Tafasitamab in relapsed follicular lymphoma: promise and remaining question

To the Editor,

Lymphoma is a cancer of the lymphatic system that starts when white blood cells called lymphocytes grow uncontrollably. Follicular lymphoma (FL) arises from germinal center B cells and is typically associated with the hallmark t(14;18)(q32;q21) translocation leading to BCL2 overexpression, with additional recurrent mutations (e.g., EZH2, KMT2D, and CREBBP) contributing to its pathogenesis^[1,2]. FL represents the most common form of indolent lymphoma. Approximately 80–85% of patients present with advanced-stage disease and require systemic therapy once symptoms arise. While it usually follows a slow course and responds well to treatment, allowing long-term survival for many patients, FL is marked by ongoing relapse risk and is still considered incurable^[2,3]. The treatment landscape for relapsed and refractory FL has evolved rapidly in recent years. While chemotherapy has historically been the foundation of treatment, the rise of innovative targeted therapies, immunomodulators, and immunotherapies is reshaping the treatment paradigm^[4]. This article aligns with the TITAN Guidelines on the importance of transparency in artificial intelligence use in healthcare^[5].

On 18 June 2025, the U.S. Food and Drug Administration approved tafasitamab-cxix for relapsed or refractory FL, based on the phase III inMIND trial^[6,7]. This randomized, double-blind, placebo-controlled study enrolled 548 patients to receive tafasitamab-cxix or placebo in combination with lenalidomide and rituximab. After a median follow-up of 14 months, tafasitamab significantly prolonged progression-free survival (PFS, 22.4 vs 13.9 months; HR 0.43) and improved overall response rates compared with control^[7]. As FL is an indolent lymphoma, these PFS improvements may not translate directly into overall survival (OS) benefit, and OS data remain immature, emphasizing the need for longer-term follow-up. The trial population had a median age of approximately 64 years, with a median of 1 prior line of therapy (44% had ≥2 prior lines), 32% with POD24, and 43% refractory to prior anti-CD20 therapy – factors that may limit generalizability to real-world populations^[7].

Tafasitamab-cxix is an Fc-engineered anti-CD19 monoclonal antibody that mediates B-cell cytotoxicity via enhanced ADCC and phagocytosis (product monograph^[8]) and has been studied clinically in the inMIND trial^[7]. While CD19 is an attractive therapeutic target in FL, its expression may influence the efficacy of subsequent CD19-directed therapies. Unlike CAR-T or CD19 bispecific therapies, tafasitamab has transient exposure, potentially permitting later CD19-targeted treatments without prolonged depletion. In the inMIND trial, tafasitamab was administered intravenously at a dose of 12 mg/kg for up to 12 cycles in combination with lenalidomide and rituximab^[7].

Limitations of the inMIND trial include the selective population and relatively short follow-up, which constrain long-term interpretation and the assessment of OS and safety^[7]. Patients with grade 3B FL or CNS involvement were excluded, restricting generalizability. Real-world tafasitamab-lenalidomide cohorts (e.g., a German/Austrian series assessing L-MIND eligibility) often include larger numbers of comorbid or heavily pretreated patients; in that series, only ~37% of patients in that real-world tafasitamab–lenalidomide cohort would have met L-MIND eligibility criteria^[9]. Real-world data, largely from DLBCL cohorts, suggest that many patients retain CD19 expression after tafasitamab, but FL-specific evidence is limited, and further study is needed^[10]. As CAR-T and CD20 bispecific antibodies become established in FL, defining the optimal sequencing of CD19- and CD20-targeted approaches will be crucial, and comparative studies are warranted.

Serious adverse events (32–36%), particularly infections (~24%), and grade ≥3 neutropenia (40–50%) were observed in the inMIND cohort^[7]; additional safety insights from broader populations are described in the product monograph^[8]. Exploratory analyses suggested that tafasitamab may provide clinical benefit beyond PFS, with trends toward longer time-to-next-treatment (median time-to-next-treatment not reached vs ~28–29 months) and improved quality of life, including higher global health scores and reduced symptom burden; these findings are preliminary and require confirmation with longer follow-up^[7].

Tafasitamab-cxix improves disease control in relapsed/refractory FL and deepens responses when added to lenalidomide–rituximab. Nevertheless, cautious interpretation is warranted given the limited duration of follow-up, selective trial population, and immature OS data. Key next steps include (1) maturation of OS and safety data from inMIND, (2) prospective real-world registries to evaluate effectiveness and safety across broader populations, and (3) translational and sequencing studies to clarify the impact on subsequent CD19-directed therapies, including CAR-T and CD20 bispecifics.

Ethical approval

Not applicable.

Consent

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Sources of funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author contributions

N.I., M.S.: conceptualization; N.I., M.S., L.R., W.S., and S.B.I.: writing – original draft preparation, N.I., M.S., L.R., W.S., and S.B.I.: writing – review and editing. All authors have reviewed the final version of the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflict of interest.

Guarantor

Sakan Binte Imran.

Research registration unique identifying number (UIN)

Not applicable.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

Not applicable.