Annals of Hematology

, Volume 96, Issue 9, pp 1441–1448 | Cite as

PD-1 signaling and inhibition in AML and MDS

  • Faysal HarounEmail author
  • Sade A. Solola
  • Samah Nassereddine
  • Imad Tabbara
Review Article


Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are clinically and molecularly heterogeneous clonal myeloid disorders with a poor prognosis especially in the relapsed refractory setting and in patients above the age of 60. While allogeneic hematopoietic stem cell transplantation (ASCT) is a potentially curative approach, high relapse, morbidity, and mortality rates necessitate the development of alternative therapies. Immune checkpoint inhibitors unmask tumoral immune tolerance and have demonstrated efficacy in the treatment of chemotherapy-resistant hematologic and solid malignancies. The rationale for the investigation of those agents in AML and MDS is supported by an observed increased expression of programmed cell death 1 protein (PD-1) and ligand 1 (PD-L1) in the hematopoietic microenvironment of AML and MDS, and its association with low TP53 and a poor prognosis. Early clinical experience in combination with a hypomethylating agent has shown encouraging responses; however, larger clinical trials are needed to determine the role of checkpoint inhibition in myeloid malignancies.


Acute myeloid leukemia Myelodysplastic syndrome AML MDS Immunotherapy PD-1 PD-L1 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Oran B, Weisdorf DJ (2012) Survival for older patients with acute myeloid leukemia: a population-based study. Haematologica 97(12):1916–1924CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Juliusson G, Lazarevic V, Hörstedt A-S, Hagberg O, Höglund M, Swedish Acute Leukemia Registry Group E et al (2012) Acute myeloid leukemia in the real world: why population-based registries are needed. Blood 119(17):3890–3899. Available from: CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stone RM, Mandrekar S, Sanford BL, Geyer S, Bloomfield CD, Dohner K et al (2015) The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with <em>FLT3</em> mutations (muts): an international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood 126(23):6 LP-6 Available from: Google Scholar
  4. 4.
    Powles RL, Russell J, Lister TA, Oliver T, Whitehouse JM, Malpas J et al (1977) Immunotherapy for acute myelogenous leukaemia: a controlled clinical study 2 1/2 years after entry of the last patient. Br J Cancer [Internet] 35(3):265–272 Available from: CrossRefPubMedCentralGoogle Scholar
  5. 5.
    Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M et al (2015) PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 372(4):311–319CrossRefPubMedGoogle Scholar
  6. 6.
    Armand P (2015) Immune checkpoint blockade in hematologic malignancies. Blood 125(22):3393–3400 Available from: CrossRefPubMedGoogle Scholar
  7. 7.
    Swerdlow SH, Campo E, Pileri SA, Lee Harris N, Stein H, Siebert R et al (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127:2375–2390Google Scholar
  8. 8.
    Deschler B, Lübbert M (2006) Acute myeloid leukemia: epidemiology and etiology. Cancer 107(9):2099–2107CrossRefPubMedGoogle Scholar
  9. 9.
    Crane MM, Strom SS, Halabi S, Berman EL, Fueger JJ, Spitz MR, et al. Correlation between selected environmental exposures and karyotype in acute myelocytic leukemia. Cancer Epidemiol Biomarkers & Prev [Internet]. 1996 1;5(8):639 LP-644 Available from:
  10. 10.
    Tamamyan G, Kadia T, Ravandi F, Borthakur G, Cortes J, Jabbour E, et al. Frontline treatment of acute myeloid leukemia in adults. Crit Rev Oncol / Hematol [Internet]. Elsevier; 2017 13;110:20–34. Available from: doi: 10.1016/j.critrevonc.2016.12.004
  11. 11.
