Introduction

Cutaneous T-cell lymphomas (CTCLs) are extranodal non-Hodgkin T-cell lymphomas characterized by the infiltration of the skin by malignant T lymphocytes which can also invade the lymphatic system, blood and visceral organs, resulting in heterogeneous clinical presentations that frequently delay diagnosis.1,2

The most common subtypes of CTCLs are mycosis fungoides (MF), and its leukemic erythrodermic variant, Sézary syndrome (SS).3 MF accounts for approximately 60% of CTCLs and typically manifests as erythematous plaques and patches, following an indolent course over years or decades.3,4 In contrast, SS is a rare (≈5%) and more aggressive CTCL subtype, that is characterized by pruritic erythroderma, lymphadenopathy, and neoplastic T-cells (Sézary cells).3–5 Although classified as distinct entities by the World Health Organization (WHO) and the European Organization for Research and Treatment of Cancer (EORTC), MF and SS are increasingly regarded as a disease spectrum, sharing a common staging system and therapeutic strategies.3,6,7

A major and clinically underappreciated challenge is the diagnostic overlap between CTCL and other mature T-cell neoplasms, particularly peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). These entities share overlapping histopathological and immunophenotypic features, and atypical presentations — including aberrant immunophenotypic profiles and initially absent skin manifestations — can create substantial diagnostic ambiguity in routine clinical practice.6,8 In such cases, an initial leukemic or nodal presentation without cutaneous involvement may lead to an erroneous PTCL-NOS classification, with direct consequences for therapeutic decision-making. The present case illustrates this challenge particularly well. Increasingly, molecular and biomarker-driven approaches are being integrated into CTCL diagnosis to resolve such ambiguity. Next-generation sequencing (NGS)-based T-cell receptor (TCR) clonality assessment has demonstrated greater sensitivity and specificity than conventional PCR for the detection of malignant clones in skin and blood,9,10 and disease-associated markers — notably KIR3DL2, a reliable marker of malignant clones in MF/SS — further improve the discrimination of CTCL from reactive conditions and other T-cell lymphomas.4 These tools are particularly valuable in atypical cases where conventional clinical and histopathological criteria are insufficient.

The stage of MF/SS drives treatment selection: skin-directed therapies are preferred in early stages (IA-IIA), whereas advanced stages (IIB-IVB) require systemic therapies — most commonly biologic response modifiers (interferon-alpha, bexarotene), histone deacetylase inhibitors (HDACis) (romidepsin, vorinostat), targeted immunotherapy (mogamulizumab, brentuximab vedotin), and chemotherapy (pralatrexate, methotrexate).6,9,11 Because of the disease’s marked heterogeneity, treatment is highly individualized rather than protocol-driven.6,9 While early-stage MF carries a near-normal overall survival, SS and advanced-stage MF have a poor prognosis (5-year survival 40–55%), with highly variable response rates, rare complete remissions, and frequent relapse.5,9,11,12 MF/SS remains incurable with current systemic treatments, the only potentially curative option being allogeneic stem cell transplantation, reserved for heavily pretreated, advanced-stage patients.4,6,9,11 Consequently, relapsed/refractory (r/r) MF/SS continues to represent a major unmet clinical need.

Belinostat is an intravenous pan-HDACi (class I, II and IV) approved by the US Food and Drug Administration (FDA) in 2014 for the treatment of r/r peripheral T-cell lymphoma (PTCL).13 In the BELIEF Phase II trial, belinostat monotherapy achieved an overall response rate (ORR) of 25.8% with a median duration of response (DoR) of 13.6 months in patients with r/r PTCL.13 To date, belinostat is not indicated in CTCL, as the pivotal BELIEF trial did not include CTCL patients. Belinostat holds accelerated approval for the treatment of r/r PTCL, with its clinical activity currently being evaluated in the ongoing CRESCENDO trial in combination with CHOP (Bel-CHOP) in newly diagnosed patients.

Here, we report an unusual case presentation of MF/SS that was initially diagnosed as PTCL-NOS, because of an atypical leukemic presentation preceding the development of cutaneous lesions. Following failure of two prior lines of therapy, the patient achieved durable disease control with belinostat, maintaining stable disease with complete cutaneous remission and a sustained partial hematologic response for six years.

Case Presentation

For clarity purpose, a diagnostic and treatment timeline is presented in Figure 1.

Figure 1 Diagnostic and treatment timeline.

Medical History

In January 2017, a 66-year-old male patient was transferred to our department of Clinical Hematology. He was initially hospitalized in the department of Cardiology for electrophysiological explorations due to a non-ischemic cardiac arrest. However, blood tests conducted at the time of his admission revealed a leukocytosis at 10,600/µL with a small lymphocytosis at 5660/µL. Blood smears showed the presence of an atypical lymphocyte population comprising small to medium-sized cells, with irregular, cerebriform nuclei and dense chromatin, which constituted 25% of the total white blood cells (Figure 2). No evidence of anemia, thrombocytopenia or tumoral involvement was identified during the clinical examination. At the time of transfer to our department, he presented with a good performance status (ECOG 1), with a body weight of 96 kg and a height of 185 cm. His current medical history included arterial hypertension, which was treated with acebutolol, a well-controlled type 2 diabetes which was managed with metformin and insulin, a bipolar disorder which was controlled by valpromide, and a calcifying alcoholic pancreatitis which was treated with long-term pancreatin. Moreover, he had previously undergone a right pulmonary lobectomy in 1999 for a hemoptysis of unknown etiology and had been implanted with a stent in 2003 because of ischemic cardiopathy. The patient reported no history of allergies and had ceased smoking 10 years before. In his family, his mother died of an unknown type of lymphoma at the age of 86.

