IIA Mycosis Fungoides Research Articles

Chlormethine Gel for Treatment of Patients with Mycosis Fungoides: Best Practices and Guidance to Clinicians.

Mycosis fungoides (MF) is the most common form of cutaneous Tcell lymphoma. While multiple guidelines provide treatment recommendations, there are currently no clear treatment algorithms for MF. Chlormethine gel is recommended by major treatment guidelines as a first-line option for stageIA-IIA disease, and, on the basis of these guidelines, used in combination with other therapies in patients with advanced-stage MF in clinical practice. To provide guidance regarding the use of chlormethine gel for patients with all stages of MF, based on clinical expertise. Opinions on best practices regarding the use of chlormethine gel were collected through discussions that involved eight clinicians with extensive experience in treating patients with MF. Chlormethine gel can be used as monotherapy in first- or second-line treatment of early-stage MF. In first-line, chlormethine gel monotherapy is prescribed for stageIA MF, and is particularly convenient for patients unable/unwilling to travel for hospital-based phototherapy, patients with thick plaques or palmoplantar involvement, when ultraviolet treatment is contraindicated, and for sanctuary sites. Chlormethine gel is also an appropriate first-line monotherapy for patients with stageIB or IIA MF; it may be used as part of combination regimens in these patients as well. For patients with late-stage MF, skin-directed treatments such as chlormethine gel should be combined with systemic therapies. Chlormethine gel is a safe and effective treatment option that can be used in all stages of MF, either as monotherapy or in combination, depending on disease stage and patient characteristics and needs.

Compatibility study of topical 0.25% hypericin (HyBryteTM) application in subjects with mycosis fungoides: Results of the HPN‐CTCL‐02 study

AbstractBackgroundHyBryteTM is a photodynamic therapy of topical hypericin that has recently been shown to be safe and efficacious in early stage cutaneous T‐cell lymphoma (CTCL). However, its efficacy, absorption, and effect on heart function parameters in patients who require greater HyBryteTM exposure is unknown.ObjectivesThe primary objectives in this study were to assess hypericin blood levels using a validated detection method with a cut‐off value of 0.05 ng/mL and to determine if topical HyBryteTM induces any electrocardiogram (EKG) changes during 8 weeks of treatment. A secondary endpoint of this study was to assess the effectiveness of HyBryteTM in this patient population as well as assessing a different additional light device than the one used in the Phase 3 HPN‐CTCL‐01/fluorescent light activated synthetic hypericin trial also entitled “A phase 3 multicenter randomised placebo‐controlled study to determine the efficacy of topical hypericin and light irradiation for the treatment of cutaneous T‐cell lymphoma”.MethodsA confirmatory, prospective, open‐label, single‐centre, interventional study focused on stage IB and IIA mycosis fungoides with more than 10% of their body surface areas involved was performed.ResultsHypericin concentration in K2EDTA whole blood samples collected before and after light activation at Weeks 4, 6 and 8 showed an average blood concentration of 0.13 ng/mL and achieved steady state by Week 4. EKGs were examined for clinical changes at each study visit, including changes in QT intervals and correction of heart rates. No significant clinical changes in EKGs were observed.ConclusionsHypericin does not appear to be significantly absorbed through the skin nor cause significant cardiac changes overall or prolong the QT interval when applied topically. A larger study is necessary to clearly define these results.

Epi-O-02 - International Cutaneous Lymphomas Pandemic Section (ICLYPS) analysis of CTCL outcomes during COVID-19

