Immune Checkpoint Inhibitors in AML-A New Frontier

Author(s): Rohit Thummalapalli, Hanna A. Knaus, Ivana Gojo, Joshua F. Zeidner*

Journal Name: Current Cancer Drug Targets

Volume 20 , Issue 7 , 2020

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Despite recent therapeutic advancements, acute myeloid leukemia (AML) remains a challenging clinical entity with overall poor outcomes. Given the evident role of T cell-mediated immunity in response to allogeneic stem cell transplantation and donor lymphocyte infusions, strategies that enhance immune activation and mitigate immune dysfunction represent attractive therapeutic platforms to improve clinical outcomes in AML. Pre-clinical data suggest that immune dysfunction is a major contributor to AML progression and relapse. Increased expression of immune checkpoints such as programmed death 1 (PD-1) contributes to AML immune evasion and is associated with disease progression. Immune checkpoint inhibition is being explored in AML with early evidence of clinical activity, particularly in combination with cytotoxic chemotherapy and hypomethylating agents. In this review, we explore the scientific rationale behind the use of immune checkpoint inhibition either as single agents or in combination with hypomethylating agents or cytotoxic chemotherapy and provide a clinical update of both completed and ongoing trials in AML.

Keywords: Acute myeloid leukemia, immune checkpoint inhibition, PD-1, PD-L1, T cell-mediated immunity, stem cell transplantation.

Schmid, C.; Labopin, M.; Nagler, A.; Niederwieser, D.; Castagna, L.; Tabrizi, R.; Stadler, M.; Kuball, J.; Cornelissen, J.; Vorlicek, J.; Socié, G.; Falda, M.; Vindeløv, L.; Ljungman, P.; Jackson, G.; Kröger, N.; Rank, A.; Polge, E.; Rocha, V.; Mohty, M. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation. Blood, 2012, 119(6), 1599-1606.
[] [PMID: 22167752]
Döhner, H.; Estey, E.H.; Amadori, S.; Appelbaum, F.R.; Büchner, T.; Burnett, A.K.; Dombret, H.; Fenaux, P.; Grimwade, D.; Larson, R.A.; Lo-Coco, F.; Naoe, T.; Niederwieser, D.; Ossenkoppele, G.J.; Sanz, M.A.; Sierra, J.; Tallman, M.S.; Löwenberg, B.; Bloomfield, C.D. European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood, 2010, 115(3), 453-474.
[] [PMID: 19880497]
Postow, M.A.; Chesney, J.; Pavlick, A.C.; Robert, C.; Grossmann, K.; McDermott, D.; Linette, G.P.; Meyer, N.; Giguere, J.K.; Agarwala, S.S.; Shaheen, M.; Ernstoff, M.S.; Minor, D.; Salama, A.K.; Taylor, M.; Ott, P.A.; Rollin, L.M.; Horak, C.; Gagnier, P.; Wolchok, J.D.; Hodi, F.S. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N. Engl. J. Med., 2015, 372(21), 2006-2017.
[] [PMID: 25891304]
Postow, M.A.; Callahan, M.K.; Wolchok, J.D. Immune Checkpoint Blockade in Cancer Therapy. J. Clin. Oncol., 2015, 33(17), 1974-1982.
[] [PMID: 25605845]
Ansell, S.M.; Lesokhin, A.M.; Borrello, I.; Halwani, A.; Scott, E.C.; Gutierrez, M.; Schuster, S.J.; Millenson, M.M.; Cattry, D.; Freeman, G.J.; Rodig, S.J.; Chapuy, B.; Ligon, A.H.; Zhu, L.; Grosso, J.F.; Kim, S.Y.; Timmerman, J.M.; Shipp, M.A.; Armand, P. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N. Engl. J. Med., 2015, 372(4), 311-319.
[] [PMID: 25482239]
Alexandrov, L.B.; Nik-Zainal, S.; Wedge, D.C.; Aparicio, S.A.; Behjati, S.; Biankin, A.V.; Bignell, G.R.; Bolli, N.; Borg, A.; Børresen-Dale, A.L.; Boyault, S.; Burkhardt, B.; Butler, A.P.; Caldas, C.; Davies, H.R.; Desmedt, C.; Eils, R.; Eyfjörd, J.E.; Foekens, J.A.; Greaves, M.; Hosoda, F.; Hutter, B.; Ilicic, T.; Imbeaud, S.; Imielinski, M.; Jäger, N.; Jones, D.T.; Jones, D.; Knappskog, S.; Kool, M.; Lakhani, S.R.; López-Otín, C.; Martin, S.; Munshi, N.C.; Nakamura, H.; Northcott, P.A.; Pajic, M.; Papaemmanuil, E.; Paradiso, A.; Pearson, J.V.; Puente, X.S.; Raine, K.; Ramakrishna, M.; Richardson, A.L.; Richter, J.; Rosenstiel, P.; Schlesner, M.; Schumacher, T.N.; Span, P.N.; Teague, J.W.; Totoki, Y.; Tutt, A.N.; Valdés-Mas, R.; van Buuren, M.M.; van ’t Veer, L.; Vincent-Salomon, A.; Waddell, N.; Yates, L.R.; Zucman-Rossi, J.; Futreal, P.A.; McDermott, U.; Lichter, P.; Meyerson, M.; Grimmond, S.M.; Siebert, R.; Campo, E.; Shibata, T.; Pfister, S.M.; Campbell, P.J.; Stratton, M.R. Australian Pancreatic Cancer Genome Initiative; ICGC Breast Cancer Consortium; ICGC MMML-Seq Consortium; ICGC PedBrain. Signatures of mutational processes in human cancer. Nature, 2013, 500(7463), 415-421.
