Release Date: 2024-06-12

Immunotherapy in Chronic Leukemias

Release Date: 2024-06-12

Chronic myelogenous leukemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. The most important immunotherapeutic drugs in the treatment of CML are tyrosine kinase inhibitors (TKI) and interferon. Chronic lymphocytic leukemia, another type of chronic leukemia, is one of the B cell chronic lymphoproliferative disorders. It is used in the treatment of three types [...]

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    Work TypeBook Chapter
    Published inImmunotherapy in Human Cancers
    First Page91
    Last Page106
    DOIhttps://doi.org/10.69860/nobel.9786053359388.7
    Page Count16
    Copyright HolderNobel Tıp Kitabevleri
    Licensehttps://nobelpub.com/publish-with-us/copyright-and-licensing
    Chronic myelogenous leukemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. The most important immunotherapeutic drugs in the treatment of CML are tyrosine kinase inhibitors (TKI) and interferon. Chronic lymphocytic leukemia, another type of chronic leukemia, is one of the B cell chronic lymphoproliferative disorders. It is used in the treatment of three types of drug groups: anti-CD20 monoclonal antibodies, anti-CD19 monoclonal antibodies and bruton thyrosine kinase inhibitors.

    Esin Oguz Kozan (Author)
    MD, Assistant Professor, Mersin University
    https://orcid.org/0000-0002-1006-8741
    3MD, Esin Oguz Kozan Education: Cumhuriyet University medicine faculty (2006-2012) Atatürk University. Department of General Practitioner (2014-2016) Cumhuriyet University. Department of Internal Medicine (2016-2019) Mersin University. Department of Hematology (2022- continue)

    Eyup Naci Tiftik (Author)
    MD, Professor of Hematology, Mersin University
    https://orcid.org/0000-0002-9009-7066
    3Prosessor Eyup Naci Tiftik Education.Ankara university medicine faculty(1983-1989) Internal Medicine specilization.Dicle university Medicine faculty(1991-1995) Haematology specilization (1995-2000) Division of Haematology, Department of internal medicine.Mersin university (2001-2024) Blood center director of mersin university hospital (2002-2023)

    • Thomas, E. D., Lochte, H. L., Lu, W. C. & Ferrebee, J. W. Intravenous Infusion of Bone Marrow in Patients Receiving Radiation and Chemotherapy. New England Journal of Medicine 257, (1957).

    • Mathé, G., Amiel, J. L., Schwarzenberg, L., Cattan, A. & Schneider, M. Adoptive Immunotherapy of Acute Leukemia: Experimental and Clinical Results. Cancer Res 25, (1965).

    • Pati, A. R., Godder, K., Lamb, L., Gee, A. & Henslee-Downey, P. J. Immunotherapy with donor leukocyte infusions for patients with relapsed acute myeloid leukemia following partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant 15, (1995).

    • Takami, A. et al. Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: A retrospective analysis by the adult acute myeloid leukemia working group of the Japan society for hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation 20, (2014).

    • Ryan, M. C. et al. SGN-CD19B, a Pyrrolobenzodiazepine (PBD)-Based Anti-CD19 Drug Conjugate, Demonstrates Potent Preclinical Activity Against B-Cell Malignancies. Blood 126, (2015).

    • Kantarjian, H. M. et al. A Phase II Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia. Clin Lymphoma Myeloma Leuk 16, (2016).

    • Jones, L. et al. Preclinical activity of the antibody-drug conjugate denintuzumab mafodotin (SGN-CD19A) against pediatric acute lymphoblastic leukemia xenografts. Pediatr Blood Cancer 66, (2019).

    • Zhou, X., Hu, W. & Qin, X. The Role of Complement in the Mechanism of Action of Rituximab for B-Cell Lymphoma: Implications for Therapy. Oncologist 13, (2008).

    • Thomas, D. A. et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome - Negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol 28, (2010).

    • Desjonquères, A. et al. Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study. Blood Cancer J 6, (2016).

    • Jabbour, E. et al. Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with Philadelphia chromosome-negative B-cell acute lymphoblastic leukaemia: a single-arm, phase 2 trial. Lancet Haematol 7, (2020).

    • Awasthi, A. et al. Obinutuzumab (GA101) compared to rituximab significantly enhances cell death and antibody-dependent cytotoxicity and improves overall survival against CD20+ rituximab-sensitive/-resistant Burkitt lymphoma (BL) and precursor B-acute lymphoblastic leukaemia (pre-B-ALL): Potential targeted therapy in patients with poor risk CD20+ BL and pre-B-ALL. Br J Haematol 171, (2015).

    • Raetz, E. A. et al. Re-induction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL): Phase II results from Children’s Oncology Group (COG) study ADVL04P2. Pediatr Blood Cancer 62, (2015).

    • Advani, A. S. et al. SWOG S0910: A phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukaemia. Br J Haematol 165, (2014).

    • Wayne, A. S. et al. Phase 1 study of the anti-CD22 immunotoxin moxetumomab pasudotox for childhood acute lymphoblastic leukemia. Blood 130, (2017).

