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Barber–Say syndrome (BSS) is a rare congenital ectodermal dysplasia with few cases reported in the literature. We describe a 9‐year‐old boy with congenital generalized hypertrichosis and multiple rhabdomyomatous mesenchymal hamartomas (RMHs) on his nose and periocular region. Next‐generation sequencing, performed in DNA from a blood sample, and RMH tissue, revealed a pathogenic variant in the TWIST2 gene, which was not detected in a salivary sample of the patient, nor in his parents. Therefore, we consider this variant as de novo mosaicism. To our knowledge, this is the first case of multiple RMHs associated with BSS. [ABSTRACT FROM AUTHOR]

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High-throughput sequencing of cell-free DNA (cfDNA) has emerged as a promising noninvasive approach in lymphomas, being particularly useful when a biopsy specimen is not available for molecular analysis, as it frequently occurs in primary mediastinal large B-cell lymphoma (PMBL). We used cfDNA for genomic characterization in 20 PMBL patients by means of a custom NGS panel for gene mutations and low-pass whole-genome sequencing (WGS) for copy number analysis (CNA) in a real-life setting. Appropriate cfDNA to perform the analyses was obtained in 18/20 cases. The sensitivity of cfDNA to detect the mutations present in paired FFPE samples was 69% (95% CI: 60–78%). The mutational landscape found in cfDNA samples was highly consistent with that of the tissue, with the most frequently mutated genes being B2M (61%), SOCS1 (61%), GNA13 (44%), STAT6 (44%), NFKBIA (39%), ITPKB (33%), and NFKBIE (33%). Overall, we observed a 75% concordance to detect CNA gains/losses between DNA microarray and low-pass WGS. The sensitivity of low-pass WGS was remarkably higher for clonal CNA (18/20, 90%) compared to subclonal alterations identified by DNA microarray. No significant associations between cfDNA amount and tumor burden or outcome were found. cfDNA is an excellent alternative source for the accurate genetic characterization of PMBL cases.

CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20dim FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development.

T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of STAT3 are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of STAT3/STAT5B, treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8+CD57+ group. Remarkably, patients included in the CD4+ group had a higher association with solid tumors (p = 0.037). STAT3 mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying STAT3 mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment (p = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of STAT3. We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of STAT3, and for the first time analyzes survival compared to a matched general Spanish population.

Summary: Diffuse large B‐cell lymphoma (DLBCL) patients with relapsed or refractory (RR) disease have poor outcomes with current salvage regimens. We conducted a phase 2 trial to analyse the safety and efficacy of adding lenalidomide to R‐ESHAP (LR‐ESHAP) in patients with RR DLBCL. Subjects received 3 cycles of lenalidomide 10 mg/day on days 1–14 of every 21‐day cycle, in combination with R‐ESHAP at standard doses. Responding patients underwent autologous stem‐cell transplantation (ASCT). The primary endpoint was the overall response rate (ORR) after 3 cycles. Centralized cell‐of‐origin (COO) classification was performed. Forty‐six patients were included. The ORR after LR‐ESHAP was 67% (35% of patients achieved complete remission). Patients with primary refractory disease (n = 26) had significantly worse ORR than patients with non‐refractory disease (54% vs. 85%, p = 0.031). No differences in response rates according to the COO were observed. Twenty‐eight patients (61%) underwent ASCT. At a median follow‐up of 41 months, the estimated 3‐year PFS and OS were 42% and 48%, respectively. The most common grade ≥3 adverse events were thrombocytopenia (70% of patients), neutropenia (67%) and anaemia (35%). There were no treatment‐related deaths during LR‐ESHAP cycles. In conclusion, LR‐ESHAP is a feasible salvage regimen with promising efficacy results for patients with RR DLBCL. [ABSTRACT FROM AUTHOR]