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Dear Editor, Two histone deacetylase (HDAC) inhibitors, vorinostat and romidepsin, have been approved by regulatory agencies in parts of the world for the treatment of relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS) based on positive phase II trial results.[[1]] Panobinostat has activity in MF/SS, and is approved in the U.S.A. for the treatment of myeloma.[3] HDAC inhibitors are of different classes, with vorinostat and panobinostat both hydroxamic acids with pan-HDAC inhibitor activity, and romidepsin a cyclic peptide with specificity to class I HDAC. Here, we now review the use of HDAC inhibitors in the treatment of patients with MF/SS at our institution, and examine TTNT for three HDAC inhibitors: romidepsin, vorinostat and panobinostat. GLO:F03/01feb20:bjd18522-fig-0001.jpg PHOTO (COLOR): Time to next treatment for patients with mycosis fungoides (MF) or Sézary syndrome (SS) treated with histone deacetylase inhibitors (N = 82). gl. [Extracted from the article]

Abstract: Variances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer-cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma-not otherwise specified and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALK- ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a "novel" single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK- ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Traditionally, Sezary syndrome (SS) has been associated with few therapeutic options and poor prognosis, with 5-year disease-specific survival (DSS) less than one-third in historical cohorts. However, newer therapies and combinations are associated with impressive time-to-next-treatment (TTNT), particularly allogeneic stem-cell transplantation (AlloSCT) and combination therapies notably those including extracorporeal photopheresis. In this multicentre, international study, we explored the prognostic outcomes of 178 patients exclusively managed for SS, diagnosed between 2012 and 2020, and treated in the modern therapeutic era. In this cohort, 58 different therapies were delivered, with 13.5% of patients receiving AlloSCT. Long-term survival exceeded historical reports with 5-year DSS and OS of 56.4% and 53.4% respectively. In those receiving AlloSCT, prognosis was excellent: 5-year DSS and OS were 90.5% and 78.0% respectively. Confirming the results from the Cutaneous Lymphoma International Consortium (CLIC), LDH and LCT had significant prognostic impact. Unlike earlier studies, stage did not have prognostic impact; we speculate that greater relative benefit favours patients with extensive lymphomatous nodal disease (Stage IVA2) compared to historical reports. For patients ineligible for AlloSCT, the prognosis remains relatively poor (5-year DSS 51.4% and OS 49.6%), representing ongoing unmet needs for more effective novel agents and investigation of improved therapeutic combinations., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Current monoclonal antibody-based treatment approaches for cutaneous T cell lymphoma (CTCL) rely heavily on the ability to identify a tumor specific target that is essentially absent on normal cells. Herein, we propose tumor associated glycoprotein-72 (TAG-72) as one such target. TAG-72 is a mucin-associated, truncated O-glycan that has been identified as a chimeric antigen receptor (CAR)-T cell target in solid tumor indications. To date, TAG-72 targeting has not been considered in the setting of hematological malignancies., Experimental Design: CD3 + cells from patients with CTCL were analyzed for TAG-72 expression by flow cytometry. Immunohistochemistry was used to assess TAG-72 expression in CTCL patient skin lesions and a TAG-72 ELISA was employed to assess soluble TAG-72 (CA 72-4) in patient plasma. TAG-72 CAR transduction was performed on healthy donor (HD) and CTCL T cells and characterized by flow cytometry. In vitro CAR-T cell function was assessed by flow cytometry and xCELLigence® using patient peripheral blood mononuclear cells and proof-of-concept ovarian cancer cell lines. In vivo CAR-T cell function was assessed in a proof-of-concept, TAG-72 + ovarian cancer xenograft mouse model., Results: TAG-72 expression was significantly higher on total CD3 + T cells and CD4 + subsets in CTCL donors across disease stages, compared to that of HDs. TAG-72 was also present in CTCL patient skin lesions, whereas CA 72-4 was detected at low levels in both CTCL patient and HD plasma with no differences between the two groups. In vitro cytotoxicity assays showed that anti-TAG-72 CAR-T cells significantly, and specifically reduced CD3 + TAG-72 + expressing CTCL cells, compared to culture with unedited T cells (no CAR). CTCL CAR-T cells had comparable function to HD CAR-T cells in vitro and CAR-T cells derived from CTCL patients eradicated cancer cells in vivo., Conclusion: This study shows the first evidence of TAG-72 as a possible target for the treatment of CTCL., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The research described in this paper was funded by Cartherics Pty Ltd. All authors except H.M.P., C.V.D.W. and R.T, are paid employees of Cartherics and hold options and/or equity in the company. R.L.B, A.O.T and I.T.N are key Cartherics executives and H.M.P. is a member of the company's Scientific Advisory Board. V.J.E, R.L.B, I.T.N, H.M.P and A.O.T are inventors on Cartherics-owned patent applications related to this work., (© 2024 The Authors. Published by Elsevier Ltd.)

