Transformed Mycosis Fungoides Research Articles

Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma

AbstractPatients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate’s performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Transformed mycosis fungoides in an atypical location

Mycosis fungoides is the most common variant of primary cutaneous T-cell lymphoma. Large cell transformation in mycosis fungoides is the histopathological transformation of neoplastic small lymphocytes to a clonally identical large cell phenotype. It is associated with a poor prognosis, although some patients have indolent disease. Clinically, it is manifested by ulcerated, tumoral lesions that may affect the entire body. The location in the external auditory canal has never been described before. Herein, we report the first case of transformed mycosis fungoides located in the external auditory canal. Key words: External auditory canal; Large cell transformation; Mycosis fungoides

Differential molecular programs of cutaneous anaplastic large cell lymphoma and CD30-positive transformed mycosis fungoides.

Discriminating between cutaneous anaplastic large cell lymphoma (cALCL) and CD30-positive transformed mycosis fungoides (CD30+ TMF) is challenging, particularly when they arise in the context of pre-existing mycosis fungoides. The development of molecular diagnostic tools was hampered by the rarity of both diseases and the limited understanding of their pathogenesis. In this study, we established a cohort comprising 25 cALCL cases and 25 CD30+ TMF cases, with transcriptomic data obtained from 31 samples. We compared the clinicopathological information and investigated the gene expression profiling between these two entities. Furthermore, we developed an immunohistochemistry (IHC) algorithm to differentiate these two entities clinically. Our investigation revealed distinct clinicopathological features and unique gene expression programs associated with cALCL and CD30+ TMF. cALCL and CD30+ TMF displayed marked differences in gene expression patterns. Notably, CD30+ TMF demonstrated enrichment of T cell receptor signaling pathways and an exhausted T cell phenotype, accompanied by infiltration of B cells, dendritic cells, and neurons. In contrast, cALCL cells expressed high levels of HLA class II genes, polarized towards a Th17 phenotype, and exhibited neutrophil infiltration. An IHC algorithm with BATF3 and TCF7 staining emerged as potential diagnostic markers for identifying these two entities. Our findings provide valuable insights into the differential molecular signatures associated with cALCL and CD30+ TMF, which contribute to their distinct clinicopathological behaviors. An appropriate IHC algorithm could be used as a potential diagnostic tool.

Spatially Resolved Transcriptomes of CD30+-Transformed Mycosis Fungoides and Cutaneous Anaplastic Large-Cell Lymphoma

Mycosis fungoides with large-cell transformation (MF-LCT) occurs in a minor proportion of aggressive lesions, which express CD30 similar to primary cutaneous anaplastic large-cell lymphoma (pcALCL). We investigated the differences in spatially resolved transcriptome profiles of MF-LCT and pcALCL using CD30 morphology markers and 28 and 24 regions of interest (ROIs) in MF-LCT and pcALCL, respectively. Differentially expressed genes, pathway analysis, and immune-cell deconvolution by selective analysis of CD30-positive tumor cells and CD30-negative extratumoral areas were undertaken. In CD30-positive ROIs of MF-LCT, 190 differentially expressed genes were upregulated (29 were directly or indirectly associated with extracellular matrix remodeling), whereas 255 differentially expressed genes were downregulated, compared with those of pcALCL. Except for cornified envelope formation and keratinization, all six pathways enriched in CD30-positive ROIs of MF-LCT were associated with extracellular matrix remodeling. In CD30-positive ROIs in MF-LCT compared with those in pcALCL, immune-cell deconvolution revealed significantly increased fibroblasts and M2 macrophages (P= 0.012 and P= 0.023, respectively) but decreased M1 macrophages (P= 0.031). In CD30-negative ROIs in MF-LCT compared with those in pcALCL, memory B (P= 0.021), plasma (P= 0.023), and CD8 memory T (P= 0.001) cells significantly decreased, whereas regulatory T cells (P= 0.024) increased. Predomination of extracellular matrix remodeling pathways and immunosuppressive microenvironment in MF-LCT indicates pathophysiological differences between MF-LCT and pcALCL.

