Severity Weighted Assessment Tool Research Articles

Effectiveness and safety of interferon α-2a combined with phototherapy for patients with early-stage mycosis fungoides - a single-arm prospective study in 13 patients

Background: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma. Objectives: This study was conducted to evaluate efficacy and safety of interferon (IFN) α-2a combined with phototherapy for early-stage MF. Methods: Thirteen patients with early-stage MF received subcutaneous injections of IFN α-2a at 3 million IU combined with phototherapy three times per week for 6 months. Treatment efficacy was measured by changes in body surface area (BSA) score and modified severity-weighted assessment tool (mSWAT) score at 1, 3, and 6 months after treatment. Histopathologic examinations of skin lesions were performed before and after treatment. Results: After 3 months of treatment, all 13 patients achieved a partial response, and BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001). After 6 months, BSA and mSWAT scores were significantly lower than those at baseline (p < 0.001) and after 3 months (p < 0.05). Eleven patients achieved complete remission and two patients achieved a partial response (overall response rate, 100%). Histopathologic examination showed a significant decrease in the number of atypical lymphocytes in both epidermis and dermis. No severe adverse effects occurred. Conclusion: IFN α-2a in combination with phototherapy may be an effective and safe alternative modality for early-stage MF.

Utility of Low-Dose Duvelisib for Advanced Mycosis Fungoides: A Single-Institution Study.

Duvelisib, a small-molecule phosphatidylinositol 3-kinase-δ,γ inhibitor, has shown efficacy for mycosis fungoides (MF) at dosage ranges of 25-100 mg twice daily (BID), but with significant toxicity. We conducted a retrospective cohort study of patients with advanced MF treated with low-dose duvelisib (15 mg every other day to BID), in an effort to minimize toxicity. A total of 7 patients were included. The overall response rate on duvelisib was 71%, with the remaining patients maintaining stable disease. Mean modified Severity Weighted Assessment Tool score improved by 57.4% and mean percent body surface area involved improved by 52%. Median progression-free survival was 10.3 months. Adverse events occurred in 4 of 7 patients, the most common being fatigue (2/7; grades 1-2), nausea (2/7; grades 1-2), and transaminitis (2/7; grade 3). Overall, low-dose duvelisib showed efficacy for advanced MF with less toxicity, providing a rationale for its use as monotherapy and potentially combinatorial therapy.

Gut microbiota analyses of cutaneous T-cell lymphoma patients undergoing narrowband ultraviolet B therapy reveal alterations associated with disease treatment.

Recent studies have shown a close relationship between cutaneous T-cell lymphoma (CTCL) and its microbiome. CTCL disease progression is associated with gut dysbiosis and alterations in bacterial taxa parallel those observed in immunologically similar atopic dermatitis. Moreover, the microbial profile of lesional skin may predict response to narrowband ultraviolet B (nbUVB), a common skin-directed therapy. However, the relationship between the gut microbiome, an immunologically vital niche, and nbUVB remains unexplored in CTCL. Herein, we performed 16S rRNA sequencing and PICRUSt2 predictive metagenomics on DNA extracted from stool swabs of 13 CTCL patients treated with nbUVB, 8 non-treated patients, and 13 healthy controls. Disease response was assessed with modified Severity Weighted Assessment Tool (mSWAT); of nbUVB-treated patients, 6 improved (decreased mSWAT), 2 remained stable, and 5 worsened (increased mSWAT). Protective commensal bacteria including Lactobacillaceae and Erysipelatoclostridiaceae were significantly less abundant in CTCL patients compared to controls. With treatment, the CTCL gut microbiome exhibited decreased phylogenetic diversity and lower relative abundance of pro-inflammatory Sutterellaceae. Sutterellaceae was also significantly more abundant in patients who worsened, and Eggerthellaceae and Erysipelotrichaceae trended higher in patients who improved. Finally, PICRUSt2 functional predictions based on shifts in abundance of bacterial sequences repeatedly identified alterations in inositol degradation, which plays a key role in host immunomodulation, including inositol phospholipid signaling relevant to T-cell survival and proliferation. Our results bolster the paradigm of gut dysbiosis in CTCL and its functional implications in disease pathogenesis, and further delineate bacterial taxa associated with nbUVB response and with nbUVB treatment itself.

Psychological Distress and Treatment Outcome in Patients With Early-Stage Mycosis Fungoides.

Skin diseases have been shown to worsen psychological distress, which, in turn, may be detrimental to treatment outcomes. Both the impact of psychological distress on response to treatment in mycosis fungoides (MF) and the effect of treatments on psychological well-being are unclear. To evaluate (1) the association between pretreatment psychological morbidity and treatment outcome in early-stage MF and (2) the impact of response to treatment on psychological well-being. This was a prospective cohort study of patients with early-stage MF who started a new stage-directed treatment for their disease. The response was determined using the modified severity-weighted assessment tool, and psychological distress was assessed using the 12-item General Health Questionnaire (GHQ-12) and Penn State Worry Questionnaire (PSWQ). Participants were followed for 1 year. In all, 24 consecutive patients were recruited. Objective response rate was 71% (17/24), consistent with existing literature. Prior to treatment, 9 patients (38%) had clinically significant psychological distress on the GHQ-12, while 8 (33%) demonstrated high-level worry on the PSWQ. Of these patients, 6 had pathologic scores on both instruments. Patients with significantly less baseline anxiety/depression on the GHQ-12 responded better to treatment than patients with higher levels (P = .004). In addition, responders' mean GHQ-12 scores decreased by 39% and their PSWQ scores by 17%, whereas nonresponders' GHQ-12 scores increased by 93% (P = .042) and their PSWQ scores by 11% (P = .019). These findings suggest that (1) baseline psychological distress is associated with worse outcomes in patients with early-stage MF and that (2) effective treatment improves psychological morbidity.

