Efficacy Predictors of the Third-Line Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase of Chronic Myeloid Leukemia: Results of a Multi-Center Study

AUTOIMMUNE THROMBOCYTOPENIA allogeneic hematopoietic stem cell transplantation, chronic myeloid leukemia, chronic phase, complete cytogenetic response, tyrosine kinase inhibitors

EG Lomaia¹, VA Shuvaev^2,3, TV Chitanava¹, YuD Matvienko¹, IS Martynkevich², SV Voloshin², EV Efremova², ES Mileeva², MS Fominykh⁴, AE Kersilova³, EV Karyagina⁵, NV Il’ina⁵, NV Dorofeeva⁶, NV Medvedeva⁶, AV Klimovich⁶, TV Shneider⁷, SA Stepanova⁷, NF Polezhaikovskaya⁷, NT Siordiya¹, EI Sbityakova¹, NS Lazorko¹, EN Tochenaya¹, DV Motorin¹, NA Shnalieva¹, YuA Alekseeva¹, DB Zammoeva¹, AYu Zaritskey¹

¹ VA Almazov National Medical Research Center, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341

² Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024

³ VV Veresaev Municipal Clinical Hospital, 10 Lobnenskaya ul., Moscow, Russian Federation, 127644

⁴ AVA-PETER, Multispecialty Clinic “Skandinaviya”, 55A Liteinyi pr-t, Saint Petersburg, Russian Federation, 191014

⁵ Municipal Hospital No. 15, 4 Avangardnaya ul., Saint Petersburg, Russian Federation, 198205

⁶ Municipal Clinical Hospital No. 31, 3 Dinamo pr-t, Saint Petersburg, Russian Federation, 197110

⁷ Leningrad Regional Clinical Hospital, 45 korp. 2A Lunacharskogo pr-t, Saint Petersburg, Russian Federation, 194291

For correspondence: Tamara Vangelevna Chitanava, 2 Akkuratova ul., Saint Petersburg, Russian Federation, 197341; e-mail: chitanava.tamara@yandex.ru

For citation: Lomaia EG, Shuvaev VA, Chitanava TV, et al. Efficacy Predictors of the Third-Line Tyrosine Kinase Inhibitor Therapy in Patients with Chronic Phase of Chronic Myeloid Leukemia: Results of a Multi-Center Study. Clinical oncohematology. 2022;15(3):271–81. (In Russ).

DOI: 10.21320/2500-2139-2022-15-3-271-281

ABSTRACT

Background. The introduction of tyrosine kinase inhibitors (TKIs) into real-world clinical practice considerably improved the prognosis for patients with chronic myeloid leukemia (CML). However, during long-term follow-up, almost 1/2 and 2/3 of patients in the chronic phase (CP) discontinue TKI therapy of the first or second line, respectively. According to the Russian and International clinical guidelines, the third-line therapy should include allogeneic hematopoietic stem cell transplantation (allo-HSCT). And yet, some patients on the third-line therapy achieve and sustain optimal response on long-term TKI administration. Up to now, no clear-cut prognostic factors of TKI efficacy in the third-line therapy have been identified. This creates a challenge for treatment decision making after the failures of two lines of TKI therapy.

Aim. To assess the efficacy of the third-line TKI therapy in real-world clinical practice and to identify the factors affecting the long-term therapy outcomes in CML-CP.

Materials & Methods. The retrospective study enrolled 73 CML-CP patients aged ≥ 18 years, treated with TKIs in the third-line at 5 specialized institutions in Saint Petersburg and Leningrad Region. Among the patients there were 26 men (35 %). The median age of the patients was 51 years (range 25–88 years).

