Chronic myeloid leukemia: clinical guidelines

List of Abbreviations

allo-HSCT — allogeneic hematopoietic stem cell transplantation

ANC — absolute neutrophil count

BC — blast crisis

MMR — major molecular response

ULN — upper limit of normal

WHO - World Health Organization

DMR — deep molecular response

G-CSF — granulocyte colony-stimulating factor (L03AA Colony-stimulating factors)

HSC — hematopoietic stem cells

DCA — additional chromosomal aberrations

TKI — BCR-ABL tyrosine kinase inhibitors

TKI1 — first-generation BCR-ABL tyrosine kinase inhibitors

TKI2 — second-generation BCR-ABL tyrosine kinase inhibitors

IFN-α — interferon-alpha (interferon alfa-2b** )

CSF — colony-stimulating factor

CT — computed tomography

PAH — pulmonary arterial hypertension

LDL - low-density lipoproteins

HDL — high-density lipoproteins

MR — molecular response

mRNA — messenger RNA

LLN — lower limit of normal

RT‑PCR — reverse transcription polymerase chain reaction

CHR — complete hematologic response

CCyR — complete cytogenetic response

PCR — polymerase chain reaction

qPCR — quantitative real-time PCR

TFR — treatment-free remission

CCgI — conventional cytogenetic investigation

CVD — cardiovascular diseases

BMT — bone marrow transplantation

Ultrasound — ultrasound examination

LER — level of evidence and recommendation

LoE – level of evidence

AP — accelerated phase

hCG - human chorionic gonadotropin

CML — chronic myeloid leukemia

CP — chronic phase

CyR — cytogenetic response

ECG — electrocardiography / electrocardiogram

Ara-C – cytarabine**

BCR::ABL1 – chimeric gene, the result of a translocation between chromosomes 9 and 22

BCR::ABL1 – protein with increased tyrosine kinase activity, product of the BCR::ABL1 gene

EBMT – European Group for Blood and Marrow Transplantation

ELN – European LeukemiaNet

ESMO – European Society for Medical Oncology

FISH – fluorescence in situ hybridization

HLA – Human Leukocyte Antigens, major histocompatibility complex

IS – laboratory standard for determining the percentage ratio of the expression level of the studied BCR::ABL1 gene to the control gene, otherwise referred to as the International Scale

NCCN – National Comprehensive Cancer Network

NCI CTCAE – National Cancer Institute Common Terminology Criteria for Adverse Events

Ph – Philadelphia chromosome – a shortened chromosome 22 resulting from the t(9;22)(q34;q11) translocation

Ph⁺ – cells containing the Philadelphia chromosome

Ph^– – cells lacking the Philadelphia chromosome

RUSSCO – Russian Society of Clinical Oncology

** - Vital and essential drugs

Terms and Definitions

BCR::ABL1 gene mutation analysis – detection of point mutations in the BCR::ABL1 gene

Hematologic toxicity – hemoglobin level reduction, neutropenia, and thrombocytopenia associated with TKI therapy.

Hematologic response, cytogenetic response, molecular response – types of treatment response characterizing the tumor clone burden and determined, respectively, based on the results of a complete blood count, cytogenetic, and molecular genetic studies.

Risk group – a characteristic assessed solely at the time of disease diagnosis, prior to initiating therapy, based on prognostically significant characteristics in patients with chronic phase (CP) CML.

Additional chromosomal aberrations – additional karyotype abnormalities in Ph+ cells detected by standard cytogenetic analysis.

Other chromosomal aberrations – karyotype abnormalities in Ph– cells detected by standard cytogenetic analysis.

Tyrosine kinase inhibitor – a drug capable of inhibiting the enzymatic activity of BCR::ABL1 tyrosine kinase

FISH assay – examination of cells by fluorescence in situ hybridization using fluorophore-labeled DNA probes.

International Scale (IS) – a standardized scale for reporting the quantitative expression level of the BCR::ABL1 gene, incorporating a conversion factor

Molecular genetic testing for the BCR::ABL1 level — measurement of BCR::ABL1 chimeric gene expression by real-time quantitative PCR.

Intolerance to therapy – the presence of adverse events from therapy that make its administration at the recommended dosage impossible.

Treatment failure – a response to TKI therapy insufficient to prevent the risk of disease progression and patient death – an indication for switching treatment to another TKI or performing allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Optimal response – a treatment response in which continuing treatment with the given TKI maximally reduces the risk of CML progression and patient death.

Warning – a response to TKI therapy indicating the need for close monitoring of response, consideration of switching TKIs, or readiness to change treatment if signs of treatment failure appear.

Adherence to therapy – patient compliance with the physician's recommendations regarding examination and treatment.

Standard cytogenetic analysis (SCA) – examination of the number and structure of chromosomes in bone marrow cells after G-banding

Phase of chronic myeloid leukemia – a characteristic defining the stage of CML and prognosis; assessed at disease onset, upon progression, or when changing treatment.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Chronic myeloid leukemia (CML) is a clonal neoplastic myeloproliferative disorder caused by the malignant transformation of hematopoietic stem cells and characterized by enhanced proliferation of the granulocytic lineage without loss of differentiation capacity, myeloid tissue hyperplasia, and myeloid metaplasia of hematopoietic organs, associated with the chromosomal abnormality – translocation t(9;22)(q34;q11), resulting in the formation of the BCR::ABL1 chimeric gene.

Previously, this chimeric gene was designated as BCR-ABL1; however, in 2021 the HUGO Gene Nomenclature Committee (HGNC) published its guidelines for designating fusion genes, including chimeric ones, indicating the need to separate the two parts of the fusion gene in a new way – with a double colon [103].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The etiology of the disease has not been established. The role of various factors – ionizing radiation, infections, toxins – is discussed, but no clear correlation between them and the onset of CML has been identified.

Pathogenetically, CML represents a clonal myeloproliferative process developing as a result of malignant transformation in early hematopoietic stem cells. The emergence of the t(9;22)(q34;q11) translocation – the so-called "Philadelphia chromosome" (Ph chromosome) – and correspondingly the BCR::ABL1 chimeric gene underlies the pathogenesis of the disease. The product of the BCR::ABL1 gene is a tyrosine kinase with abnormally increased activity that regulates signals responsible for cell growth, activation, differentiation, adhesion, and apoptosis [1]. Depending on the breakpoint location, more than 10 different variants of the BCR::ABL1 chimeric transcript with varying molecular weights can be detected. The most common are chimeric transcripts formed by the fusion of exon 13 or 14 of the BCR gene with exon 2 of the ABL1 gene. In the first case, the e13a2 chimeric transcript is formed (previously known as b2a2), and in the second, e14a2 (b3a2). In total, variants e13a2 and e14a2 account for more than 98% of CML cases. Both lead to the formation of a chimeric protein with a molecular weight of 210 kDa, designated as p210. Other BCR::ABL1 transcript variants in CML patients are termed atypical. Among them, variants formed by the fusion of exon 1 of BCR with exon 2 of the ABL1 gene (e1a2), leading to the formation of a protein with a molecular weight of 190 kDa (p190), or exon 19 of BCR with exon 2 of ABL1 (e19a2, p230) are detected more frequently than others.

The abnormal tyrosine kinase activity of the BCR::ABL1 chimeric protein determines not only an increased cell division rate, but also their growth advantage independent of signals, and the blockage of apoptosis as a mechanism of cellular self-destruction, as a result of which tumor hematopoiesis gains an advantage over normal hematopoiesis and gradually displaces it. As the tumor mass increases, clinical symptoms associated with myeloid tissue hyperplasia manifest; subsequently, with the development of genetic instability, new subclones appear, and the disease progresses to the blast crisis phase – CML-BC.

1.3 Epidemiology of the Disease or Condition

Chronic myeloid leukemia (CML) is a rare disease. According to a population-based study in 6 regions of the Russian Federation, the incidence standardized to the WHO standard population is 0.7 per 100,000 adult population [2]. The median age in adult patients is 50 years (range 18 to 82), with the peak incidence occurring at 50–59 years, although the proportion of young patients under 40 is significant – up to 33%. The disease can be detected at any age. In 2016, the Russian Chronic Myeloid Leukemia Register contained information on 7,609 CML patients, with the disease diagnosed in the chronic phase in 6,560 (93.8%) patients, in the acceleration phase in 380 (5.5%) patients, and in the blast crisis phase in 47 (0.7%) cases [3].

CML in patients under 18 years of age (hereinafter referred to as children) is an extremely rare pathology, with an annual incidence averaging 1:1,000,000 children per year, which is ten times lower than in the adult population. According to available data, the median age is 13.2 years (1–18 years) [114, 115, 116].

1.4 Features of Coding the Disease or Condition

C92.1 – chronic myeloid leukemia [CML], BCR::ABL1-positive

• Philadelphia chromosome (Ph) positive

• t(9;22)(q34;q11)

• with blast crisis.

1.5 Classification of the disease or condition

By disease phases

The course of CML includes 3 phases reflecting the degree of disease progression. The disease can be diagnosed at any stage.

• Chronic phase (CP) is the initial stage of CML and is diagnosed in the majority (up to 94%) of newly diagnosed patients [1, 4]. The diagnosis of CP is established in the absence of signs of AP and BC.

• Accelerated phase (AP) is identified in 3–5% of initial CML patients and represents a more advanced stage of the pathological process in CML compared to CP. AP may also develop during disease progression.

• Blast crisis (BC) is the most aggressive stage of CML. Disease onset in BC is an unfavorable prognostic sign and is observed in 1–2% of CML patients. The median survival time in CML blast crisis is 6–12 months [1, 4].

Assessment of the phase is performed at disease onset, during disease progression, and when changing therapy. Differential diagnostic criteria for CML phases are presented in Table 1.

Table 1. CML phases according to the ELN classification.

By risk group for CP CML

CML risk group is calculated based on prognostically significant clinical and hematological characteristics and is assessed in CP patients at the time of diagnosis, prior to initiating therapy;

J.E. Sokal risk group (predicts the probability of overall survival) [6]

• low risk;

• intermediate risk;

• high risk.

ELTS risk group (predicts the probability of overall survival, progression-free survival, and the likelihood of achieving a deep molecular response) [9]

• low risk,

• intermediate risk,

• high risk.

The combination of criteria characterizing risk groups according to the Sokal and ELTS systems is presented in Table 2.

Table 2. Determination of CML risk groups according to J.E. Sokal and ELTS

*Automatic calculation is available at: http://bloodref.com/myeloid/cml/sokal-hasford and http://www.leukemia-net.org/content/leukemias/cml/elts_score/index_eng.html

1.6 Clinical presentation of the disease or condition

The clinical presentation of CML in most cases may be asymptomatic; the initial period of the disease in most patients may last for several years. Frequently, the signs of the disease at the time of diagnosis are represented solely by changes in the complete blood count (the most common of which are leukocytosis, a myelocytic shift, basophil-eosinophil association) and splenomegaly, which may be detected during a routine preventive examination or when consulting a physician for another condition [4].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Many recommended diagnostic methods for the disease and related conditions have a limited evidence base (according to the grading scales for reliability of evidence and clinical recommendations) due to the lack of dedicated clinical studies. Despite this, they are necessary elements of patient evaluation for diagnosis and treatment planning, as more effective and proven methods have not yet been developed.

The diagnosis of CML can be definitively established only upon the detection of the disease-specific genetic abnormality: the t(9;22)(q34;q11) translocation by cytogenetic testing (CGT) and/or the BCR::ABL1 chimeric gene by PCR or FISH methods.