At the onset of the COVID-19 pandemic, the United States Cutaneous Lymphoma Consortium (USCLC) and the European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force (EORTC-CLTF) developed emergency guidelines for the management of patients with cutaneous lymphomas (CLs) during the pandemic. These emergency protocols were intended to ensure patient safety and called for dose modifications, treatment delays and treatment interruptions as necessary to minimize exposure risks to COVID-19. Because there are no established maintenance protocols for CLs, the impact of such delays or interruptions on disease outcomes was not known. The ISCL created an International Cutaneous Lymphomas Pandemic Section (ICLYPS) to collect data from the institutions around the world to assess the impact of these changes on patients’ outcomes and to determine if these measures were effective in preventing infection. We summarize the outcomes from a preliminary cohort of patients from Brazil, Greece, Italy, Spain, Switzerland, the UK and the US. Actively managed patients with an established diagnosis of CL from March to October 2020 were included according to the Institutional Protection of Human Subjects guidelines at the respective centers. We included 149 patients in this retrospective review. The average age was 61.88 years (range: 22–95). 2 patients (1.3%) had diagnoses of CD30+ lymphoproliferative disorders (LyP and pcALCL), 112 (75.2%) had mycosis fungoides (MF), and 35 (23.5%) had Sézary syndrome (SS). 77 patients (68.7%) had stages IA–IIA MF, 23 (20.5%) had Stage IIB MF, 6 (5.4%) had stage III MF, and 41 (27.5%) had Stage IV disease, of which 6 had Stage IV MF (5.4%) and 35 had SS (23.5%). Treatment was delayed for more than half (53.0%) of the patients for a mean of 3.2 months (range: 10 days to 10 months). Treatment delay was associated with a significant risk of disease relapse or progression across all stages (65.8% vs 32.9%, p<0.00001). During follow up, 6 patients (4%) died due to disease progression, including 3 patients with Stage IIB MF, one with Stage IVB MF, and two with SS. Twenty-eight patients (18.8%) had a confirmed COVID-19 infection during the capture period. Two of these cases were definitive hospital-acquired infections following prolonged hospital admission, while the remaining contracted the virus through community exposures. There were no outpatient office-acquired infections. Three of the 26 patients who contracted COVID-19 died of the infection (2 SS and 1 LyP, mean age: 80, range: 66–89). The ICLYPS analysis has revealed that treatment interruptions and delays during the COVID-19 pandemic resulted in significantly worse outcomes in patients with CLs as compared to those who did not experience treatment interruptions. No outpatient office-acquired infections were reported in this extensive review, and patients with CLs who developed COVID-19 did not do worse than expected according to their risk factors. Effective safety measures and protocols can prevent transmission of COVID-19 at physicians’ offices. Interruption of therapy leads to negative clinical outcomes and should be avoided, especially in the setting of advanced disease, as the risk of contracting COVID-19 in the outpatient setting did not outweigh the risk of morbidity and mortality due to disease progression. Ensuring continuity of treatment and maintenance therapy appears to be critical to avoiding life-threatening disease progression.

Use of chlormethine 0.04% gel for mycosis fungoides after treatment with topical chlormethine 0.02% gel: A phase 2 extension study

Use of chlormethine 0.04% gel for mycosis fungoides after treatment with topical chlormethine 0.02% gel: A phase 2 extension study

Post hoc Analysis of a Randomized, Controlled, Phase 2 Study to Assess Response Rates with Chlormethine/Mechlorethamine Gel in Patients with Stage IA–IIA Mycosis Fungoides

Background: Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Patients can be treated using chlormethine gel, a skin-directed therapy developed and approved for MF. In the randomized, controlled 201 trial, chlormethine gel was found to be noninferior to equal-strength chlormethine ointment. However, there remains a need to gain more insight into outcome measures after treatment. Objective: The aim of this study was to further investigate the potential of chlormethine gel treatment through a novel post hoc analysis of the 201 trial data (NCT00168064). Methods: Patients were randomized to chlormethine gel or ointment; response assessments included Composite Assessment of Index Lesion Severity (CAILS) and total body surface area (BSA). In this post hoc analysis, additional subgroup response analyses were performed for stage IA/IB–IIA MF. Very good partial response (75 to <100% improvement) was included as an additional response category. Time to response and overall response trends were determined. Finally, multivariate time-to-event analyses were performed to determine whether associations were observed between treatment frequency, response, and adverse events. Results: Response rates were significantly higher for patients with stage IA MF for CAILS (intent-to-treat [p = 0.0014] and efficacy-evaluable [EE; p = 0.0036] populations) and BSA (EE population [p = 0.0488]) treated with gel versus ointment. Time to first CAILS response and response trends were better for all-stage gel-treated patients overall. No association was seen between treatment frequency and response or occurrence of adverse events at the following visit. An association was observed between the occurrence of contact dermatitis and improved clinical response at the next visit (p = 0.0001). Conclusion: This post hoc analysis shows that treatment with chlormethine gel may result in higher and faster response rates compared with chlormethine ointment, which confirms and expands results reported in the original analysis. The incidence of contact dermatitis may potentially be a prognostic indicator for clinical response; this needs to be confirmed in a larger population.

