We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios [HRs] [95% confidence interval], 8.68 [3.32-22.73] and 3.24 [1.58-6.64], respectively) and death from myelofibrosis (HRs, 3.03 [1.66-5.56] and 1.77 [1.18-2.67], respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.

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Summary Chronic myelomonocytic leukaemia (CMML) is a heterogeneous haematopoietic disorder characterized by myeloproliferative or myelodysplastic features. At present, the pathogenesis of this malignancy is not completely understood. In this study, we sought to analyse gene expression profiles of CMML in order to characterize new molecular outcome predictors. A learning set of 32 untreated CMML patients at diagnosis was available for TaqMan low‐density array gene expression analysis. From 93 selected genes related to cancer and cell cycle, we built a five‐gene prognostic index after multiplicity correction. Using this index, we characterized two categories of patients with distinct overall survival (94% vs. 19% for good and poor overall survival, respectively; P = 0·007) and we successfully validated its strength on an independent cohort of 21 CMML patients with Affymetrix gene expression data. We found no specific patterns of association with traditional prognostic stratification parameters in the learning cohort. However, the poor survival group strongly correlated with high‐risk treated patients and transformation to acute myeloid leukaemia. We report here a new multigene prognostic index for CMML, independent of the gene expression measurement method, which could be used as a powerful tool to predict clinical outcome and help physicians to evaluate criteria for treatments.

Most relapses of primary central nervous system lymphoma (PCNSL) occur in the brain and are associated with a poor prognosis. Isolated intraocular relapses (IIORs) are rare and poorly described. We retrospectively selected from the French Lymphome Oculo‐Cérébral database PCNSL patients who initially presented with cerebral localization and who experienced IIOR during the course of the disease. Of the 1472 patients included in the database, 55 patients presented an IIOR. Their median age was 68 years, and median Karnofsky Performance Status 80. IL‐10 levels in the aqueous humor and/or in the vitreous were increased in 42/46 patients. 45/55 patients received systemic chemotherapy, and 11/55 received high‐dose chemotherapy with autologous stem cell transplantation (HCT‐ASCT) as consolidation treatment. After a median follow‐up of 69 months, 42/55 patients had relapsed, including 90% of the patients who did not receive HCT‐ASCT at IIOR and 40% of the patients who received HCT‐ASCT at IIOR (p < 0.001). The first relapse after the initial IIOR was exclusively in the eye in 23/42 patients, and 29/42 patients had a subsequent brain relapse during the course of the disease. The median progression‐free survival, brain‐free survival and overall survival from IIOR were 12.2, 48.6 and 57.1 months, respectively. Isolated intraocular relapse is not exceptional in the course of PCNSL and deserves systematic ophthalmological follow‐up. Its prognosis is much better than the prognosis of brain relapse, with an evolution close to that of primary vitreoretinal lymphoma. With the exception of patients who received HCT‐ASCT at IIOR, almost all patients subsequently relapsed, often with other IIORs.

Background Ruxolitinib is a current therapeutic option, which has demonstrated rapid and durable reduction in splenomegaly and improved disease-related symptoms in patients (pts) with primary myelofibrosis (PMF), post-polycythemia vera-MF (PPV-MF), and post-essential thrombocythemia-MF (PET-MF). Anemia is another frequent issue in MF, which may be managed by the use of ESA, leading to a 40-50% response rate in small studies. Consistent with its JAK2 signalling inhibition, ruxolitinib therapy has been shown to be detrimental on the hemoglobin level, increasing the depth of anemia or transfusion need, especially during the first 12-24 weeks of treatment in the COMFORT studies. Despite potential antagonistic mechanisms of action on JAK2, some responses on anemia have been reported with the addition of ESA to ruxolitinib in a small subset of pts in the COMFORT II study. The present study aimed to better assess the efficacy of ESA on anemia related to ruxolitinib and tolerance of this combination in a larger cohort of pts treated for MF in general practice. Methods We performed an observational study on patients with MF previously or currently treated with concomitant ESA and Ruxolitinib in French centers members of the FIM. Informed consent was provided by the pts. Data collected included characteristics of the disease, treatment, responses to ruxolitinib and ESA. They are reported according to the IWG-MRT/ELN 2013 criteria. Results This analysis was performed in July 2016, on the 45 first consecutive pts in 11 centers. Median age at diagnosis was 73 (range 42- 89), 30 (67%) were men. Twenty-five pts (56%) had primary MF, 11 (24%) PET-MF and 9 (20%) PPV-MF, overall diagnosed between 2004 and 2016. IPSS risk categories were low/int-1 and int-2/high in 16 (36%) and 28 (64%) pts, respectively. Twenty-nine (64%) were JAK2V617F positive, 5 harbored MPL mutation and 8 had CALR mutations. Median time between MF diagnosis and ruxolitinib was 21 (0-109) months and median follow-up from ruxolitinib starting was 13 (2 - 53) months. At time of ruxolitinib initiation 32 (71%) pts were transfusion independent and 13(29%) had transfusion need. Ten additional pts became transfusion dependent after ruxolitinib initiation. Other causes of anemia were renal insufficiency n=7, surgery n=1, 1 cytoreductive therapy with hydroxyurea. Type of ESA were darbepoetin alfa, [n=26]; epoetin alfa, [n=3], epoetin beta [n=8], epoetin zeta [n=4], epoeitin theta [n=4], with a median duration of exposure to ESA of 15 months [1-92mo]. ESA was introduced either before ruxolitinib (n= 17), simultaneously (n= 4) or afterward (n= 24) after a median of 2 months [1-26mo]. Response rate to ruxolitinib were in accordance with previous reports: For splenomegaly, 33 (73%) of pts achieved at least a partial response, 8 (17%) were stable and 4 (9%) were progressive. Thirty pts (67%) had at least partial response on constitutional symptoms. Response assessment of anemia according to IWG-MRT/ELN 2013 criteria: 7 pts (16%) achieved a RBC transfusion independency, 13 (29%) pts had an increase in hemoglobin level of Hb >2g/dl (2 pts achieved both criteria), which results in 40% of objective responses. The median time to best response on anemia after ESA initiation was 3 [1-84] months. For safety, a pulmonary embolism occurred in one patient possibly related to ESA, no other adverse event occurred, in particular no spleen enlargement was described. At time of analysis, 36/45 pts were still alive: 1 underwent allogeneic bone marrow transplant, 34 were still treated with ruxolitinib whereas 28 patients were still undergoing ESA therapy. Conclusions This retrospective analysis is the largest cohort describing the use of concomitant ESA with ruxolitinib therapy in "real life". We report 40 % of objective responses, consistent with ESA response rates without ruxolitinib for MF related anemia. Tolerance seemed acceptable without hampering efficiency of ruxolitinib. Our results suggest that ESA should be considered as a possible therapeutic for anemia in myelofibrosis patients treated with ruxolitinib. Disclosures Malak: Novartis: Membership on an entity's Board of Directors or advisory committees. Ugo:Novartis: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Novartis: Research Funding; AOP Orphan: Research Funding. Roy:AOP: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: congress travel, Research Funding.