    • Kantarjian, H. M. et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. New England Journal of Medicine 375, (2016).

    • Stelljes, M. et al. Inotuzumab Ozogamicin as Induction Therapy for Patients Older Than 55 Years With Philadelphia Chromosome–Negative B-Precursor ALL. J Clin Oncol 42, (2024).

    • Zheng, W. et al. CD30 expression in high-risk acute myeloid Leukemia and myelodysplastic syndromes. Clin Lymphoma Myeloma Leuk 13, (2013).

    • Younes, A. et al. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas. N Engl J Med 363, (2010).

    • Narayan, R. et al. A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia. Cancer 126, (2020).

    • Walter, R. B. et al. Multidrug resistance protein attenuates gemtuzumab ozogamicin-induced cytotoxicity in acute myeloid leukemia cells. Blood 102, (2003).

    • Sievers, E. L. et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. Journal of Clinical Oncology 19, (2001).

    • Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. The Lancet 379, (2012).

    • Hills, R. K. et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 15, (2014).

    • Hogan, L. E. et al. Efficacy and safety of daratumumab (DARA) in pediatric and young adult patients (pts) with relapsed/refractory T-cell acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL): Results from the phase 2 DELPHINUS study. Journal of Clinical Oncology 40, (2022).

    • Boissel, N. et al. Isatuximab monotherapy in patients with refractory T-acute lymphoblastic leukemia or T-lymphoblastic lymphoma: Phase 2 study. Cancer Med 11, (2022).

    • Stock, W. et al. Alemtuzumab can be Incorporated Into Front-Line Therapy of Adult Acute Lymphoblastic Leukemia (ALL): Final Phase I Results of a Cancer and Leukemia Group B Study (CALGB 10102). Blood 114, (2009).

    • Riether, C. et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med 26, (2020).

    • Pemmaraju, N. et al. Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. New England Journal of Medicine 380, (2019).

    • Stone, R. M. et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med 377, (2017).

    • Erba, H. P. et al. Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet 401, (2023).

    • Perl, A. E. et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3 -Mutated AML. N Eng J Med 381, (2019).

    • Kantarjian, H. et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. New England Journal of Medicine 376, (2017).

    • Pulte, E. D. et al. FDA Supplemental Approval: Blinatumomab for Treatment of Relapsed and Refractory Precursor B-Cell Acute Lymphoblastic Leukemia. Oncologist 23, (2018).

    • Advani, A. S. et al. Results of SWOG 1318: A Phase 2 Trial of Blinatumomab Followed By Pomp (Prednisone, Vincristine, Methotrexate, 6-Mercaptopurine) Maintenance in Elderly Patients with Newly Diagnosed Philadelphia Chromosome Negative B-Cell Acute Lymphoblastic Leukemia. Blood 132, (2018).

    • Foà, R. et al. Dasatinib–Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. New England Journal of Medicine 383, (2020).

    • Bondarenko, S. N. et al. Blinatumomab in the treatment of acute lymphoblastic leukemia: Russian multicenter clinical trial. Klinicheskaya Onkogematologiya/Clinical Oncohematology 12, (2019).

    • Ravandi, F. et al. Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). Journal of Clinical Oncology 38, (2020).

    • Ravandi, F. et al. Complete Responses in Relapsed/Refractory Acute Myeloid Leukemia (AML) Patients on a Weekly Dosing Schedule of Vibecotamab (XmAb14045), a CD123 x CD3 T Cell-Engaging Bispecific Antibody; Initial Results of a Phase 1 Study. Blood 136, (2020).

    • Uy, G. L. et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood 137, (2021).

    • Wiernik, A. et al. Targeting natural killer cells to acute myeloid leukemia in vitro with a CD16×33 bispecific killer cell engager and ADAM17 inhibition. Clinical Cancer Research 19, (2013).

    • Reusing, S. B. et al. CD16xCD33 Bispecific Killer Cell Engager (BiKE) as potential immunotherapeutic in pediatric patients with AML and biphenotypic ALL. Cancer Immunology, Immunotherapy 70, (2021).

    • Warlick, E. D. et al. GTB-3550 TriKETM for the Treatment of High-Risk Myelodysplastic Syndromes (MDS) and Refractory/Relapsed Acute Myeloid Leukemia (AML) Safely Drives Natural Killer (NK) Cell Proliferation At Initial Dose Cohorts. Blood 136, (2020).

    • Leong, S. R. et al. An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. Blood 129, (2017).

    • Zheng, B. et al. An anti–CLL-1 antibody–drug conjugate for the treatment of acute myeloid leukemia. Clinical Cancer Research 25, (2019).

    • van Loo, P. F. et al. MCLA-117, a CLEC12AxCD3 bispecific antibody targeting a leukaemic stem cell antigen, induces T cell-mediated AML blast lysis. Expert Opin Biol Ther 19, (2019).