Should we be imaging lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) international study.

Early-stage mycosis fungoides (MF) includes involvement of dermatopathic lymph nodes (LNs) or early lymphomatous LNs. There is a lack of unanimity among current guidelines regarding the indications for initial staging imaging in early-stage presentation of MF in the absence of enlarged palpable LNs. To investigate how often imaging is performed in patients with early-stage presentation of MF, to assess the yield of LN imaging, and to determine what disease characteristics promoted imaging. A review of clinicopathologically confirmed newly diagnosed patients with cutaneous patch/plaque (T1/T2) MF from PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) data. PROCLIPI enrolled 375 patients with stage T1/T2 MF: 304 with classical MF and 71 with folliculotropic MF. Imaging was performed in 169 patients (45%): 83 with computed tomography, 18 with positron emission tomography-computed tomography and 68 with ultrasound. Only nine of these (5%) had palpable enlarged (≥ 15 mm) LNs, with an over-representation of plaques, irrespectively of the 10% body surface area cutoff that distinguishes T1 from T2. Folliculotropic MF was not more frequently imaged than classical MF. Radiologically enlarged LNs (≥ 15 mm) were detected in 30 patients (18%); only seven had clinical lymphadenopathy. On multivariate analysis, plaque presentation was the sole parameter significantly associated with radiologically enlarged LNs. Imaging of only clinically enlarged LNs upstaged 4% of patients (seven of 169) to at least IIA, whereas nonselective imaging upstaged another 14% (24 of 169). LN biopsy, performed in eight of 30 patients, identified N3 (extensive lymphomatous involvement) in two and N1 (dermatopathic changes) in six. Physical examination was a poor determinant of LN enlargement or involvement. Presence of plaques was associated with a significant increase in identification of enlarged or involved LNs in patients with early-stage presentation of MF, which may be important when deciding who to image. Imaging increases the detection rate of stage IIA MF, and identifies rare cases of extensive lymphomatous nodes, upstaging them to advanced-stage IVA2.

Quality of Life, Anxiety, and Depression in Patients With Early-Stage Mycosis Fungoides and the Effect of Oral Psoralen Plus UV-A (PUVA) Photochemotherapy on it.

Background: Little is known about psychological discomfort and quality of life (QoL) in early stage mycosis fungoides (MF) and the effect of psoralen plus UV-A (PUVA) on it.Objective: To evaluate QoL, anxiety, and depression with validated instruments in early stage MF patients and whether PUVA treatment improves it.Methods: Patients with stage IA to IIA MF were treated with PUVA twice weekly for 12–24 weeks, followed by maintenance treatment or not, in a prospective randomized clinical trial. Patients completed a questionnaire on DLQI as well as the Hospital Anxiety and Depression Scale (HADS) prior to therapy, after their last PUVA exposure, and after the PUVA maintenance or observance phase.Results: For 24 patients with early stage MF, completed questionnaires were available and analyzed. Prior to treatment, 17% reported strong (DLQI > 10) and 29% moderate impairment (DLQI 6–10) in QoL; 33% of patients reported HADS scores indicating anxiety, and 21% reported scores indicating depression. PUVA significantly improved overall QoL by reducing mean DLQI scores by 58.6% (p = 0.003), HADS-A by 30% (p = 0.045), and HADS-D by 44% (p = 0.002). Improvements in QoL and psychological well-being seemed to be sustained, irrespective of maintenance treatment or not.Limitations: Small sample size.Conclusions: PUVA sustainably improves QoL and psychological well-being in patients with early stage MF.Clinical trial registration: ClinicalTrials.gov identifier: NCT01686594.

