Advanced Mycosis Fungoides Research Articles

Genetic alterations of class I HLA in cutaneous T-cell lymphoma

Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCL). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). Targeted DNA sequencing including coverage of HLA loci revealed at least one HLA abnormality in 26/65 patients (40%). Twelve unique somatic HLA mutations were identified across nine patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with decreased total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presentation of greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient receiving pembrolizumab, where resistance to pembrolizumab was associated with elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.

A-189 Treatment trends in advanced Mycosis fungoides and Sézary syndrome: an update from the PROCLIPI study

A-189 Treatment trends in advanced Mycosis fungoides and Sézary syndrome: an update from the PROCLIPI study

A-299 Long-term management of advanced mycosis fungoides: Challenges in routine clinical practice

A-299 Long-term management of advanced mycosis fungoides: Challenges in routine clinical practice

The skin microbiome stratifies patients with cutaneous T cell lymphoma and determines event-free survival

Mycosis fungoides (MF) is the most common entity of Cutaneous T cell lymphomas (CTCL) and is characterized by the presence of clonal malignant T cells in the skin. The role of the skin microbiome for MF development and progression are currently poorly understood. Using shotgun metagenomic profiling, real-time qPCR, and T cell receptor sequencing, we compared lesional and nonlesional skin of 20 MF patients with early and advanced MF. Additionally, we isolated Staphylococcus aureus and other bacteria from MF skin for functional profiling and to study the S. aureus virulence factor spa. We identified a subgroup of MF patients with substantial dysbiosis on MF lesions and concomitant outgrowth of S. aureus on plaque-staged lesions, while the other MF patients had a balanced microbiome on lesional skin. Dysbiosis and S. aureus outgrowth were accompanied by ectopic levels of cutaneous antimicrobial peptides (AMPs), including adaptation of the plaque-derived S. aureus strain. Furthermore, the plaque-derived S. aureus strain showed a reduced susceptibility towards antibiotics and an upregulation of the virulence factor spa, which may activate the NF-κB pathway. Remarkably, patients with dysbiosis on MF lesions had a restricted T cell receptor repertoire and significantly lower event-free survival. Our study highlights the potential for microbiome-modulating treatments targeting S. aureus to prevent MF progression.

Posttransplantation course after allogeneic stem cell transplantation in a patient with advanced mycosis fungoides—Balancing relapse and rejection

Posttransplantation course after allogeneic stem cell transplantation in a patient with advanced mycosis fungoides—Balancing relapse and rejection

Approach to Mycosis Fungoides in children: Consensus-based recommendations

Pediatric Mycosis fungoides (MF) management extrapolates from adult guidelines, despite differing clinical aspects. Recommendations are essential to address unique challenges in this distinct patient group. This project aims to derive consensus recommendations for pediatric MF management. Experts from pediatric dermatology, general dermatology, dermatopathology, and pediatric hematology-oncology (N=83) were invited to contribute to consensus recommendations. The process involved 3 electronic Delphi rounds, concluding with a final consensus meeting using a modified Nominal Group Technique for unresolved items. Consensus included more clinical severity measures than tumor-node-metastasis-blood staging: pruritus, functional or esthetic impairment (eg, palms, soles, genitalia), quality of life impact, and psychological aspects (eg,embarrassment, anxiety, depression), plus parental anxiety. Ten recommendations were made for managing early and advanced pediatric MF. Disagreement emerged in choosing therapies beyond stage I of the disease. This multinational initiative aimed to standardize optimal pediatric MF management and successfully generated consensus recommendations. Additional work is needed for structured, prospective protocols in advanced-stage pediatric MF. Lack of pediatric hematologists-oncologists and patients' representatives. Documentation of extended clinical severity and outcome measures is recommended. Addressing the need for structured protocols in advanced-stage pediatric MF and implementing systematic, prospective data collection is crucial.

Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

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.

