Mycosis fungoides/Sézary Syndrome Research Articles

Racial Disparities in Mycosis Fungoides/Sézary Syndrome–A Single-Center Observational Study of 292 Patients

Clinical presentation of Mycosis fungoides/Sézary syndrome (MF/SS) in Black and African American (AA) patients can be heterogeneous with poor survival reported in AA/black patients. In this study, we aim to characterize differences between AA/black and white patients with MF/SS. A retrospective single-center hospital-based case-control study including 292 MF/SS patients (146 AA/black matched with 146 white patients). We analyzed demographic, clinical and survival differences. AA/black patients were diagnosed at an earlier age (9 years younger), were predominantly females, had higher rates of Medicaid/Medicare insurance and lower income compared to matched white patients (P <.001). Adjusting for age, sex, insurance type, and income bracket, AA/black patients had significantly worse overall survival (hazard ratio [HR] 2.88, 95%CI 1.21-6.85, P = .017). Association of clinical MF phenotype with survival showed that hypopigmentation was associated with survival in AA/black patients but not in white patients. Erythroderma and ulceration were associated with worse survival risk in AA/black patients. AA/black patients with MF/SS have a significant worse survival outcome compared to white patients. The association between clinical phenotypes and survival differed between these groups. Further studies are required to investigate whether race-specific pathogenesis or genetic factors may explain these differences.

Overall survival in the UK in mycosis fungoides or Sézary syndrome cutaneous T-cell lymphoma: comparative effectiveness of mogamulizumab versus current standard of care.

Aim: Due to extensive treatment switching in the MAVORIC trial, lack of UK regulatory licence for the comparator, overall survival (OS) with mogamulizumab was compared with patients with previously treated advanced mycosis fungoides/Sézary syndrome (MF/SS) in real-world setting. Design, setting & participants: Data were from the Hospital Episode Statistics database (all patients in NHS secondary care system in 2009-2019). Patients were selected according to trial inclusion criteria, then trial and HES samples were matched on selected variables with significant imbalance. Outcomes: The analysis indicated significant improvement in OS for mogamulizumab treatment compared with UK clinical practice (hazard ratio: 0.36, 95% CI: 0.24, 0.53). Conclusion: Results suggest an OS advantage for patients with advanced MF/SS treated with mogamulizumab in MAVORIC trial compared with UK clinical practice.

Association of Cardiovascular Disease in Patients with Mycosis Fungoides and Sézary Syndrome Compared with that in a Matched Control Cohort

Mycosis fungoides/Sézary syndrome (MF/SS) produces a low-grade chronic inflammatory state that may be associated with an increased risk of cardiovascular (CV) events, as seen in other chronic, systemic dermatologic diseases. To assess this association, a retrospective, cross-sectional study was designed in which 421 patients with a biopsy-proven diagnosis of MF/SS were compared with a control cohort of 4,210 age-, gender-, and race-matched patients randomly selected from the National Health and Nutritional Evaluation Survey database. The MF/SS cohort had a 14% prevalence of CV events, which was not statistically different from the control population's prevalence of 13%. In the MF/SS cohort, a multivariable logistic regression model showed that older patients (OR= 1.05 for each year of age, 95% confidence interval= 1.02-1.07) and those diagnosed with hypertension (OR= 3.40, 95% confidence interval= 1.71-6.75) had a higher risk of a CV event (P < 0.001). Risk factors such as gender, race, smoking, diabetes, and obesity were not significantly associated with CV events. Findings suggest that in the MF/SS population, advancing age and hypertension are risk factors for CV events, requiring clinical recognition and management. In addition, further research is needed to understand the complex interplay of how chronic inflammation in MF/SS impacts the immune development of CV disease.

Potential role of tumor-associated macrophages and CD163/CD68 ratio in mycosis fungoides and Sézary syndrome in correlation with serum sCD163 and CCL22.

Currently, there are no curative treatment options for mycosis fungoides (MF) and Sézary syndrome (SS) other than stem cell transplant. Understanding the interplay between tumor cells and tumor microenvironment could aid in the development of new therapies. Tumor-associated macrophages (TAMs) mostly have M2 phenotype that promotes tumor progression. This study investigated CD68+ and CD163+ TAMs as well as CD163/CD68 ratio in skin lesions from different stages of MF, large-plaque parapsoriasis, and SS. Moreover, we analyzed serum levels of sCD163 and CCL22 in correlation with TAMs count and CD163/CD68 ratio. CD68+ and CD163+ TAMs count significantly increased as the disease progressed. CD163/CD68 ratio was highest at MF tumor stage and SS indicating M2 polarization with disease progression. Significant positive correlations were detected between serum levels of sCD163 and CCL22 and CD68+ and CD163+ TAMs count and CD163/CD68 ratio. We concluded that TAMs play an important role in MF progression. High CD163/CD68 ratio in tumor stage MF and SS indicates M2 polarization of TAMs with tumor progression. CD163/CD68 ratio should be considered in assessing TAMs rather than total TAMs count. Also, sCD163 and CCL22 serum levels reflect M2 load and thus could be used as markers to assess disease progression.