2.1 Complaints and Anamnesis

Comment: when collecting complaints and medical history, it is necessary to assess:

1. Tumor intoxication syndrome (weakness, decreased appetite, weight loss, sweating, low-grade fever).

2. Tumor proliferation syndrome (pain and a feeling of heaviness in the hypochondrium due to hepato- and splenomegaly).

3. Anemic syndrome (general weakness, shortness of breath, decreased exercise tolerance, pallor of the skin and mucous membranes, tachycardia).

4. Thrombotic complications in the presence of hyperthrombocytosis.

5. Hemorrhagic syndrome caused by thrombocytopenia or hyperthrombocytosis.

6. Neurological symptoms, especially if the disease presents with AP or BC.

7. Comorbidities.

8. Concomitant therapy.

9. Presence of siblings (to assess the feasibility of allo-HSCT).

The patient's general condition should be assessed using the WHO/ECOG performance status scale (see Appendix G1 of these guidelines).

The clinical presentation of CML is non-specific; the appearance of the aforementioned syndromes is most characteristic of advanced phases of the disease (AP and BC). In the majority of patients in the CP, complaints and clinical symptoms are either absent or non-specific, and signs of the disease at the time of diagnosis may be represented solely by abnormalities in the complete blood count (leukocytosis, myelocytic shift, basophil-eosinophil association) detected during a routine check-up or when consulting a physician for another condition. Given that drug therapy for CML is prescribed for a long-term period, its selection takes into account the spectrum of comorbid pathology as well as the potential for drug-drug interactions.

2.2 Physical Examination

1. Examination of the skin and visible mucous membranes.

2. Palpation of peripheral lymph nodes.

3. Determination of liver and spleen dimensions (by percussion and palpation, in centimeters below the costal margin edge).

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

2.3 Laboratory Diagnostics

Comment. Complete karyotyping of at least 20 metaphases is desirable to rule out DCA. Molecular genetic testing (FISH method) for a single chromosome pair to detect the BCR::ABL1 chimeric gene is recommended when standard cytogenetic analysis is uninformative (no mitoses, unsatisfactory material quality), in cases of cryptic rearrangements, variant translocations (complex translocations involving three or more chromosomes), as well as in the absence of BCR::ABL1 p210 expression and the inability to detect atypical chimeric transcript variants by PCR [1, 12, 13, 105].

Comment. If typical BCR::ABL1 p210 chimeric transcripts are absent, qualitative determination of atypical BCR::ABL1 p190 and p230 transcript types should be performed; if these are also absent, other rarer types should be tested in laboratories proficient in these methodologies, or a FISH molecular-cytogenetic test for a single chromosome pair should be performed to detect the BCR::ABL1 chimeric gene [13–17].

1. Determination of HLA antigens or high-resolution molecular-genetic histocompatibility testing (HLA) using sequencing for bone marrow donor selection.

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

Comment. The test is performed after a consultation at a transplant center. In patients with CML-BC, the test is performed upon achieving the 2nd CP, provided the patient is under 65 years of age.

1. Cytochemical examination of bone marrow smear: myeloperoxidase, lipids, PAS reaction, alpha-naphthyl esterase in CML blast crisis to determine the lineage commitment of blast cells when bone marrow immunophenotyping is unfeasible.

2. Immunophenotyping of biological material to detect hemoblastosis markers in CML blast crisis to determine the lineage commitment of blast cells.

3. Pathological examination of bone marrow biopsy (surgical) material (trephine biopsy) with determination of cellularity and degree of fibrosis in case of cytopenia.

4. In patients with CML-BC: lumbar puncture followed by cytological examination and/or immunophenotyping of biological material to detect hemoblastosis markers.

GCR CLOE 5Grade of Recommendations – C (Level of Evidence – 5).

Comments: HLA typing is performed to search for an HLA-compatible donor in patients indicated for allogeneic HSCT. Cytochemical and immunophenotypic studies of blast cells in CML blast crisis are required to determine blast cell lineage commitment and select the optimal chemotherapy regimen. Bone marrow histological examination is necessary to determine the cause of cytopenia and select the optimal management strategy.

2.4 Instrumental Diagnostics

2.5 Other Procedures

Comment: particular attention should be paid to the assessment of cardiovascular risks.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

General principles of treatment

The goal of modern CML therapy is the maximum suppression of the Ph-positive tumor clone, prevention of resistance, and ensuring long-term survival with a good quality of life. The mainstay of therapy and current standard of care is the use of BCR-ABL tyrosine kinase inhibitors (TKIs). These agents possess targeted activity against BCR::ABL1-positive tumor cells and should be prescribed to all patients after CML confirmation. The mechanism of action of TKIs involves blocking the ATP-binding pocket of the BCR::ABL1 molecule, which deprives the BCR::ABL1 protein of the tyrosine kinase activity that confers a proliferative advantage to tumor cells.

Adherence to the principle of continuous and constant exposure to the leukemic clone is the cornerstone of treatment efficacy. Interruptions in TKI intake may contribute to reduced therapy efficacy. Regular monitoring of treatment outcomes using molecular genetic methods, timely assessment of treatment response, and switching to the next-line TKI in case of resistance to ongoing therapy are key factors influencing long-term survival outcomes in CML. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered for CML-CP patients with failure of 2 or more lines of TKI therapy, in advanced phases of CML (AP and BP), in the presence of the T315I mutation in the BCR::ABL1 gene and inefficacy of ponatinib or asciminib, as well as in case of intolerance to all available TKIs.

TKI therapy is indicated for all CML patients. The administration regimen is daily, prolonged, and continuous. The starting dose does not depend on the patient's sex, body weight, height, or race. Treatment can be initiated at any leukocyte count. The possibility of TKI discontinuation in patients with a stable deep molecular response is described in Section 6.

Constant exposure to TKIs leads to the reduction of the leukemic clone and restoration of normal hematopoiesis, reduces the risk of disease progression, and increases the long-term survival of patients. Achieving a major molecular response (MMR) is the main target outcome of therapy and a prognostically favorable factor for long-term progression-free survival, provided therapy is continuous.

Criteria for defining hematologic, cytogenetic, and molecular responses during TKI therapy in all CML patients are presented in Table 3.

Table 3. Criteria for hematologic, cytogenetic, and molecular responses [1, 10, 11, 129, 130].

3.1. Pharmacotherapy in adult patients

3.1.1. Drugs for CML therapy and dosing regimens

The choice of TKI in all patients is made taking into account comorbidities, mutational status, and the phase of CML.

In the Russian Federation, first-generation BCR-ABL TKIs (TKI1) imatinib** and second-generation TKIs (TKI2) nilotinib**, dasatinib**, and bosutinib** are currently approved for the treatment of CML in adults. In adult patients, all of these TKIs are approved for first-line and subsequent lines of therapy.

3.1.2. First-line TKI therapy for CML patients

Comments: imatinib** is a first-generation TKI with selectivity for BCR::ABL1 tyrosine kinase, and is also capable of inhibiting c-KIT and PDGFR kinase activity. When imatinib** is used as first-line therapy, overall survival at 11 years is 83%, progression-free survival to AP and BP is 92%, and the rate of disease progression at 11 years of therapy does not exceed 7%. Complete cytogenetic response (CCyR) is achieved in 83% of patients [19].

The majority of patients maintain a good quality of life and ability to work.

No absolute contraindications for the use of imatinib** have been reported,

Patients with a low cardiac ejection fraction should be carefully monitored

Patients with a low glomerular filtration rate should be carefully monitored

The most frequent causes of poor tolerability of imatinib** are:

• fluid retention,

• gastrointestinal symptoms,

• muscle cramps,

• joint pain,

• skin rash

• fatigue

Many of these adverse events resolve over time or after a brief treatment interruption. In patients with grade 1–2 chronic toxicity, a prolonged dose reduction of imatinib** is possible, provided that MMR is achieved and maintained [101].

The dose is 400 mg of imatinib** daily for CP and 600 mg of imatinib** daily for AP and BP [19–23]. It is recommended to take the drug once daily with a meal, washed down with a full glass of water. The doses of the drug for adults depending on the phase of CML are listed in Table 4.

Dose reduction is necessary if toxicity phenomena develop.

Table 4. Doses of imatinib** in the treatment of adult patients with CML.

Comments: nilotinib** is a potent, highly selective BCR-ABL1 tyrosine kinase inhibitor. It has a higher affinity for it compared to imatinib** and is active against the majority of BCR-ABL1 mutations. It is available as 150 mg and 200 mg capsules. In first-line therapy, it is indicated for patients with CP CML at a starting dose of 600 mg/day [25]. It is administered as 300 mg twice daily at approximately 12-hour intervals. It is recommended to take the drug strictly on an empty stomach, as food significantly increases the drug's bioavailability (up to 80%), leading to an increased plasma concentration of nilotinib**. The drug should be taken no earlier than 2 hours after a meal; food should not be consumed for at least 1 hour after taking nilotinib**. The capsules should be washed down with a sufficient amount of water.

If toxicities develop, the dose of nilotinib** may be reduced to 400 mg once daily (Tab. 5).

Cardiovascular status should be monitored during therapy with nilotinib**.

A history of coronary artery disease, cerebrovascular disease, or peripheral artery occlusive disease is a strict contraindication to the use of nilotinib** as a first-line therapy.

Patients with arterial hypertension, hypercholesterolemia, and diabetes mellitus also have an increased risk when using nilotinib** [101]

Comments: dasatinib** is a multi-targeted drug that interacts with many tyrosine kinase and non-tyrosine kinase proteins. It inhibits the following tyrosine kinases: BCR::ABL and the SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, PDGFRβ, PDGFRα. It is capable of inhibiting in vitro the growth of cell lines with overexpression of BCR::ABL, activation of alternative oncogenic pathways involving SRC family kinases (LYN, HCK). The drug's ability to cross the blood-brain barrier has been demonstrated.

The recommended dose of dasatinib** for CP is 100 mg/day [26]. In case of toxicity, the dose of dasatinib** for patients in CP may be reduced to 50 mg once daily (Tab. 5). There are no data on the efficacy of increasing the dose of dasatinib** to 140 mg/day in case of resistance to the standard dose. Therefore, in clinical practice, increasing the dose of the drug when its standard dose is insufficiently effective is unjustified.

Dasatinib** therapy is associated with an increased risk of pleural effusions (up to 37%), which can develop even after several years of previously uncomplicated treatment. Pulmonary arterial hypertension develops in rare cases. A history of pleuropulmonary or pericardial diseases is a strict contraindication to the use of dasatinib** as a first-line therapy [101].

Comments: Bosutinib** is a kinase inhibitor of BCR-ABL1 and members of the SRC family, including SRC, LYN, and HCK. The drug has minimal inhibitory activity against PDGFR receptors. The standard dose for first-line therapy in chronic-phase patients is 400 mg daily. In case of adverse events preventing continuation of therapy at the standard dose, the dose may be reduced to 300 mg once daily (Table 5). There are no data on the efficacy of increasing the bosutinib** dose when the standard dose is ineffective. Therefore, in clinical practice, dose escalation due to insufficient efficacy of the standard dose is impractical.

No concomitant conditions or major contraindications for bosutinib** therapy have been identified.

Transient diarrhea usually occurs in 30% of patients, which can be a troubling side effect.

A temporary increase in aminotransferase activity may be observed, primarily during the first weeks or months of treatment [101].

