Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma

Facon, Thierry,Dimopoulos, Meletios A.,Dispenzieri, Angela,Catalano, John V.,Belch, Andrew,Cavo, Michele,Pinto, Antonello,Weisel, Katja,Ludwig, Heinz,Bahlis, Nizar J.,Banos, Anne,Tiab, Mourad,Delforge American Society of Hematology 2018 Blood Vol.131 No.3

<P>This FIRST trial final analysis examined survival outcomes in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) treated with lenalidomide and low-dose dexamethasone until disease progression (Rd continuous), Rd for 72 weeks (18 cycles; Rd18), or melphalan, prednisone, and thalidomide (MPT; 72 weeks). The primary endpoint was progression-free survival (PFS; primary comparison: Rd continuous vs MPT). Overall survival (OS) was a key secondary endpoint (final analysis prespecified >= 60 months' follow-up). Patientswere randomized to Rd continuous (n = 535), Rd18 (n = 541), or MPT (n = 547). At a median follow-up of 67 months, PFS was significantly longer with Rd continuous vs MPT (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.59-0.79; P < .00001) andwas similarly extended vs Rd18. Median OS was 10 months longer with Rd continuous vs MPT (59.1 vs 49.1 months; HR, 0.78; 95% CI, 0.67-0.92; P = .0023), and similar with Rd18 (62.3 months). In patients achieving complete or very good partial responses, Rd continuous had an approximate to 30-month longer median time to next treatment vs Rd18 (69.5 vs 39.9 months). Over half of all patients who received second-line treatment were given a bortezomib-based therapy. Second-line outcomes were improved in patients receiving bortezomib after Rd continuous and Rd18 vs after MPT. No new safety concerns, including risk for secondary malignancies, were observed. Treatment with Rd continuous significantly improved survival outcomes vsMPT, supporting Rd continuous as a standard of care for patients with transplant-ineligible NDMM.</P>

Transforming growth factor-β-induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

Kim, Ha-Jeong,Kim, Pan-Kyung,Bae, Sang Mun,Son, Hye-Nam,Thoudam, Debraj Singh,Kim, Jung-Eun,Lee, Byung-Heon,Park, Rang-Woon,Kim, In-San American Society of Hematology 2009 Blood Vol.114 No.25

<B>Abstract</B><P>Transforming growth factor-β-induced protein (TGFBIp)/βig-h3 is a 68-kDa extracellular matrix protein that is functionally associated with the adhesion, migration, proliferation, and differentiation of various cells. The presence of TGFBIp in platelets led us to study the role of this protein in the regulation of platelet functions. Upon activation, platelet TGFBIp was released and associated with the platelets. TGFBIp mediates not only the adhesion and spread of platelets but also activates them, resulting in phosphatidylserine exposure, α-granule secretion, and increased integrin affinity. The fasciclin 1 domains of TGFBIp are mainly responsible for the activation of platelets. TGFBIp promotes thrombus formation on type I fibrillar collagen under flow conditions in vitro and induces pulmonary embolism in mice. Moreover, transgenic mice, which have approximately a 1.7-fold greater blood TGFBIp concentration, are significantly more susceptible to collagen- and epinephrine-induced pulmonary embolism than wild-type mice. These results suggest that TGFBIp, a human platelet protein, plays important roles in platelet activation and thrombus formation. Our findings will increase our understanding of the novel mechanism of platelet activation, contributing to a better understanding of thrombotic pathways and the development of new antithrombotic therapies.</P>

Endothelial progenitor cell homing: prominent role of the IGF2-IGF2R-PLCβ2 axis

Maeng, Yong-Sun,Choi, Hyun-Jung,Kwon, Ja-Young,Park, Yong-Won,Choi, Kyu-Sil,Min, Jeong-Ki,Kim, Yun-Hee,Suh, Pann-Ghill,Kang, Kyung-Sun,Won, Moo-Ho,Kim, Young-Myeong,Kwon, Young-Guen American Society of Hematology 2009 Blood Vol.113 No.1

