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

PURPOSE: The aim of this study was to assess the safety and efficacy of an ultrahypofractionated low-dose total skin electron beam therapy (TSEBT) regimen in patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). METHODS AND MATERIALS: In this multicenter observational study from 5 German centers, 18 total patients with MF or SS underwent TSEBT with a total dose of 8 Gy in 2 fractions. The primary endpoint was the overall response rate. RESULTS: Fifteen of 18 patients with stage IIB-IV MF or SS were heavily pretreated with a median of 4 prior systemic therapies. The overall response rate was 88.9% (95% confidence interval [CI], 65.3-98.6), with 3 complete responses (16.9%; 95% CI, 3.6-41.4). At a median follow-up period of 13 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). A significant reduction in the modified severity-weighted assessment tool, total Skindex-29 score (Bonferroni-corrected P < .005), and all subdomains (Bonferroni-corrected P < .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. CONCLUSIONS: TSEBT with 8 Gy in 2 fractions achieves good disease control and symptom palliation with acceptable toxicity, greater convenience, and fewer hospital visits.

Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics.

Background: Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma. Objective: To compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS. Methods: We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq). Results: We scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as CCR7, IL7R and CD27. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including GZMB and NKG7. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of TXNIP, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells. Conclusions: Using scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin.

Outcome of extracorporeal photopheresis in mycosis fungoides patients is not predicted by quotients of systemic immune-inflammatory biomarkers.

BACKGROUND: Systemic immune-inflammatory biomarkers (SIIBs) have not been studied in mycosis fungoides (MF) patients undergoing extracorporeal photopheresis (ECP). OBJECTIVE: The objective was to determine whether recently proposed SIIBs are suitable to predict ECP treatment outcome and overall prognosis of patients with MF. METHODS: Twenty-nine MF patients were retrospectively evaluated who had undergone ECP. SIIBs included neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, and pan-immune-inflammation value. RESULTS: Lymphocyte count (P = .021), CD4+/CD8+ cells (P = .00006), CD4+/CD56+ NK cells (P = .00008), and LDH levels (P = .0041) significantly declined after 6-month ECP. We could not detect significant cutoff values for baseline SIIBs capable of predicting advanced disease, overall response to 6-month ECP, or 5-year lymphoma-specific (LS) survival (P > .05). Circulating baseline counts of CD4+/CD7- cells (cutoff: ≤ 12.2; P = .010) and CD4+/CD26- cells (cutoff: ≤ 19.5; P < .0001) significantly predicted ECP treatment response after 6 months. Moreover, CD4+/CD8+ ratio (cutoff: > 1.34; P = .045) and increased thrombocyte counts (cutoff: >259 000; P = .010) were baseline predictors for 5-year LS death. CONCLUSION: ECP appears to be beneficial in early-stage CTCL as well. Lower percentages of circulating CD4+/CD7- and CD4+/CD26- lymphocytes at baseline correlate with response to ECP. In this study, however, baseline SIIBs did not appear to serve as suitable biomarkers for the prediction of treatment outcome and LS survival.

Impact of extracorporeal photopheresis on blood and coagulation parameters.

Extracorporeal photopheresis (ECP) is considered a safe treatment modality. We aimed to assess blood parameters including coagulation during ECP over time. We performed a long-term retrospective single-center chart review (laboratory parameters) of adult patients (n = 172) who had received ECP for any indication. We observed a significant decrease (p < 0.05) in erythrocytes, hemoglobin, and leukocytes compared to baseline levels after only one ECP procedure. This decrease persisted after 3-, 6-, 9-, and 12-months of ECP. A significant pathological decline of hemoglobin was observed in a higher proportion (26.4% and 25.2%, respectively) of patients after 6 (p = 0.0007) and 12 (p = 0.012) months of ECP. Mean corpuscular volume as well as hematocrit was significantly decreased at 3-, 6-, 9-, and 12-months of evaluation compared to baseline (p < 0.05). After 9 and 12 months of ECP we observed a further decline in lymphocyte counts (p < 0.05). Various coagulation parameters did not change significantly during ECP treatment. Even though not all alterations observed in peripheral blood of ECP patients in the present study were of clinical significance, risk for developing persistent anemia must be considered in patients undergoing ECP.

Low-dose total skin electron beam therapy plus oral bexarotene maintenance therapy for cutaneous T-cell lymphoma.

BACKGROUND: Total skin electron beam therapy (TSEBT) combined with systemic therapy or maintenance treatment is a reasonable approach to enhance the remission rate and duration in mycosis fungoides (MF) and Sézary syndrome (SS). This study assesses the efficacy of oral bexarotene therapy after low-dose TSEBT for patients with MF and SS. METHODS: In this prospective observational study, we recruited MF/SS patients for treatment with low-dose total skin electron beam therapy (TSEBT) with or without bexarotene therapy to describe outcomes and toxicities. RESULTS: Forty-six subjects with MF or SS underwent TSEBT between 2016 and 2021 at our institute. Following TSEBT, 27 patients (59 %) received oral bexarotene treatment. The median follow-up was 13 months. The overall response rate (ORR) for the cohort was 85 %. The response rate was significantly higher with combined modality (CM) than TSEBT alone (96 % vs. 68 %, p = 0.03). Median progression-free survival (PFS) for the CM was 17 months versus five months following TSEBT alone (p = 0.001). One patient (4 %) in the retinoid group discontinued the bexarotene therapy because of adverse events. The administration of bexarotene therapy did not increase radiation-related toxicities. CONCLUSIONS: Response rate and progression-free survival might be improved with TSEBT in combination with oral bexarotene compared to TSEBT alone.

Clinical Outcomes of Advanced-Stage Cutaneous Lymphoma under Low-Dose Gemcitabine Treatment: Real-Life Data from the German Cutaneous Lymphoma Network.

BACKGROUND: Gemcitabine is an effective single-agent chemotherapy used in advanced stages of cutaneous T-cell lymphoma (CTCL). However, gemcitabine used in the current standard regimen is frequently associated with adverse events (AE), such as an increased risk for myelosuppression and severe infections. OBJECTIVES: We investigated in this retrospective study the effect of low-dose gemcitabine in pretreated advanced-stage CTCL and in blastic plasmacytoid dendritic cell neoplasia (BPDCN) regarding overall response (OR), progression-free survival (PFS), and AE. MATERIAL AND METHODS: A retrospective, multicenter study was conducted on 64 CTCL and BPDCN patients treated with gemcitabine in average absolute dosage of 1,800 mg/m2 per cycle, which is 50% lower compared to standard dosage of 3,600 mg/m2 per cycle (1,200 mg/m2 day 1, 8, 15). Evaluation of response to therapy and AE was done 4-6 weeks after the sixth cycle. RESULTS: OR was 62% with 11% demonstrating a complete response. The median time of PFS was 12 months and median time to next treatment was 7 months. Only 3/63 patients showed serious side effects, e.g., port infection or acute renal failure. Almost 73% of the patients experienced minor to moderate side effects (CTCAE grade 0-2). Fatigue (27.2%), fever (22.7%), and mild blood count alteration (18.2%) were the most common AE. CONCLUSIONS: This retrospective analysis supports the use of low-dose gemcitabine therapy in CTCL, demonstrating with 62% OR and PFS of 12 months an almost identical response rate and survival as compared to the standard dose therapy reported in previous studies but with a significantly improved safety profile and tolerability.

Impact of Extracorporeal Photopheresis on Blood Parameters of Atopic Dermatitis Patients.

BACKGROUND: Extracorporeal photopheresis (ECP) is a safe treatment modality with immunomodulatory effects. The latter may also explain efficacy of ECP in patients with atopic dermatitis (AD). OBJECTIVE: We aimed to assess various blood parameters of AD patients who underwent ECP over a maximum 1-year treatment period. METHODS: We performed a retrospective single-center chart review (clinical data, laboratory data) of adult patients with AD who had received for at least 3 ECP cycles, in part combined with other treatment modalities. RESULTS: We studied 60 patients with AD (85% extrinsic type, 15% intrinsic type) who had median number of 14 (4-23) ECP cycles within a maximum 1-year treatment. When compared with baseline, leukocytes and lymphocytes remained significantly decreased after 3-, 6-, 9-, and 12-month ECP ( P = 0.014 and P = 0.0012, respectively). A significant decline of eosinophils, as well as eosinophilic cationic protein levels, was observed after 3-, 6-, 9-, and 12-month ECPs ( P = 0.011 and P = 0.0017, respectively). Total serum immunoglobulin E (IgE), as well as lactate dehydrogenase, were significantly decreased at 3-, 6-, 9-, and 12-month evaluation compared with baseline ( P < 0.00001 and P = 0.00007, respectively). Patients with slight or marked improvement of AD after their ECP treatment period had significantly higher median baseline serum IgE levels than patients who did not respond to ECP ( P = 0.0023). CONCLUSIONS: Several laboratory parameters, including eosinophils, eosinophilic cationic protein, total serum IgE, and lactate dehydrogenase, which declined under ECP, are well-known disease biomarkers for AD patients. With normalization of the abovementioned laboratory parameters, a clinical response to ECP treatment was observed in almost two thirds of patients, confirming that ECP may be an effective combination treatment modality for AD.

Combination of brentuximab-vedotin with skin-directed therapies extends the time to the next therapeutic line in patients with cutaneous T-cell lymphoma.

BACKGROUND AND OBJECTIVES: Brentuximab vedotin (BV) is a potent therapeutic option for CD30-positive cutaneous T-cell lymphoma. Unlike existing studies, BV and other therapeutic procedures were frequently combined for our patients. In this context, the study aims to analyze the effectiveness and safety of BV in a real-world setting. PATIENTS AND METHODS: This is a retrospective monocentric study analyzing treatment outcomes for patients with CD30-positive cutaneous T-cell lymphoma treated with BV. RESULTS: 26 patients (median age: 67 years) were included in the study. Patients were treated with 1.8 or 1.2 mg/kg b.w. Complete remission (CR) was reached in 30.8 % of the patients, and the objective response rate (ORR) was 84.6 %. Side effects were seen in 19 of the 26 patients. As a reaction to progressive disease (PD) under BV monotherapy, we included skin-directed procedures such as tumor excision, local radiotherapy, and PUVA for six patients. We re-stabilized the disease and maintained the line of therapy without additional toxicities for a median of seven months longer using this concept. CONCLUSIONS: Addition of skin-directed therapies (SDT) after disease progression under BV monotherapy could stabilize the disease's continuous advancement or even lead to partial response, thereby extending the time until the next therapeutic escalation.

How do we treat cutaneous T-cell lymphoma?

Cutaneous T-cell lymphomas are a heterogeneous group of non-Hodgkin lymphomas which are based on the malignant proliferation of skin-related T lymphocytes. The clinical appearance, as well as the course and the associated therapeutic approach, are sometimes very different between the different subtypes. Since allogeneic stem cell transplantation is currently the only curative option, and the morbidity and mortality are not insignificant, a therapy concept should be developed that considers its often rather indolent but chronic course. This concept should enable a good disease control with as few side effects as possible and preserve or improve the quality of life. In the early stages of the disease, skin-oriented therapies are generally used first before systemic and increasingly aggressive therapeutic agents are used as the disease progresses. Considering the current guidelines, literature and subjective experience, we summarize in this review how we treat cutaneous T-cell lymphomas.