Results. With the median (range) third-line TKI therapy duration of 14 (1–120) months, the rate of complete cytogenetic response (CCR) was 30 % (n = 22) in the total cohort. The median time before achieving CCR was 9 (4–25) months. With the median follow-up time from the beginning of third-line TKI therapy till the last visit of 25 (3–136) months, progression to accelerated phase or blast crisis was observed only in 13 (17 %) out of 73 patients. Death was reported in 26 % (n = 19) of cases, among them 5 patients whose death was not CML-associated. At the last visit, 13/73 (18 %) patients were still on third-line TKI therapy. Direct and long-term therapy outcomes, including achievement of CCR and assessment of overall and progression-free survivals, were significantly better in patients with any cytogenetic response (CR) than in those without it or without complete hematologic response.

Conclusion. The implementation of TKIs in the third-line CML-CP therapy seems to be suitable for patients with at least some CR, especially if an optimal donor of hematopoietic stem cells is unavailable or if the risk of severe allo-HSCT complications is too high.

Keywords: chronic myeloid leukemia, chronic phase, complete cytogenetic response, tyrosine kinase inhibitors, third-line therapy, allogeneic hematopoietic stem cell transplantation, minimal residual disease.

Received: April 7, 2022

Accepted: June 20, 2022

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Russian Prospective Non-Randomized Clinical Study on Dose Reduction of Tyrosine Kinase Inhibitors with Subsequent Complete Therapy Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response (READIT-2020): Background, Aim, Main Objectives, Design, and Expected Results

AUTOIMMUNE THROMBOCYTOPENIA chronic myeloid leukemia, tyrosine kinase inhibitors

AG Turkina, MA Gurianova, EYu Chelysheva, OA Shukhov

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

For correspondence: Margarita Anatolevna Gurianova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(985)201-70-40; e-mail: margarita.samtcova@yandex.ru

For citation: Turkina AG, Gurianova MA, Chelysheva EYu, Shukhov OA. Russian Prospective Non-Randomized Clinical Study on Dose Reduction of Tyrosine Kinase Inhibitors with Subsequent Complete Therapy Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response (READIT-2020): Background, Aim, Main Objectives, Design, and Expected Results. Clinical oncohematology. 2022;15(1):54–61. (In Russ).

DOI: 10.21320/2500-2139-2022-15-1-54-61

ABSTRACT

Background. A withdrawal of tyrosine kinase inhibitor (TKI) therapy in chronic myeloid leukemia (CML) patients with optimal response, especially in patients with drug toxicity, is a matter of current interest. According to the results of numerous clinical studies, the probability of sustaining treatment-free remission (TFR) in CML patients with deep molecular response (DMR) is about 40–60 %. Great attention has recently been paid to personalized therapy consisting in TKI dose modification aimed at reducing or preventing therapy adverse events. Many large retrospective studies showed that reduced TKI doses in CML patients with major molecular response (MMR) and DMR is a safe therapy option. The follow-up of patients receiving reduced TKI doses is also carried out under prospective clinical studies as a stage prior to therapy discontinuation. This approach shows that the probability of sustaining TFR after the stage of TKI dose reduction is about 70 % which is higher than that after the withdrawal of standard TKI doses.

Aim. To present the background, aim, and main objectives of the study as well as the design and expected results.

Materials & Methods. READIT-2020 (Russian prospective study of REduction And DIscontinuation Treatment of TKI) is a Russian prospective non-randomized clinical study with the main aim of developing a safe management regimen for CML patients with MMR and DMR, who receive reduced TKI doses, with subsequent follow-up in the period of TFR under the control of minimal residual disease. The study is going to enroll 100 patients. Each stage of the clinical study will include a regular molecular genetic monitoring at the central laboratory (National Research Center for Hematology, Moscow). The primary objective is to assess survival without MMR loss (BCR-ABL > 0.1 %) both on reduced TKI doses and during TFR. The primary endpoint is the follow-up period of 12 months after TKI discontinuation.

Trial Registration No.: NCT04578847 (Clinicaltrial.gov).

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, major molecular response, deep molecular response, adverse events.

Received: June 2, 2021

Accepted: November 1, 2021

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Biological Mechanisms of Sustaining Deep Molecular Response in Chronic Myeloid Leukemia Upon Withdrawal of Tyrosine Kinase Inhibitors

AUTOIMMUNE THROMBOCYTOPENIA chronic myeloid leukemia, tyrosine kinase inhibitors

EYu Chelysheva, MA Guryanova, AG Turkina

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

For correspondence: Ekaterina Yurevna Chelysheva, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: denve@bk.ru

For citation: Chelysheva EYu, Guryanova MA, Turkina AG. Biological Mechanisms of Sustaining Deep Molecular Response in Chronic Myeloid Leukemia Upon Withdrawal of Tyrosine Kinase Inhibitors. Clinical oncohematology. 2021;14(4):427–35. (In Russ).

DOI: 10.21320/2500-2139-2021-14-4-427-435

ABSTRACT

The feasibility of treatment-free follow-up in chronic myeloid leukemia (CML) patients is an important issue in the era of tyrosine kinase inhibitors (TKI). The clinical trials of TKI withdrawal in case of a stable deep molecular response prove the probability of sustaining molecular remission in 40–60 % of patients. Treatment-free remission (TFR), even under persistence of residual leukemia cells, suggests that there are special biologically determined mechanisms of tumor cell proliferation control, which are independent of BCR-ABL kinase activity. The search for factors determining differences in residual leukemia clone kinetics upon TKI withdrawal is an objective which is crucial for understanding TFR as a new biological phenomenon. The review provides worldwide evidence dealing with the study of immunological, genetic, and other biological mechanisms underlying the control of minimal residual disease upon TKI discontinuation in CML patients.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, treatment-free remission, deep molecular response, minimal residual disease.

Received: May 10, 2021

Accepted: August 23, 2021

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Opportunities of Chronic Myeloid Leukemia Treatment with Reduced Doses of Tyrosine Kinase Inhibitors

AUTOIMMUNE THROMBOCYTOPENIA adverse events, chronic myeloid leukemia, tyrosine kinase inhibitors

MA Guryanova, EYu Chelysheva, AG Turkina

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

For correspondence: Margarita Anatolevna Guryanova, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(985)201-70-40; e-mail: margarita.samtcova@yandex.ru

For citation: Guryanova MA, Chelysheva EYu, Turkina AG. Opportunities of Chronic Myeloid Leukemia Treatment with Reduced Doses of Tyrosine Kinase Inhibitors. Clinical oncohematology. 2021;14(1):118–28. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-118-128

ABSTRACT

Tyrosine kinase inhibitor (TKI) therapy results in deep molecular response (MR) in 60–70 % of chronic myeloid leukemia (CML) patients. However, despite high efficacy of TKIs, many patients experience drug toxicity during the treatment. According to clinical studies, the probability of sustaining off-treatment remission in CML patients with deep MR is about 40–60 %. Great attention has recently been paid to personalized therapy of chronic phase CML. It consists in TKI dose modification to reduce or prevent adverse events. Major retrospective studies proved that in patients with optimal response TKI reduced doses can be considered safe from the point of view of sustaining major and deep MRs achieved with standard TKI doses. Also, prospective clinical trials deal with the follow-up using TKI reduced doses as pre-withdrawal period. But up to now, the results of only 4 of such studies have been available. To take a closer look at long-term follow-up of CML patients receiving reduced doses of TKIs, prospective clinical trials need to be carried out. The present article reviews the results of main studies dealing with management of CML patients treated with TKI reduced doses.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, major molecular response, deep molecular response, adverse events, pharmacokinetics of tyrosine kinase inhibitors.

Received: August 3, 2020

Accepted: November 20, 2020

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EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Clinical Aspects (Literature Review)

AUTOIMMUNE THROMBOCYTOPENIA acute myeloid leukemia, allo-HSCT, chronic myeloid leukemia, hypomethylating agents, myelodysplastic syndrome

NN Mamaev, AI Shakirova, EV Morozova, TL Gindina

RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation; IP Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Prof. Nikolai Nikolaevich Mamaev, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: nikmamaev524@gmail.com

For citation: Mamaev NN, Shakirova AI, Morozova EV, Gindina TL. EVI1-Positive Leukemias and Myelodysplastic Syndromes: Theoretical and Clinical Aspects (Literature Review). Clinical oncohematology. 2021;14(1):103–17. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-103-117

ABSTRACT

The present review provides the analysis of theoretical background and therapy of prognostically poorest EVI1-positive myeloid leukemias and myelodysplastic syndromes which is performed at the RM Gorbacheva Scientific Research Institute of Pediatric Oncology, Hematology and Transplantation. The focus is on the evidence of the dominating role of EVI1 gene in impaired epigenetic regulation of hematopoiesis and, thus, on the feasibility of allogeneic hematopoietic stem cell transplantation with hypomethylating agents and/or trans-retinoic acid used for these diseases treatment.

Keywords: EVI1, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, allo-HSCT, hypomethylating agents, trans-retinoic acid.

Received: September 12, 2020

Accepted: December 6, 2020

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Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial

AUTOIMMUNE THROMBOCYTOPENIA chronic myeloid leukemia, tyrosine kinase inhibitors

OA Shukhov, AN Petrova, EYu Chelysheva, AV Bykova, IS Nemchenko, AG Turkina

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

For correspondence: Oleg Aleksandrovich Shukhov, MD, PhD, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-16-36, +7(985)287-12-69; e-mail: shuhov@list.ru

For citation: Shukhov OA, Petrova AN, Chelysheva EYu, et al. Factors for Sustaining Molecular Remission after Discontinuation of Tyrosine Kinase Inhibitors Therapy in Chronic Myeloid Leukemia: Results of Non-Randomized Prospective Clinical Trial. Clinical oncohematology. 2021;14(1):1–12. (In Russ).

DOI: 10.21320/2500-2139-2021-14-1-1-12

ABSTRACT

Aim. To study the impact of different clinical and biological factors on sustaining molecular remission after discontinuation of tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients with a stable deep molecular response (MR).

Materials & Methods. The prospective multi-center trial on molecular remission sustainability after TKIs withdrawal, held from 2015 to 2019, enrolled 98 CML patients. The trial included patients with chronic phase CML treated with TKIs at least during 3 years and having a stable deep MR (≤ МО4; BCR-ABL < 0.01 %) during at least 2 years. Molecular monitoring was carried out every month during first 6 months after TKIs withdrawal, every 2 months during 0.5–1 year, and every 3 months after 1-year follow-up. In case of the loss of major MR (BCR-ABL > 0.1 %) therapy was reinitiated.

Results. Three-year molecular relapse-free survival was 51 % (95% confidence interval 41–61 %) in all patients, 25 % in patients with the failure of prior treatment discontinuation, and 53 % in patients who discontinued TKI therapy for the first time. According to univariate analysis, the following factors proved to be significant: persistance of deep MR, duration of therapy, and depth of MR. It was shown that TKI therapy duration, but not deep MR persistance, has independent prognostic value for the Russian population of CML patients. No significant differences were identified in 3-year molecular relapse-free survival in the groups of patients treated only with imatinib (55 %) compared with patients who received 2nd generation TKI (TKI2) as first-line (70 %; p = 0.26) and second-line (39 %; p = 0.09) therapy. However, duration of therapy in patients treated with TKI2 as first-line therapy was more than twice as short as in patients treated with imatinib as first-line therapy (median 41.5 vs. 96.4 months, respectively; p < 0.0001).

Conclusion. Longer therapy duration and MR depth (≤ MО4.5) before TKI withdrawal raise the probability of sustaining off-treatment remission. The study showed that molecular relapse-free survival does not significantly increase with the use of TKI2 as first-line treatment compared to imatinib. Nevertheless, TKI2 as first-line treatment enables to halve the duration of therapy needed to achieve comparable molecular relapse-free survival, as compared with imatinib.