Tre-O1-03 - Response to brentuximab vedotin in advanced stage MF/Sézary syndrome with low CD-30 expression: “real-life” data of the German Cutaneous Lymphoma Network

Introduction and objectives: Advanced stage mycosis fungoides/Sézary syndrome (MF/SS) are difficult to treat and associated with an inferior prognosis. Brentuximab vedotin (BV) is a frequently used agent in higher stages, particularly in cases with a high expression of CD30. The ALCANZA trial, which included MF patients with a CD30 expression >10%, demonstrated high response rates and a good tolerability. However, its effectiveness in advanced stage MF/SS syndrome with low CD30-expression (<10%) still has to be systematically evaluated. Therefore, the question is whether an equally good response with BV is achievable in these CTCL cases. Material and methods: Between 2018 - 2020, 32 patients in 11 centres with predominantly advanced MF/SS and low CD-30 expression (<10%) were treated with BV in the recommended dosage, retrospective evaluation of therapy response was done according to the EORTC-ISCL criteria. Results: In all patients (n=32) at least one other systemic therapy preceded BV treatment. The median number of previous treatments was 3. Thirty patients suffering from MF (IB: 2; IIA: 1; IIB: n=18; III: 1; IV: 9; total ≥IIB: 27) and 2 SS patients were analyzed. As a result, 17 of 31 patients (OR: 54.8%) responded to therapy (CR n=4/31 12.9%, PR n=13/31 41.9%) after 6 cycles. The median progression-free interval among patients with OR was 6.4 months (range: 0.5–15.5 months, mean ± SD: 6.4±3.8, n=16). In 37.5% (n=12) the CD-30 Expression was 5-9% and in 62.5% (n=20) CD-30-Expression was <5%. Conclusions: In conclusion, with 54.8% OR, BV in MF/SS with low CD-30 expression (<10%) shows a comparable response rate compared to CTCL with CD-30 expression ≥10% (56-73%) and CR (12.9% vs. 3–35%) but with a lower PFS (6.4 vs. 11 months). In summary, based on this data the treatment of MF/SS with low CD-30 expression with BV seems to be an effective therapeutical option and justifies its use in challenging cases independent of the degree of CD30 positivity. Advanced stage mycosis fungoides/Sézary syndrome (MF/SS) are difficult to treat and associated with an inferior prognosis. Brentuximab vedotin (BV) is a frequently used agent in higher stages, particularly in cases with a high expression of CD30. The ALCANZA trial, which included MF patients with a CD30 expression >10%, demonstrated high response rates and a good tolerability. However, its effectiveness in advanced stage MF/SS syndrome with low CD30-expression (<10%) still has to be systematically evaluated. Therefore, the question is whether an equally good response with BV is achievable in these CTCL cases. Between 2018 - 2020, 32 patients in 11 centres with predominantly advanced MF/SS and low CD-30 expression (<10%) were treated with BV in the recommended dosage, retrospective evaluation of therapy response was done according to the EORTC-ISCL criteria. In all patients (n=32) at least one other systemic therapy preceded BV treatment. The median number of previous treatments was 3. Thirty patients suffering from MF (IB: 2; IIA: 1; IIB: n=18; III: 1; IV: 9; total ≥IIB: 27) and 2 SS patients were analyzed. As a result, 17 of 31 patients (OR: 54.8%) responded to therapy (CR n=4/31 12.9%, PR n=13/31 41.9%) after 6 cycles. The median progression-free interval among patients with OR was 6.4 months (range: 0.5–15.5 months, mean ± SD: 6.4±3.8, n=16). In 37.5% (n=12) the CD-30 Expression was 5-9% and in 62.5% (n=20) CD-30-Expression was <5%. In conclusion, with 54.8% OR, BV in MF/SS with low CD-30 expression (<10%) shows a comparable response rate compared to CTCL with CD-30 expression ≥10% (56-73%) and CR (12.9% vs. 3–35%) but with a lower PFS (6.4 vs. 11 months). In summary, based on this data the treatment of MF/SS with low CD-30 expression with BV seems to be an effective therapeutical option and justifies its use in challenging cases independent of the degree of CD30 positivity.