Possible effects of plasminogen activator inhibitor-1 on promoting angiogenesis through matrix metalloproteinase 9 in advanced mycosis fungoides.

Mycosis fungoides (MF) progresses slowly before advancing to skin tumors followed by lymph node and visceral involvement. Among MF progression, stage IIB is an initial time point of tumor formation in MF. Since MF in tumor stage possess abundant blood vessels, it is important to evaluate the pro-angiogenic factors before and after MF in stage IIB. In this report, we investigated pro-angiogenic soluble factors in MF patients, as well as its pro-angiogenetic effects on tumor cells and stroma cells. We first evaluated the serum levels of pro-angiogenic factors in 9 MF patients without tumor formation and 8 MF patients with tumor formation. Among them, the serum MMP-9 and plasminogen activator inhibitors 1 (PAI-1) was significantly increased in MF with tumor formation compared in MF without tumor formation, leading to favorable formation of human dermal microvascular endothelial cells tube networks. Moreover, PAI-1 stimulation significantly increased the mRNA expression and protein production MMP-9 on monocytes derived M2 macrophages and HUT-78. Furthermore, since MMP-9 production from tumor cells as well as stromal cells is suppressed by bexarotene, we evaluate the baseline serum pro-angiogenic factors including MMP-9 in 16 patients with advanced cutaneous T cell lymphoma treated with bexarotene. The serum levels of MMP-2 and MMP-9 was significantly increased in bexarotene non-responded patients compared to responded patients. Our present study suggested the significance of MMP-9 and PAI-1 for the progression of MF stage toward to the tumor stage, and could be a therapeutic target in future.

P-191 - Allogeneic hematopoietic stem cell transplantation in patients with advanced mycosis fungoides and Sézary syndrome: 2023 update of the Milan experience

P-191 - Allogeneic hematopoietic stem cell transplantation in patients with advanced mycosis fungoides and Sézary syndrome: 2023 update of the Milan experience

Cost-utility analysis of mogamulizumab in advanced mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma.

Aim: This study assessed the cost-utility of mogamulizumab, a novel monoclonal antibody, versus established clinical management (ECM) in UK patients in previously treated advanced mycosis fungoides (MF)/Sézary syndrome (SS). Materials & methods: Lifetime partitioned survival model based on overall survival, next treatment-free survival and the use of allogeneic stem cell transplant was developed. Inputs were from the pivotal MAVORIC trial, real-world evidenceand published literature. Extensive sensitivity analyses were conducted. Results: Discounted incremental quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio were 3.08, £86,998and £28,233. Results were most sensitive to the survival extrapolations, utilitiesand costs after loss of disease control. Conclusion: Mogamulizumab is a cost-effective alternative to ECM in UK patients with previously treated advanced MF/SS.

Role of Neutrophil-to-Lymphocyte Ratio (NLR) in Patients with Mycosis Fungoides.

The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment.

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.

Violaceous Lesions on the Leg: What Else Apart from Kaposi Sarcoma? Differential Diagnosis with a Narrative Review of the Literature

With this work, we aimed to review the principal benign and malignant tumors (including vascular, keratinocytic/epidermal, melanocytic, hematopoietic, and lymphoid origin), primarily affecting the leg’s skin. The lesions’ location can also help focus on a spectrum of differential diagnoses in clinical practice. All the diseases present the same clinical presentation characterized by erythematous to violaceous nodules. Despite the same clinical presentation, each disease’s prognostic outcome and therapeutic management can be somewhat different. Since clinical diagnosis may sometimes be challenging, histology and immunohistochemistry play a fundamental role in recognizing and staging these types of lesions. Molecular studies can help to determine the exact nature of lesions with no specific characteristics. Kaposi’s sarcoma is an angioproliferative neoplasm that typically occurs in the lower limbs and can enter into differential diagnosis with several other rarer skin diseases. The principal differential diagnosis concerns primary cutaneous lymphomas, of which mycosis fungoides represent the most frequent primary cutaneous T-cell lymphoma. Other rare forms include primary cutaneous B-cell lymphomas, which can be divided into indolent and aggressive forms, such as the primary cutaneous diffuse large B-cell lymphoma, leg type, and lymphomatoid papulomatosis (LyP). In the case of indolent lesions, skin-directed therapies, limited-field radiotherapy, and surgical approaches can be good options. At the same time, different management, with systemic chemotherapy and allogenic bone marrow transplant, is required with aggressive neoplasms, such as blastic plasmacytoid dendritic cell neoplasia or advanced mycosis fungoides. The dermatologist’s role can be crucial in recognizing such diseases and avoiding misdiagnosis, giving the pathologist the correct clinical information for an accurate diagnosis, and starting the suitable therapy.