Evaluation of Low-Dose, Low-Frequency Oral Psoralen–UV-A Treatment With or Without Maintenance on Early-Stage Mycosis Fungoides

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. To evaluate low-dose, low-frequency PUVA, and whether maintenance treatment extends disease-free remission in patients with mycosis fungoides. 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. 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. 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. 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. ClinicalTrials.gov identifier: NCT01686594.

082 - Efficacy of chlormethine gel in patients with stage I–IIA mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL): re-analysis of a randomized phase 2 study

082 - Efficacy of chlormethine gel in patients with stage I–IIA mycosis fungoides cutaneous T-cell lymphoma (MF-CTCL): re-analysis of a randomized phase 2 study

Dermoscopy of stage llA mycosis fungoides.

OBJECTIVE:Differential diagnosis of mycosis fungoides (MF) in the early stages can be challenging. Dermoscopy has been reported to be useful in the evaluation of early MF. However, to our knowledge, there is no study that specifies these early stages as stage IA, IB or IIA. The present study aims to evaluate the dermoscopic findings of stage IIA MF in comparison with plaque psoriasis (PP).METHODS:Thirty-four patients aged between 16-70 years with stage IIA MF (n=17) and PP (n=17) were evaluated in this prospective study. Dermoscopic examinations were performed by manual dermatoscopy (Dermlite DL4). χ2 test was used.RESULTS:In patients with stage IIA MF, orange-yellow patches (88.2%), short, fine and linear vessels (82.3%), geometric white scales (70.5%), perifollicular white scales (47%) and white patches (35.2%) were common, while dotted vessels (94.1%), diffuse lamellar white scales (88.2%) and dotted and globular vessels (70.5%) were common in patients with PP. Although spermatozoa-like structures, purpuric dots, collarette white scales and Y-shaped arborizing vessels were common in patients with MF, this was not statistically significant. Geometric white scales (clinically; cigarette paper-like wrinkly scales) correlated with alternating parakeratosis and orthokeratosis in the stratum corneum histopathologically.CONCLUSION:A unique aspect of our study is that this study provides insights about the importance of scales in differentiating MF from PP. Orange-yellow and white patches, short, fine and linear vessels, geometric and perifollicular white scales may be useful in distinguishing stage IIA MF from PP by hand-held dermoscopy.

607 Anti-pruritic properties of remetinostat (SHAPE), a topical histone deacetylase inhibitor (HDACi); data from a randomized phase 2 study in patients with stage IA- IIA mycosis fungoides

607 Anti-pruritic properties of remetinostat (SHAPE), a topical histone deacetylase inhibitor (HDACi); data from a randomized phase 2 study in patients with stage IA- IIA mycosis fungoides

Therapeutic effect of narrow band - utraviolet B combined with interferon - alpha - 2b for the treatment of mycosis fungoides and its correlation with Treg/Th17 cells

