Abstract
The treatment of adult acute lymphoblastic leukemia (ALL) poses a tremendous challenge for hematologists. The use of pediatric-based chemotherapy regimens in young adults up to the age of 45 years has resulted in improved outcomes when compared retrospectively with historical controls treated with adult therapy. A better understanding of the molecular landscape of ALL and advances in the field of monoclonal antibody therapy have resulted in the development of several new agents that may provide for a reduction in the toxicity inherent in pediatric-like regimens. The anti-CD20 antibody, rituximab, anti CD22 antibody, epratuzumab, anti-CD22 antibody-drug conjugate, Inotuzumab ozogamicin, the bi-specific T-cell engager (BiTE) antibody, Blinatumomab, and chimeric receptor antigen (CAR) therapy are among the emerging agents that have demonstrated the potential to improve response rate and decrease toxicity when used alone or in combination with chemotherapy. Several role-defining phase II and phase III clinical trials with these agents are currently underway in the relapsed/refractory and newly diagnosed ALL settings.
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References
Papers of particular interest, published recently, have been highlighted as: • Of importance
Jemal A, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56(2):106–30.
Pulte D, Gondos A, Brenner H. Improvement in survival in younger patients with acute lymphoblastic leukemia from the 1980s to the early 21st century. Blood. 2009;113(7):1408–11.
Pui C-H, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354(2):166–78.
Rowe JM, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005;106(12):3760–7.
Gökbuget N, Hoelzer D. Novel antibody-based therapy for acute lymphoblastic leukaemia. Best Pract Res Clin Haematol. 2006;19(4):701–13.
Thomas DA, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106(7):1569–80.
Thomas DA, Kantarjian H, Faderl S, et al. Outcome after frontline therapy with the modified hyper-CVAD regimen with or without rituximab for de novo acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) Abst 2931. In: ASH Annual Meeting; 2008.
Rizzieri DA, Johnson J, Byrd JC, et al. Efficacy and toxicity of rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or Burkitt-like leukemia/lymphoma: Cancer and Leukemia Group B (CALGB) study 10002 Abst 858. In: ASH Annual Meeting; 2010.
Kantarjian H, et al. Monoclonal antibody-based therapies: a new dawn in the treatment of acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(31):3876–83.
FitzGerald DJ, et al. Treatment of hematologic malignancies with immunotoxins and antibody-drug conjugates. Cancer Res. 2011;71(20):6300–9.
Coiffier B, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116(12):2040–5.
Robak T, et al. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10):1756–65.
Dworzak MN, et al. CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy. Blood. 2008;112(10):3982–8.
Thomas DA, 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. 2010;28(24):3880–9.
Wierda WG, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10):1749–55.
Jabbour E, Hagop K, O’Brien S. Phase II study of the Hyper-CVAD regimen in combination with ofatumumab as frontline therapy for adults with CD-20 positive acute lymphoblastic leukemia (ALL) Abst 2664. In: ASH Annual Meeting; 2013.
Nagorsen D, et al. Blinatumomab: a historical perspective. Pharmacol Ther. 2012;136(3):334–42.
Tibes R, Keating MJ, Faderl S. Activity of alemtuzumab in patients with CD52-positive acute leukemia. Cancer. 2006;106(12):2645–51.
Bargou R, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321(5891):974–7.
Topp MS, et al. 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. 2012;120(26):5185–7.
Topp MS, Goekbuget N, Zugmaier G. Anti-CD19 BiTE blinatumomab induces high complete remission rate and prolongs overall survival in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL) Abst 670. In: ASH Annual Meeting; 2012.
Carnahan J, Wang P, Kendall R, Chen C, Hu S, Boone T, et al. Epratuzumab, a humanized monoclonal antibody targeting CD22: characterization of in vitro properties. Clin Cancer Res. 2003;9(10):3982S–90.
Leonard JP, et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21(16):3051–9.
Raetz EA, et al. Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a children’s oncology group pilot study. J Clin Oncol. 2008;26(22):3756–62.
Raetz AE, Cairo M, Borowitz MJ, et al. Reinduction chemoimmunotherapy with epratuzumab in relapsed acute lymphoblastic leukemia (ALL) in children, adolescents and young adults: results from Children’s Oncology Group (COG) study ADVL04P2. Abst 573. In: ASH Annual Meeting; 2011.
Advani A, McDonough S, Coutre S, et al. Southwest Oncology Group study S0910: a phase 2 trial of clofarabine/ cytarabine/ epratuzumab for relapsed/ refractory acute lymphocytic leukemia, Abs#2603. In: ASH Annual Meeting; 2012.
