Review article: Biomedical intelligence
Vol. 144 No. 4546 (2014)
Role of tumour angiogenesis in haematological malignancies
- Michael Medinger
- Jakob Passweg
Summary
Tumour angiogenesis plays a key role in the pathogenesis and progression of haematological malignancies. Thereby, pro- and anti-angiogenic growth factors and cytokines regulate the angiogenic process. The most important growth factor, vascular endothelial growth factor (VEGF) and its signaling through its receptors 1 and 2, is not only involved in solid tumours, but there is also emerging evidence that tumour progression in haematological malignancies also depends on the induction of new blood vessel formation. The evidence supporting this theory includes the finding of increased bone marrow microvessel density and increased levels of plasma pro-angiogenic cytokines. Leukaemia cells interact with surrounding host cells and extracellular matrix, this crosstalk affecting the most important aspects of the malignant phenotype. The pathophysiology of leukaemia induced angiogenesis involves both direct production of angiogenic cytokines by leukaemia cells and their interaction with bone marrow microenvironment. The inhibition of VEGF signalling by monoclonal antibodies or small molecules (kinase inhibitors) has already been successfully used for the treatment of different cancer entities, and multiple new drugs are being tested. This review summarises recent advances in the basic understanding of the role of angiogenesis in haematological malignancies and the translation of such basic findings into clinical studies.
References
- Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995;1:27–31.
- Perez-Atayde AR, Sallan SE, Tedrow U, Connors S, Allred E, Folkman J. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol. 1997;150:815–21.
- Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.
- Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 2001;7:1194–201.
- Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: novel targets for anti-angiogenesis therapy? Nat Rev Cancer. 2002;2:826–35.
- Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC, et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med. 2005;11:261–2.
- Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843–5.
- Dor Y, Porat R, Keshet E. Vascular endothelial growth factor and vascular adjustments to perturbations in oxygen homeostasis. Am J Physiol Cell Physiol. 2001;280:C1367–74.
- Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:669–76.
- Gille H, Kowalski J, Li B, LeCouter J, Moffat B, Zioncheck TF, et al. Analysis of biological effects and signaling properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2). A reassessment using novel receptor-specific vascular endothelial growth factor mutants. J Biol Chem. 2001;276:3222–30.
- Hattori K, Dias S, Heissig B, Hackett NR, Lyden D, Tateno M, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001;193:1005–14.
- Bellamy WT, Richter L, Frutiger Y, Grogan TM. Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res. 1999;59:728–33.
- Gill M, Dias S, Hattori K, Rivera ML, Hicklin D, Witte L, et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res. 2001;88:167–74.
- Casella I, Feccia T, Chelucci C, Samoggia P, Castelli G, Guerriero R, et al. Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood. 2003;101:1316–23.
- Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362:841–4.
- Medinger M, Mross K. Clinical trials with anti-angiogenic agents in hematological malignancies. J Angiogenes Res. 2010;2:10.
- Medinger M, Fischer N, Tzankov A. Vascular endothelial growth factor-related pathways in hemato-lymphoid malignancies. J Oncol. 2010;2010:729725.
- Aguayo A. The role of angiogenesis in the biology and therapy of myelodysplastic syndromes. Curr Hematol Rep. 2004;3:184–91.
- Medinger M, Skoda R, Gratwohl A, Theocharides A, Buser A, Heim D, et al. Angiogenesis and vascular endothelial growth factor-/receptor expression in myeloproliferative neoplasms: correlation with clinical parameters and JAK2–V617F mutational status. Br J Haematol. 2009;146:150–7.
- Padro T, Ruiz S, Bieker R, Burger H, Steins M, Kienast J, et al. Increased angiogenesis in the bone marrow of patients with acute myeloid leukemia. Blood. 2000;95:2637–44.
- Pruneri G, Bertolini F, Soligo D, Carboni N, Cortelezzi A, Ferrucci PF, et al. Angiogenesis in myelodysplastic syndromes. Br J Cancer. 1999;811398–1401.
- Tzankov A, Heiss S, Ebner S, Sterlacci W, Schaefer G, Augustin F, et al. Angiogenesis in nodal B cell lymphomas: a high throughput study. J Clin Pathol. 2007;60:476–82.
- Vacca A, Ribatti D, Roncali L, Ranieri G, Serio G, Silvestris F, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol. 1994;87:503–8.
- Loges S, Heil G, Bruweleit M, Schoder V, Butzal M, Fischer U, et al. Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival. J Clin Oncol. 2005;23:1109–17.
- Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase2 secretion parallel progression of human multiple myeloma. Blood. 1999;93:3064–73.
- Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA, et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood. 2001;97:3075–85.
- Gordon-Keylock S, Medvinsky A. Endothelio–hematopoietic relationship: getting closer to the beginnings. BMC Biol. 2011;9:88.
- Park C, Ma YD, Choi K. Evidence for the hemangioblast. Exp Hematol. 2005;33:965–70.
- Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–8.
- Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development. 1998;125:725–32.
- Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.
- Dias S, Hattori K, Zhu Z, et al. Autocrine stimulation of VEGFR-2 activates human leukemic cell growth and migration. J Clin Invest. 2000;106:511–21.
- Dias S, Shmelkov SV, Lam G, Rafii S. VEGF(165) promotes survival of leukemic cells by Hsp90–mediated induction of Bcl-2 expression and apoptosis inhibition. Blood. 2002;99:2532–40.
- Fragoso R, Elias AP, Dias S. Autocrine VEGF loops, signaling pathways, and acute leukemia regulation. Leuk Lymphoma. 2007;48:481–8.
- Santos SC, Dias S. Internal and external autocrine VEGF/ KDR loops regulate survival of subsets of acute leukemia through distinct signaling pathways. Blood. 2004;103:3883–9.
- Veiga JP, Costa LF, Sallan SE, Nadler LM, Cardoso AA. Leukemia-stimulated bone marrow endothelium promotes leukemia cell survival. Exp Hematol. 2006;34:610–21.
- Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–9.
- Yetgin S, Yenicesu I, Cetin M, Tuncer M. Clinical importance of serum vascular endothelial and basic fibroblast growth factors in children with acute lymphoblastic leukemia. Leuk Lymphoma. 2001;42:83–8.
- Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86:353–64.
- Dong X, Han ZC, Yang R. Angiogenesis and antiangiogenic therapy in hematologic malignancies. Crit Rev Oncol Hematol. 2007;62:105–18.
- Aguayo A, Kantarjian HM, Estey EH, Giles FJ, Verstovsek S, Manshouri T, et al. Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes. Cancer. 2002;95:1923–30.
- Aguayo A, Estey E, Kantarjian H, Mansouri T, Gidel C, Keating M, et al. Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia. Blood. 1999;94:3717–21.
- Fiedler W, Graeven U, Ergün S, Verago S, Kilic N, Stockschläder M, et al. Vascular endothelial growth factor, a possible paracrine growth factor in human acute myeloid leukemia. Blood. 1997;89:1870–5.
- Chen H, Treweeke AT, West DC, Till KJ, Cawley JC, Zuzel M, et al. In vitro and in vivo production of vascular endothelial growth factor by chronic lymphocytic leukemia cells. Blood. 2000;96:3181–7.
- Gianelli U, Fracchiolla NS, Bucciarelli P, Ferla V, Boiocchi L, Savi F, et al. High levels of vascular endothelial growth factor protein expression are associated with an increased risk of transfusion dependence in myelodysplastic syndromes. Am J Clin Pathol. 2013;139:380–7.
- Zhang J, Ye J, Ma D, Liu N, Wu H, Yu S, et al. Cross-talk between leukemic and endothelial cells promotes angiogenesis by VEGF activation of the Notch/Dll4 pathway. Carcinogenesis. 2013;34:667–77.
- Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays. 1991;13:31–6.
- Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
- Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for nonsmall-cell lung cancer. N Engl J Med. 2006;355:2542–50.
- Zahiragic L, Schliemann C, Bieker R, Thoennissen NH, Burow K, Kramer C, et al. Bevacizumab reduces VEGF expression in patients with relapsed and refractory acute myeloid leukemia without clinical antileukemic activity. Leukemia. 2007;21:1310–2.
- Karp JE, Gojo I, Pili R, Gocke CD, Greer J, Guo C, et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myelogenous leukemias: therapy with sequential 1–beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004;10:3577–85.
- Ossenkoppele GJ, Stussi G, Maertens J, van Montfort K, Biemond BJ, Breems D, et al. Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK). Blood. 2012;120:4706–11.
- Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al., TARGET Study Group: Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.
- Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.
- Drevs J, Müller-Driver R, Wittig C, Fuxius S, Esser N, Hugenschmidt H, et al. PTK787/ZK 222584, a specific vascular endothelial growth factor-receptor tyrosine kinase inhibitor, affects the anatomy of the tumor vascular bed and the functional vascular properties as detected by dynamic enhanced magnetic resonance imaging. Cancer Res. 2002;62:4015–22.
