Immune checkpoint inhibitors (ICIs), especially those targeting the programmed-death 1 (PD-1) receptor and its ligands, have become indispensable agents in solid tumor anti-cancer therapy. Concerning hematological malignancies, only nivolumab and pembrolizumab have been approved for the treatment of relapsed and refractory classical Hodgkin lymphoma and primary mediastinal large B cell lymphoma to date. Nevertheless, clinical research in this field is very active. The mechanism of action of ICIs is based on unblocking the hindered immune system to recognize and eliminate cancer cells, but that also has its costs in the form of ICI-specific immune related adverse events (irAEs), which can affect any organ system and can even be lethal. In this article, we have reviewed all prospective blood cancer clinical trials investigating ICIs (both monotherapy and combination therapy) with available toxicity data with the purpose of determining the incidence of irAEs in this specific setting and to offer a brief insight into their management, as the use of immune checkpoint blockade is not so frequent in hemato-oncology.

Department of Haematooncology University Hospital Ostrava Ostrava Czechia

Faculty of Medicine University of Ostrava Ostrava Czechia

Zobrazit více v PubMed

Ansell S., Armand P., Timmerman J. M., Shipp M. A., Bradley Garelik M. B., Zhu L., et al. (2015). Nivolumab in Patients (Pts) with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL): Clinical Outcomes from Extended Follow-Up of a Phase 1 Study (CA209-039). Blood 126, 583. 10.1182/blood.v126.23.583.583 DOI

Ansell S. M., Hurvitz S. A., Koenig P. A., LaPlant B. R., Kabat B. F., Fernando D., et al. (2009). Phase I Study of Ipilimumab, an Anti-CTLA-4 Monoclonal Antibody, in Patients with Relapsed and Refractory B-Cell Non-hodgkin Lymphoma. Clin. Cancer Res. 15, 6446–6453. 10.1158/1078-0432.CCR-09-1339 PubMed DOI PMC

Ansell S. M., Minnema M. C., Johnson P., Timmerman J. M., Armand P., Shipp M. A., et al. (2019). Nivolumab for Relapsed/Refractory Diffuse Large B-Cell Lymphoma in Patients Ineligible for or Having Failed Autologous Transplantation: A Single-Arm, Phase II Study. Jco 37, 481–489. 10.1200/JCO.18.00766 PubMed DOI PMC

Armand P., Engert A., Younes A., Lee H. J., Santoro A., Zinzani P. L., et al. (2018a). Nivolumab for Relapsed or Refractory Classical Hodgkin Lymphoma (cHL) after Autologous Hematopoietic Cell Transplantation (Auto-HCT): Extended Follow-Up of the Phase 2 Single-Arm CheckMate 205 Study. Blood 132, 2897. 10.1182/blood-2018-99-112067 DOI

Armand P., Lesokhin A., Borrello I., Timmerman J., Gutierrez M., Zhu L., et al. (2021). A Phase 1b Study of Dual PD-1 and CTLA-4 or KIR Blockade in Patients with Relapsed/refractory Lymphoid Malignancies. Leukemia 35, 777–786. 10.1038/s41375-020-0939-1 PubMed DOI PMC

Armand P., Rodig S. J., Melnichenko V., Thieblemont C., Bouabdallah K., Tumyan G., et al. (2018b). Pembrolizumab in Patients with Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma (PMBCL): Data from the Keynote-013 and Keynote-170 Studies. Blood 132, 228. 10.1182/blood-2018-99-110220 DOI

Armand P., Rodig S., Melnichenko V., Thieblemont C., Bouabdallah K., Tumyan G., et al. (2019). Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma. Jco 37, 3291–3299. 10.1200/JCO.19.01389 PubMed DOI PMC

Armand P., Shipp M. A., Ribrag V., Michot J.-M., Zinzani P. L., Kuruvilla J., et al. (2016). Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Long-Term Efficacy from the Phase 1b Keynote-013 Study. Blood 128, 1108. 10.1182/blood.v128.22.1108.1108 DOI

Awadalla M., Mahmood S. S., Groarke J. D., Hassan M. Z. O., Nohria A., Rokicki A., et al. (2020). Global Longitudinal Strain and Cardiac Events in Patients with Immune Checkpoint Inhibitor-Related Myocarditis. J. Am. Coll. Cardiol. 75, 467–478. 10.1016/j.jacc.2019.11.049 PubMed DOI PMC

Badros A., Hyjek E., Ma N., Lesokhin A., Dogan A., Rapoport A. P., et al. (2017). Pembrolizumab, Pomalidomide, and Low-Dose Dexamethasone for Relapsed/refractory Multiple Myeloma. Blood 130, 1189–1197. 10.1182/blood-2017-03-775122 PubMed DOI

