Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome.

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.

Lack of durable disease control with chemotherapy for mycosis fungoides and Sézary syndrome: a comparative study of systemic therapy.

Numerous systemic treatment options exist for patients with mycosis fungoides (MF) and Sézary syndrome (SS), but no large comparative studies are published. To study the efficacy of treatments, a retrospective analysis of our cutaneous lymphoma database was undertaken, with 198 MF/SS patients undergoing systemic therapies. The primary end point was time to next treatment (TTNT). Patients with advanced-stage disease made up 53%. The median follow-up time from diagnosis for all alive patients was 4.9 years (range 0.3-39.6), with a median survival of 11.4 years. Patients received a median of 3 lines of therapy (range 1-13), resulting in 709 treatment episodes. Twenty-eight treatment modalities were analyzed. The median TTNT for single- or multiagent chemotherapy was only 3.9 months (95% confidence interval [CI] 3.2-5.1), with few durable remissions. α-interferon gave a median TTNT of 8.7 months (95% CI 6.0-18.0), and histone deacetylase inhibitors (HDACi) gave a median TTNT of 4.5 months (95% CI 4.0-6.1). When compared directly with chemotherapy, interferon and HDACi both had greater TTNT (P < .00001 and P = .01, respectively). This study confirms that all chemotherapy regimens assessed have very modest efficacy; we recommend their use be restricted until other options are exhausted.

Targeting TAG-72 in cutaneous T cell lymphoma.

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.

Pralatrexate in relapsed/refractory T-cell lymphoma: a retrospective multicenter study.

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.

Lack of Durable Remission with Conventional-Dose Total Skin Electron Therapy for the Management of Sezary Syndrome and Multiply Relapsed Mycosis Fungoides.

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.