in achieving disease control for select patients. The combination of emerging targeted therapies with established treatment modalities has created a diverse and personalized treatment landscape, providing patients with more effective and tailored therapeutic strategies.

01. Key Issues in the Treatment of R/R FL

Treatment Strategies for Transformed Follicular Lymphoma (tFL)

A retrospective analysis in 2024 highlighted the potential of CAR-T therapy in overcoming the poor prognosis associated with transformed follicular lymphoma (tFL). This study compared the clinical outcomes of patients with primary diffuse large B-cell lymphoma (dnDLBCL) and tFL. Results showed that tFL patients who received CAR-T therapy had a significantly higher three-year overall survival (OS) rate compared to dnDLBCL patients (59% vs. 39%).

Additionally, CAR-T therapy appeared to mitigate the adverse prognostic impact of double-hit lymphoma (DHL) in tFL patients. These findings reinforce the growing role of CAR-T therapy as a potentially curative option for patients with transformed disease, addressing a critical unmet need in this high-risk population.

02. The Role of Transplantation in FL Treatment

Despite the growing availability of novel therapies, autologous stem cell transplantation (ASCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) continue to play a crucial role in the management of follicular lymphoma (FL). A retrospective analysis conducted by the European Society for Blood and Marrow Transplantation (EBMT) Lymphoma Working Group confirmed that both approaches can provide long-term disease control for select FL patients.

ASCT offers the potential for sustained remission with an acceptable toxicity profile, but relapse remains a concern, with a three-year relapse rate of 41%. On the other hand, allo-HSCT has shown efficacy in a subset of patients and even holds curative potential, but it carries a higher non-relapse mortality (NRM) rate, reaching 30% at five years. Given these outcomes, transplantation remains a viable treatment option for patients who lack access to CAR-T therapy or bispecific antibodies or have exhausted other therapeutic alternatives.

03. Optimizing the Chemotherapy-Free R2 Regimen

The introduction of the rituximab plus lenalidomide (R2) regimen marked a significant milestone in the shift toward chemotherapy-free treatment for FL. However, the complete response (CR) rate for R2 remains relatively low, with the AUGMENT study reporting a CR rate of only 34%. This has driven ongoing research into “R2+X” strategies to further enhance treatment outcomes.

One notable trial addressing this need is the inMIND study, a double-blind, randomized, placebo-controlled, international phase III clinical trial. This study evaluates the efficacy and safety of adding tafasitamab (Tafa) to the R2 regimen in patients with R/R FL or marginal zone lymphoma (MZL).

With a median follow-up of 14.1 months, results showed that the addition of Tafa to lenalidomide and rituximab significantly reduced the risk of disease progression, relapse, or death. The investigator-assessed median progression-free survival (PFS) reached 22.4 months, while PET-based CR rates and overall response rates (ORR) improved significantly. The regimen also demonstrated a manageable safety profile, reinforcing its potential as an optimized chemotherapy-free option for R/R FL patients.

The Epcore NHL-2 study evaluated the efficacy and safety of a fixed 12-cycle regimen of epcoritamab combined with the R2 regimen in patients with relapsed/refractory follicular lymphoma (R/R FL). The results demonstrated promising antitumor activity and a manageable safety profile, even in high-risk patient populations.

The study reported an overall response rate (ORR) of 96%, with a complete response (CR) rate of 87%. Additionally, 88% of evaluable patients achieved minimal residual disease (MRD) negativity. Long-term outcomes were also encouraging, with a 24-month progression-free survival (PFS) rate of 70% and an overall survival (OS) rate of 90%. These findings support the potential of epcoritamab plus R2 as a highly effective treatment option for patients with R/R FL.

04. The Potential of Small-Molecule Inhibitors in FL Treatment

Given the complexity of the tumor microenvironment in follicular lymphoma (FL), the B-cell receptor (BCR) signaling pathway has emerged as a critical target for therapeutic intervention, as it plays a key role in the proliferation and survival of FL tumor cells. Targeted approaches using kinase inhibitors to disrupt BCR signaling have proven to be effective treatment strategies.