Despite increasing availability of therapies, patients with Sezary syndrome (SS) commonly endure multi-line treatment journeys, mostly with partial responses of short duration. Measuring clinical benefit is challenging; time-to-next-treatment (TTNT) provides a robust, objective measurement of efficacy. This international observational study examines patterns of clinical care and therapeutic benefit as measured by TTNT. TTNT was calculated for monotherapies and combination therapies, with consideration to treatment line. 178 patients with SS (73% de novo, 27% secondary) were included, receiving 721 lines of systemic therapy, with median follow-up of 56.9 months. Across all lines, 58 different therapeutic regimens were prescribed (54 were systemic therapies) and classified into 17 treatment groups. The most common first-line treatments were extracorporeal photopheresis (ECP)-containing combination therapy (20%) and retinoid monotherapy (19%). Median TTNT for all first-line therapies was short (5.4 months). First-line, combination therapies had longer median TTNT than monotherapies, 10.0 vs 5.0 months (P = .004), respectively. Later delivery of combination therapies was associated with shorter clinical benefit, with median TTNT reduced to 6.2 and 2.2 months for mid-line (2nd-4th line) and late-line (≥5th line), respectively (P < .001). First-line ECP-containing treatments were associated with longer median TTNT than non-ECP-containing treatments, 9.0 vs 4.9 months (P = .007). For both ECP-monotherapy and ECP-containing combination therapy, significant reductions in TTNT were seen in later lines. These data suggest therapeutic benefit from first-line delivery of combination therapy for SS and favor early inclusion of ECP in the treatment algorithm for those who can access it., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The CD30-postive lymphoproliferative disorders, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma, account for up to 30% of all cutaneous T-cell lymphomas (CTCLs) and are the second most common form of CTCLs after mycosis fungoides. Both conditions differ in their clinical presentations; however, they share the expression of the CD30 antigen as a common immunophenotypic hallmark. There is a wide spectrum of management options depending on factors such as extent of disease, staging and treatment tolerability. This Clinical Practice Statement is reflective of the current clinical practice in Australia., (© 2023 Australasian College of Dermatologists.)

Background and Purpose: Primary cutaneous CD4 + small/medium T-cell lymphoproliferative disorder (PCSMLPD) is a benign behaving condition, typically manifesting as solitary head or neck papules, frequently creating cosmetic concerns. Optimal management of this rare disease is unclear. Herein, patterns of care and treatment outcomes are described, with particular focus on low-dose RT., Materials and Methods: Eligibility required biopsy-proven PCSMLPD on central review, diagnosed between 2007-2022. Patterns of care, treatment responses and relapse patterns were assessed. Freedom-from-progression (FFP) was compared between RT and surgery., Results: 41 patients were eligible. First-line treatments were: RT, 19 (46.3 %); surgery, 17 (41.5 %) (3 received adjuvant RT); watchful waiting, 5 (12.2 %). Median follow-up was 37.7 months. Overall, 24 patients received RT (19 definitive first-line, 3 adjuvant, 2 second-line). 10 (42 %) received 4 Gy in 2 fractions (with no acute toxicities); 14 (58 %) received 20-40 Gy. Complete response rate was 100 %. No post-RT relapses observed. After first-line surgery alone (n = 14, 3 with positive margins), 4 (28.5 %) experienced relapse (2 local, 2 distant). Watchful-waiting (n = 5) led to partial resolution post-biopsy in 4 patients; no complete resolution seen. 3-year FFP for RT alone was 100 % vs 61 % for surgery alone (p = 0.12)., Conclusion: RT is a successful, non-invasive option for PCSMLPD: 100 % achieved complete response, with no relapses, and FFP appearing numerically superior to surgery in this cohort. In this first series of low-dose RT for PCSMLPD, 4 Gy in 2 fractions appears an excellent treatment option, offering durable disease control, no acute toxicities and convenient treatment time of only 2 days., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

VEXAS (Vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic mutation) syndrome is a genetically defined disorder identified in 2020, describing patients with inflammatory syndromes associated with haematological dysfunction. It is a severe, treatment-resistant condition, with estimated mortality between 40% and 63%. A wide range of cutaneous manifestations have been described. Here, we report on two patients with treatment-resistant neutrophilic dermatosis and myelodysplastic syndrome, who were subsequently diagnosed with VEXAS syndrome. Our cases highlight the need for dermatologists' awareness of this novel condition and to initiate early referral to haematologists for appropriate multidisciplinary care., (© 2022 Australasian College of Dermatologists.)

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphomas that are frequently associated with a poor prognosis. For many decades, the standard-of-care has been CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based therapy, but it is well-recognized that survival outcomes are unsatisfactory, especially when compared with B-cell lymphomas. Major recent advances in cancer diagnosis and management have the potential to significantly improve PTCL outcomes. These include: (1) improved diagnostic techniques that incorporate molecular genetic data to further refine diagnosis and subtyping; (2) the development of novel agents; and (3) improved monitoring modalities, such as 18 F-fluorodeoxyglucose positron emission tomography-computed tomography scans and circulating tumor DNA. In this review, we aim to explore these 3 advances in the context of frontline management of PTCL., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The T-cell lymphomas are a rare group of Non-Hodgkin's lymphomas derived from mature T-lymphocytes. They are divided broadly into the Peripheral T-cell lymphomas and the Cutaneous T-cell lymphomas. Clinical outcomes vary widely but are generally unsatisfactory with current treatments. The development of an understanding of the various critical pathways in T-cell lymphogenesis and subsequent identification of therapeutic targets has led to a rapid expansion of the previously underwhelming T-cell lymphoma armament. This review aims to provide an up-to-date overview of the current state of targeted therapies in the T-cell lymphomas, including novel antibody-based treatments, small molecule inhibitors and immune-based therapies.

We present a retrospective multicenter study of pralatrexate treatment outcomes in an Australian practice setting for patients with relapsed/refractory T-cell lymphoma who had failed 1+ systemic therapies, treated via a compassionate access program. Endpoints assessed included response rates, toxicities, and subsequent therapies. Progression-free survival (PFS), time to next treatment (TTNT), event-free survival (EFS), overall survival (OS), and time to best response, were assessed by Kaplan-Meier analysis. The study included 31 patients, with median age 69 years. We demonstrated ORR of 35.5% ( n  = 11), including 4 complete responses (13%) and 7 partial responses (23%). The predicted median OS was 10 months, with EFS of 9 months, and PFS of 9 months. Median TTNT was 8 months. Mucositis was the most commonly observed toxicity. This study - the second largest real-world cohort reported to date - underscores the importance of pralatrexate in relapsed/refractory T-cell lymphoma, as well as its acceptable toxicity profile.

Primary cutaneous lymphomas represent a heterogeneous group of T- and B-cell lymphomas with distinct clinical presentations, histopathologic features, treatment approaches and outcomes. The cutaneous T-cell lymphomas, which include mycosis fungoides and Sézary syndrome, account for the majority of the cutaneous lymphomas. This Clinical Practice Statement is reflective of the current clinical practice in Australia. An expanded form of the Clinical Practice Statement (and updates), along with helpful patient resources and access to support groups, can be found at the following (http://www.australasianlymphomaalliance.org.au)., (© 2020 The Australasian College of Dermatologists.)

Peripheral T-cell lymphomas (PTCLs) are distinct pathological entities with clinical advancements lagging behind their B-cell lymphoma counterpart. Frequently aggressive in their clinical behaviour, clinicians are constantly challenged with low complete remission rates, early relapses and failure to achieve long-term responses despite aggressive first-line chemotherapy, resulting in poor overall survival in the majority of patients. There is currently no consensus regarding the optimal therapy for PTCL and treatment approaches are mainly derived from prospective phase II studies, registry data and retrospective studies. Despite its biological heterogeneity, a less than satisfactory "one-size-fits-all" approach has been adopted to date. Although its role remains controversial, for many years, haematopoietic stem cell transplantation has been adopted by clinicians with the aim of overcoming poor outcomes by consolidating responses. In this review, we aim to define the role of both autologous and allogeneic stem cell transplantation in PTCL in both frontline and salvage settings, especially in the context of recent advancements in this field.

Histone deacetylase inhibitors (HDACi) are active agents for peripheral T-cell lymphoma (PTCL). Anecdotally angioimmunoblastic T-cell lymphoma (AITL) appears to respond better than PTCL-not otherwise specified (NOS) to HDACi. The new World Health Organization classification shows that a subgroup of PTCL carries similarities in phenotype and gene expression profiling to AITL, comparable to T follicular helper (TFH) cells. The disease might behave similarly to AITL when treated with HDACi. We analyzed 127 patients with AITL or PTCL-NOS treated with HDACi at relapse as a single agent or in combination. We re-reviewed the pathology of all PTCL-NOS to identify the TFH phenotype. Patients received HDACi at relapse as a single agent in 97 cases (76%, 59 TFH, 38 non-TFH) or in combination in 30 cases (24%, 18 TFH, 12 non-TFH) including duvelisib, lenalidomide, lenalidomide plus carfilzomib, and pralatrexate. Seven PTCL-NOS had TFH phenotype; 2 PTCL-NOS were reclassified as AITL. Overall response rate (ORR) was 56.5% (28.9% complete response [CR]) in TFH and 29.4% (19.6% CR) in non-TFH phenotype patients (P = .0035), with TFH phenotype being an independent predictor of ORR (P = .009). Sixteen patients sufficiently responded to HDACi or HDACi in combination with another agent to proceed directly to allogeneic transplantation; 1 of 16 responded to donor lymphocyte infusion (12 TFH, 4 non-TFH). Our results, although retrospective, support that HDACi, as a single agent or in combination, may have superior activity in TFH-PTCL compared with non-TFH PTCL. This differential efficacy could help inform subtype-specific therapy and guide interpretation of HDACi trials., (© 2020 by The American Society of Hematology.)