Qol-O-05 - An update on health-related quality of life from the PROCLIPI study

Background: Health-related quality of life (HRQoL) is a multi-dimensional concept that focuses on the impact of health status on quality of life. Mycosis fungoides/Sézary syndrome (MF/SS), the prototypical forms of cutaneous T cell lymphoma, are visible cutaneous malignancies with a profound effect of HRQoL. The PROCLIPI study is a multi-national prospective study collecting pre-defined clinical, treatment and quality of life data and began recruiting 2015. Objectives: To provide an update of HRQoL data captured in the PROCLIPI study to date. Methods: HRQoL per study visit was assessed using the Skindex-29 questionnaire and data obtained from the PROCLIPI database together with demographic, clinical, and histologic information. The data was analysed using a combination of descriptive and inferential statistics. Results: To date, 1594 Skindex-29 questionnaires (median 1, min–max 1–9) have been collected from 812 individuals from 33 centres across 16 countries. Respondents included 518 males and 294 females (male:fmale ratio 1.8:1) with a median (IQR) age of 61 (48–71 years). CTCL subtypes included 75.5% with classical MF, 13.2% folliculotropic MF, 0.6% with pagetoid reticulosis and 10.7% Sézary syndrome. 76.3% had early-stage disease and 23.6% had late-stage disease. The number of skindex-29 questionnaires collected per visit included: visit 1 = 569, visit 2 = 325, visit 3 = 254, visit 4 = 186, visit 5 = 109 and visit 6+ = 150. The number of paired observations between visit 1 and visit 2 was 188. Median skindex-29 scores improved between visit 1 and visit 2 for symptoms (p=0.002), emotions (p=0.002) and global scores (p=0.007) but not for functioning (p=0.41). No significant differences were identified in Skindex-29 scores beyond visit 2. Conclusion: The PROCLIPI registry is the most extensive study to date to examine HRQoL in patients with MF/SS. Preliminary analysis of this data has shown an improved HRQoL between visit 1 and visit 2 and for both symptoms and emotions possibly due to effective treatment and education on their disease but plateaus after that. Longitudinal analysis of this data will help to identify individual, disease and treatment characteristics that influence HRQoL changes over time. Health-related quality of life (HRQoL) is a multi-dimensional concept that focuses on the impact of health status on quality of life. Mycosis fungoides/Sézary syndrome (MF/SS), the prototypical forms of cutaneous T cell lymphoma, are visible cutaneous malignancies with a profound effect of HRQoL. The PROCLIPI study is a multi-national prospective study collecting pre-defined clinical, treatment and quality of life data and began recruiting 2015. To provide an update of HRQoL data captured in the PROCLIPI study to date. HRQoL per study visit was assessed using the Skindex-29 questionnaire and data obtained from the PROCLIPI database together with demographic, clinical, and histologic information. The data was analysed using a combination of descriptive and inferential statistics. To date, 1594 Skindex-29 questionnaires (median 1, min–max 1–9) have been collected from 812 individuals from 33 centres across 16 countries. Respondents included 518 males and 294 females (male:fmale ratio 1.8:1) with a median (IQR) age of 61 (48–71 years). CTCL subtypes included 75.5% with classical MF, 13.2% folliculotropic MF, 0.6% with pagetoid reticulosis and 10.7% Sézary syndrome. 76.3% had early-stage disease and 23.6% had late-stage disease. The number of skindex-29 questionnaires collected per visit included: visit 1 = 569, visit 2 = 325, visit 3 = 254, visit 4 = 186, visit 5 = 109 and visit 6+ = 150. The number of paired observations between visit 1 and visit 2 was 188. Median skindex-29 scores improved between visit 1 and visit 2 for symptoms (p=0.002), emotions (p=0.002) and global scores (p=0.007) but not for functioning (p=0.41). No significant differences were identified in Skindex-29 scores beyond visit 2. The PROCLIPI registry is the most extensive study to date to examine HRQoL in patients with MF/SS. Preliminary analysis of this data has shown an improved HRQoL between visit 1 and visit 2 and for both symptoms and emotions possibly due to effective treatment and education on their disease but plateaus after that. Longitudinal analysis of this data will help to identify individual, disease and treatment characteristics that influence HRQoL changes over time.

Qol-O-02 - Time-to-next-treatment and time-to-next-systemic treatment in patients included in the PROCLIPI registry

Time to next treatment (TTNT), a recently established endpoint in clinical trials for primary cutaneous T-cell lymphomas (CTCL), represents a useful indication as a surrogate marker for the durtion of clinical benefit. It is a unique parameter which allows to take into consideration not only the duration of clinical activity of a specific drug regimen but also the patient compliance and tolerability of the treatment schedule. A series of data clearly support the short duration of TTNT in patients with CTCL. The present paper analyses TTNT and time to next systemic treatment (TTNsT) in the PROCLIPI cohort of patients. PROCLIPI registry was established since 2,015 and includes all the new diagnoses of mycosis fungoides/Sézary syndrome (MF/SS) patients in CTCL referral centers worldwide. Untill now, a total of 4,756 treatments were registered among which 2,647 at visit 1. According to the treatment category, 2,364 skin-directed therapies (SDT) were registered (49.7%) and 1,810 systemic (38%), while 482 patients were managed through an expectant policy. TTNT analysis was performed in 2,969 cases who received a further treatment. Median TTNT was 136 days corresponding to 4.5 months for the entire cohort (range from 1 month to 5.7 years. As to TTNsT among 1,743 cases, median values were 169 days (corresponding to 5.6 months (up to 4.3 years). This preliminary analysis confirms the short duration of TTNT and TTNsT in MF/SS patients diagnosed in treated in real life, supporting the importance of identifying clinical and biological markers with predictive value on treatment benefit as well as new treatment approaches aimed to improve disease outcome. on behalf the CLIC Alliance, CLIC Treatment Working Group, EORTC and ISCL collaborative study groups and all the PROCLIPI centers.

Bio-P-01 - Prognostic value of the clonal rearrangement of T-cell receptor genes detection in the bone marrow in patients with mycosis fungoides

