Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group

Richard Aplenc, Soheil Meshinchi, Lillian Sung, Todd Alonzo, John Choi, Brian Fisher, Robert Gerbing, Betsy Hirsch, Terzah Horton, Samir Kahwash, John Levine, Michael Loken, Lisa Brodersen, Jessica Pollard, Susana Raimondi, Edward Anders Kolb, Alan Gamis, Richard Aplenc, Soheil Meshinchi, Lillian Sung, Todd Alonzo, John Choi, Brian Fisher, Robert Gerbing, Betsy Hirsch, Terzah Horton, Samir Kahwash, John Levine, Michael Loken, Lisa Brodersen, Jessica Pollard, Susana Raimondi, Edward Anders Kolb, Alan Gamis

Abstract

New therapeutic strategies are needed for pediatric acute myeloid leukemia (AML) to reduce disease recurrence and treatment-related morbidity. The Children's Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed AML. AAML1031 randomized patients younger than 30 years of age with de novo AML to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each chemotherapy course. For those randomized to the control arm, bortezomib was not administered. In total, 1,097 patients were randomized to standard chemotherapy (n=542) or standard chemotherapy with bortezomib (n=555). There was no difference in remission induction rate between the bortezomib and control treatment arms (89% vs 91%, P=0.531). Bortezomib failed to improve 3-year event-free survival (44.8±4.5% vs 47.0±4.5%, P=0.236) or overall survival (63.6±4.5 vs 67.2±4.3, P=0.356) compared with the control arm. However, bortezomib was associated with significantly more peripheral neuropathy (P=0.006) and intensive care unit admissions (P=0.025) during the first course. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. These data do not support the addition of bortezomib to standard chemotherapy in children with de novo AML. (Trial registered at clinicaltrials.gov NCT01371981; https://www.cancer.gov/clinicaltrials/ NCT01371981).

Copyright© 2020 Ferrata Storti Foundation.

Figures

Figure 1
Figure 1
Consort diagram – AAML1031, as of December 31, 2017. High AR: W/D: Elective withdrawal. Reasons include terminating therapy to due to physician's choice or patient's refusal of further protocol therapy. SCT: stem cell transplantation; TX: therapy; n: number.
Figure 2
Figure 2
Event-free survival (EFS) and overall survival (OS) by treatment arm.

References

    1. Zwaan CM, Kolb EA, Reinhardt D, et al. Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia. J Clin Oncol. 2015;33(27):2949-2962.
    1. Tarlock K, Meshinchi S. Pediatric acute myeloid leukemia: biology and therapeutic implications of genomic variants. Pediatr Clin North Am. 2015;62(1):75-93.
    1. Gamis AS, Alonzo TA, Meshinchi S, et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group trial AAML0531. J Clin Oncol. 2014; 32(27):3021-3032.
    1. Cooper TM, Franklin J, Gerbing RB, et al. AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: A report from the children's oncology group. Cancer. 2011;118(3):761-769.
    1. Lange BJ, Smith FO, Feusner J, et al. Outcomes in CCG-2961, a children’s oncology group phase 3 trial for untreated pediatric acute myeloid leukemia: a report from the children’s oncology group. Blood. 2008;111(3):1044-1053.
    1. Gamis AS, Alonzo TA, Perentesis JP, Meshinchi S, Committee COGAML Children’s Oncology Group’s 2013 blueprint for research: acute myeloid leukemia. Pediat Blood Cancer. 2013;60(6):964-971.
    1. Matondo M, Bousquet-Dubouch MP, Gallay N, et al. Proteasome inhibitor-induced apoptosis in acute myeloid leukemia: a correlation with the proteasome status. Leuk Res. 2010;34(4):498-506.
    1. Colado E, Alvarez-Fernandez S, Maiso P, et al. The effect of the proteasome inhibitor bortezomib on acute myeloid leukemia cells and drug resistance associated with the CD34+ immature phenotype. Haematologica. 2008;93(1):57-66.
    1. Guzman ML, Neering SJ, Upchurch D, et al. Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood. 2001; 98(8):2301-2307.
    1. Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A. 2002;99(25):16220-16225.
    1. Jordan CT, Guzman ML, Noble M. Cancer stem cells. N Engl J Med. 2006;355(12): 1253-1261.
    1. 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.
    1. Niewerth D, Franke NE, Jansen G, et al. Higher ratio immune versus constitutive proteasome level as novel indicator of sensitivity of pediatric acute leukemia cells to proteasome inhibitors. Haematologica. 2013;98(12):1896-1904.
    1. Attar EC, De Angelo DJ, Supko JG, et al. Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia. Clin Cancer Res. 2008;14(5):1446-1454.
    1. Blum W, Schwind S, Tarighat SS, et al. Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia. Blood. 2012;119(25): 6025-6031.
    1. Orlowski RZ, Voorhees PM, Garcia RA, et al. Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies. Blood. 2005; 105(8):3058-3065.
    1. 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):1516-1522.
    1. Horton TM, Perentesis JP, Gamis AS, et al. A Phase 2 study of bortezomib combined with either idarubicin/cytarabine or cytarabine/etoposide in children with relapsed, refractory or secondary acute myeloid leukemia: a report from the Children’s Oncology Group. Pediatric Blood Cancer. 2014;61(10):1754-1760.
    1. Aplenc R, Alonzo TA, Gerbing RB, et al. Ethnicity and survival in childhood acute myeloid leukemia: a report from the Children’s Oncology Group. Blood. 2006; 108(1):74-80.
    1. Hasle H, Abrahamsson J, Forestier E, et al. Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 2004. Blood. 2012;120(5):978-984.
    1. Creutzig U, Zimmermann M, Bourquin JP, et al. Randomized trial comparing liposomal daunorubicin with idarubicin as induction for pediatric acute myeloid leukemia: results from Study AML-BFM 2004. Blood. 2013;122(1):37-43.
    1. Tsukimoto I, Tawa A, Horibe K, et al. Risk-stratified therapy and the intensive use of cytarabine improves the outcome in childhood acute myeloid leukemia: the AML99 trial from the Japanese Childhood AML Cooperative Study Group. J Clin Oncol. 2009;27(24):4007-4013.
    1. Getz KD, Alonzo TA, Sung L, et al. Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: a Children’s Oncology Group report. J Clin Oncol. 2017; 35(15_suppl): 10515-10515.
    1. Getz KD, Sung L, Leger K, et al. Effect of dexrazoxane on left ventricular function and treatment outcomes in patients with acute myeloid leukemia: A Children’s Oncology Group report. J Clin Oncol. 2018; 36(15_suppl):10501-10501.
    1. Hoff FW, Qiu Y, Hu W, et al. Abstract 451: Proteomic profiling of the unfolded protein response identifies patients benefiting from bortezomib in pediatric acute myeloid leukemia. Cancer Res. 2018;78(Suppl 13):451.
    1. Bolouri H, Farrar JE, Triche T, Jr, et al. The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions. Nat Med. 2018;24(1):103-112.
    1. Miller TP, Li Y, Getz KD, et al. Using electronic medical record data to report laboratory adverse events. Br J Haematol. 2017; 177(2):283-286.
    1. Miller TP, Troxel AB, Li Y, et al. Comparison of administrative/billing data to expected protocol-mandated chemotherapy exposure in children with acute myeloid leukemia: A report from the Children’s Oncology Group. Pediatric Blood Cancer. 2015;62(7):1184-1189.

Source: PubMed

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