Abstract
Background: Cytotoxic T-cell lymphomas (CTLs) are rare, comprising only 3–5% of all Mature T-cell lymphomas and have very poor outcomes. While sharing key biological features, including frequent expression of CD8, or NK-associated cytotoxic markers, and CD94 as a common molecular target, they present with wide clinical variability across anatomical compartments—cutaneous, intestinal, hepatosplenic, nodal, and leukemic. Current response criteria based on anatomic involvement have challenges in endpoint objectivity, response determination, cross-study interpretation, and regulatory approval.
Objectives: The CLyAR (Cytotoxic Lymphoma Assessment of Response) initiative aimed to harmonize response assessment by integrating existing validated criteria into a single, compartment-based framework for CTL subtypes. The goal was to improve consistency in therapeutic response evaluation and support broader patient inclusion in clinical trials for this underserved population.
Methods: An international expert panel and patient advocates convened to develop a harmonized response assessment framework for CTLs, drawing from current practices across trials and institutions. In preparation for the workshop, panelists reviewed the full spectrum of CTL histologies and provided structured evaluations of the appropriateness of existing response tools—Lugano, Olsen, and modified T-PLL—for each subtype and disease compartment. Using a structured matrix, experts rated the suitability of each modality (e.g., PET, CT, skin scoring, marrow assessment) as “Yes,” “No,” or “Maybe” based on their clinical experience. These pre-meeting assessments were developed to identify areas of consensus and divergence. During the workshop, the panel systematically revisited each histology and compartment, deliberating on discrepancies and refining criteria recommendations.
Results: The harmonized CLyAR framework applies to the heterogeneous set of cytotoxic T-cell lymphoma subtypes, including ENKTL (nasal type), EATL, MEITL, HSTCL, SPTCL, PCγδTCL, ET-CTCL, ANKL, HVLPD, PTCL-NOS, and cutaneous PTCL-NOS. The panel concluded that no single response criterion is adequate across all subtypes. Instead, they were grouped into four compartments: (1) nodal/systemic diseases. (2) leukemic or marrow-based diseases with or without organomegaly, (3) cutaneous/subcutaneous presentations, and (4) gastrointestinal (GI) presentations. The following conclusions were reached:
Nodal cytotoxic PTCLs are best evaluated using Lugano criteria with PET/CT. ENKTL, while using Lugano criteria, still requires MRI of the sino-nasal area for treatment planning, serial EBV PCR, and bone marrow evaluation.
For leukemic presentations and HSTCL, modified T-PLL criteria were adapted, combining disease-specific parameters with hematologic recovery markers. A complete response (CR) requires normalization across all areas including the bone marrow; partial response (PR) requires improvement in at least two disease-specific and one hematologic criterion.
For cutaneous and subcutaneous variants (SPTCL and PCγδTCL), a global approach is necessary for response assessment. The primary evaluation method for quantifiable cutaneous disease is the Olsen criteria, with a strong emphasis on mSWAT scoring and serial photography. PET imaging is recommended for evaluating deeper lesions.
Due to false-negative results (microscopic disease) and false-positive results (inflammatory changes), gastrointestinal lymphomas require careful PET interpretation and endoscopic confirmation.
The panel emphasized that dominant anatomical presentation, measurable sites, and imaging features should be the basis for assigning response criteria. For non-standard presentations, a decision-tree algorithm was developed to direct the assignment of criteria. This adaptable, compartment-driven model takes into account the clinical diversity of CTLs while enabling harmonized assessment.
Conclusions: The CLyAR framework offers a single, compartment-based response that encompasses the diverse CTL presentations. It provides a way forward for standardized evaluation in real-world registries as well as prospective trials. Key priorities include patient-centered outcomes, coordinating response benchmarks with regulatory authorities, and engaging biopharma sponsors to use the framework in the trial design of novel treatments. The consensus details will be forthcoming at ASH 2025.
