Immune Checkpoint Inhibitors in Acute Myeloid Leukemia: Novel Combinations and Therapeutic Targets

  • Maximilian Stahl
  • Aaron D. GoldbergEmail author
Leukemia (A Aguayo, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Leukemia


Purpose of Review

Immune checkpoint therapy has dramatically changed the therapeutic landscape of solid malignancies. Here, we review the scientific rationale and current data evaluating immune checkpoint inhibitors in acute myeloid leukemia (AML).

Recent Findings

Immune checkpoint inhibitor monotherapy has shown limited clinical activity in AML. Initial results from early-phase clinical trials suggest that rational combinations of immune checkpoint inhibition with hypomethylating agents (HMAs) are safe and potentially more promising. There are currently no data directly comparing immune checkpoint inhibition to standard therapies. Emerging immune targets more specific for leukemia cells including LILRB4 may improve future therapeutic efficacy.


The success of immune checkpoint inhibition in AML has been modest to date. However, an improved understanding of the biology and the use of rational combinations has potential to improve rates of durable responses. Multiple clinical trials in AML are currently evaluating the use of immune checkpoints alone and in combination.


Acute myeloid leukemia Immune checkpoints Immunotherapy Azacitidine Decitabine Pembrolizumab Ipilimumab Nivolumab PD-1 PD-L1 CTLA-4 LILRB4 


Compliance with Ethical Standards

Conflict of Interest

Maximilian Stahl declares that he has no conflict of interest.