[] [PMID: 23945592]
Norde, W.J.; Maas, F.; Hobo, W.; Korman, A.; Quigley, M.; Kester, M.G.; Hebeda, K.; Falkenburg, J.H.; Schaap, N.; de Witte, T.M.; van der Voort, R.; Dolstra, H. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res., 2011, 71(15), 5111-5122.
[] [PMID: 21659460]
Ott, P.A.; Hodi, F.S.; Robert, C. CTLA-4 and PD-1/PD-L1 blockade: New immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin. Cancer Res., 2013, 19(19), 5300-5309.
[] [PMID: 24089443]
Wherry, E.J. T cell exhaustion. Nat. Immunol., 2011, 12(6), 492-499.
[] [PMID: 21739672]
Knaus, H.A.; Berglund, S.; Hackl, H.; Blackford, A.L.; Zeidner, J.F.; Montiel-Esparza, R.; Mukhopadhyay, R.; Vanura, K.; Blazar, B.R.; Karp, J.E.; Luznik, L.; Gojo, I. Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. JCI Insight, 2018, 3(21)
[]] [PMID: 30385732]
Le Dieu, R.; Taussig, D.C.; Ramsay, A.G.; Mitter, R.; Miraki-Moud, F.; Fatah, R.; Lee, A.M.; Lister, T.A.; Gribben, J.G. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood, 2009, 114(18), 3909-3916.
[] [PMID: 19710498]
Schnorfeil, F.M.; Lichtenegger, F.S.; Emmerig, K.; Schlueter, M.; Neitz, J.S.; Draenert, R.; Hiddemann, W.; Subklewe, M. T cells are functionally not impaired in AML: increased PD-1 expression is only seen at time of relapse and correlates with a shift towards the memory T cell compartment. J. Hematol. Oncol., 2015, 8, 93.
[] [PMID: 26219463]
Fontenot, J.D.; Rasmussen, J.P.; Williams, L.M.; Dooley, J.L.; Farr, A.G.; Rudensky, A.Y. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity, 2005, 22(3), 329-341.
[] [PMID: 15780990]
Sakaguchi, S.; Yamaguchi, T.; Nomura, T.; Ono, M.; Regulatory, T. Regulatory T cells and immune tolerance. Cell, 2008, 133(5), 775-787.
[] [PMID: 18510923]
Shenghui, Z.; Yixiang, H.; Jianbo, W.; Kang, Y.; Laixi, B.; Yan, Z.; Xi, X. Elevated frequencies of CD4+ CD25+ CD127lo regulatory T cells is associated to poor prognosis in patients with acute myeloid leukemia. Int. J. Cancer, 2011, 129(6), 1373-1381.
[] [PMID: 21105040]
Szczepanski, M.J.; Szajnik, M.; Czystowska, M.; Mandapathil, M.; Strauss, L.; Welsh, A.; Foon, K.A.; Whiteside, T.L.; Boyiadzis, M. Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin. Cancer Res., 2009, 15(10), 3325-3332.
[] [PMID: 19417016]
Wang, X.; Zheng, J.; Liu, J.; Yao, J.; He, Y.; Li, X.; Yu, J.; Yang, J.; Liu, Z.; Huang, S. Increased population of CD4(+)CD25(high), regulatory T cells with their higher apoptotic and proliferating status in peripheral blood of acute myeloid leukemia patients. Eur. J. Haematol., 2005, 75(6), 468-476.
[] [PMID: 16313258]
Kanakry, C.G.; Hess, A.D.; Gocke, C.D.; Thoburn, C.; Kos, F.; Meyer, C.; Briel, J.; Luznik, L.; Smith, B.D.; Levitsky, H.; Karp, J.E. Early lymphocyte recovery after intensive timed sequential chemotherapy for acute myelogenous leukemia: peripheral oligoclonal expansion of regulatory T cells. Blood, 2011, 117(2), 608-617.
[] [PMID: 20935254]
Zeidner, J.F.; Knaus, H.A.; Zeidan, A.M.; Blackford, A.L.; Montiel-Esparza, R.; Hackl, H.; Prince, G.T.; Gondek, L.P.; Ghiaur, G.; Showel, M.M.; DeZern, A.E.; Pratz, K.W.; Douglas Smith, B.; Levis, M.J.; Gore, S.; Coombs, C.C.; Foster, M.C.; Streicher, H.; Karp, J.E.; Luznik, L.; Gojo, I. Immunomodulation with pomalidomide at early lymphocyte recovery after induction chemotherapy in newly diagnosed AML and high-risk MDS. Leukemia, 2020.
[] [PMID: 31900407]
Paul, S.; Lal, G. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. Front. Immunol., 2017, 8, 1124.
[] [PMID: 28955340]
Lion, E.; Willemen, Y.; Berneman, Z.N.; Van Tendeloo, V.F.I.; Smits, E.L.J. Natural killer cell immune escape in acute myeloid leukemia. Leukemia, 2012, 26(9), 2019-2026.