Reduced Skin T-Cell Receptor Diversity in Large Cell Transformed Mycosis Fungoides

Reduced Skin T-Cell Receptor Diversity in Large Cell Transformed Mycosis Fungoides

Reduced Overall T-Cell Receptor Diversity As an Indicator of Aggressive Cutaneous T-Cell Lymphoma

Introduction: Mycosis fungoides (MF) is a T-cell lymphoma that originates in the skin and can progress in late stages to involve blood, lymph nodes, or viscera. Large cell transformed mycosis fungoides (LCT-MF) is an aggressive subtype of MF associated with a higher likelihood of malignancy progression and mortality. Given that T-cell receptor (TCR) diversity is an indicator of cancer prognosis and outcome in several malignancies, we sought to investigate changes in T-cell repertoire diversity in LCT-MF. We interrogated the repertoire in non-leukemic MF, including both early-stage (patch and plaque, IA-IIA) and skin limited late-stage MF (tumor and erythroderma, IIB-IIIA). Methods: After approval by Thomas Jefferson University Institutional Review Board Committee, a review of clinical data was performed on patients with MF at the Jefferson Cutaneous Lymphoma Clinic. Patients included in the study had a confirmed diagnosis of MF based on clinical, histological, and molecular data as well as adequate specimens for analysis. We evaluated staging and disease progression by 2022 NCCN guidelines. We included 61 lesional skin samples and 43 serum samples from 32 MF patients and 23 aged-matched healthy subjects. We used high-throughput sequencing (HTS) assays to interrogate the TCRb complementarity determining region 3 (CDR3) sequences in blood and skin of enrolled patients as well as blood of healthy subjects 13 (Adaptive Biotechnologies). ImmunoSEQ Analyzer provided T-cell diversity metrics, Simpson's clonality score and maximum frequency, as well as Vb usage. Results: We first compared blood T-cell repertoire diversity among age-matched healthy subjects and MF patients without blood involvement. The diversities of the T-cell repertoire in blood of both non-leukemic MF and non-leukemic LCT-MF patients were significantly lower, compared to their age-matched healthy subjects. However, the diversity scores did not differ between the MF and LCT-MF cohorts in blood (Figure 1). In contrast, LCT-MF skin specimens possessed significantly lower T-cell clonal diversity (Figure 2) and distinct Vb usage in comparison to MF. There was no difference in T-cell diversity between early-stage and late-stage MF cohorts. Conclusion: Overall, our data demonstrate that LCT-MF T-cells in the skin, not blood, exhibit a less diverse clonal repertoire when compared to MF. We find that the transformation of malignant cells in the skin does not accompany changes in blood repertoire. Instead, the transformation events in the skin mirror a reduction of overall T-cell diversity in the skin of patients with LCT-MF, compared to their non-transformed counterparts. While skin T-cell repertoire diversity distinguishes transformed and non-transformed MF, the skin diversity metrics do not differ between early- and late-stage disease. This finding implies that the shift in skin T-cell diversity seen in LCT-MF is not related to stage. Rather, we posit that shifts in T-cell diversity may be influenced by the early transformation event itself. Figure 1: Simpson's clonality scores of blood T-cell repertoire in healthy subjects, MF, and LCT-MF. Statistically significant differences between cohort groups are marked by asterisks (** = p<0.001, *** = p <0.0001). Figure 2: Simpson's clonality scores of skin T-cell repertoire in MF and LCT-MF. Statistically significant differences between cohort groups are marked by asterisks (*** = p <0.0001). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

086 Decreased clonal diversity within the skin T-cell repertoire, but not blood, distinguishes large cell transformed mycosis fungoides from its non-transformed counterpart

Mycosis fungoides (MF) is a T-cell lymphoma that originates in the skin and can progress in late stages to involve blood, lymph nodes, or viscera. An aggressive subtype of MF is large cell transformed mycosis fungoides (LCT-MF), defined by the presence of large cells comprising greater than 25% of the lesion infiltrate. LCT-MF is associated with a higher likelihood of disease progression and mortality. LCT-MF is solely defined by the size of the T-cells in the infiltrate; however, the clonal attributes of the T-cells within the infiltrate in large cell transformation (LCT) are not known.

