Absence of FGFR3–TACC3 rearrangement in hematological malignancies with numerical chromosomal alteration

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Clonal evolution in therapy-related neoplasms

Therapy-related myeloid neoplasms (t-MN) may occur as a late effect of cytotoxic therapy for a primary malignancy or autoimmune diseases in susceptible individuals. We studied the development of somatic mutations in t-MN, using a collection of follow-up samples from 14 patients with a primary hematologic malignancy, who developed a secondary leukemia (13 t-MN and 1 t-acute lymphoblastic leukemia), at a median latency of 73 months (range 18-108) from primary cancer diagnosis.Using Sanger and next generation sequencing (NGS) approaches we identified 8 mutations (IDH1 R132H, ASXL1 Y591*, ASXL1 S689*, ASXL1 R693*, SRSF2 P95H, SF3B1 K700E, SETBP1 G870R and TP53 Y220C) in seven of thirteen t-MN patients (54%), whereas the t-ALL patient had a t(4,11) translocation, resulting in the KMT2A/AFF1 fusion gene. These mutations were then tracked backwards in marrow samples preceding secondary leukemia occurrence, using pyrosequencing and a NGS protocol that allows the detection of low variant allele frequencies ( 650.1%).Somatic mutations were detectable in the BM harvested at the primary diagnosis, prior to any cytotoxic treatment in three patients, while they were not detectable and apparently acquired by the t-MN clone in five patients.These data show that clonal evolution in t-MN is heterogeneous, with some somatic mutations preceding cytotoxic treatment and possibly favoring leukemic development

Reply to S. Zucker “The Swinging Pendulum of the Anemia of Cancer: Erythropoietin Trumps Hepcidin”

Contains fulltext : 97313.pdf (publisher's version ) (Open Access

Innovative Monoclonal Antibody Therapies in Multiple Sclerosis

The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS), especially for relapsing–remitting disease courses. In particular, the application of monoclonal antibodies provide innovative approaches allowing for blocking or depleting specific molecular targets, which are of interest in the pathogenesis of MS. While natalizumab received approval by the US Food and Drug Administration and the European Medicines Agency in 2006 as the first monoclonal antibody in MS therapy, rituximab, alemtuzumab, and daclizumab were successfully tested for relapsing-remitting MS in small cohorts in the meantime. Here, we review the data available from these recent phase II trials and at the same time critically discuss possible pitfalls which may be relevant for clinical practice. The results of these studies may not only broaden our therapeutic options in the near future, but also provide new insights into disease pathogenesis

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial

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Anemia in diffuse large B-cell non-Hodgkin lymphoma: the role of interleukin-6, hepcidin and erythropoietin

Item does not contain fulltextAnemia is a frequent sign in patients with diffuse large B-cell lymphoma (DLBCL) at diagnosis. We determined erythropoietin, hepcidin and interleukin-6 (IL-6) in plasma samples of 53 patients with DLBCL. The majority of patients (40/53, 75%) showed defective endogenous erythropoietin production, in particular when anemia was present (p = 0.01). Hepcidin plasma levels were significantly higher in patients compared to controls (p = 0.006), particularly in those with characteristics associated with a more active disease, including elevated lactate dehydrogenase (LDH) (p = 0.0004), B-symptoms (p = 0.07) and an age-adjusted international prognostic index (IPI) score > 1 (p = 0.01). Hepcidin levels correlated strongly to ferritin (r = 0.77, p < 0.0001) and weakly to IL-6 concentrations (r = 0.30, p = 0.03), but not to hemoglobin values. IL-6 inversely correlated to hemoglobin values in both univariate and multivariate analysis (p = 0.04), including hepcidin and erythropoietin as variables. Our findings suggest that elevated hepcidin levels and inadequate erythropoietin response are frequent in DLBCL, but elevated IL-6 plays the major role for the development of anemia

Long-lasting hematologic response to azacitidine in myelodysplastic syndromes: Multicenter retrospective study of 36 patients

Background: Although azacitidine (AZA) has proven effective in myelodysplastic syndromes (MDS), the duration of haematologic response is limited. Introduction: The French Group (Itzykson 2011) identified some clinical and haematologic parameters (poor ECOG performance status, IPSS intermediate and poor risk cytogenetics, circulating blasts, high transfusion need) independently associated with a a poorer outcome, and these 4 criteria were integrated in a 3-group prognostic score. Purpose: These data prompted us to retrospectively analyse our MDS pts treated with AZA who showed a favourable long-lasting response to AZA (i.e: duration of response ≥ 20 months). Materials and Methods: The type of response was defined according to IWG criteria (Cheson 2006): Complete Remission (CR), Marrow CR, Partial Remission (PR), and Hematologic Improvement (HI). Results: Thirty-six pts (M/F: 21/15), from nine Institutions, with a median age of 72 (range 52-84) yrs, showed a response duration ≥ 20 months. At AZA onset, IPSS risk was: low: 3 pts; intermediate- 1: 7 pts; intermediate-2: 21 pts; high: 5 pts. IPSS cytogenetic risk was: low: 23 pts; intermediate: 7 pts; high: 6 pts.Transfusion need was high (≥ 4 RBC units/8 weeks) in 17 pts. Following Itzykson’s AZA prognostic scoring system, the risk was low in 14 pts (38.9%), intermediate in 21 pts (58.3%), and high in 1 pt (2.8%), respectively. The pts received a median of 23.5 cycles of AZA (range: 8-59). The best response achieved was: CR in 21 pts (58.3%); marrow CR: 4 pts (11.1%); PR in 2 pts (5.5%); and HI in 9 pts (25%). Cytogenetic remission was achieved in 7 pts (19.4%). The median duration of response was 24.5 (range: 20-88) months. Twenty-two pts (61.1%) are still maintaining hematologic response, 9 pts (25%) are still alive but discontinued treatment because of disease progression, and 5 pts died (2 for AML). Median OS from the start of AZA was 35.5 (range: 22-120) months. Conclusions: Our data show that a long-lasting hematologic response can be achieved even in a significant fraction of pts presenting one or more poor risk features

Role of glutathione-S-transferase (GST) polymorphisms in patients with advanced Hodgkin lymphoma: results from the HD2000 GISL trial.

Abstract Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1 + vs GSTT1-: HR 5.02, 95% C.I., 1.16-21.8, p = 0.031, GSTM1 + /GSTT1 + vs GSTM1-and/or GSTT1-: HR 4.61, 95% C.I. 1.28- 16.6, p = 0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen