Real-world study on the use of pegylated interferon alpha-2a for treatment of mycosis fungoides/Sézary syndrome using Time to Next Treatment as a measure of clinical benefit: An EORTC CLTG study.

INTRODUCTION: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon alpha (IFN-α, subtypes 2a and 2b) has been used for MF/SS since 1984, however its production was recently stopped and so the recombinant pegylated (PEG) form of IFN α-2a remains as single IFN alternative treatment, even though not approved for MF/SS. OBJECTIVE: To assess effectiveness and safety of PEG IFN α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in real world setting. METHODS: We conducted an international and multicenter retrospective study of patients with MF and SS at any stage, treated with PEG IFN α-2a, from July 2012 to February 2022. Patients were included across 11 centers in 10 countries. Primary endpoints were to determine TTNT of PEG IFN α-2a and the adverse events (AE) in MF/SS. RESULTS: In total 105 patients were included, mean age was 61 (22-86 years); 42 (40%) with disease stage IA-IIA, 63 (60%) with stage IIB-IVB. PEG IFN α-2a was combined with other therapies in 67 (64%) patients, usually with extracorporeal photopheresis (36%) and bexarotene (22%). Fifty-seven percent of stage I-IIA patients achieved ORR, whereas 51% of stage IIB-IVB. Combination therapy showed a TTNT of 10.4 months, while 7 months in monotherapy (p=0.0099). Overall, TTNT was 9.2 months, ORR was 53% (56/105), CR and PR were 13% and 40%, respectively.AE were described in 69% (72) of the patients. Flu-like symptoms (27%), lymphopenia (23%) and elevated liver function (10%) were the most frequently reported. Grade 3-4 adverse events were reported in 23 (21%) patients, which were mostly related to myelosuppression. LIMITATIONS: retrospective data analysis and unrestricted number of combination therapies. CONCLUSIONS: PEG IFN α-2a for MF/SS showed ORR of 53%, TTNT of 9.2 months, superiority of combination regimens in comparison to monotherapy and doses of 180 mcg/weekly related to higher ORR.

Evaluation of mortality, prognostic parameters, and treatment efficacy in mycosis fungoides.

BACKGROUND AND OBJECTIVES: Mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is characterized by a variable clinical course, presenting either as indolent disease or showing fatal progression due to extracutaneous involvement. Importantly, the lack of prognostic models and predominantly palliative therapy settings hamper patient care. Here, we aimed to define survival rates, disease prediction accuracy, and treatment impact in MF. PATIENTS AND METHODS: Hundred-forty MF patients were assessed retrospectively. Prognosis and disease progression/survival were analyzed using univariate Cox proportional hazards regression model and Kaplan-Meier estimates. RESULTS: Skin tumors were linked to shorter progression-free, overall survival and a 3.48 increased risk for disease progression when compared to erythroderma. The Cutaneous Lymphoma International Prognostic Index identified patients at risk in early-stage disease only. Moreover, expression of Ki-67 >20%, CD30 >10%, CD20+, and CD7- were associated with a significantly worse outcome independent of disease stage. Only single-agent interferon-α and phototherapy combined with interferon-α or retinoids/bexarotene achieved long-term disease control in MF. CONCLUSIONS: Our data support predictive validity of prognostic factors and models in MF and identified further potential parameters associated with poor survival. Prospective studies on prognostic indices across disease stages and treatment modalities are needed to predict and improve survival.

The changing epidemiology of human leishmaniasis in the non-endemic country of Austria between 2000 to 2021, including a congenital case.

BACKGROUND: Leishmaniasis is caused by infection with intracellular protozoans of the genus Leishmania. Transmission occurs predominantly by the bite of phlebotomine sandflies, other routes, including congenital transmission, are rare. The disease manifests as either cutaneous, visceral or mucosal/mucocutaneous leishmaniasis. In recent years, changes in the epidemiological pattern have been reported from Europe. PRINCIPAL FINDINGS: A total of 311 new and 29 published leishmaniasis cases occurring between 01/01/2000 and 12/31/2021 in Austria were collected and analyzed. These encompassed 146 cutaneous (CL), 14 visceral (VL), 4 mucosal, and 3 cases with concurrent VL and CL. In addition, asymptomatic infections, comprising 11 unspecified cases with Leishmania DNA detectable only in the blood and 162 cases with anti-Leishmania antibodies were reported. Particularly since 2016, the incidence of leishmaniasis has steadily risen, mainly attributable to increasing numbers of CL and cases with positive serology against Leishmania species, whereas the incidence of VL has slowly decreased. Analysis revealed that a shift in the causative species spectrum had occurred and that a substantial number of CL cases were caused by members of the Leishmania donovani/infantum complex. Simultaneous occurrence of VL and CL was identified in immunocompromised individuals, but also in a not yet reported case of an immunocompetent child after vertical transmission. CONCLUSIONS: The incidence of leishmaniasis has risen in the recent years. The numbers are anticipated to keep rising due to increasing human mobility, including travel and forced migration, growing reservoir host populations as well as expansion and dispersal of vector species caused by climate and habitat changes, urbanization and globalization. Hence, elevated awareness for the disease, including possible transmission in previously non-endemic regions and non-vector transmission modes, support of sandfly surveillance efforts and implementation and establishment of public health interventions in a One Health approach are pivotal in the global efforts to control and reduce leishmaniasis.

Single-Cell RNA Sequencing Reveals Tissue Compartment-Specific Plasticity of Mycosis Fungoides Tumor Cells.

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. While initially restricted to the skin, malignant cells can appear in blood, bone marrow and secondary lymphoid organs in later disease stages. However, only little is known about phenotypic and functional properties of malignant T cells in relationship to tissue environments over the course of disease progression. We thus profiled the tumor micromilieu in skin, blood and lymph node in a patient with advanced MF using single-cell RNA sequencing combined with V-D-J T-cell receptor sequencing. In skin, we identified clonally expanded T-cells with characteristic features of tissue-resident memory T-cells (TRM, CD69+CD27-NR4A1+RGS1+AHR+ ). In blood and lymph node, the malignant clones displayed a transcriptional program reminiscent of a more central memory-like phenotype (KLF2+TCF7+S1PR1+SELL+CCR7+ ), while retaining tissue-homing receptors (CLA, CCR10). The skin tumor microenvironment contained potentially tumor-permissive myeloid cells producing regulatory (IDO1) and Th2-associated mediators (CCL13, CCL17, CCL22). Given their expression of PVR, TNFRSF14 and CD80/CD86, they might be under direct control by TIGIT+CTLA4+CSF2+TNFSF14+ tumor cells. In sum, this study highlights the adaptive phenotypic and functional plasticity of MF tumor cell clones. Thus, the TRM-like phenotype enables long-term skin residence of MF cells. Their switch to a TCM-like phenotype with persistent skin homing molecule expression in the circulation might explain the multi-focal nature of MF.

Long-term Therapeutic Success of Intravenous Rituximab in 26 Patients with Indolent Primary Cutaneous B-cell Lymphoma.

Systemic monotherapy with rituximab is a well-known treatment approach for primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone lymphoma. Both have excellent prognosis despite high relapse rates. To investigate the long-term effectiveness and clinical outcome of intravenous rituximab at a dose of 375 mg/m2 once weekly, data for 26 patients (17 primary cutaneous follicle centre lymphoma and 9 primary cutaneous marginal zone lymphoma) were analysed retrospectively. Complete remissions occurred in 20 (77%) and partial remissions in 6 patients (23%), demonstrating an overall response rate of 100%. The relapse rate was 52.9% in primary cutaneous follicle centre lymphoma and 88.9% in primary cutaneous marginal zone lymphoma. Ongoing complete remissions after therapy with rituximab were observed in 9 patients (34.6%) with a median progression-free survival of 161 months (13.4 years). These results confirm that intravenous rituximab is an effective and well-tolerated treatment with durable responses in a relevant percentage of patients at a median follow-up of 148 months (12.3 years).

Health-related Quality of Life in Cutaneous Lymphomas: Past, Present and Future.

Previous studies have reported that primary cutaneous lymphomas profoundly influence patients' health-related quality of life (HRQoL). However, assessment of this psycho-social concept is not common in routine patient care unless required within clinical trials. The aim of this review is to provide a comprehensive overview of HRQoL measures and outcomes in cutaneous lym-phomas in order to inform clinicians. Advanced-stage cutaneous lymphomas were found to be associated with worse HRQoL than early-stage disease. Specifically, progression of the disease, age, sex, psychosocial issues, educational level and therapy were related to the extent of impairment of HRQoL. Treatment response was linked to improved HRQoL, but notably ameliorated HRQoL scores were also reported despite objective disease response. However, the variety of instruments applied to measure HRQoL in cutaneous lymphomas makes it difficult to compare data directly. In conclusion, speciality-specific HRQoL instruments were superior to generic ones, which probably failed to recognize small, but relevant, changes, demonstrating the need for a disease-specific tool.

Evaluation of Low-Dose, Low-Frequency Oral Psoralen-UV-A Treatment With or Without Maintenance on Early-Stage Mycosis Fungoides: A Randomized Clinical Trial.

