Clinical Characterization of Mogamulizumab-Associated Rash During Treatment of Mycosis Fungoides or Sézary Syndrome.

IMPORTANCE: Mogamulizumab is a monoclonal antibody against CCR4 approved for treatment for mycosis fungoides (MF) and Sézary syndrome (SS). Mogamulizumab-associated rash (MAR) is difficult to differentiate from cutaneous MF or SS, which can lead to unnecessary discontinuation of drug use because of concern for severe drug reaction or incorrect presumption of disease relapse or progression in the skin. OBJECTIVE: To examine the most common clinical presentations of MAR in patients with MF or SS and the diagnostic and management challenges. DESIGN, SETTING, AND PARTICIPANTS: This retrospective case series assessed patients from a multidisciplinary cutaneous lymphoma clinic and supportive oncodermatology clinic at a major academic referral center who had a diagnosis of MF or SS and received mogamulizumab from January 1, 2013, to January 1, 2020. Treatment was followed by new or worsening rash with skin biopsy results compatible with drug eruption determined by clinicopathologic correlation and molecular testing to exclude active malignant disease. EXPOSURES: At least 1 dose of mogamulizumab. MAIN OUTCOMES AND MEASURES: Mogamulizumab-associated rash was characterized by clinical features, including time to onset, clinical presentation, histopathologic features, and management approach. RESULTS: The study included 19 patients with MF or SS who developed MAR (median age, 65 years; age range, 38-82 years; 10 [52.6%] male). Median time to MAR onset was 119 days (range, 56 days to 3.8 years). Patients with MAR exhibited 4 predominant clinical presentations: (1) folliculotropic MF-like scalp plaques with alopecia, (2) papules and/or plaques, (3) photoaccentuated dermatitis, and (4) morbilliform or erythrodermic dermatitis. The most common anatomical region involved was the head and neck, including the scalp. Histopathologic findings were variable and did not correspond to primary clinical morphologic findings. Immunohistochemistry and T-cell clonality ancillary testing were helpful to distinguish MAR from disease. Most patients with MAR (14 of 19) discontinued mogamulizumab treatment; however, no life-threatening severe cutaneous adverse drug reactions occurred, and the decision for drug therapy cessation was usually multifactorial. Four patients were treated again with mogamulizumab with no life-threatening drug-related events. Approaches to management of MAR include topical corticosteroids, systemic corticosteroids, and/or methotrexate. CONCLUSIONS AND RELEVANCE: This case series found that mogamulizumab-associated rash had a heterogeneous clinical presentation with variable and delayed onset in patients with MF or SS. Mogamulizumab-associated rash exhibited a predilection for the head and neck and was difficult to clinically distinguish from relapse or progression of disease. Recognition of the most common clinical presentations can help prevent unnecessary discontinuation of mogamulizumab treatment. The presence of MAR does not necessitate permanent discontinuation of or avoidance of retreatment with mogamulizumab.

Low-Dose Total Skin Electron Beam Therapy Combined With Mogamulizumab for Refractory Mycosis Fungoides and Sézary Syndrome.

PURPOSE: Management of patients with refractory mycosis fungoides and Sézary syndrome (SS) is often challenging, as available therapies lack durable response and consistent activity across disease compartments. Combining low-dose total skin electron beam therapy (LD-TSEBT) upfront with mogamulizumab could optimize the clinical outcome of these patients. LD-TSEBT is effective in clearing skin disease, and mogamulizumab is an antitumor immunotherapy with long-term tolerability, suggesting its potential as a maintenance therapy after maximal response. We examine the combination regimen in patients with SS who were previously treated. METHODS AND MATERIALS: Two patients with SS were treated with combination LD-TSEBT and mogamulizumab. Both patients received mogamulizumab 1 mg/kg weekly × 4 and then bi-weekly; LD-TSEBT (12 Gy) was initiated within 2 days of starting mogamulizumab and given over 2-3 weeks. Safety and clinical response were evaluated. RESULTS: Total skin electron beam therapy plus mogamulizumab (TSE-Moga) was well-tolerated without any unanticipated adverse events. Patient 1 (T4N2bM0B2) was a 63-year-old woman with 4 prior systemic therapies; time to global response with TSE-Moga was 9 weeks. Patient 2 (T4NxM0B2) was a 75-year-old man with 5 prior systemic therapies; time to global response was 4 weeks. Both patients lacked global response to their prior therapies but achieved global complete response (blood and skin) with TSE-Moga. After a follow-up of 72 weeks and 43 weeks, respectively, global complete response continued. CONCLUSIONS: TSE-Moga demonstrated excellent tolerability and promising clinical activity with ongoing global complete responses in 2 patients with refractory SS. This encouraging experience supports our ongoing clinical trial evaluating the efficacy and safety of TSE-Moga in mycosis fungoides and SS.

