L-asparaginase

Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase

ANTINEOPLASTIC THERAPY COMPLICATIONS , , , , , ,

GM Galstyan, OA Polevodova, AV Bazhenov, VV Troitskaya, OA Gavrilina, DG Gitel’zon, AE Vasil’ev, EN Parovichnikova

National Medical Hematology Research Center, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

For correspondence: Gennadii Martinovich Galstyan, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(916)488-50-73; e-mail: gengalst@gmail.com

For citation: Galstyan GM, Polevodova OA, Bazhenov AV, et al. Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase. Clinical oncohematology. 2018;11(1):89-99.

DOI: 10.21320/2500-2139-2018-11-1-89-99

ABSTRACT

The article provides a literature review on the use of the L-asparaginase (ASP) in acute lymphoblastic leukemia (ALL) and describes two clinical cases. During the treatment with ASP as part of remission induction therapy thrombotic and hemorrhagic complications in the central nervous system were registered. In both cases these complications were associated with reduced plasma levels of antithrombin III (АТ), hypofibrinogenemia and thrombocytopenia. The risk factors for thrombohemorrhagic complications in ALL patients during ASP treatment are reviewed including combined ASP + anthracycline therapy, oral contraceptives, glucocorticosteroids, thrombophilia and the presence of central venous catheter (CVC). Possible mechanisms of thrombosis as well as the timing of its occurrence and possible localisation are discussed. The article considers different strategies for prevention and treatment of thrombotic and hemorrhagic complications in ALL patients receiving ASP. In all ALL patients receiving ASP plasma levels of fibrinogen and AT should be assessed before treatment initiation, on day 3 after the injection and further every 5 to 7 days within a period of 3 weeks after the injection. Novel oral anticoagulants are not dependent on blood AT levels and may be used for prevention and treatment of thrombotic and hemorrhagic complications associated with ASP intake. Finally, recommendations for the correction of AT levels and hypofibrinogenemia are given.

Keywords: L-asparaginase, thrombosis, thromboelastography, antithrombin III, hypofibrinogenemia, thrombocytopenia, novel oral anticoagulants.

Received: August 16, 2017

Accepted: October 27, 2017

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REFERENCES

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Role of Enzymatic Activity in Producing an Antiproliferative Effect of L-Asparaginases

EXPERIMENTAL STUDIES , , ,

VS Pokrovskii1, MV Komarova2, SS Aleksandrova3, MV Pokrovskaya3, MS Kalish’yan1, SSh Karshieva1, EM Treshchalina1

1 N.N. Blokhin Russian Cancer Research Center, 24 Kashirskoye sh., Moscow, Russian Federation, 115478

2 S.P. Korolev Samara State Aerospace University, 34 Moskovskoye sh., Samara, Russian Federation, 443086

3 V.N. Orekhovich Scientific Research Institute of Biomedical Chemistry, 10 bld. 8 Pogodinskaya str., Moscow, Russian Federation, 119121

For correspondence: Vadim Sergeevich Pokrovskii, PhD, 24 Kashirskoye sh., Moscow, Russian Federation, 115478; Tel.: +7(499)324-14-09; e-mail: vadimpokrovsky@gmail.com

For citation: Pokrovskii VS, Komarova MV, Aleksandrova SS, et al. Role of Enzymatic Activity in Producing an Antiproliferative Effect of L-Asparaginases. Clinical oncohematology. 2015;8(2):120–8 (In Russ).

ABSTRACT

Background & Aims. E. coli (EcA) and Erwinia chrysanthemi (ErA) L-asparaginases have been used in antitumor chemotherapy for acute lymphoblastic leukemias since 1970s. Reports of their effect in a combined therapy of NK/T-cell and skin T-cell lymphomas have been published lately. The aim of this paper is to evaluate the relation between antiproliferative and enzymatic activities of L-asparaginases of different origin.

Methods. We conducted a prospective study of in vitro/in vivo enzymatic and antiproliferative activity of several new L-asparaginases: Yersinia pseudotuberculosis (YpA), Rhodospirillum rubrum (RrA), Wolinella succinogenes (WsA), Erwinia carotovora (EwA) in comparison with Escherichia coli L-asparaginase (EcA). Km, kcat and Vmax were calculated for evaluation of kinetic parameters. Cell lines of human transplantable tumors were used to analyze the cytotoxic activity, and DBA2 female mice with the body weight of 18–24 g with intraperitoneally transplanted Fisher lymphadenosis L5178Y (3–12 passage) from the bank of the N.N. Blokhin Russian Cancer Research Center were used for assessment of the antitumor activity.

Results. The use of type II L-asparaginases (EcA, EwA, YpA and WsA) permitted to determine a clear tendency: IC50 rises simultaneously with Km (r = 0.66; p = 0.007). Using single-dose range of 2000–8000 IU/kg in mice the highest efficacy was shown for L-asparaginases with Km = 0.017 and 0.054 mМ in comparison with L-asparaginases with lower enzymatic activity, as confirmed by corresponding odds ratio values in the stratified Cox proportional regression model. The pair-wise comparison of Kaplan-Meier curves and Cox regression method showed that WsA displays the best Km/antiproliferative activity ratio both in vitro and in vivo. In the L5178 mice model, it has been shown that WsA decreases the risk of treatment failure by 4–6 times, as compared to L-asparaginases with Km = 0.017 mМ (EcA and YpA) using a single-dose range of 500–1000 IU/kg and 2000–8000 IU/kg, RR = 0.16 and 0.28, respectively.

Conclusion. The obtained results confirmed the predictive value of enzymatic activity for demonstration of statistically significant antiproliferative activity both in vitro and in vivo. However, a statistical analysis demonstrated that this prognosis is not absolute for some enzymes or dose ranges. For instance, there might not be such correlation for high effective single dosed > 12 000 IU/kg.

Keywords: L-asparaginase, antitumor activity, enzymatic activity, mechanism of action.

Received: November 8, 2014

Accepted: January 28, 2015

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Enzymes in oncohematology: relevant directions of experimental studies and prospects of clinical use

REVIEWS , , , , , ,

V.S. Pokrovskiy and H.M. Treshchalina

N.N. Blokhin Russian Cancer Research Center of RAMS, Moscow, Russian Federation

ABSTRACT

Recently, the field of development of the novel enzyme-based drugs showed remarkable advances. In addition to L-asparaginase which have been already used in oncohematology for more than 30 years, the two new enzymes, L-arginine deiminase and ranpirnase, underwent the several phases of clinical trials. Anticancer activity in vivo at the preclinical stage was shown for a number of enzymes: L-methionine-gamma-lyase, L-lysine-alpha-oxydase, and binase. This review discusses the enzymes which possess anticancer activity and prospects for their use in oncohematology.

Keywords: anticancer enzymes, L-asparaginase, L-methionine gamma-lyase, L-lysine alpha-oxydase, L-arginine deiminase, L-phenylalanine ammonia-lyase, ranpirnase.

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