- Mross K, Drevs J, Müller M, Medinger M, Marmé D, Hennig J, et al. Phase I clinical and pharmacokinetic study of PTK/ZK, a multiple VEGF receptor inhibitor, in patients with liver metastases from solid tumours. Eur J Cancer. 2005;41:1291–9.
- Roboz GJ, Giles FJ, List AF, Cortes JE, Carlin R, Kowalski M, et al. Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2006;20:952–7.
- Gupta P, Mulkey F, Hasserjian RP, Sanford BL, Vij R, Hurd DD, et al.; Alliance for Clinical Trials in Oncology. A phase II study of the oral VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK222584) in myelodysplastic syndrome: Cancer and Leukemia Group B study 10105 (Alliance). Invest New Drugs. 2013;31:1311–20.
- Wedge SR, Kendrew J, Hennequin LF, Valentine PJ, Barry ST, Brave SR, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65:4389–400.
- Drevs J, Siegert P, Medinger M, Mross K, Strecker R, Zirrgiebel U, et al. Phase I clinical study of AZD2171, an oral vascular endothelial growth factor signaling inhibitor, in patients with advanced solid tumors. J Clin Oncol. 2007;25:3045–54.
- Fiedler W, Mesters R, Heuser M, Ehninger G, Berdel WE, Zirrgiebel U, et al. An open-label, Phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia. Leuk Res. 2010;34:196–202.
- Metzelder S, Wang Y, Wollmer E, Wanzel M, Teichler S, Chaturvedi A, et al. Compassionate use of sorafenib in FLT3–ITD-positive acute myeloid leukemia: sustained regression before and after allogeneic stem cell transplantation. Blood. 2009;113:6567–71.
- Zheng R, Levis M, Piloto O, Brown P, Baldwin BR, Gorin NC, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004;103:267–74.
- Safaian NN, Czibere A, Bruns I, Fenk R, Reinecke P, Dienst A, et al. Sorafenib (Nexavar) induces molecular remission and regression of extramedullary disease in a patient with FLT3–ITD+ acute myeloid leukemia. Leuk Res. 2009;33:348–50.
- Serve H, Krug U, Wagner R, Sauerland MC, Heinecke A, Brunnberg U, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol. 2013;31:3110–8.
- Guenounou S, Delabesse E, Récher C. Sorafenib plus all-trans retinoic acid for AML patients with FLT3–ITD and NPM1 mutations. Eur J Haematol. 2014. doi: 10.1111/ejh.12334. [Epub ahead of print]
- Ravandi F, Arana Yi C, Cortes JE, Levis M, Faderl S, Garcia-Manero G, et al. Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. Leukemia. 2014;28:1543–5.
- Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565–71.
- Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood. 2001;98:492–4.
- Moncada B, Baranda ML, Gonzalez-Amaro R, Urbina R, Loredo CE. Thalidomide-effect on T cell subsets as a possible mechanism of action. Int J Lepr Other Mycobact Dis. 1985; 53:201–5.
- D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci U S A. 1994;91:4082–5.
- Teo SK. Properties of thalidomide and its analogues: implications for anticancer therapy. AAPS J. 2005, 7:E14–19.
- Dredge K, Marriott JB, Macdonald CD, Man HW, Chen R, Muller GW, et al. Novel thalidomide analogues display antiangiogenic activity independently of immunomodulatory effects. Br J Cancer. 2002;87:1166–72.
- Thomas DA, Estey E, Giles FJ, Faderl S, Cortes J, Keating M, et al. Single agent thalidomide in patients with relapsed or refractory acute myeloid leukaemia. Br J Haematol. 2003;123:436–41.
- Steins MB, Padró T, Bieker R, Ruiz S, Kropff M, Kienast J, et al. Efficacy and safety of thalidomide in patients with acute myeloid leukemia. Blood. 2002;99:834–9.
- Fehniger TA, Byrd JC, Marcucci G, Abboud CN, Kefauver C, Payton JE, et al. Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood. 2009;113:1002–5.
- Sekeres MA, Gundacker H, Lancet J, Advani A, Petersdorf S, Liesveld J, et al. A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605. Blood. 2011;118:523–8.
- Shin DH, Chun YS, Lee DS, Huang LE, Park JW. Bortezomib inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated repression of hypoxia-inducible factor-1. Blood. 2008;111:3131–6.
