Long-term data on the proposed adalimumab biosimilar BCD-057 in patients with moderate to severe psoriasis: A randomized controlled trial.

INTRODUCTION: The objective of this study was to demonstrate that BCD-057 is similar to innovator adalimumab (iADA) in terms of efficacy, safety, and pharmacokinetics in steady state in the target population of patients with moderate to severe plaque psoriasis (NCT02762955). METHODS: Patients were randomized in 1:1 ratio to receive 80 mg of BCD-057 or iADA at week 0 and 40 mg thereafter every other week from week 1. At week 24 patients from iADA group were re-randomized (1:1) to continue iADA or to be switched to BCD-057. The primary efficacy endpoint was 75% improvement in Psoriasis Area and Severity Index from baseline (PASI 75), secondary endpoints included PASI percent improvement and relative change in affected Body Surface Area (BSA) from baseline at weeks 16, 24, 33, and 55. Safety was assessed through monitoring of adverse events (AEs) and antidrug antibodies. Pharmacokinetics was evaluated at steady state. RESULTS: Overall, 346 adult patients were included in the study (174/172 patients in BCD-057/iADA arms, respectively). At week 16 PASI 75 was achieved by 60.34% and 63.37% of patients in BCD-057 and iADA arms, respectively (p = 0.5622). Bounds of the calculated 95% confidence interval (CI) for the difference between PASI 75 responses in arms [-13.26%; 7.2%] fall within the equivalence margin [-15% to 15%] demonstrating equivalent efficacy of BCD-057 and iADA. At week 55 81.61%, 85.56%, and 80.49% of patients in BCD-057, iADA and iADA/BCD-057 arms achieved PASI 75. Comparison of the secondary endpoints did not show significant differences between arms. A comparable pharmacokinetics was shown at steady state. Safety profiles and proportions of patients with antidrug antibodies were similar between arms. The switch from the iADA to BCD-057 did not affect the immunogenicity profile. CONCLUSION: Obtained data demonstrate that BCD-057 and iADA are highly similar in clinical efficacy, pharmacokinetics, safety, and immunogenicity in patients with moderate to severe plaque psoriasis.

Efficacy and Safety of Netakimab, A Novel Anti-IL-17 Monoclonal Antibody, in Patients with Moderate to Severe Plaque Psoriasis. Results of A 54-Week Randomized Double-Blind Placebo-Controlled PLANETA Clinical Trial.

INTRODUCTION: Netakimab (NTK), an original humanized anti-interleukin-17 monoclonal antibody, showed therapeutic efficacy in moderate-to-severe plaque psoriasis in a phase 2 clinical study. Herein we report the results of 54 weeks of a phase 3 PLANETA trial aimed to evaluate the efficacy and safety of two NTK regimens vs. placebo. METHODS: Two hundred thirteen patients with moderate-to-severe plaque psoriasis were randomly assigned to receive NTK 120 mg once every 2 weeks (NTK Q2W), NTK 120 mg once every 4 weeks (NTK Q4W) or placebo. During the first 3 weeks, patients received subcutaneous injections of NTK or placebo (according to the allocation) once a week. Patients in the NTK Q2W group then received NTK at weeks 4, 6, 8 and 10. Subjects in the NTK Q4W group received NTK at weeks 6 and 10 and placebo at weeks 4 and 8. Patients in the placebo group received placebo injections at weeks 4, 6, 8 and 10. Treatment was unblinded at week 12. During the open-label phase, patients in both NTK groups continued to receive NTK Q4W. The primary efficacy endpoint was the proportion of patients in each group who achieved a ≥ 75% reduction from baseline in psoriasis area and severity index (PASI 75) at week 12. RESULTS: A total of 77.7%, 83.3% and 0% of patients had a PASI 75 response at week 12 in the NTK Q2W, NTK Q4W and placebo groups, respectively (P < 0.0001, Fisher's exact test, ITT). The effect was maintained throughout the 1-year treatment. NTK showed a good safety profile and low immunogenicity. CONCLUSION: Treatment with NTK results in high rates of sustained clinical response in patients with moderate-to-severe plaque psoriasis. The study is ongoing; thus, long-term use efficacy and safety data are forthcoming. CLINICAL TRIAL REGISTRATION: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT03390101).