A Case of Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Findings of Mycosis Fungoides with Large Cell Transformation Involving Cutaneous Lesions, and Metastasis to Lymph Node and Viscera

Large cell transformation (LCT) of mycosis fungoides (MF) is a histopathological transformation of neoplastic small lymphocytes with a clonally identical large cell phenotype, which is found in 20%–50% of cases of advanced MF. Some few cases and studies have been reported about the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18FFDG PET/CT) in diagnosing MF-LCT. This is a case of a 55-year-old man who had a left neck mass for 4–5 months. He underwent excisional biopsies on the skin and soft tissue. The histopathologic report showed MF-LCT. The 18F-FDG PET/CT findings revealed hypermetabolic lesions in the skin, cervical lymph node, and visceral organ. We introduce a rare case of MF-LCT involving both cutaneous and extracutaneous lesions.

Dysregulation of Plasma miR-146a and miR-155 Expression Profile in Mycosis Fungoides Is Associated with rs2910164 and rs767649 Polymorphisms.

Diagnosis of Mycosis Fungoides (MF) may be challenging, due to its polymorphic nature. The use of miRNAs as biomarkers to assist in diagnosis has been investigated, mainly in skin lesion biopsies. The purpose of this study is to evaluate the plasma levels of miR-146a and miR-155 in MF patients and to investigate their association with SNPs of their genes. Plasma miRNAs were quantified by RT-qPCR. Genomic DNA was used for SNPs' genotyping by Sanger sequencing. Plasma levels of miR-146a and miR-155 were significantly higher in patients vs. controls, in early MF patients vs. controls, and in advanced vs. early MF patients. Both miRNAs' levels were significantly higher in stage IIB vs. early-stage patients. miR-155 plasma levels were significantly higher in patients with skin tumors or erythroderma. CC genotype (rs2910164 C&gt;G) was significantly more frequent in healthy controls and associated with lower MF risk and lower miR-146a levels. The AA genotype (rs767649 T&gt;A) was significantly more frequent in patients and correlated with increased MF risk and increased miR-155 levels. The combination of GG+AA was only detected in patients and was correlated with higher MF susceptibility. Increased mir-146a and mir-155 plasma levels in MF is an important finding to establish putative noninvasive biomarkers. The presence of SNPs is closely associated with miRs' expression, and possibly with disease susceptibility.

Integrating novel agents into the treatment of advanced mycosis fungoides and Sézary syndrome

AbstractAgents targeting the unique biology of mycosis fungoides and Sézary syndrome are quickly being incorporated into clinical management. With these new therapies, we are now capable of inducing more durable responses and even complete remissions in advanced disease, outcomes which were exceedingly rare with prior therapies. Yet, even this new generation of therapies typically produce objective responses in only a minority of patients. As our therapeutic options increase, we are now challenged with selecting treatments from a growing list of options. To gain the full benefit of these novel agents, we must develop strategies to match treatments for the patients most likely to benefit from them. Here, we consider both the current approaches to treatment selection based on clinical features and the future of molecular biomarker-guided therapy for patients with this heterogeneous disease.