Dynamic Changes in Lymph Node Size and Skin Scoring Predict Response to Treatment in CTCL: An Interim Analysis

Cutaneous T-cell lymphoma (CTCL) is a heterogenous group of non-Hodgkin T-cell lymphomas with predominant skin involvement. Mycosis fungoides and Sézary syndrome are the most common subtypes and present with a wide spectrum of cutaneous and extra-cutaneous manifestations. Early-stage disease is often controlled with skin-directed therapies while advanced-stage disease can be treatment-refractory and often requires multiple lines of systemic therapy. It is therefore of great interest to identify early predictors of treatment response to tailor therapeutic management decisions. Modified Severity-Weighted Assessment Tool (mSWAT) scoring and lymph node evaluation are important components of treatment response assessment in clinical practice and in trials. A major limitation of current assessment methods is the use of relative changes in mSWAT and lymph node size which do not account for heterogeneous treatment effects. Novel assessment techniques that reflect the dynamic changes occurring within the tumor environment during treatment have the potential to offer more accurate insights into treatment response than current methods. Among these novel approaches is kinetic modeling of tumor growth rate ( g), which has been validated as a biomarker for treatment response and survival in other types of cancer but has never been used in CTCL. Kinetic modeling provides the benefit of evaluating the simultaneous rates of growth of treatment-resistant cells and regression of treatment-responsive cells. We hypothesized that dynamic changes in lymph node size and mSWAT scores over time could predict response to treatment in CTCL patients. We retrospectively analyzed clinical data and computed tomography scans from 119 patients enrolled in the MAVORIC trial. An open-source imaging platform with integrated semi-automated segmentation algorithms was used to quantify lymph node volumes for each patient. Kinetic modeling was applied to estimate the simultaneous rates of growth ( g) and regression ( d) of lymph node size and mSWAT scores during treatment. Patients were divided into two groups based on g and correlation with time to treatment failure (TTF) was evaluated. Tumor doubling times were estimated using the equation dt = 0.693/ g. For most patients, g and d could be estimated, and these values could be determined early in the treatment course. Volumetric lymph node growth rate had an inverse correlation with TTF (p &amp;lt; 0.0001). Patients with with faster rates of nodal growth (median g = 0.0077 d -1, doubling time = 90 days) had a median TTF of 2.9 months, whereas patients with slower rates of nodal growth (median g = 0.0013 d -1, doubling time = 533 days) had a median TTF of 8.8 months. Rate of growth of mSWAT scores also had an inverse correlation with TTF (p &amp;lt; 0.0001). Those with the fastest rate of increase in mSWAT scores (median g = 0.0057 d -1, doubling time = 122 days) had a median TTF of 2.9 months while those with the slowest rate of increase (median g = 0.0013 d -1, doubling time = 533 days) had a median TTF of 8.5 months. In this interim analysis, we use a novel kinetic model to demonstrate that g correlates with time to treatment failure, suggesting that lymph node and mSWAT growth kinetics may be early predictors of treatment response in CTCL. Our findings have potential implications for both clinical practice and trials. Lymph node and mSWAT growth rates may support clinicians in making early decisions about adapting treatment regimens for individual patients. In clinical trials and early drug development, the incorporation of g as an endpoint may accelerate the recognition of promising drug candidates. Our findings require validation in a larger cohort as well as prospective studies.

The effect of phototherapy on the dynamics of cytokine mRNA expression in the affected skin of patients with mycosis fungoides

