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)

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 (С_trough) and maximum (C_max) TKI plasma concentrations were measured. On imatinib/nilotinib therapy, C_trough was analyzed in 104/22 and C_max was analyzed in 63/15 plasma samples, respectively.

RESULTS. The mean plasma imatinib C_trough 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 C_max 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 C_trough values were 773.5 ± 303.0 ng/mL and 586.3 ± 308.0 ng/mL, and the mean C_max 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 C_trough values were 774.8 ± 553.0 ng/mL and 490.6 ± 175.0 ng/mL, and the mean C_max values were 2246 ± 1171 ng/mL and 1124.7 ± 281.0 ng/mL, respectively (p > 0.05). The mean plasma imatinib C_trough 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 C_trough 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 C_max 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 C_trough and C_max 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 C_trough and C_max were identified. This trial revealed no significant differences in plasma imatinib C_trough and C_max 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 C_trough values during the period of 400 mg per day administration into 4 quartiles (Q1 and Q4 included patients with the lowest and the highest C_trough values, respectively), the proportion of patients with drug toxicity appeared to be the highest in Q4 and accounted for 90 %.

• Margarita Anatolevna Gurianova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0001-9984-389X (unauthenticated)
• V.I. Kazey Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246 ; Биоаналитическая лаборатория «Экзактэ Лабс», Научный пр-д, д. 20, стр. 2, Москва, Российская Федерация, 117246 https://orcid.org/0000-0003-2032-6289 (unauthenticated)
• O.A. Shukhov Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246 ; Биоаналитическая лаборатория «Экзактэ Лабс», Научный пр-д, д. 20, стр. 2, Москва, Российская Федерация, 117246 https://orcid.org/0000-0001-5393-0816 (unauthenticated)
• E.Yu. Chelysheva National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0001-6423-1789 (unauthenticated)
• A.G. Nikiforova Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246 ; Биоаналитическая лаборатория «Экзактэ Лабс», Научный пр-д, д. 20, стр. 2, Москва, Российская Федерация, 117246 https://orcid.org/0000-0002-5719-0787 (unauthenticated)
• P.D. Sobolev Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246 ; Биоаналитическая лаборатория «Экзактэ Лабс», Научный пр-д, д. 20, стр. 2, Москва, Российская Федерация, 117246 https://orcid.org/0000-0003-3634-596X (unauthenticated)
• M.S. Dolov Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246 ; Биоаналитическая лаборатория «Экзактэ Лабс», Научный пр-д, д. 20, стр. 2, Москва, Российская Федерация, 117246 https://orcid.org/0000-0003-1265-9673 (unauthenticated)
• D.Yu. Grebenkin Exacte Labs Bioanalytical Laboratory, 20 korp. 2 Nauchnyi pr-d, Moscow, Russian Federation, 117246 ; Биоаналитическая лаборатория «Экзактэ Лабс», Научный пр-д, д. 20, стр. 2, Москва, Российская Федерация, 117246 https://orcid.org/0000-0001-9304-8000 (unauthenticated)
• A.N. Petrova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0001-5730-2593 (unauthenticated)
• A.V. Bykova National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0002-3123-8316 (unauthenticated)
• I.S. Nemchenko National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0001-9178-1428 (unauthenticated)
• E.A. Kuzmina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0002-9181-6050 (unauthenticated)
• L.V. Gavrilova Republican Clinical Hospital No. 4, 32 Ulyanova ul., Saransk, Republic of Mordovia, Russian Federation, 430032 ; ГБУЗ РМ «Республиканская клиническая больница № 4», ул. Ульянова, д. 32, Саранск, Республика Мордовия, Российская Федерация, 430032 https://orcid.org/0000-0003-0805-150X (unauthenticated)
• A.V. Kokhno National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0003-0261-5941 (unauthenticated)
• A.G. Turkina National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167 ; ФГБУ «НМИЦ гематологии» Минздрава России, Новый Зыковский пр-д, д. 4, Москва, Российская Федерация, 125167 https://orcid.org/0000-0001-9947-2371 (unauthenticated)

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