Objective To evaluate the therapeutic effect of narrow band-ultraviolet B (NB-UVB) alone or in combination with interferon-alpha-2b (INF - alpha-2b) for mycosis fungoides (MF), and to assess the correlation between the therapeutic effect and peripheral blood regulatory T (Treg)/T helper type 17 (Th17) cells. Methods Thirty-three patients with stage IA to IIA MF were randomly divided into two groups: NB-UVB group (n = 15) receiving NB-UVB radiation alone, combined group (n = 18) treated with NB-UVB radiation and intramuscular injection of INF-alpha-2b. Ten healthy volunteers were selected as the control group. Peripheral blood samples were collected before and 9 months after the start of treatment. Flow cytometry was performed to determine the percentages of Treg cells and Th17 cells. Statistical analysis was carried out by using t test, one-way analysis of variance, and Fisher's exact test. Results The average treatment duration was 9 months among these patients. Therapeutic outcomes were significantly better in the combined group than in the NB-UVB group (P= 0.023). Among the 15 patients in the NB-UVB group, 6 achieved complete remission, 3 partial remission, 6 showed no response; of the 18 patients in the combined group, 12 experienced complete remission, 5 partial remission, and 1 showed no response. Before the treatment, the percentages of both Treg and Th17 cells in peripheral blood were significantly higher in the NB-UVB group and combined group than in the control group (both P 0.05). After the treatment, the percentages of both Treg and Th17 cells in the NB - UVB group and combined group significantly decreased compared with those before the treatment, but were still higher than those in the control group (both P 0.05) after the treatment. Conclusions The therapeutic effect of NB-UVB radiation combined with intramuscular INF-alpha-2b is superior to that of NB - UVB radiation alone for MF, which may be associated with the degree of decrease in peripheral blood Treg and Th17 cells. Key words: Ultraviolet therapy; Interferon-alpha; Treatment outcomes; T-lymphocytes, regulatory; Th17 cells; Mycosis fungoides

Excimer laser in the treatment of mycosis fungoides

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, which typically presents as a patch or plaque in early-stage disease. Phototherapy including psoralen plus ultraviolet A and ultraviolet B are well-established treatment modalities in management of early-stage MF. Only a limited number of reports have evaluated the efficacy of 308-nm excimer laser in therapy of cutaneous T-cell lymphoma. We sought to evaluate the efficacy of 308-nm excimer laser (XTRAC, PhotoMedex, Montgomeryville, PA) in patients with stage IA to IIA MF. We reviewed the clinical and laboratory characteristics of 6 consecutive patients given the diagnosis of refractory MF who underwent treatment with excimer laser. We found that the 308-nm excimer laser is a safe and well-tolerated alternative therapy for early-stage MF. In addition, we were able to delineate criteria to help predict treatment response. Our data showed that 4 (66%) patients achieved clinical improvement (3 complete responses, 1 partial response), 1 had stable disease, and 1 had progressive disease. This was a retrospective study consisting of 6 patients. A prospective study with a larger sample size would be desirable for future studies. The use of 308-nm excimer laser in the treatment of stage IA to IIA MF showed clinical and pathological benefit for patients with isolated lesions or lesions in areas that may be difficult to treat because of anatomic location.

Topical Chemotherapy in Cutaneous T-cell Lymphoma

To evaluate the efficacy and safety of a novel mechlorethamine hydrochloride, 0.02%, gel in mycosis fungoides. DESIGN Randomized, controlled, observer-blinded, multicenter trial comparing mechlorethamine, 0.02%, gel with mechlorethamine, 0.02%, compounded ointment. Mechlorethamine was applied once daily for up to 12 months. Tumor response and adverse events were assessed every month between months 1 and 6 and every 2 months between months 7 and 12. Serum drug levels were evaluated in a subset of patients. Academic medical or cancer centers. In total, 260 patients with stage IA to IIA mycosis fungoides who had not used topical mechlorethamine within 2 years and were naive to prior use of topical carmustine therapy. Response rates of all the patients based on a primary clinical end point (Composite Assessment of Index Lesion Severity) and secondary clinical end points (Modified Severity-Weighted Assessment Tool and time-to-response analyses). Response rates for mechlorethamine gel vs ointment were 58.5% vs 47.7% by the Composite Assessment of Index Lesion Severity and 46.9% vs 46.2% by the Modified Severity-Weighted Assessment Tool. By the Composite Assessment of Index Lesion Severity, the ratio of gel response rate to ointment response rate was 1.23 (95% CI, 0.97-1.55), which met the prespecified criterion for noninferiority. Time-to-response analyses demonstrated superiority of mechlorethamine gel to ointment (P< .01). No drug-related serious adverse events were seen. Approximately 20.3% of enrolled patients in the gel treatment arm and 17.3% of enrolled patients in the ointment treatment arm withdrew because of drug-related skin irritation. No systemic absorption of the study medication was detected. The use of a novel mechlorethamine, 0.02%, gel in the treatment of patients with mycosis fungoides is effective and safe. clinicaltrials.gov Identifier:NCT00168064.

Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial 21011 (NCT00

Psoralen plus ultraviolet A (PUVA) is the standard treatment for early stages of mycosis fungoides. There have been no adequate randomized controlled trials with sufficient power comparing this modality with other therapies. To assess disease response and to compare the response rates of patients treated with PUVA alone or PUVA and bexarotene. EORTC 21011 (NCT 00056056) was a randomized phase III study comparing combined bexarotene (Targretin(®) ) and PUVA vs. PUVA alone in patients with stage IB and IIA mycosis fungoides (MF). The primary endpoint was the overall response rate [complete clinical response (CCR) plus partial response (PR)]. The study was prematurely closed due to low accrual after 93 of 145 required patients (65%) were randomized. Of the 93 randomized patients, 87 started treatment, 41 received PUVA and 46 received PUVA + bexarotene. Total UVA doses received were 107 J cm(-2) (range 1·4-489·9) in the PUVA arm vs. 101·7 J cm(-2) (0·2-529·9) in the combination arm. The safety profile was acceptable with few grade 3-4 toxicities observed in either arm. More drop-outs due to toxicity were observed in the combination arm compared with the PUVA-alone arm. The best overall response (CCR + PR) rate was 71% for PUVA alone and 77% for the combination arm (P = 0·57). The median duration of response was 9·7 months for PUVA vs. 5·8 months for the combination arm (P = 0·33). CCR was seen in 25 patients of whom 10 received PUVA alone (CCR 22%) and 15 received combination therapy (CCR 31%) (P = 0·45). CCR was sustained in 25% of patients regardless of therapy. There was a trend towards fewer PUVA sessions needed to achieve CCR in the combination arm (median 22) compared with the PUVA arm (median 27·5) (P = 0·11). Similarly, a trend towards lower UVA dose required to achieve CCR in the combination arm (median 55·8 J cm(-2) ) compared with the PUVA arm alone (median 117·5 J cm(-2) ) (P = 0·5) was observed. No significant difference in response rate or response duration was observed in this study. However, there was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) but this did not achieve statistical significance due to insufficient power.

Efficacy and safety of bexarotene combined with psoralen/ultraviolet A light (PUVA) compared to PUVA treatment alone in stage IB-IIa mycosis fungoides (MF): Final results from EORTC cutaneous lymphoma task force (CLTF) phase III clinical trial 21011.

8076 Background: Skin-directed treatment with methoxsalen (PUVA) is the current treatment standard in stage IB-IIA MF. A combination of PUVA and bexarotene might be of additional clinical benefit for MF stage I/II patients (pts). Methods: EORTC 21011 was a randomised, open label phase III study comparing combined bexarotene and PUVA versus PUVA alone in pts with stage IB and IIA MF. Study primary endpoint was response (complete clinical + partial response, CCR+PR) rate; secondary endpoints: cumulative dose of UVA and number of PUVA sessions necessary to achieve a CCR, duration of CCR, time to relapse, safety and percentage of drop-outs. Results: The study recruited stage IB/IIA MF pts and was prematurely closed due to low accrual after 93/145 required pts (65%) were randomized; 45 to PUVA, 48 to PUVA+bexarotene. Median number of PUVA weeks were 12 (1-17) in PUVA vs. 10.5 (1-16) in combination arm. Total UVA doses were 107J/cm2 (1.4-489.9) in PUVA vs. 101.7J/cm2 (0.2-529.9) in combination arm. Few grade 3-4 toxicities were observed in both arms (liver enzyme elevation, neutropenia, anemia, increased cholesterol, photosensitivity, pruritus, rash, hypertriglyceridemia). Best overall response (CCR/PR) rate was 71.1% (33/45) for PUVA alone and 77.1% (37/48) for combination arm (p-value=0.57). The median of duration of response was 9.6 for PUVA vs 5.8 months for combination arm (p value=0.33). CCR was seen in 25 pts, 10 in PUVA (CCR 24%) and 15 in combination therapy (CCR 33%) (pvalue=0.45). Similarily, a lower UVA dose was required to achieve a CCR in the combination arm (median of 55.8 J/cm2) compared to the PUVA arm (median of 117.58 J/cm2) (p value=0.5). Conclusions: No significant difference in response rate was observed in this study. There was a trend towards fewer PUVA sessions and lower UVA dose to achieve CCR in the PUVA/bexarotene combination arm (median of 27.5 vs. 22,p-value = 0.11) but this did not achieve statistical significance due to insufficient power. The safety profile was acceptable, as there were only few grade 3-4 toxicities observed in both arms.