Introduction. The role of the cytokine environment and immune deregulation in the pathogenesis of mycosis fungoides is unquestionable. Despite the fact that one of the methods of therapy for the early stages of mycosis fungoides is phototherapy (PUVA, UVB-311 nm), the effect of ultraviolet radiation on the lymphoproliferative substrate and pathogenetic links in mycosis fungoides has not been fully studied. Aim: to evaluate the effect of NB-UVB and PUVA therapy on the dynamics of cytokine mRNA expression in the affected skin of patients with mycosis fungoides. Material and Methods. A comparative non-randomized study of the cytokine mRNA expression dynamics in the affected skin and of the effectiveness of phototherapy was carried out in 28 patients with early stage of mycosis fungoides. The IL4, IL17A, IL17F, and IL22 mRNA expression was determined relative to the endogenous control GAPDH using the real-time reverse transcription PCR (RT-PCR). Evaluation of the effectiveness of NB-UVB and PUVA therapy was carried out using a BSA score (skin lesion area) and a modified severity-weighted assessment tool (mSWAT) score. Results. The study included 28 patients with early stages (IA–IIA) of mycosis fungoides; 9 patients received NB-UVB and 19 received PUVA therapy. 3.71-fold decrease in mSWAT (p &lt; 0.008), and 3-fold decrease in BSA scores (p &lt; 0.013) were observed in the NB-UVB-treated group. In the PUVA-treated group 3.47- and 2.19-fold lower scores of mSWAT (p &lt; 0.001) and BSA (p &lt; 0.001) were found. There were no significant differences in the expression of the studied cytokines in the NB-UVB-treated group; however, a significant 19 and 72 % increase in IL17F (p = 0.003) and IL22 (p = 0.021) was revealed afterPUVA therapy. Correlation analysis has shown a weak correlation between IL4 and IL17A (r = 0.43, p &lt; 0.027), and IL17F (r = 0.43, p &lt; 0.028) before the treatment. Under the influence of phototherapy, the formation of a cytokine network in the affected skin was observed: there were positive associations between IL4 and IL17A (r = 0.73, p &lt; 0.001), IL17F (r = 0.7, p &lt; 0.001) and IL22 (r = 0.43, p &lt; 0.024); IL17A and IL17F (r = 0.78, p &lt; 0.001); IL22 and IL17A (r = 0.63, p &lt; 0.001) and IL17F (r = 0.66, p &lt; 0.001). In the PUVA-treated group a high negative correlation between IL17A and mSWAT (r = -0.79415, p =0.010586), BSA (r = -0.75432, p = 0.018849) were found. Conclusion: The positive correlations between IL4, IL17A, IL17F and IL22 in the affected skin of patients with mycosis fungoides may underlie the positive effect of phototherapy.

Health-Related Quality of Life (HRQL) in Cutaneous T-Cell Lymphoma: A Post Hoc Analysis Examining Disease Burden and Patient Characteristics from the Phase 3 Mavoric Trial in Mycosis Fungoides and Sézary Syndrome

The MAVORIC phase 3 study (NCT01728805) evaluated the efficacy of mogamulizumab compared with vorinostat in patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) - the most common subtypes of cutaneous T-cell lymphoma (CTCL). This retrospective analysis of baseline (pre-treatment) data from the large well-defined population in the MAVORIC study describes the burden of CTCL on HRQL and identifies characteristics that are associated with poorer HRQL. The MAVORIC study enrolled patients with stage IB-IVB relapsed or refractory MF/SS that had failed to respond to one or more systemic therapies. HRQL data from the Skindex-29, ItchyQOL, and Functional Assessment of Cancer Therapy - General (FACT-G) were analysed at the item level and scored according to instrument guidelines. Bivariate analysis was used to identify factors associated with relatively poorer HRQL and guided selection of variables for the multivariate analysis. 372 participants were enrolled, 55% with MF and 45% with SS; 77% had advanced (stage IIB-IV) disease. The mean (SD) age was 63 (13.0) years and 42% were female. Disease involved the skin in all participants, blood in 66%, nodes in 66%, viscera in 2%, and other sites in 5%. ECOG performance status was 0, 1, and 2 in 56%, 43%, and 1%, respectively. The domains and total scores for Skindex-29, ItchyQoL and FACT-G are shown in table 1 For individual items, the greatest impairments were seen in skin itch, skin sensitivity, worry of worsening, annoyed by skin condition, sleep, and need to buy special soaps. In bivariate analysis, worse total score across all three HRQL measures was related to being younger, female, having moderate or severe itch, ECOG performance status 1 or 2, and higher Modified Severity-Weighted Assessment Tool (mSWAT) scores. On the Skindex-29 and ItchyQol, worse total scores were also related to Black/African American ethnicity, having disease involving nodes, and higher affected body surface area (BSA). Worse Emotional domain scores across all three HRQL measures was related to being female and having severe itch; worse Functional domain scores were related to disease involving nodes, ECOG performance status 1 or 2, higher mSWAT score, higher affected BSA, and moderate or severe itch. Worse Symptom domain scores (Skindex-29 and ItchyQol) were related to being female, ECOG performance status 1 or 2, higher mSWAT score, higher affected BSA, and severe itch. Differences across HRQL measures will also be reported. In multivariate analysis, worse HRQL was associated with being younger, female, or Black/African American, and with moderate or worse itch and ECOG stage 1 or 2 but was not generally associated with disease stage. In participants with advanced MF/SS, HRQL was most impacted by symptoms with the impact varying by patient characteristics rather than disease stage. Assessing patients' individual disease concerns may inform treatment goals and therapeutic choice.

P54 Blood tumour burden does not correlate with skin tumour burden in early-stage mycosis fungoides: analysis of the PROspective Cutaneous Lymphoma International Prognostic Index international registry

