Leukemia Research 38 (2014) 660–661
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
VEGF in chronic myeloid leukemia treated with interferon and imatinib
Before having the highly effective tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia in chronic phase (CP-CML) were routinely treated with interferon-based therapies. The driving idea behind this approach came from the best rates of cytogenetic responses (CyR) obtained by Talpaz et al. with partially pure interferon-alpha (IFN␣) [1]. With the advent of recombinant IFN-␣2b and IFN-␣2a first and, there after pegylated-IFN (peg-IFN), higher rates of CyR were confirmed in 10–40% with complete CyR (CCyR) of 5–30% which significantly modified the natural history of CP-CML [2]. Many and partially understood anti-neoplastic mechanisms of action are attributed to INF including inhibition of cell proliferation, promotion of cell differentiation and apoptosis, modulation of gene expression, regulation and restoration of the bone marrow microenvironment and induction of an immune response against CML cells [3]. In addition to several ways of cell survival is the manipulation of the angiogenic factors that provides oxygen and nutrients necessary to ensure their immortality by both, the leukemic cell and its microenvironment. The angiogenic process seems to be quite similar in solid tumors and myeloproliferative disorders being the vascular endothelial growth factor (VEGF) a common key of the process. Most of the myeloproliferative neoplasms have shown elevated concentrations of VEGF with prognostic impact [4]. Chronic myeloid leukemia represents the hematologic cancer with the highest concentrations of VEGF and this feature has been studied as a potential target. In fact imatinib have demonstrated anti-VEGF action but its clinical relevance remains under uncertain interpretation. The study by Legros et al. adds an extra piece of clinical evidence on the importance of the angiogeneic process by confirming that VEGF is an independent factor of BCR-ABL burden and that low concentrations of VEGF at diagnosis are associated with progression-free survival of 100% at 48 months supporting a clinical impact of imatinib on the concentrations of VEGF but most interesting a synergistic effect of the combination of imatinib plus IFN [5]. Antiangiogenic properties of IFN have been investigated in CML. A recent work by the Chinese group using K562 cells transfected with VEGF121 cDNA sense vector (S), anti-sense vector (AS) or vector alone (V) found that the supernatant added to bone marrow endothelial cells of the K562/AS transfectants had a 49% reduction
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2014.01.010. http://dx.doi.org/10.1016/j.leukres.2014.03.015 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
in VEGF secretion and cells transfected with the sense vector exhibit a 3-fold increase in VEGF secretion compared to vector alone. Moreover transplantation of transfected cells with the anti-sense vector into nude mice resulted in decrease tumor microvascular density and increase apoptosis when IFN was added [6]. In the French study decreased concentrations of VEGF were not associated with the CG or molecular response in different time-points, but with progression-free survival [5]. This phenomenom may support the idea that imatinib, and other potent TKIs do not eradicate a subset of quiescent malignant cells responsible of relapse. CML progenitor cells (BCR-ABL+, Lin−, CD34+) belong to a pool of cells referred as “not oncogene addicted” because they have the capacity or remain quiescent in the presence of growth factors in vitro and, most interesting in patients treated with imatinib that achieved and remain in CCyR. In other words, they may possess other mechanisms of survival that are not dependent of harboring the BCR-ABL kinase activity. These other mechanisms, besides overexpression of VEGF and angiogenesis, are activation or disregulation of major oncogenic pathways like JAK-STAT, PI3K/AKT/mTOR, WNT/beta-catetin, and hedgehog pathway among others. TKIs do most of the job by eradicating BCRABL positive cells but this heterogeneity of molecular features of the leukemic stem cell makes more complicated the therapeutic outlook. By stimulating the proliferation and recruitment of the leukemic stem cells to the BCR-ABL sensitive pool, IFN is a prime candidate to combine with imatinib or other highly potent secondor third-generation TKIs. Blockage of VEGF by IFN as adjuvant to TKI is provocative but its clinical relevance remains to be clarified. Funding source None. Conflict of interest Dr. Aguayo receive research funding from Novartis and Bristol Myers Squibb. Acknowledgements To all members of the Hematology and Oncology Department of the National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City.Contributions. Dr. Aguayo wrote all this paper.