A Case of Lymphomatoid Papulosis Type E With an Unusual Exacerbated Clinical Course.

Lymphomatoid papulosis (LyP) type E is a recently delineated variant characterized by the occurrence of large necrotic "eschar"-like lesions displaying microscopically angioinvasive and angiodestructive infiltrates composed of CD30 lymphocytes, frequently coexpressing CD8. In contrast to other LyP variants where patients develop multiple lesions, most patients with LyP type E present with few lesions (often 1 or 2 at a given time). In this article, we describe a 34-year-old man with LyP type E with an exacerbated clinical course characterized by the occurrence of almost a hundred of lesions. Initially, he presented with a single rapidly growing 2-cm large erythematous nodule on the forearm but after the administration of doxycycline multiple eschar-like lesions developed all over the body. Atypical lymphoid infiltrates with marked angiocentricity and angiotropism of CD30 medium-sized to large pleomorphic lymphocytes were seen histopathologically. After the withdrawal of the antibiotic, the lesions spontaneously regressed. Awareness of this rare LyP variant and its correct recognition, even if the clinical course is unusual and worrisome, is important to avoid aggressive treatment.

Responses to romidepsin in patients with cutaneous T-cell lymphoma and prior treatment with systemic chemotherapy.

Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin lymphomas that typically present in the skin but can progress to systemic involvement. The optimal treatment for patients who relapse from or are refractory to systemic chemotherapy remains unclear. Romidepsin is a potent, class-I selective histone deacetylase inhibitor approved for the treatment of patients with CTCL who have had ≥1 prior systemic therapy. Here, we present a subanalysis of two phase-2 trials (NCT00106431, NCT00007345) of romidepsin in patients with CTCL who had prior treatment with systemic chemotherapy. Patients with prior chemotherapy were able to achieve durable responses to romidepsin, and response rates were similar to those in patients who were chemotherapy naïve. Overall, no new safety signals emerged in patients who had received prior chemotherapy. The data presented here suggest that romidepsin is safe and effective in patients with CTCL who received prior systemic chemotherapy.

The role of intradermal proliferation of T-cells in the pathogenesis of psoriasis.

BACKGROUND:: Psoriasis is a common immune-mediated chronic inflammatory disease of the skin and joints, affecting 1-3% of the population. It is generally accepted that the pathogenesis of psoriasis involves accumulation of effector T-cells within lymph nodes and their subsequent migration into the skin through the blood system. Here we provide evidence that psoriatic plaque itself may serve as a source of inflammatory T-cells. OBJECTIVE:: We examined the intradermal proliferation of T-cells and the number of effector/memory (CD45RO+) T-cells in the skin of psoriatic patients at different periods of the disease. METHODS:: Skin samples were obtained from 41 patients with progressive psoriatic lesions; 18 of these patients also donated skin specimens during the remission of the disease. The control group consisted of 16 healthy subjects. Ki-67 immunohistochemical staining was applied to detect proliferating cells, CD3ε served as a T-cell marker, and CD45RA and CD45RO antibodies were utilized to discriminate between naive and effector/memory T-cells, respectively. RESULTS:: Progressive psoriatic lesions demonstrated Ki67 staining both in keratinocytes and in the CD3ε+ cells of dermal infiltrate. Median count of CD45RO+ cells per microscopic field was 15 in healthy controls, 59 in patients in remission and 208 in progressive psoriatic plaques. The observed differences demonstrated high level of statistical significance. STUDY LIMITATIONS:: Limited number of analyzed patients. CONCLUSION:: Progressive phase of psoriasis is characterized by intradermal proliferation of T-cells. Spots of regressed psoriatic lesions contain high number of CD45RO+ cells, which are likely to render an immunological memory.