Figure 2 Blood smear from (January 2017) showing an atypical lymphocyte population with irregular, cerebriform nuclei and dense chromatin.

Diagnostic Procedures

Due to the presence of hyperlymphocytosis, a cervico-thoraco-abdomino-pelvic computed tomography (CT) scan performed in April 2017 did not reveal any adenopathy, hepatosplenomegaly or deep tumoral burden. Flow cytometry immunophenotyping of peripheral blood was performed and confirmed the presence of a pathological T-cell population representing 15% of total cells and was characterized by the following markers: CD3+/CD2 low/CD5+/CD4 low/CD7-/CD25-/CD57-/CD56-/CD16-/CD45RO+. The CD4/CD8 ratio was 7 and lymphocytes CD4+/CD7- represents 54% of CD4+ T cell population. A molecular analysis of T-cell clonality using a TCRG multiplex PCR assay14 confirmed the presence of a majority T-cell population with two predominant clonal TCR gamma rearrangements. A bone marrow biopsy was non-contributory. Based on these results, a diagnosis of PTCL not otherwise specified (PTCL-NOS) was established, and active surveillance was initiated.

In May 2018, a positron emission tomography (PET)-scan did not reveal any evidence of pathological hypermetabolism.

In March 2019, the patient presented with erythematous cutaneous lesions on the trunk, which were non-pruritic and devoid of any associated dermographism (Figure 3). Two cutaneous biopsies showed a dense pericapillary lymphocytic infiltrate, with epidermotropism in clusters, without spongiosis or necrosis (Figure 4). The infiltrate was composed of small-sized cells which were positive in immunohistochemistry for CD2, CD3, CD4, CD5, Ki67 (60%), CD30 (30–40%), PD1 (10%) and negative for CD7, CD8 and CD20 (Figure 5). A blood test analysis identified the presence of lymphoma cells (17%).

Figure 3 Picture of the patient’s trunk (March 2019).

Figure 4 Histology of skin biopsy performed in March 2019. (A) Hematoxylin-eosin-saffron (HES) stain, original magnification x3. Skin biopsy shows a predominantly superficial dermal lymphocytic infiltrate with marked epidermotropism and minimal deep perivascular extension. (B) Hematoxylin-eosin-saffron (HES) stain, original magnification x11. Centered on the superficial dermal lymphocytic infiltrate, with subtle cytonuclear atypia, resulting in marked epidermotropism with multiple Pautrier’s abscesses.

Figure 5 Immunohistochemistry of skin biopsy performed in March 2019. (A) CD2+; (B) CD3+; (C) CD5+; (D) CD7−; (E) CD4+; (F) CD8−; (G) Ki67+ (x11).

In November 2019, a third abdominal biopsy was performed following the discovery of a new non-pruritic maculopapular rash on the trunk; it revealed the presence of a lymphomatous proliferation comprising small, medium and large cells within the dermis, as well as exocytosis within the epidermis. Immunohistochemical analyses of the aforementioned cells showed a phenotype of CD3+, CD4+, CD25+ 30%, CD30+ 60%, PD1+ 30%, Ki67+ 60%. Serological testing for the human T-lymphotropic virus type 1 (HTLV-1) was negative. A PET-scan performed in December 2019 did not indicate the presence of any tumoral involvement.

In March 2024, a post-hoc analysis using next-generation sequencing (NGS) on a cutaneous biopsy collected in 2019 revealed the presence of a non-sense variant in the TP53 gene (p.[Arg342*]), with a variant allele frequency (VAF) of 17%. T-cell clonality using a TCRG multiplex PCR assay showed similar clonal TCR gamma rearrangements in blood and skin biopsy (Figure 6). In May 2024, a supplementary immunophenotyping of the blood, detected the presence of a CD3+ CD4+ CD7- CD26- KIR3DL2+ population (Figure 7). The final anapathological diagnosis was a CD4+ epidermotropic T-cell lymphoma. The expression of KIR3DL2 by the tumoral cells, which was not analyzed in the initial blood immunophenotyping in 2017, is a positive marker for MF/SS, providing further evidence to suggest this diagnosis of CTCL.15,16 Ultimately, the diagnosis, was retrospectively revised to as a highly probable MF with an incomplete, non-erythrodermic SS phenotype.

Figure 6 Genescan profiles (y-axis: fluorescence intensity; x-axis: PCR product length in base pairs) of T-cell clonality, performed on the 2019 blood sample (A) and the 2017 skin biopsy (B), display two clonal rearrangements of the gamma TCR.