    Gardin C, Chevret S, Pautas C, Turlure P, Raffoux E, Thomas X et al (2013) Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older. J Clin Oncol 31(3):321–327CrossRefPubMedGoogle Scholar
  12. 12.
    Wiernik PH, Banks PL, Case DCJ, Arlin ZA, Periman PO, Todd MB, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood [Internet]. 1992 Jan 15;79(2):313 LP-319 Available from:
  13. 13.
    Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P et al (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med [Internet] 331(14):896–903. Available from: CrossRefGoogle Scholar
  14. 14.
    Dail M, Yang L, Green C, Ma C, Robert A, Kadel EE, et al. Distinct patterns of PD-L1 and PD-L2 expression by tumor and non-tumor cells in patients with MM, MDS and AML. Blood [Internet]. 2016 Dec 1;128(22):1340 LP-1340 Available from:
  15. 15.
    Daver N, Basu S, Garcia-Manero G, Cortes JE, Ravandi F, Ning J, et al. Defining the immune checkpoint landscape in patients (pts) with acute myeloid leukemia (AML). Blood [Internet]. 2016 Dec 1;128(22):2900 LP-2900 Available from:
  16. 16.
    Wang S, Wang T, Li M, Cheng X, Li X (2016) Expression of microRNA miR-34a inhibits leukemia stem cells and its metastasis. Eur Rev Med Pharmacol Sci 20:2878–2883PubMedGoogle Scholar
  17. 17.
    Zajac M, Zaleska J, Dolnik A, Siwiec A, Jankowska-Lecka O, Mlak R, et al. Analysis of the PD-1/PD-L1 axis points to association of unfavorable recurrent mutations with PD-L1 expression in AML. Blood [Internet]. 2016 Dec 1;128(22):1685 LP-1685 Available from:
  18. 18.
    Yang S, Huang XJ. The poorer-risk AML, the weaker immunologic surveillance?—higher PD-L1 expression on non-APL AML cells is associated with poorer risk status according to cytogenetics and molecular abnormailties. Blood [Internet]. 2016 Dec 1;128(22):1619 LP-1619 Available from:
  19. 19.
    Daver N, Basu S, Garcia-Manero G, Cortes JE, Ravandi F, Jabbour EJ, et al. Phase IB/II study of nivolumab in combination with azacytidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML). Blood [Internet]. 2016 Dec 1;128(22):763 LP-763 Available from:
  20. 20.
    Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood [Internet]. 2011 Feb 24;117(8):2307 LP-2318 Available from:
  21. 21.
    Frey NV, Porter DL (2010) Hematopoietic stem cell transplantation: ASBMT/CIBMTR 2010 tandem meeting highlights and discussion. Am J Hematol 85(7):519–523CrossRefGoogle Scholar
  22. 22.
    Pasquini MC WZ, Pasquini M, Wang Z. Current use and outcome of hematopoietic stem cell transplantation. [Internet]. CIBMTR Summary Slides 2013. Available from:
  23. 23.
    Kong Y, Zhang J, Claxton DF, Ehmann WC, Rybka WB, Zhu L, et al. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation. Blood Cancer J [Internet]. Nature Publishing Group; 2015 Jul 31;5(7):e330 Available from:
  24. 24.
    Merryman RW, Kim HT, Zinzani PL, Carlo-stella C, Ansell SM, Perales M, et al. Safety and ef fi cacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed / refractory lymphoma. 2017;129(10):1380–9.Google Scholar
  25. 25.
    Haverkos BM, Schowinksy J, Kaplan J, Kamdar M, Kanate AS, Saad A, et al. Checkpoint blockade for treatment of relapsed lymphoma following allogeneic hematopoietic cell transplant: use may be complicated by onset of severe acute graft versus host disease. Blood [Internet]. 2016 Dec 1;128(22):1163 LP-1163 Available from:
  26. 26.
    Davids MS, Kim HT, Bachireddy P, Costello C, Liguori R, Savell A et al (2016) Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med [Internet] 375(2):143–153 Available from: CrossRefGoogle Scholar
  27. 27.
    Ma X, Does M, Raza A, Mayne ST (2007) Myelodysplastic syndromes: incidence and survival in the United States. Cancer 109(8):1536–1542CrossRefPubMedGoogle Scholar
