Effect of Dupilumab on Blood Eosinophil Counts in Patients With Asthma, Chronic Rhinosinusitis With Nasal Polyps, Atopic Dermatitis, or Eosinophilic Esophagitis.

BACKGROUND: Transient increases in blood eosinophil counts have been observed in dupilumab clinical trials. OBJECTIVE: To assess eosinophil counts and eosinophilia-related treatment-emergent adverse events (TEAEs) across 11 dupilumab clinical trials, comparing adult and adolescent patients with asthma and adult patients with chronic rhinosinusitis with nasal polyps (CRSwNP), atopic dermatitis, and eosinophilic esophagitis. METHODS: Eosinophil counts, rates of eosinophilia-related TEAEs or treatment-emergent eosinophilia (>1,500 cells/µL), discontinuations, clinical symptoms, and efficacy in patients with asthma or CRSwNP with treatment-emergent eosinophilia are presented. RESULTS: Transient increases in mean eosinophil counts were observed in dupilumab-treated patients with asthma (mean range across studies at baseline: 349-370 cells/µL; week 4: 515-578 cells/µL), CRSwNP (baseline: 440-448 cells/µL; week 16: 595 cells/µL), and atopic dermatitis (baseline: 434-600 cells/µL; week 4: 410-710 cells/µL), followed by a decline starting by week 24 to baseline or lower. No increases were seen in patients with eosinophilic esophagitis (baseline: 310 cells/µL; week 4: 230 cells/µL). In dupilumab-treated patients across all studies, rates of eosinophilia TEAEs were 0% to 13.6%. Clinical symptoms associated with increased eosinophils were rare (seven of 4,666 dupilumab-treated patients, including six cases of eosinophilic granulomatosis with polyangiitis) and occurred only in patients with asthma or CRSwNP. Eosinophilia was not associated with reduced dupilumab efficacy. CONCLUSIONS: Transient increases in eosinophil counts with dupilumab treatment did not affect efficacy and were rarely of clinical consequence. It remains important for physicians to base judgment on individual patient history and baseline eosinophil counts and to be alert to hypereosinophilic symptoms.

Respiratory Infections and Anti-Infective Medication Use From Phase 3 Dupilumab Respiratory Studies.

BACKGROUND: Patients with asthma and/or chronic rhinosinusitis with nasal polyps (CRSwNP) experience recurrent respiratory tract infections. Dupilumab targets type 2 inflammation, a common underlying pathophysiology of both conditions, with proven efficacy. OBJECTIVE: To examine investigator-reported respiratory infection adverse events and anti-infective medication use with dupilumab versus placebo in patients with moderate-to-severe asthma or severe CRSwNP. METHODS: We performed a post hoc analysis of the pivotal phase 3 trials LIBERTY ASTHMA QUEST (NCT02414854) and LIBERTY NP SINUS-52 (NCT02898454) in moderate-to-severe asthma and severe CRSwNP, respectively. RESULTS: Investigator-reported respiratory infection events occurred at a significantly lower incidence in patients treated with dupilumab versus placebo, in both asthma (22% lower; P < .0001; 95% CI 0.71-0.85) and CRSwNP (38% lower; P <.0001; 95% CI 0.51-0.75). Reported upper and lower respiratory tract infection events were numerically or significantly lower in dupilumab-treated patients in both conditions, as were the number of patients experiencing investigator-reported infections. Significantly less systemic anti-infective medication use occurred in dupilumab versus placebo in asthma (24% lower; P < .0001; 95% CI 0.70-0.83) and CRSwNP patients (49% lower; P < .0001; 95% CI 0.43-0.61), and significantly fewer dupilumab-treated patients used anti-infective medications. When examined by season and month, the data indicated that investigator-reported respiratory infections and anti-infective medication use were less frequent in dupilumab- versus placebo-treated patients throughout the calendar year. CONCLUSIONS: Dupilumab treatment was associated with a reduced incidence of investigator-reported respiratory infections in patients with moderate-to-severe asthma or severe CRSwNP. Further studies are required to determine the mechanism behind this reduction.

TdT expression in acute myeloid leukemia with minimal differentiation is associated with distinctive clinicopathological features and better overall survival following stem cell transplantation.