<B>Abstract</B><P>Homing of endothelial progenitor cells (EPCs) to the neovascular zone is now considered to be an essential step in the formation of vascular networks during embryonic development and also for neovascularization in postnatal life. We report here the prominent role of the insulin-like growth factor 2 (IGF2)/IGF2 receptor (IGF2R) system in promoting EPC homing. With high-level expression of IGF2R in EPCs, IGF2-induced hypoxic conditions stimulated multiple steps of EPC homing in vitro and promoted both EPC recruitment and incorporation into the neovascular area, resulting in enhanced angiogenesis in vivo. Remarkably, all IGF2 actions were exerted predominantly through IGF2R-linked G(i) protein signaling and required intracellular Ca2+ mobilization induced by the β2 isoform of phospholipase C. Together, these findings indicate that locally generated IGF2 at either ischemic or tumor sites may contribute to postnatal vasculogenesis by augmenting the recruitment of EPCs. The utilization of the IGF2/IGF2R system may therefore be useful for the development of novel means to treat angiogenesis-dependent diseases.</P>

Undifferentiated hematopoietic cells are characterized by a genome-wide undermethylation dip around the transcription start site and a hierarchical epigenetic plasticity

Chung, Yun Shin,Kim, Hye Joung,Kim, Tae-Min,Hong, Sung-Hyun,Kwon, Kyung-Rim,An, Sungwhan,Park, Jung-Hoon,Lee, Suman,Oh, Il-Hoan American Society of Hematology 2009 Blood Vol.114 No.24

<B>Abstract</B><P>Evidence for the epigenetic regulation of hematopoietic stem cells (HSCs) is growing, but the genome-wide epigenetic signature of HSCs and its functional significance remain unclear. In this study, from a genome-wide comparison of CpG methylation in human CD34+ and CD34− cells, we identified a characteristic undermethylation dip around the transcription start site of promoters and an overmethylation of flanking regions in undifferentiated CD34+ cells. This “bivalent-like” CpG methylation pattern around the transcription start site was more prominent in genes not associated with CpG islands (CGI−) than CGI+ genes. Undifferentiated hematopoietic cells also exhibited dynamic chromatin associated with active transcription and a higher turnover of histone acetylation than terminally differentiated cells. Interestingly, inhibition of chromatin condensation by chemical treatment (5-azacytidine, trichostatin A) enhanced the self-renewal of “stimulated” HSCs in reconstituting bone marrows but not “steady-state” HSCs in stationary phase bone marrows. In contrast, similar treatments on more mature cells caused partial phenotypic dedifferentiation and apoptosis at levels correlated with their hematopoietic differentiation. Taken together, our study reveals that the undifferentiated state of hematopoietic cells is characterized by a unique epigenetic signature, which includes dynamic chromatin structures and an epigenetic plasticity that correlates to level of undifferentiation.</P>

Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector-transduced CD34+ cells

Kim, Yoo-Jin,Kim, Yoon-Sang,Larochelle, Andre,Renaud, Gabriel,Wolfsberg, Tyra G.,Adler, Rima,Donahue, Robert E.,Hematti, Peiman,Hong, Bum-Kee,Roayaei, Jean,Akagi, Keiko,Riberdy, Janice M.,Nienhuis, Ar American Society of Hematology 2009 Blood Vol.113 No.22