CD30+ Transformed Mycosis Fungoides Associated with Sweet-like Dermatosis.

Abstract is missing (Short communication)

Alliance A059102: A randomized phase II U.S. intergroup study of CHO(E)P versus CC-486-CHO(E)P versus duvelisib-CHO(E)P in previously untreated, CD30-negative, peripheral T-cell lymphomas.

TPS7593 Background: While PTCL is treated for curative intent, 5-year (yr) overall survival (OS) remains 20-25% with CHOP based therapy. For pts &lt;60 yrs old, the addition of etoposide to CHOP has been associated with improved outcomes. Brentuximab vedotin in combination with chemotherapy demonstrated an OS benefit in PTCL with CD30 &gt;10% by immunohistochemistry, and most significantly improved outcomes in anaplastic large cell lymphoma. This served as proof of principle that biomarker driven therapy can lead to improved outcomes in this rare disease (Horwitz et al Lancet 2019). Duvelisib is a gamma delta PI3 kinase inhibitor with a 50% overall response rate in PTCL and a trend toward a higher response rate in PTCL with a T-follicular helper (TFH) phenotype (Brammer et al. Blood 2021). Azacitidine is a hypomethylating agent that has shown a 75% overall response rate (ORR) in PTCL with TFH phenotype. CC-486, oral azacitidine, has been safely combined with CHOP and showed a 75% ORR with a higher ORR in PTCL with TFH phenotype (Ruan et al. Blood 2021). Methods: A051902 is a 3 arm randomized phase II US intergroup study in previously untreated PTCL with CD30 expression &lt;10% comparing standard chemotherapy (CHOP or CHOEP) to CHOP/CHOEP with duvelisib 25mg PO BID or CHOP/CHOEP with azacitidine 300mg PO. Pts will be stratified by age (&gt;60, ≤60) and TFH phenotype. Pts over age 60 will receive CHOP and those ≤60 will receive CHOEP. Prior to the randomized study, there is a safety lead-in study for the first 12 pts combining duvelisib 15mg BID with CHOP/CHOEP. The primary endpoint of the phase II study is complete remission (CR) rate by the Lugano 2014 criteria. The phase II study is powered for a 25% improvement in CR rate (45% vs 70%) in an experimental arm compared to CHOP/CHOEP with a 90% power and type I error rate of 10%. The phase II will enroll 159 pts (53 per arm). Key eligibility: 1. untreated PTCL (nodal T-cell lymphoma with TFH phenotype, follicular T-cell lymphoma, PTCL-NOS, angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma) with CD30 expression &lt;10%, 2. Stage I-IV, PS 0-2. Pts with transformed mycosis fungoides or anaplastic large cell lymphoma are excluded. Standard CHOP and CHOEP are administered every 21 days with growth factor support. Azacitadine 300mg will be taken on days -6 to -1 prior to cycle 1 and then on days 8 to 21 for cycles 1-5. Duvelisib 25mg BID will be taken continuously. Correlative studies include evaluation of TFH phenotype (by immunohistochemistry, gene expression profiling and DNA sequencing) and cell free DNA evaluation to predict outcomes as well as patient reported outcomes. The study was activated 7/30/2021 and the safety lead-in portion is currently enrolling. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04803201.

Identification of a Distinct miRNA Regulatory Network in the Tumor Microenvironment of Transformed Mycosis Fungoides.