The use of second-generation TKIs (nilotinib**, dasatinib**, bosutinib**) in the first-line setting compared to imatinib** is significantly more effective in reducing the probability of CML progression and achieving a higher rate of deep molecular response (MR) at earlier time points. First-line administration of nilotinib** at a dose of 600 mg/day enabled major molecular response (MMR) achievement in 77% of patients after 1 year of therapy compared to 60% of patients receiving imatinib** at 400 mg/day. By 5 years of therapy, deep MR4.5 was achieved in 54% of patients in the nilotinib** 600 mg/day group compared to 31% in the imatinib** group [25]. Comparison of dasatinib** at 100 mg/day with imatinib** at 400 mg/day in the first line also demonstrated superiority in MMR achievement by 1 year of treatment: 76% of patients receiving dasatinib** versus 64% of patients on imatinib** therapy [26]. First-line administration of bosutinib** at 400 mg/day enabled MMR achievement in 67% of patients after 2 years of therapy compared to 57.5% of patients receiving imatinib** at 400 mg/day

Nilotinib** and dasatinib** provide higher rates of achieving MR4 and MR4.5 compared to imatinib**, which may increase the number of patients potentially eligible for treatment-free remission (TFR). By 5 years of therapy, deep MR4.5 was achieved in 42% of patients in the dasatinib** group compared to 33% in the imatinib** group [25,26]. There are also data showing a higher rate of MR4.5 with bosutinib** treatment compared to imatinib**: 47.4% and 36.6%, respectively, by 5 years of therapy [106]. At the same time, the potential for adverse events (e.g., peripheral arterial occlusive disease with nilotinib**, pleural effusion with long-term dasatinib** therapy) requires evaluation of respective risk factors in patients [26,29–31]. The toxicity profile of imatinib** is the safest, and clinical experience in first-line therapy is the longest compared to other TKIs. It is also currently the most affordable drug. However, the probability of rapidly achieving MMR and deep MR with imatinib** treatment is lower than with second-generation TKIs [25,26]. Imatinib** may be the optimal therapy for low-risk patients, individuals older than 60 years, and/or patients with comorbidities that limit the prescription of second-generation TKIs.

3.1.3. Second- and subsequent-line TKI therapy for CML patients

Comments: second-line therapy with second-generation TKIs in CML is effective both in cases of intolerance and resistance to imatinib**. In second-line therapy, nilotinib** is prescribed at a dose of 800 mg/day in CP and AP [34]. The use of dasatinib** as a second-line therapy in patients with CML in CP with intolerance or resistance to imatinib** allowed achieving MMR in 55% of patients with intolerance and in 43% with resistance [32]. The use of dasatinib** in AP allowed achieving CCyR in 24% of patients [27]. The use of this drug in BP resulted in a major cytogenetic response in 25% of patients with myeloid BP and 50% of patients with lymphoid BP within 24 months, although these responses were not durable [35]. The recommended dose of dasatinib** in the second and subsequent lines is 100 mg/day for CP, and 140 mg/day for AP and BP.

Bosutinib** has also proven effective in patients with resistance or intolerance to prior imatinib** therapy. At a median follow-up of ≥24 months, the cumulative rates of achieving CHR and CCyR were 77% and 46%, respectively, while MMR and deep molecular response were obtained in 35% and 28% [37]. Bosutinib** also demonstrated efficacy in patients with treatment failure not only on imatinib**, but also on second-generation TKIs (dasatinib**, nilotinib**). CHR, CCyR, and MMR were achieved by 62/86 (72%), 16/72 (22%), and 20/78 (25%) patients, respectively, after imatinib** and dasatinib** therapy. The same parameters were recorded in 20/26 (77%), 5/24 (21%), and 1/19 (5%) patients previously treated with imatinib** and nilotinib** [33]. Thus, a small proportion of patients with prior failure of two TKI therapies receiving bosutinib** could achieve not only CHR, but also deeper (cytogenetic and molecular) responses.

Comment: ponatinib belongs to the 3rd generation of TKIs. Ponatinib has also demonstrated efficacy in patients with the T315I mutation in the BCR::ABL1 gene. In patients with resistance to second-generation TKIs, ponatinib is preferred over an alternative second-generation TKI, provided there are no risk factors for cardiovascular complications [107, 108]. The recommended starting dose of ponatinib is 45 mg once daily. Cardiovascular adverse reactions (arterial occlusions or venous thromboses) occur in approximately 30% of cases and are dose-dependent. Upon achieving a complete cytogenetic response, the dose of ponatinib can be reduced to 15 mg daily. In patients with CML in CP without the T315I mutation and with cardiovascular risk factors, it is advisable to reduce the starting dose of ponatinib to 30 mg or 15 mg once daily. Dose escalation to 45 mg daily may be considered in patients without an optimal response to reduced doses of ponatinib, if clinically indicated, taking cardiovascular risk factors into account.

Comment: Asciminib is a STAMP inhibitor (specifically targeting the ABL myristoyl pocket) that has demonstrated high efficacy and a favorable safety profile in Phase I and III clinical trials in chronic myeloid leukemia patients with prior TKI treatment failure, including those with the T315I mutation in the BCR::ABL1 gene [109, 110]. In patients with resistance to second-generation TKIs, asciminib is preferred over an alternative second-generation TKI. In patients with CML-CP harboring the T315I mutation in the BCR::ABL1 gene and cardiovascular risk factors, asciminib is preferred over ponatinib. The recommended daily dose of asciminib is 80 mg in patients without the T315I mutation in the BCR::ABL1 gene. Asciminib can be taken orally either at a dose of 80 mg once daily at approximately the same time each day, or at a dose of 40 mg twice daily at approximately 12-hour intervals. In patients with CML-CP and the T315I mutation in the BCR::ABL1 gene, the total daily dose is 400 mg administered orally as 200 mg twice daily at approximately 12-hour intervals. To manage adverse reactions, the dose of asciminib can be reduced to 40 mg daily (40 mg once daily or 20 mg twice daily) in patients without the T315I mutation in the BCR::ABL1 gene, and to 160 mg twice daily in patients with the T315I mutation.

3.1.4. Principles of TKI selection when switching therapy

Comment: Taking into account the toxicity profile, TKIs are used with caution in certain diseases and conditions listed below.

Nilotinib**

• History of symptomatic pancreatitis – rare cases of pancreatitis exacerbation have been reported; elevations in amylase and lipase activity may be observed

• Diabetes mellitus – hyperglycemia may occur during nilotinib** therapy

• Atherosclerotic vascular disease, cardiovascular ischemic events, peripheral artery occlusive disease – an increased probability of their development has been demonstrated in patients with pre-existing cardiovascular risk factors compared to the general population [39].

Dasatinib**

• History of chronic cardiovascular diseases, chronic obstructive pulmonary disease, bronchial asthma, pleural or pericardial effusion, pneumonia, chest trauma – factors affecting the incidence of pleural effusions [26, 29, 30, 40]

• Chronic gastrointestinal diseases with a high risk of bleeding, concurrent use of antiplatelet agents (ATC B01AC Platelet aggregation inhibitors excluding heparin) – dasatinib** exhibits an antiplatelet effect [41].

Bosutinib**

• severe hepatic and renal impairment [42].

Ponatinib

• Atherosclerotic vascular disease, cardiovascular ischemic events, peripheral artery occlusive disease, history of thrombosis — an increased probability of developing arterial occlusions has been demonstrated [42].

All TKIs should be used with caution in patients with prolonged QT interval, as well as with clinically significant heart failure, left ventricular dysfunction, and arrhythmias. Concomitant use of TKIs with both CYP3A isoenzyme inducers and inhibitors, as well as with QT interval-prolonging drugs, should be avoided [43].

Comments: BCR::ABL mutations determine the sensitivity of leukemic cells to specific TKIs. At the time of diagnosis, it is advisable to determine the mutational status at CML onset in the accelerated phase and blast crisis. The presence of mutations in the tyrosine kinase domain of BCR::ABL1 should also be investigated in case of treatment failure and prior to switching TKIs. The study of BCR::ABL1 point mutations can be performed using Sanger sequencing or next-generation sequencing (NGS). The most common mutations can also be detected using allele-specific PCR. It should be noted that the sensitivity of these methods varies significantly, being 15%–20% for Sanger sequencing, 2%–3% for next-generation sequencing [ELN 2020], and 1% for allele-specific PCR

Choice of TKI depending on detected BCR::ABL1 mutations:

• F317L/V/I/C, T315A — nilotinib**, bosutinib**, asciminib, or ponatinib

• V299L — nilotinib**, asciminib, or ponatinib

• Y253H, E255V/K, F359V/I/C — dasatinib**, bosutinib**, asciminib, or ponatinib

• T315I — asciminib or ponatinib

1st- and 2nd-generation TKI therapy (imatinib**, nilotinib**, dasatinib**, bosutinib**) is ineffective in the presence of the T315I mutation [50, 51]. If this mutation is detected, therapy with the 3rd-generation TKI ponatinib or the STAMP inhibitor asciminib is recommended. [107, 108, 109, 110]

• If switching to ponatinib or asciminib is not feasible, adult patients are recommended to search for an HLA-identical donor and undergo allogeneic hematopoietic stem cell transplantation [52–54].

LoR CLoE 4Level of Recommendations — C (Level of Evidence — 4).

Comments: Prior to performing allo-HSCT or switching to TKIs potentially effective in the presence of the T315I mutation, it is possible to continue therapy with the drug that provides the maximum clinical effect (maintenance of CHR, good tolerability)

Table 5. Doses of nilotinib**, dasatinib**, and bosutinib** for adult CML patients (see corresponding guideline statements).

3.1.5. Diagnostics during treatment (monitoring of TKI therapy efficacy in CML patients)

Comment: for timely evaluation of treatment outcomes and potential adverse events, it is necessary to regularly monitor clinical and laboratory parameters (Table 6). Considering the need for long-term drug intake, regular discussions with the patient are advisable to monitor treatment adherence.

Table 6. Frequency of dynamic examination of CML patients receiving TKIs.

Notes:

¹ In patients with atypical BCR::ABL1 transcripts, as well as cryptic variants of the t(9;22) translocation, the FISH method is recommended for monitoring. It should be emphasized that values less than or equal to 1% of BCR::ABL-positive cells correspond to complete cytogenetic response (0% Ph⁺). However, at values greater than 1% according to FISH data, there is no correlation between standard cytogenetic analysis and FISH results [N. Testoni et al. 2009].

² the results of BCR::ABL1 expression determination should be reported as a percentage on the International Scale (IS). This can be achieved in three ways: using a conversion factor obtained by the laboratory during standardization; using certified calibrators or commercial test systems that present their results in % on the IS.

³ It is necessary to indicate the number of copies of the control gene ABL1. If the number of copies of the control gene ABL1 is less than 10,000 copies, the result cannot be reported, and the analysis must be repeated.

⁴More frequent monitoring is possible to assess the stability of deep molecular response before the treatment-free remission phase. See "Possibility of TKI discontinuation in patients with deep molecular response" in section 7

⁵ For patients without treatment failure, standard bone marrow cytogenetic testing is performed when standardized molecular monitoring is not feasible.

3.1.6. Management tactics based on therapy outcomes

Comment: the effect of 1st-line therapy can be assessed as optimal, treatment failure, or warning (Table 7).

In case of imatinib** failure in the 1st line of therapy, a switch to a second-generation TKI is indicated, taking into account tolerability and mutational status. In conditions of limited access to second-generation TKIs upon imatinib** failure in the 1st line, it is necessary to urgently increase the imatinib** dose to 600–800 mg taking into account tolerability, as a temporary measure before switching to a second-generation TKI. In patients with a high risk group according to J.E. Sokal or ELTS (Table 2), or with additional chromosomal aberrations in Ph-positive cells (which are prognostic adverse factors), a prompt switch to a second-generation TKI is preferable to increasing the imatinib** dose.

In case of treatment failure with a second-generation TKI in the 1st line of therapy, switching the drug to another second-generation TKI is indicated; in the interests of patients, to consider experimental treatment options within clinical trials, and it is indicated to perform HLA typing of siblings if available. The efficacy of increasing the dose of a second-generation TKI in the 1st line is insufficiently proven and therefore not advisable.