[] [PMID: 22446501]
Costello, R.T.; Sivori, S.; Marcenaro, E.; Lafage-Pochitaloff, M.; Mozziconacci, M.J.; Reviron, D.; Gastaut, J.A.; Pende, D.; Olive, D.; Moretta, A. Defective expression and function of natural killer cell-triggering receptors in patients with acute myeloid leukemia. Blood, 2002, 99(10), 3661-3667.
[] [PMID: 11986221]
Sanchez-Correa, B.; Morgado, S.; Gayoso, I.; Bergua, J.M.; Casado, J.G.; Arcos, M.J.; Bengochea, M.L.; Duran, E.; Solana, R.; Tarazona, R. Human NK cells in acute myeloid leukaemia patients: analysis of NK cell-activating receptors and their ligands. Cancer Immunol. Immunother., 2011, 60(8), 1195-1205.
[] [PMID: 21644031]
Norbert, V. Randomized phase 2 trial of lirilumab (anti-KIR monoclonal antibody, mAb) as maintenance treatment in elderly patients (pts) with acute myeloid leukemia (AML): Results of the effikir trial. Oral Abstract #889: ASH 59th Annual Meeting and Exposition, Atlanta, GA., 2011.
Pyzer, A.R.; Stroopinsky, D.; Rajabi, H.; Washington, A.; Tagde, A.; Coll, M.; Fung, J.; Bryant, M.P.; Cole, L.; Palmer, K.; Somaiya, P.; Karp Leaf, R.; Nahas, M.; Apel, A.; Jain, S.; McMasters, M.; Mendez, L.; Levine, J.; Joyce, R.; Arnason, J.; Pandolfi, P.P.; Kufe, D.; Rosenblatt, J.; Avigan, D. MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia. Blood, 2017, 129(13), 1791-1801.
[] [PMID: 28126925]
Kline, D.E.; MacNabb, B.W.; Chen, X.; Chan, W.C.; Fosco, D.; Kline, J. CD8α+ dendritic cells dictate leukemia-specific CD8+ T cell fates. J. Immunol., 2018, 201(12), 3759-3769.
[] [PMID: 30420437]
Stahl, M.; Goldberg, A.D. Immune checkpoint inhibitors in acute myeloid leukemia: Novel combinations and therapeutic targets. Curr. Oncol. Rep., 2019, 21(4), 37.
[] [PMID: 30904967]
Teague, R.M.; Kline, J. Immune evasion in acute myeloid leukemia: current concepts and future directions. J. Immunother. Cancer, 2013, 1(13), 13.
[] [PMID: 24353898]
Curran, E.K.; Godfrey, J.; Kline, J. Mechanisms of immune tolerance in leukemia and lymphoma. Trends Immunol., 2017, 38(7), 513-525.
[] [PMID: 28511816]
Zhou, Q.; Munger, M.E.; Highfill, S.L.; Tolar, J.; Weigel, B.J.; Riddle, M.; Sharpe, A.H.; Vallera, D.A.; Azuma, M.; Levine, B.L.; June, C.H.; Murphy, W.J.; Munn, D.H.; Blazar, B.R. Program death-1 signaling and regulatory T cells collaborate to resist the function of adoptively transferred cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood, 2010, 116(14), 2484-2493.
[] [PMID: 20570856]
Jia, B.; Wang, L.; Claxton, D.F.; Ehmann, W.C.; Rybka, W.B.; Mineishi, S.; Rizvi, S.; Shike, H.; Bayerl, M.; Schell, T.D.; Hohl, R.J.; Zheng, H. Bone marrow CD8 T cells express high frequency of PD-1 and exhibit reduced anti-leukemia response in newly diagnosed AML patients. Blood Cancer J., 2018, 8(3), 34.
[] [PMID: 29563517]
Dolen, Y.; Esendagli, G. Myeloid leukemia cells with a B7-2(+) subpopulation provoke Th-cell responses and become immuno-suppressive through the modulation of B7 ligands. Eur. J. Immunol., 2013, 43(3), 747-757.
[] [PMID: 23175469]
Zhang, L.; Gajewski, T.F.; Kline, J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood, 2009, 114(8), 1545-1552.
[] [PMID: 19417208]
Berthon, C.; Driss, V.; Liu, J.; Kuranda, K.; Leleu, X.; Jouy, N.; Hetuin, D.; Quesnel, B. In acute myeloid leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors. Cancer Immunol. Immunother., 2010, 59(12), 1839-1849.
[] [PMID: 20814675]
Flutter, B.; Edwards, N.; Fallah-Arani, F.; Henderson, S.; Chai, J.G.; Sivakumaran, S.; Ghorashian, S.; Bennett, C.L.; Freeman, G.J.; Sykes, M.; Chakraverty, R. Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation. J. Clin. Invest., 2010, 120(11), 3855-3868.