Keating MJ, et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99(10):3554–61.
Matthews D, et al. Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood. 1995;85(4):1122–31.
Lozanski G, et al. Quantitative measurement of CD52 expression and alemtuzumab binding in adult acute lymphoblastic leukemia (ALL) Abst:2386. In: ASH Annual conference; 2007.
Stock W, Sanford S. 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) Abst 838. In: ASH Annual Meeting; 2009.
Cruz RI, et al. CD52 over-expression affects rituximab-associated complement-mediated cytotoxicity but not antibody-dependent cellular cytotoxicity: preclinical evidence that targeting CD52 with alemtuzumab may reverse acquired resistance to rituximab in non-Hodgkin lymphoma. Leuk Lymphoma. 2007;48(12):2424–36.
Thorson JS, Sievers EL, Ahlert J, et al. Understanding and exploiting natures chemical arsenal: the past, present and future of calicheamicin research; 2000
Advani A, et al. Safety, pharmacokinetics, and preliminary clinical activity of inotuzumab ozogamicin, a novel immunoconjugate for the treatment of B-cell non-Hodgkin’s lymphoma: results of a phase I study. J Clin Oncol. 2010;28(12):2085–93.
Kantarjian H, et al. Inotuzumab ozogamicin, an anti-CD22–calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13(4):403–11.
Kebriaei P, et al. Feasibility of allografting in patients with advanced acute lymphoblastic leukemia after salvage therapy with inotuzumab ozogamicin. Clin Lymphoma Myeloma Leuk. 2013;13(3):296–301.
O’Brien S, Thomas D, Jorgensen JL, et al. Experience with 2 dose schedules of inotuzumab ozogamicin, single dose, and weekly, in refractory-relapsed acute lymphocytic leukemia (ALL) Abst 671. In: ASH Annual Meeting; 2012.
Kantarjian H, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119(15):2728–36.
Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011;17(20):6398–405.
Wayne AS, et al. Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial. Clin Cancer Res. 2010;16(6):1894–903.
Wayne AS, Bhojwani D, Silverman LB, et al. Novel anti-CD22 immunotoxin, moxetumomab pasudotox: phase I study in pediatric acute lymphoblastic leukemia. Abst 248. In: ASH Annual Meeting; 2011.
Herrera L, et al. A phase 1 study of combotox in pediatric patients with refractory B-lineage acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2009;31(12):936–41. doi:10.1097/MPH.0b013e3181bdf211.
Chevallier P, Bodet-Milin C, Robillard N, Eugene T, Kraeber-Bodere F. BCR-ABL1 molecular remission after 90y-epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph + B-ALL: a potential new treatment paradigm. Abst 3910. In: ASH Annual Meeting; 2013.
Park JH, Brentjens R. Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells. Discov Med. 2010.
Park JH, Sauter C, Brentjens R. Cellular therapies in acute lymphoblastic leukemia. Hematol Oncol Clin N Am. 2011;25(6):1281–301.
Brentjens RJ, et al. CD19-targeted t cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177):177ra38.
Grupp SA, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.
Grupp SA, Frey NV, et al. Acute lymphoblastic leukemia: therapy, excluding transplantation: novel immune-based therapies and novel targets Abst 67. In: ASH Annual Conference; 2013.
Lee DW III, Shah NN, et al. Anti-CD19 Chimeric Antigen Receptor (CAR) T cells produce complete responses with acceptable toxicity but without chronic B-cell aplasia in children with relapsed or refractory acute lymphoblastic leukemia (ALL) even after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Abst 68. In: ASH Annual Meeting; 2013. Emerging Therapy CAR.
Davila ML, Riviere I, Wang X, et al. Acute lymphoblastic leukemia: therapy, excluding transplantation: novel immune-based therapies and novel targets Abst 69. In: ASH Annual Meeting; 2013. Emerging Therapy CAR.
Haso W, et al. Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood. 2013;121(7):1165–74.
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Dr. Samith T. Kochuparambil declares no potential conflict of interest relevant to this article.
Dr. Mark R. Litzow is a consultant and has received honoraria from Amgen.
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Kochuparambil, S.T., Litzow, M.R. Novel Antibody Therapy in Acute Lymphoblastic Leukemia. Curr Hematol Malig Rep 9, 165–173 (2014). https://doi.org/10.1007/s11899-014-0202-9
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DOI: https://doi.org/10.1007/s11899-014-0202-9