Figure 7 Immunophenotyping by flow cytometry of circulating tumoral cells in May 2024. (A) Subsets compatible with Sézary cells (represented in Orange) were first identified as CD4+ KIR3DL2+ within not NK, not CD8+ and not TCRgd+ lymphocytes (“lymphocytes not [NK CD8 gd]”). (B) CD3+CD4+ lymphocytes were visualized according to CD7 and CD26 expression.17 (C) To refine the definition of clonal stem cells, we employed the radar-plot method available in KaluzaTM software (Beckman-Coulter). This graphical technique captures multidimensional data in a single plot, facilitating cluster visualization. TRBC-restriction was evaluated within KIR3DL2 subset and the benign counterpart of CD4+ T-cells (green). (D) The patient presents a typical polytypic “biphasic distribution” of benign CD4+ T-cells and of CD7+CD26+ cells with a monotypic “clonal pattern” in the “other subsets”. Orange: Sézary cells; green: benign CD4+ T-cells.

Abbreviation: TCR, T-cell receptor.

Treatment and Outcomes

Between September and October 2019, the patient received three cycles of cyclophosphamide (750 mg/m2, Day 19), doxorubicin (50 mg/m2, Day 1), etoposide (100 mg/m2, Day 1 to Day 3), vincristine (1.4 mg/m2, Day 1) and prednisone (40 mg/m2, Day 1 to Day 5) (CHOEP)-based chemotherapy as first-line treatment. Despite the disease stabilizing, erythematopapular skin lesions on the flanks and trunk persisted. In November 2019, a positive skin biopsy for CD30+ lymphoma cells was observed, along with the presence of 20% circulating T-lymphoma cells in the blood. The subsequent PET-scan performed did not identify any hypermetabolic foci. Consequently, a second-line treatment was initiated between November 2019 and January 2020 with bendamustine (90 mg/m2, Day 1 and Day 2) and aracytine (750 mg/m2, Day 1 and Day 2) for the first cycle and the combination bendamustine - a bifunctional cytotoxic agent - coupled with the anti-CD30 antibody-drug conjugate brentuximab vedotin (B-BV) (1.8 mg/kg, Day 1) for the second cycle. This was prompted by the identification of CD30+ cells in the skin biopsy. Following the completion of those two cycles, a physical examination showed a regression of the skin lesions and a partial hematological response, characterized by a reduction in the T-cell population from 30% to 3% of total white blood cell count. The third cycle of treatment was postponed due to the patient’s sustained neutropenia (50 neutrophils/µL), and a febrile state resulting from a non-severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) viral pneumonia. Following the third cycle of bendamustine and the second cycle of BV, the skin lesions on the trunk reappeared coupled with the presence of circulating lymphoma cells estimated at 35% of total white blood cells. In March 2020, a course of corticosteroid therapy (30 mg/day) was started for the apparition of pruritus, which rapidly disappeared under treatment.

Considering the initial diagnosis of PTCL-NOS at this time, belinostat (1000 mg/m2, Day 1 to Day 5 every 21 days) was introduced as third-line treatment at the end of March 2020. This therapy represented the best therapeutic option at the time, with a favorable toxicity profile. After three cycles of this treatment, a skin examination demonstrated a complete regression of the lesions; however, a persistence of circulating lymphoma cells was observed, with a >50% decrease in the quantitative measurement of tumor cells compared to baseline. According to the response criteria of the Consensus Statement of the ISCL, the USCLC and the Cutaneous Lymphoma Task Force of the EORTC,7 the patient was deemed to have achieved a global partial response (PR), encompassing a complete response (CR) for the skin lesions and a partial response in blood.

Between March 2020 and May 2026, the patient has been undergoing continuous belinostat therapy (79 cycles), with the disease remaining stable in partial remission (PR). Following 18 months of treatment, the intervals between courses of treatment were gradually extended to every four and then five weeks. It is noteworthy that the cutaneous involvement fluctuated, with exacerbations occurring when the intervals exceeding four weeks. Conversely, the blood phase remains stable. A complete cutaneous remission and a stable circulating tumor cell population were achieved through the administration of belinostat injection every three to four weeks. To simplify the patient’s therapeutic regimen, the initial treatment session is conducted at the hospital, while the subsequent four sessions are administered at home. Since March 2020, the treatment was generally well tolerated, with no significant adverse events. The only notable adverse effect was grade 1 anemia. At the patient’s most recent clinical follow-up in May 2026, he was in good overall condition, without any skin lesions related to his lymphoma.

Discussion

The diagnosis and classification of T-cell lymphomas represent a significant challenge for medical practitioners. This patient never fulfilled the complete formal ISCL/EORTC diagnostic criteria for SS at any point during the disease course.7 Specifically, he never developed erythroderma. While the circulating tumor burden was clearly clonal and persistent, it did not consistently meet the B2 hematologic threshold required for a formal SS diagnosis. This case demonstrates the significant diagnostic ambiguity that can be caused by atypical immunophenotypic profiles and the absence of skin manifestations at the time of initial diagnosis.

