ALBERT

Description: The emergence of B cell receptor (BCR) kinase inhibitors has proved effective for the treatment of a number of B-cell malignancies including chronic lymphocytic leukemia (CLL). BTK and PI3K inhibitors have clear efficacy in suppressing tumor progression but have not been curative. A number of patients have developed resistance to these drugs following mutation of the BTK or PLCγ2 gene. Whilst, other patients are unable to tolerate these drugs due to adverse events or progress whilst on therapy for unknown reasons. Thus the development of novel drugs which are still effective once other BCR-kinases inhibitors become ineffective is of paramount importance. Spleen tyrosine kinase (Syk) is essential for B cell receptor signalling pathways as well as a variety of other surface receptors such as MHCII, FC receptors and integrins, all of which have been shown to play a role in CLL biology. Importantly, Syk inhibition has been shown to overcome resistance to ibrutinib, identifying Syk inhibition as a promising strategy to treat these patients. Furthermore, we have previously shown that IL-4 is found in CLL lymph nodes and can promote resistance to ibrutinib and idelalisib by restoring αIgM induced calcium flux and phosphorylated ERK (ASH 2014, abstract #3299). IL-4 signalling is mediated through the JAK/STAT signalling pathways via JAK1 and JAK3, therefore simultaneous inhibition of both Syk and JAK1/3 may be therapeutically beneficial over BCR kinase inhibitors alone. Cerdulatinib (PRT062070) is a dual JAK/Syk inhibitor in a phase I open label dose escalation study and is currently demonstrating clinical activity in patients with relapsed/refractory B cell malignancies including CLL. Our group has now demonstrated in vitro that cerdulatinib, at plasma concentrations achievable in patients, can induce apoptosis of CLL cells in a concentration and time dependent manner with a mean IC50 of 3µM and 1µM at 48 and 72h respectively, defined by annexin V/PI and cleavage of caspase 3 and poly ADP ribose polymerase (PARP). Apoptosis was caspase dependent since treatment with the pan caspase inhibitor ZVAD.fmk significantly inhibited cerdulatinib induced cell death at 24h. Cerdulatinib induced apoptosis coincided with an increase in pro-apoptotic proteins Noxa and Puma and a decrease in the anti-apoptotic protein Mcl-1. Cerdulatinib significantly inhibited IL-4 induced phosphorylation of STAT6 at 300nM (p=.005), BCR induced phosphorylation of AKTS473 with soluble (p=.008) and bead immobilised (BI) (p=.025) αIgM at 30nM and phosphorylation of AKTT308 with BI αIgM at 300nM (p=.008). Furthermore, in patients with CLL, it is thought that CD40L and IL-4 are key factors, which promote survival of CLL cells in proliferation centres within the lymph node microenvironment. Therefore, we cultured CLL cells with a vehicle control or IL-4CD40L, prior to treatment with cerdulatinib. Cerdulatinib alone induced similar levels of apoptosis irrespective of IL-4/CD40L treatment, suggesting cerdulatinib may be able to overcome microenvironmental signals and target cells within the lymph node. Next we explored the possibility of augmenting cerdulatinib induced apoptosis by simultaneous inhibition with the Bcl-2Bcl-XL inhibitor ABT-199. In vitro in the presence of IL-4/CD40L, ABT-199 synergised with cerdulatinib to induce significantly greater cell death than with either agent alone. Therefore these data provide in vitro evidence for the use of cerdulatinib in clinical trials for the treatment of CLL as either a single agent or in combination with other therapies such as ABT-199. Disclosures Strefford: Roche: Research Funding. Davies:Seattle Genetics: Research Funding; Takeda: Honoraria. Coffey:Portola Pharmaceuticals Inc: Employment, Equity Ownership, Research Funding. Steele:Portola Pharmaceuticals: Other: Travel bursary to ASH 2015; Janssen: Other: Travel bursary to EHA 2015.