Lymphomatoid papulosis: is a second lymphoma commoner among East Asians?

Lymphomatoid papulosis (LyP) is a low-grade cutaneous lymphoma, which lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Around 10-20% of LyP cases are associated with a second lymphoma. To analyse a cohort of Asian patients with LyP, diagnosed from 1987 to 2007 at the National Skin Centre (NSC), Singapore, in terms of epidemiology, treatment and association with a second lymphoma. Patients were identified through the NSC clinical and histological databases. During this period, 13 patients were diagnosed with LyP based on clinicopathological criteria. The mean age at diagnosis was 41 years, the male : female ratio was 2.3 : 1, and 92% of the patients were Chinese. Recurrent papulonecrotic lesions were present for a mean of 3 years before diagnosis. Treatment of LyP comprised monotherapy (n = 4) or combination therapy (n = 9) using corticosteroids, oral antibiotics, methotrexate and/or phototherapy. Mean duration of follow-up was 6.4 years. Eight patients (61.5%) were diagnosed with a second lymphoma, either before (n = 2), concurrently with (n = 1) or after (n = 5) the diagnosis of LyP. Mycosis fungoides (MF) was the commonest lymphoma (78%, n = 7), followed by primary cutaneous anaplastic large-cell lymphoma (12%, n = 2). There was one death (mortality rate 7.7%), which occurred in a patient who had developed stage IIA MF after LyP, which subsequently progressed to systemic T-cell lymphoma. LyP is a chronic, relapsing disease with considerable morbidity, but an overall good prognosis. A strikingly large proportion of our Asian patients (61.5%) had a second lymphoma, compared with previous studies. This emphasizes the importance of regular lifetime surveillance for associated lymphomas in all patients with LyP.

A phase II open-label study of recombinant human interleukin-12 in patients with stage IA, IB, or IIA mycosis fungoides

Interleukin-12 (IL-12) increases Th(1) cytokines, natural killer (NK) cells, and cytotoxic T-cell activities. Progression of mycosis fungoides is associated with Th(2) cytokines produced by a clonal proliferation of epidermotropic T-helper cells. To determine the safety and efficacy of subcutaneous recombinant human IL-12 (rhIL-12) in early mycosis fungoides (MF; stage IA-IIA) in a multi-center, open label clinical trial. rhIL-12 was administered biweekly (100 ng/kg for 2 weeks; 300 ng/kg thereafter). A modified severity-weighted assessment tool (SWAT) and the longest diameter of 5 index lesions measured efficacy. Twenty-three MF patients (stage IA, 12 patients; IB, 9; and IIA, 2) had previously received >3 therapies. Ten of 23 patients (43%) achieved partial responses (PR); 7 (30%) achieved minor responses; and 5 (22%) had stable disease. The duration of PRs ranged from 3 to more than 45 weeks. Twelve (52%) ultimately progressed with mean time to progressive disease of 57 days (range, 28-805). Ten completed 6 months of therapy; 1 completed 24 months. Of patients not completing 6 months of therapy, 6 progressed and 6 others discontinued because of adverse events or withdrew consent. Seventeen patients had treatment-related adverse events that were generally mild or moderate in severity, including asthenia, headache, chills, fever, injection site reaction, pain, myalgia, arthralgia, elevated aspartate and alanine aminotransferase levels, anorexia, and sweating. One patient in PR died of hemolytic anemia, possibly exacerbated by rhIL-12 treatment. The original company was purchased during the conduct of the trial and rhIL-12 is currently unavailable. The quality of life data were not available for inclusion. Twice-weekly subcutaneously administered rhIL-12 (100 ng/kg escalated to 300 ng/kg) showed antitumor activity with a response rate of 43% in refractory patients. It was relatively well-tolerated in early-stage MF.