PTCLs exhibit common clinical and histopathological characteristics with other T-cell lymphoma subtypes, and CTCLs may demonstrate significant overlap with benign conditions.6,8 Consequently, molecular techniques are now frequently employed in clinical practice. The role of NGS as an important technology for understanding, diagnosing and classifying T-cell lymphomas is now well established.8,10 The characterization of the molecular profile of tumors, for example through the sequencing of the T-cell receptor gene, has demonstrated the value of NGS as a powerful tool for the diagnosis of T-cell lymphomas, including CTCLs.4,6,9,18,19

Immunophenotyping of Sézary cells using flow cytometry17 has largely replaced traditional blood work, which relied on manual microscopy to detect morphologically atypical mononuclear cells with convoluted, cerebriform nuclei. It allows a comprehensive characterization of the phenotype of neoplastic cells in peripheral blood, and it is commonly used in the management of CTCL.20–22 Flow cytometry enables the detection and quantification of circulating tumor cells, as well as the assessment of blood tumor burden.17 Detailed longitudinal data on the circulating tumor burden helped to better characterize the durability of the hematologic response; specifically, we reported on the evolution of the circulating malignant T-cell fraction during the disease course (eg, 25% of leukocytes at the initial presentation in 2017; ~17–20% during 2019; a reduction from 30% to 3% after B-BV; a reduction of >50% from the initial level after three cycles of belinostat; and a stable partial hematologic response thereafter) which illustrates sustained control of the blood-compartment under belinostat treatment. This provides valuable information for diagnosis, disease staging, prognosis evaluation and patient management.3,20,21,23

In this case report, the patient presented with an unusual form of a highly probable MF/SS which was diagnosed retrospectively and refractory to two prior lines of treatment. Because of the presentation with only blood and bone marrow localization without skin lesion, the initial clinical data indicated a diagnosis of PTCL-NOS, and the selection of the first two lines of chemotherapy was consistent with the recommended therapeutic strategy for this particular subtype of T-cell lymphoma.24 Indeed, eligible patients with newly diagnosed PTCL are frequently treated with anthracycline-based chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CHOEP or EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin).25,26 The identification of CD30-positivity in the patient’s skin lesions led to a prompt replacement of the CHOEP-based chemotherapy regimen with B-BV. A high response rate (ORR, 68%; CR, 49%) was observed with the combination B-BV in patients with r/r PTCL in a retrospective study from the LYSA group.27 Despite a rapid regression of his cutaneous lesions after a single cycle of this treatment (the hematological response remained partial), the disease progressed after another cycle of B-BV. Following the introduction of belinostat as third‑line treatment, the patient achieved a complete cutaneous remission and a partial hematological response, both sustained for six years, with belinostat therapy still ongoing

The positivity of malignant T-cells for the KIR3DL2 marker in peripheral blood immunophenotyping supported the diagnosis of MF/SS.15,16,28,29

KIR3DL2 was initially identified on the surface of natural killer (NK) cells and is a member of the killer cell immunoglobulin-like receptor (KIR) family. It has also been described on rare circulating T-lymphocytes.16 Furthermore, the aberrant expression of this NK cell receptor has been demonstrated on the erythrodermic T-cells of most SS patients. Additionally, several studies have confirmed that KIR3DL2, alone or in combination with other expressed genes, is a reliable diagnostic marker for the detection of malignant clones in CTCL.16,28,29 We do not know if the KIR3DL2 marker was expressed in the initial blood immunophenotyping in 2017, as this marker was not available in the test panel. It is therefore possible that malignant cells have acquired KIR3DL2 expression over time, which is typical of the plasticity of this lymphoma (epigenetic regulation). Alternatively, a very small proportion of KIR3DL2+ cells may have expanded between both analyses. This finding is consistent with the number of KIR3DL2-expressing lymphoid cells, which has been demonstrated to increase with the severity of the disease stage by Battistella et al.28

Beyond its diagnostic value, KIR3DL2 has become an actionable therapeutic target in CTCL. Lacutamab, a first-in-class anti-KIR3DL2 cytotoxicity-inducing monoclonal antibody, is currently in clinical development for r/r MF/SS, which has been granted EMA PRIME and FDA Breakthrough Therapy and Fast Track designations, as well as orphan drug status in the European Union and the USA. In the Phase 2 TELLOMAK trial (NCT03902184) with long-term follow-up, lacutamab achieved an ORR of 42.9% and a median DoR of 25.6 months in heavily pretreated patients with SS;30 in patients with MF, an ORR of 19.6% and a median DoR of 13.8 months were obtained with lacutamab.31 Notably, antitumor activity was observed irrespective of baseline KIR3DL2 expression level. A confirmatory Phase 3 trial (TELLOMAK 3) has received FDA clearance to proceed.32 The KIR3DL2 positivity identified in our patient therefore not only supported the diagnosis of MF/SS but also illustrates the growing relevance of biomarker-driven, KIR3DL2-targeted therapeutic strategies in this population.

T-cell clonality (TCRG multiplex PCR) was assessed in the 2017 blood sample and the 2019 skin biopsy, demonstrating concordant clonal TCR-gamma rearrangements between the two samples. Moreover, NGS performed post hoc in 2024 on the 2019 cutaneous biopsy identified the TP53 nonsense variant. However, serial molecular reassessment of residual disease during belinostat therapy was not systematically performed. Advances in molecular diagnostics are improving the classification of CTCL, particularly in diagnostically challenging MF/SS. Next-generation sequencing and T-cell clonality assessment can demonstrate shared TCR rearrangements in blood and skin samples, indicating a common malignant clone. Additionally, biomarkers such as KIR3DL2 improve the identification of circulating Sézary cells. In the present case, the combination of shared TCR-gamma clonality, TP53 alterations, and KIR3DL2 expression supported the retrospective reclassification of PTCL-NOS to MF/SS, underscoring the importance of integrated molecular and immunophenotypic assessments.18,22,29,33,34