Ther-O-01 - Lacutamab in patients with advanced mycosis fungoides according to KIR3DL2 expression: stage 1 results from the TELLOMAK phase 2 trial

Ther-O-01 - Lacutamab in patients with advanced mycosis fungoides according to KIR3DL2 expression: stage 1 results from the TELLOMAK phase 2 trial

Adjusting for treatment crossover in the MAVORIC trial: survival in advanced mycosis fungoides and Sézary syndrome.

Background: Relative overall survival (OS) estimates reported in the MAVORIC trial are potentially confounded by a high proportion of patients randomized to vorinostat switching to mogamulizumab; furthermore, vorinostat is not used in clinical practice in the UK. Methods: Three methods were considered for crossover adjustment. Survival post-crossover adjustment was compared with data from the Hospital Episode Statistics (HES) to contextualize estimates. Results: Following adjustment, the OS hazard ratio for mogamulizumab versus vorinostat was 0.42 (95% CI: 0.18, 0.98) using the method considered most appropriate based on an assessment of assumptions and comparison with HES. Conclusions: OS of mogamulizumab relative to vorinostat may be underestimated in MAVORIC due to the presence of crossover. The HES database was used to validate this adjustment.

Impact of Mogamulizumab in Real-Life Advanced Cutaneous T-Cell Lymphomas: A Multicentric Retrospective Cohort Study.

Simple SummaryMogamulizumab is a recent monoclonal antibody prescribed in the second line to treat advanced mycosis fungoides and Sézary syndromes. We collected data from all patients who used mogamulizumab in six French university hospitals until 1 September 2021. Our primary objective was to determine the median progression free survival (PFS). Secondary objectives were to consider tolerance regarding side effect occurrence and severity. Twenty-one patients were included, with a median time of follow-up of 11.6 months, and progression-free survival was estimated at 22 months. Twenty patients presented adverse events, of which 10 were severe. The median time between the introduction of mogamulizumab and the first adverse event was 21 days. Our study suggests that mogamulizumab is a significant treatment option to extend PFS in patients with advanced refractory cutaneous T-cell lymphomas (CTCL). The long-term safety of mogamulizumab was determined to be acceptable since we reported few grade III–IV adverse events (AEs) compared to other systemic treatments.Background: Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are rare, aggressive cutaneous T-cell lymphomas that may be difficult to treat. Mogamulizumab is a recent monoclonal antibody targeting the CCR4 receptor expressed on the surface of Sézary cells. It can be prescribed in MF/SS stages III to IV in the second line after systemic therapy or in stages IB-II after two unsuccessful systemic therapies. We lack data on long-term efficiency and potential side effects in real-life conditions. Our study aims to determine efficacy considering the median PFS of advanced CTCL with mogamulizumab. Secondary objectives were to consider tolerance and estimate delay until side effects appeared. Methods: Data on patients with advanced cutaneous T-cell lymphomas were collected since French Authorization, in six French university hospitals. Patients were followed until they stopped mogamulizumab because of relapse or toxicity. For those still treated by mogamulizumab, the end point was 1 September 2021. We excluded 3 patients as they had already been included in the MAVORIC study and data was not available. Results: The median time of follow-up was 11.6 months. Of the 21 patients included, we reported four full-response patients, eight in partial response, one in stability, three in progression, and five were deceased. One patient had visceral progression, and seven had new lymphadenopathy. Progression-free survival was estimated at 22 months. Twenty patients presented adverse events, of which 10 were severe, i.e., grade III-IV. The median time between the introduction of mogamulizumab and the first adverse event was 21 days. Conclusions: Our study suggests that mogamulizumab can give patients with advanced refractory CTCL a consequent PFS, estimated at 22 months. The long-term safety of mogamulizumab was determined to be acceptable since we reported few grade III–IV AEs, comparable with other studies. No other study using real-life data has been performed to investigate the AEs of mogamulizumab.