    • Davids, M. S. et al. Ipilimumab for Patients with Relapse after Allogeneic Transplantation. New England Journal of Medicine 375, (2016).

    • Penter, L. et al. Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease. Blood 141, (2023).

    • Daver, N. et al. Phase IB/II Study of Nivolumab in Combination with Azacytidine (AZA) in Patients (pts) with Relapsed Acute Myeloid Leukemia (AML). Blood 128, (2016).

    • Liu, H. et al. TCR Clonal Evolution in AML Patients in Morphologic Remission Treated with Anti-PD1 Antibody, Nivolumab. Blood 128, (2016).

    • Zeidner, J. F. et al. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Blood Cancer Discov 2, (2021).

    • Rutella, S. et al. Immune dysfunction signatures predict outcomes and define checkpoint blockade–unresponsive microenvironments in acute myeloid leukemia. Journal of Clinical Investigation 132, (2022).

    • Boss, I. et al. Epigenetic and immunomodulatory effects of azacitidine (AZA) in combination with the anti-PD-L1 durvalumab (DURVA) in AML and MDS: results from a large, international, randomized phase 2 study. Hemasphere 4, (2020).

    • Boissel, N. & Rabian, F. Immunotherapies in acute leukemia. Therapies 77, (2022).

    • Webster, J. et al. Blinatumomab in Combination with Immune Checkpoint Inhibitors of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Preliminary Results of a Phase I Study. Blood 132, (2018).

    • Brunner, A. M. et al. Efficacy and Safety of Sabatolimab (MBG453) in Combination with Hypomethylating Agents (HMAs) in Patients (Pts) with Very High/High-Risk Myelodysplastic Syndrome (vHR/HR-MDS) and Acute Myeloid Leukemia (AML): Final Analysis from a Phase Ib Study. Blood 138, (2021).

    • Veillette, A. & Tang, Z. Signaling regulatory protein (SIRP)a-CD47 blockade joins the ranks of immune checkpoint inhibition. Journal of Clinical Oncology 37, (2019).

    • Daver, N. et al. Phase I/II Study of Azacitidine (AZA) with Venetoclax (VEN) and Magrolimab (Magro) in Patients (pts) with Newly Diagnosed (ND) Older/Unfit or High-Risk Acute Myeloid Leukemia (AML) and Relapsed/Refractory (R/R) AML. Blood 140, (2022).

    • Grosso, J. F. et al. Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells. The Journal of Immunology 182, (2009).

    • Buecklein, V. L. et al. Trial in Progress: An Open-Label Phase II Study of Relatlimab with Nivolumab in Combination with 5-Azacytidine for the Treatment of Patients with Relapsed/Refractory and Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia (AARON). Blood 140, (2022).

    • Xu, L. et al. PD-1 and TIGIT Are Highly Co-Expressed on CD8+ T Cells in AML Patient Bone Marrow. Front Oncol 11, (2021).

    • Guillaudeux, T., Sridhar, S., Frazier, E., Ovechkina, Y. & Iadonato, S. Abstract P21: VISTA a potential new Immuno-oncology therapeutic target to treat human Acute Myeloid Leukemia. Blood Cancer Discov 5, (2024).

    • Sermer, D. & Brentjens, R. CAR T-cell therapy: Full speed ahead. Hematol Oncol 37, (2019).

    • Maus, M. V., Grupp, S. A., Porter, D. L. & June, C. H. Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123, (2014).

    • Smith, A. J., Oertle, J., Warren, D. & Prato, D. Chimeric antigen receptor (CAR) T cell therapy for malignant cancers: Summary and perspective. Journal of Cellular Immunotherapy 2, (2016).

    • Kagoya, Y. et al. A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects. Nat Med 24, (2018).

    • Maude, S. L. et al. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. New England Journal of Medicine 371, (2014).

    • Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. The Lancet 385, (2015).

    • Gattinoni, L. et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. Journal of Experimental Medicine 202, (2005).

    • Maude, S. L. et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. New England Journal of Medicine 378, (2018).

    • Pasquini, M. C. et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv 4, (2020).

    • Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med 21, (2015).

    • Shah, B. D. et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. The Lancet 398, (2021).

    • Roddie, C. et al. Obecabtagene Autoleucel (obe-cel, AUTO1) for Relapsed/Refractory Adult B-cell Acute Lymphoblastic Leukemia (R/R B-ALL): Pooled Analysis of the Ongoing FELIX Phase Ib/II Study. Blood 142, (2023).

    • Cordoba, S. et al. CAR T cells with dual targeting of CD19 and CD22 in pediatric and young adult patients with relapsed or refractory B cell acute lymphoblastic leukemia: a phase 1 trial. Nat Med 27, (2021).

    • Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med 24, (2018).

    • Mamonkin, M., Rouce, R. H., Tashiro, H. & Brenner, M. K. A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood 126, (2015).

    • Cooper, M. L. et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 32, (2018).

    • Saxena, A. et al. Biologic and clinical significance of CD7 expression in acute myeloid leukemia. Am J Hematol 58, (1998).

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