Aaron D. Goldberg has received research funding from Arog Pharmaceuticals, Pfizer, ADC Therapeutics, the American Society of Clinical Oncology, and the American Society of Hematology; and has received speaker’s honorarium and travel reimbursements from DAVA Oncology and compensation from Abbvie, Celgene, and Daiichi-Sankyo for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.CrossRefGoogle Scholar
  2. 2.
    Podoltsev NA, Stahl M, Zeidan AM, et al. Selecting initial treatment of acute myeloid leukaemia in older adults. Blood Rev. 2017;31(2):43–62.
  3. 3.
    Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.CrossRefGoogle Scholar
  4. 4.
    Terwijn M, van Putten WL, Kelder A, et al. High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study. J Clin Oncol. 2013;31:3889–97.CrossRefGoogle Scholar
  5. 5.
    Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood. 2013;122:1813–21.CrossRefGoogle Scholar
  6. 6.
    Kayser S, Walter RB, Stock W, et al. Minimal residual disease in acute myeloid leukemia-current status and future perspectives. Curr Hematol Malig Rep. 2015;10(2):132–44.
  7. 7.
    Anthias C, Dignan FL, Morilla R, Morilla A, Ethell ME, Potter MN, et al. Pre-transplant MRD predicts outcome following reduced-intensity and myeloablative allogeneic hemopoietic SCT in AML. Bone Marrow Transplant. 2014;49:679–83.CrossRefGoogle Scholar
  8. 8.
    Araki D, Wood BL, Othus M, Radich JP, Halpern AB, Zhou Y, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission? J Clin Oncol. 2016;34:329–36.CrossRefGoogle Scholar
  9. 9.
    Ivey A, Hills RK, Simpson MA, Jovanovic JV, Gilkes A, Grech A, et al. Assessment of minimal residual disease in standard-risk AML. N Engl J Med. 2016;374:422–33.CrossRefGoogle Scholar
  10. 10.
    Kadia TM, Ravandi F, Cortes J, Kantarjian H. New drugs in acute myeloid leukemia. Ann Oncol. 2016;27:770–8.CrossRefGoogle Scholar
  11. 11.
    Yates JW, Wallace HJ Jr, Ellison RR, et al. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep. 1973;57:485–8.PubMedGoogle Scholar
  12. 12.
    Stahl M, Lu BY, Kim TK, Zeidan AM. Novel therapies for acute myeloid leukemia: are we finally breaking the deadlock? Target Oncol. 2017;12:413–47.CrossRefGoogle Scholar
  13. 13.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.CrossRefGoogle Scholar
  14. 14.
    Stamm H, Klingler F, Grossjohann E-M, Muschhammer J, Vettorazzi E, Heuser M, et al. Immune checkpoints PVR and PVRL2 are prognostic markers in AML and their blockade represents a new therapeutic option. Oncogene. 2018;37:5269–80.CrossRefGoogle Scholar
  15. 15.
    Lesokhin AM, Callahan MK, Postow MA, et al. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci Transl Med. 2015;7:280sr1.CrossRefGoogle Scholar
  16. 16.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.CrossRefGoogle Scholar
  17. 17.
    Barbee MS, Ogunniyi A, Horvat TZ, Dang TO. Current status and future directions of the immune checkpoint inhibitors ipilimumab, pembrolizumab, and nivolumab in oncology. Ann Pharmacother. 2015;49:907–37.CrossRefGoogle Scholar
  18. 18.
    Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33:1974–82.CrossRefGoogle Scholar
  19. 19.
    Curran E, Corrales L, Kline J. Targeting the innate immune system as immunotherapy for acute myeloid leukemia. Front Oncol. 2015;5:83.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Armand P. Immune checkpoint blockade in hematologic malignancies. Blood. 2015;125:3393–400.CrossRefGoogle Scholar
  21. 21.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372:311–9.CrossRefGoogle Scholar
  22. 22.
    •• Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143–53. This study demonstrates a significant benefit of high-dose ipilimumab in a small subgroup of patients with extramedullary AML relapse after allogeneic stem cell transplant.CrossRefGoogle Scholar
  23. 23.
    Kolb HJ. Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood. 2008;112:4371–83.CrossRefGoogle Scholar
  24. 24.
    Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer. 2004;4:371–80.CrossRefGoogle Scholar
  25. 25.
    Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044–51.Google Scholar
  26. 26.
    Ravandi FD. Dea: phase 2 study of combination of cytarabine, idarubicin, and nivolumab for initial therapy of patients with newly diagnosed acute myeloid leukemia. Atlanta: American Society of Hematology 59th Annual Meeeting; 2017. p. 2017.Google Scholar
  27. 27.
    Zeidner JV. Bea: phase II study of high dose cytarabine followed by pembrolizumab in relapsed/refractory acute myeloid leukemia (AML). Atlanta: American Society of Hematology 59th Annual Meeeting; 2017.Google Scholar