Description: Pharmacological inhibition of specific B cell receptor signalling pathways within chronic lymphocytic leukemia (CLL) cells offers the potential for improved therapeutic options with reduced off target toxicity. Idelalisib, the PI3Kδ selective inhibitor, has been approved for CLL and significantly improved overall survival among patients with relapsed CLL in combination with rituximab compared to rituximab alone. In addition to PI3Kδ however, there are three other Class I PI3K isoforms, PI3Kα, PI3Kβ and PI3Kγ, with PI3Kα known to have a role in CLL survival and chemotaxis. In neutrophils, functional redundancy between PI3K isoforms is evident, with inhibition of at least three PI3K isoforms required for maximal apoptosis. Inhibition of mTOR is known to induce cell cycle arrest and apoptosis in CLL cells, however prolonged inhibition of mTOR results in activation of a positive feedback loop resulting in PI3KAkt reactivation. To overcome these caveats, pan PI3K inhibition alongside mTOR inhibition may achieve superior cytotoxicity against CLL cells compared to PI3Kδ or mTOR inhibition alone. We therefore sought to investigate the effect of a dual pan PI3K and mTOR inhibitor, PF-04691502, on primary CLL cells and in the Eµ-TCL1 mouse model of CLL. Twenty five primary CLL samples were treated with PF-04691502 and downstream signalling and subsequent apoptosis assessed by immunoblotting and Annexin V/PI staining respectively. In primary CLL cells, PF-04691502 induced 80% apoptosis after 24 hours at 10µM concentration. PF-04691502 had an IC50 value of 1µM as assessed by Annexin V/PI staining, with minimal toxicity to normal human B or T cells and a trend towards more specific killing in unmutated CLL (p=0.09) compared to mutated CLL. PF-04691502 inhibited both soluble and immobilised anti-IgM induced signalling and overcame anti-IgM induced survival signals. PF-04691502 abrogated CXCL12 induced signalling and impaired subsequent CLL migration towards the chemokine in a transwell chemotaxis assay. Finally, PF-04691502 was able to overcome protection from co-culture with stroma inducing significant apoptosis of CLL cells when added continuously and in wash out experiments. To assess the effect of PF-04691502 in vivo, twenty Eµ-TCL1 mice were inoculated with tumour cells and after day 21 dosed once daily with vehicle, 5mg/kg or 10mg/kg PF-04691502 for a further 14 days. Mice were assessed for leukemic cell counts, spleen size and white blood cell count throughout the duration of the experiment. The effect of PF-04691502 on B cell receptor and chemokine receptor induced signalling in ex vivo Eµ-TCL1 cells was assessed by immunoblotting. Near identical results to the CLL data above were observed. Using Eµ-TCL1 cells isolated from the spleen, PF-04691502 was shown to profoundly inhibit anti-IgM and CXCL12 induced signalling and chemotaxis as well as induce substantial apoptosis as measured by Annexin V/PI staining. Therefore, we subsequently assessed the effect of PF-04691502 in vivo using this model. Mice treated with PF-04691502 displayed a transient increase in leukemic cell numbers in the blood persisting for 1-4 days, followed by a reduction to levels significantly below that of the vehicle control. The whole white blood cell count remained stable in the PF-04691502 treated mice during the course of treatment, whilst the vehicle treated mice showed significant increases in tumour load up to 40×106 cells/ml 33 days post inoculation. Spleen sizes increased steadily over time in the control mice, whilst PF-04691502 treatment prevented this. After 33 days, PF-04691502 treated mice had spleen sizes comparable to non tumor-recipient control animals. In addition, CD5+ B220+ Eµ-TCL1 cells were significantly reduced in the bone marrow, spleen and lymph nodes following PF-04691502 treatment compared to control mice (p=0.0198; p〈 0.0001; p=0.0151 respectively). These results demonstrate that PF-04691502 induces substantial apoptosis of primary CLL cells in vitro and significantly prolongs survival in an in vivo murine model of CLL. Such data indicate that dual pan PI3K/mTOR inhibitors may prove efficacious in the treatment of CLL patients. Disclosures No relevant conflicts of interest to declare.