<h3>Introduction:</h3> Mycosis fungoides constitutes more than 60% of primary cutaneous T-cell lymphomas. The course of disease is progradient: the gradual changes of macular, plaque and tumor stages are noted. The evaluation of the spreading process is critically important for the prognosis determination and therapy choosing. T-cell clonality detection by rearranging genes of the gamma chain of the T-cell receptor in the blood and bone marrow aspirates can be detected at the early stages. It is known to be a prognostically unfavorable factor for diagnostics in peripheral blood, while the value of the rearranging presence of T-cell receptor gene in the bone marrow aspirates has not been fully studied. <h3>Aim:</h3> To evaluate the frequency and prognostic value of the T-cell clonality detection by the gamma chain of the T-cell receptor in the bone marrow in patients with mycosis fungoides/Sézary syndrome (MF/SS). <h3>Materials and methods:</h3> The patients with mycosis fungoides/Sézary syndrome were observed at the National Research Centre of Hematology during the period from 2000 to 2015. <h3>Results:</h3> 45 patients diagnosed with mycosis fungoides/Sézary syndrome (MF/SS) corresponded to inclusion criteria. Men/women 1:1. The age of the participants is varied from 20 to 81 years. The diagnosis of mycosis fungoides was made in 36 cases (80%) and the diagnosis of Sézary syndrome was made in 9 cases (20%) respectively. The early stages were diagnosed in 13 patients (29%), the later stages were diagnosed in 32 patients. T-cell clonality by the gamma chain rearrangement of the T-cell receptor was detected in the bone marrow in 15 out of 45 patients (33%). 13 cases were the patients with the late disease stages and clonality at the early Ib stage was detected only in 2 cases. The morphological bone marrow involvement was identified in 5 patients, but in two cases T-cell clonality was not detected. The median survival of patients with morphologically confirmed bone marrow damage was 3 months. The median survival of patients with defined T-cell clonality in the bone marrow was 21 months. The median survival with no molecular damages of bone marrow was 41 months. <h3>Conclusions:</h3> T-cell clonality by gamma chain rearranging of the T-cell receptor in the bone marrow in patients with mycosis fungoides/Sézary syndrome is determined in a third of patients mainly at the late MF stages. This is an unfavorable prognostic factor.

A Phase 1a/1b Trial of ST-001, a Fenretinide Phospholipid Suspension for 4-Hour Intravenous Infusion in Relapsed/Refractory T-Cell Non-Hodgkin's Lymphoma

A phase 1a/1b trial is planned for specific types of T-cell non-Hodgkin's lymphoma (T-NHL) using a new formulation of fenretinide for intravenous (IV) administration (ST-001, IND# 135475). Despite documented anticancer properties, clinical development of fenretinide has been hampered by poor bioavailability of the oral preparations and poor water solubility for IV infusion although some progress has been made. A phase 1 clinical trial of a 20% soy oil-in-water emulsion containing 2mg/mL of fenretinide, administered via 24-hour daily infusions x5 q3wks, demonstrated activity in mycosis fungoides /Sézary syndrome (MF/SS) and in angioimmunoblastic T-cell lymphoma (AITL) (Mohrbacher et al 2017). However, all doses exhibiting disease activity were associated with grade 4 hypertriglyceridemia. ST-001 from SciTech Development, LLC is a second generation, triglyceride-free, phospholipid-based nano-dispersion formulation of higher potency fenretinide (12.5mg/mL) suitable for IV infusion. The SciTech Delivery Vehicle (SDV) is composed of 4 clinically acceptable phospholipids (DPPC, DOPC, DMPC, and DMPG) which, in the presence of fenretinide, form lamellar bilayer structures &lt;200nm in diameter. Pharmacokinetic (PK) studies showed that IV administration of ST-001 in the Sprague-Dawley rat model achieved fenretinide blood levels required for in vitro cytotoxicity to human cancer cell lines (including T- and B-NHL). The planned US multicenter phase 1a trial utilizes an Accelerated Titration (Simon) 4B design, with 100% dose escalation in single-patient cohorts until first instance of grade 3 or higher toxicity is encountered, at which point the trial reverts to a 'standard', 3 patient-cohort approach and 40% dose escalation. To maximize each patient's chance to be treated at a potentially active dose, intrapatient dose escalation is allowed for patients who remain on study and have no evidence of toxicity once the safety of the next dose level is established in a drug-naïve patient. The primary study objective is determining the maximum tolerated dose (MTD) of ST-001 in adult patients with T-NHL. Secondary objectives are to describe the toxicity profile of ST-001, observe and record anti-tumor activity of ST-001 in patients with T-NHL, describe the PK of ST-001 when given at the specified dose/schedule in this study, and evaluate potential mechanisms of action of ST-001 using pharmacodynamic (PD) biomarkers. Eligible patients will be 18 years or older with histologically confirmed diagnosis of MF/SS (stages IB-IV according to TNMB system), or Ann Arbor stage II-IV non-cutaneous peripheral T-cell NHL (PTCL), AITL, or follicular T-NHL (FTCL) as defined in the 2016 WHO classification of lymphoid malignancies. Patients must have received at least 2 prior systemic therapies, have good performance status, and acceptable organ function. The drug will be administered IV over 4 hours daily for 5 consecutive days as outpatient starting at a dose of 1.25mg/m2/day. Treatment will be repeated every 3 weeks for up to 8 cycles. Once MTD is determined, an expanded cohort (phase 1b) will be conducted at MTD for diseases that demonstrate efficacy signals in phase 1a; however, patients must have at least one measurable disease site to be eligible for 1b. Up to 44 patients are projected to be enrolled (24 for phase 1a, and 20 for 1b). All patients who receive at least one dose of ST-001 will be evaluated for safety and toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Patients with at least one measurable site of disease and have received at least one full cycle (5-day infusion) of ST-001 are eligible for response evaluation. Descriptive statistics will be used for PK analysis to characterize the range, median and mean of calculated values of clearance, volume of distribution, and half-lives of distribution and elimination phases across all evaluable patients. PD analysis will use each patient's baseline value as the control and normalize PD values as % change from baseline. Effect of ST-001 on specific immune functions including cytokines and immune effector cell function will be evaluated at baseline and after therapy. It is anticipated that ST-001 will demonstrate activity in T-NHL in the absence of excipients that contribute to triglyceride elevations. Disclosures Kuzel: SciTech Development, LLC: Membership on an entity's Board of Directors or advisory committees. Parchment:SciTech Development, LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Outcomes and prognostic factors in African American and black patients with mycosis fungoides/Sézary syndrome: Retrospective analysis of 157 patients from a referral cancer center