Barta S. K., Zain J., MacFarlane A. W., Smith S. M., Ruan J., Fung H. C., et al. (2019). Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-Cell Lymphoma. Clin. Lymphoma Myeloma Leuk. 19, 356–364.e3. 10.1016/j.clml.2019.03.022 PubMed DOI PMC

Bashey A., Medina B., Corringham S., Pasek M., Carrier E., Vrooman L., et al. (2009). CTLA4 Blockade with Ipilimumab to Treat Relapse of Malignancy after Allogeneic Hematopoietic Cell Transplantation. Blood 113, 1581–1588. 10.1182/blood-2008-07-168468 PubMed DOI PMC

Bröckelmann P. J., Goergen H., Keller U., Meissner J., Ordemann R., Halbsguth T. V., et al. (2020). Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma. JAMA Oncol. 6, 872–880. 10.1001/jamaoncol.2020.0750 PubMed DOI PMC

Buchbinder E. I., Desai A. (2016). CTLA-4 and PD-1 Pathways. Am. J. Clin. Oncol. 39, 98–106. 10.1097/COC.0000000000000239 PubMed DOI PMC

Cassaday R. D., Garcia K.-L. A., Fromm J. R., Percival M.-E. M., Turtle C. J., Nghiem P. T., et al. (2020). Phase 2 Study of Pembrolizumab for Measurable Residual Disease in Adults with Acute Lymphoblastic Leukemia. Blood Adv. 4, 3239–3245. 10.1182/bloodadvances.2020002403 PubMed DOI PMC

Čelutkienė J., Pudil R., López-Fernández T., Grapsa J., Nihoyannopoulos P., Bergler-Klein J., et al. (2020). Role of Cardiovascular Imaging in Cancer Patients Receiving Cardiotoxic Therapies: a Position Statement on Behalf of the Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC). Eur. J. Heart Fail. 22, 1504–1524. 10.1002/ejhf.1957 PubMed DOI

Chang L.-S., Barroso-Sousa R., Tolaney S. M., Hodi F. S., Kaiser U. B., Min L. (2019). Endocrine Toxicity of Cancer Immunotherapy Targeting Immune Checkpoints. Endocr. Rev. 40, 17–65. 10.1210/er.2018-00006 PubMed DOI PMC

Chen R., Zinzani P. L., Fanale M. A., Armand P., Johnson N. A., Brice P., et al. (2017). Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. Jco 35, 2125–2132. 10.1200/JCO.2016.72.1316 PubMed DOI PMC

Chhabra N., Kennedy J. (2021). A Review of Cancer Immunotherapy Toxicity: Immune Checkpoint Inhibitors. J. Med. Toxicol. 10.1007/s13181-021-00833-8 PubMed DOI PMC

Cohen Y. C., Oriol A., Wu K. L., Lavi N., Vlummens P., Jackson C., et al. (2021). Daratumumab with Cetrelimab, an Anti-PD-1 Monoclonal Antibody, in Relapsed/Refractory Multiple Myeloma. Clin. Lymphoma Myeloma Leuk. 21, 46–54.e4. 10.1016/j.clml.2020.08.008 PubMed DOI

D'Souza A., Hari P., Pasquini M., Braun T., Johnson B., Lundy S., et al. (2019). A Phase 2 Study of Pembrolizumab during Lymphodepletion after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma. Biol. Blood Marrow Transpl. 25, 1492–1497. 10.1016/j.bbmt.2019.04.005 PubMed DOI

Daver N., Garcia-Manero G., Basu S., Boddu P. C., Alfayez M., Cortes J. E., et al. (2019). 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. 9, 370–383. 10.1158/2159-8290.CD-18-0774 PubMed DOI PMC

Davids M. S., Kim H. T., Bachireddy P., Costello C., Liguori R., Savell A., et al. (2016). Ipilimumab for Patients with Relapse after Allogeneic Transplantation. N. Engl. J. Med. 375, 143–153. 10.1056/NEJMoa1601202 PubMed DOI PMC

Davids M. S., Kim H. T., Costello C., Herrera A. F., Locke F. L., Maegawa R. O., et al. (2020). A Multicenter Phase 1 Study of Nivolumab for Relapsed Hematologic Malignancies after Allogeneic Transplantation. Blood 135, 2182–2191. 10.1182/blood.2019004710 PubMed DOI PMC

Delaunay M., Prévot G., Collot S., Guilleminault L., Didier A., Mazières J. (2019). Management of Pulmonary Toxicity Associated with Immune Checkpoint Inhibitors. Eur. Respir. Rev. 28, 190012. 10.1183/16000617.0012-2019 PubMed DOI PMC

