Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia.

Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. Significance Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.

[1]  D. Sallman.  The First-in-Class Anti-CD47 Antibody Magrolimab Combined with Azacitidine Is Well-Tolerated and Effective in AML Patients: Phase 1b Results , 2020 .

[2]  T. Yau,et al.  TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. , 2020, Blood advances.

[3]  A. N. Davydov,et al.  Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans , 2020, Nature immunology.

[4]  D. Berry,et al.  Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis. , 2020, JAMA oncology.

[5]  S. Rutella,et al.  Flotetuzumab as Salvage Immunotherapy for Refractory Acute Myeloid Leukemia. , 2020, Blood.

[6]  D. Neuberg,et al.  A peripheral immune signature of responsiveness to PD-1 blockade in patients with classical Hodgkin lymphoma , 2020, Nature Medicine.

[7]  Troxel,et al.  Checkpoint Blockade Treatment May Sensitize Hodgkin Lymphoma to Subsequent Therapy. , 2020, The oncologist.

[8]  Shaohua Chen,et al.  Expression patterns of immune checkpoints in acute myeloid leukemia , 2020, Journal of Hematology & Oncology.

[9]  A. Kamphorst,et al.  An intra-tumoral niche maintains and differentiates stem-like CD8 T cells , 2019, Nature.

[10]  R. Larson,et al.  Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3-Mutated AML. , 2019, The New England journal of medicine.

[11]  P. Sharma,et al.  Idarubicin, cytarabine, and nivolumab in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a single-arm, phase 2 study. , 2019, The Lancet. Haematology.

[12]  M. Minden,et al.  Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia , 2019, Science Translational Medicine.

[13]  J. Maciejewski,et al.  A Phase I/II Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib for Relapsed Refractory Acute Myeloid Leukemia , 2019, Clinical Cancer Research.

[14]  F. Hodi,et al.  Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade , 2019, Nature Immunology.

[15]  Aviv Regev,et al.  Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD‐1−CD8+ Tumor‐Infiltrating T Cells , 2019, Immunity.

[16]  Daniel E. Speiser,et al.  Intratumoral Tcf1+PD‐1+CD8+ T Cells with Stem‐like Properties Promote Tumor Control in Response to Vaccination and Checkpoint Blockade Immunotherapy , 2019, Immunity.

[17]  P. Sharma,et al.  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 , 2018, Cancer.

[18]  M. Nykter,et al.  Immunogenomic landscape of hematological malignancies , 2018, bioRxiv.

[19]  H. Kantarjian,et al.  Salvage Therapy Outcomes in a Historical Cohort of Patients with Relapsed or Refractory Acute Myeloid Leukemia , 2018, Blood.

[20]  M. Carroll,et al.  A randomized trial of three novel regimens for recurrent acute myeloid leukemia demonstrates the continuing challenge of treating this difficult disease , 2018, American journal of hematology.

[21]  P. Sharma,et al.  Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. , 2018, Cancer discovery.

[22]  H. Hackl,et al.  Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. , 2018, JCI insight.

[23]  Mark D. Robinson,et al.  diffcyt: Differential discovery in high-dimensional cytometry via high-resolution clustering , 2018, Communications Biology.

[24]  R. Collins,et al.  Durable Remissions with Ivosidenib in IDH1‐Mutated Relapsed or Refractory AML , 2018, The New England journal of medicine.

[25]  I. Flinn,et al.  Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. , 2017, Blood.

[26]  B. Becher,et al.  CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets , 2017, F1000Research.

[27]  C. Rudin,et al.  Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  Nicola D. Roberts,et al.  Genomic Classification and Prognosis in Acute Myeloid Leukemia. , 2016, The New England journal of medicine.

[29]  J. Taube,et al.  Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer. , 2016, Cancer research.

[30]  Arnaud Pigneux,et al.  Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. , 2015, The Lancet. Oncology.

[31]  E. Estey,et al.  Empiric definition of eligibility criteria for clinical trials in relapsed/refractory acute myeloid leukemia: analysis of 1,892 patients from HOVON/SAKK and SWOG , 2015, Haematologica.

[32]  Jedd D. Wolchok,et al.  Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma , 2015, Journal of Immunotherapy for Cancer.

[33]  D. Neuberg,et al.  Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. , 2015, Blood.

[34]  M. Gobbi,et al.  International randomized phase III study of elacytarabine versus investigator choice in patients with relapsed/refractory acute myeloid leukemia. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Shohei Koyama,et al.  Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. , 2014, Cancer cell.

[36]  C. Blank,et al.  Interferon‐induced programmed death‐ligand 1 (PD‐L1/B7‐H1) expression increases on human acute myeloid leukemia blast cells during treatment , 2014, European journal of haematology.

[37]  G. Esendagli,et al.  Myeloid leukemia cells with a B7‐2+ subpopulation provoke Th‐cell responses and become immuno‐suppressive through the modulation of B7 ligands , 2013, European Journal of Immunology.

[38]  R. Collins,et al.  Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  D. Munn,et al.  Regulatory T cells in acute myelogenous leukemia: is it time for immunomodulation? , 2011, Blood.

[40]  Christopher G. Kanakry,et al.  Early lymphocyte recovery after intensive timed sequential chemotherapy for acute myelogenous leukemia: peripheral oligoclonal expansion of regulatory T cells. , 2011, Blood.

[41]  D. Munn,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. , 2010, Blood.

[42]  B. Quesnel,et al.  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 , 2010, Cancer Immunology, Immunotherapy.

[43]  Guido Marcucci,et al.  Mutations of the Wilms tumor 1 gene (WT1) in older patients with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. , 2010, Blood.

[44]  Bob Löwenberg,et al.  Review Articles (434 articles) , 2008 .

[45]  H. Kantarjian,et al.  Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy. , 2009, Blood.

[46]  T. Robak,et al.  Cladribine combined with high doses of arabinoside cytosine, mitoxantrone, and G‐CSF (CLAG‐M) is a highly effective salvage regimen in patients with refractory and relapsed acute myeloid leukemia of the poor risk: a final report of the Polish Adult Leukemia Group , 2007, European journal of haematology.

[47]  Bob Löwenberg,et al.  Prognostic index for adult patients with acute myeloid leukemia in first relapse. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  A. Pettitt.  Mechanism of action of purine analogues in chronic lymphocytic leukaemia , 2003, British journal of haematology.

[49]  M. Grever,et al.  A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study. , 1999, Leukemia research.

[50]  H. Kantarjian,et al.  A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. , 1996, Blood.

[51]  Malgorzata Nowicka,et al.  CyTOF workflow: differential discovery in high-throughput high-dimensional cytometry datasets. , 2017, F1000Research.

[52]  K. Döhner,et al.  Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways. , 2015, Blood.

[53]  J. Mesirov,et al.  The Molecular Signatures Database (MSigDB) hallmark gene set collection. , 2015, Cell systems.

[54]  Lieping Chen,et al.  Interferon- (cid:1) and tumor necrosis factor- (cid:2) induce an immunoinhibitory molecule, B7-H1, via nuclear factor- (cid:3) B activation in blasts in myelodysplastic syndromes , 2022 .