A Long-Term Study of Persistent Sézary Syndrome: Evidence for Antigen Shift by Multiparameter Flow Cytometry and Its Significance in Overall Survival.

Sézary syndrome (SS) is a peripheral T-cell lymphoma characterized by erythroderma, diffuse lymphadenopathy, and circulating neoplastic T cells, which classically show a helper T-cell immunophenotype with loss of CD7 and CD26. Flow cytometry is often used to identify and enumerate populations of Sézary cells in the peripheral blood; however, the significance and frequency of antigen shift over time is unclear. In this article, we follow the immunophenotype of the neoplastic T-cell population from 28 patients with SS across 415 flow cytometry studies. Antigen shift for each patient was assigned as none, minimal = 1-2 markers by 1°, moderate = up to 3 markers, or marked ≥ 4 markers. Sixty-four percent (18/28) of patients showed antigen shift, and among those with antigen shift, the majority showed minimal (8/18) or moderate antigen shift (7/18) with fewer demonstrating marked shift (3/18). Patients without antigen shift showed a trend toward improved overall survival in comparison with patients demonstrating any degree of antigen shift. Antigen shift is seen in a significant proportion of cases of SS with long-term follow-up and may be a marker of more aggressive disease.

Role of imaging in low-grade cutaneous B-cell lymphoma presenting in the skin.

BACKGROUND: Whole-body imaging is the current standard of care for staging all patients presenting with skin lesions of B-cell lymphomas (BCLs), regardless of skin disease extent; however, supporting data are lacking. OBJECTIVE: To determine the clinical utility of imaging in the detection of systemic involvement in low-grade cutaneous BCLs in the skin. METHODS: Retrospective cohort analysis of patients presenting with cutaneous lesions of BCLs at Memorial Sloan Kettering Cancer Center and Stanford University during 1997-2016. RESULTS: At initial staging, of the 522 patients, extracutaneous disease was noted in 3.6% and 8.8% of patients with marginal zone lymphoma (MZL, n = 306) and follicle center lymphoma (FCL, n = 216) histology, respectively. In patients with systemic involvement, imaging alone identified 81.8% (9/11) of MZL cases and 89.4% of follicular lymphoma cases. In primary cutaneous MZL, 1.7% of patients subsequently had extracutaneous involvement (median follow-up 45 months), and in primary cutaneous FCL. 3.0% subsequently had extracutaneous involvement (median follow-up 47 months). LIMITATIONS: This was a retrospective study. CONCLUSION: Imaging is effective at identifying patients with systemic involvement in indolent BCLs present in the skin; however, incidence is low. After negative initial staging, primary cutaneous MZL patients may be followed clinically without routine imaging.

Utility of CD30, Ki-67, and p53 in assisting with the diagnosis of mycosis fungoides with large cell transformation.