Abstract Blood involvement B1, defined as absolute counts 250–1000 IU of an aberrant CD4+CD7– or CD4+CD26– phenotype, may be found in early-stage mycosis fungoides (MF). There is a suggestion that B1 blood involvement is a poor prognostic marker, but there is limited evidence investigating the prognostic significance of B0 or B1 blood involvement in early-stage MF. Loss of CD26 and/or CD7 expression on CD4 cells may occur in MF; however, it is unclear whether loss of either one of these immunophenotypic markers bears more significance on prognosis. For B2 blood involvement (&amp;gt; 1000 IU), the International Society for Cutaneous Lymphomas (ISCL) criteria define Sézary syndrome as CD26 loss of &amp;gt; 30% or CD7 loss of &amp;gt; 40%. Understanding the impact of B1 and comparative loss of CD26 and/or CD7 in early-stage MF may allow patients at higher risk of stage progression to be identified and selected for better therapeutic options. The aims of this study were to analyse B0 vs. B1 blood involvement at diagnosis in patients with early-stage MF (IA–IIA) and evaluate the relative CD4+CD7– and CD4+CD26– absolute cell counts. Prospective data from the PROCLIPI registry were analysed. Ninety-four patients with early-stage MF were identified from our database, 67 (71%) of whom were B0 [stage IA, n = 23 (34%); stage IB, n = 24 (36%); stage IIA, n = 20 (30%)] and 27 (29%) were B1 [stage IA, n = 12 (44%); stage IB, n = 10 (37%); stage IIA, n = 5 (18%)]. Median age at diagnosis in B0 patients was 59 years (range 20–91) vs. 61 years (range 21–81) in B1 patients. Median CD4+CD7– cell count was 16.4% (range 0–41%) in patients with B0 involvement and 28.1% (range12–45%) in B1 patients. Median CD4+CD26– cell count was 16% (range 0–39.1%) in B0 and 28% (range 0–44%) in B1 patients. The Median Modified Severity-Weighted Assessment Tool score in B1 patients was 11 (range 1–73) vs. 20 (range 0.5–100) in B0 patients. There was no significant difference in progression to the advanced stage between B0 and B1 (P = 0.112) patients or overall survival between B0 and B1 patients during median follow-ups of 49 months and 45 months, respectively. These results suggest that blood tumour burden in early-stage MF, measured by the percentage aberrancy in CD4+CD7– and CD4+CD26– cell counts, does not correlate with clinical stage, skin tumour burden or stage progression. This suggests that in B1 involvement, atypical lymphocytes may lose their skin-homing properties. Interestingly, levels of CD4+7– and CD26– are similar in B1 involvement, despite the ISCL criteria defining B2 involvement as a lower relative loss of CD26–. Identifying B1 patients is important as certain therapeutic options such as extracorporeal photopheresis and mogamulizumab may be indicated in patients with early-stage MF, refractory to skin-directed therapies.

LYMPH NODE AND SKIN SCORING GROWTH KINETICS PREDICT OUTCOMES IN CUTANEOUS T‐CELL LYMPHOMA: AN INTERIM ANALYSIS

In cutaneous T-cell lymphoma (CTCL), skin scoring and lymph node (LN) assessment are essential for scoring disease response in both clinical practice and in trials. Current assessment methods rely on calculating relative changes in the Modified Severity-Weighted Assessment Tool (mSWAT) and target LN size during a patient’s treatment course. However, measuring relative changes fails to account for mixed treatment effects comprising the simultaneous regression of treatment-responsive cells and growth of treatment-resistant cells. Additionally, the clinical significance of LN size on imaging scans remains uncertain in CTCL. LNs are currently measured using linear dimensions that may not capture the extent of nodal involvement or be sensitive enough to track clinically meaningful changes over time. The aim of this study was to perform kinetic analysis using mSWAT data and computed tomography LN measurements from the MAVORIC trial to determine if dynamic changes over time correlate with overall survival (OS) in CTCL. Kinetic modeling evaluated simultaneous rates of growth (g) and regression (d) using a two-phase equation. Unidimensional and volumetric LN sizes were measured using a novel radiomics imaging platform. Tumor doubling times can be estimated based on g, using the equation dt = 0.693/g. An initial cohort of 119 patients were included, and in most patients, g and d values could be estimated. Patients were divided into two groups based on g, and correlation with OS was evaluated. The median g was 0.0013d−1 in the half with slowest rate of increase in SWAT scores (doubling time = 533 days); with g of 0.0057d1 in those with fastest growth (doubling time = 122 days). For unidimensional LN size, volumetric LN size, and mSWAT, g was highly correlated with OS; faster rates of nodal growth or increase in SWAT scores were associated with shorter OS. Median OS for patients with faster unidimensional LN, volumetric LN, and mSWAT growth rates were 29, 27.7, and 17 months, respectively, whereas median OS were not reached for patients with slower growth rates (p = 0.012, 0.0035, and 0.0012, respectively). Our interim analysis demonstrates that skin scoring and lymph node growth kinetics predict survival in CTCL. Thus, g has potential as a novel biomarker for prognostication and treatment response assessment. It may also serve as a clinical trial endpoint that allows for earlier readout of trial results than conventional survival endpoints. Further validation in a larger cohort, and ultimately with prospective studies, is needed. The research was funded by: Kyowa Kirin Keywords: Diagnostic and Prognostic Biomarkers, Cutaneous non-Hodgkin lymphoma, Imaging and Early Detection - Other Conflicts of interests pertinent to the abstract L. J. Geskin Consultant or advisory role Kyowa Kirin Research funding: Kyowa Kirin

Dimethyl fumarate treatment in relapsed and refractory cutaneous T-cell lymphoma: a multicenter phase 2 study

