Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors: a systematic review and meta-analysis

<p><b>Background</b>: A previous meta-analysis demonstrated that 3 of the new-generation BCR-ABL tyrosine kinase inhibitors (TKIs) (dasatinib, nilotinib and ponatinib) are associated with an increased risk of vascular occlusive events in patients with Ph+ chronic myeloid leukemia compared with imatinib. This meta-analysis of randomized controlled trials aims at assessing these risks separately.</p> <p><b>Methods</b>: The literature search was performed by two independent reviewers following the previous protocol (PROSPERO 2014:CRD42014014147). A random-effects model and a fixed-effect model were used according to the characteristics of the included studies. Peto odds ratios with 95%CI were computed.</p> <p><b>Results</b>: Overall, 4.78% of patients developed arterial occlusive events with new generation TKIs compared with 0.96% with imatinib. Ponatinib (OR_PETO:3.26; 95%CI:1.12 to 9.50), nilotinib (OR_PETO: 3.69; 95%CI:2.29 to 5.95) and dasatinib (OR_PETO:3.32; 95%CI:1.37 to 8.01) are all associated with a higher risk of arterial occlusive events than imatinib. Venous occlusive events occur in 0.72% of patients treated with new generation TKIs and in 0.27% of imatinib-treated patients. Overall, a trend toward an increase of the rate of venous occlusive events with new-generation TKIs (OR_PETO:2.17; 95%CI:0.90 to 5.25) was highlighted but stratifications by treatment gave nonsignificant results.</p> <p><b>Conclusions</b>: Vascular occlusive events associated with new-generation BCR-ABL TKIs are driven by arterial occlusive events.</p

Supplementary_Material – Supplemental material for Circulating MicroRNAs as Biomarkers in Diffuse Large B-cell Lymphoma: A Pilot Prospective Longitudinal Clinical Study

<p>Supplemental material, Supplementary_Material for Circulating MicroRNAs as Biomarkers in Diffuse Large B-cell Lymphoma: A Pilot Prospective Longitudinal Clinical Study by Céline Bouvy, Adeline Wannez, Fabienne George, Carlos Graux, Christian Chatelain and Jean-Michel Dogné in Biomarkers in Cancer</p

Localization of the 3p13/<i>FOXP1</i> breakpoints mapped by FISH in cases with t(3;14)(p13;q32) and non-<i>IG</i> rearrangements of <i>FOXP1</i>.

<p>Schematic representation of the genomic structure of <i>FOXP1</i> is shown in the middle panel and the applied FISH probes are indicated in the lower panel.</p

QRT-PCR analysis of <i>FOXP1</i> mRNA expression.

<p>Examples of QRT-PCR analysis performed in cases with non-<i>IG</i> aberration of <i>FOXP1</i> (cases 3), t(3;14)(p13;q32)/<i>IGH-FOXP1</i> (case 5), FOXP1-positive DLBCL without <i>FOXP1</i> rearrangements (case 8), FOXP1-negative DLBCL (case 16), non-malignant lymph node (NL1) and sorted CD19+ B cells. RPM1-8402, T-ALL cell line expressing <i>FOXP1</i> transcript on low level was used as control. The analyzed exons are marked in the right side of the panel.</p

Partial karyotypes and examples of FISH analysis performed in the index cases.

<p>The applied probes included RP11-79P21-SG and RP11-905F6-SO (<b>a, h</b>), RP11-183N07-SG and RP11-56107-SO (<b>b</b>), FOXP1 BA (<b>c, e, g</b>), RP11-2F13-SO and RP11-346A7-SG (<b>d</b>) and CTD-2234G15-SG and RP11-778P17-SO (<b>f</b>). Note split/separated <i>FOXP1</i> signals in all index cases (<b>a, c, e, g, h</b>), split of RP11-183N07 spanning <i>AP1S3</i>/2q36.1 in case 1 (<b>b</b>), separation of signals flanking the 10q24 breakpoint in case 2 (<b>d</b>) and cohybridization of CTD-2234G15/3p11 and RP11-778P17/3q11 on 3p of inv(3) in case 3 (<b>f</b>).</p

Interaction network of genes differentially expressed by three FOXP1_NT-positive DLBCLs when compared with case 5 expressing FOXP1_FL with the important cancer genes found by IPA.

<p>Continuous and discontinuous lines indicate direct and indirect interactions, respectively. Note that all differentially genes are dysregulated (marked in green). The intensity of the green color reflects the expression level (more intense = lower fold change).</p

Characterization of the <i>PLEKHG1/FOXP</i>1 fusion.

<p>(<b>a</b>) Schematic representation of the <i>PLEKHG1-FOXP1</i> fusion identified by 5′-RACE PCR in case of FOXP1-positive DLBCL (case 7). Sequence analysis showed a fusion between an approximately 270 bp 5′ fragment of <i>PLEKHG1</i> (breakpoint in the intronic region between exon 1 and 2) and exon 7 of <i>FOXP1</i>. (<b>b</b>) Fusion transcript was confirmed by RT- PCR using reverse primer on exon 7 of <i>FOXP1</i> and two forward primers (P1 and P2) on <i>PLEKHG1.</i></p

DataSheet_1_Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis.pdf

IntroductionPoor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT.MethodsWe prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330).ResultsWithin 90 days post-MSC infusion, 53% (95% CI, 35 – 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 109/L, Hb > 80g/L and platelet count > 20 x 109/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 109/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 – 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention.DiscussionIn conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.</p