Simple SummaryTransformed mycosis fungoides (LCT-MF) is a histopathological marker of poor prognosis and associated with worse survival. We compared miRNA and mRNA expression profiles of LCT-MF with classic MF and found a distinct miRNA regulatory network modulated immunosuppressive tumor microenvironment in LCT-MF. Our findings provide novel insights and therapeutic targets for LCT-MF.Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20–50% of advanced MF and is generally associated with poor response and dismal prognosis. Although different mechanisms have been proposed to explain the pathogenesis, little is known about the role of microRNAs (miRs) in transcriptional regulation of LCT-MF. Here, we investigated the miR and mRNA expression profile in lesional skin samples of patients with LCT-MF and non-LCT MF using RNA-seq analysis. We found miR-146a and miR-21 to be significantly upregulated, and miR-708 the most significantly downregulated miR in LCT-MF. Integration of miR and mRNA expression profiles revealed the miR-regulated networks in LCT-MF. Ingenuity pathway analysis (IPA) demonstrated the involvement of genes for ICOS-ICOSL, PD1-PDL1, NF-κB, E2F transcription, and molecular mechanisms of cancer signaling pathways. Quantitative real time (qRT)-PCR results of target genes were consistent with the RNA-seq data. We further identified the immunosuppressive tumor microenvironment (TME) in LCT-MF. Moreover, our data indicated that miR-146a, -21 and -708 are associated with the immunosuppressive TME in LCT-MF. Collectively, our results suggest that the key LCT-MF associated miRs and their regulated networks may provide insights into its pathogenesis and identify promising targets for novel therapeutic strategies.

Transformed Mycosis Fungoides: Clinical and Pathologic Characteristics in a Single Center Retrospective Analysis

IntroductionLarge cell transformation (LCT) in mycosis fungoides is defined as 25% large cells and is traditionally associated with a poor prognosis and a median survival of 3-5 years. There is no consensus on the appropriate management for these patients. We aimed to characterize clinical and pathologic features of patients with transformed mycosis fungoides (tMF) at our institution and to describe treatment patterns and patient outcomes.MethodsWe performed a retrospective review of 63 patients with a histopathologic diagnosis of tMF seen at the Winship Cancer Institute of Emory University from 1990-2021. Clinical data collected from the electronic medical record included demographics, baseline laboratory values, disease characteristics, pathologic characteristics, and therapy. Kaplan-Meier curves for OS and PFS were generated for the whole cohort. Descriptive analysis was performed for covariates. The association of baseline variables with OS was modeled by Cox proportional hazards model.ResultsAmong 63 patients with tMF, there was even distribution among male (54%) and female (46%) patients (Figure 1A). The median age at the time of large cell transformation (LCT) was 63 years (range, 20-87). This population included 46% African American (AA), 50.8% White, 1.6% other races (n=1). At the time of diagnosis, the stage was 1A-1B in 23 (36.5%), 2A in 11 (17.5%), 2B in 20 (31.7%), 3A-3B in 3 (4.8%), 4A in 5 (7.9%) and 4B in 1. The ECOG performance status (PS) was 0-1 in 49 (77.8%), 2 in 7 patients (11.1%), 3 in 3 patients, and 4 in one patient. Most patients had patches and plaques at diagnosis, 23 (36.5%) had tumors, and 9 (14.3%) had ulceration. Only 2 patients had hypopigmented MF. The most common therapies prior to LCT were topical steroids (n=34), phototherapy (n=25), topical nitrogen mustard (n=20), oral retinoids (n=14), and oral methotrexate (n=8). Radiation (RT) was received in 22 patients prior to transformation with 16 having localized RT and 9 total skin electron beam therapy (TSEB).The median time from diagnosis to LCT was 2.1 years (range, 0-32 years). Most patients had advanced stage at the time of LCT (n=45, 86%), with stage 2B the most frequent 23 (36.5%). Other stages at LCT were 1A in 1 patient, 2A in 6, 3A-B in 6, 4A in 14 and 4B in 11. Overall, 47 (74.6%) patients experienced progression in their TNMB stage following LCT. LCT occurred in the skin in 51 patients (81%), lymph nodes in 21 (33.3%), and viscera in 5 (7.9%). The percentage of large cells was >50% in 24 patients (38.1%), and < 50% in 13 (20.6%). CD30 percentage was missing in the majority of patients (n=37, 58.7%). T-cell rearrangement in blood, skin, and lymph nodes was not consistently characterized with data missing in nearly half the patients (n=30, 47.6%). In those with TCR checked in at least one location, it was non-clonal in 19, had clonal persistence in 6 (9.5%), clonality in at least one sample but either not rechecked, or not persistent in 6 (9.5%), and oligoclonal in 2 (n=3.2). The most common treated for LCT was total skin electron beam therapy (TSEB, n=16) and chemotherapy (n=14), followed by brentuximab vedotin and localized RT in 9 patients each. Other treatments included topical corticosteroids (N=2), histone deacetylase inhibitors (n=4), and mogamulizumab (n=4). The median overall survival was 2.3 years from LCT (95% CI 1.1-3.5 years), and the median PFS was 2.6 years (95% CI, 1.1-4.1 years) (Figure 1B) . The median time to treatment following LCT was 30 days (range, -1 day to 2.3 years). By cox regression, neither baseline demographic factors, tumor characteristics, treatment, nor time to LCT were associated with progression-free or overall survival. Only response to treatment for LCT (complete response, partial response, or stable disease) was associated with survival (p=0.041, Figure 1C).ConclusionsWe characterized the clinical features and outcomes of a cohort of patients with tMF seen at Emory University over a 30 year period. We found poor outcomes despite many patients receiving novel and targeted therapies in the modern era. Key pathologic and clinical variables such as CD30 percentage and t-cell gene rearrangement studies were not reported for many patients, suggesting standardized practices are needed in the diagnosis and pathologic evaluation of patients with tMF. Additional pathologic correlatives will be updated at the time of the presentation. [Display omitted] DisclosuresAllen: ADC Therapeutics: Consultancy; Kyowa Kirin: Consultancy; Secure Bio: Consultancy.

ICOS Is Widely Expressed in Cutaneous T-Cell Lymphoma and Its Targeting Promotes Potent Killing of Malignant Cells

Background: Advanced cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE), do not deliver significant long-term improvements in patient outcomes. More recently, mogamulizumab and anti-KIR3DL2 provided encouraging results but new targeted therapies are needed. Inducible Co-Stimulator (ICOS), a T-cell costimulatory receptor involved in the development of CTCLs, arouses interest.Methods: We used immunohistochemistry to study ICOS expression in skin biopsies of 23 patients with early-stage mycosis fungoides (MF), 12 with transformed MF (TMF) and 17 with Sézary Syndrome (SS), at diagnosis or in relapse. Skin samples from 12 patients with B-cell lymphomas, 14 with CD30 + lymphoproliferative disease (LPD), 12 with primary cutaneous CD4+ small/medium T-cell lympho-proliferative disorder and 13 with angioimmunoblastic T-cell lymphoma (AITL) were used as controls. ICOS expression by circulating Sézary cells and regulatory T cells (Tregs) in patients with SS was evaluated using flow cytometry and compared to healthy donors (HD) lymphocytes. In 5 patients with SS, we also analyzed concomitant biopsies from involved nodes.Then, we investigated the efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS 314.8 monoclonal antibodies with MMAE and pyrrolobenzodiazepine (PBD), in comparison to BV. We used ICOS + CTCL cell lines (MyLa, MJ and HUT78), murine xenograft models with MyLa and ICOS + Patient Derived Xenografts (PDXs) from patients with SS and AITL.In order to identify the best anti-ICOS clone that we should develop for a clinical trial, we evaluated the affinity of the antibody on the receptor, the internalization capacity of the antibody using pHAb Reactive Dyes kit (Promega®), and the ability of the antibody to act as an ADC using a secondary conjugate (Mab-ZAP kit, Advanced Targeting Systems®).Results: ICOS was highly expressed by the cutaneous atypical lymphocytic infiltrates in respectively 61%, 75% and 88% of patients with early-stage MF, TMF and SS, such as in all the involved nodes. Double staining experiments which were performed in both skin and lymph node revealed that ICOS expression appears mainly restricted to neoplastic CD4 + T-cells, with rare ICOS +CD8 + T-cells in the tumor micro-environment. ICOS expression by circulating Sézary cells was strong: 69 ± 7.3% versus 38.8 ± 7.1% of non-tumoral CD4 + cells (p<0.009; CI95%: 8.7-51.6); and 31 ± 3.2% of CD4+ cells in HD (p<0.0001; CI95%: 20.3-46.3). Percentages of ICOS + Tregs were significantly higher in patients with SS than in HD.In CTCL cell lines, we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS-MMAE (IC50 = 8.2ng/mL) and anti-ICOS-PBD (IC50 = 1.2ng/mL) ADCs. In a mouse xenograft model (MyLa), anti-ICOS-MMAE ADCs provided a longer overall survival (OS) than BV (HR=15.2; CI95%: 3.2-71.1; p<0.0006). Finally, in ICOS + PDXs, anti-ICOS-MMAE ADCs significantly improved OS, and reduced the number of tumor cells in the blood, spleen, and bone marrow. No evidence of ADC toxicity was observed in treated mice.Among 8 different anti-ICOS clones, clone 314.8 had the best affinity on MyLa and MJ cell lines. Clones 53.3, 293.1, 92.17, 88.2 and 279.1 also had good affinity to receptor, whereas clones 145.1 and 121.4 had poor affinity. Using the internalization pHAb reactive dyes kit, we found that clones 314.8, 53.3, 92.17, 88.2 internalized significantly better and faster than the other ones. In order to verify if there is a correlation between internalization capacity and ADC effect, clones 53.3, 92.17 and 145.1 were coupled to MMAE. While anti-ICOS-53.3 and anti-ICOS-92.17 ADCs had similar efficacy to anti-ICOS-314.8 ADCs on MyLa, anti-ICOS 145.1 ADCs resulted in significantly lower cell death. Finally, all clones showed good ability to act as ADCs with Mab-ZAP, excluding clones 279.1, 145.1 and 121.4.Discussion: ICOS is a promising therapeutic target because it is expressed both by tumor T-cells and regulatory T-cells. We report for the first time the strong and frequent expression of ICOS in CTCLs, as well as the preclinical efficacy of anti-ICOS ADCs on CTCL cell line and PDXs. These results could be extended to the spectrum of follicular variant peripheral T-cell lymphomas.Conclusion: Collectively, our findings provide the preliminary basis for a therapeutic trial [Display omitted] DisclosuresLopez: Emergence Therapeutics: Current holder of individual stocks in a privately-held company. Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees. Olive: ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees.