  28. 28.
    •• Daver N, Garcia-Manero G, Basu S, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a non-randomized, open-label, phase 2 study. Cancer Discov. 2018. First study showing a favorably response and survival rate with azacitidine and nivolumab in RR-AML patients compared to historical survival with azacitidine monotherapy in a similar patient population. Google Scholar
  29. 29.
    Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114:1545–52.CrossRefGoogle Scholar
  30. 30.
    Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, et al. 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;116:2484–93.CrossRefGoogle Scholar
  31. 31.
    Kronig H, Kremmler L, Haller B, et al. 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;92:195–203.CrossRefGoogle Scholar
  32. 32.
    Sehgal A, Whiteside TL, Boyiadzis M. Programmed death-1 checkpoint blockade in acute myeloid leukemia. Expert Opin Biol Ther. 2015;15:1191–203.CrossRefGoogle Scholar
  33. 33.
    • Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–8. This study demonstrated that immune checkpoint inhibition is upregulated in response to hypomethylating agents leading to acquired hypomethylating agent resistance. These findings also argue for trials examining the combination of hypomethylating agents with immune checkpoint inhbitors in AML and MDS. CrossRefGoogle Scholar
  34. 34.
    Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MGD, et al. 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;71:5111–22.CrossRefGoogle Scholar
  35. 35.
    Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375:143–53.CrossRefGoogle Scholar
  36. 36.
    Morrissey KM, Yuraszeck TM, Li CC, Zhang Y, Kasichayanula S. Immunotherapy and novel combinations in oncology: current landscape, challenges, and opportunities. Clin Transl Sci. 2016;9:89–104.CrossRefGoogle Scholar
  37. 37.
    Rizvi NA, Hellmann MD, Brahmer JR, Juergens RA, Borghaei H, Gettinger S, et al. Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol. 2016;34:2969–79.CrossRefGoogle Scholar
  38. 38.
    Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39:74–88.CrossRefGoogle Scholar
  39. 39.
    Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.CrossRefGoogle Scholar
  40. 40.
    Galluzzi L, Senovilla L, Zitvogel L, Kroemer G. The secret ally: immunostimulation by anticancer drugs. Nat Rev Drug Discov. 2012;11:215–33.CrossRefGoogle Scholar
  41. 41.
    Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011;8:151–60.CrossRefGoogle Scholar
  42. 42.
    Wemeau M, Kepp O, Tesniere A, et al. Calreticulin exposure on malignant blasts predicts a cellular anticancer immune response in patients with acute myeloid leukemia. Cell Death Dis. 2010;1:e104.CrossRefGoogle Scholar
  43. 43.
    Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61.CrossRefGoogle Scholar
  44. 44.
    Fucikova J, Kralikova P, Fialova A, Brtnicky T, Rob L, Bartunkova J, et al. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res. 2011;71:4821–33.CrossRefGoogle Scholar
  45. 45.
    Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64:1140–5.CrossRefGoogle Scholar
  46. 46.
    Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580–7.CrossRefGoogle Scholar
  47. 47.
    Heninger E, Krueger TE, Lang JM. Augmenting antitumor immune responses with epigenetic modifying agents. Front Immunol. 2015;6:29.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Chiappinelli KB, Strissel PL, Desrichard A, Li H, Henke C, Akman B, et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell. 2015;162:974–86.CrossRefGoogle Scholar
  49. 49.
    Roulois D, Loo Yau H, Singhania R, Wang Y, Danesh A, Shen SY, et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell. 2015;162:961–73.CrossRefGoogle Scholar
  50. 50.
    Kim K, Skora AD, Li Z, Liu Q, Tam AJ, Blosser RL, et al. Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells. Proc Natl Acad Sci U S A. 2014;111:11774–9.CrossRefGoogle Scholar
  51. 51.
    Wang L, Amoozgar Z, Huang J, Saleh MH, Xing D, Orsulic S, et al. Decitabine enhances lymphocyte migration and function and synergizes with CTLA-4 blockade in a murine ovarian cancer model. Cancer Immunol Res. 2015;3:1030–41.CrossRefGoogle Scholar
  52. 52.
    Daver N, Boddu P, Garcia-Manero G, Yadav SS, Sharma P, Allison J, et al. Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes. Leukemia. 2018;32:1094–105.CrossRefGoogle Scholar
  53. 53.
    Almstedt M, Blagitko-Dorfs N, Duque-Afonso J, Karbach J, Pfeifer D, Jäger E, et al. 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;34:899–905.CrossRefGoogle Scholar