INTRODUCTION: Mycosis fungoides (MF) with large cell transformation (LCT) is an advanced stage of cutaneous lymphoma with a poor prognosis. Identification of LCT is critical and especially challenging when the number of large abnormal lymphocytes is near but below 25%. We propose that Ki-67 and p53 may be useful in making this diagnosis. METHODS: We identified 17 patients with advanced stage (T3 or T4) MF without LCT and 38 patients with a biopsy-confirmed new diagnosis of MF with LCT treated at our institution's cutaneous lymphoma clinic from 2012 to 2016. Seventeen patients underwent 22 biopsies with advanced stage MF (control), and 38 patients with 46 biopsies of MF with LCT were included in this study. RESULTS: The MF cohort had an average CD30 expression of 4%, while the MF-LCT cohort had an average CD30 expression of 22% (P < 0.05). The MF cohort had an average Ki-67 staining of 13%, while the MF-LCT group had an average Ki-67 staining of 57% (P < 0.05). Forty-seven percent of the MF-LCT group was positive for p53; on the other hand, none of the MF control group showed increased p53 expression (P < 0.05). DISCUSSION: While CD30 shows some value in delineating large cell transformation, Ki-67 and p53 appear to be useful immunohistochemical markers in the diagnosis of LCT.

Preclinical Studies Support Combined Inhibition of BET Family Proteins and Histone Deacetylases as Epigenetic Therapy for Cutaneous T-Cell Lymphoma.

Advanced-stage cutaneous T-cell lymphoma (CTCL) is usually a fatal malignancy despite optimal use of currently available treatments. In this preclinical study of novel CTCL therapy, we performed in vitro and ex vivo experiments to determine the efficacy of combination treatment with a panel of BET bromodomain inhibitors (BETi) (JQ1, OTX015, CPI-0610, I-BET762) and HDAC inhibitors (HDACi) (SAHA/Vorinostat, Romidepsin). BETi/HDACi combinations were synergistic (combination index <1) against cell viability and induced G0/G1 cell cycle arrest. Apoptosis was uniformly enhanced. From a mechanistic standpoint, proliferative drivers c-Myc, Cyclin D1, NFkB, and IL-15Rα were reduced. Inhibitory CDKN1A was increased. CDKN1B, IL-7R, IL-17Rα, STAT3, and STAT5 alterations varied. There were significant increases in extrinsic apoptotic pathway death receptors and ligands (FasL, DR4, DR5, TRAIL, and TNFR1). At clinically tolerable levels of single agents, Romidepsin (1 nM) + OTX015 (125 nM) induced the greatest apoptosis (60%_80%) at 96 hours. Ex vivo studies of leukemic CTCL cells obtained from patients with Sezary syndrome also showed higher levels of apoptosis (about 60%-90%) in response to combination treatments relative to single agents. In contrast, combination treatment of normal CD4+ T cells induced only minimal apoptosis (<10%). Our findings show that the mechanism of action of BETi/HDACi therapy in CTCL involves induction of both cell cycle arrest and apoptosis with reduced proliferative drivers and enhanced expression of apoptotic extrinsic pathway death receptors and ligands. Relative to single agents, the superior anti-CTCL effects of BETi/HDACi combinations in vitro and ex vivo provide a rationale for clinical trials exploring their efficacy as therapy for CTCL.

The Use of Central Pathology Review With Digital Slide Scanning in Advanced-stage Mycosis Fungoides and Sézary Syndrome: A Multi-institutional and International Pathology Study.

This pathology PILOT study aims to define the role and feasibility of centralized pathology review in a cohort of 75 patients from different centers in the United States and Europe using digital slide scanning. The pathologic material from 75 patients who had been diagnosed with mycosis fungoides/Sézary syndrome and were clinically staged as IIb or above was retrieved from 11 participating centers. Each pathology reviewer was provided with the pathologic diagnosis (by the referring pathologist), and the following list of histopathologic criteria (presence or absence) from the initial report: epidermotropism, folliculotropism (FT), large cell transformation, syringotropism, and granulomas. Patients with advance stage were selected for this study as this is a population where there is significant variability in the diagnosis of pathologic prognostic and predictive biomarkers. The slides were digitally scanned with an Aperio scanner and consensus review of cases occurred when major or minor discrepancies between the referral diagnosis and central pathology review occurred. Among the 75 cases, 70 (93.3%) had a final consensus diagnosis between the 3 central review pathologists. The overall agreement between the consensus review and the referring pathologist was 60%. The overall agreement was also higher between the reviewers and consensus review, compared with the referring pathologist and consensus. 65.3% of cases had some type of discrepancy (major or minor) between the outside and consensus review. Major discrepancies were seen in 34 of 73 cases (46.6%; 73 cases indicated a yes or no response). Minor discrepancies were seen in 32 of 75 (42.7%) of cases. Most of the major discrepancies were accounted by a difference in interpretation in the presence or absence of large cell transformation or FT. Most minor discrepancies were explained by a different interpretation in the expression of CD30. We found digital slide scanning to be a beneficial, reliable, and practical for a methodical approach to perform central pathology review in the context of a large clinical prospective study.

