Blinatumomab for the treatment of acute lymphoblastic leukemia
Tóm tắt
Acute lymphoblastic leukemia (ALL) is a potentially fatal disease that involves clonal expansion of early lymphoid progenitor cells. Much of drug development for ALL treatment involves targeting antigens of the clonal cell surface. Blinatumomab belongs to an emerging class of anti-cancer therapeutics referred to as bispecific T-cell engaging antibodies. The Food and Drug Administration approved its use in relapsed or refractory adult Philadelphia chromosome-negative B-cell precursor ALL in December of 2014. Blinatumomab contains both an anti-CD3 and anti-CD19 arm, allowing for the juxtaposition of CD3+ T-cells to malignant CD19+ B-cells, thereby resulting in granzyme- and perforin-mediated B-cell apoptosis. Preclinical studies suggest that blinatumomab’s efficacy is related to the effector-to-target ratio and to the difference between its affinity for CD19 and CD3. Preclinical and early phase clinical studies have allowed for the characterization of the pharmacokinetics of blinatumomab, including the determination of its short half-life. The metabolic pathway has not been fully characterized but is thought to be similar to that of other antibodies. Phase I and II studies led to the identification of an ideal stepwise dose, involving long-term continuous intravenous infusion (CIVI), to optimize its efficacy and reduce the risk of certain toxicities. A high remission rate and duration were noted among a relapsed/refractory population of patients. The results of clinical trials have identified cytokine release syndrome and neurotoxicity, among others, as serious drug-related toxicities, leading to the institution of a Risk Evaluation and Mitigation Strategy. Blinatumomab represents a significant addition to the treatment options for ALL, but it is not without its limitations, of which are its short-half life, necessitating long-term CIVI, and the eventual emergence of CD19-negative clones. Continual development of the agent involves assessing its role in the frontline setting and in combination with chemotherapy.
Tài liệu tham khảo
Dores M, Devesa SS, Curtis RE, Linet MS, Morton LM (2012) Acute leukemia incidence and patient survival among children and adults in the United States. Blood 119(1):2001–7
Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29
Vardiman JW, Arber DA, Brunning RD et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia : rationale and important changes. Blood 114(5):937–51
Moorman AV, Harrison CJ, Buck GA et al (2007) Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 109(8):3189–97
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Acute Lymphoblastic Leukemia [Internet]. NCCN 2014. Available from: http://www.nccn.org/professionals/physician_gls/pdf/all.pdf
Thomas DA, O’Brien S, Faderl S et al (2010) 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(24):3880–9
Hoelzer D, Huettmann A, Kaul F et al (2010) Immunochemotherapy with rituximab improves molecular CR rate and outcome in CD20+ B-lineage standard and high risk patients; results of 263 CD20+ patients studied prospectively in GMALL study 07/2003. ASH Annu Meet Abstr 116(21):170
Ribera J-M (2013) Optimal approach to treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: how to best use all the available tools. Leuk Lymphoma 54(1):21–7
Pulte D, Redaniel MT, Jansen L, Brenner H, Jeffreys M (2013) Recent trends in survival of adult patients with acute leukemia: overall improvements, but persistent and partly increasing disparity in survival of patients from minority groups. Haematologica 98(2):222–9
Pui C-H, Evans WE (2013) A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 50(3):185–96, Elsevier
Stock W, La M, Sanford B et al (2008) What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood 112(5):1646–54
Ten Cate B, de Bruyn M, Wei Y, Bremer E, Helfrich W (2010) Targeted elimination of leukemia stem cells; a new therapeutic approach in hemato-oncology. Curr Drug Targets 11(1):95–110
Bruggemann M, Raff T, Kneba M (2012) Has MRD monitoring superseded other prognostic factors in adult ALL? Blood 120(23):4470–81
Fielding AK, Richards SM, Chopra R et al (2007) Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109(3):944–50
O’Brien S, Thomas D, Ravandi F et al (2008) Outcome of adults with acute lymphocytic leukemia after second salvage therapy. Cancer 113(11):3186–91
Dombret H, Cluzeau T, Huguet F, Boissel N (2014) Pediatric-like therapy for adults with ALL. Curr Hematol Malig Rep. doi:10.1007/s11899-014-0210-9
Wetzler M, Thomas DA, Wang ES et al (2013) Phase I/II trial of nanomolecular liposomal annamycin in adult patients with relapsed/refractory acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk 13(4):430–4, Elsevier Inc
Robak P, Robak T (2013) Older and new purine nucleoside analogs for patients with acute leukemias. Cancer Treat Rev 39(8):851–61, Elsevier Ltd
Ai J, Advani A (2014) Current status of antibody therapy in ALL. Br J Haematol. doi:10.1111/bjh.13205, 1–10
Advani AS (2013) New immune strategies for the treatment of acute lymphoblastic leukemia: antibodies and chimeric antigen receptors. Hematol Am Soc Hematol Educ Program 2013:131–7
Chevallier P, Huguet F, Raffoux E et al (2014) Vincristine, dexamethasone and epratuzumab for older relapsed/refractory CD22+ B-acute lymphoblastic leukemia patients: a Phase 2 Study. Haematologica 100(4):e128–31