AbstractTargeted therapies for cutaneous T-cell lymphoma (CTCL) are limited and curative approaches are lacking. Furthermore, relapses and drug induced side effects are major challenges in the therapeutic management of patients with CTCL, creating an urgent need for new and effective therapies. Pathologic constitutive NF-κB activity leads to apoptosis resistance in CTCL cells and, thus, represents a promising therapeutic target in CTCL. In a preclinical study we showed the potential of dimethyl fumarate (DMF) to block NF-κB and, specifically, kill CTCL cells. To translate these findings to applications in a clinical setting, we performed a multicentric phase 2 study evaluating oral DMF therapy in 25 patients with CTCL stages Ib to IV over 24 weeks (EudraCT number 2014-000924-11/NCT number NCT02546440). End points were safety and efficacy. We evaluated skin involvement (using a modified severity weighted assessment tool [mSWAT]), pruritus, quality of life, and blood involvement, if applicable, as well as translational data. Upon skin analysis, 7 of 23 (30.4%) patients showed a response with >50% reduction in the mSWAT score. Patients with high tumor burden in the skin and blood responded best to DMF therapy. Although not generally significant, DMF also improved pruritus in several patients. Response in the blood was mixed, but we confirmed the NF-κB–inhibiting mechanism of DMF in the blood. The overall tolerability of the DMF therapy was very favorable, with mostly mild side effects. In conclusion, our study presents DMF as an effective and excellently tolerable therapeutic option in CTCL to be further evaluated in a phase 3 study or real-life patient care as well as in combination therapies. This trial was registered at www.clinicaltrials.gov as #NCT02546440.

Ultrahypofractionated Low-Dose Total Skin Electron Beam in Advanced-Stage Mycosis Fungoides and Sézary Syndrome

To assess the safety and efficacy of ultra-hypofractionated low-dose total skin electron beam therapy (TSEBT) regimen in patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). In this multicenter observational study from five German centers, 18 total patients with MF/SS underwent TSEBT with a total dose of 8 Gy in two fractions. The primary endpoint was the overall response rate (ORR). 15 of 18 patients with stage IIB-IV MF or SS were heavily pre-treated with a median of four prior systemic therapies. The ORR was 88.9% (95%-confidence interval (CI): 65.3-98.6), with three complete responses (17%). At a median follow-up period of thirteen months, the median time to next treatment (TTNT) was 12 months (95%-CI: 8.2-15.8), and the median progression-free survival was 8 months (95%-CI: 2-14). Asignificant reduction in the modified severity-weighted assessment tool (mSWAT), total Skindex-29 score (Bonferroni-corrected P-value < 0.005), and all subdomains (Bonferroni-corrected P-values < 0.05) was observed after TSEBT. Half of the irradiated patients (N=9) developed grade 2 acute and subacute toxicities. One patient had confirmed grade 3 acute toxicity. Chronic grade 1 toxicity has been observed in 33% of patients. Patients with erythroderma/SS or prior radiation therapy appear at higher risk of skin toxicities. TSEBT with 8 Gy in 2 fractions achieves good disease control and symptom palliation with acceptable toxicity, greater convenience, and fewer hospital visits.

Efficacy and Safety of E7777 (improved purity Denileukin diftitox [ONTAK]) in Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma: Results from Pivotal Study 302

