Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors. Additionally, this manuscript discusses the impact of diagnostic approaches on management of ALL. Specifically, minimal residual disease is increasingly felt to be important and will likely dramatically impact the care of ALL patients in the near future.
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Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. Elsevier Ltd; 2013;381(9881):1943–55.
Pui C-H. Recent research advances in childhood acute lymphoblastic leukemia. J Formos Med Assoc. Formosan Medical Association & Elsevier; 2010;109(11):777–87.
Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children’s oncology group. J Clin Oncol. 2012;30(14):1663–9.
• Annesley CE, Brown P. Novel agents for the treatment of childhood acute leukemia. Ther Adv Hematol. 2015;6(2):61–79. This reference provides high-yield information regarding drugs with newer mechanisms of action being investigated, some of which were not able to be mentioned within the scope of our manuscript.
Gökbuget N, Stanze D, Beck J, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. Blood. 2012;120(10):2032–41.
Seibel NL. Acute lymphoblastic leukemia: an historical perspective. Am Soc Hematol Educ Progr. 2008;365
• Thomas DA, Faderl S, O’Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, 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. This reference provides useful information regarding mechanisms of action being studied. Specifically, it contains detailed discussion regarding monoclonal antibodies and their increasingly important role in the care of ALL.
DeAngelo DJ, Stevenson KE, Dahlberg SE, Silverman LB, Couban S, Supko JG, et al. Long-term outcome of a pediatric-inspired regimen used for adults aged 18–50 years with newly diagnosed acute lymphoblastic leukemia. Leukemia. Nature Publishing Group; 2015;29(3):526–34.
Papadantonakis N, Advani AS. Recent advances and novel treatment paradigms in acute lymphocytic leukemia. Ther Adv Hematol. 2016;7(5):252–69.
Jabbour E, Brien SO, Ravandi F, et al. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010–6.
Maury S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016;375:1044–53.
Jabbour E, Kantarjian H. Immunotherapy in adult acute lymphoblastic leukemia: the role of monoclonal antibodies. Blood Adv. 2016;1(3):260–4.
Thomas DA, Brien SO, Jorgensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood. 2014;113(25):6330–7.
Sasaki K, Kantarjian HM, Ravandi F, et al. Frontline ofatumumab in combination with hyper-CVAD for adult patients with CD-20 positive acute lymphoblastic leukemia (ALL): interim result of a phase II clinical trial. In: American Society of Hematology Annual Meeting & Exposition. 2016. p. Abstract 2783.
Beers SA, French RR, Chan HTC, et al. Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection. Blood. 2010;115(25):5191–201.
Awasthi A, Ayello J, Van de Ven C, 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. Br J Haematol. 2015;171(5):763–75.
Tedder TF. CD19: a promising B cell target for rheumatoid arthritis. Nat Rev Rheumatol. Nature Publishing Group; 2009;5(10):572–7.
Amgen. Blincyto (R) [package insert]. California, USA. 2014. p. 19.
Topp MS, Stein A, Nicola Gökbuget N et al. Blinatumomab nearly doubles survival in acute lymphoblastic leukemia. In: 2016 European Hematology Association Congress. 2016. p. Abstr S149.
Van Epps HA, Heiser R, Cao A, et al. Denintuzumab mafodotin stimulates immune responses and synergizes with CD20 antibodies to heighten anti-tumor activity in preclinical models of non-hodgkin lymphoma. In: American Society of Hematology Annual Meeting & Exposition. 2016. p. Abstract 4177.
Fathi AT, Borate U, Deangelo DJ, et al. A phase 1 study of denintuzumab mafodotin (SGN-CD19A) in adults with relapsed or refractory B-lineage acute leukemia (B-ALL) and highly aggressive lymphoma. Blood. 2015;126(23):1328.
Zammarchi F, Williams DG, Adams L, et al. Pre-clinical development of Adct-402, a novel pyrrolobenzodiazepine (PBD)-based antibody drug conjugate (ADC) targeting CD19-expressing B-cell malignancies. Blood. 2015;126(23):1564.
Sullivan-Chang L, O’Donnell RT, Tuscano JM. Targeting CD22 in B-cell malignancies: current status and clinical outlook. BioDrugs. 2013;27(4):293–304.
Shah N, Stevenson M, Yuan C, et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr. 2015;62:964–9.
DiJoseph JF, Armellino DC, Boghaert ER, et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004;103(5):1807–14.
Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740–53.
Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011;17(20):6398–405.
Kantarjian HM, Lioure B, Kim SK, et al. A phase II study of coltuximab ravtansine (SAR3419) monotherapy in patients with relapsed or refractory acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2016;16(3):139–45.
Raetz E, Cairo M, Borowitz M, 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. 2015;62:1171–5.
Hu Y, Turner MJ, Shields J, Gale MS, Hutto E, Roberts BL, et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology. 2009;128:260–70.
Genzyme Corporation. Campath (R) [package insert]. Massachusetts, USA. 2009. p. 1–2.
Neri LM, Cani A, Martelli AM, et al. Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential. Leukemia. 2014;28(4):739–48.
Brown VI, Fang J, Alcorn K, et al. Rapamycin is active against B-precursor leukemia in vitro and in vivo, an effect that is modulated by IL-7-mediated signaling. Proc Natl Acad Sci U S A. 2003;100(25):15113–8.
Teachey DT, Obzut DA, Cooperman J, et al. The mTOR inhibitor CCI-779 induces apoptosis and inhibits growth in preclinical models of primary adult human ALL. Clin Oncol. 2006;107(3):1149–55.