Diefenbach C. S., Hong F., Ambinder R. F., Cohen J. B., Robertson M. J., David K. A., et al. (2020). Ipilimumab, Nivolumab, and Brentuximab Vedotin Combination Therapies in Patients with Relapsed or Refractory Hodgkin Lymphoma: Phase 1 Results of an Open-Label, Multicentre, Phase 1/2 Trial. Lancet Haematol. 7, e660–e670. 10.1016/S2352-3026(20)30221-0 PubMed DOI PMC

Fan Y., Xie W., Huang H., Wang Y., Li G., Geng Y., et al. (2021). Association of Immune Related Adverse Events with Efficacy of Immune Checkpoint Inhibitors and Overall Survival in Cancers: A Systemic Review and Meta-Analysis. Front. Oncol. 11, 633032. 10.3389/fonc.2021.633032 PubMed DOI PMC

Haanen J. B. a. G., Carbonnel F., Robert C., Kerr K. M., Peters S., Larkin J., et al. (2017). Management of Toxicities from Immunotherapy: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann. Oncol. 28, iv119–iv142. 10.1093/annonc/mdx225 PubMed DOI

Herrera A. F., Moskowitz A. J., Bartlett N. L., Vose J. M., Ramchandren R., Feldman T. A., et al. (2018). Interim Results of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma. Blood 131, 1183–1194. 10.1182/blood-2017-10-811224 PubMed DOI PMC

Hradska K., Kascak M., Hajek R., Jelinek T. (2020). Identifying and Treating Candidates for Checkpoint Inhibitor Therapies in Multiple Myeloma and Lymphoma. Expert Rev. Hematol. 13, 375–392. 10.1080/17474086.2020.1733405 PubMed DOI

Jamal S., Hudson M., Fifi-Mah A., Ye C. (2020). Immune-related Adverse Events Associated with Cancer Immunotherapy: A Review for the Practicing Rheumatologist. J. Rheumatol. 47, 166–175. 10.3899/jrheum.190084 PubMed DOI

Jelinek T., Hajek R. (2016). PD-1/PD-L1 Inhibitors in Multiple Myeloma: The Present and the Future. Oncoimmunology 5, e1254856. 10.1080/2162402X.2016.1254856 PubMed DOI PMC

Jelinek T., Mihalyova J., Kascak M., Duras J., Hajek R. (2017). PD-1/PD-L1 Inhibitors in Haematological Malignancies: Update 2017. Immunology 152, 357–371. 10.1111/imm.12788 PubMed DOI PMC

Jelinek T., Paiva B., Hajek R. (2018). Update on PD-1/pd-L1 Inhibitors in Multiple Myeloma. Front. Immunol. 9, 2431. 10.3389/fimmu.2018.02431 PubMed DOI PMC

Kazandjian D., Dew A., Hill E., Ramirez E. G., Morrison C., Mena E., et al. (2021). Avelumab, a PD‐L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma. Oncol. 26, 288–e541. 10.1002/onco.13712 PubMed DOI PMC

Khodadoust M., Rook A. H., Porcu P., Foss F. M., Moskowitz A. J., Shustov A. R., et al. (2016). Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study. Blood 128, 181. 10.1182/blood.v128.22.181.181 DOI

Khouri I. F., Fernandez Curbelo I., Turturro F., Jabbour E. J., Milton D. R., Bassett R. L., et al. (2018). Ipilimumab Plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies. Clin. Cancer Res. 24, 1011–1018. 10.1158/1078-0432.CCR-17-2777 PubMed DOI PMC

Lesokhin A. M., Ansell S. M., Armand P., Scott E. C., Halwani A., Gutierrez M., et al. (2016). Nivolumab in Patients with Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. Jco 34, 2698–2704. 10.1200/JCO.2015.65.9789 PubMed DOI PMC

Liu Y., Wang C., Li X., Dong L., Yang Q., Chen M., et al. (2021). Improved Clinical Outcome in a Randomized Phase II Study of Anti-PD-1 Camrelizumab Plus Decitabine in Relapsed/refractory Hodgkin Lymphoma. J. Immunother. Cancer 9, e002347. 10.1136/jitc-2021-002347 PubMed DOI PMC

Martinez-Calle N., Rodriguez-Otero P., Villar S., Mejías L., Melero I., Prosper F., et al. (2018). Anti-PD1 Associated Fulminant Myocarditis after a Single Pembrolizumab Dose: the Role of Occult Pre-existing Autoimmunity. Haematologica 103, e318–e321. 10.3324/haematol.2017.185777 PubMed DOI PMC