[] [PMID: 20978352]
Toffalori, C.; Zito, L.; Gambacorta, V.; Riba, M.; Oliveira, G.; Bucci, G.; Barcella, M.; Spinelli, O.; Greco, R.; Crucitti, L.; Cieri, N.; Noviello, M.; Manfredi, F.; Montaldo, E.; Ostuni, R.; Naldini, M.M.; Gentner, B.; Waterhouse, M.; Zeiser, R.; Finke, J.; Hanoun, M.; Beelen, D.W.; Gojo, I.; Luznik, L.; Onozawa, M.; Teshima, T.; Devillier, R.; Blaise, D.; Halkes, C.J.M.; Griffioen, M.; Carrabba, M.G.; Bernardi, M.; Peccatori, J.; Barlassina, C.; Stupka, E.; Lazarevic, D.; Tonon, G.; Rambaldi, A.; Cittaro, D.; Bonini, C.; Fleischhauer, K.; Ciceri, F.; Vago, L. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat. Med., 2019, 25(4), 603-611.
[] [PMID: 30911134]
Williams, P.; Basu, S.; Garcia-Manero, G.; Hourigan, C.S.; Oetjen, K.A.; Cortes, J.E.; Ravandi, F.; Jabbour, E.J.; Al-Hamal, Z.; Konopleva, M.; Ning, J.; Xiao, L.; Hidalgo Lopez, J.; Kornblau, S.M.; Andreeff, M.; Flores, W.; Bueso-Ramos, C.; Blando, J.; Galera, P.; Calvo, K.R.; Al-Atrash, G.; Allison, J.P.; Kantarjian, H.M.; Sharma, P.; Daver, N.G. The distribution of T-cell subsets and the expression of immune checkpoint receptors and ligands in patients with newly diagnosed and relapsed acute myeloid leukemia. Cancer, 2019, 125(9), 1470-1481.
[] [PMID: 30500073]
Liu, L.; Chang, Y.J.; Xu, L.P.; Zhang, X.H.; Wang, Y.; Liu, K.Y.; Huang, X.J. Reversal of T Cell exhaustion by the first donor lymphocyte infusion is associated with the persistently effective antileukemic responses in patients with relapsed aml after allo-HSCT. Biol. Blood Marrow Transplant., 2018, 24(7), 1350-1359.
[] [PMID: 29649617]
Noviello, M.; Manfredi, F.; Ruggiero, E.; Perini, T.; Oliveira, G.; Cortesi, F.; De Simone, P.; Toffalori, C.; Gambacorta, V.; Greco, R.; Peccatori, J.; Casucci, M.; Casorati, G.; Dellabona, P.; Onozawa, M.; Teshima, T.; Griffioen, M.; Halkes, C.J.M.; Falkenburg, J.H.F.; Stölzel, F.; Altmann, H.; Bornhäuser, M.; Waterhouse, M.; Zeiser, R.; Finke, J.; Cieri, N.; Bondanza, A.; Vago, L.; Ciceri, F.; Bonini, C. Bone marrow central memory and memory stem T-cell exhaustion in AML patients relapsing after HSCT. Nat. Commun., 2019, 10(1), 1065.
[] [PMID: 30911002]
Koestner, W.; Hapke, M.; Herbst, J.; Klein, C.; Welte, K.; Fruehauf, J.; Flatley, A.; Vignali, D.A.; Hardtke-Wolenski, M.; Jaeckel, E.; Blazar, B.R.; Sauer, M.G. PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. Blood, 2011, 117(3), 1030-1041.
[] [PMID: 21063028]
Bashey, A.; Medina, B.; Corringham, S.; Pasek, M.; Carrier, E.; Vrooman, L.; Lowy, I.; Solomon, S.R.; Morris, L.E.; Holland, H.K.; Mason, J.R.; Alyea, E.P.; Soiffer, R.J.; Ball, E.D. CTLA4 blockade with ipilimumab to treat relapse of malignancy after allogeneic hematopoietic cell transplantation. Blood, 2009, 113(7), 1581-1588.
[] [PMID: 18974373]
Davids, M.S.; Kim, H.T.; Bachireddy, P.; Costello, C.; Liguori, R.; Savell, A.; Lukez, A.P.; Avigan, D.; Chen, Y.B.; McSweeney, P.; LeBoeuf, N.R.; Rooney, M.S.; Bowden, M.; Zhou, C.W.; Granter, S.R.; Hornick, J.L.; Rodig, S.J.; Hirakawa, M.; Severgnini, M.; Hodi, F.S.; Wu, C.J.; Ho, V.T.; Cutler, C.; Koreth, J.; Alyea, E.P.; Antin, J.H.; Armand, P.; Streicher, H.; Ball, E.D.; Ritz, J.; Bashey, A.; Soiffer, R.J. Leukemia and lymphoma society blood cancer research partnership. ipilimumab for patients with relapse after allogeneic transplantation. N. Engl. J. Med., 2016, 375(2), 143-153.
[] [PMID: 27410923]
Kadia, T.M. Nivolumab (Nivo) maintenance (maint) in high-risk (HR) acute myeloid leukemia (AML) patients. J. Clin. Oncol., 2018, 36, 7014-7014.
Liu, H. TCR clonal evolution in aml patients in morphologic remission treated with anti-PD1 antibody, nivolumab. Blood, 2016, 128, 2325-2325.
Wong, E. Nivolumab for relapsed or residual haematological malignancies after allogeneic haematopoietic stem cell transplantation (NIVALLO). Blood, 2018, 132, 4633-4633.
Davids, M.S. A phase I/Ib study of nivolumab for relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation (alloHCT). Blood, 2018, 132, 705-705.