Keywords: chronic myeloid leukemia, tyrosine kinase inhibitors, deep molecular response, off-treatment remission.

Received: July 30, 2020

Accepted: December 1, 2020

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Chronic Myeloid Leukemia: Role of Allogeneic Hematopoietic Stem Cell Transplantation in the Era of Tyrosine Kinase Inhibitors

AUTOIMMUNE THROMBOCYTOPENIA allo-HSCT, chronic myeloid leukemia

EV Morozova, YuYu Vlasova, MV Barabanshchikova, NN Mamaev, IM Barkhatov, AL Alyanskii, EI Darskaya, MV Vladovskaya, SN Bondarenko, IS Moiseev, BV Afanasyev

For correspondence: Elena Vladislavovna Morozova, MD, PhD, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; e-mail: dr_morozova@mail.ru

For citation: Morozova EV, Vlasova YuYu, Barabanshchikova MV, et al. Chronic Myeloid Leukemia: Role of Allogeneic Hematopoietic Stem Cell Transplantation in the Era of Tyrosine Kinase Inhibitors. Clinical oncohematology. 2020;13(2):193–8 (In Russ).

DOI: 10.21320/2500-2139-2020-13-2-193-198

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a radical method of chronic myeloid leukemia (CML) treatment. In the 1990s CML became the most frequent indication for allo-HSCT worldwide. CML treatment drastically changed after tyrosine kinase inhibitors (TKI) had been introduced into clinical practice. However, despite considerable progress achieved in treatment, low survival rate is observed in patients with CML either diagnosed at an advanced stage or characterized with resistance, TKI intolerance, and loss of response. For such patients allo-HSCT remains the only and the best treatment solution. The present article discusses current views on the importance of allo-HSCT for CML treatment in the era of extensive use of TKIs.

Keywords: allo-HSCT, chronic myeloid leukemia, TKI.

Received: November 20, 2019

Accepted: February 28, 2020

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Comparative Analysis of Cardiovascular Disorders in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitor Therapy

AUTOIMMUNE THROMBOCYTOPENIA chronic myeloid leukemia, dasatinib

LM Makeeva¹, EI Emelina¹, AV Bykova², GE Gendlin¹, GA Gusarova², IG Nikitin¹, EYu Chelysheva², OYu Vinogradova^1,3,4, IE Lazarev³, EG Arshanskaya³, AG Turkina²

¹ NI Pirogov Russian National Research Medical University, 1 Ostrovityanova str., Moscow, Russian Federation, 117997

²National Research Center for Hematology, 4 Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

³SP Botkin Municipal Clinical Hospital, 5 2-i Botkinskii pr-d, Moscow, Russian Federation, 125284

⁴ Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela str., Moscow, Russian Federation, 117997

For correspondence: Prof. Gennadii Efimovich Gendlin, MD, PhD, 1 Ostrovityanova str., Moscow, Russian Federation, 117997; e-mail: rgmugt2@mail.ru

For citation: Makeeva LM, Emelina EI, Bykova AV, et al. Comparative Analysis of Cardiovascular Disorders in Patients with Chronic Myeloid Leukemia on Tyrosine Kinase Inhibitor Therapy. Clinical oncohematology. 2020;13(1):104–111 (In Russ).

DOI: 10.21320/2500-2139-2020-13-1-104-111

ABSTRACT

Aim. To analyze adverse cardiovascular events in chronic myeloid leukemia (CML) patients who received various tyrosine kinase inhibitors (TKI).

Materials & Methods. The trial included 97 CML patients with nilotinib, dasatinib or imatinib indications. By the time of examination the patients had undergone TKI therapy for 1–138 months. The three of them were sequentially treated with 2 drugs over the monitoring period. All CML patients were aged 22–79 years (median 53.5 years): 55 women were aged 22–71 years (median 53.5 years) and 42 men were aged 24–79 years (median 53 years).