Daver N, Boumber Y, Kantarjian H, et al. A phase I/II study of the mTOR inhibitor everolimus in combination with hyperCVAD chemotherapy in patients with relapsed/refractory acute lymphoblastic leukemia. Clin Cancer Res. 2015;21(12):2704–14.
Cortes J, Thomas D, Koller C, et al. Phase I study of bortezomib in refractory or relapsed acute leukemias phase I study of bortezomib in refractory or relapsed acute leukemias. Clin Cancer Res. 2004;10:3371–6.
Horton TM, Pati D, Plon SE, et al. A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: a Children’s Oncology Group study. Clin Cancer Res. 2007;13(5):1516–22.
Messinger YH, Gaynon PS, Sposto R, et al. Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia : therapeutic advances in childhood Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: therapeutic advance. Blood. 2012;120(2):285–90.
Horton TM, Gannavarapu A, Blaney SM, et al. Bortezomib interactions with chemotherapy agents in acute leukemia in vitro. Cancer Chemother Pharmacol. 2006;58(1):13–23.
Messinger Y, Gaynon P, Raetz E, et al. Phase I study of bortezomib combined with chemotherapy in children with relapsed childhood acute lymphoblastic leukemia (ALL): a report from the therapeutic advances in childhood leukemia (TACL) consortium. Pediatr Blood Cancer. 2010;55:254–9.
Horton T, Lu X., O’Brien M, et al. Bortezomib reinduction therapy to improve response rates in pediatric ALL in first relapse: a Children’s Oncology Group (COG) study (AALL07P1). In: ASCO Annual Meeting. 2013. p. Abstract 10003.
Garcia-Manero G, Yang H, Bueso-ramos C, et al. Phase 1 study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid [SAHA]) in patients with advanced leukemias and myelodysplastic syndromes. Blood. 2008;111(3):1060–6.
Bhatla T, Wang J, Morrison DJ, et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood. 2012;119(22):5201–10.
Sun W, Gaynon PS, Sposto R, et al. A phase 1 study of azacitidine (AZA) in combination with fludarabine and cytarabine in relapse/refractory childhood leukemia: a Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) study. Blood2. 2014;124(21):3764.
Kim E, Koehrer S, Rosin NY, et al. Activity of bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) in B-cell acute lymphoblastic leukemia (B-ALL). Blood. 2012;120(21):2569.
Kim E, Koehrer S, Rosin NY, et al. Brutonʼs tyrosine kinase inhibitor ibrutinib interferes with constitutive and induced pre-B cell receptor signaling in B-cell acute lymphoblastic leukemia. Blood. 2013;122(21):1399.
Suryani S, Carol H, Chonghaile TN, Frismantas V, Sarmah C, High L, et al. Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts. Clin Cancer Res. 2014;20(17):4520–31.
Suryani S, Evans K, Richmond J, Robbins A, Bracken L, Kurmasheva R, et al. Evaluation of the Bcl-2 inhibitor ABT-199 in xenograft models of acute lymphoblastic leukemia by the pediatric preclinical testing program. In: AACR Annual Meeting. 2015. p. Abstr nr 3276.
Maude S, Tasian S, Vincent T, et al. Targeting JAK1/2 and mTOR in xenograft models of Ph-like acute lymphoblastic leukemia. Blood. 2012;120(17):3510–8.
Batlevi CL, Matsuki E, Brentjens RJ, Younes A. Novel immunotherapies in lymphoid malignancies. Nat Rev Clin Oncol [Internet]. 2015;13:25–40.
Irving J, Matheson E, Minto L, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood. 2014;124(23):3420–30.
Canté-Barrett K, Spijkers-Hagelstein JAP, Buijs-Gladdines JGCAM, et al. MEK and PI3K-AKT inhibitors synergistically block activated IL7 receptor signaling in T-cell acute lymphoblastic leukemia. Leukemia [Internet]. Nature Publishing Group; 2016;30:1832–43.
Bai XT, Moles R, Chaib-Mezrag H, et al. Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells. J Hematol Oncol Journal of Hematology & Oncology. 2015;8(117):1–12.
Pui C-H, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with response-adapted therapy. Leukemia. Nature Publishing Group; 2016;(August):1–28.
Schrappe M, Zimmermann M, Möricke A, et al. Reduced intensity delayed intensification in standard-risk patients defined by minimal residual disease in childhood acute lymphoblastic leukemia: Results of an International Randomized Trial in 1164 Patients (Trial AIEOP- BFM ALL 2000). In: American Society of Hematology Annual Meeting & Exposition. 2016. p. Plenary 4.
National Comprehensive Cancer Network. Acute lymphoblastic leukemia (Version 2.2016) [Internet].
Van Dongen JJM, Van Der Velden VHJ, Bruggemann M, et al. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. 2015;125(26):3996–4009.
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The authors declare that they have no conflicts of interest.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
This article is part of the Topical Collection on Acute Lymphocytic Leukemias
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Man, L.M., Morris, A.L. & Keng, M. New Therapeutic Strategies in Acute Lymphocytic Leukemia. Curr Hematol Malig Rep 12, 197–206 (2017). https://doi.org/10.1007/s11899-017-0380-3
- Acute lymphoblastic leukemia
- Acute lymphocytic leukemias
- Therapeutic approaches
- Purine nucleoside analogs
- Monoclonal antibodies
- Antibody drug conjugates