With an optimal response, treatment with the same TKI drug is continued.

In the absence of an optimal response, it is recommended to check the patient's adherence to therapy and potential drug interactions.

When a warning is ascertained during therapy with imatinib** and second-generation TKIs, it is advisable to consider changing therapy or continuing the drug at the previous dose against the background of careful monitoring of treatment efficacy and ensuring readiness to change therapy in case of confirmed failure.

Table 7. Criteria for response to TKI therapy in the first and second lines of treatment in patients in chronic phase and accelerated phase.

Notes. The BCR::ABL1 expression value specified in the table refers to the BCR::ABL1/ABL1 ratio on the International Scale

For patients planning treatment-free remission, the optimal response (at any time) is BCR::ABL1≤ 0.01% (MR⁴).

3.1.8. Therapy upon failure of second and subsequent lines of treatment

Commentary: Criteria for response to first- and second-line TKI therapy are presented in Table 7. Therapeutic options are limited in case of failure of 2 or more lines of TKI therapy. Therapeutic options include switching to another second-generation TKI, performing allo-HSCT, enrolling the patient in clinical trials or early access programs for third- and subsequent-generation TKIs not registered in Russia. In the absence of alternatives, regular TKI intake is indicated even in the absence of a cytogenetic response to therapy to reduce the risks of progression and death compared to cytostatic therapy alone. All registered TKI drugs can be used as second or subsequent lines of therapy. [101]

3.1.9. Cytoreductive and cytostatic therapy

Commentary: In the chronic phase of CML, chemotherapy is administered as monotherapy, which is prescribed in the following cases:

• to reduce tumor burden during the work-up period until the results of cytogenetic or molecular genetic testing are obtained and to maintain a hematologic response;

• when other therapy is impossible: intolerance to all TKIs.

For cytoreductive purposes in adults, hydroxycarbamide** is used at a dose of 20–30 mg/kg/day, taking into account blood count parameters, along with mercaptopurine**. Hydroxycarbamide** intake must be regular, as discontinuation leads to a rapid rebound in leukocyte counts. Monitoring of blood leukocyte levels and other hemogram parameters (complete blood count + platelet count + differential leukocyte count) must be performed weekly.

To treat complications associated with tumor lysis syndrome (hyperuricemia, nephropathy) during the cytoreduction period, it is mandatory to administer adequate fluid volume (up to 2–2.5 L/m² of body surface area in the absence of heart failure) and allopurinol** at a dose of 300–600 mg/day. In case of signs of leukostasis (microcirculatory disturbances: encephalopathy, vision loss, renal failure), leukapheresis is indicated for symptomatic purposes.

Commentary: The choice of therapy intensity depends on the patient's current performance status, age, and allo-HSCT prospects. Allo-HSCT is indicated only after achieving a hematologic remission of blast crisis.

3.1.10. Interferon therapy

Commentary: therapy with #IFN-α** preparations is performed in special cases when TKI therapy is not indicated. The use of #IFN-α** is possible during pregnancy and in case of intolerance to all available TKIs in patients in the chronic phase. The efficacy of #IFN-α** in the accelerated phase and blast crisis has not been proven.

3.2. Other treatment

3.2.1. Indications for allogeneic HSCT in CML

Commentary: allogeneic HSCT is indicated in the chronic phase of CML — in case of failure of 2 lines of TKI therapy or second-generation TKI therapy in the first line and/or in the presence of the T315I mutation (when ponatinib or asciminib are ineffective or cannot be prescribed) and/or in case of TKI intolerance (recurrent prolonged grade 3–4 cytopenias on any line of therapy, especially when additional chromosomal abnormalities are detected in Ph-negative cells, as well as in case of bone marrow aplasia or fibrosis according to bone marrow trephine biopsy morphological data, persistent non-hematological grade 2–4 toxicity on all available TKIs) in the absence of an optimal response [52,53].

In case of CML onset in the accelerated phase — upon failure of first-line TKI therapy and/or failure to achieve an optimal response to 2 lines of TKIs and/or at any time in the presence of the T315I mutation (when ponatinib is ineffective or cannot be prescribed). In case of CML onset in blast crisis or upon progression to blast crisis.

In the accelerated phase developed during TKI therapy, as well as in blast crisis — for all patients immediately after achieving the chronic phase on TKI therapy and/or a combination of TKIs with chemotherapy. Performing allo-HSCT outside of a hematologic response (reduction of blast infiltration <10% in blood and bone marrow, regression of all extramedullary foci, and cerebrospinal fluid clearance) is not indicated. [73,74].

3.2.2. Supportive therapy

In the event of acute or chronic pain syndrome, the patient receives analgesic therapy in accordance with existing pain management protocols [77, 78].

When cytopenic or hemorrhagic syndrome develops during TKI therapy or other antineoplastic drugs, blood component transfusion support may become necessary.

It should be noted that the patient may present with atypical disease manifestations, as well as a combination of a specific disease with other pathologies, which may dictate changes by the attending physician in the algorithm for choosing optimal diagnostic and treatment tactics.

3.3. Pharmacotherapy for CML in children

In general, similarly to young and middle-aged adult patients, the initial therapy for all patients in the chronic and accelerated phases is the use of TKIs, while for the treatment of patients diagnosed in the blast crisis phase, it is the combined use of second-generation TKIs with chemotherapy dictated by the lineage of the blast population (lymphoblastic, myeloblastic, mixed-lineage). Currently, the approved TKIs for pediatric CML are imatinib** (in children older than 2 years), dasatinib** (in children older than 3 years), and #nilotinib**. Studies on the use of bosutinib**, asciminib, and ponatinib in the population under 18 years of age are ongoing.

• Allo-HSCT is currently recommended for patients diagnosed in blast crisis after chemotherapy combined with second-generation TKIs. Furthermore, allo-HSCT is recommended for patients meeting treatment failure criteria after switching to a second-generation TKI, provided that treatment failure is not due to non-adherence. [114,115,116]

GOM CLoE 5Grade of Recommendation — C (Level of Evidence — 5).

First-line TKI therapy for children with CML in chronic phase

Commentary: Phase 1, 2, and 3 clinical trials have been conducted for all three drugs, demonstrating similar efficacy in terms of survival; meanwhile, the probability of achieving optimal response criteria was slightly higher in patient groups receiving second-generation TKIs. Drug dosages are specified in Table 13 [117, 118, 119, 120, 121].

Due to the lack of randomized trials, the criteria for choosing a starting drug for the treatment of patients with chronic phase are largely non-medical—the availability of guarantees for timely and continuous supply and the convenience of administration. In particular, #nilotinib**, administration of which, unlike imatinib** and dasatinib**, must be carried out twice a day on an empty stomach, may pose significant challenges for use in the age group under 18 years.

Table 13. TKI dosing in first-line therapy of children with CP CML [120].

Note: For patients unable to swallow the capsule whole, administration in a diluted form using water or apple juice is permitted.

Phase 1 trials have not identified maximum tolerated doses of imatinib** in the range of 200–570 mg/m² per day; furthermore, the use of various imatinib** dosages has not shown significant advantages in achieving optimal response criteria.

Supportive care for children with CML starting TKI therapy is carried out in accordance with guidelines for adults and is aimed at preventing tumor lysis syndrome (see above).

A significant side effect of TKI therapy, particularly imatinib**, in children is growth retardation, especially in the prepubertal period [122]. An additional factor that may affect the growth and development of the child is the increased risk of hypothyroidism during TKI use [123]. In addition to the previously mentioned disorders, endocrine dysfunction may manifest as hyperglycemia, infertility, and low vitamin D levels [127].

Second-line TKI therapy for children with CML in chronic phase

• In case of failure to achieve an optimal response at 12 months from the start of therapy, treatment failure at any stage (see response evaluation criteria above), or imatinib intolerance, switching therapy to a second-generation TKI (TKI2) is recommended after performing BCR::ABL1 kinase domain mutation analysis. If mutations are present, the TKI to which the mutation(s) are sensitive is selected [128, 129, 130].

GCR CLEL 5Grade of Recommendations — C (Level of Evidence — 5).

• In case of failure to achieve an optimal response or treatment failure with 2nd-generation TKIs (see above), it is recommended to prescribe an alternative 2nd-generation TKI (dasatinib** (in children over 3 years of age) or #nilotinib**) if mutation analysis has not revealed "resistant" mutations of the BCR::ABL1 kinase domain [128, 129, 130].

GPR CLEL 5Grade of Recommendation C (Level of Evidence - 5).

• In case of second-generation TKI intolerance, prescription of an alternative second-generation TKI or imatinib** (in children older than 2 years) is recommended [128, 129, 130].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Third- and subsequent-line therapy for children with CML in chronic phase

In case of treatment failure at any stage (see criteria above) or intolerance to imatinib**, #nilotinib**, and dasatinib**, the patient is a candidate for allogeneic HSCT. By decision of the medical board, any 3rd-generation TKI may be prescribed in accordance with the BCR::ABL1 mutation status [128, 129, 130].

First-line TKI therapy for children newly diagnosed in the AP of CML

• All children diagnosed in the AP of CML are recommended treatment with a second-generation TKI. Second-generation TKI dosages: #nilotinib** 230 mg/m² twice daily (max 400 mg twice daily) [124], dasatinib** (in children older than 3 years) at doses specified in Table 13. Dose adjustment is carried out in accordance with the TKI drug labeling [128, 129, 130].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: Efficacy criteria for second-generation TKIs in patients diagnosed in the AP of CML are the same as for second-generation TKI treatment in adults. If an optimal response is not achieved at efficacy control "time points" or upon disease progression, the patient is a candidate for allo-HSCT and third-generation TKI bridging therapy ("bridge therapy").

First-line TKI therapy for children newly diagnosed in the BC of CML

• All children diagnosed in the BC of CML are recommended treatment with a second-generation TKI. Dosage of #nilotinib** 230 mg/m² twice daily (max 400 mg twice daily), dasatinib** (in children older than 3 years) at doses specified in Table 13 in combination with chemotherapy, according to the lineage of the blast cells. In lymphoid BC, the use of dasatinib** is preferred due to its better CNS penetration and potentially better activity against possible central nervous system leukemia [128, 129, 130].

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: Efficacy criteria for second-generation TKIs in children diagnosed in the AP of CML are the same as for second-generation TKI treatment in adults. If an optimal response is not achieved at efficacy control "time points" or upon disease progression, the patient is a candidate for allo-HSCT and third-generation TKI bridging therapy ("bridge therapy").

Therapy for children with progression to AP or BC during TKI therapy.

Patients with progression during TKI therapy are candidates for allogeneic HSCT, which should be performed as soon as possible. Bridging therapy with alternative TKIs in such cases should be based on the results of BCR::ABL1 mutation analysis, and additional chemotherapy based on the results of molecular genetic analysis and cytogenetic data [128, 129, 130].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: There are no specific rehabilitation methods for CML. Rehabilitation of patients with CML should be comprehensive, covering medical, social, and psychological aspects of the patient's adaptation to normal life. The scope of medical rehabilitation is developed individually for each patient by a medical rehabilitation physician with the participation of a hematologist and depends on the course and manifestations of the disease and interventions performed (HSCT, complications after polychemotherapy in BC CML, organ and system dysfunctions during TKI therapy). In addition, the rehabilitation program must take into account the social and psychological problems of the patient and requires, alongside medical care, the mandatory participation of social workers and psychologists. Rehabilitation for complications occurring during the course of the disease and treatment is carried out within the framework of the respective nosologies.