Introduction: Denileukin diftitox (Dd) is a recombinant fusion protein of diphtheria toxin and human interleukin-2. Dd was approved and marketed as ONTAK in the US from 1999-2014 for treatment of pts with relapsed/refractory CTCL. ONTAK was voluntarily taken off the market in 2014 due to manufacturing difficulties. E7777 was developed as a result of a refined manufacturing process and has an increased percentage of protein monomer species, with a concomitant decrease in levels of misfolded protein and protein aggregates. E7777 has ~1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK and is considered a new drug by the FDA. Methods: Objectives: Study 302 (NCT01871727) is a multicenter, open-label, single-arm registrational trial designed to assess efficacy and safety of E7777 in patients with relapsed/refractory CTCL. E7777 was given IV at 9 mcg/kg/day (established from Lead-in) over 60 min for 5 days every 21 days up to 8 cycles. Key inclusion/exclusion criteria included histopathologic diagnosis of CTCL (MF or SS); ECOG performance status 0 or 1; no prior exposure to ONTAK. The primary efficacy endpoint was objective response rate (ORR; CR+PR) per Independent Review Committee (IRC) assessment based on Global Response Score GRS (Olsen, et al., 2011). Secondary efficacy endpoints included duration of response (DOR), time-to-response (TTR), skin response (according to modified Severity Weighted Assessment Tool [mSWAT]), safety and tolerability of E7777, PK, and immunogenicity. Exploratory objectives included progression free survival (PFS), time to progression (TTP), pruritus improvement, and quality of life assessment. Results: A total of 112 patients with CTCL stage I-IV were enrolled in the study: 21 in the Lead-in and 91 in the Main Study. The primary efficacy population is comprised of 69 patients with stage I-III CTCL treated at 9 mcg/kg/day. Median number of prior anticancer therapies in Study 302 were 4.0 (range: 1 to 18). Forty-five patients (65.2%) received ≥4 prior anticancer therapies. Approximately half (34 of 69; 49.3%) of patients had prior exposure to 1 or more FDA-approved targeted therapeutics: romidepsin, brentuximab, or mogamulizumab. Demographic and baseline characteristics of patients included a median age of 64 (range 28-87); ECOG status 0 (56.5%) and 1 (43.5%); Race: 72.5% White, 18.8% Black; 9% Other. There disease stages were 43.5% IA/IB/IIA; 34.8% IIB; and 21.7% IIIA/IIIB. The median (range) number of cycles of E7777 received was 6.0 (1, 42). The primary efficacy endpoint, ORR (95% CI) by IRC, was 36.2% (95% CI: 25.0%, 48.7%), with 8.7% achieving a CR. ORR (95% CI) by Investigator was 42.3% (30.6%, 54.6%), with 8.5% achieving a CR (Table 1). DOR was at least 6 months for 13 (52.0%) responders and at least 12 months for 5 (20.0%) responders. TTR was rapid (median=1.41 months); the majority of responders (~70%) had a response after 1 to 2 cycles of treatment. Treatment with E7777 did not demonstrate any new or unexpected safety findings as compared to prior ONTAK experience. Most patients (98.6%) experienced at least 1 TEAE. Most common TEAEs were nausea (43.5%); fatigue (31.9%); and increased ALT, chills, and peripheral edema (27.5% each). Mean numbers of TEAEs per subject were higher in the first 1 to 2 treatment cycles, then decreased and remained low/stable over the remainder of therapy. Key adverse events of special interest (AESIs) associated with ONTAK in the past (i.e. capillary leak syndrome, hepatotoxicity, infusion reaction, and visual impairment) were primarily Grade 1/2 in our current study and will be discussed in detail in a separate abstract. Conclusions: In study 302, E7777 at a dose of 9 mcg/kg/day demonstrated clinical efficacy and clinically meaningful benefit in heavily pre-treated patients with relapsed/refractory CTCL. The ORR of 36.2% per IRC (42.3% by investigator assessment) showed that a substantial proportion of these heavily pretreated patients experienced clinical benefit after E7777 treatment similar to ONTAK. The observed tumor responses were rapid, durable, and deep. A BLA submission to the FDA is planned for the 2nd half of 2022. E7777 will provide a novel, efficacious, safe, and non-cross-resistant therapeutic option for CTCL patients who have failed other treatments and thus fulfill a serious unmet need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Narrowband ultraviolet B response in cutaneous T-cell lymphoma is characterized by increased bacterial diversity and reduced Staphylococcus aureus and Staphylococcus lugdunensis.

Skin microbiota have been linked to disease activity in cutaneous T-cell lymphoma (CTCL). As the skin microbiome has been shown to change after exposure to narrowband ultraviolet B (nbUVB) phototherapy, a common treatment modality used for CTCL, we performed a longitudinal analysis of the skin microbiome in CTCL patients treated with nbUVB. 16S V4 rRNA gene amplicon sequencing for genus-level taxonomic resolution, tuf2 amplicon next generation sequencing for staphylococcal speciation, and bioinformatics were performed on DNA extracted from skin swabs taken from lesional and non-lesional skin of 25 CTCL patients receiving nbUVB and 15 CTCL patients not receiving nbUVB from the same geographical region. Disease responsiveness to nbUVB was determined using the modified Severity Weighted Assessment Tool: 14 (56%) patients responded to nbUVB while 11 (44%) patients had progressive disease. Microbial α-diversity increased in nbUVB-responders after phototherapy. The relative abundance of Staphylococcus, Corynebacterium, Acinetobacter, Streptococcus, and Anaerococcus differentiated nbUVB responders and non-responders after treatment (q<0.05). Microbial signatures of nbUVB-treated patients demonstrated significant post-exposure depletion of S. aureus (q=0.024) and S. lugdunensis (q=0.004) relative abundances. Before nbUVB, responder lesional skin harboured higher levels of S. capitis (q=0.028) and S. warneri (q=0.026) than non-responder lesional skin. S. capitis relative abundance increased in the lesional skin of responders (q=0.05) after phototherapy; a similar upward trend was observed in non-responders (q=0.09). Post-treatment skin of responders exhibited significantly reduced S. aureus (q=0.008) and significantly increased S. hominis (q=0.006), S. pettenkoferi (q=0.021), and S. warneri (q=0.029) relative abundances compared to that of no-nbUVB patients. Staphylococcus species abundance was more similar between non-responders and no-nbUVB patients than between responders and no-nbUVB patients. In sum, the skin microbiome of CTCL patients who respond to nbUVB is different from that of non-responders and untreated patients, and is characterized by shifts in S. aureus and S. lugdunensis. Non-responsiveness to phototherapy may reflect more aggressive disease at baseline.