Maruyama D., Terui Y., Yamamoto K., Fukuhara N., Choi I., Kuroda J., et al. (2020). Final Results of a Phase II Study of Nivolumab in Japanese Patients with Relapsed or Refractory Classical Hodgkin Lymphoma. Jpn. J. Clin. Oncol. 50, 1265–1273. 10.1093/jjco/hyaa117 PubMed DOI PMC

Mateos M.-V., Blacklock H., Schjesvold F., Oriol A., Simpson D., George A., et al. (2019a). Pembrolizumab Plus Pomalidomide and Dexamethasone for Patients with Relapsed or Refractory Multiple Myeloma (KEYNOTE-183): a Randomised, Open-Label, Phase 3 Trial. The Lancet Haematol. 6 (9), e459–e469. 10.1016/S2352-3026(19)30110-3 PubMed DOI

Mateos M. V., Orlowski R. Z., Ocio E. M., Rodríguez‐Otero P., Reece D., Moreau P., et al. (2019b). Pembrolizumab Combined with Lenalidomide and Low‐dose Dexamethasone for Relapsed or Refractory Multiple Myeloma: Phase I KEYNOTE ‐023 Study. Br. J. Haematol. 186. 10.1111/bjh.15946 PubMed DOI

Matsuki E., Younes A. (2016). Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-hodgkin Lymphoma. Curr. Treat. Options. Oncol. 17, 31. 10.1007/s11864-016-0401-9 PubMed DOI PMC

Mei Q., Zhang W., Liu Y., Yang Q., Rasko J. E. J., Nie J., et al. (2020). Camrelizumab Plus Gemcitabine, Vinorelbine, and Pegylated Liposomal Doxorubicin in Relapsed/Refractory Primary Mediastinal B-Cell Lymphoma: A Single-Arm, Open-Label, Phase II Trial. Clin. Cancer Res. 26, 4521–4530. 10.1158/1078-0432.CCR-20-0514 PubMed DOI

Pudil R., Mueller C., Čelutkienė J., Henriksen P. A., Lenihan D., Dent S., et al. (2020). Role of Serum Biomarkers in Cancer Patients Receiving Cardiotoxic Cancer Therapies: a Position Statement from the Cardio‐Oncology Study Group of the Heart Failure Association and the Cardio‐Oncology Council of the European Society of Cardiology. Eur. J. Heart Fail. 22, 1966–1983. 10.1002/ejhf.2017 PubMed DOI

Ramchandren R., Domingo-Domènech E., Rueda A., Trněný M., Feldman T. A., Lee H. J., et al. (2019). Nivolumab for Newly Diagnosed Advanced-Stage Classic Hodgkin Lymphoma: Safety and Efficacy in the Phase II CheckMate 205 Study. Jco 37, 1997–2007. 10.1200/JCO.19.00315 PubMed DOI PMC

Ransohoff J. D., Kwong B. Y. (2017). Cutaneous Adverse Events of Targeted Therapies for Hematolymphoid Malignancies. Clin. Lymphoma Myeloma Leuk. 17, 834–851. 10.1016/j.clml.2017.07.005 PubMed DOI

Ravandi F., Assi R., Daver N., Benton C. B., Kadia T., Thompson P. A., et al. (2019). 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. 6, e480–e488. 10.1016/S2352-3026(19)30114-0 PubMed DOI PMC

Ribrag V., Avigan D. E., Green D. J., Wise‐Draper T., Posada J. G., Vij R., et al. (2019). Phase 1b Trial of Pembrolizumab Monotherapy for Relapsed/refractory Multiple Myeloma: KEYNOTE ‐013. Br. J. Haematol. 186, e41–e44. 10.1111/bjh.15888 PubMed DOI

Ribrag V., Lee S. T., Rizzieri D., Dyer M. J. S., Fayad L., Kurzrock R., et al. (2021). A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination with Tremelimumab or Danvatirsen in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Clin. Lymphoma Myeloma Leuk. 21, 309–317. e3. 10.1016/j.clml.2020.12.012 PubMed DOI

Rocha M., Correia de Sousa J., Salgado M., Araújo A., Pedroto I. (2019). Management of Gastrointestinal Toxicity from Immune Checkpoint Inhibitor. GE Port J. Gastroenterol. 26, 268–274. 10.1159/000494569 PubMed DOI PMC

Roth P., Winklhofer S., Müller A. M. S., Dummer R., Mair M. J., Gramatzki D., et al. (2021). Neurological Complications of Cancer Immunotherapy. Cancer Treat. Rev. 97, 102189. 10.1016/j.ctrv.2021.102189 PubMed DOI