The prognosis for patients with advanced CTCL is poor, with current therapeutic strategies resulting in frequent relapses and short-lived remissions.5,9,11 Given the absence of a standard of care for patients with r/r MF/SS, medical teams must adopt an individualized approach for each patient, relying on the available therapeutic arsenal of molecules developed for CTCL or even for other T-cell lymphomas such as PTCL.2,6,9 A review of the literature reveals the lack of data on the use of belinostat in the treatment of MF/SS. To date, only one clinical trial has been conducted involving patients with r/r CTCL; this phase 2, open-label, multicenter study evaluated the efficacity of belinostat at a dose of 1000 mg/m2 administered from Day 1 to Day 5 of a 21-day cycle in patients with r/r PTCL or r/r CTCL.35 A total of 17 patients with MF and seven patients with SS were included in the study. Among the 24 patients with PTCL, six (25.0%) achieved an objective response (CR, 8.3%; PR, 16.7%), while among the 29 patients with CTCL, four (13.8%) were responders (CR, 10.3%; PR 3.4%). The median DoR reached 109 days [95% CI, 7–460] for the PTCL group and 83 days [95% CI, 56–129] for the CTCL group.35

Two additional HDACis, vorinostat and romidepsin, have demonstrated efficacy in the treatment of patients with r/r CTCL, including cases of MF/SS. Vorinostat is an oral pan-HDACi that has been approved in the USA and Japan as monotherapy for the treatment of cutaneous manifestations of CTCL in patients who have failed at least two prior systemic therapies. In two phase 2 trials, patients with persistent, progressive or refractory CTCL treated with vorinostat reached an ORR of 24–30%, with the majority of responses being partial.36,37 In the trial reported by Olsen et al, which exclusively included MF/SS patients, the median DoR with vorinostat was not reached, with an estimated range of ≥185 days (range: 34+ to 441+) In contrast, in the trial by Duvic et al, which included CTCL patients, the median DoR was 1057 days (range: 65.8 to 135.8).36,37 Romidepsin is an intravenous selective class I HDACi that received accelerated approval from the US FDA in 2009 for the treatment of CTCL in patients who have received at least one previous systemic therapy, and for the treatment of PTCL in patients who have received at least one previous treatment line. However, following the negative outcome of a confirmatory phase 3 trial in patients with PTCL, the PTCL indication was withdrawn in 2021. In the phase 2 pivotal registration study for the CTCL indication, 96 patients with r/r CTCL (including MF/SS) were administered romidepsin (14 mg/m2, Day 1-8-15 every 28 days); the ORR was 34% (CR, 6%) and the median DoR reached 15.0 months (range: 0.0+ to 19.8+). In patients with an advanced stage of disease (≥IIB), an objective response was achieved in 38% of cases (CR, 7%).38

Mogamulizumab - a targeted immunotherapy- has been granted approved in the USA, Europe and Japan for the treatment of patients with MF/SS who have received at least one prior systemic therapy. Mogamulizumab is a novel specific monoclonal antibody directed against C-C chemokine receptor 4, a protein overexpressed on the surface of tumoral cells of CTCL including MF and SS. In the MAVORIC randomized, controlled phase 3 trial comparing the efficacy of mogamulizumab with vorinostat in 372 patients with r/r MS/SS after at least one systemic therapy, treatment with mogamulizumab resulted in a longer median progression-free survival (PFS) (7.7 vs 3.1 months; p<0.0001) and greater ORR (28.0 vs 4.8%; p<0.0001) compared to vorinostat. The median DoR with mogamulizumab reached 20.6 months in the skin and 25.5 months in the blood, while the median DoR with vorinostat was 10.7 months and not estimable, respectively.20

According to the consensus guidelines of the ISCL, USCLC and the Cutaneous Lymphoma Task Force of the EORTC,7 the patient achieved a global PR, which was obtained after only three cycles of belinostat therapy, ie in two months. The patient’s DoR is over six years, which is considerably longer than the median response duration observed above with other HDACis or even mogamulizumab in CTCL patients, which ranges from a few months to approximately two years.35–39 Interestingly, the global partial response observed in the patient persisted despite the presence of a mutation in the TP53 gene, which is known to be associated with a poorer prognosis in patients with PTCL,40,41 as well as the presence of the KIR3DL2 marker, which is associated with a worse survival in CTCL patients.28,29

The biological basis for this patient’s unusually durable response remains uncertain, and several non-exclusive hypotheses can be considered. First, MF/SS is characterized by significant heterogeneity between patients and within the disease;42 this heterogeneity may result in highly variable sensitivity to HDAC inhibition. Therefore, the present case may represent a disease subset that is particularly dependent on epigenetic regulation. Second, the malignant clone may have exhibited heightened epigenetic dependence, making it especially susceptible to pan-HDAC inhibition. This interpretation is consistent with belinostat’s mechanism of action and the disease’s apparent plasticity, as suggested by the probable acquisition of KIR3DL2 expression over time.43 Indeed, KIR3DL2 expression is epigenetically regulated through DNA methylation and histone acetylation of the gene promoter, Third, the malignant clone harbored a TP53 nonsense variant (p.[Arg342*]); although TP53 alterations have generally been associated with a poorer prognosis in T-cell lymphomas,41 their prognostic role in Sézary syndrome specifically remains uncertain.44 This patient achieved a sustained response, raising the possibility that the antitumor activity of HDAC inhibitors may be relatively independent of TP53 status in this setting.44 Finally, the immunophenotypic profile of the malignant cells (CD4+, CD7-, KIR3DL2+, PD1+) may have contributed to treatment sensitivity. These hypotheses are speculative and should be regarded as possible explanations, not established mechanisms. They warrant confirmation in larger, biologically annotated cohorts.