Description: The tumor B-cell receptor (BCR) is the key to survival and proliferation in chronic lymphocytic leukemia (CLL) and is now a therapeutic target of very effective BCR-associated kinase inhibitors. CLL cells are typically characterized by a variable state of anergy, defined by low surface IgM (sIgM) levels and signaling ability with consequent relatively low proliferation rate. The subset with unmutated IGHV (U-CLL) is generally less anergic with a poorer prognosis than that with mutated IGHV (M-CLL), and appears more sensitive to BCR-inhibitors (Byrd et al., NEJM, 2013). However it remains unclear if the variable anergy reflects the nature of the cell of origin and/or the functional state of the BCR, thereby determining clinical behavior. In this study we investigated if variations of BCR sIgM levels and signaling correlate with clinical behavior of CLL and assessed the phenotypic and genetic associations with the variations. The study included samples at diagnosis or prior to treatment from 222 patients with sIgM/D CLL diagnosed according to the iWCLL2008 criteria (99 months median follow up). sIgM levels on the CD19+/CD5+ CLL cells and signaling [% intracellular Ca2+ mobilization (iCa2+)] were determined using soluble F(ab’)2 polyclonal antibodies (Mockridge at al, Blood, 2007). sIgM levels were analyzed for their association with i) survival, ii) phenotype (CD38, ZAP70 and BCR regulators CD5, CD19, CD20, CD22) and iii) genetic lesions (Del13q, Trisomy12, Del11q/ATM, Del17p/TP53, or NOTCH1 and SF3B1 mutants). Time from diagnosis to progression requiring first treatment (TTFT) was used as primary endpoint, while overall survival (OS) was used as a secondary endpoint to avoid the influences of chemotherapy. Best cut-offs for progression requiring treatment were determined with ROC and Youden’s T-tests (treatment as a state variable). Levels of sIgM (5th-95th percentile 12-378, median 52) varied markedly between patients. Levels were higher at more advanced stage of disease and sIgM expression (MFI〉56) and signaling (iCa2+〉6%) associated with significantly more rapid TTFT. Although sIgD levels and signaling also associated with shorter TTFT, multivariate Cox regression adjusted for IGHV status, sIgM levels, sIgM signaling, sIgD levels and sIgD signaling revealed that only U-IGHV (p

Description: A remarkable feature of chronic lymphocytic leukemia (CLL) is the existence of quasi-identical, stereotyped B-cell receptor immunoglobulins (BcR IGs), strongly supporting an antigen-driven pathway to CLL development. Subsets of cases with distinct stereotyped BcRs collectively account for almost one-third of all CLL. Furthermore, just a handful of major stereotyped subsets represent a substantial fraction of the entire cohort and, perhaps more importantly, an even larger fraction of clinically aggressive CLL. In several major subsets, stereotypy extends from shared primary IG sequences to shared clinical and biological features, including immune signaling, mRNA and miRNA expression, DNA methylation, and genomic aberrations. Regarding the latter, recent evidence indicates that different subsets display distinct profiles of recurrent gene mutations, even when limiting the analysis to subsets with similar IGHV gene mutational status. However, it should be emphasized that even the largest subsets account for only ∼3% of the cases with available IGHV-D-J sequence information, indicating that for meaningful conclusions to be reached, large patient cohorts are essential. Here, taking advantage of a series of 2482 CLL cases consolidated in the context of a multicenter collaboration coordinated by ERIC, the European Research Initiative on CLL, we systematically explored the genetic background of stereotyped subsets. Our main focus was on recurrent mutations in the NOTCH1 (entire exon 34 or targeted analysis for del7544-45), TP53 (exons 4-9), SF3B1 (exons 14-16), BIRC3 (exons 6-9) and MYD88 (exon 5) genes. Overall, 1313 cases (52.9%) carried mutated IGHV genes (M-CLL), whereas the remaining 1169 cases (47.1%) carried unmutated IGHV genes (U-CLL). Cases were sub-classified into the following major subsets: (i) U-CLL: #1, n=72; #3, n=25; #5, n=11; #6, n=22; #7, n=37; #8, n=20; (ii) M-CLL: #4, n=32; #77, n=12; #148, n=20; and, (iii) subset #2 (IGHV3-21, variable mutational status), n=57. Mutations in the MYD88 and BIRC3 genes were relatively rare, with no clear bias to any subset. With regards to the other three genes, only a single mutation in the TP53 gene was identified in a total of 80 M-CLL subset cases. Among U-CLL subsets and clinically aggressive subset #2, we noted asymmetric mutation frequencies, summarized as follows. (1) TP53 mutations were (a) enriched in subsets #3 and #7 (frequency 〉10%) and, in contrast, absent in subsets #5 and #6, though all these subsets utilize the IGHV1-69 gene; (b) enriched in subset #1 (9%) and, interestingly, subset #99, a less populated subset that is highly similar to subset #1 (2/4 cases positive for TP53 mutations); (c) absent in subset #2; and, (d) relatively infrequent in subset #8 (5%), the latter known to display the highest risk for Richter’s transformation among all CLL. Differences between these subsets showed a trend for statistical significance (p=0.09). (2) NOTCH1 mutations exhibited (a) increased frequency in subsets #1 (28%) and #8 (25%); (b) among IGHV1-69 expressing subsets, lower frequencies in subsets #3 (8%), #5 (10%) and #7 (3%) compared to subset #6 (25%); and (c) intermediate frequency (9%) in subset #2 (p=0.0078 for comparison between subsets). (3) SF3B1 mutations were (a) significantly (p

Description: The classification of CLL patients according to the somatic hypermutation status (SHM) of the immunoglobulin heavy variable (IGHV) genes, namely mutated (M-CLL) versus unmutated (U-CLL), reflects fundamental differences in disease biology and clinical course. Realizing this, here we followed a compartmentalized approach and addressed the issue of prognostication separately for M-CLL and U-CLL. In a multi-institutional cohort of 2366 patients [M-CLL, n=1364 (58%); U-CLL, n=1002 (42%)] consolidated within ERIC, the European Initiative in CLL, we assessed the clinical impact of 'traditional' (age and clinical stage at the time of diagnosis, gender, CD38 expression, FISH detected abnormalities included in the Döhner hierarchical model of cytogenetic aberrations), and novel prognosticators (recurrent mutations within the TP53, SF3B1, NOTCH1, MYD88, and BIRC3 genes; IGHV gene usage; membership in stereotyped subsets) within M-CLL and U-CLL. Our statistical approach was based both on Cox regression models and recursive partitioning algorithms; internal validation was performed via bootstrapping procedures. Given the retrospective nature of our study, time-to-first-treatment (TTFT) was the primary endpoint. As expected, M-CLL exhibited significantly longer TTFT compared to U-CLL [median TTFT: not yet reached (M-CLL) vs 1.9 years (95% CI: 0.01-12.3 years, U-CLL), p

Description: In chronic lymphocytic leukemia (CLL), genomic aberrations identify subgroups of patients with distinct treatment outcomes. In particular, patients with deletion of chromosome 17p and/or TP53 gene mutations have inferior prognosis with standard therapy. Hence, screening for these abnormalities is mandatory prior to enrolling patients in clinical trials (CT) and can be also useful in general practice (GP). Recent studies suggest that aberrant p53 function (p53ab), due to TP53 gene mutations and/or del(17p), is only one of several mechanisms underlying clinical aggressiveness. Indeed, mutations in the NOTCH1, SF3B1 and BIRC3 genes have been reported as recurrent in CLL and correlated to poor outcome which is in contrast to mutations in MYD88. An important caveat stemming from published studies is the relative small and hetereogeneous sample size thus making it difficult to draw conclusions regarding the actual incidence and prognostic relevance of these mutations in CLL. The European Research Initiative on CLL (ERIC) is pursuing several studies to shed light on these issues in large and well-annotated CLL series, comprising both GP CLL and CT CLL cases, and here we report the initial results of this project. To date, a total of 3185 patients have been included in the analysis; 596 (18.7%) are CT cases and 2589 (81.3%) GP cases. Mutational screening provided data on NOTCH1 (entire exon 34 or targeted analysis for del7544-45), TP53 (exons 4-9), SF3B1 (exons 14-16), BIRC3 (exons 6-9) and MYD88 (exon 5). For each gene, almost two-thirds of the cases were analyzed within a year of diagnosis. Overall, BIRC3 and MYD88 mutations were relatively rare [25/923 (2.7%) and 24/1085 (2.2%) respectively], however: (i) BIRC3 mutations were significantly (p