The diagnostic criteria for acute myeloid leukemia (AML), not otherwise specified, with minimal differentiation (AML-M0, French-American-British classification), have been refined in the 2008 World Health Organization (WHO) classification. Terminal deoxynucleotidyl transferase (TdT) expression in AML-M0 has been proposed by others as a surrogate for RUNX1 (runt-related transcription factor 1) mutations, a mutation associated with distinct gene expression profiles in AML-M0. In this study, we investigated the significance of TdT expression in AML-M0 cases defined using the 2008 WHO classification criteria. Demographic, laboratory and clinical information were obtained from the hospital medical records. Statistical analysis was performed using Student's t-test, log-rank test and Fisher's exact test. The study group included 30 AML-M0 patients (male:female=19:11; median age: 60 years). In all, 10 cases of AML-M0 were positive for TdT(+) and 20 cases were negative for TdT(-). Patients with TdT+ AML-M0 had higher peripheral blood and bone marrow blast counts compared to patients with TdT- AML-M0 (P=0.01). TdT expression in AML-M0 was not associated with a distinct immunophenotype. Monoclonal IgH and TCR gene rearrangements were frequent, but independent of TdT expression in AML-M0. TdT expression in AML-M0 correlated with trisomy 13 and inversely correlated with aberrations of chromosomes 5 and 17. Among six patients with AML-M0 who received a stem cell transplant, overall survival was significantly longer for the three TdT+ patients compared with the three TdT- patients (P=0.03). In the TdT+AML-M0 subgroup, the three patients with stem cell transplant had better overall survival compared with five patients who did not receive stem cell transplant (P=0.01). We conclude that AML-M0, as currently defined in the 2008 WHO classification, can be divided into two groups based on TdT expression. Although there is a need to assess a greater number of patients, our results suggest that TdT positivity in AML-M0 identifies a subset of patients with a better prognosis after stem cell transplant.

Angioimmunoblastic T-cell lymphoma in bone marrow: a morphologic and immunophenotypic study.

Angioimmunoblastic T-cell lymphoma is known to frequently involve bone marrow. However, the histologic and immunophenotypic features of angioimmunoblastic T-cell lymphoma at this site are poorly defined. We assessed 27 bone marrow specimens involved by angioimmunoblastic T-cell lymphoma from 20 patients. Histologically, bone marrow involvement was predominantly multifocal (74%) and exhibited a nodular pattern (78%), often associated with other patterns. Using immunohistochemistry, programed death-1 and CD10 were expressed by atypical lymphocytes in 17 (85%) of 20 and 5 (18.5%) of 27 specimens, respectively. CXCL13 was not expressed by atypical lymphocytes in all cases but did stain stromal cells consistent with follicular dendritic cells in 1 case. BCL-6 as a single antibody was difficult to interpret because many normal bone marrow cells are dimly positive, but BCL-6/CD3 dual staining highlighted BCL-6+ T-cells in all cases assessed. Antibodies specific for CD21 and CD35 did not highlight follicular dendritic cells in any biopsy specimens. Flow cytometry immunophenotyping revealed a CD3+CD10+ T-cell population in 2 (25%) of 8 cases assessed. We conclude that the recognition and classification of angioimmunoblastic T-cell lymphoma in bone marrow are made difficult by the uncommon expression of CD10 (25%), rarity of follicular dendritic cells, and lack of CXCL13 expression at this site. This is most likely attributable to the very different microenvironment of the bone marrow relative to lymph nodes and, in particular, the absence of follicles in bone marrow. By contrast, programed death-1 immunohistochemical staining and double labeling using antibodies specific for BCL-6 and CD3 were helpful in appreciating the follicular T-helper cell immunophenotype of angioimmunoblastic T-cell lymphoma.

Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma.

Dysregulation of the sonic hedgehog (SHH) signaling pathway has been shown in several cancer types, but has not been explored in diffuse large B-cell lymphoma. We assessed 67 cases of diffuse large B-cell lymphoma for expression of SHH (ligand), GLI1, GLI2 and GLI3 (transcriptional effectors of SHH signaling), and the ATP-binding cassette (ABC)G2 (a downstream target of SHH signaling), using immunohistochemistry. For comparison, we assessed the expression levels of these proteins in 28 cases of follicular lymphoma, 5 chronic lymphocytic leukemia/small lymphocytic lymphoma, and 5 reactive lymph nodes. In diffuse large B-cell lymphoma, SHH was expressed in 61 of 67 (91%) cases, GLI1 in 62 of 67 (93%), GLI2 in 41 of 56 (73%), and GLI3 in 22 of 56 (39%). Expression of ABCG2 was detected in 52 of 55 (95%) cases and was high in 15 (27%) cases. SHH expression positively correlated with expression levels of ABCG2 (P=0.05). Patients with diffuse large B-cell lymphoma with high ABCG2 expression showed significantly shorter overall survival (P=0.031) and failure-free survival (P=0.029) compared with patients with tumors with low or no expression of ABCG2. Diffuse large B-cell lymphomas expressed SHH, and GLI1, GLI2, and GLI3 more frequently and more intensely than cases of follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma. In conclusion, our data show that SHH signaling proteins and ABCG2 are aberrantly expressed in diffuse large B-cell lymphoma and that ABCG2 expression has prognostic implications. These findings also provide evidence that dysregulation of the SHH pathway may be involved in the pathogenesis of diffuse large B-cell lymphoma.