Editorial / Leukemia Research 38 (2014) 660–661
References [1] Talpaz M, Kantarjian HM, McCredie KB, Keating MJ, Trujillo J, Gutterman JU. Clinical investigation of human alfa interferon in chronic myelogenous leukemia. Blood 1987;69:1280–8. [2] Kantarjian HM, O’Brien S, Anderlini P, Talpaz M. Treatment of myelogenous leukemia: current status and investigational options. Blood 1996;87: 3069–81. [3] Talpaz M, Hehlmann R, Quintas-Cardama A, Mercer J, Cortes J. Re-emerge of interferon-␣ in the treatment of chronic myeloid leukemia. Leukemia 2013;27:803–12. [4] Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, et al. Angiogenesis in acute and chornic leukemias and myelodysplastic syndromes. Blood 2000;96:2240–5. [5] Legros L, Guilhot J, Huault S, Mahon FX, Preudhomme C, Guilhot F, et al. Interferon decreases VEGF levels in patients with chronic myeloid leukemia treated with imatinib. Leuk Res 2014;38:662–5. [6] Ruan GR, Liu YR, Chen SS, Fu JY, Chang Y, Qin YZ, et al. Effect of antisense VEGF cDNA transfection on the growth of chronic myeloid leukemia K562 cells in vitro and in nude mice. Leuk Res 2004;28:763–9.
661
Alvaro Aguayo ∗ Head of the Department of Hematology and Oncology, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico ∗ Corresponding
author at: Vasco de Quiroga 15, Col. Seccion XVI, Delegacion Tlalpan, Mexico Distrito Federal, C.P. 014000, Mexico. Tel.: +52 5554 87 0900x2700; fax: +52 555485 1760. E-mail addresses: [email protected], [email protected]. 6 March 2014 10 March 2014 16 March 2014 Available online 25 March 2014
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
VEGF in chronic myeloid leukemia treated with interferon and imatinib
Before having the highly effective tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia in chronic phase (CP-CML) were routinely treated with interferon-based therapies. The driving idea behind this approach came from the best rates of cytogenetic responses (CyR) obtained by Talpaz et al. with partially pure interferon-alpha (IFN␣) [1]. With the advent of recombinant IFN-␣2b and IFN-␣2a first and, there after pegylated-IFN (peg-IFN), higher rates of CyR were confirmed in 10–40% with complete CyR (CCyR) of 5–30% which significantly modified the natural history of CP-CML [2]. Many and partially understood anti-neoplastic mechanisms of action are attributed to INF including inhibition of cell proliferation, promotion of cell differentiation and apoptosis, modulation of gene expression, regulation and restoration of the bone marrow microenvironment and induction of an immune response against CML cells [3]. In addition to several ways of cell survival is the manipulation of the angiogenic factors that provides oxygen and nutrients necessary to ensure their immortality by both, the leukemic cell and its microenvironment. The angiogenic process seems to be quite similar in solid tumors and myeloproliferative disorders being the vascular endothelial growth factor (VEGF) a common key of the process. Most of the myeloproliferative neoplasms have shown elevated concentrations of VEGF with prognostic impact [4]. Chronic myeloid leukemia represents the hematologic cancer with the highest concentrations of VEGF and this feature has been studied as a potential target. In fact imatinib have demonstrated anti-VEGF action but its clinical relevance remains under uncertain interpretation. The study by Legros et al. adds an extra piece of clinical evidence on the importance of the angiogeneic process by confirming that VEGF is an independent factor of BCR-ABL burden and that low concentrations of VEGF at diagnosis are associated with progression-free survival of 100% at 48 months supporting a clinical impact of imatinib on the concentrations of VEGF but most interesting a synergistic effect of the combination of imatinib plus IFN [5]. Antiangiogenic properties of IFN have been investigated in CML. A recent work by the Chinese group using K562 cells transfected with VEGF121 cDNA sense vector (S), anti-sense vector (AS) or vector alone (V) found that the supernatant added to bone marrow endothelial cells of the K562/AS transfectants had a 49% reduction
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2014.01.010. http://dx.doi.org/10.1016/j.leukres.2014.03.015 0145-2126/© 2014 Elsevier Ltd. All rights reserved.