Description: SF3B1 is a critical component of the RNA splicing machinery that achieves successful transcription and provides the functional diversity of protein species through alternative splicing. Recent studies have identified SF3B1 mutations in several tumours. In chronic lymphocytic leukemia (CLL) these mutations are associated with altered splicing, reduced survival and resistance to treatment. We therefore hypothesised that inhibition of the spliceosome may be an effective therapeutic strategy in SF3B1 mutated individuals. Initially, we utilized Spliceostatin A (SSA), an agent known to inhibit SF3B1 and alter gene splicing in various cell types. We showed that in CLL cells (SF3B1 WT and mutated samples), SSA treatment resulted in a dose-dependent increase in the un-spliced mRNA of DNAJB1 and RIOK3, two genes known to be regulated by SF3B1. We then assessed the ability of SSA to kill CLL cells with an SF3B1 mutant (n=12) or wild-type (n=28) genotype over a 24 hour period. CLL cells, regardless of SF3B1 mutational status, underwent apoptosis in a dose- (Figure A) and time-dependent manner (data not shown), with a mean IC50 of 5.1 nM. Interestingly, SSA induced more apoptosis in IGHV unmutated-CLL (U-CLL) compared to mutated-CLL samples (M-CLL) (p=0.037) and was active in 17p-deleted CLL (n=7), an aggressive disease sub-type that exhibits pronounced resistance to standard treatments. Normal B and T cells were significantly more resistant to SSA treatment than CLL samples purified from age-matched normal donors (B-cells p=0.006, T-cells p=0.001) and CLL derived T cells (p=0.003). SSA-induced apoptosis proceeded via a caspase-dependent mechanism (inhibited by ZVAD.FMK) coincident with elevations in Noxa. No changes in Bcl-2 or Bcl-xL were observed. Given the known ability of Noxa to interact with, and destabilise, Mcl-1, we next assessed the ability of SSA to modulate Mcl-1, and observed a substantial decrease in protein expression (Figure B, p=0.028). SSA treatment also altered the splicing of MCL-1; reducing the proportion of full length MCL-1L and increasing the amount of MCL-1s transcripts produced. The key role of Mcl-1 in regulating SSA-induced apoptosis was also observed in Ramos cells where over-expression of Mcl-1L, significantly protected them from SSA-induced apoptosis (p=0.001). Furthermore, in CLL cells exposed to CD40L and IL-4, factors known to induce Mcl-1 expression, SSA-induced apoptosis was significantly reduced (p=0.008). Taken together, these data implicate aberrant Mcl-1 splicing and Noxa upregulation in the apoptosis induced after SSA exposure. CD40L and IL-4 are proposed to be key factors preventing the apoptosis of CLL cells in the proliferative niche. Therefore, to explore possible strategies for overcoming this resistance, we investigated combining SSA with the Bcl-2/Bcl-xL inhibitor ABT-263 and showed that dual exposure to both inhibitors significantly increased apoptosis overcoming the protective effects of IL-4/CD40L (p=0.004; Figure C). In conclusion, our data shows that SSA induces apoptosis at nanomolar concentrations in CLL cells, independently of SF3B1 mutational status, through effects on Mcl-1. In combination with ABT-263, we show that SSA is particular active and can overcome the protective effects of CD40L and IL-4, suggesting promising clinical utility. Figure Legend. (A) Annexin V /PI analysis of CLL cells treated with SSA, (B) CLL cells treated with SSA for 24 h followed by immunoblotting for various proteins. (C) Drug combination studies with ABT-263 and SSA at a 1:1 ratio at 10 nM or 20 nM following IL-4/CD40L treatment. Figure Legend. (A) Annexin V /PI analysis of CLL cells treated with SSA, (B) CLL cells treated with SSA for 24 h followed by immunoblotting for various proteins. (C) Drug combination studies with ABT-263 and SSA at a 1:1 ratio at 10 nM or 20 nM following IL-4/CD40L treatment. Disclosures No relevant conflicts of interest to declare.