The role of intradermal proliferation of T-cells in the pathogenesis of psoriasis

Abstract: BACKGROUND: Psoriasis is a common immune-mediated chronic inflammatory disease of the skin and joints, affecting 1-3% of the population. It is generally accepted that the pathogenesis of psoriasis involves accumulation of effector T-cells within lymph nodes and their subsequent migration into the skin through the blood system. Here we provide evidence that psoriatic plaque itself may serve as a source of inflammatory T-cells. OBJECTIVE: We examined the intradermal proliferation of T-cells and the number of effector/memory (CD45RO+) T-cells in the skin of psoriatic patients at different periods of the disease. METHODS: Skin samples were obtained from 41 patients with progressive psoriatic lesions; 18 of these patients also donated skin specimens during the remission of the disease. The control group consisted of 16 healthy subjects. Ki-67 immunohistochemical staining was applied to detect proliferating cells, CD3ε served as a T-cell marker, and CD45RA and CD45RO antibodies were utilized to discriminate between naive and effector/memory T-cells, respectively. RESULTS: Progressive psoriatic lesions demonstrated Ki67 staining both in keratinocytes and in the CD3ε+ cells of dermal infiltrate. Median count of CD45RO+ cells per microscopic field was 15 in healthy controls, 59 in patients in remission and 208 in progressive psoriatic plaques. The observed differences demonstrated high level of statistical significance. STUDY LIMITATIONS: Limited number of analyzed patients. CONCLUSION: Progressive phase of psoriasis is characterized by intradermal proliferation of T-cells. Spots of regressed psoriatic lesions contain high number of CD45RO+ cells, which are likely to render an immunological memory.

A Rare Case of Solitary Hemorrhagic Mycosis Fungoides With Angiocentric Features.

Unilesional (solitary) mycosis fungoides (MF) is a rare variant characterized clinically by the presence of a single contiguous area of skin involvement covering less than 5% of the body surface and histopathologically by features identical to those seen in classical MF. Angiocentricity (angiodestruction) is mostly a feature of primary or secondary cutaneous lymphomas with an aggressive course and poor outcome, with only very few reports of MF with angiocentric pattern. The authors report an unusual case of solitary patch-stage MF with hemorrhagic features, characterized histologically by epidermotropic and angiocentric (angiodestructive) infiltrate and a reactive B-cell component appearing as lymphoid follicles.

Clinically significant responses achieved with romidepsin across disease compartments in patients with cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas that arises in the skin but can progress to systemic disease (lymph nodes, blood, viscera). Historically, in clinical trials of CTCL there has been little consistency in how responses were defined in each disease "compartment"; some studies only assessed responses in the skin. The histone deacetylase inhibitor romidepsin is approved by the US Food and Drug Administration for the treatment of CTCL in patients who have received at least one prior systemic therapy. Phase II studies that led to approval used rigorous composite end points that incorporated disease assessments in all compartments. The objective of this analysis was to thoroughly examine the activity of romidepsin within each disease compartment in patients with CTCL. Romidepsin was shown to have clinical activity across disease compartments and is suitable for use in patients with CTCL having skin involvement only, erythroderma, lymphadenopathy and/or blood involvement.

Clinically meaningful reduction in pruritus in patients with cutaneous T-cell lymphoma treated with romidepsin.

Patients with cutaneous T-cell lymphoma (CTCL) frequently experience severe pruritus that can significantly impact their quality of life. Romidepsin is approved by the US Food and Drug Administration (FDA) for the treatment of patients with CTCL who have received at least one prior systemic therapy, with a reported objective response rate of 34%. In a phase 2 study of romidepsin in patients with CTCL (GPI-04-0001), clinically meaningful reduction in pruritus (CMRP) was evaluated as an indicator of clinical benefit by using a patient-assessed visual analog scale. To determine the effect of romidepsin alone, confounding pruritus treatments including steroids and antihistamines were prohibited. At baseline, 76% of patients reported moderate-to-severe pruritus; 43% of these patients experienced CMRP, including 11 who did not achieve an objective response. Median time to CMRP was 1.8 months, and median duration of CMRP was 5.6 months. Study results suggest that the clinical benefit of romidepsin may extend beyond objective responses.

Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma.

PURPOSE: The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells). RESULTS: Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients. CONCLUSION: Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

Unusual clinicopathological presentation of primary cutaneous diffuse large B-cell lymphoma, leg type, with multiple nodules and widespread garland-like lesions.