<B>Abstract</B><P>We previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus hematopoietic repopulating cells. To evaluate the persistence of vector-containing and -expressing cells long term, and the safety implications of SIV lentiviral vector-mediated gene transfer, we followed 3 rhesus macaques for more than 4 years after transplantation with transduced CD34+ cells. All 3 animals demonstrated significant vector marking and expression of the GFP transgene in T cells, B cells, and granulocytes, with mean GFP+ levels of 6.7% (range, 3.3%-13.0%), 7.4% (4.2%-13.4%), and 5.6% (3.1%-10.5%), respectively. There was no vector silencing in hematopoietic cells over time. Vector insertion site analysis of granulocytes demonstrated sustained highly polyclonal reconstitution, with no evidence for progression to oligoclonality. A significant number of clones were found to contribute at both 1-year and 3- or 4-year time points. No vector integrations were detected in the MDS1/EVI1 region, in contrast to our previous findings with a γ-retroviral vector. These data show that lentiviral vectors can mediate stable and efficient long-term expression in the progeny of transduced hematopoietic stem cells, with an integration profile that may be safer than that of standard Moloney murine leukemia virus (MLV)-derived retroviral vectors.</P>

Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production

Choi, Yeon-Sook,Choi, Hyun-Jung,Min, Jeong-Ki,Pyun, Bo-Jeong,Maeng, Yong-Sun,Park, Hongryeol,Kim, Jihye,Kim, Young-Myeong,Kwon, Young-Guen American Society of Hematology 2009 Blood Vol.114 No.14

<P>Interleukin-33 (IL-33), a member of the IL-1 cytokine family, is emerging as a new regulator of immune responses and inflammatory vascular diseases. Although IL-33 and its cognate receptor ST2 appear to be expressed in vascular cells, the precise role of IL-33 in the vasculature has not been determined. In this study, we report a novel role of IL-33 as a potent endothelial activator, promoting both angiogenesis and vascular permeability. IL-33 increased proliferation, migration, and morphologic differentiation of human endothelial cells, consistently with increased angiogenesis in vivo. IL-33 also increased endothelial permeability with reduced vascular endothelial-cadherin-facilitated cell-cell junctions in vitro and induced vascular leakage in mouse skin. These effects of IL-33 were blocked by knockdown of ST2. Ligation of IL-33 with ST2 rapidly increased endothelial nitric oxide (NO) production through TRAF6-mediated activation of phosphoinoside-3-kinase, Akt, and endothelial NO synthase. Moreover, pharmacologic or genetic blockage of endothelial NO generation resulted in the inhibition of angiogenesis and vascular hyperpermeability induced by IL-33. These data demonstrate that IL-33 promotes angiogenesis and vascular leakage by stimulating endothelial NO production via the ST2/TRAF6-Akt-eNOS signaling pathway. These findings open new perspectives for the role of IL-33 in the pathogenesis of angiogenesis-dependent and inflammatory vascular diseases.</P>

Cognate CD4 help is essential for the reactivation and expansion of CD8 memory T cells directed against the hematopoietic cell-specific dominant minor histocompatibility antigen, H60

Ryu, Su Jeong,Jung, Kyung Min,Yoo, Hyun Seung,Kim, Tae Woo,Kim, Sol,Chang, Jun,Choi, Eun Young American Society of Hematology 2009 Blood Vol.113 No.18

<B>Abstract</B><P>In contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cell-specific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L−/− hosts. In the CD40−/− hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptide-loaded CD40−/− cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigen-specific CD8 T-cell responses, to maximize the graft-versus-leukemia response.</P>

Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages

Kang, Shinae,Lee, Seung-Pyo,Kim, Kyung Eun,Kim, Hak-Zoo,Mé,met, Sylvie,Koh, Gou Young American Society of Hematology 2009 Blood Vol.113 No.11

<P>The lymphatic vessel is a major conduit for immune cell transport; however, little is known about how lymphatic vessels regulate immune cell trafficking and how lymphatic vessels themselves respond to inflammation. Toll-like receptor 4 (TLR4) plays a central role in lipopolysaccharide (LPS)-induced inflammation, but the role of TLR4 in lymphatic endothelial cells (LECs) is poorly understood. Here, we found that LECs express high amounts of TLR4 in the intracellular region, and that the TLR4 of LECs is the main mediator of nuclear factor-κB (NF-κB) activation by LPS. LPS-TLR4 signaling in LECs resulted in the production of various chemokines for chemotaxis of macrophage. In addition, TLR4 in LECs actively contributed to the recruitment of macrophages to the draining lymphatic vessel. Furthermore, the macrophages that infiltrated into the lymphatic vessel induced lymphangiogenesis by secreting lymphangiogenic growth factors. These phenomena were largely attenuated not only in the mice defective in TLR4 signaling but also in the chimeric mice defective in TLR4 signaling that were recipients for bone marrow transplantation from normal TLR4-signaling mice. In conclusion, TLR4 in LECs plays an essential role in LPS-induced inflammatory lymphangiogenesis by chemotactic recruitment of macrophages.</P>