in VEGF secretion and cells transfected with the sense vector exhibit a 3-fold increase in VEGF secretion compared to vector alone. Moreover transplantation of transfected cells with the anti-sense vector into nude mice resulted in decrease tumor microvascular density and increase apoptosis when IFN was added [6]. In the French study decreased concentrations of VEGF were not associated with the CG or molecular response in different time-points, but with progression-free survival [5]. This phenomenom may support the idea that imatinib, and other potent TKIs do not eradicate a subset of quiescent malignant cells responsible of relapse. CML progenitor cells (BCR-ABL+, Lin−, CD34+) belong to a pool of cells referred as “not oncogene addicted” because they have the capacity or remain quiescent in the presence of growth factors in vitro and, most interesting in patients treated with imatinib that achieved and remain in CCyR. In other words, they may possess other mechanisms of survival that are not dependent of harboring the BCR-ABL kinase activity. These other mechanisms, besides overexpression of VEGF and angiogenesis, are activation or disregulation of major oncogenic pathways like JAK-STAT, PI3K/AKT/mTOR, WNT/beta-catetin, and hedgehog pathway among others. TKIs do most of the job by eradicating BCRABL positive cells but this heterogeneity of molecular features of the leukemic stem cell makes more complicated the therapeutic outlook. By stimulating the proliferation and recruitment of the leukemic stem cells to the BCR-ABL sensitive pool, IFN is a prime candidate to combine with imatinib or other highly potent secondor third-generation TKIs. Blockage of VEGF by IFN as adjuvant to TKI is provocative but its clinical relevance remains to be clarified. Funding source None. Conflict of interest Dr. Aguayo receive research funding from Novartis and Bristol Myers Squibb. Acknowledgements To all members of the Hematology and Oncology Department of the National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico City.Contributions. Dr. Aguayo wrote all this paper.
Editorial / Leukemia Research 38 (2014) 660–661
References [1] Talpaz M, Kantarjian HM, McCredie KB, Keating MJ, Trujillo J, Gutterman JU. Clinical investigation of human alfa interferon in chronic myelogenous leukemia. Blood 1987;69:1280–8. [2] Kantarjian HM, O’Brien S, Anderlini P, Talpaz M. Treatment of myelogenous leukemia: current status and investigational options. Blood 1996;87: 3069–81. [3] Talpaz M, Hehlmann R, Quintas-Cardama A, Mercer J, Cortes J. Re-emerge of interferon-␣ in the treatment of chronic myeloid leukemia. Leukemia 2013;27:803–12. [4] Aguayo A, Kantarjian H, Manshouri T, Gidel C, Estey E, Thomas D, et al. Angiogenesis in acute and chornic leukemias and myelodysplastic syndromes. Blood 2000;96:2240–5. [5] Legros L, Guilhot J, Huault S, Mahon FX, Preudhomme C, Guilhot F, et al. Interferon decreases VEGF levels in patients with chronic myeloid leukemia treated with imatinib. Leuk Res 2014;38:662–5. [6] Ruan GR, Liu YR, Chen SS, Fu JY, Chang Y, Qin YZ, et al. Effect of antisense VEGF cDNA transfection on the growth of chronic myeloid leukemia K562 cells in vitro and in nude mice. Leuk Res 2004;28:763–9.
661
Alvaro Aguayo ∗ Head of the Department of Hematology and Oncology, National Institute of Medical Sciences and Nutrition Salvador Zubiran, Mexico ∗ Corresponding
author at: Vasco de Quiroga 15, Col. Seccion XVI, Delegacion Tlalpan, Mexico Distrito Federal, C.P. 014000, Mexico. Tel.: +52 5554 87 0900x2700; fax: +52 555485 1760. E-mail addresses: [email protected], [email protected]. 6 March 2014 10 March 2014 16 March 2014 Available online 25 March 2014