The prevalence of mycosis fungoides/Sézary syndrome (MF/SS) is higher in the blackpopulation than in the white population in the United States and worse outcomes have been observed in black patients. To describe the outcomes and to identify prognostic factors in African American and black patients with MF/SS. Clinical features and follow-up data were analyzed in 157 self-identifiedAfrican American or black patients seen during 1994-2018. We included 122 patients with early stage MF and 35 patients with advanced-stage disease (median follow-up of 25months). Overall, >80% of the patients who died from disease or progressed had erythema or hyperpigmentationwithout hypopigmentation. Patients with hypopigmentation, either as the sole manifestation or in combination with other lesions, had better overall survival (P=.002) and progression-free survival (P=.014). Clinical stage, TNMB classification, plaque disease, and elevated serum lactate dehydrogenase were also significantly associated with outcomes. Demographic and socioeconomic parameters were not associated with prognosis. A retrospective study at a single cancer center. MF/SS manifestations and outcomes in African American and black patients are heterogeneous. Demographic and socioeconomic factors do not seem to have a prognostic role, while clinical characteristics might help in the stratification of risk of progression and shorter survival, allowing for individually tailored therapeutic interventions.

Quality of life in patients with mycosis fungoides and Sezary syndrome is significantly worse in female patients, Sézary syndrome and those with more extensive skin involvement

Background: Patients with Mycosis fungoides/Sézary Syndrome (MF/SS) have a poor quality of life (QoL) and a combination of skin, pruritus and cancer QOL questionnaires are usually used in combination in clinical trials. The Skindex-29 is a self-administered questionnaire to comprehensively measure the effects of skin disease on patient's quality of life (QoL). We sought to evaluate QOL in patients with MF/SS enrolled in the PROCLIPI (Prospective Cutaneous Lymphoma International Prognostic Index) study using Skindex-29.

The First Year of the AEVD Primary Cutaneous Lymphoma Registry

Background and objectivePrimary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. Patients and methodsDisease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. ResultsIn December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30+ T-cell lymphoproliferative disorder (CD30+ CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical corticosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30+ CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). ConclusionThe characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate clinical research by the AEDV's lymphoma group.

Registro de linfomas cutáneos primarios de la AEDV: primer año de funcionamiento

Background and objectivePrimary cutaneous lymphomas are uncommon. This article describes the Primary Cutaneous Lymphoma Registry of the Spanish Academy of Dermatology and Venereology (AEDV) and reports on the results from the first year. Patients and methodsDisease registry for patients with primary cutaneous lymphoma. The participating hospitals prospectively recorded data on diagnosis, treatment, tests, and disease stage for all patients with primary cutaneous lymphoma. A descriptive analysis was performed. ResultsIn December 2017, the registry contained data on 639 patients (60% male) from 16 university hospitals. The most common diagnoses, in order of frequency, were mycosis fungoides/Sézary syndrome (MF/SS) (348 cases, 55%), primary cutaneous B-cell lymphoma (CBCL) (184 cases, 29%), primary cutaneous CD30+ T-cell lymphoproliferative disorder (CD30+ CLPD) (70 cases, 11%), and other types of T-cell lymphoma (37 cases, 5%). In total, 105 (16.5%) of the cases recorded were incident cases. The most common diagnosis in the MF/SS group was classic MF (77.3%). Half of the patients with MF had stage IA disease when diagnosed, and the majority were either in partial remission (32.5%) or had stable disease (33.1%). The most widely used treatments were topical corticosteroids (90.8%) and phototherapy. The most common form of primary CBCL was marginal zone lymphoma (50%). Almost all of the patients had cutaneous involvement only and nearly half had stage T1a disease. Most (76.1%) were in complete remission. The main treatments were surgery (55.4%) and radiotherapy (41.9%). The most common diagnosis in patients with CD30+ CLPD was lymphomatoid papulosis (68.8%). Most of the patients (31.4%) had stage T3b disease and half were in complete remission. The most common treatments were topical corticosteroids (68.8%) and systemic chemotherapy (32.9%). ConclusionThe characteristics of patients with primary cutaneous lymphoma in Spain do not differ from those described in other series in the literature. The registry will facilitate clinical research by the AEDV's lymphoma group.

Population-Based Analysis of Elderly Patients (>70 YEARS) with Peripheral T-CELL Lymphoma: A Results from Czech Lymphoma Study Group (CLSG) Registry

INTRODUCTIONPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with usually poor prognosis. Age was identified as the independent risk factors in many studies. Elderly patients suffer from comorbidities, impaired organ functions, and poor performance status resulting in worse tolerance of therapy and its efficacy. Data on outcome, prognosis and treatment efficacy for elderly patients with PTCLs are sparse. METHODSWe used data of 941 newly diagnosed PTCLs registered into CLSG database between January 1999 and March 2015 with last follow-up in February 2016. CLSG database covers approximately 85% of all newly diagnosed NonHodgkin´s lymphomas (NHLs) in Czech Republic. For the analysis, 208 patients with age >70 years at diagnosis were selected. RESULTSTotally, PTCLs accounted for about 8.7% (454/5210) patients of all NHLs in population younger 60 years, but only about 5.8% (208/3561) NHL patients older 70 years. Median age was 76ys (71-91ys), 94 (45%) were women, lactate dehydrogenase (LDH) was elevated in 130/208 (62.5%) pts., ECOG ≥2 had 80 (38%) pts., and advanced clinical stage III-IV presented 132/208 (63.5%) pts. We identified following PTCL subtypes: PTCL-NOS (Peripheral T-cell lymphoma not otherwise specified) 89/208 (43%), Anaplastic large cell lymphoma (ALCL) 34/208 (16.3%), Cutaneous Anaplastic large cell lymphoma (C-ALCL) 10/208 (4.8%), Mycosis fungoides/ Sézary syndrome (MF/SS) together 29/208 (14%), NK/T nasal lymphoma (NK/T) 2/208 (1%), Angioimmunoblastic lymphoma (AITL) 17/208 (8.1%), Cutaneous CD30+ T lymphoproliferative disease 1/208 (0.5%), T-lymphoblastic lymphoma/leukemia (T-LBL) 3/208 (1.4%), T-cell lymphoma without specification (T-NHL) 17/208 (8.1%). Distribution of PTCL subtypes changed significantly with age. There was higher proportion of PTCL-NOS (43% vs. 34%; p.001) and MF/SS (14% vs. 4.8%; p<.001) in elderly patients (>70ys) compared to younger cohort (≤70ys; n=725). Contrary, percentage of ALCL (16.3% vs. 27%; p<.001) with main difference in ALK+ cases (2% vs. 11%; p<.001), and NK/T (1% vs. 5%; p.003) was lower in elderly PTCLs, whereas the incidence of AITL (8.1% vs. 6.6%) or EATL (3.4% vs. 3%) was similar in both age subgroups.For the whole cohort of PTCLs (>70ys), the 5-year overall survival (OS) was 30% and 5-year progression free survival (PFS) was 21% regardless of subtype or stage. Progression is fatal event in elderly patients with median survival about 8 months only. There were significant survival differences between patients (>70ys vs. ≤70ys) according to PTCL subtype; PTCL-NOS 5 yr-OS 23% vs. 43% (p.00001), ALCL ALK+ 5-yr OS not reached vs. 79% (p.01), ALCL ALK- 5 yr-OS 24% vs. 50% (p.001). Patients with AITL or EATL showed no age-related survival differences.First-line chemotherapy was administered in majority of cases (67%); CHOP-like regimen was given in 78 (37%) pts., COP-like in 44 (21%) pts., and other chemotherapy in 18 (9%) cases. Local therapy (surgery, radiotherapy) was administered in first line in 17 (8%) pts., no or palliative therapy (corticoids) was given in 34 (17%) pts., initial therapy was unknown in 17 (8%) cases.We compared two subgroups of patients according to first line chemotherapy CHOP (n=75) vs. COP (n=41). Median age was 74ys (71-84) vs. 79ys (71-89), high IPI was presented in 29% vs. 50% of patients (p.001). Complete response (CR) was achieved in 35/75 (47%) CHOP treated patients, and in 7/41 (17%) patients managed with COP (p.001). Contrary, there were 12/75 (16%) progression in CHOP arm compared to 10/41 (24%) COP treated pts. Five-year OS was 28% vs. 15% better in CHOP group (p.029) and 5-yr PFS 25% vs. 10%, respectively. CONCLUSIONSIn population-based analysis of adult Caucasian PTCL patients, we identified mild decreasing incidence with age. There were significant age-related distribution differences of PTCL subtypes with shift to preponderance of PTCL-NOS, Mycosis fungoides, and NK/T nasal lymphoma in elderly. Worse survival in elderly PTCLs in comparison to younger patients was evident especially for PTCL-NOS and ALCL subtypes. Despite the baseline differences (COP managed pts. had higher IPI), there is tendency that anthracycline-based chemotherapy (CHOP) brings better results with higher proportion of CR and lower progression/relapse rate projected in longer survival. DisclosuresBelada:Seattle Genetics: Research Funding. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding.

The miRNA Profile of Cutaneous T Cell Lymphoma Correlates with the Dysfunctional Immunophenotype of the Disease