33870 Mechlorethamine gel as a maintenance treatment regimen in patients with mycosis fungoides

Background: Cutaneous T-cell lymphomas (CTCLs) are malignant proliferations in the skin that can invade blood, lymph nodes, or viscera. Mycosis fungoides (MF), the most common CTCL, is treated with topical agents, such as mechlorethamine gel 0.016%, in skin-limited stages. Currently, no data exist on maintenance therapy for patients in remission. Thomas Jefferson University has developed a unique protocol to use mechlorethamine as a maintenance regimen after total skin electron beam therapy. Purpose: To determine progression-free survival and efficacy of mechlorethamine as maintenance and active treatment regimens for MF. Methods: A retrospective review of MF patients seen at Thomas Jefferson University from 2012 to 2020 was conducted. Patients of all stages treated with mechlorethamine as maintenance or active treatment with 2 consecutive mSWATs (modified Severity Weighted Assessment Tool) documented were included. Treatment outcomes were assessed by change in mSWAT and progression-free survival. Dermatology Life Quality Index surveys before and after treatment were analyzed. Results: Of 186 MF patients, 44 met inclusion criteria. Patients on maintenance therapy had a 65.22% progression-free survival rate with median time to progression of 29.45 months. By-time analysis for responders on active and maintenance treatment showed an increased response over time. Peak responses were seen at last mSWAT recorded. Both cohorts experienced improved quality-of-life scores from initiation to discontinuation of mechlorethamine. Conclusions: Patients on maintenance and active mechlorethamine treatment regimens demonstrated improvement in mSWAT and quality-of-life. Mechlorethamine treatment showed progression-free survival for a median of 29.45 months, indicating this therapy may be an effective maintenance regimen.

Lifestyle, demographic and Skindex measures associated with cutaneous T-cell lymphoma: a single institution cohort study.

Cutaneous T-cell lymphoma (CTCL) risk factors and associated quality of life are poorly understood. Previous studies of CTCL risk factors explored patient comorbidities and lifestyle exposures, but not in conjunction with disease stage, subtype, severity, or health-related quality of life (HRQoL). We investigated lifestyle exposures and demographic factors associated with advanced-stage disease, increased disease severity, and poorer HRQoL outcomes in this single-center cohort study. A cohort survey study was conducted at Northwestern's Multidisciplinary Cutaneous Lymphoma specialty clinic between April 2019 and June 2021. REDCap surveys were administered to 140 patients with CTCL, investigating patients' demographics, lifestyle and chemical exposures. QoL was evaluated using the Skindex survey; pain and itch with ten-point Likert scales. Modified Severity Weighted Assessment Tool (mSWAT), disease stage, and disease subtype were confirmed upon enrollment in the study by a single board-certified dermatologist specializing in CTCL. Factors were compared by t test or Fischer's exact test. Median age was 63years (range 14-92) with male-to-female ratio of 1.2:1. The most common diagnosis was CD4 + MF (n = 94, 67.1%). Common lifestyle exposures included smoking (past or current) (52.3%) and chemical exposure history (all sources [53.7%]; industrial only [33.0%]). History of chemical exposures were associated with advanced stage disease (p = 0.003) and worse QoL outcomes (p = 0.001). There were significant racial differences, respectively, in early (I-IIA) vs late (IIB-IV) stage disease (p = 0.003). Obesity, hygiene, smoking, recent sun exposure, education and atopy were not significantly associated with disease stage or severity. We provide an analysis of lifestyle and demographic factors in the context of CTCL disease severity, stage, and HRQoL. We identified race as a potential risk factor for advanced stage disease and both skin phototype and chemical exposures as a risk factor for increased disease severity as measured by mSWAT. QoL outcomes were multifactorial and significantly associated with history of chemical exposure, severe pain/itch, race, disease stage and subtype. An improved understanding of these associations may lead to better individualized care. As chemical exposure and race were found to be significant factors associated with advanced-stage disease, taking exposure histories and addressing racial disparities may improve care for CTCL patients.

Chlormethine gel is effective for the treatment of skin lesions in patients with early- and late-stage mycosis fungoides in clinical practice.

Chlormethine gel is a skin-directed therapy used for patients with mycosis fungoides (MF) that showed a favourable risk/benefit profile in a randomized clinical trial. Currently, data on chlormethine gel use in real-world settings are limited. The aim of this study was to assess safety and efficacy of chlormethine gel treatment in patients treated during daily clinical practice and investigate associations between response and disease stage, lesion type, mono- or combination therapy, and occurrence of dermatitis. Clinical data from patients using chlormethine gel from three sites in Greece were analysed. Efficacy was assessed through modified Severity-Weighted Assessment Tool (mSWAT) scores. Safety assessments included analysis of the occurrence and severity of dermatitis. The Skindex-29 questionnaire was used for quality-of-life assessments. Fifty-eight patients were included. The overall response rate (ORR) increased from 37.9% at month 1 to 80.8% at month 9. For 64.2% of patients, response was maintained for at least 4 months (ORR4). At month 3, a higher ORR was seen for patients with patches (69.7%) than patients with plaques/tumours (both 15.2%). A higher ORR4 was observed for patients with early- vs late-stage disease (71.4% vs. 36.4%) and patients on mono- vs combination therapy (75% vs. 47.6%). Dermatitis was observed in the majority of patients (72.4%), but the presence or severity of dermatitis was not directly correlated with treatment response. Both mSWAT and Skindex-29 scores decreased significantly during treatment, and changes in these scores from baseline to month 6 showed a positive correlation (r = 0.55, P = 0.026). Chlormethine gel was effective for the treatment of skin lesions in patients with early- and late-stage MF in clinical practice. Response rates increased over time, indicating that continued treatment with the gel is important. Dermatitis may be managed by reducing the treatment frequency; the occurrence of dermatitis did not affect the response to treatment.