Fenaux, P.; Mufti, G.J.; Hellstrom-Lindberg, E.; Santini, V.; Finelli, C.; Giagounidis, A.; Schoch, R.; Gattermann, N.; Sanz, G.; List, A.; Gore, S.D.; Seymour, J.F.; Bennett, J.M.; Byrd, J.; Backstrom, J.; Zimmerman, L.; McKenzie, D.; Beach, C.; Silverman, L.R. International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol., 2009, 10(3), 223-232.
[] [PMID: 19230772]
Fenaux, P.; Mufti, G.J.; Hellström-Lindberg, E.; Santini, V.; Gattermann, N.; Germing, U.; Sanz, G.; List, A.F.; Gore, S.; Seymour, J.F.; Dombret, H.; Backstrom, J.; Zimmerman, L.; McKenzie, D.; Beach, C.L.; Silverman, L.R. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J. Clin. Oncol., 2010, 28(4), 562-569.
[] [PMID: 20026804]
Dombret, H.; Seymour, J.F.; Butrym, A.; Wierzbowska, A.; Selleslag, D.; Jang, J.H.; Kumar, R.; Cavenagh, J.; Schuh, A.C.; Candoni, A.; Récher, C.; Sandhu, I.; Bernal del Castillo, T.; Al-Ali, H.K.; Martinelli, G.; Falantes, J.; Noppeney, R.; Stone, R.M.; Minden, M.D.; McIntyre, H.; Songer, S.; Lucy, L.M.; Beach, C.L.; Döhner, H. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood, 2015, 126(3), 291-299.
[] [PMID: 25987659]
Al-Ali, H.K.; Jaekel, N.; Niederwieser, D. The role of hypomethylating agents in the treatment of elderly patients with AML. J. Geriatr. Oncol., 2014, 5(1), 89-105.
[] [PMID: 24484723]
Kantarjian, H.M.; Thomas, X.G.; Dmoszynska, A.; Wierzbowska, A.; Mazur, G.; Mayer, J.; Gau, J.P.; Chou, W.C.; Buckstein, R.; Cermak, J.; Kuo, C.Y.; Oriol, A.; Ravandi, F.; Faderl, S.; Delaunay, J.; Lysák, D.; Minden, M.; Arthur, C. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J. Clin. Oncol., 2012, 30(21), 2670-2677.
[] [PMID: 22689805]
Blum, W.; Garzon, R.; Klisovic, R.B.; Schwind, S.; Walker, A.; Geyer, S.; Liu, S.; Havelange, V.; Becker, H.; Schaaf, L.; Mickle, J.; Devine, H.; Kefauver, C.; Devine, S.M.; Chan, K.K.; Heerema, N.A.; Bloomfield, C.D.; Grever, M.R.; Byrd, J.C.; Villalona-Calero, M.; Croce, C.M.; Marcucci, G. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc. Natl. Acad. Sci. USA, 2010, 107(16), 7473-7478.
[] [PMID: 20368434]
Short, N.J.; Kantarjian, H.M.; Loghavi, S.; Huang, X.; Qiao, W.; Borthakur, G.; Kadia, T.M.; Daver, N.; Ohanian, M.; Dinardo, C.D.; Estrov, Z.; Kanagal-Shamanna, R.; Maiti, A.; Benton, C.B.; Bose, P.; Alvarado, Y.; Jabbour, E.; Kornblau, S.M.; Pemmaraju, N.; Jain, N.; Gasior, Y.; Richie, M.A.; Pierce, S.; Cortes, J.; Konopleva, M.; Garcia-Manero, G.; Ravandi, F. Treatment with a 5-day versus a 10-day schedule of decitabine in older patients with newly diagnosed acute myeloid leukaemia: a randomised phase 2 trial. Lancet Haematol., 2019, 6(1), e29-e37.
[] [PMID: 30545576]
Stahl, M.; DeVeaux, M.; Montesinos, P.; Itzykson, R.; Ritchie, E.K.; Sekeres, M.A.; Barnard, J.D.; Podoltsev, N.A.; Brunner, A.M.; Komrokji, R.S.; Bhatt, V.R.; Al-Kali, A.; Cluzeau, T.; Santini, V.; Fathi, A.T.; Roboz, G.J.; Fenaux, P.; Litzow, M.R.; Perreault, S.; Kim, T.K.; Prebet, T.; Vey, N.; Verma, V.; Germing, U.; Bergua, J.M.; Serrano, J.; Gore, S.D.; Zeidan, A.M. Hypomethylating agents in relapsed and refractory AML: Outcomes and their predictors in a large international patient cohort. Blood Adv., 2018, 2(8), 923-932.
[] [PMID: 29685952]
DiNardo, C.D.; Pratz, K.; Pullarkat, V.; Jonas, B.A.; Arellano, M.; Becker, P.S.; Frankfurt, O.; Konopleva, M.; Wei, A.H.; Kantarjian, H.M.; Xu, T.; Hong, W.J.; Chyla, B.; Potluri, J.; Pollyea, D.A.; Letai, A. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood, 2019, 133(1), 7-17.
[] [PMID: 30361262]
Potluri, J.; Xu, T.; Hong, W-J.; Mabry, M.H. Phase 3, randomized, double-blind, placebo-controlled study of venetoclax combined with azacitidine versus azacitidine in treatment-naïve patients with acute myeloid leukemia. J. Clin. Oncol., 2017, 35, TPS7069-TPS7069.