Comments: Traditional views regarding contraindications to any type of physiotherapeutic and sanatorium-resort treatment for patients with CML in the pre-TKI era are currently being revised. There are currently no universally accepted recommendations, but in patients with deep response levels (CCgR, MMR), treatment in local sanatoriums using local physiotherapeutic methods should be permitted. Potential triggering factors for worsening the disease course may include ultraviolet radiation (sun exposure) and electromagnetic therapy methods. Additional contraindications may include manifestations of TKI therapy side effects.

5. Prevention and Dispensary Observation

Due to the current impossibility of identifying the etiological factors of the disease, the development of specific recommendations for the primary prevention of CML is currently impossible.

After the disease is detected, the most important factors for preserving the life and health of patients are the promptest possible initiation of TKI therapy and strict patient adherence to treatment recommendations and monitoring of response to therapy [10, 11].

Modern medical treatment for patients with CML is highly effective in the vast majority of patients. Existing recommendations for managing TKI adverse events and the possibility of alternative drug selection allow for the almost complete preservation of physical condition and daily activity levels.

Comments: Clinical follow-up is carried out by a hematologist, pediatric hematologist-oncologist, or, in their absence, an oncologist, pediatric oncologist, pediatrician, or general practitioner/internist. Follow-up examinations must be performed at least once every trimester during the first year of therapy and at least once every six months in the subsequent treatment period.

6. Organization of Medical Care

Medical care, with the exception of medical care within the framework of clinical trials, in accordance with Federal Law No. 323-FZ of November 21, 2011 (as amended on May 25, 2019) "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation", is organized and provided:

1. in accordance with the regulations on the organization of the provision of medical care by types of medical care, which is approved by the authorized federal executive body;

2. in accordance with the procedure for the provision of care for the profile "hematology", mandatory for execution on the territory of the Russian Federation by all medical organizations;

3. based on clinical guidelines;

4. taking into account the standards of medical care approved by the authorized federal executive body.

When chronic myeloid leukemia (CML) is detected in a patient or suspected, general practitioners, district general practitioners, general family physicians, medical specialists, and mid-level medical personnel shall refer the patient, in the established manner, for consultation to an outpatient hematological/oncological care center or to a primary hematological office.

An outpatient or inpatient hematology care physician organizes diagnostic tests necessary to establish the diagnosis, including the disease phase and risk group.

If it is impossible to perform diagnostic tests, the attending physician refers the patient to a medical organization providing medical care to patients with hematological diseases to establish a diagnosis and provide specialized, including high-tech, medical care.

When CML is detected or suspected during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with hematological diseases to determine the management strategy and the need for additional other methods of specialized anti-tumor treatment.

Specialized, including high-tech, medical care is provided by hematologists in medical organizations providing medical care to CML patients, holding a license, the necessary material and technical base, certified specialists, in inpatient and day-hospital settings, and includes the prevention, diagnosis, and treatment of hematological diseases requiring the use of special methods and complex unique medical technologies, as well as medical rehabilitation.

In a medical organization providing medical care to CML patients, the strategy of medical examination and treatment is determined by hematologists, with the involvement of other medical specialists if necessary, and with a medical board (consilium) if necessary. The decision of the medical board is formalized in a protocol, signed by the members of the medical board, and entered into the patient's medical documentation.

Indications for hospitalization in a 24-hour or day hospital of a medical organization providing specialized, including high-tech, medical care in the profile "hematology" are determined by a hematologist/medical board with the involvement of other medical specialists if necessary.

Indications for planned hospitalization:

1. performance of planned blood component transfusions for anemia, grade 3 thrombocytopenia;

2. correction of side effects of CML therapy, including therapy with BCR-ABL tyrosine kinase inhibitors and anti-tumor drugs;

3. the need for examination in an inpatient setting in order to select the optimal patient management strategy;

4. performance of planned therapy with BCR-ABL tyrosine kinase inhibitors and cytostatic therapy in patients with complex comorbid pathology requiring monitoring in an inpatient setting.

Indications for emergency hospitalization:

1. performance of urgent blood component transfusions for thrombocytopenia accompanied by hemorrhagic syndrome, and anemia with hypoxic syndrome;

2. acute conditions, including infectious complications and grade 3–4 therapy toxicity following courses of therapy with cytostatic drugs or BCR-ABL tyrosine kinase inhibitors;

3. correction of life-threatening conditions.

Indications for patient discharge from the hospital:

1. relief of acute, life-threatening, and other conditions that led to hospitalization;

2. the possibility of continuing treatment on an outpatient basis;

3. refusal of the patient or their legal representative from specialized, including high-tech, medical care in a 24-hour or day hospital setting established by the medical board of the medical organization providing medical care in the hematology profile, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

4. in cases of non-compliance by the patient with prescriptions or internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

5. the need to transfer the patient to another medical organization in the relevant profile of medical care.

The conclusion on the advisability of transferring the patient to a specialized medical organization is made after prior consultation based on the provided medical documents and/or a preliminary examination of the patient by medical specialists of the medical organization to which the transfer is planned.

7. Additional Information

Patient management strategy for the development of adverse events of TKI therapy (adult population)

The antileukemic effect is the absolute priority of CML therapy. However, to maintain the principle of maximum and continuous impact on the tumor clone, it is important to minimize the adverse effects of therapy, given the need for long-term drug intake [10, 11].

Most adverse effects of TKI therapy are well-controlled and of low toxicity. Long-term results of imatinib** use for over 15 years have not revealed additional or life-threatening toxicities. Second-generation TKIs have a shorter follow-up period, and data on new adverse events continue to accumulate at present.

Toxicity of therapy during TKI use can be divided into hematological and non-hematological. The severity of adverse events is assessed in accordance with the CTCAE ver 5.0 toxicity criteria [79]. Some types of TKI toxicity are presented in Appendix G2.

Hematologic toxicity

Hematological toxicity includes decreased hemoglobin levels, neutropenia, and thrombocytopenia.

Grade 1–3 anemia in all phases of CML is not an indication for interrupting TKI therapy. Additional examination of the patient is indicated to rule out other causes of anemia, taking into account the clinical situation. In case of clinically significant manifestations of anemia syndrome, replacement transfusions of red blood cell mass (suspension) are indicated. The advisability of prescribing erythropoiesis-stimulating agents (B03XA Other antianemic drugs) is controversial. For grade 1–2 neutropenia and thrombocytopenia in any phase of CML, dose reduction of TKIs and treatment breaks are not required. In the chronic phase (CP) of CML with grade 3–4 neutropenia and/or thrombocytopenia, temporary discontinuation of TKIs is indicated with a complete blood count monitored once a week [10, 11].

After the absolute neutrophil count (ANC) recovers to a level of more than 1.0 x 10⁹/L and platelets to more than 50 x 10⁹/L, resume TKI therapy) [10, 11].

• if the treatment break is less than 2 weeks, treatment is resumed at the previous dose; if the break is more than 2 weeks, at a dose reduced by one level (see Table 4 and Table 5 – TKI doses);

• if the TKI dose was previously reduced, with stable hemogram parameters after 1 month, it is advisable to return to the standard dosage;

• for prolonged neutropenia, short-term use of granulocyte colony-stimulating factor (G-CSF) (L03AA Colony-stimulating factors) is possible: filgrastim** at a dose of 5 mcg/kg/day subcutaneously; if there is no effect from G-CSF administration, dose reduction or switching TKIs is necessary, taking into account the results of the leukemic clone assessment – the BCR::ABL1 level;

• for prolonged recurrent cytopenias, it is necessary to perform an examination (cytological examination of a bone marrow smear (myelogram), acquisition of a bone marrow histological specimen) to rule out disease progression and the development of bone marrow fibrosis.

In the accelerated phase (AP) and blast crisis (BC) of CML, even in the presence of grade 3–4 neutropenia and thrombocytopenia, in order to induce remission during the first 4 weeks, TKI therapy should not be interrupted. For grade 3–4 thrombocytopenia and hemorrhagic syndrome, platelet concentrate transfusions are indicated. If myelosuppression persists after 1 month of therapy, obtaining a bone marrow cytological specimen via puncture (sternal puncture) with myelogram counting is indicated to rule out disease progression [10, 11].

If the blast cell count is less than 5% and bone marrow cellularity is decreased, therapy interruption should be continued. Monitor complete blood count at least once a week. Resume therapy after neutrophil count recovery to > 0.5 × 10⁹/L and platelet count to > 50 × 10⁹/L. In case of recurrent myelosuppression, the TKI dose should be reduced. In prolonged and/or recurrent episodes of neutropenia and in the absence of blasts in peripheral blood and bone marrow, G-CSF may be used [80];

If the blast count is greater than 5% and the bone marrow is hypercellular, the issue of changing the treatment strategy should be discussed. When switching from one TKI to another, there is a possibility of cross-hematological toxicity, since the development of cytopenias in CML patients is apparently associated not so much with the specific mechanism of action of a particular TKI, but rather with the depletion of normal hematopoiesis reserves. This is particularly pronounced in patients with advanced phases of CML, as well as in patients resistant to 1st–2nd line TKI therapy. In case of recurrent grade 3–4 cytopenias that hinder continuous TKI therapy and, consequently, contribute to a decrease in treatment efficacy, discussing allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated.

Non-hematological toxicity

In addition to hematological toxicity, TKI therapy can be complicated by other adverse effects. The most frequent side effects of TKI treatment include nausea, vomiting, diarrhea, fluid retention with edema, skin rash, pruritus, fatigue, sleep disturbances, muscle and joint pain, and laboratory abnormalities. These side effects are of particular importance due to the need for continuous TKI administration. Even mild persistent side effects can lead to decreased treatment adherence (compliance)—patients skipping doses or reducing the dose, which leads to reduced therapeutic efficacy. The non-hematological toxicity profiles of imatinib**, nilotinib**, dasatinib**, and bosutinib** differ.

In the event of non-hematological toxicity, TKI adverse effects should be differentiated from potential clinical manifestations of comorbid conditions. Additional examination of the patient is advisable to rule out other pathologies. Appropriate symptomatic therapy is required to minimize toxicity.

General management tactics for patients with various manifestations of non-hematological toxicity during TKI therapy are presented in Table 10. It should be emphasized that treatment interruptions and dose reductions are permissible for prolonged and/or recurrent grade 2 toxicity episodes and for a single episode of grade 3–4 toxicity. TKI therapy intolerance can be stated if grade 2 toxicity persists for a prolonged period (more than 2–3 months) despite adequate supportive therapy, as well as upon recurrent episodes of grade 3–4 toxicity. Therapy intolerance is an indication for switching to another TKI, since the non-hematological toxicity profiles of the drugs differ and cross-intolerance is minimal [10,11].

Table 10. General management strategy for TKI non-hematological toxicity.

It should be noted that exceeding certain parameters (such as cholesterol levels) formally defined within grades I–II according to CTCAE criteria during nilotinib** therapy requires special attention and correction, given the increased probability of ischemic vascular events with this drug [31, 39]. Pleural effusions during dasatinib** therapy, despite the low toxicity grade determined by CTCAE, do not always allow continuous therapy due to their recurrent nature [26, 29]. Grade 1–2 diarrhea according to CTCAE during bosutinib** treatment can significantly impair patients' quality of life, but responds well to management with a decrease in severity and frequency during treatment [33].

Management strategies for specific types of non-hematological toxicity require separate consideration.

Most frequent non-hematological toxicity events

Hypercholesterolemia and risk of ischemic vascular events

Lipid metabolism disorders and hypercholesterolemia were reported in 22% of patients treated with nilotinib**, compared to only 3% with imatinib**; this adverse event can be registered as early as 3 months after starting nilotinib** and was associated with the occurrence of ischemic vascular events, specifically peripheral artery occlusion [31,39]. A cholesterol level greater than 240 mg/dL (6.2 mmol/L) is considered a high-risk indicator. According to the American Association of Clinical Endocrinologists (AACE) guidelines, hypercholesterolemia is also one of the factors included in the vascular mortality risk scale [81].