We present a case of primary cutaneous diffuse large B-cell lymphoma, leg type, with an unusual clinical picture. A 41-year-old man presented with a 2-year history of slowly progressive plaques, nodules, and garland-like patches on his chest, right upper arm, and back. Complete staging investigations revealed no extracutaneous involvement. Histological examination of a nodule revealed a diffuse nonepidermotropic infiltrate mainly composed of large blast cells with features of immunoblasts and centroblasts and spindle cells seen at the periphery of the infiltrate. Histological examination of a garland-like lesion showed perivascular infiltrates composed predominantly of small lymphocytes admixed with only occasional large blasts. The blasts from the nodule and garland-like lesions and spindle cells identified in the nodule exhibited an identical phenotype: they stained positively for CD20, CD79a, and bcl-2 and tested negative for bcl-6, CD5, CD10, and TdT. CD35 revealed no networks of follicular dendritic cells. Widespread garland-like lesions are not a typical feature of primary cutaneous diffuse large B-cell lymphoma.

A patient with clinicopathologic features of small plaque parapsoriasis presenting later with plaque-stage mycosis fungoides: report of a case and comparative retrospective study of 27 cases of "nonprogressive" small plaque parapsoriasis.

BACKGROUND: It is unsettled whether small plaque parapsoriasis (SPP) represents an inflammatory dermatosis or has a potential to transform into mycosis fungoides (MF) or is, in fact, MF. The literature contains no fully documented example of progression of SPP into MF. OBJECTIVE: The purpose of our study was to present a patient with clinical features of SPP who later developed plaque-stage MF, as seen both clinically and pathologically and to compare the clinicopathologic features of this unique case with 27 "nonprogressive" SPP cases. METHODS: This study is a prospective and retrospective evaluation of 28 patients, using light microscopy, immunohistochemistry, and molecular biology. RESULTS: A 56-year-old man with a 3-year history of persistent SPP with typical small (<5 cm), elongated and "digitate" lesions presented with newly developed larger patches and plaques. Whereas histologic examination of the patch lesion revealed relatively nonspecific features, a specimen of the crusted plaque showed a dense lymphoid infiltrate composed of small cerebriform lymphocytes, medium-sized lymphoid cells, and occasional large hyperchromatic cells that infiltrated the basal layer of the epidermis and formed small collections. There were atypical mitotic figures. Immunohistochemically, an aberrant immunophenotype with the loss of CD5 expression was found in the plaque specimen. T-cell receptor (TCR)-gamma gene rearrangement studies detected clones in the plaque and in the peripheral blood (biallelic in blood), while the patch tested polyclonal. The 27 SPP patients included 23 men and 4 women, ranging in age from 29 to 75 years. They were followed up and treated for 1.2 to 52 years (mean 10); no patient's SPP progressed into MF. All patients presented with small patch lesions measuring 3 to 6 cm lengthwise and 0.5 to 2 cm in width. Histologic features were nonspecific. Molecular genetic studies revealed the following results: two cases tested polyclonal, 3 cases demonstrated the oligoclonal pattern, whereas the remaining 13 specimens showed a pattern which can be interpreted as oligoclonal or pseudomonoclonal. LIMITATIONS: Oligoclonal and monoclonal patterns were overrepresented in the SPP group, which may be due to the low amount and, probably, suboptimal quality of DNA used in the TCR-gamma rearrangement studies. CONCLUSIONS: Occasionally patients with the clinical and pathologic presentation of SPP may develop typical features for MF. This event seems to be extremely rare; at present there appears to be no means to predict such a course. The vast majority of SPP patients will never have disease progression to MF.

Primary cutaneous plasmacytoma: a clinicopathological study of two cases with a long-term follow-up and review of the literature.

BACKGROUND: Primary cutaneous plasmacytoma (PCP) is a rare type of cutaneous B-cell lymphoma arising primarily in the skin and derived from clonally expanded plasma cells with a various degrees of maturation and atypia. The disease is rare with only 30 cases reported so far. METHODS: Two cases of PCP with long-term follow-up of 17 and 15 years are presented. RESULTS AND CONCLUSIONS: Both patients were men with nodular lesions on the face. Histologically, the lesions were composed predominantly of variably maturated plasma cells with monotypic expression of immunoglobulin (Ig) lambda chains. Polymerase chain reaction for IgH genes did not reveal clonal rearrangement. Our cases are discussed in the context of previously reported cases of PCP with a long-term follow-up. We also include a review of all cases of PCP with known tumor progression earlier in the course of the disease (local relapse or visceral spread) to determine the clinical course of this primary cutaneous lymphoma.