The ROSEWOOD study, a global randomized phase II trial, investigated the efficacy and safety of zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) monotherapy in patients with relapsed/refractory FL. The results demonstrated superior efficacy in the ZO group, with the independent review committee (IRC) reporting an overall response rate (ORR) of 69% in the ZO group versus 45.8% in the O group. The complete response (CR) rate was also significantly higher in the ZO group at 39.3% compared to 19.4% in the O group.

Moreover, the median progression-free survival (PFS) was 28.0 months in the ZO group, compared to only 10.4 months in the O group. These findings highlight the promise of BCR pathway inhibition as a key therapeutic approach in FL, further supporting the potential role of small-molecule inhibitors in expanding treatment options for patients with R/R FL.

BGB-16673 is a bivalent small-molecule degrader that specifically binds to both BTK and E3 ligase, leading to BTK degradation and offering the potential to overcome resistance mutations such as BTK C481S, C481F, C481Y, L528W, and V416L.

The CaDAnCe-101 study, a phase 1/2 open-label, dose-escalation and dose-expansion trial, is evaluating the efficacy and safety of BGB-16673 as a BTK degrader in patients with relapsed/refractory (R/R) B-cell malignancies.

Preliminary results demonstrated that BGB-16673 monotherapy achieved an overall response rate (ORR) of 50% in heavily pretreated FL patients (median of 4.5 prior lines of therapy), with a complete response (CR) rate of 12.5% (1/8 patients). The treatment was well-tolerated, with a favorable safety profile and high tolerability. These findings highlight the potential of BTK degradation as a novel therapeutic strategy for R/R FL, particularly in patients with BTK inhibitor resistance.

02. Real-World Considerations in Clinical Decision-Making

In real-world clinical practice, the treatment of relapsed/refractory follicular lymphoma (R/R FL) presents a range of complex challenges, particularly for patients in the early stages of relapse or those experiencing multiple recurrences. When developing a treatment plan, clinicians must carefully assess various factors, including the patient’s treatment burden, disease progression rate, tumor volume, symptoms, age, overall physical condition, personal preferences, and financial considerations.

For younger, physically fit patients or those with rapidly progressing or early-relapsing high-risk disease, a more aggressive and innovative treatment approach may be appropriate. Treatment sequencing is particularly critical, requiring a thorough evaluation of the patient’s T-cell immune status and an assessment of the feasibility of CAR-T therapy following bendamustine-based treatment.

In contrast, elderly patients are generally more susceptible to treatment-related toxicities and may experience altered immune responses. For this population, dose-reduced or lower-intensity immunochemotherapy regimens should be considered, alongside non-chemotherapy-based immunotherapeutic options, including the R2 regimen, EZH2 inhibitors, BTK inhibitors, and bispecific antibodies. The final treatment choice should be based on a deep understanding of the toxicity profile of each option and should involve shared decision-making with the patient.

While the R2 regimen follows a fixed treatment course, dose adjustments may be necessary for patients with impaired renal function or hematologic toxicity. In addition, EZH2 inhibitors are generally well tolerated, and the zanubrutinib plus obinutuzumab (ZG regimen) has demonstrated a low incidence of infusion-related reactions, making it a suitable option for frail or physically compromised patients.

2024 Summary

With deeper insights into the biological characteristics of FL and the emergence of next-generation therapies, clinical treatment strategies have significantly expanded, bringing both new opportunities and challenges. As therapeutic innovations for FL—particularly R/R FL—continue to evolve, optimizing treatment sequencing, timing, and drug combinations has become a key challenge for clinicians.

For transformed FL (tFL), real-world retrospective studies have confirmed that CAR-T therapy can provide significant clinical benefits for certain patients. While the role of stem cell transplantation in FL treatment has somewhat diminished, it remains a viable option in select cases.