Long-term safety and efficacy are observed after implantation of Zotarolimus-Eluting stent in real-world clinical practice.

AIMS: Zotarolimus-eluting stents (ZESs) have been shown to be safe and effective in randomised trials. We sought to report the clinical outcomes after implantation of ZES in real-world clinical practice. METHODS AND RESULTS: ZES have been approved for clinical use in Singapore since April 2005. Until December 31, 2007, a total of 219 patients had undergone implantation of ZES. After excluding 11 foreign patients with whom contact was lost, 208 patients (246 lesions, 305 stents) formed the study cohort. A high-proportion of diabetic patients (n=90, 43.3%) was included. Recommended dual antiplatelet therapy was at least 3 months (n=147) for patients treated before or 12 months (n=61) after January 2007. As of January 2008, the median follow-up duration was 19 months (range: 1 to 33 months). There were 10 (4.8%) deaths, including 7 (3.4%) cardiac deaths. Myocardial infarction occurred in 11 (5.3%) patients. The numbers of patients requiring target vessel revascularisation and target lesion revascularisation were 10 (4.8%) and 5 (2.4%) respectively. Using the ARC definition, there were two cases of definite stent thrombosis on days 7 and 17, and one case of probable stent thrombosis on day 15. CONCLUSIONS: In this real-world clinical experience, ZES was associated with a low incidence of adverse cardiac events at a medium follow-up of one and half years.

Interrelation of coronary calcification, myocardial ischemia, and outcomes in patients with intermediate likelihood of coronary artery disease: a combined positron emission tomography/computed tomography study.

BACKGROUND: Although the value of coronary artery calcium (CAC) for atherosclerosis screening is gaining acceptance, its efficacy in predicting flow-limiting coronary artery disease remains controversial, and its incremental prognostic value over myocardial perfusion is not well established. METHODS AND RESULTS: We evaluated 695 consecutive intermediate-risk patients undergoing combined rest-stress rubidium 82 positron emission tomography (PET) perfusion imaging and CAC scoring on a hybrid PET-computed tomography (CT) scanner. The frequency of abnormal scans among patients with a CAC score > or = 400 was higher than that in patients with a CAC score of 1 to 399 (48.5% versus 21.7%, P<0.001). Multivariate logistic regression supported the concept of a threshold CAC score > or = 400 governing this relationship (odds ratio 2.91, P<0.001); however, the frequency of ischemia among patients with no CAC was 16.0%, and its absence only afforded a negative predictive value of 84.0%. Risk-adjusted survival analysis demonstrated a stepwise increase in event rates (death and myocardial infarction) with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging. Among patients with normal PET myocardial perfusion imaging, the annualized event rate in patients with no CAC was lower than in those with a CAC score > or = 1000 (2.6% versus 12.3%, respectively). Likewise, in patients with ischemia on PET myocardial perfusion imaging, the annualized event rate in those with no CAC was lower than among patients with a CAC score > or = 1000 (8.2% versus 22.1%). CONCLUSIONS: Although increasing CAC content is generally predictive of a higher likelihood of ischemia, its absence does not completely eliminate the possibility of flow-limiting coronary artery disease. Importantly, a stepwise increase occurs in the risk of adverse events with increasing CAC scores in patients with and without ischemia on PET myocardial perfusion imaging.