Hypercholesterolemia can be reduced through a combination of non-pharmacological methods: diet, physical exercise, and also successfully managed medically using various lipid-lowering agents, such as HMG-CoA reductase inhibitors (statins). Therefore, interventions aimed at lowering cholesterol levels are advisable to reduce the risk of vascular ischemic events in CML patients with CML. Target levels of cholesterol and its atherogenic fractions (LDL) are detailed in the Russian guidelines for the diagnosis and management of lipid metabolism disorders for the prevention and treatment of atherosclerosis [82]. The decision to initiate lipid-lowering therapy should be made after consulting a cardiologist.

When nilotinib** therapy is administered for life-saving indications, appropriate correction of adverse risk factors must be ensured. When necessary, continuous monitoring by specialist physicians (cardiologist, endocrinologist) is indicated, who determine the final scope of examination and additional assessment methods in each specific case: ankle-brachial index measurement, detection of atherosclerotic plaques via duplex angioscanning, CT scans, etc.

In cases of high cardiovascular disease risk, therapy with imatinib**, dasatinib**, or bosutinib** is preferred [39].

Pleural effusion and fluid accumulation in serous cavities (most commonly the pleural cavity, less frequently pericardial or abdominal)

This adverse event is most characteristic of dasatinib** therapy, occurring more frequently at a dose of 140 mg daily compared to lower doses, and may occur less frequently in patients receiving other TKIs. The probability of development during dasatinib** therapy ranges from 14% to 37% according to various studies [29, 26]. Patients should be warned that if they develop symptoms of pleural effusion (dyspnea, cough, tachycardia), urgent medical evaluation and additional diagnostics are required: percussion of lung borders, lung auscultation, targeted chest X-ray, and pleural ultrasound to assess the volume of the pleural effusion. This adverse event can develop at various delayed time points during therapy (2.5–5.5 years of treatment), including in patients with previously good tolerance to dasatinib** [29]. The volume of effusion can be estimated using radiological criteria and ultrasound diagnostics depending on the proportion of the pleural cavity occupied (Table 11).

Table 11. Classification of pleural effusion grades.

The presence of symptoms and the volume of accumulated fluid often may not correlate. The presence of clinical symptoms and the severity of respiratory failure are of greater importance for determining the management strategy.

- treatment interruption, with a possible subsequent resumption of the drug at a reduced dose;

- prescription of diuretics (furosemide**, torasemide, in accordance with the instructions for use, depending on the dosage form and taking into account the age category) with monitoring of electrolyte levels (blood sodium and potassium levels);

- oxygen therapy if necessary;

- for severe forms of pleural effusion (grades 3–4, observed in 4% of patients) with grade II–III respiratory failure – thoracentesis with fluid evacuation.

- pleural puncture in life-threatening conditions (mediastinal shift, marked dyspnea at rest) or for diagnostic purposes when the cause of pleural effusion is unclear. [10]

GCR CLOE 5Grade of Recommendation C (Level of Evidence - 5).

Comments: the mere occurrence of pleural effusion does not worsen the prognosis. With an optimal response to therapy, it is possible to reduce the dose of the drug. If the response to treatment is insufficient, switching the patient to an alternative TKI is indicated. Given that pleural effusion is often recurrent in nature, switching to another TKI is advisable in such cases.

Pulmonary arterial hypertension (PAH)

An extremely rare (0.45% of cases) yet severe complication associated with the use of dasatinib**. At the time of diagnosis, the majority of patients exhibited significant hemodynamic disorders as well as heart failure requiring intensive care unit monitoring. The median time to development of PAH is 34 months (range 8–48 months) of dasatinib** therapy [30, 40]. It can be detected both in patients with pleural effusion (68% of cases) and without it. Dyspnea and syncope are the leading clinical features; weakness, fatigue, and cardiac pain refractory to organic nitrates may also be present. ECG may reveal signs of right ventricular hypertrophy and overload. Diagnostic methods to confirm PAH include transthoracic echocardiography and right heart catheterization.

It has been established that this phenomenon may be reversible upon discontinuation of dasatinib**. When PAH develops, cessation of dasatinib** therapy and the administration of other TKIs are indicated.

Pneumonitis

An extremely rare complication requiring differential diagnosis. In most cases, it has been described with the use of imatinib** and is also more common in Asian countries; it can be reversible or irreversible [82–84].

When using dasatinib** in the 2nd line at a dose of 70 mg twice daily, pulmonary parenchymal changes resembling ground-glass opacity or interlobular septal thickening have been described in 17% of patients. Switching to other TKIs is advisable.

Nausea

Comments: nausea is most characteristic during treatment with imatinib** or bosutinib**. Nilotinib** and dasatinib** rarely cause nausea. In case of nausea, taking imatinib** on an empty stomach should be excluded; patients should be advised to take the drug with food and drink plenty of water. The last dose of imatinib** should be taken no later than 2 hours before bedtime, especially in patients with a history of esophagitis. If toxicity persists at grade ≥2 despite all measures taken, prescribing antiemetic drugs (metoclopramide**, ondansetron**, others) is advisable. However, it should be considered that antiemetics may prolong the QT interval. Antacids reduce the efficacy of TKIs.

Fluid retention with edema

Dietary salt intake and fluid consumption should be restricted. In more severe cases, diuretics are prescribed, with drugs selected on an individual basis.

Muscle cramps

A symptom characteristic of imatinib** treatment. It is more common at the start of therapy but can also be very prolonged. Cramps (usually of the calf muscles and foot muscles) typically occur at night, following physical exertion. Correction of mineral deficiencies (potassium, calcium, magnesium, phosphorus) can alleviate the spastic effect of imatinib**. In cases of pronounced toxicity (grades 3–4), a temporary interruption of TKI intake (3–5 days) is possible, which often reduces clinical manifestations, or a temporary dose reduction by 1 level.

Bone and joint pain

Usually occur at the beginning of treatment, and their frequency decreases after 1–2 months of therapy. A short-term (3–5 days) interruption of drug intake and a short course of nonsteroidal anti-inflammatory and antirheumatic drugs can relieve these symptoms.

Skin rashes

Usually resolve with the administration of systemic antihistamines, calcium chloride, and/or topical glucocorticoid ointments. With more severe dermatitis, interrupting TKI therapy becomes necessary. In patients with a high baseline blood basophil count (>30%), the appearance of urticarial rashes may be caused by the release of histamine-like substances from basophilic granules; as the basophil count decreases, the intensity of the rash diminishes.

Moderate skin rashes during nilotinib** therapy are a frequent adverse event that is not accompanied by pruritus or discomfort and rarely requires dose adjustment.

Bleeding and hemorrhages

Bleeding is most commonly observed from the gastrointestinal tract (in 4% of patients), while cerebral hemorrhages are less frequent (severe in less than 1% of patients). They occur predominantly during dasatinib** treatment. As a rule, they arise in the setting of pronounced thrombocytopenia. In most cases, bleeding can be managed by temporarily withholding the drug and administering blood component transfusions, primarily platelet concentrate.

During imatinib** therapy, scleral hemorrhages may be noted in 11% of cases, which generally resolve after a short treatment break or dose reduction.

Diarrhea

Managed by a diet excluding foods that enhance intestinal motility, along with the prescription of symptomatic antidiarrheal, intestinal anti-inflammatory, and antimicrobial agents. During bosutinib** therapy, it is effectively managed by a temporary dose reduction.

Hepatotoxicity

Elevated activity of "hepatic" aminotransferases may occur at various times during TKI treatment. In some cases, severe liver injury has been described with the use of imatinib** and paracetamol**, as well as in the presence of viral hepatitis B. Therefore, viral hepatitis should be ruled out, and potential hepatotoxins (alcohol, canned foods, medications with hepatotoxic potential) discontinued. When TKI hepatotoxicity occurs, general principles of toxic (drug-induced) hepatitis treatment apply. If grade 2 hepatotoxicity persists after its resolution, temporarily reducing the drug dose is advisable. If hepatic toxicity recurs, a more thorough investigation of liver function must be performed; switching to another TKI therapy, taking into account the absence of cross-hepatotoxicity, should be discussed.

Weight gain

A slight weight gain may be due to fluid retention, and in some cases, to an overall improvement in well-being against the background of intoxication symptom regression and appetite normalization. Overweight patients must be warned about the possibility of weight gain when taking TKIs and advised to restrict salt intake, follow a low-calorie diet, and increase physical activity levels.

Prolongation of the QTcF interval

All TKIs are agents capable of prolonging the QT interval. With significant QT prolongation (greater than 480 ms), there is a risk of developing life-threatening arrhythmia — torsades de pointes. When assessing the QT interval, it is essential to use heart rate-corrected values, for example, QTcF (QT corrected by Fridericia's method). Cases of QTcF prolongation are extremely rare, occurring in less than 1% of patients. Patients with baseline QTcF prolongation, as well as those with comorbid cardiac pathology, require careful monitoring of ECG changes. Before initiating TKI therapy, factors that also contribute to the prolongation of this interval should be ruled out whenever possible. Specifically, potassium and magnesium levels must be normalized; if the patient is taking medications for comorbid conditions that also prolong the QT interval, the possibility of substituting them should be considered. It should be remembered that congenital QT prolongation exists, which requires special attention to such patients during TKI treatment. The management algorithm for patients with QTcF prolongation is presented in Table 12.

Table 12. Management of patients with QTcF interval prolongation during TKI therapy.

Hyperbilirubinemia

The most frequent laboratory abnormality encountered during treatment with nilotinib** (69% of any grade, 7% of grade 3–4). This phenomenon is associated with impaired conjugation of unconjugated bilirubin, therefore the increase occurs predominantly due to this fraction. It is more common in patients with a polymorphism in the promoter region of the UGT1A1 gene ((TA)7/(TA)7; (TA)7/(TA)6 phenotypes, etc.), characteristic of benign hyperbilirubinemias (Gilbert, Rotor, Dubin-Johnson syndromes). If hemolysis is ruled out, amylase and lipase activities are not elevated, and the degree of bilirubinemia is 1–2, treatment with nilotinib** should be continued at the previous dose. According to most researchers, even grade 3 toxicity is not a reason to discontinue therapy or reduce the dose. With prolonged hyperbilirubinemia, it is advisable to prescribe drugs for the treatment of gallbladder diseases.

Asymptomatic Increase in Amylase and/or Lipase Activity

May be frequently observed during treatment with nilotinib**. Phenomena of pancreatitis (abdominal symptoms combined with laboratory changes) were observed in less than 1% of patients in phase II clinical trials. For grade 1–2 severity of these events, dynamic monitoring is required (repeat biochemical tests, assessment of the clinical picture). If grade 3–4 toxicity develops, therapy should be discontinued, and contrast-enhanced abdominal CT should be performed to rule out pancreatic pathology; if signs of pancreatitis are detected, treat it. With a normal CT scan after symptoms decrease to ≤1 grade, nilotinib** treatment should be resumed at a reduced dose (400 mg/day). With a recurrent asymptomatic increase in amylase and lipase activity to grade 3–4, nilotinib** treatment may be discontinued or continued at the physician's discretion.

Hyperglycemia

Also occurs only during treatment with nilotinib**. For any grade of this adverse event, correction should begin immediately upon its detection (hypoglycemic diet). If glucose levels do not normalize on the background of diet, an initial consultation (examination, appointment) with an endocrinologist is indicated to rule out diabetes mellitus.

Hypophosphatemia

Occurs during therapy with all TKIs, as a rule, clinically insignificant (low grade, rapid normalization). A diet with an increased intake of phosphorus-rich dairy and fish products and a reduced intake of glucose is recommended; oral administration of phosphate-containing drugs (vitamins, food supplements) is advised.