A Meta-Analysis of Pivotal Pralatrexate Studies in Relapsed/Refractory Mature T-Cell Lymphoma (r/r TCL)

A Meta-Analysis of Pivotal Pralatrexate Studies in Relapsed/Refractory Mature T-Cell Lymphoma (r/r TCL)

Bio-O1-02 - Deciphering discrepancies in cutaneous lymphomas genetics

In several instances, our group has reported opposite findings to others when analyzing the genetic features of primary cutaneous T-cell or B-cell lymphomas (CTCL or CBCL). This was especially the case for the absence of NAV3 rearrangements in CTCL, the low rate of BCL2 or MYC rearrangement in primary cutaneous follicle center lymphomas (CFCL) or primary cutaneous large B-cell lymphomas, leg-type (CLBCL, LT), respectively. Here, we review bias accounting for such discrepancies. Primary cutaneous lymphoma usually present with characteristic clinical and pathological features which serve as universal criteria for initial diagnosis and treatment. When required, extensive staging including CT scan, blood analysis and for some groups bone marrow staging, is mandatory to eliminate a secondary CTCL or CBCL. Early spreading may change the initial diagnosis and a long-term follow-up is also necessary to determine the risk for extracutaneous involvement. Non-uniform inclusion criteria and follow-up time may contribute to discrepancies, especially for studies claiming for a high rate of BCL2 rearrangement in CBCL. Most CBCL or CTCL usually display an indolent course except for aggressive subtypes arising de novo such as Sézary syndrome (SS), tumor or transformed mycosis fungoides (T-MF) or CLBCL-LT. Borderline cases between indolent and aggressive cutaneous lymphomas exist and may be called for example as leukemic CTCL or CBCL, not-otherwise specified (NOS) leading to heterogeneous terminology between centers. Moreover, aggressive CL are rare occurring mainly in adults or elderly that limits therapeutic options and comparison of small groups in retrospective series. The distribution of diagnosis between the three main primary CBCL including marginal-zone lymphoma (MZL), CFCL and CLBCL, LT has considerably evolved and its heterogeneity between centers may also hamper uniform findings. Our proposal to classify large CBCL according to germinal center or non-germinal center origin has so far not been validated by others while in systemic lymphomas genomic profiling appears mandatory to identify patients with impaired prognosis. In the most frequent cutaneous lymphomas, no highly recurrent genetic mutation is commonly used for diagnosis purpose. Some genetic lesion such as CCND1 rearrangement in mantle cell lymphoma can serve a positive criteria of secondary skin involvement. Alternatively, exceptional primary anaplastic large cell lymphoma (ALCL) bear ALK rearrangement preventing to use such criteria as a hallmark of secondary skin ALCL. BCL2 rearrangement in primary CFCL contributes to identify patients at risk for extracutaneous spreading. Most reports found negative data for NAV3 rearrangement in CTCL that may not be a primary oncogenic driver but a secondary event. Interestingly, MYC rearrangement or double-hits may have a low impact on prognosis in CBCL while they are usually associated with impaired prognosis in systemic or nodal lymphomas. Alternatively, some highly recurrent mutation such as those of MYD88 in CLBCL, LT should be routinely assessed. While clinical presentation will remain a basis for CL diagnosis and treatment, it is now time to integrate molecular profiling in research studies or clinical trials to standardize diagnosis and to identify patients which will exhibit therapeutic resistance to conventional first-line treatment.