Importance: Psoralen-UV-A (PUVA) photochemotherapy is standard first-line treatment for skin-limited, early-stage mycosis fungoides capable of producing high initial complete response (CR) rates. However, much remains unknown about PUVA's therapeutic mechanisms, optimal duration and frequency of treatment, dose escalation, or use as maintenance therapy. Objectives: To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides. Design, Setting, and Participants: This prospective randomized clinical trial with defined PUVA dosing regimen was carried out in 5 centers (Graz, Vienna, Hietzing, Innsbruck, and Salzburg) across Austria. Patients with stage IA to IIA mycosis fungoides (n = 27) were enrolled in the study beginning March 13, 2013, with the last patient enrolled March 21, 2016. These patients were treated with oral 8-methoxypsoralen followed by UV-A exposure 2 times per week for 12 to 24 weeks until CR. Patients with CR were randomized to PUVA maintenance for 9 months (14 total exposures) or no maintenance. The study was conducted from April 27, 2012, to July 27, 2018. Data analysis of the primary end point was of the intention-to-treat population, and the secondary end point analysis was of the evaluable population. Main Outcomes and Measures: Efficacy of the PUVA regimen was determined by the rate of CR as defined by a modified severity-weighted assessment tool (mSWAT) score reduction to 0. Levels of proinflammatory molecules in serum and histologic features and percentage of clonal T cells in skin were assessed to search for biomarkers of clinical response. Results: In 27 patients with mycosis fungoides, 19 (70%) were male with mean (range) age 61 (30-80) years. At baseline, patients with CR had a mean (range) mSWAT score of 18.6 (1-66) compared with 16.8 (3-46) in patients with partial response. The 12- to 24-week PUVA induction regimen reduced the mSWAT score in all patients and led to CR in 19 (70%) of 27 patients and a low mean cumulative UV-A dose of 78.5 J/cm2. The subsequent standardized 9-month PUVA maintenance phase prolonged median (range) disease-free remission from 4 (1-20) months to 15 (1-54) months (P = .02). High density of histologic infiltrate and high percentage of clonal TCR sequences in skin biopsy specimens at baseline were inversely associated with therapeutic response. No severe adverse effects were seen during the PUVA induction or maintenance phase. Conclusions and Relevance: This proof-of-concept study identifies potential biomarkers for therapeutic response to PUVA in mycosis fungoides; it also demonstrates that low-dose, low-frequency PUVA appears to be highly effective, and maintenance treatment may extend disease-free remission. Trial Registration: ClinicalTrials.gov identifier: NCT01686594.

Patients' Illness Perception as a Tool to Improve Individual Disease Management in Primary Cutaneous Lymphomas.

The Revised Illness Perception Questionnaire (IPQ-R) has been shown to assess illness perception reproducibly in primary cutaneous T-cell lymphomas (CTCL). Illness perception reflects patients' individual concepts of understanding and interpretation of the disease, influencing illness behaviour and health-related quality of life (HRQOL). This study investigated the clinical relevance of the relationships between illness perception, illness behaviour, and HRQOL in CTCL and cutaneous B-cell lymphomas (CBCL). A total of 92 patients completed the IPQ-R, the Scale for the Assessment of Illness Behavior (SAIB), and a skin-specific HRQOL tool (Skindex-29). Data on illness behaviour were not evidently related to illness perception, whereas illness perception was significantly associated with HRQOL. Both, IPQ-R and HRQOL results correlated with disease entity, stage, and socio-demographics. Only IPQ-R results provided practical information on patients' needs to train personal coping strategies. IPQ-R assessment in CTCL and CBCL might be a useful instrument to improve individual disease management.

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.

PURPOSE: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients.

A prospective study of mobile phones for dermatology in a clinical setting.

We evaluated the accuracy of diagnoses made from pictures taken with the built-in cameras of mobile phones in a 'real-life' clinical setting. A total of 263 patients took part, who photographed their own lesions where possible, and provided clinical information via a questionnaire. After the teledermatology procedure, each patient was examined face-to-face and a gold standard diagnosis was made. The telemedicine data and pictures were diagnosed by 15 dermatologists. The 299 cases contained 1-22 clinical images each (median 3). Nine dermatologists finished all the cases and the remaining six completed some of them, thus providing 2893 decisions. Overall, 61% of all cases were rated as possible to diagnose and of those, 80% were correct in comparison with the face-to-face diagnosis. Image quality was evaluated and the median was 5 on a 10-point scale. There was a significant correlation between the correct diagnosis and the quality of the photographs taken (P < 0.001). In nearly two-thirds of all cases, a teledermatology diagnosis was possible; however, there was insufficient information to make a telemedicine diagnosis in about one-third of the cases. If applied carefully, mobile phones could be a powerful tool for people to optimize their health care status.