Hypocalcemia

Hypomagnesemia, Hypokalemia

Given the risk of QT interval prolongation in electrolyte deficiency, correction of their plasma levels is required.

Drug Interactions During TKI Therapy

The metabolism of all TKIs occurs predominantly in the liver with the participation of enzymes belonging to the cytochrome P450 system; mainly via CYP3A4, and to a lesser extent by other of its isoforms, such as CYP1A2, CYP2D6, CYP2C9 [43].

Concomitant administration of drugs that activate or inhibit cytochrome P450 activity can lead to changes in the concentration of both the TKI and the co-administered drug, which should be considered in clinical practice. If a CML patient is taking several drugs simultaneously as concomitant therapy, and treatment failure or severe toxicity of therapy is observed, the presence of drug interactions affecting blood TKI levels can be suspected. Therefore, to maximize treatment efficacy when toxicity occurs or worsens, it is important to exclude or minimize the simultaneous administration of drugs that activate or inhibit cytochrome P450 activity, and to give preference to analogs with other metabolic pathways.

With simultaneous administration of drugs that increase CYP3A4 P450 activity, a decrease in plasma TKI concentration may be observed, which reduces TKI efficacy. Accordingly, inhibitors of the CYP3A4 P450 enzyme can lead to an increase in plasma TKI concentration, which is clinically manifested by an enhancement of therapy toxicity manifestations.

In addition, as noted above, TKIs can potentially prolong the QT interval. Therefore, their use simultaneously with other drugs that affect QT interval prolongation is not recommended.

Reproductive Function in Chronic Myeloid Leukemia

Family planning issues should be discussed in detail with patients of childbearing potential.

Fatherhood in CML

TKI drugs approved for use in CML do not have genotoxic effects. In some cases, spermogram changes have been described during imatinib** therapy, but no decrease in fertility has been noted. No increase in the number of congenital anomalies has been noted in the children of female partners receiving TKI therapy [85, 86].

Interruption of TKI intake in male CML patients for conception is not required. If pregnancy does not occur, further evaluation is indicated to search for known factors leading to infertility.

Pregnancy in Female CML Patients

According to preclinical study results, all TKIs except nilotinib** have shown the potential to cause fetal congenital anomalies. The highest risk of TKI use is observed in the 1st trimester during the main organogenesis period (6–12 weeks of pregnancy); for dasatinib**, the risk exists at any stage of pregnancy [86, 87]. At the same time, the prescribing information for all TKIs contains contraindications for use during pregnancy. On the other hand, discontinuation of TKIs during pregnancy can lead to an increase in tumor clone burden and the development of CML relapse.

Pregnancy Planning

Pregnancy planning and TKI discontinuation are safest when deep molecular response (MR4.5) is maintained for 2 years. Considering that pregnancy may not occur immediately, TKI discontinuation for conception is a matter of debate. In 50–70% of cases, pregnancy is diagnosed during TKI therapy [88]; when TKIs are discontinued immediately after pregnancy confirmation, a normal course of pregnancy and the birth of healthy children are observed. Therefore, conception while on TKI therapy is permissible with immediate discontinuation of TKIs as soon as early pregnancy is confirmed (hCG, ultrasound examination).

Up to 15 weeks of gestation (until the establishment of the hematoplacental barrier), observation without TKI therapy is performed. If there are indications for therapy in the II–III trimesters of pregnancy, the use of #imatinib** at a dose of 400 mg and #nilotinib** at a dose of 400 mg may be considered in the same regimen as in non-pregnant patients [88, 89, 102], taking into account the limited penetration of these TKIs through the placenta. Dasatinib** and any other TKIs are contraindicated at any stage of pregnancy.

Alternative therapy during pregnancy may be #interferon alfa-2b** at a dose of 3–6 million IU daily [90]. This approach is most effective with a low tumor burden. For cytoreductive purposes when the leukocyte count exceeds 100 thousand, leukapheresis may be used (symptomatic effect).

Management of pregnancy in the absence of a stable major molecular response

A deep molecular response (MR) for less than 2 years and MMR may be acceptable clinical situations for observation without therapy or the use of #interferon alfa-2b**. In the absence of MMR, breaks in TKI therapy are prognostically unfavorable for subsequent response to therapy. Upon loss of MR2 and an increase in BCR‑ABL levels >1% during pregnancy, it is advisable to consider the use of #imatinib** or #nilotinib** after 15 weeks of gestation [88, 89, 102].

CML newly diagnosed during pregnancy

If CML is diagnosed in the I trimester of pregnancy, it is necessary to discuss with the patient the termination or continuation of pregnancy, taking into account her individual characteristics (age, social factors, comorbid conditions) and the phase of the disease. In the chronic phase of CML, continuation of pregnancy is possible. In the accelerated phase and blast crisis of CML, termination is indicated. In early pregnancy, observation without therapy or therapy with #interferon alfa-2b** at a dose of 3–6 million IU daily is possible [90]; after 15 weeks of gestation, it is recommended to initiate #imatinib** therapy in the same regimen as in non-pregnant patients [88, 89, 102]. If CML is detected in the II–III trimesters of pregnancy, continuation of CML and #imatinib** therapy in the same regimen as in non-pregnant patients is recommended. If CML is detected in the III trimester, with relatively mild leukocytosis and an expected delivery date within 1–2 months, it is possible to postpone the initiation of therapy until delivery. In case of thrombocytosis, antiplatelet agents may be prescribed, excluding heparin.

Delivery and lactation

The timing and mode of delivery are chosen taking into account obstetric indications. If sufficient control of CML clinical manifestations is maintained, there are no indications for premature delivery. If CML progresses, the issue of preterm delivery should be resolved. Resumption of TKI therapy after delivery in the absence or loss of MMR is recommended promptly.

TKIs pass into breast milk. It has been established that the doses of the TKIs imatinib** and nilotinib** that an infant may receive during breastfeeding are significantly lower than therapeutic doses [91], however, the effects of even small doses of TKIs on infants under one year of age are unknown. If therapy is required immediately after delivery, lactation suppression is recommended.

If a deep MR is maintained by the time of delivery, a prolonged break in therapy and breastfeeding are possible with molecular monitoring every 4–6 weeks and the patient's willingness to stop feeding upon resumption of TKI therapy.

Feasibility of TKI therapy discontinuation in patients with a deep molecular response

Studies regarding the possibility of maintaining molecular remission after discontinuation of TKI therapy show that about 40–60% of CML patients who have achieved a stable deep MR can safely discontinue TKI therapy without recurrence. In the event of a molecular remission relapse, timely return to TKI therapy allows the vast majority of patients to achieve a deep MR again [92–94]. A molecular relapse after cessation of therapy is considered to be a single increase in the relative expression of BCR::ABL1 above 0.1% on the IS (loss of MMR). Based on accumulated information on treatment-free remission (TFR), current guidelines suggest changing the management tactics for those CML patients who achieved a stable deep MR during long-term TKI therapy.

Mandatory criteria and conditions for monitoring CML patients in molecular remission without TKI therapy in clinical practice:

• Age over 18 years

• Presence of chronic phase CML

• Total duration of therapy in patients who received imatinib** as first-line >5 years, second-line TKIs in first-line >4 years.

• History of a typical p210 transcript (b3a2(14a2) or b2a2(e13a2)) confirmed by quantitative real-time PCR.

• Stable deep molecular response (at least MR4; BCR::ABL1 ≤0.01% on IS) for at least 2 years.

• Confirmed MR4.5 (BCR::ABL1 ≤0.0032% on IS) in at least 2 assays over the year prior to discontinuation, including mandatory testing in an IS-standardized laboratory with a sensitivity of at least MR4.5.

• Ability to conduct molecular monitoring after cessation of therapy in an IS-standardized laboratory (sensitivity of at least MR4.5), with a frequency of monthly for the first 6 months of monitoring, every 2 months from 6 months to a year, and subsequently every 3 months after one year of TKI discontinuation.

• Availability of the option to resume therapy within a month in case of molecular relapse (single loss of MMR / BCR::ABL1 ≥0.1% on IS, does not require repeat assay for confirmation) after therapy discontinuation and continued molecular monitoring every three months until recovery of deep MR after treatment resumption.

Monitoring of CML patients in molecular remission without TKI therapy is not indicated in clinical practice:

• Patients under 18 years of age

• Patients with a history of accelerated phase or blast crisis

• Total duration of therapy less than 5 years

• Total duration of deep MR less than 2 years

• Absence of quantitative PCR-confirmed typical BCR::ABL1 p210 transcript (b3a2(14a2) or b2a2(e13a2)) or presence of atypical BCR::ABL1 transcripts p190 (e1a2), p230 (e19a2).

• Inability to perform regular molecular monitoring after cessation of therapy in an IS-standardized laboratory (sensitivity of at least MR4.5).

Factors for remission maintenance and patient selection for TKI therapy discontinuation

Favorable factors indicating the feasibility of maintaining TFR are currently a subject of debate. Most studies have shown that a molecular response level of MR4.5 and deeper, as well as a longer treatment duration and/or duration of deep MR, are associated with a higher probability of maintaining TFR [92,94]. Contradictory data have been obtained regarding such factors as: resistance to prior TKI therapy, high Sokal risk group, age, depth of molecular response prior to TKI discontinuation, and the generation of TKI in first-line therapy [92,94–97]. One should avoid generalizing the prognostic value of any single factor and evaluate the risk and benefit of therapy discontinuation in each individual patient based on the totality of all data.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Lyubov S. Al-Radi, Cand. Sc. (Med.), Senior Research Fellow at the Department of Diagnostics and Treatment of Hematological Diseases, National Research Center for Hematology, Russian Ministry of Health; Member of the National Hematology Society.

2. Olga Yu. Vinogradova, Dr. Sc. (Med.), Professor at the Department of Hematology, Oncology and Radiation Therapy, Pirogov Russian National Research Medical University, Russian Ministry of Health; Head of the Moscow City Hematology Center at Botkin City Clinical Hospital; Chief Research Fellow at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health; Member of the Russian Professional Society of Oncohematologists and the National Hematology Society.

3. Larisa A. Kuzmina, Cand. Sc. (Med.), Head of the Scientific and Clinical Department of High-Dose Chemotherapy and Bone Marrow Transplantation, National Research Center for Hematology, Russian Ministry of Health; Expert of the Russian Academy of Sciences; Member of the National Hematology Society.

4. Elza G. Lomaia, Cand. Sc. (Med.), Leading Research Fellow at the Research Laboratory of Oncohematology, Institute of Hematology, Almazov National Medical Research Centre; Member of the National Hematology Society (Saint Petersburg, Russia).

5. Irina S. Martynkevich, Dr. Sc. (Biol.), Head of the Laboratory of Molecular Genetics, Russian Research Institute of Hematology and Transfusiology, Federal Medical-Biological Agency; Member of the National Hematology Society.

6. Elena V. Morozova, Cand. Sc. (Med.), Head of the Department of Oncology, Hematology and Transplantology for Adolescents and Adults, RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology; Associate Professor at the Department of Hematology, Transfusiology and Transplantology, Pavlov University; Member of European LeukemiaNet (ELN) (Saint Petersburg, Russia).

7. Tatyana N. Obukhova, Cand. Sc. (Med.), Medical Laboratory Geneticist, Head of the Karyology Laboratory, National Research Center for Hematology, Russian Ministry of Health; Member of the National Hematology Society, Russian Society of Oncohematologists, and European Cytogeneticists Association.