Epi-P-04 - Cutaneous T-cell lymphoma (CTCL) exacerbation after viral vector COVID-19 vaccination

Introduction:We are living an ongoing global COVID-19 pandemic associated with a considerable number of fatal cases worldwide. Cancer patients seem to exhibit exacerbated conditions and higher mortality rates. Vaccines are a promising solution to minimize the problem amongst cancer patients but there are limitations to be considered.Case summary:Herein, we present two cutaneous T-cell lymphoma (CTCL) cases which were in long-term remission and experienced a flare after immunization with a viral vector COVID-19 vaccine (Vaxzevria, Oxford/AstraZeneca). The first case was a 60-year-old male with early-stage (T1a) folliculotropic mycosis fungoides (MF) clinically presented as alopecia areata-like lesions. The patient was in clinical remission during the last two years, maintaining a T1aN0M0 stage with only a single, stable alopecic patch on the scalp. Four weeks after the first COVID-19 vaccine dose, a minor lichenoid induration was observed in the periphery of the lesion, while a week after the second dose, small nodules surrounding the lesion were also noted. Histology confirmed the diagnosis of CD30+ Large cell transformation (LCT) of tumor-stage MF. The second case was a 73-year-old female with early-stage MF (T1a/IA) and Lymphomatoid papulosis (LyP). Clinically, she presented with pruritic erythematous patches and nodules on the trunk and upper legs. The patient was successfully treated with psoralen plus ultraviolet A (PUVA) phototherapy remaining in clinical remission for six years. After vaccination, she developed multiple erythematous papules and nodules on the trunk and limbs. A flare of LyP was confirmed from the pathology, which correlated to her clinical picture.Discussion:These cases raise the question of whether and via which pathways the vaccine might induce disease exacerbation of both MF and LyP. According to the literature, the education of T (CD4+ and CD8+) and B cells against SARS-CoV-2 spike protein appears to be the main strategy for COVID-19 vaccine production. Both cancers and viral infections can provide a chronic and persistent antigenic load, leading to up-regulated programmed cell death protein 1 (PD1) expression and ultimately T cell exhaustion. CD30 is known to be expressed in a small subset of activated T and B cells, as well as a variety of lymphoid neoplasms. Initial studies showed that CD30 expression on lymphocytes could be induced via in vitro antigenic stimulation by mitogens or viruses. CD30 expression also appears to be higher on CD4+ and CD8+ T cells producing a Th2-type cytokine profile. In our cases, the viral vector-based vaccines used do not contain a live virus but specific parts of the coronavirus attached to adenovirus, which can also stimulate an anti-viral immune response.Conclusion:The reported cases suggest that disease flare-ups may be associated with overproduction and exhaustion of CD4+/CD8+ T cells expressing CD30 after stimulation by the adenovirus. Expression of CD30, which can be a marker for disease progression, was high in biopsy samples of our patients.