Mycosis fungoides (MF) and Sezary syndrome (SS) are multi-relapsing, morbid, cutaneous T-cell lymphomas. Optimal treatment sequencing remains undefined. Total skin electron therapy (TSE) is a highly technical, skin-directed treatment, uniquely producing symptom-free and treatment-free intervals. Recent publications favour low-dose TSE for reduced toxicity, but early data support conventional-dose TSE (cdTSE) for longer disease control. Patient selection requires weighing-up tolerability against response durability. We investigated duration of benefit from cdTSE in patients with poorer prognosis diseases: SS and heavily pre-treated MF. Endpoints were overall survival, and "time to next treatment" (TTNT) as surrogate for clinical benefit duration. Seventy patients (53 MF, 17 SS) were eligible: median prior treatments, 4; median cdTSE dose, 30 Gy; median follow-up, 5.8 years. SS patients had worse prognosis (HR = 5.0, p < 0.001) and shorter TTNT (HR = 4.5, p < 0.001) than MF patients; median TTNT was only 3.7 months. Heavily pre-treated MF patients had inferior prognosis (HR = 1.19 per additional line, p = 0.005), and shorter TTNT (HR = 1.13 per additional line, p = 0.031). Median TTNT for MF patients with ≥3 prior treatments was 7.1 months, versus 23.2 months for 0-2 prior treatments. In conclusion, cdTSE has a limited role in SS. TTNT is reduced in heavily pre-treated MF patients, suggesting greater benefit when utilized earlier in treatment sequencing.

Extracorporeal photopheresis (ECP) has demonstrated therapeutic benefit in patients with Sézary syndrome (SS) and erythrodermic mycosis fungoides (e-MF). To examine the efficacy of ECP in the modern era of novel therapies, we conducted a retrospective analysis of 65 patients with a diagnosis of SS or e-MF with blood involvement who were treated with ECP at our institute. Overall survival (OS), time to next treatment (TTNT), and skin response rate (RR) were used as the study end points to determine patient outcome. The median follow-up from diagnosis was 48 months (range 1-225 months), with a median predicted OS of 120 months. The majority (88%) of patients commenced ECP at treatment lines 1 to 3, either as a monotherapy or in conjunction with other systemic agents. The use of ECP monotherapy resulted in a significantly longer median TTNT when compared with interferon-α (P = .0067), histone deacetylase inhibitors (P = .0003), novel immunotherapy agents (P = .028), low-dose methotrexate (P < .0001), and chemotherapy (P < .0001). In particular, early commencement of ECP at treatment lines 1 to 3 yielded a TTNT of 47 months. The results of our study support the utilization of ECP for SS/e-MF, and we recommend that ECP should be considered as early as possible in the treatment paradigm for these patients., (© 2019 by The American Society of Hematology.)

Introduction: Brentuximab vedotin is an antibody-drug conjugate, which combines a CD30 monoclonal antibody with the microtubule-disrupting agent monomethylauristatin E. The utility of brentuximab vedotin has been explored in a number of diseases, with a recent focus on T-cell lymphoma, particularly systemic anaplastic large-cell lymphoma (sALCL) and cutaneous T-cell lymphoma (CTCL), as well as other peripheral T-cell lymphoma (PTCL) histologies. Areas covered: This review surveys current data on the efficacy of brentuximab vedotin in T-cell lymphoma, as well as embedding it in a therapeutic context by reviewing potential competitor agents in the clinic. Data are drawn from published literature, with a focus on clinical trial data rather than preclinical studies or case reports. Expert opinion: Brentuximab vedotin has a clear clinical benefit in CTCL and sALCL, and can achieve durable responses in a number of patients. Toxicities, particularly peripheral neuropathy, may limit treatment in some patients; however, the agent is generally well tolerated. In this context, brentuximab vedotin has been globally approved for use in sALCL and certain CTCL subtypes, however, further information is required to enhance our understanding of when and in whom to best employ this agent, as well as exploring rational combinations to augment responses.