Cutaneous T cell lymphoma (CTCL) is thought to originate from clonally expanded, effector/central memory CD4+ T-cells in a background of chronic inflammation. Our recent investigations have provided evidence for T-cell exhaustion in CTCL with high levels of PD1 and other immune checkpoints (1. Gonzalez BR, Zain J, Rosen ST, Querfeld C. Current Opinion in Oncology. 2016; 28(1): 88-96. 2. Querfeld C, Curran SA, Leung S, Myskowski PL, Horwitz SM, Halpern AC, Young JW. Blood. 2014;124[21, abstract #1695). One potential mechanism by which immune checkpoint protein synthesis can be modulated is by the induction of miRNAs. A subset of miRNAs contributes to the pathogenesis and progression of mycosis fungoides/Sézary syndrome (MF/SS)), but no experimental research has evaluated the effects of miRNAs on immune checkpoints and T-cell exhaustion in CTCL. To address whether miRNA expression correlates with disease and is involved in regulating key immune checkpoint molecules linked to T cell exhaustion, we performed miRNA and gene expression profiling on 50 MF/SS patient samples using high-throughput sequencing, to achieve further insight into the molecular pathogenesis of CTCL disease. Total RNA, which includes miRNA, was extracted from CTCL (MF and SS) samples. Library preparation and high-throughput next generation small RNA sequencing were performed by the City of Hope Integrative Genomics Core. Reads were aligned to human genome assembly hg19, and miRNA expression levels were counted based on miRBase mature miRNA sequences. Differences in miRNA and gene expression between MF and SS patients were measured. Aberrantly expressed miRNAs specific for infiltrated plaques and tumor stage MF were compared. Our preliminary results have identified molecular signatures in CTCL that are linked to disease progression and key immunomodulatory molecules. Unsupervised cluster analysis of skin samples from patients using a heat map was performed (Fig 1). Patients were subdivided into 2 distinct clusters. The top cluster contains all tumor samples with few plaques, while the bottom cluster contains all patch/plaque samples. The clusters also correlated with clinical stage (top cluster = advanced stage ≥IIB; bottom cluster = early stage IA-IIA). Comparison analysis between the top and bottom cluster identified the 20 most significant up-regulated miRNAs that correlate with immune checkpoint (PD1, PD-L1, CTLA4, LAG3, TIM3, and ICOS) expression. For one, miR-146 showed the highest correlation (Table 1). The 20 most significant down-regulated miRNAs were also identified by class comparison analysis performed between top and bottom clusters and correlated with immune checkpoint expression. In conclusion, CTCL develops in a complex microenvironment. The expression of both miRNA and immune checkpoint proteins suggest patterns that provide insight into pathogenesis and potential therapeutic options. [Display omitted] [Display omitted] DisclosuresQuerfeld:Celgene: Consultancy, Research Funding; Actelion: Consultancy; Miragen: Consultancy. Zain:Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Atypical Cutaneous Lymphoproliferative Disorder: A Fatal Mimic of Cutaneous T-Cell Lymphoma in a Patient with HIV Infection

Atypical cutaneous lymphoproliferative disorder (ACLD) is a rare condition that has been associated with HIV infection. Patients with ACLD present with diffuse, erythematous and pruritic skin lesions accompanied by generalized lymphadenopathy. The clinical characteristics of ACLD overlap most notably with several other conditions including Mycosis Fungoides/Sézary Syndrome (MF/SS), a cutaneous lymphoma of T-cell lineage. Unlike Mycosis Fungoides, the noxious infiltrates of ACLD are not monoclonal but polyclonal and consist of cytotoxic CD8+ T-cells instead of CD4+ T-cells or B-cells. Highly active antiretroviral therapy (HAART) has been reported to improve ACLD. We describe the case of a Caucasian man with longstanding HIV infection who presented with severe erythroderma. Skin and lymph node biopsies showed polyclonal CD8+ T-cell infiltrates. Gene rearrangement studies did not reveal an obvious clonal disorder. Hallmark peripheral blood findings consisting of a severe depletion of CD4+ T-lymphocytes and markedly elevated CD8+ cells provided an important diagnostic clue. Despite the purported benefits of HAART in ameliorating this disorder, erythroderma and extreme pruritus improved only after the patient began taking mycophenolate mofetil and hydroxyurea. Unfortunately, he succumbed to complications of methicillin-resistant Staphylococcus aureus septicemia. We alert readers to this rare HIV-associated condition which may mimic other benign and malignant skin conditions and briefly discuss diagnostic and therapeutic options.

Multicenter Phase II Trial of Temozolomide in Mycosis Fungoides/Sézary Syndrome: Correlation with O6-Methylguanine-DNA Methyltransferase and Mismatch Repair Proteins

Temozolomide (TMZ) is an oral derivative of dacarbazine that induces DNA damage by methylating nucleotide bases. Resistance has been associated with high levels of O⁶-methylguanine-DNA methyltransferase (MGMT). Malignant CD4(+) T cells of patients with mycosis fungoides/Sézary syndrome (MF/SS) have been shown to have low levels of MGMT and may be particularly sensitive to this methylator. The efficacy of TMZ was evaluated in a multicenter phase II trial of patients with advanced stages of MF/SS. TMZ was given orally at daily doses of 200 mg/m² for 5 days every 28 days. MGMT and mismatch repair protein expression was assessed by quantitative immunofluorescence and immunohistochemistry in skin and blood samples. Twenty-six patients (stages IB-IVB) were evaluable for response. Patients had a median of four prior treatments. Median follow-up time was 19 months (range, 1-95). The overall response was 27% with two complete remissions (8%) and five partial remissions (19%). Median disease-free survival was 4 months. The median overall survival was 24 months. The most frequent toxicities included constitutional symptoms, gastrointestinal symptoms, and hematologic toxicities. Treatment was discontinued in three patients following grade 3 thrombocytopenia, lymphopenia, and skin reaction. The relationship between pretreatment MGMT and mutL homolog 1 (MLH1)/mutS homolog 2 (MSH2) mismatch repair protein expression levels in skin biopsies of cutaneous lesions and clinical response to TMZ were evaluated. Pretreatment levels of MGMT and MLH1/MSH2 protein levels are not predictive of response to TMZ in MF/SS, suggesting that other resistance mechanisms are important.