- Williams S, Pettaway C, Song R, Papandreou C, Logothetis C, McConkey DJ. Differential effects of the proteasome inhibitor bortezomib on apoptosis and angiogenesis in human prostate tumor xenografts. Mol Cancer Ther. 2003;2:835–43.
- Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, et al. Bortezomib mediates antiangiogenesis in multiple myeloma via direct and indirect effects on endothelial cells. Cancer Res. 2006;66:184–91.
- Attar EC, Johnson JL, Amrein PC, Lozanski G, Wadleigh M, DeAngelo DJ, et al. Bortezomib added to daunorubicin and cytarabine during induction therapy and to intermediate-dose cytarabine for consolidation in patients with previously untreated acute myeloid leukemia age 60 to 75 years: CALGB (Alliance) study 10502. J Clin Oncol. 2013;31:923–9.
- Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, et al. Expression of VEGF and its receptors by myeloma cells. Leukemia. 2003;17:2025–31.
- Munshi NC, Wilson C. Increased bone marrow microvessel density in newly diagnosed multiple myeloma carries a poor prognosis. Semin Oncol. 2001;28:565–9.
- Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood. 2001;98:428–35.
- Podar K, Anderson KC. The pathophysiological role of VEGF in hematological malignancies: Therapeutic implications. Blood. 2005;105:1383–95.
- Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood. 2001;98:492–4.
- Rajkumar SV, Blood E, Vesole D, Fonseca R, Greipp PR; Eastern Cooperative Oncology Group. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006;24:431 6.
- Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, et al.; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–32.
- Weber DM, Chen C, Niesvizky R, Wang M, Belch A, Stadtmauer EA, et al.; Multiple Myeloma (009) Study Investigators. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133–42.
- De Luisi A, Ferrucci A, Coluccia AM, et al. Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. Clin Cancer Res. 2011;17:1935–46.
- Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O’Donnell MR, et al. Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory multiple myeloma: a California Cancer Consortium trial. Br J Haematol. 2011;154:533–5.
- White D, Kassim A, Bhaskar B, Yi J, Wamstad K, Paton VE. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer. 2013;119:339–47.
- Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al. A gain-of-function mutation of JAK2 in myeloproliferative isorders. N Engl J Med. 2005;352:1779–90.
- Kralovics R, Teo SS, Li S, Theocharides A, Buser AS, Tichelli A, et al. Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood. 2006;108:1377–80.
- Klampfl T, Gisslinger H, Harutyunyan AS, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013;369:2379–90.
- Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med. 2013;369:2391–405.
- Lundberg LG, Lerner R, Sundelin P, Rogers R, Folkman J, Palmblad J. Bone marrow in polycythemia vera, chronic myelocytic leukemia, and myelofibrosis has an increased vascularity. Am J Pathol. 2000;157:15–19.
- Gianelli U, Vener C, Raviele PR, Savi F, Somalvico F, Calori R, et al. VEGF expression correlates with microvessel density in Philadelphia chromosomenegative chronic myeloproliferative disorders. Am J Clin Pathol. 2007;128:966–73.
- Sozer S, Fiel MI, Schiano T, Xu M, Mascarenhas J, Hoffman R. The presence of JAK2V617F mutation in the liver endothelial cells of patients with Budd-Chiari syndrome. Blood. 2009;113:5246–9.
- Giles FJ, List AF, Carroll M, Cortes JE, Valickas J, Chen BL, et al. PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor of vascular endothelial growth factor (VEGF), has modest activity in myelofibrosis with myeloid metaplasia. Leuk Res. 2007;31:891–7.
- Thomas DA, Giles FJ, Albitar M, Cortes JE, Verstovsek S, Faderl S, et al. Thalidomide therapy for myelofibrosis with myeloid metaplasia. Cancer. 2006;106:1974–84.
- Abgrall JF, Guibaud I, Bastie JN, Flesch M, Rossi JF, Lacotte-Thierry L, et al.; Groupe Ouest-Est Leucémies et Maladies du Sang (GOELAMS). Thalidomide versus placebo in myeloid metaplasia with myelofibrosis: a prospective, randomized, double-blind, multicenter study. Haematologica. 2006;91:1027–32.
- Tefferi A, Cortes J, Verstovsek S, Mesa RA, Thomas D, Lasho TL, et al. Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood. 2006;108:1158–64.
- Quintás-Cardama A, Kantarjian HM, Manshouri T, Thomas D, Cortes J, Ravandi F, et al. Lenalidomide plus prednisone results in durable clinical, histopathologic, and molecular responses in patients with myelofibrosis. J Clin Oncol. 2009;27:4760–6.