  28. 28.
    Parikh A, Olnes MJ, Barrett AJ (2012) Immunomodulatory treatment of myelodysplastic syndromes: antithymocyte globulin, cyclosporine, and alemtuzumab. Semin Hematol [Internet] 49(4):304–311 Available from: CrossRefGoogle Scholar
  29. 29.
    Saunthararajah Y, Nakamura R, Wesley R, Wang QJ, Barrett AJ. A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome. Blood [Internet]. 2003 Oct 3;102(8):3025 LP-3027 Available from:
  30. 30.
    Fenaux P, Ades L (2013) How we treat lower-risk myelodysplastic syndromes. Blood 121(21):4280–4286CrossRefPubMedGoogle Scholar
  31. 31.
    Sekeres MA, Cutler C (2014) How we treat higher-risk myelodysplastic syndromes. Blood 123:829–836CrossRefPubMedGoogle Scholar
  32. 32.
    Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M et al (2011) A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low−/intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118(14):3765–3776CrossRefPubMedGoogle Scholar
  33. 33.
    Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al (2009) 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 [Internet] 10(3):223–232 Available from: CrossRefGoogle Scholar
  34. 34.
    Kantarjian H, Rosenfeld CS, Bennett JM, Albitar M, DiPersio J, Klimek V, Slack J, de Castro C, Ravandi F, Helmer R, Shen L, Nimer SD, Leavitt R, Raza A, Saba HIJP (2006) Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer [Internet] 106(8):1794 Available from: CrossRefGoogle Scholar
  35. 35.
    Wolff F, Leisch M, Greil R, Risch A, Pleyer L (2017) The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation. Cell Commun Signal [Internet] 15(1):13 Available from: CrossRefGoogle Scholar
  36. 36.
    Coats T, Smith A E, Mourikis TP, Irish JM, Kordasti S, Mufti GJ. Mass cytometry reveals PD1 upregulation is an early step in MDS disease progression. Blood [Internet]. 2016 Dec 1;128(22):4296 LP-4296 Available from:
  37. 37.
    Yang H, Bueso-Ramos C, DiNardo C, Estecio MR, Davanlou M, Geng Q-R et al (2014) Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia [Internet] 28(6):1280–1288 Available from: CrossRefGoogle Scholar
  38. 38.
    Ørskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M et al (2015) 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 [Internet]. Impact Journals LLC 6(11):9612–9626 Available from: Google Scholar
  39. 39.
    Garcia-Manero G, Tallman MS, Martinelli G, Ribrag V, Yang H, Balakumaran A, et al. Pembrolizumab, a PD-1 Inhibitor, in patients with myelodysplastic syndrome (MDS) after failure of hypomethylating agent treatment. Blood [Internet]. 2016 Dec 1;128(22):345 LP-345 Available from:
  40. 40.
    Garcia-Manero G, Daver NG, Montalban-Bravo G, Jabbour EJ, DiNardo CD, Kornblau SM, et al. A phase II study evaluating the combination of nivolumab (Nivo) or ipilimumab (Ipi) with azacitidine in Pts with previously treated or untreated myelodysplastic syndromes (MDS). Blood [Internet]. 2016 Dec 1;128(22):344 LP-344 Available from:
  41. 41.
    Bally C et al (2013) Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone Des Myelodysplasies (GFM). Leuk Res 37(6):637–640CrossRefPubMedGoogle Scholar
  42. 42.
    Porkka, Kimmo et al. An open-label, phase 1b, dose-escalation study (CA180-373) of dasatinib plus nivolumab, an investigational anti-programmed cell death 1 (PD-1) antibody, in patients (pts) with previously treated chronic myeloid leukemia (CML) [abstract]. In: ASCO 50th Annual Meeting; 2014 May 30- Jun 3; Chicago, IL. J Clin Oncol 32: 5s, 2014. Abstarct nr TPS7119.Google Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.George Washington UniversityWashington, DCUSA
  2. 2.Drexel University College of MedicineWashington, DCUSA

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