Long‐term experience with low‐dose interferon‐α and PUVA in the management of early mycosis fungoides

Combined high-dose Interferon-alpha and psoralen plus ultraviolet A irradiation (PUVA) have been reported to be effective in the treatment of early mycosis fungoides (MF); however, our study is the first controlled prospective study in the literature exploring the activity and tolerability of the combination with low dosages and evaluating further clinical outcome of early-MF patients. We carried out a multicentric prospective Phase II clinical study on 89 patients with early-stage IA to IIA MF treated for 14 months with low-dose IFN-alpha2b (6-18 MU/wk) and PUVA. Treatment success was analysed in terms of freedom from treatment failure. Complete remission (CR) was achieved in 84% and an overall response rate in 98% of cases: six-month CR was associated with a non-confluent skin infiltrate at histology (P = 0.044) and 14-month CR with high epidermal CD1a+ dendritic-cell density (P = 0.030). The combination protocol was successfully tolerated and the most common reason of 'failure' was related to relapse and not to toxicity. Sustained remissions were achieved in 20% of patients. High CD8+ lymphoid T-cell density was associated with a lower relapse rate (P = 0.002). We think that our combination therapy can be considered an alternative approach compared with other modalities. Good immunological host surveillance in the skin lesions seems to be an optimal basis for the therapeutic success.

Long-term Follow-up of Patients With Early-Stage Cutaneous T-Cell Lymphoma Who Achieved Complete Remission With Psoralen Plus UV-A Monotherapy

To evaluate long-term outcomes, impact of maintenance therapy and potential curability of patients with mycosis fungoides (MF) treated with psoralen plus UV-A (PUVA) monotherapy. Single-center retrospective cohort analysis. Academic referral center for cutaneous lymphoma. A total of 66 of 104 patients with clinical stages IA to IIA MF who achieved complete remission (CR) after PUVA monotherapy between 1979 and 1995. Kaplan-Meier actuarial survival and disease-free survival curves were compared between stage IA and IB/IIA cases. Patients were stratified into relapse and nonrelapse groups based on whether their MF relapsed during study follow-up. Baseline characteristics and treatment were compared between these groups. Median follow-up time was 94 months (range, 5-242 months). Thirty-three patients maintained CR for 84 months (range, 5-238 months), and 33 patients experienced relapse with a median disease-free interval of 39 months (range, 2-127 months). There was no significant difference in baseline characteristics between patients in the nonrelapse and relapse groups. Those in the nonrelapse group received a higher cumulative dosage to CR (P = .03) and required longer treatment periods to achieve CR (P = .03). Disease-free survival rates at 5 and 10 years for all patients with stage IA were 56% and 30%, respectively, and for stage IB/IIA, 74% and 50%. Actuarial survival rates at 5, 10, and 15 years were 94%, 82%, and 82%, respectively, in patients with stage IA, and 80%, 69%, and 58% in patients with stage IB/IIA. The overall survival rate for the nonrelapse and relapse groups did not show any statistical difference. One third of the patients developed signs of chronic photodamage and secondary cutaneous malignancies. Psoralen UV-A is an effective treatment for MF, inducing long-term remissions and perhaps in some cases disease "cure." Thirty percent to 50% of patients remain disease free for 10 years, but late relapses occur. Long-term survival is not affected by relapse status, and the risk of photodamage needs to be measured against the possible benefit of greater disease elimination.