8. Tatyana I. Pospelova, Dr. Sc. (Med.), Professor, Honored Doctor of Russia, Vice-Rector for Research, Novosibirsk State Medical University, Russian Ministry of Health; Head of the Department of Therapy, Hematology and Transfusiology, Faculty of Advanced Training and Professional Retraining, Novosibirsk State Medical University; Head of the City Hematology Center, Novosibirsk; Chief Hematologist of the Siberian Federal District and Novosibirsk Region; Chair of the Association of Hematologists (Novosibirsk, Russia).

9. Andrey B. Sudarikov, Dr. Sc. (Biol.), Head of the Laboratory of Molecular Oncology, National Research Center for Hematology, Russian Ministry of Health; Expert of the Russian Foundation for Basic Research, Russian Science Foundation, and FSVOK.

10. Anna G. Turkina, Dr. Sc. (Med.), Professor, Head of the Clinical and Diagnostic Department of Hematology of Myeloproliferative Diseases, National Research Center for Hematology, Russian Ministry of Health; Chair of the Chronic Myeloid Leukemia Working Research Group of the National Hematology Society (NHS); Head of the Russian Group and Member of the ELN Expert Council, European Hematology Association; Russia Representative Member in the International Committee on Leukemias and Associated Diseases (IACRLRD World Committee); Member of the European Investigators of Chronic Myeloid Leukemia (EICML), American Society of Hematology (ASH), and Siberian Society of Hematology.

11. Grigory A. Tsaur, Dr. Sc. (Med.), Head of the Laboratory of Molecular Biology, Immunophenotyping and Pathomorphology, Regional Children's Clinical Hospital, Yekaterinburg; Clinical Laboratory Diagnostics Physician, Institute of Medical Cell Technologies, Yekaterinburg; Member of the National Society of Pediatric Hematologists and Oncologists, and ELN.

12. Ekaterina Yu. Chelysheva, Dr. Sc. (Med.), Leading Research Fellow at the Department of Diagnostics and Treatment of Hematological Diseases, National Research Center for Hematology, Russian Ministry of Health; Member of the National Hematology Society and ELN.

13. Vasily A. Shuvaev, Dr. Sc. (Med.), Hematologist at the Department of Antineoplastic Drug Therapy, A.F. Tsyb Medical Radiological Research Center – Branch of the National Medical Research Radiological Center, Russian Ministry of Health; Professor at the Department of Hematology and Transfusiology, Russian Medical Academy of Continuous Professional Education, Russian Ministry of Health; Member of the National Hematology Society.

14. Oleg A. Shukhov, Cand. Sc. (Med.), Head of the Department of Drug Supply Analysis and Medical Device Circulation in the Regions of the Russian Federation, Senior Research Fellow at the Department of Diagnostics and Treatment of Hematological Diseases, National Research Center for Hematology, Russian Ministry of Health; Member of the National Hematology Society, EHA, and ELN.

15. Alexey A. Maschan, MD, DSc, Professor, Director of the Institute of Hematology, Immunology and Cell Technologies, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Russian Ministry of Health

Conflict of interest: none among all members of the working group.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for clinical guidelines: healthcare professionals with higher medical education in the following specialties:

1. Hematologists

2. Oncologists.

3. Pediatric oncologists-hematologists.

4. Pediatric oncologists.

5. Pediatricians

6. Internists

7. Obstetricians-gynecologists.

8. General practitioners.

9. Clinical pharmacologists.

10. Medical students, residents, and postgraduate students.

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Methods used for evidence collection/selection:

• searching electronic databases;

• analyzing current scientific developments regarding esophageal cancer in the Russian Federation and abroad;

• summarizing the practical experience of Russian and foreign specialists.

To assess the levels of trustworthiness of evidence (LTE) and grades of recommendations (GOR) for each recommendation statement, a separate systematic review of the efficacy and/or safety of the medical intervention was performed, including the following stages:

1. Definition of search and selection criteria for publications on clinical trials (CT) regarding the efficacy and/or safety of the medical intervention described in the recommendation statement.

2. Systematic search and selection of clinical trial publications in accordance with predefined criteria.

3. Determination of LTE and GOR based on the results of the systematic search and selection of clinical trial publications.

Methods used for assessing the quality and strength of evidence:

• Expert consensus.

• Assessment of LTE and GOR is carried out using uniform scales presented in (Tables App. 1–3).

Table App. 1. Scale for assessing the levels of trustworthiness of evidence (LTE) for diagnostic methods (diagnostic interventions)/

Table App. 2. Scale for assessing the levels of trustworthiness of evidence (LTE) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, rehabilitation interventions)/

Table App. 3. Scale for assessing the grades of recommendation (GOR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)/

Good Practice Points (GPPs):

Good practice points are based on the qualifications and clinical experience of the authoring team.

Methods used for formulating recommendations: expert consensus.

Economic analysis: cost analysis was not performed, and pharmacoeconomic publications were not analyzed.

Method of recommendation validation:

• External peer review

• Internal expert review

Description of the guideline validation method:

The preliminary version of these guidelines has been reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations is accessible and understandable.

Comments were received from primary care pediatric oncologists regarding the clarity of the guidelines and their perceived importance as a working tool in daily practice.

Comments received from experts were carefully systematized and discussed by the chairman and members of the working group. Each item was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultations and expert review: the draft guidelines were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the guidelines.

For the final editing and quality control, the guidelines were re-analyzed by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account, and the risk of systematic bias in the development of the guidelines was minimized.

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines involves their systematic revision at least once every 3 years, as well as upon the emergence of new evidence-based data regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or the presence of justified additions/comments to previously approved clinical guidelines, but no more than once every 6 months.

The decision to update is made by the Russian Ministry of Health based on proposals submitted by medical non-profit professional organizations. The formulated proposals must take into account the results of comprehensive assessments of medicinal products and medical devices, as well as the results of clinical testing.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Order of the Russian Ministry of Health No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

2. Order of the Russian Ministry of Health No. 930n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to the Population Profiled in 'Hematology'."

Current package inserts for medicinal products mentioned in these clinical guidelines can be found at http://grls.rosminzdrav.ru.

Appendix B. Physician Action Algorithms

Algorithm for choosing therapy in CML

Appendix C. Patient Information

Dear ...!

You have been diagnosed with chronic myeloid leukemia (CML). The development of CML involves the emergence of a clone of leukemic cells that displaces normal hematopoietic cells in the bone marrow. Leukemic cells contain the marker of this disease—the Philadelphia chromosome (Ph+) and/or the BCR::ABL1 transcript. These markers are detected by cytogenetic examination of the bone marrow or molecular genetic testing of peripheral blood. CML is frequently detected during routine blood tests, and clinical symptoms of the disease may be absent at the time of diagnosis. However, in the absence of specific treatment, gradual disease progression inevitably occurs.

To treat patients with CML, modern targeted therapy—tyrosine kinase inhibitor (TKI) drugs—is used, which allows for a significant reduction in the number of leukemic cells and determines a favorable long-term prognosis of the disease. Currently, 1st and 2nd generation BCR-ABL tyrosine kinase inhibitors are available in the Russian Federation. The choice of drug for your therapy is made taking into account the phase of the disease, comorbid conditions, and side effects of each TKI, in accordance with modern CML treatment guidelines. In most cases, CML is detected in the chronic phase (CP), and treatment is carried out on an outpatient basis. However, hospitalization may be performed if indications are present.

The main principle of CML therapy is the induction of a treatment response and the suppression of the leukemic Ph+ cell clone in order to reduce the risk of disease progression. The results of a complete blood count alone, after achieving complete hematologic remission, are not sufficiently informative to assess the response to therapy. The main methods for assessing the burden of the leukemic clone and the parameters characterizing treatment efficacy in CML are cytogenetic and molecular genetic research methods.

The key aspect in CML is timely switching to more effective drugs in case of first-line treatment failure and timely addressing the performance of allogeneic hematopoietic stem cell transplantation. To determine the indications for continuing treatment or changing therapy, the response to treatment in CML is defined as optimal, failure, or warning. At each observation time point, there are specific criteria for these definitions.

An optimal response to CML treatment is considered to be: a reduction in the BCR::ABL1 transcript level to ≤10% at 3 months, ≤1% at 6 months, and ≤0.1% at 12 months of treatment. An optimal response, accompanied by good treatment tolerance, indicates a favorable prognosis and long-term progression-free survival. With an optimal response, therapy will be continued in the same regimen.

Treatment failure implies an increased risk of disease progression and serves as the basis for discussing the feasibility of changing therapy. Criteria for treatment failure are: a BCR::ABL1 level >10% confirmed by repeat analysis in 1–3 months, Ph+ >95%, or lack of hematologic response at 3 months; BCR::ABL1 ≥10% at 6 months; BCR::ABL1 ≥1% at 12 months. If the inadequate response is not related to medication non-adherence, BCR::ABL1 gene mutation analysis will be performed. In the case of imatinib** therapy, a switch to a 2nd-generation TKI or an increase in the imatinib** dose will be performed. The choice of TKI when changing treatment will be made taking into account comorbid conditions, side effects, and BCR::ABL1 mutation analysis.

The warning category includes intermediate response values. In the presence of adverse factors and a high-risk group, dose escalation or TKI substitution is considered for this category of patients.

Thus, your treatment efficacy is planned to be assessed at 3, 6, and 12 months from the start of TKI therapy. Peripheral blood will be drawn regularly to determine the relative expression of BCR::ABL1, while bone marrow puncture will be performed only in specific clinical situations as decided by your physician.

At each doctor's visit, the tolerability of TKI therapy is evaluated based on a conversation with the patient, physical examination, and assessment of clinical and laboratory parameters: complete blood count and biochemical blood analysis. If toxicity occurs, additional recommendations will be provided, taking into account the grades of toxicity and its duration.

Currently, CML is one of those diseases that are well-controlled with TKI therapy. Achieving deep disease remission—the so-called deep molecular response, where the level of BCR::ABL1 expression is undetectable—can be established after several years of therapy. With a stable deep molecular response, the possibility of managing remission without TKI therapy may be considered if all necessary criteria for safe discontinuation of treatment are met.

It is important to note that the success of treatment will largely depend on your treatment adherence—i.e., following the specialist's recommendations and taking medications consistently, considering that treatment will be carried out over a number of years. Given the optimistic results of long-term patient survival (12-year overall survival up to 85%), there is a realistic prospect of an overall life expectancy comparable to that of the general population.

In the event of disease resistance, unresponsiveness to ongoing treatment, or treatment intolerance, all measures will be taken to select the next optimal management strategy for you. Your attending physicians are always ready to provide you with consultative, therapeutic, and diagnostic support.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. WHO/ECOG Performance Status Scale

Russian title: WHO/ECOG Performance Status Scale.

Original title: The Eastern Cooperative Oncology Group/World Health Organization Performance Status (ECOG/WHO PS).

Source (official developer website, validation publication): https://ecogacrin.org/resources/ecog-performance-status;

Oken M.M., Creech R.H., Tormey D.C. et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649–55 [98].

Type: rating scale.

Purpose: to describe the patient's level of functioning in terms of their ability to care for themselves, daily activities, and physical abilities (walking, work, etc.).

Content (template):

Key (interpretation): Provided within the scale itself.

Appendix G2. NCI CTCAE Toxicity Criteria

Russian title: National Cancer Institute Common Toxicity Criteria

Original title (if applicable): National Cancer Institute Common Toxicity Criteria

Source (official developer website, validation publication): https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

Type: rating scale

Purpose: NCI CTCAE v5.0 toxicity criteria help determine the severity grade of an adverse event in order to guide management tactics. Table G2.1 presents the criteria for hematological and non-hematological toxicity that may be observed during TKI therapy.

Assessment tool, content, key (interpretation): see Table G2.1

Table G2.1. NCI CTCAE v5.0 Toxicity Criteria (selected)/