DiNardo, C.D.; Rausch, C.R.; Benton, C.; Kadia, T.; Jain, N.; Pemmaraju, N.; Daver, N.; Covert, W.; Marx, K.R.; Mace, M.; Jabbour, E.; Cortes, J.; Garcia-Manero, G.; Ravandi, F.; Bhalla, K.N.; Kantarjian, H.; Konopleva, M. Clinical experience with the BCL2-inhibitor venetoclax in combination therapy for relapsed and refractory acute myeloid leukemia and related myeloid malignancies. Am. J. Hematol., 2018, 93(3), 401-407.
[] [PMID: 29218851]
Aldoss, I.; Yang, D.; Aribi, A.; Ali, H.; Sandhu, K.; Al Malki, M.M.; Mei, M.; Salhotra, A.; Khaled, S.; Nakamura, R.; Snyder, D.; O’Donnell, M.; Stein, A.S.; Forman, S.J.; Marcucci, G.; Pullarkat, V. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. Haematologica, 2018, 103(9), e404-e407.
[] [PMID: 29545346]
Tsai, H-C.; Li, H.; Van Neste, L.; Cai, Y.; Robert, C.; Rassool, F.V.; Shin, J.J.; Harbom, K.M.; Beaty, R.; Pappou, E.; Harris, J.; Yen, R.W.; Ahuja, N.; Brock, M.V.; Stearns, V.; Feller-Kopman, D.; Yarmus, L.B.; Lin, Y.C.; Welm, A.L.; Issa, J.P.; Minn, I.; Matsui, W.; Jang, Y.Y.; Sharkis, S.J.; Baylin, S.B.; Zahnow, C.A. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell, 2012, 21(3), 430-446.
[] [PMID: 22439938]
Wrangle, J.; Wang, W.; Koch, A.; Easwaran, H.; Mohammad, H.P.; Vendetti, F.; Vancriekinge, W.; Demeyer, T.; Du, Z.; Parsana, P.; Rodgers, K.; Yen, R.W.; Zahnow, C.A.; Taube, J.M.; Brahmer, J.R.; Tykodi, S.S.; Easton, K.; Carvajal, R.D.; Jones, P.A.; Laird, P.W.; Weisenberger, D.J.; Tsai, S.; Juergens, R.A.; Topalian, S.L.; Rudin, C.M.; Brock, M.V.; Pardoll, D.; Baylin, S.B. Alterations of immune response of non-small cell lung cancer with Azacytidine. Oncotarget, 2013, 4(11), 2067-2079.
[] [PMID: 24162015]
Chiappinelli, K.B.; Strissel, P.L.; Desrichard, A.; Li, H.; Henke, C.; Akman, B.; Hein, A.; Rote, N.S.; Cope, L.M.; Snyder, A.; Makarov, V.; Budhu, S.; Slamon, D.J.; Wolchok, J.D.; Pardoll, D.M.; Beckmann, M.W.; Zahnow, C.A.; Merghoub, T.; Chan, T.A.; Baylin, S.B.; Strick, R. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell, 2015, 162(5), 974-986.
[] [PMID: 26317466]
Roulois, D.; Loo Yau, H.; Singhania, R.; Wang, Y.; Danesh, A.; Shen, S.Y.; Han, H.; Liang, G.; Jones, P.A.; Pugh, T.J.; O’Brien, C.; De Carvalho, D.D. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell, 2015, 162(5), 961-973.
[] [PMID: 26317465]
Li, H.; Chiappinelli, K.B.; Guzzetta, A.A.; Easwaran, H.; Yen, R.W.; Vatapalli, R.; Topper, M.J.; Luo, J.; Connolly, R.M.; Azad, N.S.; Stearns, V.; Pardoll, D.M.; Davidson, N.; Jones, P.A.; Slamon, D.J.; Baylin, S.B.; Zahnow, C.A.; Ahuja, N. Immune regulation by low doses of the DNA methyltransferase inhibitor 5-azacitidine in common human epithelial cancers. Oncotarget, 2014, 5(3), 587-598.
[] [PMID: 24583822]
Yang, H.; Bueso-Ramos, C.; DiNardo, C.; Estecio, M.R.; Davanlou, M.; Geng, Q.R.; Fang, Z.; Nguyen, M.; Pierce, S.; Wei, Y.; Parmar, S.; Cortes, J.; Kantarjian, H.; Garcia-Manero, G. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia, 2014, 28(6), 1280-1288.
[] [PMID: 24270737]
Ørskov, A.D.; Treppendahl, M.B.; Skovbo, A.; Holm, M.S.; Friis, L.S.; Hokland, M.; Grønbæk, K. Hypomethylation and up regulation of PD-1 in T cells by azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1 and DNA methylation. Oncotarget, 2015, 6(11), 9612-9626.
[] [PMID: 25823822]
Almstedt, M.; Blagitko-Dorfs, N.; Duque-Afonso, J.; Karbach, J.; Pfeifer, D.; Jäger, E.; Lübbert, M. The DNA demethylating agent 5-aza-2′-deoxycytidine induces expression of NY-ESO-1 and other cancer/testis antigens in myeloid leukemia cells. Leuk. Res., 2010, 34(7), 899-905.
[] [PMID: 20381863]
Srivastava, P.; Paluch, B.E.; Matsuzaki, J.; James, S.R.; Collamat-Lai, G.; Blagitko-Dorfs, N.; Ford, L.A.; Naqash, R.; Lübbert, M.; Karpf, A.R.; Nemeth, M.J.; Griffiths, E.A. Induction of cancer testis antigen expression in circulating acute myeloid leukemia blasts following hypomethylating agent monotherapy. Oncotarget, 2016, 7(11), 12840-12856.
[] [PMID: 26883197]
Goodyear, O.; Agathanggelou, A.; Novitzky-Basso, I.; Siddique, S.; McSkeane, T.; Ryan, G.; Vyas, P.; Cavenagh, J.; Stankovic, T.; Moss, P.; Craddock, C. Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood, 2010, 116(11), 1908-1918.
[] [PMID: 20530795]
Peng, D.; Kryczek, I.; Nagarsheth, N.; Zhao, L.; Wei, S.; Wang, W.; Sun, Y.; Zhao, E.; Vatan, L.; Szeliga, W.; Kotarski, J.; Tarkowski, R.; Dou, Y.; Cho, K.; Hensley-Alford, S.; Munkarah, A.; Liu, R.; Zou, W. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature, 2015, 527(7577), 249-253.
[] [PMID: 26503055]
Kim, K.; Skora, A.D.; Li, Z.; Liu, Q.; Tam, A.J.; Blosser, R.L.; Diaz, L.A., Jr; Papadopoulos, N.; Kinzler, K.W.; Vogelstein, B.; Zhou, S. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc. Natl. Acad. Sci. USA, 2014, 111(32), 11774-11779.
[] [PMID: 25071169]
Daver, N.; Garcia-Manero, G.; Basu, S.; Boddu, P.C.; Alfayez, M.; Cortes, J.E.; Konopleva, M.; Ravandi-Kashani, F.; Jabbour, E.; Kadia, T.; Nogueras-Gonzalez, G.M.; Ning, J.; Pemmaraju, N.; DiNardo, C.D.; Andreeff, M.; Pierce, S.A.; Gordon, T.; Kornblau, S.M.; Flores, W.; Alhamal, Z.; Bueso-Ramos, C.; Jorgensen, J.L.; Patel, K.P.; Blando, J.; Allison, J.P.; Sharma, P.; Kantarjian, H. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: A nonrandomized, open-label, phase II study. Cancer Discov., 2019, 9(3), 370-383.
[] [PMID: 30409776]
Daver, N. Azacitidine (AZA) with nivolumab (Nivo), and AZA with Nivo + Ipilimumab (Ipi) in relapsed/refractory acute myeloid leukemia: a non-randomized, prospective, phase 2 study; ASH, 2019.
Gojo, I. multi-center phase 2 study of pembroluzimab (pembro) and azacitidine (AZA) in patients with relapsed/refractory acute myeloid leukemia (Aml) and in newly diagnosed (≥65 years) aml patients; ASH 2019.
Zeidan, A. Efficacy and safety of azacitidine (AZA) in combination with the anti-pd-l1 durvalumab (durva) for the front-line treatment of older patients (pts) with acute myeloid leukemia (AML) who are unfit for intensive chemotherapy (IC) and pts with higher-risk myelodysplastic syndromes (HR-MDS): results from a large, international, randomized phase 2 study; ASH, 2019.
Hay, A.E. Accrual barriers and detection of early toxicity signal in older less-fit patients treated with azacitidine and nivolumab for newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) in the SWOG 1612 platform randomized phase II/III clinical trial. Blood, 2019, 134, 3905-3905.
Fucikova, J.; Kralikova, P.; Fialova, A.; Brtnicky, T.; Rob, L.; Bartunkova, J.; Spísek, R. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res., 2011, 71(14), 4821-4833.
[] [PMID: 21602432]
Ersvaer, E.; Hampson, P.; Hatfield, K.; Ulvestad, E.; Wendelbo, Ø.; Lord, J.M.; Gjertsen, B.T.; Bruserud, Ø. T cells remaining after intensive chemotherapy for acute myelogenous leukemia show a broad cytokine release profile including high levels of interferon-gamma that can be further increased by a novel protein kinase C agonist PEP005. Cancer Immunol. Immunother., 2007, 56(6), 913-925.
[] [PMID: 17115221]
Krönig, H.; Kremmler, L.; Haller, B.; Englert, C.; Peschel, C.; Andreesen, R.; Blank, C.U. Interferon-induced programmed death-ligand 1 (PD-L1/B7-H1) expression increases on human acute myeloid leukemia blast cells during treatment. Eur. J. Haematol., 2014, 92(3), 195-203.
[] [PMID: 24175978]
Behl, D.; Porrata, L.F.; Markovic, S.N.; Letendre, L.; Pruthi, R.K.; Hook, C.C.; Tefferi, A.; Elliot, M.A.; Kaufmann, S.H.; Mesa, R.A.; Litzow, M.R. Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia. Leukemia, 2006, 20(1), 29-34.