New evidence suggests that belinostat may be an effective treatment option for other challenging clinical situations involving lymphomas. For instance, one case report indicated that belinostat could induce a long-term response in patients with highly refractory angioimmunoblastic lymphoma.45 Additionally, two other case reports demonstrated the efficacy of belinostat as a bridge for ASCT, enabling durable and complete hematological responses in patients presenting with r/r angioimmunoblastic T-cell lymphoma.46,47

Throughout this extended treatment period, belinostat was generally well tolerated by our patient, with no serious adverse events observed. The only noteworthy adverse effect was a grade 1 anemia. This favorable safety profile is in accordance with the safety data of the phase 2 trial of belinostat monotherapy in r/r CTCL, wherein the majority of treatment-emergent adverse events (TRAEs) were of grade 1 or 2, and the incidence of thrombocytopenia was low (<10%).35 A systemic review of belinostat safety in 16 studies involving 512 patients with multiple malignancies revealed that the most commonly reported adverse events (≥8%) associated with belinostat were nausea, vomiting, fatigue, constipation, diarrhea, anorexia, fever, dyspnea and hypersensitivity or injection site reaction.48

This case report is limited by the inherent constraints of single-patient observations, which are hypothesis-generating and cannot establish efficacy. Additionally, the durable response described here may not be generalizable, and the retrospective nature of the diagnostic reassessment is an additional constraint. Controlled, prospective data are necessary before any therapeutic implications can be drawn.

Conclusions

This case underscores the diagnostic and therapeutic challenges of MF/SS and highlights belinostat’s potential as a valuable treatment option for patients with relapsed/refractory disease. In a patient with highly probable and atypical MF/SS who had failed two prior therapies, belinostat achieved durable and well-tolerated disease control that lasted for six years. Although belinostat is most effective against certain lymphoma subtypes such as angioimmunoblastic T-cell lymphoma (AITL), this case demonstrates its meaningful therapeutic potential against MF/SS. This case also reinforces the critical role of accurate immunophenotyping in classifying CTCL and other lymphomas correctly to avoid misdiagnosis. Together, these observations meaningfully contribute to the broader discussion about the potential of HDAC inhibitors in treating T-cell lymphomas. However, these observations are based on a single patient and should be considered hypothesis-generating rather than practice-changing. The durable response described here may not be applicable to the broader MF/SS population. Therefore, prospective evaluation of belinostat in dedicated CTCL cohorts is therefore warranted to confirm its efficacy and to identify the clinical, histopathological, and molecular features that best predict which patients with r/r MF/SS are most likely to benefit.

Ethics Approval and Informed Consent

This case report was published with the patient’s written informed consent for publication of the case details, including for the publication of the images. Moreover, under the applicable local/institutional regulations, no institutional ethics committee or IRB approval was required to publish this single-patient case report.

Acknowledgments

The authors would like to thank Hélène Moins, M.D., for providing the flow cytometry image, and Florence Boulmé, Ph.D., for writing assistance.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. They had full access to all the data and take full responsibility for its integrity, the accuracy of the analysis, and the final content of the manuscript.

Funding

This work was published with the support of IDEOGEN AG (Switzerland), whose contribution was limited to providing external medical writing assistance. IDEOGEN AG did not participate in the clinical management of the patient, nor did the sponsor exercise any editorial control or influence over the content of the manuscript or the decision to publish. The IDEOGEN AG-affiliated author contributed according to standard authorship criteria. The authors are solely responsible for all clinical data, their interpretation, and the final conclusions. The authors had full access to the data and final approval of the manuscript.

Disclosure

Maria Vittoria Sepporta is affiliated with IDEOGEN AG. Sylvain Choquet reports personal fees from Ideogen, during the conduct of the study. Karim Maloum reports publication fees from Ideogen, during the conduct of the study. The authors report no other conflicts of interest in this work.

References

1. Olsen EA, Whittaker S, Willemze R, et al. Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC. Blood. 2022;140(5):419–13. doi:10.1182/blood.2021012057

2. Morgenroth S, Roggo A, Pawlik L, Dummer R, Ramelyte E. What is new in cutaneous T cell lymphoma? Curr Oncol Rep. 2023;25(11):1397–1408. doi:10.1007/s11912-023-01464-8

3. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas. Blood. 2019;133(16):1703–1714. doi:10.1182/blood-2018-11-881268

4. Miyashiro D, Sanches JA. Mycosis fungoides and Sézary syndrome: clinical presentation, diagnosis, staging, and therapeutic management. Front Oncol. 2023;13:1141108. doi:10.3389/fonc.2023.1141108

5. Dalal M, Mitchell S, McCloskey C, Zagadailov E, Gautam A. The clinical and humanistic burden of cutaneous T-cell lymphomas and response to conventional and novel therapies: results of a systematic review. Exp Rev Hematol. 2020;13(4):405–419. doi:10.1080/17474086.2020.1717945