Response to Chlormethine/Mechlorethamine gel Maintenance Treatment Regimen in Patients With Mycosis Fungoides: A Single-center Retrospective Study

BackgroundMycosis fungoides (MF), the most common subtype of Cutaneous T-cell lymphomas, is caused by malignant T-cell proliferations in the skin that can invade blood, lymph nodes, or viscera. Currently, data on efficacy of maintenance therapies in MF are lacking. We developed a unique protocol to use chlormethine/mechlorethamine 0.016% gel formulation as maintenance regimen for MF patients in remission. PurposeTo determine progression-free survival and efficacy of chlormethine/mechlorethamine as maintenance and active treatment regimens for MF. Materials and MethodsA retrospective review of MF patients seen at Thomas Jefferson University from 2012 to 2020 was conducted. Patients of all stages treated with chlormethine/mechlorethamine as maintenance or active treatment with 2 consecutive mSWATs (modified Severity Weighted Assessment Tool) documented were included. Treatment outcomes were assessed by change in mSWAT and progression-free survival. Dermatology Life Quality Index surveys before and after treatment were analyzed. ResultsOf 186 MF patients, 44 met inclusion criteria. Patients on maintenance therapy had a 65.22% progression-free survival rate with median time to progression of 29.45 months. By-time analysis for responders on active and maintenance treatment showed an increased response over time. Peak responses were seen at last mSWAT recorded. Both cohorts experienced improved quality-of-life scores from initiation to discontinuation of chlormethine/mechlorethamine. ConclusionPatients on maintenance and active chlormethine/mechlorethamine treatment regimens demonstrated improvement in mSWAT and quality-of-life. Chlormethine/mechlorethamine treatment showed progression-free survival for a median of 29.45 months, indicating this therapy may be an effective maintenance regimen.

Comparison of the Efficacy and Safety of Bexarotene and Photo(Chemo)Therapy Combination Therapy and Bexarotene Monotherapy for Cutaneous T-Cell Lymphoma.

IntroductionCutaneous T-cell lymphoma (CTCL) is a chronic condition with low malignancy. The combined use of therapeutic agents and photo(chemo)therapy is widely applied for the treatment of CTCL. The efficacy and safety of bexarotene and photo(chemo)therapy combination therapy were previously confirmed in Japanese patients with CTCL. The efficacy and safety of the bexarotene and photo(chemo)therapy combination therapy was compared with bexarotene monotherapy in Japanese patients with CTCL.MethodsThis was a randomized, open-label, two-parallel-group, active-control specified clinical study in Japanese patients diagnosed with CTCL carried out over 8 weeks with a study extension conducted at two institutions. This study was registered in Japan Registry of Clinical Trials (jRCTs041180094).ResultsIn the combination therapy group, 22 subjects received oral bexarotene (300 mg/m2 body surface area) once daily, followed by bath-psoralen and ultraviolet (UV) A or narrowband UVB. In the monotherapy group, 24 subjects received oral bexarotene (300 mg/m2) once daily. The efficacy analysis using the modified Severity-Weighted Assessment Tool, which included 39 patients, showed a response rate of 81.0% (17/21) in the combination therapy group and 83.3% (15/18) in the monotherapy group. No statistically significant difference was detected between groups. In the combination therapy group, four subjects showed a complete clinical response or complete response, and subjects with a partial response exhibited a high rate of skin lesion resolution, significantly better than in the monotherapy group. In the safety analysis, which included 46 treated subjects (22 in the combination therapy group and 24 in the monotherapy group), no adverse events or adverse drug reactions were reported in either group.ConclusionBoth bexarotene and photo(chemo)therapy combination therapy and bexarotene monotherapy were therapeutically effective in Japanese patients with CTCL and well tolerated. Combination therapy led to a higher skin lesion resolution rate and greater therapeutic effects compared with monotherapy.Trial RegistrationjRCTs041180094.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00655-0.

Experience with IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Frontline Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Experience with IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Frontline Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Determining the immune environment of cutaneous T-cell lymphoma lesions through the assessment of lesional blood drops

Detailed analysis of the cells that infiltrate lesional skin cannot be performed in skin biopsy specimens using immunohistochemistry or cell separation techniques because enzyme treatments applied during the isolation step can destroy small amounts of protein and minor cell populations in the biopsy specimen. Here, we describe a method for isolating T cells from drops of whole blood obtained from lesions during skin biopsy in patients with cutaneous T-cell lymphoma. Lesional blood is assumed to contain lesional resident cells, cells from capillary vessels, and blood overflowing from capillary vessels into the lesion area. The lesional blood showed substantial increases in distinct cell populations, chemokines, and the expression of various genes. The proportion of CD8+CD45RO+ T cells in the lesional blood negatively correlated with the modified severity-weighted assessment tool scores. CD4+CD45RO+ T cells in the lesional blood expressed genes associated with the development of cancer and progression of cutaneous T-cell lymphoma. In addition, CD8+CD45RO+ T cells in lesional blood had unique T-cell receptor repertoires in lesions of each stage. Assessment of lesional blood drops might provide new insight into the pathogenesis of mycosis fungoides and facilitate evaluation of the treatment efficacy for mycosis fungoides as well as other skin inflammatory diseases.