Grupp SA, Kalos M, Barrett D et al (2013) Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 368(16):1509–18
Maude SL, Frey N, Shaw PA et al (2014) Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 371(16):1507–17
Depoil D, Fleire S, Treanor BL et al (2008) CD19 is essential for B cell activation by promoting B cell receptor-antigen microcluster formation in response to membrane-bound ligand. Nat Immunol 9(1):63–72
Nadler LM, Anderson KC, Marti G et al (1983) B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. J Immunol 131:244–50
Wang K, Wei G, Liu D (2012) CD19: a biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol 1(1):36
Carter RH, Fearon DT (1992) CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105–7
Van Zelm MC, Reisli I, van der Burg M et al (2006) An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 354:1901–12
Raponi S, De Propris MS, Intoppa S et al (2011) Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma 52(June):1098–107
Uckun FM, Jaszcz W, Ambrus JL et al (1988) Detailed studies on expression and function of CD19 surface determinant by using B43 monoclonal antibody and the clinical potential of anti-CD19 immunotoxins. Blood 71(1):13–29
Uckun FM, Manivel C, Arthur D et al (1992) In vivo efficacy of B43 (anti-CD19)-pokeweed antiviral protein immunotoxin against human pre-B cell acute lymphoblastic leukemia in mice with severe combined immunodeficiency. Blood 79:2201–14
Mitchell P, Lee F-T, Hall C et al (2003) Targeting primary human Ph(+) B-cell precursor leukemia-engrafted SCID mice using radiolabeled anti-CD19 monoclonal antibodies. J Nucl Med 44:1105–12
Nagorsen D, Kufer P, Baeuerle PA, Bargou R (2012) Blinatumomab: a historical perspective. Pharmacol Ther 136(3):334–42, Elsevier Inc
Zimmerman Z, Maniar T, Nagorsen D (2014) Unleashing the clinical power of T cells: CD19/CD3 bi-specific T cell engager (BiTE®) antibody construct blinatumomab as a potential therapy. Int Immunol 27(1):31–7
Staerz UD, Kanagawa O, Bevan MJ (1985) Hybrid antibodies can target sites for attack by T cells. Nature 314(6012):628–31, England
Mack M, Riethmüller G, Kufer P (1995) A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc Natl Acad Sci U S A 92(July):7021–5
Frankel SR, Baeuerle PA (2013) Targeting T cells to tumor cells using bispecific antibodies. Curr Opin Chem Biol 17(3):385–92, Elsevier Ltd
Dreier T, Lorenczewski G, Brandl C et al (2002) Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody. Int J Cancer 100(6):690–7
Hoffmann P, Hofmeister R, Brischwein K et al (2005) Serial killing of tumor cells by cytotoxic T cells redirected with a CD19-/CD3-bispecific single-chain antibody construct. Int J Cancer 115(1):98–104
Rabinovich GA, Gabrilovich D, Sotomayor EM (2007) Immunosuppressive strategies that are mediated by tumor cells. Annu Rev Immunol 25:267–96
Schub A, Nagele V, Zugmaier G, et al (2013) Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). J Clin Oncol (suppl; abstr 7020)
Brandl C, Haas C, D’Argouges S et al (2007) The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Immunother 56(10):1551–63
Dreier T, Baeuerle PA, Fichtner I et al (2003) T cell costimulus-independent and very efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct. J Immunol 170(8):4397–402
Onyx Pharmaceuticals (2015) BLINCYTO (blinatumomab) Prescribing Information
Wu B, Hijazi Y, Wolf A, Brandl C, Sun Y-N, Zhu M (2013) Pharmacokinetics (PK) of blinatumomab and its clinical implications. ASCO Meet Abstr 31(15_suppl):3048
Nagorsen D, Baeuerle PA (2011) Immunomodulatory therapy of cancer with T cell-engaging BiTE antibody blinatumomab. Exp Cell Res 317(9):1255–60, Elsevier Inc
FDA Drug Approval Package [Internet]. [cited 2015 Mar 2]. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125557Orig1s000TOC.cfm
Goebeler M-E, Viardot A, Kufer P, Topp MS, Knop S, Mackensen L (2013) Final results from a phase 1 study of blinatumomab in patients with relapsed/refractory Non-Hodgkin’s lymphoma. Hematol Oncol 31(Abstract 302):197
Locatelli F, Gore L, Zugmaier G, Handgretinger R, Rizzari C, Trippett T (2014) Blinatumomab in pediatric patients with Relapsed/Refractory (R/R) B-cell Precursor Acute Lymphoblastic Leukaemia (BCP-ALL): a phase I/II study. Bone Marrow Transplant 37(Abstract PH-P545):S361
Topp MS, Kufer P, Gökbuget N et al (2011) Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol 29(18):2493–8
Topp MS, Gökbuget N, Zugmaier G et al (2012) Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood 120(26):5185–7
Topp MS, Gokbuget N, Zugmaier G et al (2014) Phase II trial of the anti-CD19 bispecific T cell-engager blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol 32(36):4134–40
Topp MS, Gökbuget N, Stein AS et al (2014) Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol 15:57–66
Goekbuget N, Dombret H, Bonifacio M et al (2014) BLAST: a confirmatory, single-Arm, phase 2 study of blinatumomab, a Bispecific T-cell Engager (BiTE®) antibody construct, in patients with minimal residual disease B-precursor Acute Lymphoblastic Leukemia (ALL). Blood 124(21):Abstract 379
Ruella M, Gill S (2015) How to train your T cell: genetically engineered chimeric antigen receptor T cells versus bispecific T-cell engagers to target CD19 in B acute lymphoblastic leukemia. Expert Opin Biol Ther 15(6):761–6
Thomas X (2014) Blinatumomab: a new era of treatment for adult ALL? Lancet Oncol 16(1):6–7, Elsevier Ltd