6. Hristov AC, Tejasvi T, Wilcox RA. Cutaneous T-cell lymphomas: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98(1):193–209. doi:10.1002/ajh.26760

7. Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and response criteria in mycosis fungoides and Sézary syndrome: a consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer. J Clin Oncol. 2011;29(18):2598–2607. doi:10.1200/JCO.2010.32.0630

8. Drieux F, Lemonnier F, Gaulard P. How molecular advances may improve the diagnosis and management of PTCL patients. Front Oncol. 2023;13:1202964. doi:10.3389/fonc.2023.1202964

9. Mehta-Shah N, Horwitz SM, Ansell S, et al. NCCN guidelines insights: primary cutaneous lymphomas, version 2.2020. J Natl Compr Cancer Netw. 2020;18(5):522–536. doi:10.6004/jnccn.2020.0022

10. Ondrejka SL, Amador C, Climent F, et al. Follicular helper T-cell lymphomas: disease spectrum, relationship with clonal hematopoiesis, and mimics. A report of the 2022 EA4HP/SH lymphoma workshop. Virchows Arch. 2023;483(3):349–365. doi:10.1007/s00428-023-03607-5

11. Latzka J, Assaf C, Bagot M, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023. Eur J Cancer. 2023;195:113343. doi:10.1016/j.ejca.2023.113343

12. Scarisbrick JJ, Prince HM, Vermeer MH, et al. Cutaneous lymphoma international consortium study of outcome in advanced stages of mycosis fungoides and Sézary syndrome: effect of specific prognostic markers on survival and development of a prognostic model. J Clin Oncol. 2015;33(32):3766–3773. doi:10.1200/JCO.2015.61.7142

13. O’Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the Pivotal Phase II BELIEF (CLN-19) Study. J Clin Oncol. 2015;33(23):2492–2499. doi:10.1200/JCO.2014.59.2782

14. Armand M, Derrieux C, Beldjord K, et al. A new and simple TRG multiplex PCR assay for assessment of T-cell clonality: a comparative study from the EuroClonality Consortium. Hemasphere. 2019;3(3):e255. doi:10.1097/hs9.0000000000000255

15. Roelens M, de Masson A, Ram-Wolff C, et al. Revisiting the initial diagnosis and blood staging of mycosis fungoides and Sézary syndrome with the KIR3DL2 marker. Br J Dermatol. 2020;182(6):1415–1422. doi:10.1111/bjd.18481

16. Schmitt C, Marie-Cardine A, Bensussan A. Therapeutic antibodies to KIR3DL2 and other target antigens on cutaneous T-cell lymphomas. Front Immunol. 2017;8:1010. doi:10.3389/fimmu.2017.01010

17. Ta VA, Ram-Wolff C, Annabi E, et al. Computational free flow cytometry for Sézary cells identification and quantification. J Invest Dermatol. 2025;145(10):2632–2635.e3. doi:10.1016/j.jid.2025.03.003

18. Shinohara MM, Rieger KE, Sundram U, Fung MA, Hristov AC. Assessing T-cell receptor clonality by next-generation sequencing in atypical cutaneous lymphoid infiltrates and cutaneous T-cell lymphoma: a scoping review. J Cutan Pathol. 2024;51(10):813–819. doi:10.1111/cup.14694

19. Zimmermann C, Boisson M, Ram-Wolff C, et al. Diagnostic performance of high-throughput sequencing of the T-cell receptor beta gene for the diagnosis of cutaneous T-cell lymphoma. Br J Dermatol. 2021;185(3):679–680. doi:10.1111/bjd.20432

20. Najidh S, Tensen CP, van der Sluijs-Gelling AJ, et al. Improved Sézary cell detection and novel insights into immunophenotypic and molecular heterogeneity in Sézary syndrome. Blood. 2021;138(24):2539–2554. doi:10.1182/blood.2021012286

21. Vermeer MH, Nicolay JP, Scarisbrick JJ, Zinzani PL. The importance of assessing blood tumour burden in cutaneous T-cell lymphoma. Br J Dermatol. 2021;185(1):19–25. doi:10.1111/bjd.19669

22. Lefebvre MN, Borcherding N, Reis RJ, Mou E, Liu V, Jabbari A. Molecular techniques drive cutting edge advancements in management of cutaneous T cell lymphoma. Front Immunol. 2023;14:1228563. doi:10.3389/fimmu.2023.1228563

23. Vermeer MH, Moins-Teisserenc H, Bagot M, Quaglino P, Whittaker S. Flow cytometry for the assessment of blood tumour burden in cutaneous T-cell lymphoma: towards a standardized approach. Br J Dermatol. 2022;187(1):21–28. doi:10.1111/bjd.21053

24. NCCN Guidelines Version 4.2024 T-Cell Lymphomas. 2024. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1483. Accessed August11, 2026.