Disease characteristics, prognosis, and response to therapy in patients with large-cell transformed mycosis fungoides: A single-center retrospective study

Mycosis fungoides with large-cell transformation (MF-LCT) is associated with an aggressive clinical course, yet data comparing treatment outcomes in MF-LCT are sparse. To compare treatment outcomes and to determine disease prevalence and characteristics associated with survival in MF-LCT. A retrospective review was conducted of mycosis fungoides patients from 2012 to 2020 treated at Thomas Jefferson University. Patients with histopathologic diagnosis of MF-LCT were included. Treatment outcomes were assessed by mean changes in the modified Severity Weighted Assessment Tool (mSWAT) and stage. Of 171 patients with mycosis fungoides, 23 (13.4%) had histologic diagnosis of MF-LCT. The overall 5-year survival rate for MF-LCT was 74% and was not significantly associated with sex, age, or initial stage at the time of MF-LCT diagnosis. Brentuximab vedotin showed the greatest mean decrease in mSWAT (-20.53) and stage progression (change in Δ stage: -0.4) in MF-LCT compared to oral bexarotene (ΔmSWAT: +4.51; Δstage: +0.27), skin-directed therapy (ΔmSWAT: -5.93; Δstage: -0.08), and chemotherapy (ΔmSWAT: +4.97; Δstage: +0.85). Single-center retrospective design, and patients often on multiple treatment modalities. We report superior treatment outcomes for brentuximab vedotin compared to oral bexarotene, skin-directed therapy, and chemotherapy in MF-LCT in both early and advanced disease.

Prognostic Significance of CD30 in Transformed Mycosis Fungoides

Several studies suggested that CD30 expression is a favorable prognostic marker in transformed mycosis fungoides (tMF). However, evidence in this field is still unclear. This systematic review and meta-analysis aimed to evaluate the prognostic significance of CD30 in tMF. Electronic databases were searched from their inception to June 2020 for all studies assessing the prognostic value of CD30 in tMF. Pooled hazard ratio (HR) for death was calculated; a P value less than .05 was considered significant. Inconsistency index (I2) was used to assess statistical heterogeneity among studies. Seven studies with 323 patients were included. CD30 expression in tMF was significantly associated with a decreased hazard of death both on univariate (HR, 0.459; 95% confidence interval [CI], 0.319-0.660; P < .001) and multivariate analysis (HR, 0.503; 95% CI, 0.345-0.734; P < .001), and the statistical heterogeneity among studies was null in all analyses (I2 = 0%). tMF cases with CD30 expression in large cells have a hazard of death two times lower than CD30-negative cases.

Role of B-cells in Mycosis Fungoides.

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. The inflammatory micro-environment in mycosis fungoides is complex. There is accumulating evidence that the neoplastic T-cells take control of the microenvironment and thereby promote their own expansion by suppressing cellular immunity. B-cells have proved to be upregulated in large-cell transformed mycosis fungoides, and could potentially play a role in disease progression. To investigate the presence of B-cells in mycosis fungoides compared with controls, this study analysed 85 formalin-fixed and paraffin-embedded mycosis fungoides biopsies. MS4A1 gene expression was significantly upregulated in mycosis fungoides compared with controls (p < 0.0001) and further upregulated in disease progression, (p = 0.001). Digital quantification of PAX5+/CD20+ cells confirmed the increased presence of B-cells in mycosis fungoides compared with controls. No co-labelling of CD3/CD20 was observed in the neoplastic T-cells. This study found a significantly increased presence of B-cells in the tumour-associated microenvironment in mycosis fungoides. These findings could potentially lead to new treatment strategies for mycosis fungoides.

Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

AVAIL-T: A Phase 2a Trial of Avelumab, and Anti-PD-L1 Antibody, in Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL)

AVAIL-T: A Phase 2a Trial of Avelumab, and Anti-PD-L1 Antibody, in Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL)