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Th17 cells have never been explored in human GvHD. We studied the correlation between the presence of Th17 cells in the gastro-intestinal (GI) tract and in the skin with histological and clinical parameters. We first analyzed a cohort of 40 patients with suspected GvHD of the GI tract. TNF, TNF receptors, and Fas expression, and apoptotic cell, CD4+IL-17+ cells (Th17) and CD4+Foxp3+ cells (Treg) were quantified. A Th17/Treg ratio<1 correlated both with the clinical diagnosis (p<0.001), and ≥ 2 pathologic grade (p<0.001). A Th17/Treg ratio<1 also correlated with the intensity of apoptosis of epithelial cells (p=0.03), Fas expression in the cellular infiltrate (p=0.003), TNF and TNF receptors expression (p<0.001). We then assessed Th17/Treg ratio in two other independent cohorts; a second cohort of 30 patients and confirmed that Th17/Treg ratio<1 correlated with the pathological grade of GI GvHD. Finally 15 patients with skin GvHD and 11 patients with skin rash but without pathological GvHD were studied. Results in this third cohort of patients with skin disease confirmed those found in patients with GI GvHD. These analyses in 96 patients suggest that Th17/Treg ratio could be a sensitive and specific pathological in situ biomarker of GvHD.

Atrial fibrillation (AF) occurs in 5-9% of patients treated with ibrutinib for chronic lymphocytic leukaemia (CLL); the clinical consequences and optimal management are unclear. We retrospectively studied 56 CLL patients who received ibrutinib and developed AF. Median time to onset was 3·8 months. AF was persistent in 35/56 (62%) cases despite treatment. Clinical consequences included: three episodes of severe cardiac failure (one fatal) and one stroke; eight non-thrombocytopenic patients (14%) experienced severe bleeding adverse events. Altogether, ibrutinib was permanently discontinued in 26/56 cases (46%). Data to guide optimal management are lacking and clinical practice guidelines are urgently needed.

Mutational analyses performed following acquired ibrutinib resistance have suggested that chronic lymphocytic leukemia (CLL) progression on ibrutinib is linked to mutations in Bruton tyrosine kinase (BTK) and/or phospholipase Cγ2 (PLCG2) genes. Mutational information for patients still on ibrutinib is limited. We report a study aimed to provide a “snapshot” of the prevalence of mutations in a real-life CLL cohort still on ibrutinib after at least 3 years of treatment. Of 204 patients who initiated ibrutinib via an early-access program at 29 French Innovative Leukemia Organization (FILO) centers, 63 (31%) were still on ibrutinib after 3 years and 57 provided a fresh blood sample. Thirty patients had a CLL clone ≥0.5 × 109/L, enabling next-generation sequencing (NGS); BTK and PLCG2 mutations were detected in 57% and 13% of the NGS samples, respectively. After median follow-up of 8.5 months from sample collection, the presence of a BTK mutation was significantly associated with subsequent CLL progression (P = .0005 vs no BTK mutation). Our findings support that mutational analysis should be considered in patients receiving ibrutinib who have residual clonal lymphocytosis, and that clinical trials are needed to evaluate whether patients with a BTK mutation may benefit from an early switch to another treatment.

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for longterm AIHA response.

95:274-281. wileyonlinelibrary.com/journal/ajh IgM, median (range), mg/dL 512.5 (31-6500) LDH, median (range), U/L 289 (99-3191) LDH high, n (%) 19 (53) Hemoglobin, median (range), g/dL 11.5 (3.5-15.4) Platelet count, median (range), 10 9 /L 199 (9-576) β-2 microglobulin, median (range), μg/dL 4.9 (3.3-15) Bone marrow involvement by transformed lymphoma, median % (range) 50 (5-80) Abbreviations: FLCR, free light chain ratio; GCB, germinal center B-cell; LDH, lactate dehydrogenase. ZANWAR ET AL. 277

As a result of significant recent developments, the management of patients with chronic lymphocytic leukemia (CLL) is changing, and new therapeutic options will continue to emerge in the near future. The recommendations of the French Innovative Leukemia Organization (FILO-CLL) group presented here are intended to provide practical recommendations for physicians taking care of CLL patients, taking into account the availability of both biological tests and therapies in daily practice in France at the time of publication. This text details the documented information and guidelines on diagnosis, indications for treatment, infectious complications and therapeutic strategies in frontline and relapsed CLL as well as in particular conditions such as autoimmune cytopenia or Richter syndrome.

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