Results. The comparative analysis demonstrated significantly higher impact of nilotinib on QTc duration compared with other TKIs. The patients who received nilotinib (n = 15) throughout 38 months had QTc of 0.47 s (interquartile range [IQR] 0.46–0.47 s), in imatinib group (n = 17) QTc was 0.43 s (IQR 0.43–0.44 s), and in dasatinib group (n = 4) QTc was 0.43 s (IQR 0.42–0.44 s) (p = 0.0008). Among all patients treated with nilotinib there were 62 % (31/50) with QTc > 0.46 s, in imatinib (6/41) and dasatinib (2/18) groups it was detected in 14.6 % and 11.1 % of patients, respectively (p = 0.0008). Five patients had QTc > 0.48 s, which is the criterion for discontinuation of treatment or dose reduction. In two patients the identified changes of QTc duration required TKI temporary suspension. After nilotinib dose reduction or discontinuation QTc duration normalized in all cases within 2 weeks. Decreased ankle-brachial index (ABI) < 0.9 without pronounced clinical symptoms was identified in two patients who received nilotinib. Afterwards they showed peripheral occlusive disease of lower extremities, and nilotinib treatment was discontinued. In patients treated with other TKIs no occlusive vascular lesions were observed. A case of chronic heart failure with reduced left ventricular ejection fraction developing on nilotinib therapy was revealed and described.

Conclusion. Despite high specificity for BCR-ABL tyrosine kinase, new TKIs can, although rarely, induce cardiovascular adverse events. Prior to TKI treatment assignment CML patients should be examined with ECG and EchoCG with systolic function evaluation, and the measurement of pulmonary artery pressure as well as ABI. The examination should be repeated in the end of the 1st year TKI treatment if there is no reason for extra examinations. It is recommended to hold 24-hour ECG monitoring with QTc max measurement prior to nilotinib assignment, then once a year within 2 years of nilotinib treatment, and once in 6 months after 3 years of therapy.

Keywords: imatinib, dasatinib, nilotinib, chronic myeloid leukemia, QTc prolongation, sudden cardiac death, peripheral occlusive disease of lower extremities, chronic heart failure, cardiomyopathy, pulmonary arterial hypertension.

Received: September 8, 2019

Accepted: December 21, 2019

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Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Practical Recommendations)

MYELOID TUMORS bosutinib, chronic myeloid leukemia, dasatinib, pregnancy, tyrosine kinase inhibitors, беременность

EYu Chelysheva¹, AG Turkina¹, ES Polushkina², MA Vinogradova², RG Shmakov²

¹ National Medical Hematology Research Center, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167

²VI Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 4 Akademika Oparina str., Moscow, Russian Federation, 117997

For correspondence: Ekaterina Yur’evna Chelysheva, MD, PhD, 4a Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; Tel.: +7(495)612-48-60; e-mail: denve@bk.ru

For citation: Chelysheva EYu, Turkina AG, Polushkina ES, et al. Management of Chronic Myeloid Leukemia Patients During Pregnancy (Analysis of Literature and Clinical Experience). Clinical oncohematology. 2019;12(2):202–10.

DOI: 10.21320/2500-2139-2019-12-2-202-210

ABSTRACT

Background. The tyrosine kinase inhibitors (TKI) era is marked by a long-term favorable prognosis of chronic myeloid leukemia (CML). In this context CML patients of reproductive age are faced with major issues of family planning with due regard to the risk of TKI treatment interruption during pregnancy. Additionally, TKI impact is another potential risk to the fetus.

Aim. To develop differentiated approach to CML treatment during pregnancy.

Materials & Methods. Analysis includes literature data and clinical experience based on 166 pregnancies of 120 CML patients from CML Pregnancy Registry.