  54. 54.
    Srivastava P, Paluch BE, Matsuzaki J, James SR, Collamat-Lai G, Karbach J, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res. 2014;38:1332–41.CrossRefGoogle Scholar
  55. 55.
    Goodyear O, Agathanggelou A, Novitzky-Basso I, Siddique S, McSkeane T, Ryan G, et al. 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;116:1908–18.CrossRefGoogle Scholar
  56. 56.
    Orskov AD, Treppendahl MB, Skovbo A, et al. 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;6:9612–26.CrossRefGoogle Scholar
  57. 57.
    Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E, et al. PRC2 epigenetically silences Th1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res. 2016;76:275–82.CrossRefGoogle Scholar
  58. 58.
    Dear AE. Epigenetic modulators and the new immunotherapies. N Engl J Med. 2016;374:684–6.CrossRefGoogle Scholar
  59. 59.
    Srivastava P, Paluch BE, Matsuzaki J, et al. Induction of cancer testis antigen expression in circulating acute myeloid leukemia blasts following hypomethylating agent monotherapy. Oncotarget. 2016.Google Scholar
  60. 60.
    Peng D, Kryczek I, Nagarsheth N, Zhao L, Wei S, Wang W, et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature. 2015;527:249–53.CrossRefGoogle Scholar
  61. 61.
    Steinmann J, Bertz H, Wasch R, et al. 5-Azacytidine and DLI can induce long-term remissions in AML patients relapsed after allograft. Bone Marrow Transplant. 2015;50(5):690–5.
  62. 62.
    Zappasodi R, Merghoub T, Wolchok JD. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer Cell. 2018;33:581–98.CrossRefGoogle Scholar
  63. 63.
    Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2:393–8.CrossRefGoogle Scholar
  64. 64.
    Andrews LP, Marciscano AE, Drake CG, Vignali DAA. LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev. 2017;276:80–96.CrossRefGoogle Scholar
  65. 65.
    Lichtenegger FS, Rothe M, Schnorfeil FM, Deiser K, Krupka C, Augsberger C, et al. Targeting LAG-3 and PD-1 to enhance T cell activation by antigen-presenting cells. Front Immunol. 2018;9:385.CrossRefGoogle Scholar
  66. 66.
    Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010;7:708–17.CrossRefGoogle Scholar
  67. 67.
    Paola Dama MT, Fulton N, et al. Profiling the immune checkpoint pathway in acute myeloid leukemia: American Society of Clinical Oncology (ASCO) meeting; 2018.Google Scholar
  68. 68.
    Rosenblatt J, Stone RM, Uhl L, et al. Individualized vaccination of AML patients in remission is associated with induction of antileukemia immunity and prolonged remissions. Sci Transl Med. 2016;8:368ra171.CrossRefGoogle Scholar
  69. 69.
    Versteven M, Van den Bergh JMJ, Marcq E, et al. Dendritic cells and programmed death-1 blockade: a joint venture to combat cancer. Front Immunol. 2018;9:394.
  70. 70.
    •• Deng M, Gui X, Kim J, et al. LILRB4 signalling in leukaemia cells mediates T cell suppression and tumour infiltration. Nature. 2018;562:605–9. This paper demonstrated that leukocyte immunoglobulin–like receptor B4 (LILRB4) is a promising new target for immune checkpoint inhibition in monocytic AML. CrossRefGoogle Scholar
  71. 71.
    Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.CrossRefGoogle Scholar
  72. 72.
    Yarchoan M, Hopkins A, Jaffee EM. Tumor mutational burden and response rate to PD-1 inhibition. N Engl J Med. 2017;377:2500–1.CrossRefGoogle Scholar
  73. 73.
    Lamble AJ, Lind EF. Targeting the immune microenvironment in acute myeloid leukemia: a focus on T cell immunity. Front Oncol. 2018;8:213.CrossRefGoogle Scholar
  74. 74.
    Patrick Williams SB, Garcia-Manero G, et al. Treg infiltration and the expression of immune checkpoints associated with T cell exhaustion in AML: American Society of Clinical Oncology (ASCO) meeting; 2018.Google Scholar
  75. 75.
    Pyzer AR, Stroopinsky D, Rajabi H, Washington A, Tagde A, Coll M, et al. MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia. Blood. 2017;129:1791–801.CrossRefGoogle Scholar
  76. 76.
    El Kholy NM, Sallam MM, Ahmed MB, et al. Expression of indoleamine 2,3-dioxygenase in acute myeloid leukemia and the effect of its inhibition on cultured leukemia blast cells. Med Oncol. 2011;28(1):270–8.
  77. 77.
    Mabuchi R, Hara T, Matsumoto T, Shibata Y, Nakamura N, Nakamura H, et al. High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia. Leuk Lymphoma. 2016;57:92–8.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Medicine, Division of Hematologic MalignanciesMemorial Sloan Kettering Cancer CenterNew YorkUSA

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