Description: Histone methyltransferases (HMTs) are important epigenetic regulators of gene transcription and have been found disrupted at the genomic level in a spectrum of human tumors including hematological malignancies. In CLL, recurring genomic lesions targeting chromatin modifiers are emerging in the literature (Puente 2015, Nature) but their biological and clinical significance remain uncertain. We studied 802 CLL patients, divided into a discovery [n=261, sampled pre-treatment] and two validation cohorts [n=541, 431 pre-treatment and 110 ultra-high risk], using high-resolution SNP-arrays [n=572, Affymetrix SNP6.0 and HumanOmniS-8] and high-throughput re-sequencing [n=320, Haloplex and TruSeq] to identify genomic lesions targeting HMT genes. In our discovery cohort, we identified nine novel regions of copy-number changes; the prime finding was a recurrent deletion of chromosome 3p in 4% of patients between genomic positions 47.12-47.36Mb. This region included SETD2, KIF9 and KLHL18 (Fig 1A), with SETD2 being the most significantly under-expressed gene (p=0.001) in 3p-deleted [n=6] versus non-deleted cases [n=8]. Further validation in two independent cohorts showed that SETD2 deletions were enriched in ultra high-risk CLL and associated with loss of TP53 (p=0.003), genomic complexity (in TP53 wild-type cases, p=0.01) and chromothripsis. Next, we screened for somatic mutations in SETD2 using targeted re-sequencing and identified non-synonymous mutations in four (4.5%) discovery cases (p.D99G, p.W1306X, p.Q1545K, p.E1955Q), and 7/231 (3%) in the pre-treatment validation cases (p.A50T, p.P167L, p.E670K, p.M1742L, p.M1889T (x2), p.I2295M) (Fig 1B). Mutations were somatic in all samples tested [n=5]. To study the clonal nature of the SETD2 deletions, we assigned each genomic CNA with a relative copy-number by normalizing CNA intensity values from array features, and could infer that the 3p deletion was in the dominant clonal population in 14/21 cases with data available for analysis. Employing either the ABSOLUTE algorithm for our discovery cohort or manually correcting for tumor sample purity and local copy-number changes in our validation cohort, we observed that 10/11 SETD2 mutations exhibited a clonal cell fraction. These data strongly imply that SETD2 aberrations represent early clonal events in the pathobiology of CLL. Next, we extended our gene expression analysis to include additional wild-type, deleted, and mutated patients, showing reduced expression both in deleted and mutant cases (p=0.035), thus confirming haplo-insufficiency also for the SETD2-mutant cases. W e reviewed the DNA methylation status of the SETD2 gene body and promoter regions (15 & 9 CpG probes, respectively) from published data, and found no correlation between SETD2 methylation and RNA expression, suggesting that DNA methylation does not play a substantial role in regulating SETD2 expression in CLL. Finally, we analyzed the impact of SETD2 lesions on treatment-free survival (TFS) and overall survival (OS). For TFS and OS, we observed a significantly worse outcome (TFS: 44 vs. 105 months; p=0.004, OS: 85 vs. 199 months; p=0.002) in SETD2 deleted cases that were wild-type for TP53/ATM, compared to cases wild type for TP53/ATM/SETD2 (Fig 1D). Mutant SETD2 cases (wild-type for TP53/ATM) and those wild-type for TP53/ATM/SETD2 exhibited median TFS of 74 and 106 months respectively, differences that did not reach significance (p=0.1). Whilst these data suggest that SETD2 lesions may be clinically relevant, further investigations in larger materials are warranted to understand their full impact on survival. In conclusion, we report for the first time somatic deletions and mutations in SETD2, a gene found disrupted invarious human solid and hematological tumors, in ~7% of CLL patients requiring treatment. These are likely to be early clonal events and associate with TP53 dysfunction, genomic complexity and chromothripsis, with deletions enriched in ultra high-risk CLL. Figure 1. SETD2 lesions. A. SNP6.0 data for the del(3p) cases. B. Schematic diagram highlighting the prevalence and positioning of SETD2 mutations. C. Clonal cell fraction data for SETD2 and other gene mutations. D. Treatment-free survival (TFS). Figure 1. SETD2 lesions. A. SNP6.0 data for the del(3p) cases. B. Schematic diagram highlighting the prevalence and positioning of SETD2 mutations. C. Clonal cell fraction data for SETD2 and other gene mutations. D. Treatment-free survival (TFS). Disclosures Tausch: Gilead: Other: Travel support. Steele:Portola Pharmaceuticals: Other: Travel bursary to ASH 2015; Janssen: Other: Travel bursary to EHA 2015. Hillmen:Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dyer:Gilead: Research Funding; Roche Pharmaceuticals: Speakers Bureau; ONO Pharmaceuticals: Research Funding. Stilgenbauer:AbbVie, Amgen, Boehringer-Ingelheim, Celgene, Genentech, Genzyme, Gilead, GSK, Janssen, Mundipharma, Novartis, Pharmacyclics, Roche: Consultancy, Honoraria, Research Funding. Schuh:Acerta Pharma BV: Research Funding. Strefford:Roche: Research Funding.

Description: Background: Although MYD88 L265P is highly frequent in WM, by itself is insufficient to explain disease progression since most cases with IgM MGUS also have mutated MYD88. In fact, the percentage of MYD88 L265P in CD19+ cells isolated from WM patients is typically

Description: Key Points PF-04691502 induces potent apoptosis in CLL cells and suppresses prosurvival anti–immunoglobulin M signaling and CXCL12-induced migration. PF-04691502 displays powerful antitumor effects in vivo in the Eμ-TCL1 mouse model.