ISSN (print) 1997-6933     ISSN (online) 2500-2139
Vol. 17 No. 4 (2024), CLINICAL TRIALS
Vol. 17 No. 4 (2024)
CLINICAL TRIALS

Interim Results of the Russian Prospective Multi-Center Clinical Trial READIT-2020 (Reduction of Tyrosine Kinase Inhibitor Doses in CML Patients, Plasma Imatinib/Nilotinib Concentrations, Sustaining Molecular Response, and Drug Toxicity)

Published 01.10.2024
Margarita Anatolevna Gurianova
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0001-9984-389X
V.I. Kazey
Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246
https://orcid.org/0000-0003-2032-6289
O.A. Shukhov
Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246
https://orcid.org/0000-0001-5393-0816
E.Yu. Chelysheva
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0001-6423-1789
A.G. Nikiforova
Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246
https://orcid.org/0000-0002-5719-0787
P.D. Sobolev
Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246
https://orcid.org/0000-0003-3634-596X
M.S. Dolov
Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246
https://orcid.org/0000-0003-1265-9673
D.Yu. Grebenkin
Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246
https://orcid.org/0000-0001-9304-8000
A.N. Petrova
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0001-5730-2593
A.V. Bykova
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0002-3123-8316
I.S. Nemchenko
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0001-9178-1428
E.A. Kuzmina
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0002-9181-6050
L.V. Gavrilova
Republican Clinical Hospital No. 4, 32 Ulyanova ul., Saransk, Republic of Mordovia, Russian Federation, 430032
https://orcid.org/0000-0003-0805-150X
A.V. Kokhno
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0003-0261-5941
A.G. Turkina
National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167
https://orcid.org/0000-0001-9947-2371
2024-4
PDF_2024-17-4_347-359 (Russian)

Keywords

chronic myeloid leukemia
tyrosine kinase inhibitors
plasma concentration of tyrosine kinase inhibitors
reduction of tyrosine kinase inhibitor doses
major molecular response
deep molecular response
adverse events

How to Cite

Gurianova M.A., Kazey V.I., Shukhov O.A., Chelysheva E.Y., Nikiforova A.G., Sobolev P.D., Dolov M.S., Grebenkin D.Y., Petrova A.N., Bykova A.V., Nemchenko I.S., Kuzmina E.A., Gavrilova L.V., Kokhno A.V., Turkina A.G. Interim Results of the Russian Prospective Multi-Center Clinical Trial READIT-2020 (Reduction of Tyrosine Kinase Inhibitor Doses in CML Patients, Plasma Imatinib/Nilotinib Concentrations, Sustaining Molecular Response, and Drug Toxicity). Clinical Oncohematology. 2024;(4):347–359. doi:10.21320/2500-2139-2024-17-4-347-359.
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Abstract

AIM. To measure the trough and maximum plasma concentrations of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients on standard and reduced doses of the drugs, to evaluate the impact of TKI plasma concentration on the loss of major/deep molecular response (MR) after dose reduction and the impact of TKI plasma concentration on drug toxicity changes.

MATERIALS & METHODS. The trial enrolled 46 imatinib and 16 nilotinib recipients. The trough (Сtrough) and maximum (Cmax) TKI plasma concentrations were measured. On imatinib/nilotinib therapy, Ctrough was analyzed in 104/22 and Cmax was analyzed in 63/15 plasma samples, respectively.

RESULTS. The mean plasma imatinib Ctrough values on daily 400 mg, 300 mg, and 200 mg of the drug were 1092 ± 346 ng/mL, 809.5 ± 313.0 ng/mL, and 570.9 ± 280.0 ng/mL, respectively. The mean plasma imatinib Cmax on daily 300 mg and 200 mg were 1944 ± 577 ng/mL and 1233.4 ± 44.0 ng/mL, respectively. In the group of patients without deep MR-loss, on daily 300 mg and 200 mg imatinib, the mean plasma Ctrough values were 773.5 ± 303.0 ng/mL and 586.3 ± 308.0 ng/mL, and the mean Cmax values were 1866.5 ± 532.0 ng/mL and 1283.7 ± 481.0 ng/mL, respectively. In the group of patients with deep MR-loss, on daily 300 mg and 200 mg imatinib, the mean plasma Ctrough values were 774.8 ± 553.0 ng/mL and 490.6 ± 175.0 ng/mL, and the mean Cmax values were 2246 ± 1171 ng/mL and 1124.7 ± 281.0 ng/mL, respectively (p > 0.05). The mean plasma imatinib Ctrough values on daily 400 mg, 300 mg, and 200 mg of the drug in the group of patients with drug toxicity were 1120.6 ± 303.0 ng/mL, whereas in the group without adverse effects these values were 998.4 ± 402.0 ng/mL (p = 0.09). The mean nilotinib Ctrough values on daily 600 mg, 400 mg, and 200 mg were 651.4 ± 397.0 ng/mL, 468.7 ± 220.0 ng/mL, and 376.7 ± 151.0 ng/mL, respectively. The mean nilotinib Cmax values on daily 400 mg and 200 mg were 655.3 ± 189.0 ng/mL and 628 ± 293 ng/mL, respectively.

CONCLUSION. This clinical trial yielded differences in plasma imatinib Ctrough and Cmax values in CML patients treated with standard and reduced doses of the drug, which turned out to be significant (p < 0.05). No significant differences in plasma nilotinib Ctrough and Cmax were identified. This trial revealed no significant differences in plasma imatinib Ctrough and Cmax on daily 400 mg and 300 mg of the drug in the groups of patients with and without adverse events. However, while dividing plasma imatinib Ctrough values during the period of 400 mg per day administration into 4 quartiles (Q1 and Q4 included patients with the lowest and the highest Ctrough values, respectively), the proportion of patients with drug toxicity appeared to be the highest in Q4 and accounted for 90 %.

PDF_2024-17-4_347-359 (Russian)

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