LETTER TO BLOOD| AUGUST 13, 2020
Phase 1 study of lenzilumab, a recombinant anti–human GM-CSF antibody, for chronic myelomonocytic leukemiaMrinal M. Patnaik, David A. Sallman, Abhishek A. Mangaonkar, Rachel Heuer, Jeffery Hirvela, Darci Zblewski, Aref Al-Kali, Moritz Binder, Maria E. Balasis, Hannah Newman, Christopher Letson, Traci L. Kruer, Naseema Gangat, Rami S. Komrokji, Ayalew Tefferi, Adrian Lo, Ted Shih, Cameron Durrant, Alan F. List, Eric Padron
Blood (2020) 136 (7): 909–913.
https://doi.org/10.1182/blood.2019004352
Subjects:
Clinical Trials and Observations, Myeloid Neoplasia
Topics:
antibodies, granulocyte-macrophage colony-stimulating factor, leukemia, myelomonocytic, chronic
TO THE EDITOR:
Chronic myelomonocytic leukemia (CMML), an aggressive hematological neoplasm characterized by sustained peripheral blood monocytosis (≥1 × 109/L, ≥10% of white cell count), is associated with a median overall survival of 28 to 32 months, with no current therapies that improve its natural history.1,2 Although hypomethylating agents (HMAs) have been approved for the management of CMML, the overall response and complete response rates are 40% to 50% and <20% respectively, with no impact on mutational allele burdens, even in responding patients.3,4 We have previously demonstrated that primary CMML samples exhibit granulocyte-macrophage colony-stimulating factor (GM-CSF)–dependent hypersensitivity by hematopoietic progenitor colony-formation assays and by phospho-STAT5 (pSTAT5) flow cytometry and that the GM-CSF axis is a viable therapeutic target in CMML.5 Lenzilumab (KB003) is a novel engineered human immunoglobulin G1κ monoclonal antibody, with high affinity for human...
REFERENCES1.Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management. Am J Hematol. 2018;93(6):824-840.
2.Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28(11):2206-2212.
3.Merlevede J, Droin N, Qin T, et al. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents. Nat Commun. 2016;7(1):10767.
4.Coston T, Pophali P, Vallapureddy R, et al. Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients. Am J Hematol. 2019;94(7):767-779.
5.Padron E, Painter JS, Kunigal S, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121(25):5068-5077.
6.Molfino NA, Kuna P, Leff JA, et al. Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma. BMJ Open. 2016;6(1):e007709.
7.Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia [published correction appears in Blood. 2016;128(3):462-463]. Blood. 2016;127(20):2391-2405.
8.Savona MR, Malcovati L, Komrokji R, et al; MDS/MPN International Working Group. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125(12):1857-1865.
9.Yoshimi A, Balasis ME, Vedder A, et al. Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML [published correction appears in Blood. 2017;130(13):1602]. Blood. 2017;130(4):397-407.
10.Lehtonen A, Matikainen S, Miettinen M, Julkunen I. Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced STAT5 activation and target-gene expression during human monocyte/macrophage differentiation. J Leukoc Biol. 2002;71(3):511-519.
11.Stieglitz E, Taylor-Weiner AN, Chang TY, et al. The genomic landscape of juvenile myelomonocytic leukemia [published correction appears in Nat Genet. 2016;48(1):101]. Nat Genet. 2015;47(11):1326-1333.
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