Inverse relation between diastolic blood pressure and long-term outcomes in patients undergoing pharmacoinvasive therapy for myocardial infarction: the J-shaped relation in the contemporary era of revascularisation.

OBJECTIVE: In the thrombolytic era, it was reported that in the presence of significant coronary stenosis, lowering diastolic blood pressure (DBP) below a critical threshold would result in a paradoxical increase in the occurrence of myocardial infarction (MI). We sought to re-evaluate this J-shaped relation in the era of pharmacoinvasive therapy. METHODS: A total of 182 patients who underwent early (<1 week, mean 2.3 days) coronary angioplasty after thrombolysis were analysed. RESULTS: Thrombolytic agents (streptokinase in 60%, tissue plasminogen activator in 40%) were administered in an average door-to-needle time of 66 min (<=30 min in 43 [24%] patients). A thrombolysis in myocardial infarction (TIMI) 3 flow was achieved in 56% of patients after thrombolysis, and it was enhanced to 92% after angioplasty. During an average follow-up period of 26 +/-13 months, the adverse event (death, re-MI, target vessel revascularisation or stroke) rate was 21%. Older age, low systolic blood pressure and DBP, fast heart rate, high creatine kinase, hypercholesterolaemia, thrombus-laden lesion, baseline TIMI 0-2 flow were associated with higher occurrence of adverse events. After adjusting for the differing clinical and procedural factors, low DBP (odds ratio 1.10, 95% confidence interval 1.01-1.20, P = 0.041), fast heart rate (odds ratio 1.08, 95% confidence interval 1.02-1.14, P = 0.008) and anterior MI (odds ratio 18.98, 95% confidence interval 2.13-169.19, P = 0.008) were all independent predictors of long-term adverse rate occurrence. CONCLUSIONS: A low DBP is an independent predictor of long-term adverse event rates in patients undergoing routine early coronary angioplasty after thrombolysis. This suggests that excessive lowering of DBP may not be desirable before complete revascularisation.

The relationship between symptoms, depression, and quality of life in peritoneal dialysis patients.

Measurement of patient outcome by mental and social indexes such as quality of life (QOL) in addition to survival is a growing trend. We examined the feasibility of using a single global QOL question in peritoneal dialysis (PD) patients. We also examined the relationship that QOL has with uremic symptoms and depression in these patients. During a clinic visit, each PD patient completed a single-question QOL measure (0-10 scale, 10 being best). Patients' symptoms were assessed using a 10-symptom checklist, with each symptom scored on a Likert scale of 0 (none) to 5 (severe). We evaluated for depression using two questions from the Primary Care Evaluation of Mental Disorders. Serum albumin, hemoglobin, and phosphorus were obtained, but only phosphorus was associated with QOL on univariate analysis (p = 0.05) and therefore included in the multivariate model. Results (checklist score, depression, phosphorus, age, diabetes, and race) were analyzed using a sequential multivariate analysis with QOL as the dependent variable. The study population consisted of 64 PD patients [mean age: 47 +/- 16 years; 25% black; 23% with diabetes; 31% incident (< or =3 months)]. The median score on the single QOL question was 7 (range: 1-10). Patients scored a median of 9 (range: 0-31) out of 50 on the total symptom checklist. Among responding patients, 34% answered yes to at least one depression question. The sequential incremental r2 values associated with a poorer QOL were higher checklist score (r2 = 0.16, p < 0.02), presence of depression (r2 = 0.13, p < 0.00002), younger age (r2 = 0.06, p < 0.03), and presence of diabetes (r2 = 0.04, p < 0.05). In this model, PO4 and race were nonsignificant. Total r2 in the model was 0.48. The single measure of QOL, the checklist score, and the depression screening score were simple and easy to obtain during a routine clinic visit. We conclude that physical symptoms and depression are strongly associated with a simple single measure of QOL. The extent to which symptoms and depression can be improved by clinical intervention, and the subsequent effect on quality of life and survival, should be examined in longitudinal studies.

A novel class of AMPA receptor allosteric modulators. Part 1: design, synthesis, and SAR of 3-aryl-4-cyano-5-substituted-heteroaryl-2-carboxylic acid derivatives.

The synthesis and initial SAR studies of novel, highly potent positive allosteric modulators of AMPA receptors based on 3-(4-tert-butylphenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (6a) are described. SAR studies at the thioether moiety indicated that substitution at this position was mandatory and better potency was achieved with small groups.

Transesophageal echocardiography during mitral valve repair underestimates mitral valve area by pressure half-time calculation.

BACKGROUND: Mitral valve repair (MVRr) has become the mainstay of surgical treatment for mitral valvular regurgitation. Evaluation of MVRr by intraoperative transesophageal echocardiography (IOE) has been routinely employed to guide the operation. While the main objective of IOE is to assess for residual mitral regurgitation, it is also important to exclude significant mitral stenosis. Utilisation of pressure half-time (PHT) to estimate mitral valve area (MVA) has been shown to be reliable in normal clinical situations. However, in MVRr, the accuracy of MVA calculation by PHT needs to be ascertained. METHODS AND RESULTS: Data from IOE and post-MVRr transthoracic echocardiography (TTE) from the year 1998 to 2002 were analysed and when required, offline PHT measurements were made. The mean time interval between the two echocardiographic examinations was 10.6 (1 to 56) weeks. In our 36 cases, the IOE MVA was found to be 2.1+/-0.5 cm2, with the corresponding TTE MVA to be 2.7+/-1.0 cm2. MVA by PHT with IOE underestimated TTE findings by 0.6+/-0.9 cm2 (95% CI: -0.85 to -0.24, P=0.001). In 6 patients, the IOE MVA was moderately reduced. Subsequent TTE in these patients showed that the MVA was adequate and was significantly underestimated by IOE in 5 of these patients. In all these cases, IOE underestimated MVA by a margin, which may result in a need to revise the repair. CONCLUSION: We find that IOE immediately after MVRr tends to underestimate MVA by PHT calculation. The underestimation by IOE may have clinical importance in cases when MVA by IOE is moderately reduced. Therefore, pressure half-time measurement should not be used to assess mitral valve areas during mitral valve repair.

Impact of glycemic control on occurrence of no-reflow and 30-day outcomes in diabetic patients undergoing primary angioplasty for myocardial infarction.

Diabetes mellitus is associated with endothelial dysfunction and platelet activation that may contribute to the occurrence of no-reflow. We postulate that optimal glycemic control is associated with the lower risk of no-reflow and better outcomes. Diabetic patients who underwent primary angioplasty for myocardial infarction from January 2001 to June 2004 were analyzed. No-reflow was defined as TIMI flow < 3 in the absence of mechanical obstruction. Patients were divided into 2 glycemic control groups according to the HbA1c value: optimal (less than or equal to 7%), and suboptimal (> 7%). A total of 183 diabetic patients (93% noninsulin-requiring) were included for analysis. The median HbA1c of the optimal (n = 37) and suboptimal (n = 146) glycemic control groups were 6.5% and 8.5%, respectively. Compared to the suboptimal glycemic control group, the optimal glycemic control group was older, likely to have hypertension, previously suffered a stroke, have renal failure and a higher baseline creatinine. No-reflow occurred in 16% of the optimal and 18% of the suboptimal glycemic control groups. Multivariate analysis showed that optimal glycemic control was not associated with a lesser occurrence of no-reflow (OR 1.27, 95% CI 0.19-8.29; p = 0.807). The optimal glycemic control group had 30-day survival (90% versus 93%; p = 0.698) and 30-day event-free survival (84% versus 86%; p = 0.695) rates similar to the suboptimal glycemic control group. Among diabetic patients undergoing primary angioplasty, optimal glycemic control was not associated with a lesser occurrence of no-reflow or better 30-day outcomes.