Peripheral T‐Cell Lymphoma with Secondary Epithelioid Granulomatous Cutaneous Involvement: A Clinicopathologic Study of Four Cases

Epithelioid granuloma formation has rarely been observed in specific cutaneous lesions from T-cell lymphomas other than those of mycosis fungoides/Sézary syndrome (MF/SS). Three patients diagnosed with nodal and/or extranodal (tonsillar) non-Hodgkin's peripheral T-cell lymphoma (PTCL) and one patient with angioimmunoblastic T-cell lymphoma (AILD), developed specific cutaneous involvement showing prominent epithelioid cell and/or granulomatous inflammation. The original diagnostic lesions had no granulomatous features. In addition to a specific lymphomatous infiltrate, prominent dermal and/or subcutaneous granulomatous infiltrates were observed. Sarcoid-like granulomas were observed in two patients (one of them presented a granuloma annulare-like pattern in early lesions), granulomatous panniculitis was noted in one patient and in one patient with AILD, masses of epithelioid cells were noted. The clinicopathological features of cutaneous involvement by PTCL showing a florid epithelioid and/or granulomatous cell reaction are reviewed. Various histopathological patterns can be observed. The diagnostic difficulties of these cases are stressed.

Marked Improvement in Staging Accuracy in Mycosis Fungoides/Sézary Syndrome Using Integrated Positron Emission Tomography and Computed Tomography (PET/CT).

Staging of mycosis fungoides/Sézary syndrome (MF/SS), the most common cutaneous T cell lymphoma (CTCL), is primarily based on the type and extent of skin involvement and the presence or absence of extracutaneous disease. In patients with large cell transformation, tumors, erythroderma, or abnormal lymph nodes on physical exam, staging includes CT scan to look for visceral or lymph node (LN) disease followed by biopsy of enlarged LN. Integrated PET/CT combines anatomic data from CT with functional data from PET and has been useful in the staging of many non-Hodgkin's lymphomas. To date, however, its role in staging MF/SS has not been investigated. We assessed the utility of integrated PET/CT in staging thirteen patients with MF (T2=1,T3=4,T4=1) or SS (T4B2=7) at high-risk for LN disease. Based on anatomic data from the CT component alone, only five of thirteen had enlarged LN (axillary/inguinal LN short axis ≥1.5cm or cervical LN short axis ≥1.0cm) and would have been referred for biopsy. In comparison, PET showed that all thirteen patients had hypermetabolic activity in at least one LN region. All patients had excisional LN biopsy and the extent of LN involvement was classified according to NCI criteria (LN1-4 classification). Six patients had LN1-3 and seven had effacement of LN architecture by lymphoma cells (LN4). Of the seven LN4 patients, four had SS and three had tumor MF. PET/CT helped identify the most suspicious LN region for biopsy, which led to the accurate stage of IVA. Notably, two patients had LN smaller than the CT size criteria and would have been incorrectly staged without the use of integrated PET/CT. Furthermore, we quantified the intensity of PET activity using standardized uptake value (SUV) and correlated this with LN grade. Patients with LN1-3 had a mean SUV of 2.7, median 2.2 (2.0–4.7) and patients with LN4 had a mean SUV of 5.4, median 3.9 (2.1– 11.8); p value 0.08. Ongoing analysis of additional patients may further define whether PET/CT can be used to significantly differentiate between LN1-3 vs LN4. Thus, for staging MF/SS, integrated PET/CT was more sensitive and specific in detecting malignant LN compared to CT alone and consequently provided more accurate staging and prognostic information. A larger scale study would be essential to confirm the superior staging capability of PET/CT over CT alone in MF/SS.Summary of PET/CT correlation with LN pathology results in MF/SSPatientT classMax SUVLN size (SA,cm)LN regionNCI gradeWHO gradeFinal stage1T32.01.2AxillaryLN11IIB2T42.11.3AxillaryLN11IIIB3T22.21.0InguinalLN21IIA4T44.71.0AxillaryLN21IIIB5T43.01.2InguinalLN21IIIB6T42.01.1InguinalLN32IIIB7T33.71.4CervicalLN43IVA8T43.21.5InguinalLN43IVA9T33.91.3InguinalLN43IVA10T411.83.2InguinalLN43IVA11T46.61.3InguinalLN43IVA12T46.32.1InguinalLN43IVA13T32.12.1AxillaryLN43IVAAbbreviations: T, tumor; SUV, standardized uptake value; LN, lymph node; SA, short axis; cm, centimeter

Overview of Cutaneous T-Cell Lymphoma: Prognostic Factors and Novel Therapeutic Approaches

The cutaneous T-cell lymphomas (CTCL) comprise a heterogeneous group of entities. The WHO classification distinguishes indolent low-risk entities, including mycosis fungoides/Sézary syndrome (MF/SS), from aggressive entities, including peripheral T-cell lymphoma and its variants and HTLV-1 associated acute T-cell leukemia/lymphoma. Mycosis fungoides represents the most benign of the cutaneous T-cell lymphomas, with 10-year relative survival ranging from 100% to 41%, depending on the degree of skin involvement. Probability of progression to extracutaneous disease within 20 years of diagnosis can be up to 40%, depending on stage. Treatment strategies for early stage CTCL include topical therapies with or without interferon-α or oral agents, while advanced stage patients often progress and are treated with chemotherapy and novel agents. Multiagent cytotoxic regimens are palliative with no demonstrated survival benefit. Among the novel therapies for CTCL is bexarotene, a retinoid X-receptor (RXR)-selective agonist, which has demonstrated efficacy in advanced refractory CTCL. Other novel agents include the interleukin (IL)-2 fusion toxin (ONTAK), pentostatin (a potent adenosine deaminase inhibitor), histone deacetylase inhibitors such as depsipeptide, NF-κB inhibitors, cytokine receptor antagonists, immunomodulatory therapies and allogeneic stem cell therapy. The value of new therapeutic approaches to CTCL urgently needs to be assessed.