Shi Y., Wu J., Wang Z., Zhang L., Wang Z., Zhang M., et al. (2021). Efficacy and Safety of Geptanolimab (GB226) for Relapsed or Refractory Peripheral T Cell Lymphoma: an Open-Label Phase 2 Study (Gxplore-002). J. Hematol. Oncol. 14, 12. 10.1186/s13045-021-01033-1 PubMed DOI PMC

Smyth M. J., Teng M. W. (2018). 2018 Nobel Prize in Physiology or Medicine. Clin. Transl Immunol. 7, e1041. 10.1002/cti2.1041 PubMed DOI PMC

Song Y., Gao Q., Zhang H., Fan L., Zhou J., Zou D., et al. (2020). Treatment of Relapsed or Refractory Classical Hodgkin Lymphoma with the Anti-PD-1, Tislelizumab: Results of a Phase 2, Single-Arm, Multicenter Study. Leukemia 34, 533–542. 10.1038/s41375-019-0545-2 PubMed DOI PMC

Tian Y., Abu-Sbeih H., Wang Y. (2018). Immune Checkpoint Inhibitors-Induced Hepatitis. Adv. Exp. Med. Biol. 995, 159–164. 10.1007/978-3-030-02505-2_8 PubMed DOI

Tinawi M., Bastani B. (2020). Nephrotoxicity of Immune Checkpoint Inhibitors: Acute Kidney Injury and beyond. Cureus 12, e12204. 10.7759/cureus.12204 PubMed DOI PMC

Tocchetti C. G., Cadeddu C., Di Lisi D., Femminò S., Madonna R., Mele D., et al. (2019). From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview. Antioxid. Redox Signaling 30, 2110–2153. 10.1089/ars.2016.6930 PubMed DOI PMC

Tuscano J. M., Maverakis E., Groshen S., Tsao-Wei D., Luxardi G., Merleev A. A., et al. (2019). A Phase I Study of the Combination of Rituximab and Ipilimumab in Patients with Relapsed/Refractory B-Cell Lymphoma. Clin Cancer Res. 25, 7004–7013. 10.1158/1078-0432.CCR-19-0438 PubMed DOI PMC

Upadhrasta S., Elias H., Patel K., Zheng L. (2019). Managing Cardiotoxicity Associated with Immune Checkpoint Inhibitors. Chronic Dis. Translational Med. 5, 6–14. 10.1016/j.cdtm.2019.02.004 PubMed DOI PMC

Usmani S. Z., Schjesvold F., Oriol A., Karlin L., Cavo M., Rifkin R. M., et al. (2019). Pembrolizumab Plus Lenalidomide and Dexamethasone for Patients with Treatment-Naive Multiple Myeloma (KEYNOTE-185): a Randomised, Open-Label, Phase 3 Trial. Lancet Haematol. 6 (9), e448–e458. 10.1016/S2352-3026(19)30109-7 PubMed DOI

Wang Y., Wu L., Tian C., Zhang Y. (2018). PD-1-PD-L1 Immune-Checkpoint Blockade in Malignant Lymphomas. Ann. Hematol. 97, 229–237. 10.1007/s00277-017-3176-6 PubMed DOI

Younes A., Brody J., Carpio C., Lopez-Guillermo A., Ben-Yehuda D., Ferhanoglu B., et al. (2019). Safety and Activity of Ibrutinib in Combination with Nivolumab in Patients with Relapsed Non-hodgkin Lymphoma or Chronic Lymphocytic Leukaemia: a Phase 1/2a Study. Lancet Haematol. 6, e67–e78. 10.1016/S2352-3026(18)30217-5 PubMed DOI

Younes A., John B. M., Diefenbach C. S., Ferrari S., Kahn C., Sharman J. P., et al. (2017). Safety and Efficacy of Atezolizumab in Combination with Obinutuzumab and Bendamustine in Patients with Previously Untreated Follicular Lymphoma: An Interim Analysis. Blood 130, 481.

Zeidan A. M., Knaus H. A., Robinson T. M., Towlerton A. M. H., Warren E. H., Zeidner J. F., et al. (2018). A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes Following Hypomethylating Agent Failure. Clin. Cancer Res. 24, 3519–3527. 10.1158/1078-0432.CCR-17-3763 PubMed DOI PMC

Zinzani P. L., Santoro A., Gritti G., Cunningham D., Johnsone N. A., Manleyh T. Francis. S., et al. (2019). Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety from the Phase II CheckMate 436 Study. Jco 37, 3081–3089. 10.1200/JCO.19.01492 PubMed DOI PMC