[] [PMID: 16281063]
Ravandi, F.; Assi, R.; Daver, N.; Benton, C.B.; Kadia, T.; Thompson, P.A.; Borthakur, G.; Alvarado, Y.; Jabbour, E.J.; Konopleva, M.; Takahashi, K.; Kornblau, S.; DiNardo, C.D.; Estrov, Z.; Flores, W.; Basu, S.; Allison, J.; Sharma, P.; Pierce, S.; Pike, A.; Cortes, J.E.; Garcia-Manero, G.; Kantarjian, H.M. Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study. Lancet Haematol., 2019, 6(9), e480-e488.
[] [PMID: 31400961]
Zeidner, J. Final clinical results of a phase ii study of high dose cytarabine followed by pembrolizumab in relapsed/refractory AML; ASH, 2019.
Lu, S.; Stein, J.E.; Rimm, D.L.; Wang, D.W.; Bell, J.M.; Johnson, D.B.; Sosman, J.A.; Schalper, K.A.; Anders, R.A.; Wang, H.; Hoyt, C.; Pardoll, D.M.; Danilova, L.; Taube, J.M. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: A systematic review and meta-analysis. JAMA Oncol., 2019, 5, 1195-1204.
[] [PMID: 31318407]
Yarchoan, M.; Hopkins, A.; Jaffee, E.M. Tumor mutational burden and response rate to PD-1 inhibition. N. Engl. J. Med., 2017, 377(25), 2500-2501.
[] [PMID: 29262275]
Le, D.T.; Uram, J.N.; Wang, H.; Bartlett, B.R.; Kemberling, H.; Eyring, A.D.; Skora, A.D.; Luber, B.S.; Azad, N.S.; Laheru, D.; Biedrzycki, B.; Donehower, R.C.; Zaheer, A.; Fisher, G.A.; Crocenzi, T.S.; Lee, J.J.; Duffy, S.M.; Goldberg, R.M.; de la Chapelle, A.; Koshiji, M.; Bhaijee, F.; Huebner, T.; Hruban, R.H.; Wood, L.D.; Cuka, N.; Pardoll, D.M.; Papadopoulos, N.; Kinzler, K.W.; Zhou, S.; Cornish, T.C.; Taube, J.M.; Anders, R.A.; Eshleman, J.R.; Vogelstein, B.; Diaz, L.A., Jr PD-1 Blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med., 2015, 372(26), 2509-2520.
[] [PMID: 26028255]
Nakamura, Y. Biomarkers for immune checkpoint inhibitor-mediated tumor response and adverse events. Front. Med. (Lausanne), 2019, 6, 119.
[] [PMID: 31192215]
Jenkins, R.W.; Thummalapalli, R.; Carter, J.; Cañadas, I.; Barbie, D.A. Molecular and genomic determinants of response to immune checkpoint inhibition in cancer. Annu. Rev. Med., 2018, 69, 333-347.
[] [PMID: 29099676]
Chao, M.P.; Takimoto, C.H.; Feng, D.D.; McKenna, K.; Gip, P.; Liu, J.; Volkmer, J.P.; Weissman, I.L.; Majeti, R. Therapeutic targeting of the macrophage immune checkpoint CD47 in myeloid malignancies. Front. Oncol., 2020, 9, 1380.
[] [PMID: 32038992]
Sallman, D.A. The first-in-class anti-CD47 antibody magrolimab (5F9) in combination with azacitidine is effective in MDS and AML patients: Ongoing phase 1b results. Blood, 2019, 134, 569-569.
Greiner, J.; Hofmann, S.; Schmitt, M.; Götz, M.; Wiesneth, M.; Schrezenmeier, H.; Bunjes, D.; Döhner, H.; Bullinger, L. Acute myeloid leukemia with mutated nucleophosmin 1: An immunogenic acute myeloid leukemia subtype and potential candidate for immune checkpoint inhibition. Haematologica, 2017, 102(12), e499-e501.
[] [PMID: 28935849]
Brodská, B.; Otevřelová, P.; Šálek, C.; Fuchs, O.; Gašová, Z.; Kuželová, K. High PD-L1 expression predicts for worse outcome of leukemia patients with concomitant NPM1 and FLT3 mutations. Int. J. Mol. Sci., 2019, 20(11)
[]] [PMID: 31185600]
Zajac, M.; Zaleska, J.; Dolnik, A.; Bullinger, L.; Giannopoulos, K. Expression of CD274 (PD-L1) is associated with unfavourable recurrent mutations in AML. Br. J. Haematol., 2018, 183(5), 822-825.
[] [PMID: 29265177]
Goltz, D.; Gevensleben, H.; Grünen, S.; Dietrich, J.; Kristiansen, G.; Landsberg, J.; Dietrich, D. PD-L1 (CD274) promoter methylation predicts survival in patients with acute myeloid leukemia. Leukemia, 2017, 31(3), 738-743.
[] [PMID: 27840427]
Rutella, S. Immune landscapes predict chemotherapy resistance and anti-leukemic activity of flotetuzumab, an investigational CD123×CD3 Bispecific Dart® Molecule. Patients with Relapsed/Refractory Acute Myeloid Leukemia; ASH, 2019.
Vadakekolathu, J. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. bioRxiv, 2019.702001
Sallman, D.A. Abstract CT068: Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Cancer Res., 2018, 78, CT068-CT068.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Published on: 20 April, 2020
Page: [545 - 557]
Pages: 13
DOI: 10.2174/1568009620666200421081455
Price: $65

Article Metrics

PDF: 76
PRC: 1