25. Carson KR, Horwitz SM, Pinter-Brown LC, et al. A prospective cohort study of patients with peripheral T-cell lymphoma in the United States. Cancer. 2017;123(7):1174–1183. doi:10.1002/cncr.30416

26. Saleh K, Michot J-M, Ribrag V. Updates in the treatment of peripheral T-cell lymphomas. J Exp Pharmacol. 2021;13:577–591. doi:10.2147/JEP.S262344

27. Aubrais R, Bouabdallah K, Chartier L, et al. Salvage therapy with brentuximab-vedotin and bendamustine for patients with R/R PTCL: a retrospective study from the LYSA group. Blood Adv. 2023;7(19):5733–5742. doi:10.1182/bloodadvances.2022008524

28. Battistella M, Leboeuf C, Ram-Wolff C, et al. KIR3DL2 expression in cutaneous T-cell lymphomas: expanding the spectrum for KIR3DL2 targeting. Blood. 2017;130(26):2900–2902. doi:10.1182/blood-2017-06-792382

29. Hurabielle C, Thonnart N, Ram-Wolff C, et al. Usefulness of KIR3DL2 to diagnose, follow-up, and manage the treatment of patients with Sézary syndrome. Clin Cancer Res. 2017;23(14):3619–3627. doi:10.1158/1078-0432.Ccr-16-3185

30. Porcu P, Bagot M, Kim YH, et al. Lacutamab in patients with relapsed and refractory Sézary syndrome: long term follow-up from the TELLOMAK phase 2 trial. J Clin Oncol. 2025;43(suppl 16):2522.

31. Porcu P, Kim YH, Bagot M, et al. Lacutamab in patients with relapsed and/or refractory mycosis fungoides: long-term follow-up and translational data from the TELLOMAK phase 2 trial. J Clin Oncol. 2025;43(Suppl 16):2523.

32. Innate Pharma announces FDA clearance to proceed with TELLOMAK 3, a confirmatory phase 3 trial of lacutamab in CTCL. News release. Innate Pharma; 2025. Available from: https://www.innate-pharma.com/media/all-press-releases/innate-pharma-announces-fda-clearance-proceed-tellomak-3-confirmatory-phase-3-trial-lacutamab-ctcl. Accessed June30, 2026.

33. Mandel J, Gleason L, Joffe D, Bhatti S, Nikbakht N. Immunosequencing applications in cutaneous T-cell lymphoma. Front Immunol. 2023;14:1300061. doi:10.3389/fimmu.2023.1300061

34. Park J, Daniels J, Wartewig T, et al. Integrated genomic analyses of cutaneous T-cell lymphomas reveal the molecular bases for disease heterogeneity. Blood. 2021;138(14):1225–1236. doi:10.1182/blood.2020009655

35. Foss F, Advani R, Duvic M, et al. A phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. Br J Haematol. 2015;168(6):811–819. doi:10.1111/bjh.13222

36. Duvic M, Olsen EA, Breneman D, et al. Evaluation of the long-term tolerability and clinical benefit of vorinostat in patients with advanced cutaneous T-cell lymphoma. Clil lymph myelom. 2009;9(6):412–416. doi:10.3816/CLM.2009.n.082

37. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood. 2007;109(1):31–39. doi:10.1182/blood-2006-06-025999

38. Whittaker SJ, Demierre M-F, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(29):4485–4491. doi:10.1200/JCO.2010.28.9066

39. Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol. 2018;19(9):1192–1204. doi:10.1016/S1470-2045(18)30379-6

40. Watatani Y, Sato Y, Miyoshi H, et al. Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Leukemia. 2019;33(12):2867–2883. doi:10.1038/s41375-019-0473-1

41. Johnson WT, Ganesan N, Epstein-Peterson ZD, et al. TP53 mutations identify high-risk events for peripheral T-cell lymphoma treated with CHOP-based chemotherapy. Blood Adv. 2023;7(17):5172–5186. doi:10.1182/bloodadvances.2023009953

42. Andrews JM, Schmidt JA, Carson KR, Musiek AC, Mehta-Shah N, Payton JE. Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma. EBioMedicine. 2019;46:170–183. doi:10.1016/j.ebiom.2019.07.053

43. Decroos A, Cheminant M, Bruneau J, et al. KIR3DL2 may represent a novel therapeutic target in aggressive systemic peripheral T-cell lymphoma. Haematologica. 2023;108(10):2830–2836. doi:10.3324/haematol.2022.282220

44. Wooler G, Melchior L, Ralfkiaer E, Rahbek Gjerdrum LM, Gniadecki R. TP53 gene status affects survival in advanced mycosis fungoides. Front Med. 2016;3:51. doi:10.3389/fmed.2016.00051

45. Atalay F, Yeşilaltay A. Long-term successful use of belinostat in a patient with relapsed-refractory angioimmunoblastic lymphoma who has previously been heavily treated. J Cancer Res Ther. 2024;20(3):1049–1052. doi:10.4103/jcrt.jcrt_1213_22

46. Camus V, Etancelin P, Drieux F, et al. Complete hematologic response after belinostat treatment and allogeneic stem cell transplantation for multiple relapsed/refractory angioimmunoblastic T-cell lymphoma: a case report. Clin Case Rep. 2023;11(6):e7623. doi:10.1002/ccr3.7623

47. De Wilde S, Graux C. Complete hematologic response in a patient with multiple pretreated angioimmunoblastic T-cell lymphoma after belinostat therapy followed by allogeneic stem cell transplantation: a case report. Clin Case Rep. 2024;12(7):e9159. doi:10.1002/ccr3.9159

48. Allen PB, Lechowicz MJ. Hematologic toxicity is rare in relapsed patients treated with belinostat: a systematic review of belinostat toxicity and safety in peripheral T-cell lymphomas. Cancer Manage Res. 2018;10:6731–6742. doi:10.2147/CMAR.S149241