Currently, the treatment landscape for R/R FL is shifting toward chemotherapy-free approaches, offering patients higher response rates and a broader range of treatment options. However, in clinical practice, individualized treatment planning remains crucial. Decisions must take into account the patient’s specific condition, treatment goals, drug characteristics, safety profile, and accessibility to ensure the most suitable therapy is selected.

Dr. Huilai Zhang

Tianjin Medical University Cancer Institute and Hospital

• Chief physician, Master’s supervisor, Ph.D. supervisor
• Currently serving as the Director of the Hematology Department and Head of the Hematopoietic Malignancies Research Team at Tianjin Medical University Cancer Institute and Hospital
• Specializing in the comprehensive treatment and precision therapy of malignant lymphoma and hematologic tumors

Professional Affiliations:

• Vice Chairman of the Chinese Anti-Cancer Association’s Lymphoma Committee
• Member of the Chinese Medical Association Hematology Branch’s Lymphoma Group
• Member of the China International Exchange and Promotive Association for Medical and Healthcare’s Hematology Branch
• Executive Committee Member of the Chinese Society of Clinical Oncology (CSCO) Lymphoma Expert Committee
• Expert Member of the National Health Commission’s Lymphoma Standardized Diagnosis and Treatment Guidelines Panel
• Vice Chairman of the Hematology Branch of Tianjin Medical Association
• Vice Chairman of the Tianjin Anti-Cancer Association Hematologic Tumors Committee
• Member of the Tianjin Society of Integrative Medicine

Honors and Achievements:

• Selected for the “New Medical Talent” program in Tianjin
• Awarded First Prize for Medical Science and Technology Progress in Tianjin
• Recipient of the National Natural Science Foundation of China (NSFC) Projects
• Led and participated in multiple provincial and national-level research projects
• Published over 120 research articles in high-impact journals
• Active participant in domestic and international lymphoma research collaborations

Editorial and Review Board Roles:

• Editorial board member for Hematological Oncology and Blood Research
• Reviewer for Discovery Oncology and several leading journals, including Blood, Cancer Research, J Exp Med, JTC, Leukemia, CTM, AJH, BJH, Blood Adv, and Int J Cancer

Professor Zhang has long been committed to the diagnosis, treatment, and research of hematologic malignancies, contributing significantly to the advancement of lymphoma treatment strategies in China.

Tianjin Medical University Cancer Institute and Hospital’s 2024 Research Achievements

In 2024, the Lymphoma Department at Tianjin Medical University Cancer Institute and Hospital made significant contributions to FL research. The team conducted an in-depth investigation into the clinical and genetic characteristics of different histological subtypes of FL, utilizing whole-exome sequencing to map the genetic landscape from FL1-2, FL3A, and FL3B to FL/DLBCL. Notably, their findings revealed that FL3B exhibits distinct clinical and genetic features associated with poor prognosis, providing a valuable reference for clinical decision-making.

In the field of primary gastrointestinal follicular lymphoma (PGI-FL), the Tianjin lymphoma team successfully developed a nomogram model to predict patient survival outcomes. This model was validated as an effective tool for individualized risk stratification, dividing patients into low-risk, intermediate-risk, and high-risk groups. This stratification enables clinicians to accurately identify high-risk patients and tailor personalized treatment strategies to achieve optimal therapeutic outcomes.

Additionally, the team conducted a retrospective study evaluating the safety and efficacy of obinutuzumab-based first-line therapy for FL. The study included 153 FL patients treated with obinutuzumab plus bendamustine (GB regimen) and 148 patients treated with obinutuzumab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (G-CHOP regimen). The results demonstrated that both obinutuzumab-based regimens (GB and G-CHOP) provided effective treatment outcomes with manageable safety profiles. The consistency in therapeutic efficacy between the two regimens offers greater flexibility in clinical decision-making, allowing clinicians to personalize treatment selection based on patient characteristics.