Expression of Livin, an antiapoptotic protein, is an independent favorable prognostic factor in childhood acute lymphoblastic leukemia

Choi, Jaewon,Hwang, Yu Kyeong,Sung, Ki Woong,Lee, Soo Hyun,Yoo, Keon Hee,Jung, Hye Lim,Koo, Hong Hoe,Kim, Hee-Jin,Kang, Hyong Jin,Shin, Hee Young,Ahn, Hyo Seop American Society of Hematology 2007 Blood Vol.109 No.2

<B>Abstract</B><P>Livin, a member of the inhibitor of apoptosis proteins, has been considered to be a poor prognostic marker in malignancies. However, little is known about the clinical relevance of Livin expression in childhood acute lymphoblastic leukemia (ALL). In this study, the expression of Livin was analyzed in 222 patients with childhood ALL using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) to investigate a possible association with the clinical features at diagnosis and treatment outcomes. Both Livin expression rates and expression levels were higher in patients with favorable prognostic factors. The expression rate was also higher in patients with a favorable day 7 bone marrow response to induction chemotherapy (P < .001). The Livin expression was related to the absence of relapse (P < .001). Similarly, the relapse-free survival rate (± 95% CI) was higher in patients with Livin expression than in patients without Livin expression (97.9% ± 4.0% versus 64.9% ± 11.8%, P < .001). Multivariate analysis for relapse-free survival demonstrated that Livin expression was an independent favorable prognostic factor in childhood ALL (P = .049). This study suggests that Livin expression is a novel prognostic marker in childhood ALL and thus needs to be incorporated into the patient stratification and treatment protocols.</P>

The cell polarity PTK7 receptor acts as a modulator of the chemotherapeutic response in acute myeloid leukemia and impairs clinical outcome

Prebet, Thomas,Lhoumeau, Anne-Catherine,Arnoulet, Christine,Aulas, Anaï,s,Marchetto, Sylvie,Audebert, Sté,phane,Puppo, Francesca,Chabannon, Christian,Sainty, Danielle,Santoni, Marie-Jos&eacu American Society of Hematology 2010 Blood Vol.116 No.13

<B>Abstract</B><P>The pseudo tyrosine kinase receptor 7 (PTK7) is an orphan tyrosine kinase receptor assigned to the planar cell polarity pathway. It plays a major role during embryogenesis and epithelial tissue organization. Here we found that PTK7 is also expressed in normal myeloid progenitors and CD34+ CD38− bone marrow cells in humans. We performed an immunophenotyping screen on more than 300 patients treated for hematologic malignancies. We demonstrated that PTK7 is expressed in acute myeloid leukemia (AML) and is mostly assigned to granulocytic lineage differentiation. Patients with PTK7-positive AML are more resistant to anthracycline-based frontline therapy with a significantly reduced leukemia-free survival in a multivariate analysis model. In vitro, expression of PTK7 in cultured leukemia cells promotes cell migration, cell survival, and resistance to anthracycline-induced apoptosis. The intracellular region of PTK7 is required for these effects. Furthermore, we efficiently sensitized primary AML blasts to anthracycline-mediated cell death using a recombinant soluble PTK7-Fc protein. We conclude that PTK7 is a planar cell polarity component expressed in the myeloid progenitor compartment that conveys promigratory and antiapoptotic signals into the cell and that represents an independent prognosis factor of survival in patients treated with induction chemotherapy.</P>