Results. Pregnancy planning is recommended after achieving stable and deep molecular response (with BCR-ABL > 0.01 %, IS) within the period of at least 2 years. At conception TKI therapy does not have to be interrupted. However, early pregnancy detection and TKI treatment interruption after pregnancy confirmation are of vital importance due to teratogenic risks. Furthermore, no TKI may be administered during organogenetic period, i.e. up to the 15^th week of gestation. In the absence or loss of complete hematologic response and growth of BCR-ABL > 1 % after the 15^th week of gestation imatinib or nilotinib administration is justified in the interest of pregnant patients taking into account limited transfer of these drugs through placenta. In the absence of complete hematologic response before the 15^th week of gestation interferon-α can be administered. With BCR-ABL < 1 % patients can be either followed-up without therapy or they can receive interferon-α throughout pregnancy. Dasatinib, bosutinib, and other TKI are contraindicated at any stage of pregnancy. There are no special recommendations for childbirth, delivery is to be adapted to obstetric conditions. Breast feeding is not recommended because of the lack of practical evidence for its safety.

Conclusion. A regular molecular monitoring of BCR-ABL and hematologic status is indispensable, health condition of fetus should be continuously monitored as well. CML patient management should be conducted by cooperating hematologists and gynecologists.

Keywords: chronic myeloid leukemia, pregnancy, tyrosine kinase inhibitors, imatinib, nilotinib, dasatinib, bosutinib.

Received: January 9, 2019

Accepted: March 20, 2019

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Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ)

MYELOID TUMORS chronic myeloid leukemia, TKI switch, tyrosine kinase inhibitors

OA Shukhov, AG Turkina, EYu Chelysheva, AV Bykova, AN Petrova, GA Gusarova, IS Nemchenko, AO Abdullaev, TN Obukhova, AB Sudarikov

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

For correspondence: Oleg Aleksandrovich Shukhov, MD, PhD, 4а Novyi Zykovskii pr-d, Moscow, Russian Federation, 125167; e-mail: shuhov@list.ru

For citation: Shukhov OA, Turkina AG, Chelysheva EYu, et al. Treatment of Chronic Myeloid Leukemia According to Current Guidelines: The Results of the Pilot Prospective Study “Early Induction Therapy and Monitoring” (РИТМ). Clinical oncohematology 2019;12(2):194–201.

DOI: 10.21320/2500-2139-2019-12-2-194-201

ABSTRACT

Background. Current clinical guidelines on diagnosis and treatment of chronic myeloid leukemia (CML) define indications for substitution of first-line tyrosine kinase inhibitor (TKI) at therapy failure during different phases of disease progression.

Aim. To assess the efficacy of CML treatment with implementing the protocol of timely monitoring and switching to another TKI.

Materials & Methods. Patients were included into pilot prospective study РИТМ during 5 years. Data on 100 CML patients were analyzed. Therapy and monitoring were conducted according to the Federal clinical guidelines on CML diagnosis and therapy, 2013.

Results. Median follow-up after initiation of treatment was 46 months (range 12–74). Imatinib mesylate was administered as first-line therapy to 91 (91 %) patients, 9 (9 %) patients received 2nd generation TKI (TKI2). Therapy failure was registered in 31 (31 %) patients; 26 (84 %) of them were switched to TKI2. At the time of analysis 95 (95 %) patients were followed-up. Cumulative incidence of CML-associated mortality was 2 %. By the fifth year of follow-up cumulative probability of complete cytogenetic, major and deep molecular responses was 93 %, 88 % and 66 %, respectively.

Conclusion. CML treatment according to current guidelines yields the results comparable with those achieved by first-line TKI2 therapy. This approach reduces CML treatment costs and lowers the risk of TKI2-associated adverse events. Due to a high rate of deep molecular response the proportion of CML patients in remission without treatment can be increased in the future.

Keywords: chronic myeloid leukemia, monitoring, tyrosine kinase inhibitors, TKI switch.

Received: October 21, 2018

Accepted: February 4, 2019

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